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Impregnated Cobalt, Nickel, Copper and Palladium Oxides on Magnetite: Nanocatalysts
for Organic Synthesis
Juana Pérez Galera
Instituto de Síntesis Orgánica
Facultad de Ciencias
Impregnated Cobalt, Nickel, Copper and Palladium
Oxides on Magnetite: Nanocatalysts for
Organic Synthesis
Manuscript thesis submitted for the degree of PhD at the University of
Alicante by:
JUANA M. PEREZ GALERA
Alicante, 27th
May 2016
INTERNATIONAL MENTION IN THE TITLE OF DOCTOR
Scientific advisor:
DIEGO J. RAMÓN
Instituto de Síntesis Orgánica
Institute of Organic Synthesis
FRANCISCO ALONSO VALDÉS, Director del Instituto de Síntesis Orgánica de
la Facultad de Ciencias de la Universidad de Alicante,
CERTIFICA:
Que la presente memoria titulada “Impregnated Cobalt, Nickel, Copper and
Palladium Oxides on Magnetite: Nanocatalysts for Organic Synthesis”
presentada por la Licenciada Dña. Juana M. Pérez Galera para aspirar al grado de
Doctora en Química (mención internacional), ha sido realizada en este Instituto
bajo la dirección del catedrático Diego J. Ramón.
Alicante, 27 de Mayo de 2016
Francisco Alonso Valdés
PROLOGUE
3 Prologue
Part of the results reported on this thesis has been already published:†
“Cobalt-Impregnated Magnetite as General Heterogeneous Catalyst for the
Hydroacylation Reaction of Azodicarboxylates” J. M. Pérez, D. J. Ramón, Adv. Synth.
Catal. 2014, 356, 3039-3047.
“Copper-Impregnated Magnetite as a Heterogeneous Catalyst for the Homocoupling of
Terminal Alkynes” J. M. Pérez, R. Cano, M. Yus, D. J. Ramón, Synthesis 2013, 45,
1373-1379.
“Straightforward Synthesis of Aromatic Imines from Alcohols and Amines or
Nitroarenes Using an Impregnated Copper Catalyst” J. M. Pérez, R. Cano, M. Yus, D. J.
Ramón, Eur. J. Org. Chem. 2012, 4548-4554.
“Cross-Dehydrogenative Coupling Reaction using Copper Oxide Impregnated on
Magnetite in Deep Eutectic Solvents” X. Marset, J. M. Pérez, D. J. Ramón, Green Chem.
2016, 18, 826-833.
“Impregnated Copper(II) Oxide on Magnetite as Catalyst for the Synthesis of
Benzo[b]furans from Alkynes and 2-Hydroxyarylcarbonyl derivatives” J. M. Pérez, D. J.
Ramón, to be submitted.
“Multicomponent Azide-Alkyne Cycloaddition Catalysed by Impregnated Bimetallic
Nickel and Copper on Magnetite” J. M. Pérez, R. Cano, D. J. Ramón, RSC Adv. 2014, 4,
23943-23951.
“Impregnated palladium on magnetite as catalyst for direct arylation of heterocycles” R.
Cano, J. M. Pérez, D. J. Ramón, G. P. McGlacken, Tetrahedron 2016, 72, 1043-1050.
“Palladium(II) Oxide Impregnated on Magnetite as Catalyst for the Synthesis of 4-
Arylcoumarins via a Heck-arylation/cyclization process” J. M. Pérez, R. Cano, G. P.
McGlacken, D. J. Ramón, RSC Adv. 2016, DOI: 10.1039/C6RA01731B.
“Synthesis of 3,5-Disubstituted Isoxazoles and Isoxazolines in Deep Eutectic Solvents”
J. M. Pérez, D. J. Ramón, ACS Sustainable Chem. Eng. 2015, 3, 2343-2349.
† This research has been generously supported by the Spanish Ministerio de Economía y
Competitividad (MICINN; CTQ2011-24151) and the University of Alicante.
RESUMEN
SUMMARY
RESUM
7 Resumen
En la siguiente memoria se describe la aplicación de diferentes
nanocatalizadores derivados de óxidos metálicos impregnados sobre la superficie
de la magnetita en varias reacciones de interés general en Química Orgánica.
En el Primer Capítulo, un catalizador derivado de cobalto fue usado en la
reacción de hidroacilación de azodicarboxilatos con aldehídos.
En el Segundo Capítulo, un catalizador derivado de cobre fue usado para
llevar a cabo diferentes reacciones, incluidas la reacción de homoacoplamiento
de alquinos terminales y la subsecuente reacción de hidratación para obtener los
correspondientes benzofuranos 2,5-disustituidos, la reacción de alcoholes y
aminas (o nitroarenos) para la obtención de las correspondientes iminas
aromáticas, el acoplamiento deshidrogenante cruzado de tetrahidroisoquinolinas
usando mezclas eutécticas y aire como oxidante final y, por último, la formación
de benzofuranos a partir de aldehídos y alquinos a través de una reacción tándem
de acoplamiento-alenilación-ciclación.
En el Tercer Capítulo, un catalizador bimetálico derivado de niquel y
cobre fue usado en el estudio de la reacción de cicloadición multicomponente
entre bromuros bencílicos, azida de sodio y alquinos para la obtención de los
correspondientes triazoles.
En el Cuarto Capítulo, un catalizador derivado de paladio fue usado en la
arilación directa de heterociclos usando sales de iodonio y en la síntesis de 4-
arilcumarinas a través de una arilación mediante reacción Heck seguida de
ciclación.
En el último Capítulo, se estudió el uso de mezclas eutécticas como
medios alternativos para llevar a cabo en un único recipiente la reacción de
ciclación de cloruros de N-hidroxi imidoilo y alquinos, sin ningún tipo de
catalizador y en condiciones oxidantes.
Summary 8
In this manuscript, the application of different nanocatalysts derived
from metal oxides impregnated on the surface of the magnetite in different
reaction of general interest in Organic Chemistry is described.
In the First Chapter, a cobalt derived catalyst was used to study the
hydroacylation reaction of azodicarboxylates with aldehydes.
In the Second Chapter, a catalyst derived from copper was used to
perform different reactions, including homocoupling of terminal alkynes and the
subsequent hydration reaction to obtain the corresponding 2,5-disubstituted
benzofurans, the reaction of alcohols and amines (or nitroarenes) to obtain the
corresponding aromatic imines, the cross-dehydrogenative coupling reaction of
N-substituted tetrahydroisoquinolines using deep eutectic solvents and air as final
oxidant. Finally, the formation of benzofurans from aldehydes and alkynes
through a tandem coupling-allenylation-cyclization process has been performed.
In the Third Chapter, a bimetallic catalyst derived from nickel and
copper was used to study the multicomponent reaction between benzyl bromides,
sodium azide and alkynes to obtain the corresponding triazoles.
In the Fourth Chapter, a catalyst derived from palladium was used in the
direct arylation of heterocycles using iodonium salts. Also the synthesis of 4-aryl
coumarins through the Heck arylation reaction and subsequent cyclization using
the same catalyst is described.
In the last Chapter, the use of different eutectic mixtures were studied as
alternative media to perform in a single vessel the cyclation reaction of N-
hydroxy imidoyl chlorides and alkynes, without any type of catalyst under
oxidizing conditions.
9 Resum
En aquest treball es descriu la aplicació de diferents nanocatalitzadors
derivats d’òxids metàl·lics impregnats sobre la superfície de la magnetita en
diverses reaccions d’interès general en Química Orgànica.
En el Primer Capítol, es va usar el catalitzador de cobalt en la reacció de
hidroacilació de azodicarboxilats amb aldehids.
En el Segon Capítol, es va usar un catalitzador derivat de coure per a
portar a cap diferents reaccions, incloses el homoacoplament d’alquins terminals
amb la subseqüent reacció de hidratació per a obtindre els corresponents
benzofurans 2,5-disubstituits, la reacció d’alcohols i amines (o nitroarens) per a
obtindre les corresponents imines aromàtiques, l’acoblament deshidrogenant
creuat de tetrahidroisoquinolines N-substituïts usant mescles eutèctiques i aire
com oxidant final i, per últim, s’ha realitzat la formació de benzofurans a partir
de aldehids y alquins a través d’un procés tàndem d’acoblament-allenylation-
ciclació.
En el Tercer Capítol, un catalitzador bimetàl·lic de níquel i coure
impregnats en magnetita va ser emprat per a l’estudi de la reacció de cicloaddició
multicomponent entre bromurs benzílics, azida de sodi i alquins per a obtindre
els corresponents triazols.
En el Quart Capítol, es va usar un catalitzador de pal·ladi en la arilació
directa de heterocicles emprant sals de iodoni i en la síntesis de 4-arilcumarines a
partir de una arilació mitjançant una reacció Heck seguida de una ciclació.
En l’últim Capítol, es va estudiar l’ús de mescles eutèctiques com medis
alternatius per a realitzar en un únic recipient la reacció de ciclació de clorurs
d’hidroxil imidoil i alquins, sense cap catalitzador en condicions oxidants.
PREFACE
13 Preface
At the Department of Organic Chemistry (Alicante University), the
group of Prof. Ramón has been developing a new research idea inside the area of
heterogeneous catalysts since 2007, using magnetite as non-innocent support.
The final aim of this study is the development of a new series of metal oxide
catalysts impregnated on magnetite and their use in Organic Synthesis.
Heterogeneous catalysis presents obvious advantages, from the
environmental point of view compared to the homogeneous one, being one of
them their easy recycling and reuse. The magnetic systems present an extra
advantage, as it is the possibility of their confinement, or their isolation through
magnetic fields (magnetic decantation). Despite the obvious advantages, the
impregnation is the simplest method to support different metallic oxides on
magnetite and had not been extensively prepared and studied.
The present research work is inspired by this central idea and on this
basis, some metal oxides impregnated on magnetite have been employed as
catalysts in different Organic Chemistry reactions.
The results and conclusions of this research work would be presented
following this structure:
I. GENERAL INTRODUCTION
II. RESULTS
CHAPTER I: “Reactions performed using nanoparticles of
impregnated cobalt(II) oxide on magnetite”
CHAPTER II: “Reactions performed using nanoparticles of
impregnated copper(II) oxide on magnetite”
CHAPTER III: “Reactions performed using the impregnated
bimetallic nickel(II) oxide/copper(0) on magnetite”
CHAPTER IV: “Reactions performed using nanoparticles of
impregnated palladium(II) oxide on magnetite”
CHAPTER V: “Reactions without catalyst”
Preface 14
III. EXPERIMENTAL PART
IV. CONCLUSIONS
V. BIOGRAPHY
VI. INDEX*
* The references have been included as footnote.
GENERAL INTRODUCTION
17 General Introduction
1. MAGNETITE
Magnetite,1 Fe3O4, is a mixed iron(II) and (III) oxide having a cubic
inverse spinel structure where the oxygen atoms form a unit cell cubic centered
on their faces and the iron atoms occupy the interstitial places. The octahedral
holes are occupied by ions of Fe3+
, while the tetrahedral ones are occupied by
ions of Fe2+
and Fe3+
equally.2 Electrons can move between the cations of Fe
2+
and Fe3+
on the octahedral holes at room temperature, providing magnetite
properties of semimetal (Figure 1).
Fe+3
Fe+2
Oxygen
Figure 1. Cristal structure of Fe3O4.
Magnetite can act as Brönsted base through the oxygen atoms and as
Lewis acid through the Fe atoms. The nature of the surface of magnetite3 hs been
analysed by Low Energy Electron Diffraction (LEED) and Scanning Tunnelling
Microscope (STM), demonstrating that the surface of magnetite (Figure 2)
present ¼ of monolayer of tetrahedral iron atoms forming a 2 x 2 structure with a
unit cell of 5.94 Å, with oxygen atoms (marked with X) that are not totally
coordinated. Due to this fact, both active places are present at the surface and are
accessible to substrates.
1 P. Majewski, B. Thierry, Crit. Rev. Solid State Mater. Sci. 2007, 32, 203-215. 2 M. Ritter, W. Weiss, Surf. Sci. 1999, 432, 81-94. 3 a) Y. Joseph, M. Wühn, A. Niklewski, W. Ranke, W. Weiss, C. Wöll, R. Schlögl, Phys. Chem.
Chem. Phys. 2000, 2, 5314-5319; b) K. T. Rim, D. Eom, S.-W. Chan, M. Flytzani-
Stephanopoulos, G. W. Flynn, X.-D. Wen, E. R. Batista, J. Am. Chem. Soc. 2012, 134, 18979-
18985.
General Introduction 18
Figure 2. Magnetite surface.
Nanoparticles of magnetite, among other iron oxides, present
superparamagnetism at room temperature due to their small size (ranging
between 1-100 nm). Therefore, these nanoparticles do not have a permanent
magnetic moment and can be only magnetised when an external magnetic field is
applied. This transient magnetization of the nanoparticles stops as soon as the
external field is ceased. The superparamagnetism phenomenon is not only
beneficial because it partially avoids the agglomeration but also because it can be
applied for purification purposes. For this reason, magnetite can be easily
removed from the reaction4 mixture or confined through the application of an
external magnetic field, greatly facilitating its reuse and making the whole
process more sustainable.5
A wide variety of metals and molecules can be easily immobilised and
supported on the magnetite surface. When compared with other nanosupports, the
differences between the rest of metal oxides and nanomagnetite are evident.
Nanoparticles possess different physical and chemical properties compare to their
bulk oxides. They have obvious advantages in terms of the activity, especially in
terms of the higher surface area of the active specie and the higher dispersability.
This fact favours a closer contact with the reactants. Therefore, they have being
4 G. M. Whitesides, C. L. Hill, J.-C. Brunie, Ind. Eng. Chem., Process Des. Dev. 1976, 15, 226-
227. 5 S. Shylesh, V. Schünemann, W. R. Thiel, Angew. Chem. Int. Ed. 2010, 49, 3428-3459.
19 General Introduction
considered for many authors as a bridge between homogeneous and
heterogeneous catalysis.6
For catalysts that consist of metal nanoparticles supported on a reducible
oxide, like magnetite, an oxygen spill over from the oxide to the metal may also
occur, which possibly induces the formation of an oxide film on the active metal
surface.7 As a result of this so-called strong metal-support interaction, in extreme
cases, the metal can be incorporated and then covered by a thin layer of the
support oxide. This ultra-thin oxide films may alter the catalytic activity of the
metal phase considerably. In several cases, it has been found that these native
oxides enhance the whole reactivity.
1.1. SYNTHETIC METHODS
Magnetite nanoparticles are readily accessible by different synthetic
methodologies,8 as follows:
Co-precipitation:9 It is the simplest way to gain access to magnetite
nanoparticles. It consists in the addition, under an inert atmosphere, of a base to
an aqueous solution containing Fe(II)/Fe(III) salts. The size and the shape of the
particles depend on different factors, such as pH, salt precursor, Fe(II)/Fe(III)
molar ratio, temperature, etc. However, once the conditions are fixed, the
synthesis is highly reproducible. Moreover, those features (especially the size)
can be controlled by using organic additives such as, polyvinylalcohol (PVA),
oleic acid, etc.
Thermal Decomposition:10
This methodology allows the synthesis of
magnetic nanoparticles with a narrow size distribution and high shape control
6 D. Astruc, F. Lu, J. R. Aranzaes, Angew. Chem. Int. Ed. 2005, 44, 7852-7872. 7 a) L. Giordano, G. Pacchioni, C. Noguera, J. Goniakowski, ChemCatChem 2014, 6, 185-190;
b) K. Zhang, S. Shaikhutdinov, H.-J. Freund ChemCatChem 2015, 7, 3725-3730. 8 A.-H. Lu, E. L. Salabas, F. Schüth, Angew. Chem. Int. Ed. 2007, 46, 1222-1244. 9 a) J. Lee, T. Isobe, M. Senna, Colloids Surf. A 1996, 109, 121-127; b) D. K. Kim, Y. Zhang, W.
Voit, K. V. Rao, M. Muhammed, J. Magn. Magn. Mater. 2001, 225, 30-36; c) B. L. Cushing,
V. L. Kolesnichenko, C. J. O’Connor, Chem. Rev. 2004, 104, 3893-3946; d) A. K. Gupta, A. S.
G. Curtis, Biomater. 2004, 25, 3029-3040; e) A. L. Willis, N. J. Turro, S. O’Brien, Chem.
Mater. 2005, 17, 5970-5975. e) A. K. Gupta, M. Gupta, Biomaterials 2005, 26, 3995-4021. 10 a) S. Sun, H. Zeng, D. B. Robinson, S. Raoux, P. M. Rice, S. X. Wang, G. Li, J. Am. Chem.
Soc. 2004, 126, 273-279; b) F. X. Redl, C. T. Black, G. C. Papaefthymiou, R. L. Sandstrom, M.
Yin, H. Zeng, C. B. Murray, S. P. O’Brien, J. Am. Chem. Soc. 2004, 126, 14583-14599; c) Z.
Li, Q. Sun, M. Gao, Angew. Chem. Int. Ed. 2005, 44, 123-126.
General Introduction 20
from organometallic iron precursors, using the above mentioned additives (fatty
acids, polyalcohols, among others). To be successful, the control of high
temperatures (ranging between 100 and 320 ºC depending on the iron precursor),
as well as the use of inert atmosphere, is mandatory.
Microemulsion:11
It could be regarded as a co-precipitation methodology
variation which permits a better control of size and morphology, although with
notably poorer yields and rather complicated manipulation.
Hydrothermal Synthesis:12
It is also a variation of the thermal
decomposition method, but using high pressure and temperature. The size and
shape control obtained is as high as in the aforementioned methodology but the
process itself can be considered fairly simple. Conversely, the yields are lower.
1.2. APPLICATIONS
Iron-based catalysts are becoming very popular in the Organic Synthesis
community, since iron is abundant, eco-friendly, relatively non-toxic, and
inexpensive element.13
However, these catalysts have also some drawbacks, in
comparison with other commonly employed supports, such as silica, titania,
ceria, etc. On the one hand, magnetite, like most of the iron oxides, is dissolved
in strong acid media. This could be a limitation for the use of magnetite
nanoparticles supports under those conditions. However, in Organic Synthesis,
the use of such extreme reaction media is not very common.14
On the other hand,
the main problem associated with ‘naked’ magnetite nanoparticles, Fe3O4, is their
tendency to slowly oxidize to the more stable maghemite (γ-Fe2O3) or even to the
most stable iron oxide hematite (α-Fe2O3). This oxidation processes affect the
properties of the support and can lead to morphologic changes, which could
result in loss of magnetism and dispersability.
Even though, and as a consequence of the interesting properties that it
presents, in the last years the number of applications of the magnetite has
11 M. Igartua, P. Saulnier, B. Heurtault, B. Pech, J. E. Proust, J. L. Pedraz, J. P. Benoit, Int. J.
Pharm. 2002, 233, 149-157. 12 a) H. Deng, X. Li, Q. Peng, X. Wang, J. Chen, Y. Li, Angew. Chem. Int. Ed. 2005, 44, 2782-
2785; b) X. Wang, J. Zhuang, Q. Peng, Y. Li, Nature 2005, 437, 121-124. 13 B. Plietker in Iron Catalysis in Organic Chemistry; Wiley VCH, Wienheim, 2008. 14 a) P. S. Sidhu, R. J. Gilkes, R. M. Cornell, A. M. Posner, J. P. Quirk, Clays Clay Miner. 1981,
29, 269-276; b) J. Tang, M. Myers, K. A. Bosnick, L. E. Brus, J. Phys. Chem. B. 2003, 107,
7501-7506.
21 General Introduction
increased in a wide range of fields such as magnetic fluids,15
data storage,16
and
biomedicine.17
Iron oxide compounds have been traditionally used, by the chemical
industry, as heterogeneous catalysts or as promoters of several chemical
transformations of global importance due to its natural occurrence. Thus, iron
oxides have been involved in the Haber-Bosch process for producing ammonia,18
in the Fischer-Tropsch process for producing synthetic fuel,19
and in the water-
gas shift reaction, among others.20
However, during this century, more efficient
transition metal catalysts have been discovered, with iron compounds being used
not so often. However, during the last decade, iron species have suffered a new
renaissance. This is due to the discovery of new reactivity modes,21
and also to
the use of iron oxides, such magnetite, as magnetically recoverable support for
other metal species.
15 a) R. Hiergeist, W. Andrä, N. Buske, R. Hergt, I. Hilger, U. Richter, W. Kaiser, J. Magn.
Magn. Mater. 1999, 201, 420-422; b) A. Jordan, R. Scholz, K. Maier-Hauff, M. Johannsen, P.
Wust, J. Nadobny, H. Schirra, H. Schmidt, S. Deger, S. Loening, W. Lanksch. R. Felix, J.
Magn. Magn. Mater. 2001, 225, 118-126; c) L.-Y. Zhang, H.-C. Gu, X.-M. Wang, J. Magn.
Magn. Mater. 2007, 311, 228-233. 16 G. Reiss, A. Hütten, Nat. Mater. 2005, 4, 725-726. 17 a) Q. A. Pankhurst, J. Connolly, S. K. Jones, J. Dobson, J. Phys. D: Appl. Phys. 2003, 36, 167-
181; b) D. L. Graham, H. A. Ferreira, P. P. Freitas, Trends Biotechnol. 2004, 22, 455-462; c) T.
Neuberger, B. Schöpf, H. Hofmann, M. Hofmann, B. V. Rechenberg, J. Magn. Magn. Mater.
2005, 293, 483-496; d) J. Gao, H. Gu, B. Xu, Acc. Chem. Res. 2009, 42, 1097-1107; e) A.
Akbarzadeh, M. Samiei, S. Davaran, Nanoscale Res. Lett. 2012, 7, 144. 18 a) G. Ert, Chem. Rec. 2001, 1, 33-45; b) T. Kandemir, M. E. Schuster, A. Senyshyn, M.
Behrens, R. Schlögl, Angew. Chem. Int. Ed. 2013, 52, 12723-12726; c) L. C. A. Oliveira, J. D.
Fabris, M. C. Pereira, Quim. Nova 2013, 36, 123-130; d) K. Grubel, W. W. Brennessel, B. Q.
Mercado, P. L. Holland, J. Am. Chem. Soc. 2014, 136, 16807-16816; e) N. Cherkasov, A. O.
Ibhadon P. Fitzpatrick, Chem. Eng. Process. Process Intensif. 2015, 90, 24-33. 19 a) L. S. Glebov, G. A. Kliger, T. P. Popova, V. E. Shiryaeva, V. P. Ryzhikov, E. V.
Marchevskaya, O. A. Lesik, S. M. Loktev, V. G. Beryezkin, J. Mol. Catal. 1986, 35, 335-348;
b) M. M. Khalaf, H. G. Ibrahimov, E. H. Ismailov, Chem. J. 2012, 2, 118-125; c) A. Y.
Krylova, Kinet. Catal. 2012, 53, 742-746; d) D. W. Lee, B. R. Yoo, J. Ind. Eng. Chem. 2014,
20, 3947-3959. 20 a) C. R. F. Lund, J. E. Kubsh, J. A. Dumesic in Solid State Chemistry in Catalysis, Vol. 279
(Eds.: R. K. Grasselli, J. F. Brazdil), ACS, Washington DC, 1985, pp. 313-338; b) Q. Liu, W.
Ma, R. He, Z. Mu, Catal. Today 2005, 106, 52-56; c) A. Patlolla, E. V. Carino, S. N. Ehrlich,
E. Stavitski, A. I. Frenkel, ACS Catal. 2012, 2, 2216-2223; d) D.-W. Lee, M. S. Lee, J. Y. Lee,
S. Kim, H.-J. Eom, D. J. Moon, K.-Y. Lee, Catal. Today 2013, 210, 2-9; e) X. Yan, H. Guo, D.
Yang, S. Qiu, X. Yao, Curr. Org. Chem. 2014, 18, 1335-1345. 21 a) C. Bolm, J. Legros, J, Le Paih, L. Zani, Chem. Rev. 2004, 104, 6217-6254; b) S. Enthaler, K.
Junge, M. Beller, Angew. Chem. Int. Ed. 2008, 47, 3317-3321; c) A. Correa, O. García
Mancheño, C. Bolm, Chem. Soc. Rev, 2008, 37, 1108-1117; d) B. D. Sherry, A. Fürstner, Acc.
Chem. Res. 2008, 41, 1500-1511; e) A. A. O. Sarhan, C. Bolm, Chem. Soc. Rev. 2009, 38,
2730-2744.
General Introduction 22
Magnetite nanoparticles have been employed as catalyst in different
reduction reactions overcoming the traditional non catalytic process (Béchamp
reduction), where nitroarenes are treated with stoichiometric amounts of Fe metal
under acidic conditions, generating large amounts of waste. Nitroarenes have
been efficiently transformed to the corresponding anilines employing 20 mol% of
catalyst and hydrazine as hydrogen source.22
This transformation has been further
expanded by implementing an in situ formation of magnetite nanoparticles in a
continuous flow reaction under microwave radiation (Scheme 1). Thus, making
the whole process highly attractive from the environmental point of view, since
the only by-products were N2 and H2O.23
In this case, the magnetite particles
were unambiguously identified as a single phase cubic Fe3O4 by means of XRD
(X-Ray Diffraction) analysis, being the particle size 6±2 nm according to
HRTEM images.
Scheme 1. Reduction of nitroarenes catalysed by in situ formed Fe3O4.
Magnetite nanoparticles have been also employed as recoverable
catalysts for different oxidation reactions.24
The magnetite-catalysed styrene
oxidation to afford benzaldehydes has been studied by different groups. The
particle sizes of magnetite in all the cases ranged from 16 to 22 nm.25
However,
the reactions were not very selective. Other oxidation products, such as the
corresponding epoxide, alcohol and carboxylic acid, among others, were also
obtained. Better results, in terms of yield and selectivity, were achieved for the
oxidation of aldehydes to carboxylic acids.26
In this case, ethyl acetoacetate was
used as 1,3-dicarbonyl compound additive and 20 mol% of Fe3O4 was needed to
obtain good results, with the catalyst being recyclable up to four times without a
decrease in the reaction yield (Scheme 2).
22 S. Kim, E. Kim, B. M. Kim, Chem. Asian. J. 2011, 6, 1921-1925. 23 a) D. Cantillo, M. Baghbanzadeh, C. O Kappe, Angew. Chem. Int. Ed. 2012, 51, 10190-10193;
b) D. Cantillo, M. M. Moghaddam, C. O. Kappe, J. Org. Chem. 2013, 78, 4530-4542. 24 S. Zhang, X. Zhao, H. Niu, Y. Shi, Y. Cai, G. Jiang, J. Hazard. Mater. 2009, 167, 560-566. 25 a) M. J. Rak, M. Lerro, A. Moores, Chem. Commun. 2014, 50, 12482-12485; b) J. Liang, Q.
Zhang, H. Wu, G. Meng, Q. Tang, Y. Wang, Catal. Commun.2004, 5, 665-669; c) D. Guin, B.
Baruwati, S. V. Manorama, J. Mol. Catal. A: Chem. 2005, 242, 26-31. 26 R. Villano, M. R. Acocella, A. Scettri, Tetrahedron Lett. 2014, 55, 2242-2245.
23 General Introduction
Scheme 2. Oxidation of aldehydes using Fe3O4.
It should be also pointed out that the dehydrogenation of ethylbenzene
derivatives to give the corresponding styrenic compounds has been reported with
little success. Probably, as pointed out by the authors, this was due to a blockage
of the Fe3O4 (111) surface by both the product and the starting material.3a,27
during the last years, numerous multicomponent transformations, in
which the nucleophilic addition to an in situ formed imine represents a key step,
have been published using magnetite as catalyst. One of the first examples
reported was a four-component aza-Sakurai type reaction yielding the
corresponding N-protected amines. After 15th catalytic cycles (Scheme 3), similar
yields were achieved. The remaining magnetite particle was almost the same that
the fresh sample, as revealed by TEM, XRD and BET surface measurements.28
Scheme 3. Four-component aza-Sakurai reaction.
27 A. Schüle, U. Nieken, O. Shekhah, W. Ranke, R. Schlögl, G. Kolios, Phys. Chem. Chem. Phys.
2007, 9, 3619-3634. 28 R. Martínez, D. J. Ramón, M. Yus, Adv. Synth. Catal. 2008, 350, 1235-1240.
General Introduction 24
Different three-component reactions involving the formation of imines
have been reported. Some examples are the phosphite addition to imines29
(Pudovik-type reaction), Strecker reaction30
and alkyne addition to imines,31
among others.32
In all these cases, the catalyst was recycled several times without
a substantial loss of activity. More recently, the one-pot synthesis of β-acetamido
carbonyl compounds in a four-component reaction has been reported employing
magnetite as catalyst (Scheme 4).33
Scheme 4. Synthesis of β-acetamido carbonyl compounds.
The successful application of magnetite as catalyst for the synthesis of
quinoxalines34
by condensation of 1,2-dicarbonyl compounds and 1,2-diamine
derivatives has been recently published (Scheme 5). Remarkably, the highest
yield was obtained when water was employed as solvent, with the catalyst being
recycled up to five times. It is also important to note that the XRD pattern
confirmed the magnetite structure before and after recycling experiments, with
the particle size being around 20 nm.
Scheme 5. Synthesis of quinoxalines by condensation reaction.
29 B. V. Subba-Reddy, A. Siva-Krishna, A. V. Ganesh, G. G. K. S. Narayana-Kumar,
Tetrahedron Lett. 2011, 52, 1359-1362. 30 M. M. Mojtahedi, M. Saed-Abaee, T. Alishiri. Tetrahedron Lett. 2009, 50, 2322-2325. 31 T. Zeng, W.-W. Chen, C. M. Cirtiu, A. Moores, G. Song, C.-J. Li, Green Chem. 2010, 12, 570-
573. 32 J. Deng, L.-P. Mo, F.-Y. Zhao, L.-L. Hou, Z.-H. Zhang, Green Chem. 2011, 13, 2576-2584. 33 B: Movassagh, F. Talebsereshki, Helv. Chim. Acta 2013, 96, 1943-1947. 34 H.-Y. Lü, S.-H. Yang, J. Deng, Z.-H. Zhang, Aust. J. Chem. 2010, 63, 1290-1296.
25 General Introduction
The related synthesis of imidazoles35
has also been described. The
reaction has been accomplished in the absence of solvent, being the magnetite
recycled ten times with a slight decrease on the reaction yield.
The aldol condensation followed by a Michael-type addition has been
catalysed by microparticles of magnetite.36
The subsequent dehydration has led to
the synthesis of 4-substituted-4H-pyrans, in a cascade process (Scheme 6).
Scheme 6. Synthesis of 4H-pyrans.
The reaction proceeds smoothly at room temperature in the presence of
acetyl chloride as dehydrating agent. Although a rather high amount of catalyst
was employed (65 mol%) and its recyclability was not possible, it should be
pointed out that the protocol is simple and applicable to a broad range of
substrates. This protocol reduced the previously described reaction times from
weeks to hours. Remarkably, similar results were obtained when Fe2O3 was
employed as catalyst, not discarding Fe(III) species acting as the real catalyst of
the reaction. Shortly after this pioneer report, different research groups have
published the synthesis of several heterocycles with a Knoevenagel condensation
as starting step.37
The C(sp3)-C(sp
2) coupling between terminal alkynes and aryl iodides
(Sonogashira-Hagihara reaction) has been alsodescribed. Only 5 mol% of
recoverable magnetite in ethylene glycol as solvent was required in this late-
transition metal-free process.38
More recently, the synthesis of alkynyl
chalcogenides by reaction between terminal acetylenes and diorganyl
dichalcogenides has been also reported.39
35 N. Montazeri, K. Pourshamsian, H. Rezaei, M. Fouladi, S. Rahbar, Asian J. Chem. 2013, 25,
3463-3466. 36 R. Cano, D. J. Ramón, M. Yus, Synlett, 2011, 14, 2017-2020. 37 a) B. Karami, S. J. Hoseini, K. Eskandari, A. Ghasemi, H. Nasrabadi, Catal. Sci. Technol.
2012, 2, 331-338; b) M. Nikpassand, L. Zare, T. Shafaati, S. Shariati. Chin. J. Chem. 2012, 30,
604-608; c) M. Kidwai, A. Jain, S. Bhardwaj, Mol. Divers. 2012, 16, 121-128. 38 H. Firouzabadi, N. Iranpoor, M. Gholinejad, J. Hoseini, Adv. Synth. Catal. 2011, 353, 125-132. 39 M. Godoi, D. G. Liz, E. W. Ricardo, M. S. T. Rocha, J. B. Azeredo, A. L. Braga, Tetrahedron
2014, 70, 3349-3354.
General Introduction 26
The reaction between different acyl chlorides and acetylenic compounds
using nanoparticles of magnetite as catalyst has been studied, producing in one
hour the corresponding β-chlorovinyl ketones in good yields and moderate to
excellent Z-selectivity (Scheme 7). The reaction products were further elaborated
to the corresponding furans using iridium oxide impregnated on magnetite (IrO2-
Fe3O4) catalyst. In addition, cyclopenten-2-ones and cyclopenta[a]naphtalen-1-
ones can be obtained in high yields in a Nazarov-type cyclization, by choosing
the appropriate acyl chloride. Unfortunately, the catalyst could not be recycled.40
Scheme 7. Addition of acyl chlorides to alkynes using Fe3O4 NPs.
The hydrogen autotransfer process is a high selective, environmentally
friendly and atom-economic process for the synthesis of monalkylated amines.41
However, the employed catalysts are normally based on expensive transition
metals, which are sometimes toxic and difficult to handle. The use of magnetite
nanoparticles for the monoalkylation of anilines, and other electron-poor
heteroaromatic amines, using benzylic alcohols as electrophiles has been reported
(Scheme 8). The catalyst was recycled eight times with only slight variations in
yields.42
This high recyclability could arise from the fact that no apparent
sinterization occurred in the process, since no significant differences were
observed between the fresh catalyst and the recycled one, according to TEM
images and BET area measurement experiments.
40 R. Cano, M. Yus, D. J. Ramón, Tetrahedron 2013, 69, 7056-7065. 41 For different reviews , see: a) G. Guillena, D. J. Ramón, M. Yus, Angew. Chem. Int. Ed. 2007,
46, 2358-2364; b) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth. Catal.
2007, 349, 1555-1575; c) T. D. Nixon, M. K. Whittlesey, J. M. J. Williams, Dalton Trans.
2009, 753-762; d) K.-I. Fujita, R. Yamaguchi in Iridium Complexes in Organic Synthesis (Eds.:
L. A. Oro, C. Claver), Wiley-VCH, Weinheim, 2009, pp 107-143; e) G. E. Dobereiner, R. H.
Crabtree, Chem. Rev. 2010, 110, 681-703; f) G. Guillena, D. J. Ramón, M. Yus, Chem. Rev.
2010, 110, 1611-1641; g) R. Yamaguchi, K.-I. Fujita, M. Zhu, Heterocycles 2010, 81, 1093-
1140; h) F. Alonso, F. Foubelo, J. C. González-Gómez, R. Martínez, D. J. Ramón, P. Riente,
M. Yus, Mol. Divers. 2010, 14, 411-424; i) A. J. A. Watson, J. M. J. Williams, Science 2010,
329, 635-636; j) H. Kimura, Catal. Rev. Sci. Eng. 2011, 53, 1-90; k) S. Bähn, S. Imm, L.
Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem 2011, 3, 1853-1864; l) D.
Hollmann, ChemSusChem 2014, 7, 2411-2413; m) Y. Obora, ACS Catal. 2014, 4, 3972-3981;
n) K.-I. Shimizu, Catal. Sci. Technol. 2015, 5, 1412-1427. 42 R. Martínez, D. J. Ramón, M. Yus, Org. Biomol. Chem. 2009, 7, 2176-2181.
27 General Introduction
Scheme 8. Amine alkylation by a hydrogen autotransfer.
Finally, it is also worth mentioning that magnetite has been used in
several studies as reusable initiating system for living cationic or radical
polymerizations.43
2. MAGNETITE AS CATALYST SUPPORT
Magnetite has been employed not only as an excellent catalyst, as it has
been mentioned previously, but also as a support for a great variety of catalysts.
Numerous approaches in order to introduce metal on a solid support surface have
been reported.44
The first advantage to use magnetite as support it is the facility
of isolation that this material shows due to the superparamagnetic behaviour.
Different methodologies have been developed to support metals as catalysts on
the magnetite surface.8
2.1. COATED CATALYST
Coating45
of metal nanoparticles is a commonly employed procedure in
material science. Silica has been chosen from all the different oxide-based
coatings to support magnetite nanoparticles due mainly to economy reasons, as
well as its high stability under different conditions. The procedure is based on the
formation of a SiO2 layer on the magnetite surface, which is normally generated
employing the sol-gel strategy, and subsequent formation of a second layer
containing particles of the active metal specie onto the SiO2 coating (Figure 3).
43 a) A. Kanazawa, S. Kanaoka, S. Aoshima, J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 916-
926; b) A. Kanazawa, S. Kanaoka, N. Yagita, Y. Oaki, H. Imai, M. Oda, A. Arakaki, T.
Matsunaga, S. Aoshima, Chem. Commun. 2012, 48, 10904-10906; c) A. Kanazawa, K. Satoh,
M. Kamigaito, Macromolecules 2011, 44, 1927-1933. 44 a) J.-F. Lambert, M. Che, J. Molec. Catal. A 2000, 162, 5-18; b) Supported Metals in Catalysis
(Eds.: J. A. Anderson, M. Fernández-García), Imperial College Press, London, 2005; c)
Catalyst Preparation, Science and Engineering (Eds.: J. Regalbuto), CRC Press, Taylor &
Francis Group, Boca Ratón, 2007. 45 M. B. Gawande, Y. Monga, R. Zboril, R. K. Sharma, Coord. Chem. Rev. 2015, 288, 118-143.
General Introduction 28
This procedure has been developed in order to prevent the problems associated
with the use of ‘naked’ magnetite, especially regarding the oxidation issues.
Figure 3. General scheme for a coated catalyst: Cat-SiO2@Fe3O4.
Different metal catalysts have been prepared through this methodology
and the obtained recoverable materials have been used in a wide range of
catalytic reactions, including oxidation,46
hydrogenation,47
asymmetric
synthesis,48
hydration,49
Knoevenagel condensation,50
reductions,51
and
biocatalytic reactions.52
For instance, the Pd-SiO2@Fe3O4 catalyst53
has been used in the Suzuki
type cross-coupling reaction of organoboronic acids with alkynyl bromides. The
C-C bond formation54
could be performed with only 0.5 mol% of palladium
loading and it could be recycled up to 16 times without significant loss of
catalytic activity (Scheme 9).
46 a) M. J. Jacinto, O. H. C. F. Santos, R. F. Jardim, R. Landers, L. M. Rossi, Appl. Catal. A: Gen.
2009, 360, 177-182; b) J. Wegner, S. Ceylan, C. Friese, A. Kirschning, Eur. J. Org. Chem.
2010, 4372-4375. 47 a) D. Guin, B. Baruwati, S. V. Manorama, Org. Lett. 2007, 9, 1419-1421; b) L. M. Rossi, F. P.
Silva, L. L. R. Vono, P. K. Kiyohara, E. L. Duarte, R. Itri, R. Landers, G. Machado, Green
Chem. 2007, 9, 379-385. 48 B. Panella, A. Vargas, A. Baiker, J. Catal. 2009, 261, 88-93. 49 R. B. N. Baig, R. S. Varma, Chem. Commun. 2012, 48, 6220-6222. 50 R. K. Karma, Y. Monga, A. Puri, Catal Commun. 2013, 35, 110-114. 51 K. S. Shin, Y. K. Cho, J.-Y. Choi, K. Kim, Appl. Catal. A: Gen. 2012, 413-414, 170-175. 52 S. Wang, Z. Zhang, B. Liu, J. Li, Catal. Sci. Technol. 2013, 3, 2104-2112. 53 X. Zhang, P. Li, Y. Ji, L. Zhang, L. Wang, Synthesis, 2011, 2975-2983. 54 Z. Wang, P. Xiao, B. Shen, N. He, Colloid Surface A 2006, 276, 116-121.
29 General Introduction
Scheme 9. Suzuki cross-coupling catalysed by Pd-SiO2@Fe3O4.
2.2. GRAFTED CATALYSTS
Another widespread strategy to support metals on magnetite is based on
the grafting of active metal species, using tailored ligands which are able to bind
effectively to the magnetite surface. In addition, when this procedure is used, the
ligands are supposed to protect the magnetite surface against oxidation,
conferring stability to the iron oxide particles (Figure 4).
Figure 4. General scheme for a grafted catalyst.
A great variety of catalysts, using different metals, have been prepared
with this methodology. These catalysts have been used to perform some reactions
such as, atom transfer radical polymerization,55
hydration,56
oxidations,57
C-C
bond formation through Suzuki coupling58
or o-allylation,59
amoung others.60
55 S. Ding, Y. Xing, M. Radosz, Y. Shen, Macromolecules 2006, 39, 6399-6405. 56 V. Polshettiwar, R. S. Varma, Chem. Eur. J. 2009, 15, 1582-1586. 57 V. Polshettiwar, R. S. Varma, Org. Biomol. Chem. 2009, 7, 37-40. 58 Y.-Q. Zhang, X.-W. Wei, R. Yu, Catal. Lett. 2010, 135, 256-262. 59 A. Saha, J. Leazer, R. S. Varma, Green Chem. 2012, 14, 67-71. 60 U. Laska, C. G. Frost, P. K. Plucinski, G. J. Price, Catal. Lett. 2008, 122, 68-75.
General Introduction 30
For instance, the hydrogenation reaction of alkyne and the transfer
hydrogenation of ketones could be carried out using nickel grafted catalyst,61
obtaining high yields. Due to the magnetic properties of the catalyst, it could be
recycled five times without any change in its activity (Scheme 10).
Scheme 10. Ni grafted catalyst for hydrogenation and hydrogen transfer
reaction.
2.3. COATED-GRAFTED CATALYST
A third way of immobilizing ctalysts over magnetite is preferred by
many other research groups. This procedure can be considered as a combination
of the two aforementioned methods. Thus, onto a SiO2-coated magnetite, metal
species are grafted by using a ligand bearing a triethoxysilane derivative, capable
to bind the silica (Figure 5). In this way, an effective protection of the magnetite
is obtained, along with the introduction of specific anchoring metal points.62
61 V. Polshettiwar, B. Baruwati, R. S. Varma, Green Chem. 2009, 11, 127-131. 62 a) A. Schätz, O. Reiser, W. J. Stark, Chem. Eur. J. 2010, 16, 8950-8967; b) K. V. S. Ranganath,
F. Glorius, Catal. Sci. Tehcnol. 2011, 1, 13-22; c) V. Polshettiwar, R. Luque, A. Fihri, H. Zhu,
M. Bouhrara, J.-M. Basset, Chem. Rev. 2011, 111, 3036-3075; d) D. Zhang, C. Zhou, Z, Sun,
L.-Z. Wu, C.-H. Tung, T. Zhang, Nanoscale 2012, 4, 6244-6255; e) S. Liu, S.-Q. Bai, Y.
Zheng, K. W. Shah, M.-Y. Han, ChemCatChem 2012, 4, 1462-1484; f) R. B. Baig, R. S.
Varma, Chem. Commun. 2013, 49, 752-770; g) H.-J. Xu, X. Wan, Y. Geng, X.-L. Xu, Curr.
Org. Chem. 2013, 17, 1034-1050; h) M. B. Gawande, A. K. Rathi, P. S. Branco, R. S. Varma,
Appl. Sci. 2013¸ 3, 656-674; i) L. M. Rossi, N. J. S. Costa, F. P. Silva, R. Wojcieszak, Green
Chem. 2014, 16, 2906-2933; j) M. B. Gawande, R. Luque, R. Zboril, ChemCatChem 2014, 6,
3312-3313; k) Q. M. Kainz, O. Reiser, Acc. Chem. Res. 2014, 47, 667-677.
31 General Introduction
Figure 5. General scheme for a coated-grafted catalyst.
Using the aforementioned coated-grafted catalysts, important catalytic
applications have been performed including hydroformylation,63
reduction,64
hydrogenations,65
CO oxidation,66
C-C bond formation,67
water gas shift
reaction,68
CO2 and biomass conversion,69
amoung others.
For instance, the cross-coupling reaction between acrylic acid and
iodobenzene has been performed using coated and grafted Pd catalyst70
affording
good yields (Scheme 11). The catalytic activity decreased after five cycles due to
the aggregation into big particles of the catalyst.
63 R. Abu-Reziq, H. Alper, D. Wang, M. L. Post, J. Am. Chem. Soc. 2006, 128, 5279-5282. 64 a) J. Ge, T. Huynh, Y. Hu, Y. Yin, Nano Lett. 2008, 8, 931-934; b) Y. Deng, Y. Cai, Z. Sun, J.
Liu, C. Liu, J. Wei, W. Li, C. Liu, Y. Wang, D. Zhao, J. Am. Chem. Soc. 2010, 132, 8466-8473. 65
a) R. Abu-Reziq, D. Wang, M. Post, H. Alper, Adv. Synth. Catal. 2007, 349, 2145-2150; b) M.
J. Jacinto, P. K. Kiyohara, S. H. Masunaga, R. F. Jardim, L. M. Rossi, Appl. Catal. A-Gen.
2008, 338, 52-57; c) M. J. Jacinto, F. P. Silva, P. K. Kiyohara, R. Landers, L. M. Rossi,
ChemCatChem 2012, 4, 698-703. 66 H.-P. Zhou, H.-S. Wu, J. Shen, A.-X. Yin, L.-D. Sun, C.-H. Yan, J. Am. Chem. Soc. 2010, 132,
4998-4999. 67 a) G. Lv, W. Mai, R. Jin, L. Gao, Synlett 2008, 9, 1418-1422; b) Q. Du, W. Zhang, H. Ma, J.
Zheng, B. Zhou, Y. Li, Tetrahedron, 2012, 68, 3577-3584. 68 M. Shekhar, J. Wang, W.-S. Lee, W. D. Williams, S. M. Kim, E. A. Stach, J. T. Miller, W. N.
Delgass, F. H. Ribeiro, J. Am. Chem. Soc. 2012, 134, 4700-4708. 69 D. Preti, C. Resta, S. Squarcialupi, G. Fachinetti, Angew. Chem. Int. Ed. 2011, 50, 12551-
12554. 70 Z. Wang, B. Shen, Z. Aihua, N. He, Chem. Eng. J. 2005, 113, 27-34.
General Introduction 32
Scheme 11. Coated and grafted Pd-catalysed cross-coupling reaction.
2.4. CO-PRECIPITATION AND DUMBELL-LIKE COMPOSITES
Although they differ in the synthesis and structure, co-precipitation and
dumbell-like composites can be considered as a magnetite possessing a metal
catalyst domain in its structure. For the co-precipitation strategy, two metal salts
are precipitated together at basic pH. A spinel structure is formed after
evaporation of the solvent and treatment at high temperatures. The spinel
structure has different metal oxide domains normally located in a multiple region
within the nanoparticles. In the extreme case, all positions of Fe(II) are
substituted by different transition metal cation(II), leading to the ferrites.71
For
the dumbell-like cases, the domain is perfectly located in a specific region, and
can be conceived as a metal nanoparticle which has grown onto the magnetite
surface. In fact, most of the dumbbell-like metal nanoparticles are produced by
precipitation of a metal salt onto the surface of a preformed magnetite
nanoparticle (Figure 6).
Figure 6. General scheme of a co-precipitation or dumbbell-like catalyst
M/Fe3O4.
Different metal catalysts have been prepared through this methodology.
Catalyst Fe0/Fe3O4
72 has been used in the treatment of waste-water using the
71 a) J. Lee, S. Zhang, S. Sun, Chem. Mater. 2013, 25, 1293-1304; b) A. S. Burange, S. R. Kale,
R. Zboril, M. B. Gawande, R. V. Jayaram, RSC Adv. 2014, 4, 6597-6601; c) D. Gherca, A. Pui,
V. Nica, O. Caltun, N. Cornei, Ceram. Int. 2014, 40, 9599-9607; d) A. Goyal, S. Bansal, S.
Singhal, Int. J. Hydrogen Energy 2014, 39, 4895-4908. 72 a) F. C. C. Moura, M. H. Araujo, R. C. C. Costa, J. D. Fabris, J. D. Ardisson, W. A. A.
Macedo, R. M. Lago, Chemosphere 2005, 60, 118-1123; b) F. C. C. Moura, G. C. Oliveira, M.
H. Araujo, J. D. Ardisson, W. A. A. Macedo, R. M. Lago, Appl. Catal. A-Gen. 2006, 307, 195-
204.
33 General Introduction
Fenton oxidation process. On the other hand, catalyst Ni/Fe3O473
has been used in
the synthesis of different N-substituted carbamates (Scheme 12). This catalyst
could be recycled five times with stable activity.
Scheme 12. Synthesis of N-substituted carbamates.
Magnetic Cu/Fe3O4 nanoparticles have been used in the Huisgen
cycloaddition in water yielding triazoles.74
The catalyst could be recycled five
times with no appreciable decrease in yield.
Using this methodology different Pd/Fe3O475
and Pt/Fe3O476
catalysts
have been prepared. The first one was used to perform the thermal decomposition
of methanol to give CO/CO2 and CH4, and in the Suzuki-Miyaura coupling
reaction. The second one was used in the hydrogenation reaction of nitroarenes
and alkenes. To perform the hydrogenation reaction, other catalysts like
Au/Fe3O477
and Rh/Fe3O478
were used, using siloxanes and hydrazine as source of
hydrogen, respectively. In both cases, the catalyst was recycled without any loss
of activity.
73 a) Z. Li, Y. Deng, B. Shen, W. Hu, Mater. Sci. Eng. 2009, 164, 112-115; b) J. Shang, X. Guo,
F. Shi, Y. Ma, F. Zhou, Y. Deng, J. Catal. 2011, 279, 328-336. 74 R. Hudson, C.-J. Li, A. Moores, Green Chem. 2012, 14, 622-624. 75 a) Y. Usami, K. Kagawa, M. Kawazoe, Y. Matsumura, H. Sakurai, M. Haruta, Appl. Catal. A:
Gen. 1998, 171, 123-130; b) K. Mori, Y. Kondo, H. Yamashita, Phys. Chem. Chem. Phys.
2009, 11, 8949-8954. 76 a) A. Figuerola, A. Fiore, R. D. Corato, A. Falqui, C. Giannini, E. Micotti, A. Lascialfari, M.
Corti, R. Cingolani, T. Pellegrino, P. D. Cozzoli, L. Manna, J. Am. Chem. Soc. 2008, 130,
1477-1487; b) C. Wang, H. Daimon, S. Sun, Nano Lett. 2009, 9, 1493-1496; c) K. Mori, N.
Yoshioka, Y. Kondo, T. Takeuchi, H. Yamashita, Green Chem. 2009, 11, 1337-1342. 77 a) H. Yu, M. Chen, P. M. Rice, S. X. Wang, R. L. White, S. Sun, Nano Lett. 2005, 5, 379-382;
b) H. Yin, C. Wang, H. Zhu, S. H. Overbury, S. Sun, S. Dai, Chem. Commun. 2008, 4357-
4359; c) Y. Lee, M. A. García, N. A. F. Huls, S Sun, Angew. Chem. Int. Ed. 2010, 49, 1271-
1274; d) J. S. Beveridge, M. R. Buck, J. F. Bondi, R. Misra, P. Schiffer, R. E. Schaak, M. E.
Williams, Angew. Chem. Int. Ed. 2011, 50, 9875-9879; e) S. Park, I. S. Lee, J. Park, Org.
Biomol. Chem. 2013, 11, 395-399. 78 Y. Jang, S. Kim, S. W. Jun, B. H. Kim, S. Hwang, I. K. Song, B. M. Kim, T. Hyeon, Chem.
Commun. 2011, 47, 3601-3603.
General Introduction 34
Furthermore, the Au/Fe3O4 catalyst has been used in the oxygen
reduction reaction79
and CO oxidation.80
The epoxidation of alkenes was performed with the Ag/Fe3O481
catalyst
obtaining after 13 hours of reaction full conversion of the starting material and 84
% yield of styrene epoxide. After five reaction cycles no deactivation was
observed.
The Ru/Fe3O482
catalyst was obtained through the co-precipitation
methodology and after that was used in the coupling reaction between alcohols
and sulphonamides through the hydrogen autotransference mechanism.
2.5. IMPREGNATED CATALYST
The impregnation method83
is one of the oldest ways employed to deposit
metal catalysts on the surface of inorganic materials. From all the possible ways
to immobilize or support a metal in the surface of a particle,44
the impregnation is
the most straightforward, simple and less expensive protocol. It consists either in
the evaporation or in the precipitation of a solution which contains the metal salt
or metal oxide precursors and the desired support, followed by an ulterior drying
process. Although the procedure is simple, the particle distribution and
morphology of the supported catalyst is governed by various factors such as the
possible interactions between the support and the metal specie, the porosity of the
support, the pH, the viscosity of the solution and the drying rates (Figure 7).
Metal-support interactions are frequently invoked to explain the
enhanced catalytic activity of metal nanoparticles dispersed over reducible metal
oxide supports, for some cases the atomic surface scale pathway is known.84
79 Y. Lee, A. Loew, S. Sun, Chem. Mater. 2010, 22, 755-761. 80 B. Wu, H. Zhang, C. Chen, S. Lin, N. Zheng, Nano Res. 2009, 2, 975-983. 81 a) D.-H. Zhang, G.-D. Li, J.-X. Li, J.-S. Chen, Chem. Commun. 2008, 3414-3416; b) S. Peng,
C. Lei, Y. Ren, R. E. Cook, Y. Sun, Angew. Chem. Int. Ed. 2011, 50, 3158-3163. 82 F. Shi, M. K. Tse, S. Zhou, M.-M. Pohl, J. Radnik, S. Hübner, K. Jähnisch, A. Brückner, M.
Beller, J. Am. Chem. Soc. 2009, 131, 1775-1779. 83 M. B. Gawande, P. S. Branco, R. S. Varma, Chem. Soc. Rev. 2013, 42, 3371-3393. 84 R. Bliem, J. van der Hoeven, A. Zavodny, O. Gamba, J. Pavelec, P. E. de Jongh, M. Schmid, U.
Diebold, G. S. Parkinson, Angew. Chem. Int. Ed. 2015, 54, 13999-14002.
35 General Introduction
Figure 7. General scheme for an impregnated catalyst: Cat-Fe3O4.
Different metal oxides derived from cobalt, nickel, copper, niobium,
molybdenum, rhodium, palladium, cerium, tungsten, osmium, iridium, platinum,
gold, amoung others,85
have been impregnated on magnetite surface and used to
perform a great variety of organic transformations. In this chapter, only a few
examples of them will be discussed. In order to avoid avoid a too long chapter,
we will focus this section on the catalysts which are related to the ones used in
the thesis studies.
2.5.1 COBALT CATALYST
The use of cobalt in organic synthesis has been traditionally linked to
reactions involving carbonylations, π-bonds activation and radicals. However,
recently, the use of cobalt catalysts in organic transformations such as coupling
reactions, C-H bond activations, among others, has experimented a significant
growth. This is an alternative to other noble transition metals. However, despite
the multiple applications of cobalt complexes in organic synthesis and their
general instability, there are few examples in literature of impregnated cobalt
species onto magnetite as catalysts as far as we know.
One of the interesting reports deals with the use of a Co3O4-Fe3O4
obtained by wet impregnation in basic media and subsequent reduction of the
corresponding oxide. This catalyst was used for the oxidation of alcohols, mainly
benzylic ones, to the corresponding carbonyl compounds (Scheme 13). For this
transformation, TBHP was the chosen oxidant, with products being obtained, at
80 ºC and after six hours of reaction, with yields between 79 and 94 %. Notably,
the catalyst was recycled up to seven times with a slight loss of activity and
85 a) D. J. Ramón, Johnson Matthey Technol. Rev. 2015, 59, 120-122; b) A. Baeza, G. Guillena,
D. J. Ramon, ChemCatChem 2016, 8, 49-67.
General Introduction 36
negligible metal leaching.86
The TEM image of the catalyst presented a spherical
morphology of the nanoparticles with an average diameter ranging from 10 to 30
nm. The active catalytic specie was identified by XPS as Co3O4, excluding the
existence of CoO and Co(OH)2.
Scheme 13. Oxidation of alcohols catalysed by Co3O4-Fe3O4.
2.5.2 NICKEL CATALYST
Despite the number of applications of nickel complexes in homogeneous
catalysis, there are only a two studies where the use of impregnated nickel
species onto magnetite surfaces has been reported so far.
A NiO-Fe3O4 catalyst hs been applied to the reduction of nitroarenes and
carbonyl compounds using glycerol as the hydrogen-transfer reagent. Different
nitroarenes and aromatic carbonyl compounds have been successfully
hydrogenated using Ni-Fe3O4 magnetic nanoparticles (8.85 mol%) in glycerol
and in basic media at 80 ºC. The corresponding amines and alcohols have been
obtained in high yields with short reaction times (Scheme 14). Remarkably, even
halogen substituted arenes are hydrogenated without observing any
dehalogenation process. The study of the surface composition by XPS revealed
that the impregnated Ni species on the magnetite correspond to NiO, despite the
authors claimed to obtain Ni(0) nanoparticles by using a reducing agent after the
impregnation methodology. The morphology observed by TEM images revealed
spherical particles with an average size range of 15-30 nm. Finally, the catalyst
has shown high performance even after eight cycles. Applying the hot filtration
method, metal leaching was discarded.87
86 M. B. Gawande, A. Rathi, I. D. Nogueira, C. A. A. Ghumman, N. Bundaleki, O. M. N. D.
Teodoro, P. S. Branco, ChemPlusChem 2012, 77, 865-871. 87 M. B. Gawande, A. Rathi, P. S. Branco, I. D. Nogueira, A. Velhinho, J. J. Bundaleski, O. M. N.
Teodoro, Chem Eur. J. 2012, 18, 12628-12632.
37 General Introduction
Scheme 14. Transfer hydrogenation of nitroarenes and carbonyl compounds
catalysed by NiO-Fe3O4.
2.5.3 COPPER CATALYST
Copper salts and complexes are one of the most employed catalysts in
Organic Synthesis. This is due to the availability of copper compounds and their
versatility. They have proven to be high efficient catalysts for a wide variety of
organic transformations. Therefore, copper impregnated magnetite could be a
recyclable catalyst, prone to be tested in a large variety of organic reactions.
In 2010, the first study about the use of impregnated copper on magnetite
as catalysts for a three-component acetylene-Mannich reaction to give
propargylamines was reported (Scheme 15). The reaction took place in only three
hours at 120 ºC, giving the expected amines in quantitatively yields. The catalyst
was recycled up to ten-fold without losing its initial activity. Studies about a
possible degradation of the catalyst under the reaction conditions, by means of
the determination of BET surface area and TEM images, concluded that no
significant sinterization process occurred.88
Scheme 15. Acetylene-Mannich reaction catalysed by CuO-Fe3O4.
88 M. J. Aliaga, D. J. Ramón, M. Yus, Org. Biomol. Chem. 2010, 8, 43-46.
General Introduction 38
The borylation of double bonds could be carried out using the same
catalyst. After an exhaustive search for the optimal reaction conditions, it was
observed that only 2.5 mol% for the recyclable catalyst was enough to effectively
promote the addition of alkoxy diboron reagents to both electron-rich and
electron-poor olefins (Scheme 16). As expected, the obtained yields with
electron-poor olefins were higher. The performance of the catalyst remained high
(ranging between 88-99 %) after eight recycling experiments.89
Scheme 16. Borilation of olefins catalysed by CuO-Fe3O4.
The same impregnated CuO on magnetite catalyst was subsequently used
for other organic transformations. The synthesis of benzofurans through a
domino Sonogashira-cyclization protocol, by reaction of 2-iodophenol and
different alkynes has been reported. The corresponding heterocycles were
synthetized in good to excellent yields (Scheme 17). The catalyst employed was
reused up to ten times with the results remaining almost constant. In addition, the
hot test filtration experiment excluded a possible metal leached catalysed
process. Importantly, neither the reaction catalysed by Fe3O4, nor by CuO took
place. These results can also reveal the importance of the CuO nanoparticles size,
which are far more active than the bulk oxide, as well as the presence of a
possible synergistic effect between both metal oxides.90
89 R. Cano, D. J. Ramón, M. Yus, J. Org. Chem. 2010, 75, 3458-3460. 90 R. Cano, M. Yus, D. J. Ramón, Tetrahedron 2012, 68, 1393-1400.
39 General Introduction
Scheme 17. Domino Sonogashira-cyclization reaction catalysed by CuO-Fe3O4.
A similar catalyst has been successfully applied for the arylation of
phenols with aryl halides. Good to high yields were achieved using bromo or
iodoarenes. However, poor yields were obtained using chloroarenes as reagents
(Scheme 18). These results were maintained for 3 cycles. Although the activity of
the catalyst decreased notably after the third cycle, the spherical shape remained
almost unaltered.91
Scheme 18. Arylation of phenols catalysed by CuO-Fe3O4.
2.5.4 PALLADIUM CATALYST
The enormous amount of applications and organic transformations in
which homogeneous palladium species are involved, together with the high cost
of the palladium compounds has led to a plethora of scientific work about the
synthesis and use of supported palladium nanoparticles.
It is not surprising that several studies dealing with the synthesis and use
of supported palladium species on magnetite nanoparticles have been reported.
The first one describes the use of a palladium(0) supported nanoparticles for the
carbonylative Sonogashira coupling reaction of aryl iodides with terminal
alkynes in a phosphine-free transformation. The employed catalyst was prepared
by the classical impregnation methodology. The process normally rendered the
91 Y.-P. Zhang, A.-H. Shi, Y.-S. Yang, C.-L. Li, Chin. Chem. Lett. 2014, 25, 141-145.
General Introduction 40
coupling products in high yields using only 0.2 mol% of catalyst. Its recycling
was possible up to seven times with a slight loss of activity.92
Later on, in 2010, an important breakthrough in the use of impregnated
metal species on magnetite was reported. The work describes the use of chiral-
carbene decorated Pd-Fe3O4 catalyst for the asymmetric α-arylation of cyclic
ketones (Scheme 19).93
Scheme 19. Enantioselective arylation of ketones catalysed by Chiral NHC-Pd-
Fe3O4.
Although the reached yields and enantiomeric excess were moderate to
good, this challenging transformation represents the first and unique example in
which impregnated metal specie has been employed in an enantioselective
process.94
The heterogeneous nature of the catalyst was demonstrated by XPS,
ATR-IR, SEM-EDX and TEM analyses. The catalyst was recycled five times
without a significant decrease in yield and enantioselectivity.
Shortly after, the use of PdO-Fe3O4 catalyst for the multicomponent
reductive amination reaction was also reported. Under the optimised reaction
conditions, several primary amines were obtained in high yields at room
temperature independently of the nature of the amine employed. The reaction
became sluggish when poor nucleophilic amines were employed, being necessary
harsh reaction conditions and longer reaction times (Scheme 20). Notably, this
catalytic system also turned out to be effective in the reductive amination process
92 J. Liu, X. Peng, W. Sun, Y. Zhao, C. Xia, Org. Lett. 2008, 10, 3933-3936. 93 K. V. S. Ranganath, J. Kloesges, A. H. Schäfer, F. Glorius, Angew. Chem. Int. Ed. 2010, 49,
7786-7789. 94 R. B. N. Baig, M. N. Nadagouda, R. S. Varma, Coord. Chem. Rev. 2015, 287, 137-156.
41 General Introduction
when employing secondary amines. However, the catalyst recycling was
unsuccessful and after the third use the yield dropped dramatically. A possible
explanation arises from the fact that the exposure of the catalyst to a reducing
media produces a Pd(II) reduction to the less active and more prone to leach
Pd(0) nanoparticles.95
Scheme 20. Reductive amination reaction catalysed by PdO-Fe3O4.
The same impregnated catalyst has been also reported for the ligand-free
Suzuki-Miyaura cross-coupling reaction.96
The reaction works especially well for
electron-rich aryl iodides and a wide variety of boronic acids. However, the
catalyst recycling was not possible probably due to the poisoning as consequence
of the different salt adsoption on the metal surface.
Finally, PdO-Fe3O4 or Pd-Fe3O4 catalysts have been also employed for
other interesting transformations such as, the Buchwald-Hartwing amination
reaction,97
the hydrogenation of acetylenic derivatives,98
or nitrocompounds,99
and the selective dehalogenation of organic compounds from aqueous wastes.100
95 R. Cano, M. Yus, D. J. Ramón, Tetrahedron 2011, 67, 8079-8085. 96 R. Cano, D. J. Ramón, M. Yus, Tetrahedron 2011, 67, 5432-5436. 97 S. Sá, M. B. Gawande, A. Velhinho, J. P. Veiga, N. Bundaleski, J. Trigueiro, A. Tolstogouzov,
O. M. N. D. Teodoro, R. Zboril, R. S. Varma, P. S. Branco, Green Chem. 2014, 16, 3494-3500. 98 F. Parra da Silva, L. M. Rossi, Tetrahedron 2014, 70, 3314-3318. 99 K. Jiang, H.-X. Zhang, Y.-Y. Yang, R. Mothes, H. Lang, W.-B. Cai, Chem. Commun. 2011, 47,
11924-11926. 100 H. Hilderbrand, K. Mackenzie, F.-D. Kopinke, Appl. Catal. B: Env. 2009, 91, 389-396.
RESULTS
CHAPTER I
Reactions performed using
nanoparticles of impregnated
Cobalt(II) Oxide on Magnetite
47 Chapter I. Reactions performed by nanoparticles of Cobalt
1. HYDROACYLATION REACTION OF AZODICARBOXYLATES
1.1 INTRODUCTION
The C-N bond formation is one of the most important reactions in
Organic Synthesis, which has found a wide application in the synthesis of many
organic substances, including natural products.101
This type of bond has been constructed using polar, radical and transition
metal-catalysed reactions,102
with dialkyl azodicarboxylate compounds being
used during the last few decades to perform this type of transformations.
The synthesis of dialkyl azodicarboxylate compounds, that normally are
orange liquids, can be carried out using the corresponding chloroformate and
hydrazine followed by oxidation of the resulting substituted hydrazine
dicarboxylate with chlorine. (Scheme 21).103
Scheme 21. Synthesis of azodicarboxylates.
These reagents are sensitive to heat and light and should be stored in a
dark container under refrigerated conditions. Azodicarboxylates contain a vacant
orbital and a strong electron-withdrawing group which contributes to make them
good nucleophilic acceptors, favouring their reaction. Several types of reactions
(Scheme 22), such as the zwitterion intermediate reaction, the electrophilic α-
amination of carbonyl compounds, the C-H activation at the α-position of amines
101 a) O. Mitsunobu in Comprehensive Organic Synthesis, Vol 6 (Eds.: B. M. Trost), Pergamon
Press, Oxford, 1991, pp. 65-101; b) O. Mitsunobu in Comprehensive Organic Synthesis, Vol 6
(Eds.: B. M. Trost), Pergamon Press, Oxford, 1991, pp. 381-411; c) C. M. Manson, A. D.
Hobson in Comprehensive Organic Functional Group Transformations, Vol 2 (Eds.: A. R.
Katritzky, O. Meth-Cohn, C. W. Rees), Pergamon, Cambridge, 1995, pp. 297-332; d) P. D.
Bailey, I. D. Collier, K. M. Morgan in Comprehensive Organic Functional Group
Transformations, Vol 5 (Eds.: A. R. Katritzky, O. Meth-Cohn, C. W. Rees), Pergamon,
Cambridge, 1995, pp 257-307. 102 a) J. F. Hartwig, Science 2002, 297, 1653; b) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew.
Chem. Int. Ed. 2004, 43, 3368-3398; c) V. Nair, R. S. Menon, A. R. Sreekanth, N. Abhilash, A.
T. Biju, Acc. Chem. Res. 2006, 39, 520-530; d) R. Matsubara, S. Kobayashi, Acc. Chem. Res.
2008, 41, 292-301. 103 N. Rabjohn, Org. Syntheses, Coll. 1955, 3, 375.
Chapter I. Reactions performed by nanoparticles of Cobalt 48
and ethers, and the ene-type reaction with olefins have been extensively studied
using these compounds.104
However, the hydroacylation reaction with aldehydes
has been less considered.105
Azodicarboxylates
hydroacylation of
aldehydes
α-amination carbonilic
compounds
C-H activation α-position
amine and ethers
Scheme 22. Reaction involving azodicarboxylates.
104 V. Nair, A. T. Mathew, B. P. Babu, Chem. Asian J. 2008, 38, 810-820. 105 a) C. González-Rodríguez, M. C. Willis, Pure Appl. Chem. 2011, 83, 577-585; b) P. W. N. M.
van Leeuwen in Science of Synthesis: Stereoselective Synthesis, Vol. 1 (Eds.: J. G. de Vries),
Thieme, Stuttgart, 2011, pp. 409-475; c) S. Brase, Nachr. Chem. 2012, 60, 265-299; d) J. C.
Leung, M. J. Krische, Chem. Sci. 2012, 3, 2202-2209.
49 Chapter I. Reactions performed by nanoparticles of Cobalt
The first example of hydroacylation of azodicarboxylates using an excess
of formaldehyde106
was introduced in 1914 and after that, the scope of aliphatic
aldehydes for the reaction was increased, affording in all cases moderate yields
after several days of reaction time.107
Recently, the use of unusual solvents, such
as ionic liquids108
or water109
has been introduced in order to increase the reaction
scope, as well as to overcome other previous drawbacks. However, the reaction
using arenecarbaldehydes is still very challenging and unsuccessful.
The first metal-catalysed process was introduced in 2004 using
[Rh(OAc)2]2 (2 mol%), but still arenecarbaldehydes were not reacting under this
conditions.110
The use of copper(II) acetate,111
as well as zinc112
catalyst, allowed
to carry out the reaction with aliphatic and aromatic aldehydes with similar yields
for both substrates, but increasing the reaction time for 10 h for aliphatic
aldehydes to several days for arenecarbaldehydes.
It should be pointed out that there was only one example of a
heterogeneous catalyst performing the hydroacylation of azodicarboxylate
derivatives.113
The reaction using CuO nanoparticles supported on silica (10
mol%) as catalyst, gave similar results, in terms of yields and reaction times (12-
30 h), independently of the nature of the used aldehyde. With these protocol in
hand, we believed that heterogeneous catalysts derived from copper, iridium or
any other transition metal with two closed oxidation states could be a catalytic
alternative for this process.
106 O. Diels, E. Fisher, Ber. Dtsch. Chem. Ges. 1914, 47, 2043-2047. 107 a) K. Alder, T. Noble Ber. Dtsch. Chem. Ges. 1943, 76B, 54-57; b) R. Huisgen, F. Jakob Justus
Liebigs Ann. Chem. 1954, 590, 37-54; c) G. O. Schenck, H. Formaneck Angew. Chem. 1958,
70, 505; d) M. E. González-Rosende, O. Lozano-Lucia, E. Zaballos-García, J. Sepúlveda-
Arques J. Chem. Res., Synop 1995, 260-261; e) E. Zaballos-García, M. E. González-Rosende,
J. M. Jorda-Gregori, J. Sepúlveda-Arques, Tetrahedron 1997, 53, 9313-9322. 108 B. Ni, Q. Zhang, S. Garre, A. D. Headley, Adv. Synth. Catal. 2009, 351, 875-880. 109 a) Q. Zhang, E. Parker, A. D. Headley, B. Ni, Synlett 2010, 2453-2456; b) V. Chudasama, J. M.
Ahern, D. V. Dhokia, R. J. Fitzmaurize, S. Caddick, Chem. Commun. 2011, 47, 3269-3271; c)
V. Chudasama, A. R. Akhbar, K. A. Bahou,, R. J. Fitzmaurice, S. Caddick, Org. Biomol. Chem.
2013, 11, 7301-7317. 110 a) D. Lee, R. D. Otte, J. Org. Chem. 2004, 69, 3569-3571; b) Y. J. Kim, D. Lee, Org. Lett.
2004, 6, 4351-4353. 111 Y. Qin, Q. Peng, J. Song, D. Zhou, Tetrahedron Lett. 2011, 52, 5880-5883. 112 Y. Qin, D. Zhou, M. Li, Lett. Org. Chem. 2012, 9, 1875-1876. 113 S. M. Inamdar, V. K. More, S. K. Mandal, Chem. Lett. 2012, 41, 1484-1486.
Chapter I. Reactions performed by nanoparticles of Cobalt 50
1.2 RESULTS
The hydroacylation reaction of diisopropyl azodicarboxylate (DIAD, 1a)
using benzaldehyde (2a) catalysed by impregnated iridium on magnetite was
selected as the model for the optimization of the reaction conditions (Table 1).
Table 1. Optimization of the reaction conditions.a
Entry T (ºC) Solvent Yield 3a (%)
b Yield 4a (%)
b
1 25 CH3CN 2 0
2 40 CH3CN 18 0
3 50 CH3CN 32 0
4 60 CH3CN 65 5
5 70 CH3CN 15 0
6 100 CH3CN 9 0
7 60 - 54 7
8 60 THF 7 92
9 60 H2O 70 21
10 60 PhMe 30 4
11 60 (ClCH2)2 69 2
12 60 CHCl3 24 9
13 60 CCl4 25 4
14 60 Cl3CCH3 12 5
15c 60 Cl2C=CHCl 80 10
a Reaction carried out using compounds 1a (1mmol), and 2a (1.2 mmol) in 1 mL of
solvent. b Isolated yield after column chromatography.
c Reaction carried out during 24 h.
Benzaldehyde was chosen for its limited success in previous protocols,
and the iridium catalyst for its tendency to have an easy electronic state change.
Initially, the effect of temperature on the results was examined (entries 1-6),
achieving the best result at 60 ºC (entry 4). Then, different solvents were tested
(entries 4 and 7-15), with the reaction affording similar results in water and
51 Chapter I. Reactions performed by nanoparticles of Cobalt
dichloroethane and best results being reched in trichloroethylene. It should be
pointed out that the hydrazine by-product 4a was obtained as the main compound
in THF (entry 8).
In order to establish the hydrogen donor for the process, the reaction was
repeated using THF-d8. After quenching the reaction by addition of toluene and
magnetic decantation, the GC-MS of the crude mixture showed the
corresponding deuterated by-product 4a, with the incorporation of the second
deuterium being lower than 25 %. Then, the reaction was conducted with α-
deuterobenzaldehyde and THF, with the mono-incorporation of deuterium to the
by-product 4a being negligible.
Once the optimal conditions were determined, the reaction was repeated
with a variety of catalysts prepared by the simple impregnation protocol (Table
2). The reaction without a catalyst gave a poor yield (entry 1). Then, the activity
of the support was evaluated using magnetite as the unique catalyst.
Nanoparticles (size < 50 nm) or microparticles (size < 5 μm) of magnetite
(entries 2 and 3) were used with the results showing the inactivity of the support,
reaching the same yield as that obtained without catalyst.
Once the activity of magnetite was tested, different metal oxides
impregnated on magnetite (entries 4, 7, 10-18) were evaluated as catalyst,
achieving surprisingly the best result using the cobalt catalyst in only 3 h (entry
4). To the best of our knowledge, this is the first time that a cobalt catalyst has
shown its great activity in the hydroacylation reaction. This reaction time is the
shortest ever reported for this type of reaction. Molecular oxygen seems to have
an important role in the initial radical acyl formation the in non-catalysed
processes.109c
In order to clarify this aspect, the reaction was repeated but in an
inert atmosphere, obtaining similar result (entry 4, footnote d). Then, the reaction
was carried out with different bimetallic catalysts (entries 19 and 20), obtaining
worse results. Different amounts of catalyst were tested (entries 5, 6, 8, and 9)
finding that increasing the amount of nickel or cobalt, the amount of by-product
4a was increased, whereas the decrease of the catalyst amount, decreased the
yield of 3a.
Reactions using cobalt oxide or nickel oxide alone, gave moderate yields
(entries 21 and 22), with these results pointing out the high activity of these
nanostructured catalysts. It should be highlighted that the optimal amount of
catalyst is the lowest one ever reported for this type of transformations.
Chapter I. Reactions performed by nanoparticles of Cobalt 52
Table 2. Optimization of the catalyst.a
Entry Catalyst (mol%) Yield 3a (%)
b Yield 4a (%)
b
1c - 42 7
2 Micro-Fe3O4 (21.6) 45 7
3 Nano-Fe3O4 (21.6) 52 8
4 CoO-Fe3O4 (1.42) 90 (93)d 6
5 CoO-Fe3O4 (2.8) 78 18
6 CoO-Fe3O4 (0.28) 60 8
7 NiO-Fe3O4 (1.03) 83 6
8 NiO-Fe3O4 (2.06) 70 27
9 NiO-Fe3O4 (0.21) 66 6
10 CuO-Fe3O4 (0.91) 40 10
11 Ru2O3-Fe3O4 (1.03) 51 7
12 Rh2O3-Fe3O4 (0.42) 50 7
13 PdO-Fe3O4 (1.22) 69 8
14 Ag2O/Ag-Fe3O4 (1.25) 49 8
15 WO3-Fe3O4 (0.57) 51 7
16 OsO-Fe3O4 (0.51) 38 9
17 PtO/PtO2-Fe3O4 (0.54) 49 8
18 Au2O3/Au-Fe3O4 (0.14) 43 9
19 NiO/Cu-Fe3O4 (0.91/0.88) 43 12
20 PdO/Cu-Fe3O4 (1.53/0.90) 4 11
21 CoO (1.42) 46 9
22 NiO (1.03) 46 8 a Reaction carried out using compounds 1a (1mmol), and 2a (1.2 mmol).
b Isolated yield after column chromatography.
c Reaction carried out during 5 h.
d Reaction performed in argon atmosphere.
Having established the similar catalytic activity for cobalt and nickel
derivatives, the problem of recycling was faced (Figure 8). When the catalyst was
recovered from the reaction mixture by magnetic decantation, washed with
toluene, and reused under the same reaction conditions, the expected product 3a
was obtained in good yields with both catalysts. These catalysts could be
53 Chapter I. Reactions performed by nanoparticles of Cobalt
recycled up to 10 times with only a slight loss of their activity for the case of
NiO-Fe3O4 in which the yield decreased to 53 %. However, the CoO-Fe3O4
catalyst kept its activity practically constant and only in the last reaction cycle the
yield decreased slightly.
Figure 8. Recycling of the NiO-Fe3O4 and CoO-Fe3O4 catalyst.
In order to study the effect of the reaction conditions on the cobalt
catalyst, the nanosize distribution of the cobalt catalyst was measured through
Transmission Electron Microscopy (TEM) images (Figure 9), before, after only
one reaction process, and after ten runs, observing a small sinterization process of
the nanoparticles.
Figure 9. TEM images: a) before and b) after 10 times of recycling cobalt
catalyst.
a) b)
Chapter I. Reactions performed by nanoparticles of Cobalt 54
Before the reaction, the size of 77 % of the cobalt oxide particles on the
surface of the catalyst was between 1 and 4 nm. After the first recycling of the
catalyst, the average of the cobalt oxide particles was practically the same, as the
fresh one. However, after ten reactions, the recycled catalyst suffered a small
sinterization process, with the 73 % of cobalt oxide particles measuring between
2 and 6 nm (Figure 10).
0
10
20
30
40
50
0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-1010-15
Par
ticl
es
Particle size (nm)
Ten-fold recycled catalyst
First recycled catalyst
Fresh catalyst
Figure 10. Cobalt particle size distribution.
The X-Ray Photoelectron Spectroscopy (XPS) study of catalyst showed
the transformation of cobalt(II) oxide to the corresponding cobalt(II) hydroxide
(Figure 11). These small changes in particle size as well as the initial cobalt
species seemed not to affect the activity of the catalyst, since it could be reused
ten times with similar results.
0
2000
4000
6000
8000
10000
12000
14000
16000
770 775 780 785 790
Inte
nsi
ty/
arb.
Un
its
Binding energy (eV)
Fit
CoO 2p3/2
CoO 2p3/2
-50
50
150
250
350
450
550
650
750
770 775 780 785 790 795
Inte
nsi
ty/
arb
. U
nit
s
Binding energy (eV)
Fit
Co(OH)2 2p3/2
Co(OH)2 2p3/2
Figure 11. XPS of cobalt catalyst: a) before and b) after ten reactions.
a) b)
55 Chapter I. Reactions performed by nanoparticles of Cobalt
To know if the reaction took place by the leached cobalt species to the
organic medium, we performed the standard reaction (Table 3, entry 1). After
that, the catalyst was removed carefully by a magnet at high temperature, and
washed with trichloroethylene. The solvents of the above solution, without
catalyst, were removed under low pressure, and DIAD (1a) and 3-
methylbenzaldehyde (2c), as well as 1 mL of Cl2CCHCl, were added to the above
residue. The resulting solution was heated again at 60 ºC for 3 h. The analysis of
the crude mixture, after hydrolysis, revealed the formation of compound 3a in 93
% (catalysed process) and product 3c in 72 % yield by GC analysis (compare
with entry 3 in Table 3). It seems that the reaction takes place under
homogeneous conditions. Finally, Inductively Coupled Plasma-Mass
Spectroscopy (ICP-MS) analysis of the crude reaction solution showed the
leaching of a small amount of cobalt (1.4 % of the initial amount) and iron
(0.17% of the initial amount).
All these data seem to point out that the initial cobalt-impregnated
magnetite catalyst is only a reservoir for homogeneous cobalt species at high
temperatures, and after the reaction has taken place in the homogeneous solvent
phase, the cobalt species is efficiently re-adsorbed by the magnetite surface at
low temperatures, keeping its activity.
The evolution of the yield for compound 3a with the time at different
catalyst and reactive loadings is depicted in Figure 12. Assuming that the
equation rate is simple and that the reaction conditions permit a pseudo-first
order approximation for all reagents, with [A] being the initial concentration of
catalyst or reagents, the equation rate could be expressed as Ln roi=a Ln [A]oi +
constant. The estimation of the initial reaction rate for each trial and their
representation allowed us to estimate the value of the reaction order for the
catalyst and for both reagents, with the obtained value being very close to 1/2 for
both reagents and 3/4 for the cobalt catalyst. These results pointed out that the
mechanism is not very simple and could be an indirect indication of a previously
reported radical mechanism. To verify this fact, a radical scavenger (TEMPO)
was added to the initial reaction solution, recovering the starting reagents
unchanged after 6 h. In order to know if the sun light had some impact on the
possible radical reaction pathway, the reaction was performed in a light protected
tube, affording a similar result (88 %) to that presented in Table 2, entry 4.
Chapter I. Reactions performed by nanoparticles of Cobalt 56
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200
Yie
ld (
%)
t (min)
2 mol% Co
1.42 mol% Co
0.6 mol% Co
Ln roi = 0,7306 Ln [Catlyst]o + 0,376
R² = 0,9996
0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1
-0,6 -0,4 -0,2 0 0,2 0,4 0,6 0,8
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200
Yie
ld (
%)
t (min)
1 mmol DIAD
0,5 mmol DIAD
0,1 mmol DIAD
Ln roi = 0,4991 Ln [DIAD]o + 0,8435
R² = 0,9995
-0,4
-0,2
0
0,2
0,4
0,6
0,8
1
-2,5 -2 -1,5 -1 -0,5 0
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200
Yie
ld (
%)
t (min)
1,2 mmol aldehyde
0,5 mmol aldehyde
0,1 mmol aldehyde
Ln roi = 0,5055 Ln [aldehyde]o + 0,5902
R² = 0,9995
-0,8
-0,6
-0,4
-0,2
0
0,2
0,4
0,6
0,8
-2,5 -2 -1,5 -1 -0,5 0 0,5
Figure 12. Plot-time yield and correlation between initial rates and the
corresponding catalyst and reagents.
With the best conditions in hands, the scope of the reaction was
evaluated using cobalt and nickel catalysts (Table 3). The reaction gave excellent
and consistent results when diisopropyl azodicarboxylate reagent was employed
using different arenecarbaldehydes bearing electron-withdrawing groups (Table
3, entries 7–10). However, the presence of electron-donating groups at the aryl
moiety decreased somehow the yields (entries 2-5), with the reaction using 3,4,5-
trimethoxybenzaldehyde giving the worse result (entry 6).
57 Chapter I. Reactions performed by nanoparticles of Cobalt
Table 3. Preparation of hydroacylation products.a
Entry R
1 R
2 No Yield 3 (%)
b
1 i-Pr Ph 3a 89 (83)
2 i-Pr 2-MeC6H4 3b 86 (75)
3 i-Pr 3-MeC6H4 3c 79 (99)
4 i-Pr 4-MeC6H4 3d 72 (78)
5 i-Pr 4-MeOC6H4 3e 67 (41)
6 i-Pr 3,4,5-(MeO)3C6H2 3f 26 (8)
7 i-Pr 4-FC6H4 3g 90 (86)
8 i-Pr 2-ClC6H4 3h 95 (38)
9 i-Pr 3-ClC6H4 3i 97 (88)
10 i-Pr 4-ClC6H4 3j 87 (65)
11 i-Pr 1-naphthyl 3k 87 (79)
12 i-Pr 1-thienyl 3l 60 (60)
13 i-Pr C6H5CH=CH 3m 74 (82)
14c i-Pr CH3(CH2)2 3n 99
15c i-Pr CH3(CH2)7 3o 99
16c i-Pr (CH3CH2)2CH 3p 99 (99)
17c i-Pr (CH3)3C 3q 75 (88)
18 i-Pr (Z)-EtCH=CH(CH2)5 3r 99
19 Et Ph 3s 99 (99)
20 t-Bu Ph 3t 40 (62)
21 i-Pr Me2N 3u 0 a Reaction carried out using compounds 1 (1mmol), and 2 (1.2 mmol).
b Isolated yield after column chromatography. In brackets the yield obtained using
NiO-Fe3O4 catalyst (1.03 mol%). c Reaction carried out during 30 min.
Interestingly, the reaction using cobalt catalyst led to higher yields than
using nickel. The reaction reached good results when other aromatic aldehydes,
including heteroaromatic (entry 12) or α,β-unsaturated aldehydes (entry 13), were
used. The reaction with aliphatic aldehydes also gave excellent results
independently of the substitution at the α-position or the presence of an isolated
carbon-carbon double bond (entries 14-18). It should be pointed out that the
Chapter I. Reactions performed by nanoparticles of Cobalt 58
reaction using diethyl azodicarboxylate (entry 19), gave practically the same
result as the diisopropyl derivative. However, when the steric hindrance of the
azoderivative was increased the final yield decreased (compare entries 1, 19 and
20). Finally, the reaction was performed using N,N-dimethylformamide (2u)
(entry 21) recovering the starting material unchanged after 3 h.
CHAPTER II
Reactions performed using
nanoparticles of impregnated
Copper(II) Oxide on Magnetite
61 Chapter II. Reactions performed by nanoparticles of Copper
1. HOMOCOUPLING OF TERMINAL ALKYNES
1.1 INTRODUCTION
The homocoupling of terminal alkynes114
to give 1,3-diynes has attracted
great deal of attention in Organic Chemistry due to of their role as building
blocks in the synthesis of many natural products115
or for pharmaceuticals with
anti-inflammatory, antibacterial, antitumor, or antifungal activities. Furthermore,
1,3-diynes have attracted the attention of chemists as interesting material that are
useful as precursors of polymers,116
macrocycles,117
or supramolecular
structures.118
The symmetric coupling of simple terminal acetylenes,119
known as the
Glaser-Hay reaction, was discovered over a century ago, and the methodology
for this reaction was improved shortly afterwards.120
Among the various metallic
salts that were used, copper emerged as the best metal for catalysing this
transformation. In fact, the number of copper complexes that have been identified
as being capable of successfully inducing this transformation continues to
increase.121
However, homogeneous catalysts have some important drawbacks,
114 a) Modern Acetylene Chemistry, (Eds.: P. J. Stang, F. Diederich), VCH, Weinheim, 1995; b) L.
Brandsma in Synthesis of Acetylenes, Allenes and Cumulenes: Methods and Techniques;
Elsevier Academic Press, Amsterdam, 2004; c) Acetylene Chemistry, (Eds.: F. Diederich, P. J.
Stang, R. R. Tykwinski), Wiley-VCH, Weinheim, 2005. 115 A. L. K. S. Shun, R. R. Tykwinski, Angew. Chem. Int. Ed. 2006, 45, 1034-1057. 116 a) T. X. Neenan, G. M. Whitesides, J. Org. Chem. 1988, 53, 2489-2496; b) J. M. Tour, Chem.
Rev. 1996, 96, 537-553; c) U. H. F. Bunz, Y. Rubin, Y. Tobe, Chem. Soc. Rev. 1999, 28, 107-
119. 117 a) M. Ladika, T. E. Fisk, W. W. Wu, S. D. Jons, J. Am. Chem. Soc. 1994, 116, 12093-12094; b)
M. Ohkita, K. Ando, T. Suzuki, T. Tsuji, J. Org. Chem. 2000, 65, 4385-4390; c) J. A. Marsden,
M. M. Haley, J. Org. Chem. 2005, 70, 10213-10226. 118 J. D. Crowley, S. M. Goldup, A.-L. Lee, D. A. Leigh, R. T. McBurney, Chem. Soc. Rev. 2009,
38, 1530-1541. 119 a) P. Siemsen, C. Livingston, F. Diederich, Angew. Chem. Int. Ed. 2000, 39, 2632-2657; b) H.
A. Stefani, A. S. Guarezemini, R. Cella, Tetrahedron 2010, 66, 7871-7918; c) F. Alonso, M.
Yus, ACS Catal. 2012, 2, 1441-1451. 120 a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422-424; b) A. S. Hay, J. Org. Chem. 1962, 27,
3320-3321. 121 a) J. S. Yadav, B. V. S. Reddy, K. B. Reddy, K. U. Gayathri, A. R. Prasad, Tetrahedron Lett.
2003, 44, 6493-6496; b) X. Lu, Y. Zhang, C. Luo, Y. Wang, Synth. Commun. 2006, 36, 2503-
2511; c) H.-F. Jiang, J.-Y. Tang, A.-Z. Wang, G.-H. Deng, S.-R. Yang, Synthesis 2006, 1155-
1161; d) V. Kumar, A. Chipeleme, K. Chibale, Eur. J. Org. Chem. 2008, 43-46; e) K. Yin, C.
Li, J. Li, X. Jia, Green Chem. 2011, 13, 591-593; f) S. Zhang, X. Liu, T. Wang, Adv. Synth.
Catal. 2011, 353, 1463-1466; g) R. Schmidt, R. Thorwirth, T. Szuppa, A. Stolle, B.
Ondruschka, H. Hopf, Chem. Eur. J. 2011, 17, 8129-8138.
Chapter II. Reactions performed by nanoparticles of Copper 62
such the need of high metal loadings and the inability to recycle the catalyst. A
homogeneous copper acetate-poly(ethylene glycol) catalyst system121b
has been
recycled up to five times, although this was accompanied by a decrease in
activity after each reactivation step of treatment with acetic acid.
Heterogeneous catalysts have been designed to perform this
transformation and to facilitate their removal, recovery, and recycling of the
catalysts. Although, there are several examples of insoluble copper derivatives
that are able to induce the Glaser-Hay reaction,122
the most widely used strategy
has involved the use of copper salts supported on various inert oxides, such as
hydrotalcite,123
alumina,124
zeolites,125
titania,126
silicotungstate complexes,127
molecular sieves,128
or mesoporous silica.129
However, the use of such catalysts
entails some drawbacks that require elimination, such as the need for a high
metal loading,122-129
and high temperatures.125,126a,127,128
Furthermore, most
procedures used non-environmentally benign solvents,122,123b,c,125,126a,127-129
and
pressurized oxygen.123a,b,126a,127,128
Moreover, in some cases, the lack of
recyclability of the catalyst.122a,b,123b,124,125,126a
An interesting cooperative effect was observed when the reaction was
carried out in the presence of homogeneous mixtures containing a copper and an
iron salts.130
In this case, the loading of the copper salt could be reduced to 0.1
mol% in the presence of 10 mol% of iron(III) acetylacetonate. For all these
reasons, we thought that impregnated copper on magnetite would be an
alternative to known catalysts.
122 a) F. Toda, Y. Tokumaru, Chem. Lett. 1990, 987-990; b) F. Nador, L. Fortunato, Y. Moglie, C.
Vitale, G. Radivoy, Synthesis 2009, 4027-4031; c) D. Wang, J. Li, N. Li, T. Gao, S. Hou, B.
Chen, Green Chem. 2010, 12, 45-48. 123 a) S. M. Auer, M. Schneider, A. Baiker, J. Chem. Soc., Chem. Commun. 1995, 2057-2058; b) S.
M. Auer, R. Wandeler, U. Göbel, A. Baiker, J. Catal. 1997, 169, 1-12; c) B. C. Zhu, X. Z. Jiang,
Appl. Organometal. Chem. 2007, 21, 345-349. 124 A. Sharifi, M. Mirzaei, M. R. Naimi-Jamal, Monatsh. Chem. 2006, 137, 213-217. 125 P. Kuhn, A. Alix, M. Kumarraja, B. Louis, P. Pale, J. Sommer, Eur. J. Org. Chem. 2009, 423-
429. 126 a) T. Oishi, T. Katayama, K. Yamaguchi, N. Mizuno, Chem. Eur. J. 2009, 15, 7539-7542; b) F.
Alonso, T. Melkonian, Y. Moglie, M. Yus, Eur. J. Org. Chem. 2011, 2524-2530. 127 K. Kamata, S. Yamaguchi, M. Kotani, K. Yamaguchi, N. Mizuni, Angew. Chem. Int. Ed. 2008,
47, 2407-2410. 128 T. Oishi, K. Yamaguchi, N. Mizuno, ACS Catal. 2011, 1, 1351-1354. 129 R. Xiao, R. Yao, M. Cai, Eur. J. Org. Chem. 2012, 4178-4184. 130 X. Meng, C. Li, B. Han, T. Wang, B. Chen, Tetrahedron 2010, 66, 4029-4031.
63 Chapter II. Reactions performed by nanoparticles of Copper
1.2 RESULTS
The homocoupling of ethynylbenzene (5a) in the presence of piperidine
as a base, was selected as a model reaction for optimising the reaction conditions
(Table 4). Initially, the reaction was examined in various solvents (Table 4,
entries 1-9), and the best results were found in the absence of any solvent.
Increasing the temperature of the reaction did not improve the results (entry 10),
whereas the reaction at room temperature only gave traces of product 6a (entry
11). The reaction failed in the absence of the base (entry 12).
The effects of changing the base was also examined by using various
amines (entries 13-15), and similar yields were obtained in only four hours with
various similar amines; however, the corresponding amides were also obtained as
by-products. When other organic or inorganic bases were used (entries 16-20),
lower yields were obtained. The product 6a was obtained in quantitative yield
only when potassium tert-butoxide was used as base (entry 21).
When the reaction was carried out in the presence of 50 mol% of base,
the yield decreased (entry 22). Therefore, we concluded that a stoichiometric
amount of the base was mandatory for the homocoupling (entries 21 and 22).
Increasing the amount of base did not reduce the reaction time further (entry 23).
When the reaction was performed under an argon atmosphere, the yield
decreased to 38 % (entry 24). This confirmed that the oxygen present in the air
played an important role in the process and that it acted as the ultimate source of
oxidant reagent.
Then, the effect of the amount of catalyst used was evaluated (entries 25-
27). Decreasing the amount of catalyst to 0.26 mol% gave 6a in 99 % yield of 6a,
although a longer reaction time (48 hours) was needed (entry 25). Reactions with
higher or lower loading of the metal did not improve the results (entries 26 and
27). Finally, when the reaction was repeated under the optimised conditions but
in the absence of catalyst, the starting material was recovered after one week
(entry 28). Note that performing the reaction under an atmosphere of pure
oxygen did not change the results (entries 21 and 29).
Chapter II. Reactions performed by nanoparticles of Copper 64
Table 4. Optimization of the reaction conditions.a
Entry Base (mol%) Solvent T (ºC) t (h) Yield (%)
b
1 Piperidine (100) THF 60 24 84
2 Piperidine (100) PhMe 60 24 85
3 Piperidine (100) MeCN 60 24 57
4 Piperidine (100) 1,4-Dioxane 60 24 87
5 Piperidine (100) DMF 60 24 54
6 Piperidine (100) H2O 60 24 6
7 Piperidine (100) DMSO 60 24 14
8 Piperidine (100) EtOH 60 24 0
9 Piperidine (100) - 60 24 90
10 Piperidine (100) - 90 24 73
11 Piperidine (100) - 25 24 2
12 - - 60 24 0
13c
BuNH2 (100) - 60 4 87
14 Et3N (100) - 60 24 5
15 DABCO (100) - 60 24 79
16 KOAc (100) - 60 24 0
17 t-BuONa (100) - 60 24 16
18 MeONa (100) - 60 24 2
19 CsOH·H2O (100) - 60 24 60
20 KOH (100) - 60 24 88
21 t-BuOK (100) - 60 24 99
22 t-BuOK (50) - 60 24 75
23 t-BuOK (200) - 60 24 99
24d
t-BuOK (100) - 60 24 38
25e
t-BuOK (100) - 60 48 99
26f
t-BuOK (100) - 60 48 26
27g
t-BuOK (100) - 60 24 99
28h
t-BuOK (100) - 60 168 0
29i
t-BuOK (100) - 60 24 99 a Reaction carried out using compound 5a (2 mmol) under air atmosphere.
b Isolated yields after column chromatography.
c N-Butyl-2-phenylacetamide was isolated in 13 % yield.
d Reaction carried out under argon atmosphere.
e Reaction carried out with 0.26 mol% of catalyst.
f Reaction carried out with 0.13 mol% of catalyst.
g Reaction carried out with 2.6 mol% of catalyst.
65 Chapter II. Reactions performed by nanoparticles of Copper
Table 4. Continuation.
h Reaction carried out in the absence of the catalyst.
i Reaction carried out under O2.
Having determined the optimal conditions, other catalysts prepared by a
simple impregnation protocol were explored (Table 5). First, the activity of the
support by using magnetite as the sole catalyst was tested. Nanoparticles (size <
50 nm) or microparticles (size < 5 μm) of magnetite were used, and the results
showed that ‘naked’ magnetite had a lower activity than the copper-impregnated
form, needing longer reaction times and giving lower yields (Table 5, entries 1,
2, and 3).
Table 5. Optimization of catalyst.a
Entry Catalyst (mol%) t (d) Yield (%)
b
1 CuO-Fe3O4 (0.26) 2 99
2 Micro-Fe3O4 (0.13) 7 68
3 Nano-Fe3O4 (0.13)
7 78
4 Ru2O3-Fe3O4 (0.28) 2 0
5 CoO-Fe3O4 (0.35) 2 0
6 IrO2-Fe3O4 (0.03) 2 0
7 NiO-Fe3O4 (0.20) 2 41
8 PdO-Fe3O4 (0.24) 2 1
9 PtO/PtO2-Fe3O4 (0.12) 2 1
10 PdO/Cu-Fe3O4 (0.30/0.16) 2 89
11 NiO/Cu-Fe3O4 (0.18/0.22) 2 99
12 CuO (0.26) 2 89
13 CuO (0.26) + Fe3O4 (0.13) 2 88 a Reactions were carried out by using compound 5a (2 mmol) under air atmosphere.
b Isolated yields after column chromatography.
Ruthenium,131
cobalt,131
iridium,132
palladium,95
and platinum133
did not
show any activity in this transformation (entries 4-6, 8 and 9). The nickel
catalyst131
showed a moderate activity, giving the expected product in 41 % yield
(entry 7). Reactions using bimetallic catalysts gave the expected product in high
131 R. Cano, D. J. Ramón, M. Yus, J. Org. Chem. 2011, 76, 5547-5557. 132 R. Cano, M. Yus, D. J. Ramón, Chem. Commun. 2012, 48, 7628-7630. 133 R. Cano, M. Yus, D. J. Ramón, ACS Catal. 2012, 2, 1070-1078.
Chapter II. Reactions performed by nanoparticles of Copper 66
yields (entries 10 and 11), with the copper-nickel95
catalyst attaining a
quantitative yield. Reactions using copper oxide alone or together with magnetite
gave slightly lower yields than those obtained with the impregnated catalyst
(compare entries 1, 12 and 13), but we do not have any clear explanation for this
cooperative effect.
Having established the optimal reaction conditions, the problem of
recycling was examined (Figure 13). When the catalyst was recovered from the
reaction mixture by using a magnet, washed with methanol, and reused under the
same conditions, the expected product 6a was obtained in 99 % yield. However,
in the fourth cycle, the yield was only 75 %, indicating that there is a small
decrease in the activity of the catalyst. In the fifth cycle, the yield fell sharply to
20 %.
0
20
40
60
80
100
12
34
5
Yie
ld (
%)
6a
Cycle
Figure 13. Yields obtained with recycled CuO-Fe3O4.
The nanosize distribution of the catalyst, as measured from TEM images,
remained about the same before and after the reaction. Before the reaction, 73 %
of the copper oxide particles on the surface of the catalyst measured between 2
and 6 nm, whereas the corresponding particle size distribution after the reaction
was 68 % (Figure 14).
67 Chapter II. Reactions performed by nanoparticles of Copper
0
20
40
60
0-1
1-2
2-3
3-4
4-5
5-6
6-7
7-8
8-9
9-1
0
10
-11
11
-12
12
-13
13
-14
14
-15
15
-20
20
-25
Par
ticl
es
Particle size (nm)
Recycled catalyst
Fresh catalyst
Figure 14. TEM images: a) before and b) after recycling copper catalyst. c)
Copper particle size distribution.
XPS and Auger Electron Spectroscopy (AES) studies on the used catalyst
showed that copper was partially reduced from an initial 4:1 mixture of Cu(II)
and Cu(0) to a 2:1 mixture of these oxidation states (Figure 15 and 16).
b) a)
c)
Chapter II. Reactions performed by nanoparticles of Copper 68
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
927 932 937 942 947 952
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Fit
Cu 2p3/2
CuO 2p3/2
75000
80000
85000
90000
95000
100000
903 908 913 918 923
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu L3VV
Figure 15. a) XPS of fresh catalyst; b) Auger spectroscopy of fresh catalyst.
0
2000
4000
6000
8000
10000
12000
926 931 936 941 946
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Fit
Cu 2p3/2
CuO 2p3/2
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
904 909 914 919 924
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu L3VV
Figure 16. a) XPS of recycled catalyst; b) Auger spectroscopy of recycled
catalyst.
The ICP-MS analysis of the reaction solution showed the presence of
copper (6.2 % of the initial amount) and iron (0.22 % of the initial amount). A
similar result was obtained when the catalyst was removed before the mixture
was cooled. These results seems to show that not all copper on the surface of
magnetite has the same activity, and that the most-active species leach fastest.
The optimized conditions were applied to other substrates. Reaction
using various substituted alkynes 5 gave the expected products 6 (Table 6). The
reaction seem to be more affected by the presence of chelating groups at the aryl
moiety of substituted alkyne than by the electronic nature of the substrates, and
reactants with the strongest chelating ability gave the lowest yields (entries 1-5).
The presence of steric hindrance in the aryl moiety decreased the yield (entry 6).
Finally, the reaction could also be performed by using less-reactive aliphatic
alkynes, and the expected products 6 were obtained in all the cases, albeit in
slightly lower yields (entries 10-14).
a) b)
a) b)
69 Chapter II. Reactions performed by nanoparticles of Copper
Table 6. Preparation of various 1,3-diynes.a
Entry R Product t (d) Yield (%)
b
1 Ph 6a 2 99 (99)c
2 4-Me2NC6H4 6b 6 20
3 4-MeOC6H4 6c 7 57
4 4-MeC6H4 6d 2 (1)c
91 (99)c
5 4-ClC6H4 6e 4 99
6 2-ClC6H4 6f 2 32
7 4-F3CC6H4 6g 2 99
8 4-BrC6H4 6h 7 26 (17)c
9 3-MeC6H4 6i 3 99
10 c-Hex 6j 3 70 (88)c
11 (CH2)5Me 6k 3 92
12 (CH2)7Me 6l 7 (3)c
50 (74)c
13 (CH2)9Me 6m 7 31
14 (CH2)3Cl 6n 2 99 a Reactions were carried out by using compound 5 (2 mmol) under air atmosphere.
b Isolated yields after column chromatography.
c With NiO/Cu-Fe3O4 (0.18/0.22 mol%) catalyst.
Encouraged by the success that was achieved in homocoupling of
terminal alkynes, the hydration reaction of 1,3-diynes to afford the corresponding
2,5-disubstituted furans was examined. This reaction is catalysed by various
copper salts.134
The reaction was performed with compound 6a in dimethyl
sulfoxide in the presence of potassium hydroxide and the impregnated copper
oxide on magnetite as catalyst at 80 ºC. To our delight, the desired furan 7a was
obtained in quantitative yield. However, it should be pointed out that the
hydration reaction performed in the absence of the catalyst also, surprisingly,
gave furan 7a in the same yield.
Then, a direct, two-step, one-pot transformation of various alkynes into
the corresponding 2,5-disubstituted furans 7 was attempted (Table 7). Having
obtained the diyne in the first reaction step, the catalyst with a magnet was
removed, and without purification of the reagents, dimethyl sulfoxide and
aqueous potassium hydroxide were added. Excellent results were obtained for
134 H. Jiang, W. Aeng, Y. Li, W. Wu, L. Huang, W. Fu, J. Org. Chem. 2012, 77, 5179-5183.
Chapter II. Reactions performed by nanoparticles of Copper 70
various types of 4-substituted aryl diynes (entries 1-4). Unfortunately, when a
cycloaliphatic diyne was used, the reaction failed (entry 5) and the substrate was
recovered unchanged.
Table 7. One-Pot preparation of 2,5-Furans.a
Entry R Product t (d) Yield (%)
b
1 Ph 7a 3 99
2 4-MeOC6H4 7b 8 59
3 4-MeC6H4 7c 3 90
4 4-F3CC6H4 7d 3 99
5 c-Hex 7e 5 0 a Reaction carried out by using compound 5 (1 mmol) under an air atmosphere.
b Isolated yield after column chromatography.
Finally, the decarboxylative coupling reaction135
of 3-phenylprop-2-ynoic
acid (8) was examined. The copper catalyst gave only a 21 % yield of the
expected diyne 6a. However, this product was obtained quantitatively when we
used NiO/Cu-Fe3O4 as catalyst (Scheme 23).
Scheme 23. Decarboxylative coupling reaction of 3-phenylprop-2-yonic acid.
135 M. Yu, D. Pan, W. Jia, W. Chen, N. Jiao, Tetrahedron Lett. 2010, 51, 1287-1289.
71 Chapter II. Reactions performed by nanoparticles of Copper
2. SYNTHESIS OF AROMATIC IMINES FROM ALCOHOLS AND
AMINES OR NITROARENES
2.1 INTRODUCTION
Imines are crucial intermediates and their reactions are fundamental and
ubiquitous in the synthesis of biologically active nitrogen compounds, such as β-
lactams, dyes, fragances, pharmaceuticals, fungicides, and agricultural
chemicals.136
Generally, imines, including Schiff bases, are produced from the
condensation of primary amines with carbonyl compounds. However, several
new synthetic strategies have been developed in recent years, including the
metal-catalysed oxidation (or dehydrogenation) of primary amines to give the
corresponding imines.137
Imines have also been prepared from symmetrical secondary amines.138
However, the variety of compounds obtained in this manner was very limited; the
136 a) R. W. Layer, Chem. Rev. 1963, 63, 489-510; b) K. A. Tehrani, N. De Kimpe in Science of
Synthesis, vol. 27 (Ed.: A. Padwa), Thieme, Stuttgart, 2004, pp. 245-312; c) C. D. Meyer, C. S.
Joiner, J. F. Stoddart, Chem. Soc. Rev. 2007, 36, 1705-1723; d) S. F. Martin, Pure Appl. Chem.
2009, 81, 195-204. 137 a) R. E. Miller, J. Org. Chem. 1960, 25, 2126-2128; b) S. Minakata, Y. Ohshima, A. Takemiya,
I. Ryu, M. Komatsu, Y. Ohshiro, Chem. Lett. 1997, 311-312; c) B. Zhu, M. Lazar, B. G.
Trewyn, R. J. Angelici, J. Catal. 2008, 260, 1-6; d) L. Aschwanden, B. Panella, P. Rossbach, B.
Keller, A. Baiker, ChemCatChem 2009, 1, 111-115; e) S. Komada, J. Yoshida, A. Nomoto, Y.
Ueta, S. Yano, M. Ueshima, A. Ogawa, Tetrahedron Lett. 2010, 51, 2450-2452; f) A. Prades,
E. Peris, M. Albrecht, Organometallics 2011, 30, 1162-1167; g) R. D. Patil, S. Adimurthy, Adv.
Synth. Catal. 2011, 353, 1695-1700; h) S. Furukawa, Y. Ohno, T. Shishido, K. Teramura, T.
Tanaka, ACS Catal. 2011, 1, 1150-1153. 138 a) F. Porta, C. Crotti, S. Cenini, G. Palmisano, J. Mol. Chem. 1989, 50, 333-341; b) A. J.
Bailey, B. R. James, Chem. Commun. 1996, 2343-2344; c) K. Mori, K. Yamaguchi, T.
Mizugaki, K. Ebitani, K. Kaneda, Chem. Commun. 2001, 461-462; d) Y. Maeda, T. Nishimura,
S. Uemura, Bull. Chem. Soc. Jpn. 2003, 76, 2399-2403; e) B. Zhu, R. J. Angelici, Chem.
Commun. 2007, 2157-2159; f) L. Aschwanden, T. Mallat, J.-D. Grunwaldt, F. Krumeich, A.
Baiker, J. Mol. Cal. A: Chem. 2009, 300, 111-115; g) L. Aschwanden, T. Mallat, F. Krumeich,
A. Baiker, J. Mol. Cal. A: Chem. 2009, 309, 57-62; h) A. Grirrane, A. Corma, H. García, J.
Catal. 2009, 264, 138-144; i) G. Jiang, J. Chen, J.-S. Huang, C.-M. Che, Org. Lett. 2009, 11,
4568-4571; j) L. Aschwanden, T. Mallat, M. Maciejewski, F. Krumeich, A. Baiker,
ChemCatChem 2010, 2, 666-673; k) H. Miyamura, M. Morita, T. Inasaki, S. Kobayashi, Bull.
Chem. Soc. Jpn. 2011, 84, 588-599.
Chapter II. Reactions performed by nanoparticles of Copper 72
use of secondary arylamine derivatives circumvented this restriction enabling
access to a wider range of products.139
The in situ oxidative imine formation process, starting from alcohols and
amines, by manganese oxides and molecular sieves, formally permitted access to
several types of imines.140
It should be pointed out that the same intermediates
have been detected in the alkylation41a,b,c,e,h
of amines by alcohols through the
hydrogen autotransfer reaction.41f,g,j,k
The use of stoichiometric amounts of
manganese oxidants is highly undesirable from both economical and
environmental points of view. Therefore, much attention has been paid to the use
of other catalysts to effectively carry out this transformation. In fact, some
complexes and compounds derived from transition metals of the second and third
row, such as ruthenium,131,141
palladium,142
osmium,143
iridium,144
platinum,145
and gold146
have shown promise for this imine synthesis strategy. However, the
toxicities, pricing, and stability of these metals prohibit their general use for
industrial purposes. We thought that impregnated copper on magnetite could be a
catalyst capable to overcome the aforementioned problems.
139 a) K. Yamaguchi, N. Mizuno, Angew. Chem. Int. Ed. 2003, 42, 1480-1483; b) K. Yamaguchi,
N. Mizuno, Chem. Eur. J. 2003, 9, 4353-4361; c) J.-R. Wang, Y. Fu, B.-B. Zhang, X. Cui, L.
Liu, Q.-X. Guo, Tetrahedron Lett. 2006, 47, 8293-8297; d) S.-I. Murahashi, Y. Okano, H. Sato,
T. Nakae, N. Komiya, Synlett 2007, 1675-1678; e) R. Yamaguchi, C. Ikeda, Y. Takahashi, K.-i.
Fujita, J. Am. Chem. Soc. 2009, 131, 8410-8412; f) M.-H. So, Y. Liu, C.-M. Ho, C.-M. Che,
Chen. Asian J. 2009, 4, 1551-1561. 140 a) L. Blackburn, R. J. K. Taylor, Org. Lett. 2001, 3, 1637-1639; b) S. Sithambaram, R. Kumar,
Y.-C. Son, S. L. Suib, J. Catal. 2008, 253, 269-277. 141 a) J. W. Kim, J. He, K. Yamaguchi, N. Mizuno, Chem. Lett. 2009, 38, 920-921; b) B.
Gnanaprakasam, J. Zhang, D. Milstein, Angew. Chem. Int. Ed. 2010, 49, 1468-1471; c) H. Li,
X. Wang, F. Huang, G. Lu, J. Jiang, Z.-X. Wang, Organometallics 2011, 30, 5233-5247. 142 a) M. S. Kwon, S. Kim, S. Park, W. Bosco, R. K. Chidrala, J. Park, J. Org. Chem. 2009, 74,
2877-2879; b) W. He, L. Wang, C. Sun, K. Wu, S. He, J. Chen, P. Wu, Z. Yu, Chem. Eur. J.
2011, 17, 13308-13317; c) L. Jiang, L. Jin, H. Tian, X. Yuan, X. Yu, Q. Xu Chem. Commun.
2011, 47, 10833-10835. 143 M. A. Esteruelas, N. Honczek, M. Oliván, E. Oñate, M. Valencia, Organometallics 2011, 30,
2468-2471. 144 a) H. Aramoto, Y. Obara; Y. Ishii, J. Org. Chem. 2009, 74, 628-633; b) C. Xu, L. Y. Goh, S. A.
Pullarkat, Organometallics 2011, 30, 6499-6502. 145 Y. Shiraishi, M. Ikeda, D. Tsukamoto, S. Tanaka, T. Hirai, Chem. Commun. 2011, 47, 4811-
4813. 146 a) H. Sun, F.-Z. Su, J. Ni, Y. Cao, H.-Y. He, K.-N. Fan, Angew. Chem. Int. Ed. 2009, 48, 4390-
4393; b) S. Kegnæs, J. Mielby, U. V. Mentzel, C. H. Christensen, A. Riisager, Green Chem.
2010, 12, 1437-1441.
73 Chapter II. Reactions performed by nanoparticles of Copper
2.2 RESULTS
The first process evaluated using the impregnated copper on magnetite as
catalyst was the reaction between benzyl alcohol (9a) and aniline (10a) under an
argon atmosphere to give the corresponding imine 11a as depicted in Table 8,. It
should be pointed out that simple copper(II) acetate gave, in similar process,147
the typical monoalkylated amine, rendering, in this case, N-benzylaniline.
However, using the new copper catalyst, imine could be isolated after a few days
of reaction in the absence of oxygen. Thus, the reaction using NaOH as base gave
the expected imine 11a with a small amount of the corresponding N-
benzylaniline, which came from the aforementioned hydrogen autotransfer
process.
Studying of the influence of base, as well as its absence, showed that
NaOH rendered the best results (Table 8, compare entries 1-7). The effect of
reaction temperature was also investigated. Temperatures below 130 ºC were
found to minimize the formation of by-product N-benzylaniline and to the
enhance imine formation; ideal yields routinely resulted from reactions run at
100 ºC (Table 8, entries 1 and 8-10). Choice of solvent was also found to
influence the reaction yield (Table 8, entries 10-12), with toluene providing the
best results. In addition, increasing the amount of base had a significantly
negative effect (Table 8, entries 13 and 14); an increase in the amount of benzyl
alcohol (Table 8, entry 15) also had a negative effect, whereas an increase in the
amount of aniline had a beneficial effect on the yield, being practically
quantitative (Table 8, entry 16).
The influence of catalyst concentration was also studied. While lower
catalyst concentrations, led to lower reaction yields, higher catalyst
concentrations produced only marginal increment of the yield (Table 8, entries 17
and 18). The reaction was repeated in the presence of air to see if this might be
the actual source of oxidant in these reactions. However, no difference in yield or
the required reaction time between the reactions performed with or without air
(Table 8, entries 16 and 19) was found. The reaction was performed also using
the commercial micro-magnetite support, giving the expected imine 11a in
moderate yield (Table 8, entry 20), whereas the use of the most active nano-
powder magnetite42
afforded a comparable yield (63 %).
147 a) A. Martínez-Asencio, D. J. Ramón, M. Yus, Tetrahedron Lett. 2010, 51, 325-327; b) A.
Martínez-Asencio, D. J. Ramón, M. Yus, Tetrahedron 2011, 67, 3140-3149.
Chapter II. Reactions performed by nanoparticles of Copper 74
Table 8. Optimization of the reaction conditions.a
Entry Base (mol%) Solvent T (ºC) t (d) Yield (%)
b
1 NaOH (140) PhMe 130 4 65c
2 KOH (140) PhMe 130 4 2d
3 LiOH (140) PhMe 130 4 39
4 Na2CO3 (140) PhMe 130 4 3
5 K2CO3 (140) PhMe 130 4 27
6 NaOAc (140) PhMe 130 4 1
7 - PhMe 130 7 2
8 NaOH (140) PhMe 25 7 27
9 NaOH (140) PhMe 70 7 71
10 NaOH (140) PhMe 100 4 91
11 NaOH (140) 1,4-Dioxane 100 6 61
12 NaOH (140) MeCN 100 6 18e
13 NaOH (300) PhMe 100 4 59f
14 NaOH (500) PhMe 100 4 25
15g
NaOH (140) PhMe 100 4 20
16h NaOH (140) PhMe 100 4 98
17h,i
NaOH (140) PhMe 100 4 81
18h,j
NaOH (140) PhMe 100 4 98
19h,k
NaOH (140) PhMe 100 4 95
20h,l
NaOH (140) PhMe 100 4 57
a Reaction carried out using compounds 9a (1.3mmol), and 10a (1.0 mmol) in solvent
(3 mL) and under an Ar atmosphere, unless otherwise stated. b Isolated yield after bulb-to-bulb distillation.
c N-Benzylaniline was isolated in 14 % yield.
d N-Benzylaniline was isolated in 89 % yield.
e N-Benzylaniline was isolated in 51 % yield.
f N-Benzylaniline was isolated in 19 % yield.
g Reaction carried out using compounds 9a (2.6 mmol), and 10a (1.0 mmol).
h Reaction carried out using compounds 9a (1.0 mmol), and 10a (2.0 mmol).
i Reaction carried out using 0.3 mol% of catalyst.
j Reaction carried out using 2.3 mol% of catalyst.
k Reaction carried out under air atmosphere.
l Reaction performed using only magnetite support (powder < 5μm; 65 mol%).
75 Chapter II. Reactions performed by nanoparticles of Copper
The standard catalyst89
was routinely prepared from copper dichloride.
To know the possible effect of anion on catalyst activity, similar catalysts were
prepared from copper(II) dibromide or nitrate. The X-Ray Fluorescence (XRF)
analysis revealed that the total incorporation of copper was 1.26 and 1.35 % for
bromide- and nitrate-derived catalyst, respectively; both incorporations were
similar to the observed for the standard chloride-derived catalyst (1.12 %).
Through XPS and Auger analysis we could obtain that the relationship between
Cu(0):Cu(II) was 1:1 in both catalysts (Figure 17).
-100
4900
9900
14900
19900
24900
925 930 935 940 945 950 955 960 965
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu 2p 3/2
CuO 2p 3/2
Cu 2p 1/2
CuO 2p 1/2
19000
21000
23000
25000
27000
29000
31000
33000
905 910 915 920 925 930
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu L3VV
-100
1900
3900
5900
7900
9900
11900
13900
925 935 945 955 965
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu 2p 3/2
CuO 2p 3/2
Cu 2p 1/2
CuO 2p 1/2
18000
19000
20000
21000
22000
23000
24000
25000
26000
27000
907 912 917 922 927 932
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu L3VV
Figure 17. a) XPS catalyst prepared from CuBr2; b) Auger spectroscopy of
catalyst prepared from CuBr2; c) XPS of catalyst prepared from
Cu(NO3)2·5/2H2O; d) Auger spectroscopy of catalyst prepared from
Cu(NO3)2·5/2H2O.
TEM images were analysed obtaining similar particle size distribution
than the previously prepared with copper(II) chloride (compare Figure 14c with
Figure 18). When these catalysts were used under the reaction conditions
presented in Table 8, entry 16, similar yields were obtained (95 and 99 % using
bromide- and nitrate-derived catalysts, respectively), indicating only a marginal
effect of the counterion of the catalyst on catalytic activity.
a) b)
c) d)
Chapter II. Reactions performed by nanoparticles of Copper 76
0
20
40
60
80
Par
ticl
es
Particle Size (nm)
Cu(NO3)2·5/2H2O
CuBr2
Figure 18. a) TEM image of catalyst prepared from CuBr2. b) TEM image of
catalyst prepared from Cu(NO3)2·5/2H2O. c) Copper particle size distribution of
both catalysts.
Once the optimal reaction conditions were established, the prospect of
catalyst recycling was examined (Figure 19). The catalyst was recovered using a
magnet, washed with toluene and re-used under the same reaction conditions, to
render the expected product 11a but in only 72 % yield. A third cycle of
recovered catalyst provided a modest yield of 11a (44 %).
c)
a) b)
77 Chapter II. Reactions performed by nanoparticles of Copper
0
20
40
60
80
100
12
3
Yiel
d1
1a
(%)
Cycle
Figure 19. Recycling of the CuO-Fe3O4 catalyst.
The phenomenon of leaching was studied by ICP-MS analysis of the
resulting reaction solution mixture, 17 % of the initial amount of copper was
detected (0.002 % for iron), which could be due to the formation of different
soluble imine-copper complexes. To validate this hypothesis, the process was
repeated in the absence of amine. After 4 days of reaction with benzyl alcohol
and NaOH in toluene at 100 ºC, the solution obtained after trapping the catalyst
by a magnet was analysed by ICP-MS which revealed the presence of only 9.8 %
of the initial amount of copper, lower than that obtained under typical reaction
conditions involving the presence of amine.
In another trial, quinoline (100 mol%) was heated at 100 ºC in toluene
with the catalyst. A subsequent ICP-MS analysis showed an incorporation of 18
% of copper to the final solution which is similar to that obtained from typical
reaction conditions and substantially higher than that obtained in the absence of
amines. These data support our hypothesis of a leaching process. Moreover, the
TEM images of the recycled catalyst showed a drastic change in the copper
particle size from 7.0 ± 6 nm (maximum at 3 nm) of freshly prepared catalyst to
13.0 ± 6 nm for the recycled catalyst (Figure 20).
This change in particle size may affect the reactivity of the recycled
catalyst. However, the BET surface area did not suffer a great change, from 6.2
m2g
-1 for the initial catalyst, to 11.4 m
2g
-1, for the used catalyst, which is
practically the same specific area.
Chapter II. Reactions performed by nanoparticles of Copper 78
0
20
40
60
Par
ticl
es
Particle size (nm)
Recycled catalyst
Fresh catalyst
Figure 20. a) TEM image of fresh CuO-Fe3O4 catalyst. b) TEM image of
recycled CuO-Fe3O4 catalyst. c) Copper particle size distribution.
It should be pointed out that the TEM images of the recycled catalyst
from the aforementioned treatment without amine showed a similar particle size
distribution (3.7 ± 1.5 nm) to that of the initial catalyst. However, the results
obtained from treatment with quinolone were slightly different (9.2 ± 1.9 nm),
indicating that nitrogen-containing compounds may not only favour the leaching
process but may also facilitate the sinterization of CuO-nanoparticles (Figure 21).
a) b)
c)
79 Chapter II. Reactions performed by nanoparticles of Copper
0
30
60
90
0-1
1-2
2-3
3-4
4-5
5-6
6-7
7-8
8-9
9-1
0
10
-11
11
-12
12
-13
13
-14
14
-15
Par
ticl
es
Particle size (nm)
Without amine
Quinoline
Figure 21. a) TEM image of CuO-Fe3O4 catalyst after reaction without amine. b)
TEM image of CuO-Fe3O4 catalyst after reaction with quinoline. c) Copper
particle size distribution of with different conditions reactions.
The optimised protocol was then applied to other substrates in order to
study the scope of the reaction (Table 9). The protocol gave excellent results in
the case of aromatic alcohols, independently of the presence of electron-
withdrawing or electron-donating groups; even the relative position of this
substituent had no influence on the reaction efficiency. However, the reaction
failed when aliphatic 3-methyl-1-butanol was used as a substrate (Table 9, entry
19). The methodology could be applied to aromatic amines, with different
functional groups as well as to aliphatic amines. However, the use of aliphatic
amines rendered slightly lower yields than those obtained for aromatic ones
(compare, for instance, Table 9, entries 1 and 5-7).
c)
a) b)
Chapter II. Reactions performed by nanoparticles of Copper 80
Table 9. Preparation of imines derivatives.a
Entry Ar R Product Yield (%)
b
1 Ph Ph 11a 98
2 Ph 3-ClC6H4 11b 71
3 Ph 4-MeOC6H4 11c 73
4 Ph 2,5-Me2C6H3 11d 41
5 Ph n-Bu 11e 75
6 Ph t-BuCH2 11f 45
7 Ph Me(CH2)11 11g 77
8 4-ClC6H4 Ph 11h 80
9 4-ClC6H4 3-ClC6H4 11i 98
10 4-MeC6H4 Ph 11j 69
11 4-MeOC6H4 Ph 11k 97
12 4-MeOC6H4 3-ClC6H4 11l 30
13 3-MeC6H4 Ph 11m 99
14 3-MeOC6H4 Ph 11n 62
15 3,5-Me2C6H3 Ph 11o 74
16 3,5-Me2C6H3 3-ClC6H4 11p 86
17 3,5-(MeO)2C6H3 Ph 11q 93
18 3,5-(MeO)2C6H3 3-ClC6H4 11r 89
19 i-PrCH2 Ph 11s 0 a
Reaction carried out using compounds 9 (1.0 mmol), and 10 (2.0 mmol) in 3 mL of
toluene. b Isolated yield after bulb-to-bulb distillation.
The success obtained in preparing imines using our impregnated copper
on magnetite catalyst inspired us to formulate a process to synthetise aldehydes
from alcohols (Table 10). Thus, the above standard reaction of arylmethanol
derivatives 9 with aniline catalysed by impregnated copper on magnetite was
followed by treatment with aqueous HCl, following by catalyst removal with a
magnet. The whole process provided an organic layer in which the aldehyde
could be isolated in good yields and with excellent purity simply by solvent
removal under low pressure. Addition of Na2CO3 to the aqueous solution and
extraction of the resulting mixture rendered the pure aniline (10a) in good yields
(76-96 %), showing the possible recyclability of the integrated process. The
81 Chapter II. Reactions performed by nanoparticles of Copper
reaction was found to proceed with excellent yields regardless of the presence of
electron-donating or electron-withdrawing groups on the aromatic ring. Only in
the case of the 2,6-dichlorophenyl derivative the yield of the corresponding
arenecarbaldehyde 2t was significantly lower (Table 10, entry 7). This is perhaps
due to the steric hindrance of the starting reagent, since the related 3,4-
dichlorophenyl derivative gave the corresponding aldehyde 2u in good yield
(Table 10, entry 8).
Table 10. Preparation of arenecarbaldehydes.a
Entry Ar Product Yield (%)
b
1 Ph 2a 99
2 4-ClC6H4 2j 93
3 4-MeC6H4 2d 88
4 4-MeOC6H4 2e 96
5 3-MeC6H4 2c 85
6 3-MeOC6H4 2s 95
7 2,6-Cl2C6H3 2t 32
8 3,4-Cl2C6H3 2u 88
9 3,5-Me2C6H3 2v 98
10 3,5-(MeO)2C6H3 2w 94
11 3,4,5-(MeO)3C6H2 2f 81 a
Reaction carried out using compounds 9 (1.0 mmol), and 10a (2.0 mmol) in 3 mL of
toluene for the first step; and HCl (2 mL) and Et2O (2 mL) for the second step. b Isolated yield after extraction.
Very recently, a new entry to the synthesis of imines has been
accomplished using nitroarenes as the nitrogen-containing moiety and an excess
of alcohol as the source of both the aldehyde and the reducing agent of the nitro
moiety. The reaction of nitrobenzene (12a) with four equivalents of alcohol 9
catalysed by the impregnated copper catalyst gave the expected imines 11 with
reasonable yields, independently of the used alcohols and of the substitution at
the aromatic ring (Table 11). Although the process using simple amines is more
effective than the one using nitroarenes, it is interesting to note that the same
Chapter II. Reactions performed by nanoparticles of Copper 82
copper catalyst could be used for both processes and demonstrated similar
activities in both scenarios.
Table 11. Preparation of N-phenyl imine derivatives.a
Entry Ar Product Yield (%)
b
1 Ph 11a 70
2 4-MeC6H4 11j 61
3 4-MeOC6H4 11k 84
4 3-MeC6H4 11m 58 a
Reaction carried out using compounds 9 (4.0 mmol), and 12 (1.0 mmol) in 3 mL of
toluene. b Isolated yield after bulb-to-bulb distillation.
Finally, we studied the possible catalytic activity of the impregnated
copper on magnetite for the preparation of imines starting from primary amines
(13). Thus, the treatment of arylmethylamines with a base and substoichiometric
amounts of the copper catalyst under the same reaction conditions gave the
expected imines 14 in good yields (Table 12); the apparent discrepancy of yield
in the formation of 14b was more a matter of isolation difficulties rather than of
the product formation.
Table 12. Preparation of aryl imine derivatives.a
Entry Ar Product Yield (%)
b
1 Ph 14a 95
2 4-MeC6H4 14b 49
3 3-MeC6H4 14c 71 a Reaction carried out using compound 13 (2.0 mmol) in 3 mL of toluene.
b Isolated yield after bulb-to-bulb distillation.
83 Chapter II. Reactions performed by nanoparticles of Copper
3. CROSS-DEHYDROGENATIVE COUPLING REACTION IN DEEP
EUTECTIC SOLVENTS
3.1 INTRODUCTION
Tretrahydroisoquinolines are widely present in Nature.148
The synthesis
of these compounds has been payed much attention in industrial and academic
research due to their biological and pharmaceutical applications, such as
anticancer149
and anticonvulsant agents,150
enzyme inhibitors,151
ligand
receptors152
and therapeutic agents.153
The C-C bond formation via C-H activation154
is one of the most
challenging reactions in organic synthesis. Various strategies for transition-
metal-catalysed C-H bond activation have been of significant interest, as they are
environmentally friendly processes, and no functionalization step is needed.
The C(sp3)-H bond activation at the α-position of nitrogen has been
broadly used in different transformations. The key step, in this transformation, is
the generation of an iminium intermediate assisted by the lone pair of nitrogen
atom, via a single-electron transfer (SET) mechanism.155
For this purpose an important number of different methods have been
developed, with metal-catalysed protocols being well stablished. Different
148 J. D. Phillipson, M. F. Roberts in The Chemistry and Biology of Isoquinoline Alkaloids,
Springer-Verlag, Berlin, 1985. 149 a) Y. Li, H. B. Zhang, W. L. Huang, X. Zhen, Y. M. Li, Chinese Chem. Lett. 2008, 19, 169-
171; b) M. P. Chelopo, S. A. Pawar, M. K. Sokhela, T. Govender, H. G. Kruger, G. E. M.
Maguire, Eur. J. Med. Chem. 2013, 66, 407-414; c) T. Ramanivas, B. Sushma, V. L. Nayak, K.
C. Shekar, A. K. Srivastava, Eur. J. Med. Chem. 2015, 92, 608-618. 150 R. Gitto, R. Caruso, B. Pagano, L. D. Luca, R. Citraro, E. Russo, G. D. Sarro, A. Chimirri, J.
Med. Chem. 2006, 49, 5618-5622. 151 G. L. Grunewald, V. H. Dahanukar, T. M. Caldwell, K. R. Criscione, J. Med. Chem. 1997, 40,
3997-4005. 152 a) A. J. Bojarski, M. J. Mokrosz, S. C. Minol, A. Koziol, A. Wesolowska, E. Tatarczynska, A.
Klodzinska, E. Chojnacka-Wójcik, Bioorg. Med. Chem. 2002, 10, 87-95; b) J. Renaud, S. F.
Bischoff, T. Buhl, P. Floersheim, B. Fournier, C. Halleux, J. Kallen, H. Keller, J.-M. Schaeppi,
W. Stark, J. Med. Chem. 2003, 46, 2945-2957; c) M. E. Ashford, V. H. Nguyen, I. Greguric, T.
Q. Pham, P. A. Keller, A. Katsifis, Org. Biomol. Chem. 2014, 12, 783-794. 153 J. H. Kang, BMB rep. 2011, 114-119. 154 a) B. Ye, N. Cramer, Acc. Chem. Res. 2015, 48, 1308-1318; b) J. Pedroni, N. Cramer, Chem.
Commun. 2015, 51, 17647-17657. 155 C.-J. Li, Acc. Chem. Res. 2009, 42, 335-344.
Chapter II. Reactions performed by nanoparticles of Copper 84
catalysts derived from vanadium,156
iron,157
copper,158
ruthenium,159
rhodium,160
palladium,161
antimonium,162
iridium163
or gold,164
among others have been
recently introduced. In all cases, the protocols needed a highly reactive oxidising
agent such as peroxides or high oxygen pressure. Moreover, the lack of
recyclability, and the high catalyst loading (5-20 mol%) made these protocols
unsustainable for large chemical production.
156 K. M. Jones, P. Karier, M. Klussmann, ChemCatChem 2012, 4, 51-54. 157 a) T. Zeng, G. Song, A. Moores, C.-J. Li, Synlett 2010, 13, 2002-2008; b) W. Han, P. Mayer,
A. R. Ofial, Adv. Synth. Catal. 2010, 352, 1667-1676; c) P. Liu, C.-Y. Zhou, S. Xiang, C.-
M.Che, Chem. Commun. 2010, 46, 2739-274; d) M. O. Ratnikov, X. Xu, M. P. Doyle, J. Am.
Chem. Soc. 2013, 135, 9475-9479. 158 a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2004, 126, 11810-11811; b) Z. Li, C.-J. Li, Org. Lett.
2004, 6, 4997-4999; c) Z. Li, D. S. Bohle, C.-J. Li, PNAS 2006, 103, 8928-8933; d) Z. Li, P. D.
MacLeod, C.-J. Li, Tetrahedron: Assymetry 2006, 17, 590-597; e) O. Baslé, C.-J. Li, Green
Chem. 2007, 9, 1047-1050; f) D. Sureshkumar, A. Sud, M. Klussmann, Synlett 2009, 10, 1558-
1561; g) W. Su, J. Yu, Z. Li, Z. Jiang, J. Org. Chem. 2011, 76, 9144-9150; h) E. Boess, C.
Schmitz, M. Klussmann, J. Am. Chem. Soc. 2012, 134, 5317-5325; i) R. Hudson, S. Ishikawa,
C.-J. Li, A. Moores, Synlett 2013, 24, 1637-1642; j) J. Yu, Z. Li, K. Jiang, M. Liu, W. Su,
Tetrahedron Lett. 2013, 54, 2006-2009; k) F.-F. Wang, C.-P. Luo, G. Deng, L. Yang, Green
Chem. 2014, 16, 2428-2431; l) G. H. Dang, D. T. Nguyen, D. T. Le, T. Truong, N. T. S. Phan,
J. Mol. Catal. A-Chem. 2014, 395, 300-306; m) X. Liu, J. Zhang, S. Ma, Y. Ma, R. Wang,
Chem. Commun. 2014, 50, 15714-15717; n) S. Sun, C. Li, P. E. Floreacing, H. Lou, L. Liu,
Org. Lett. 2015, 17, 1684-1687; o) I. Perepichka, S. Kundu, Z. Hearne, C.-J. Li, Org. Biomol.
Chem. 2015, 13, 447-451. 159 a) Q.-Y.Meng, Q. Liu, J.-J. Zhong, H.-H. Zhang, Z.-J. Li, B. Chen, C.-H. Tung, L. Z. Wu, Org.
Lett. 2012, 14, 5992-5995; b) M. Rueping, R. M. Koenigs, K. Poscharny, D. C. Fabry, D.
Leonori, C. Vila, Chem. Eur. J. 2012, 18, 5170-5174; c) D. B. Freeman, L. Furst, A. G. Condie,
C. R. J. Stephenson, Org. Lett. 2012, 14, 94-97; d) P. Kohls, D. Jadhav, G. Pandey, O. Reiser,
Org. Lett. 2012, 14, 672-675; e) J. W. Trucker, Y. Zhang, T. F. Jamison, C. R. J. Stephenson,
Angew. Chem. Int. Ed. 2012, 51, 4144-4147; f) L. R. Espelt, E. M. Wiensch, T. P. Yoon, J.
Org. Chem. 2013, 78, 4107-4114; g) Q.-Y. Meng, J.-J. Zhong, Q. Liu, X.-W. Gao, H.-H.
Zhang, T. Lei, A.-J. Li, K. Feng, B. Chen, C.-H. Tung, L.-Z. Wu, J. Am. Chem. Soc. 2013, 135,
19052-19055; h) G. Bergonzini, C. S. Schindler, C.-J. Wallentin, E. N. Jacobsen, C. R. J.
Stephenson, Chem. Sci. 2014, 5, 112-116. 160 R. Pollice, N. Dastbaravardeh, N. Marquise, M. D. Mihovilovic, M. Schnürch, ACS Catal.
2015, 5, 587-595. 161 J. Xuan, T.-T. Zeng, Z.-J. Feng, Q.-H. Deng, J.-R. Chen, L.-Q. Lu, W.-J. Xiao, H. Alper,
Angew. Chem. Int. Ed. 2015, 54, 1625-1628. 162 a) A. Tanoue, W.-J. Yoo, S. Kobayashi, Adv. Synth. Catal. 2013, 355, 269-273; b) C. Huo, C.
Wang, M. Wu, X. Jia, X. Wang, Y. Yuan, H. Xie, Org. Biomol. Chem. 2014, 12, 3123-3128. 163 a) A. G. Condie, J. C. González-Gómez, C. R. J. Stephenson, J. Am. Chem. Soc. 2010, 132,
1464-1465; b) Z.-J. Feng, J. Xuan, X.-D. Xia, W. Ding, W. Guo, J.-R. Chen, Y.-Q. Zou, L.-Q.
Lu, W.-J. Xiao, Org. Biomol. Chem. 2014, 12, 2037-2040. 164 T. Amaya, T. Ito, T. Hirao, Heterocycles 2012, 86, 927-932.
85 Chapter II. Reactions performed by nanoparticles of Copper
The metal-free version using organic radical promoters, recently
published, has similar drawbacks.165
Within the framework of green chemistry, solvents occupy a strategic
place. In order to be qualified as a green medium, the components of the solvent
have to meet different criteria such as availability, non-toxicity, biodegradability,
recyclability, inflammability, renewability and low price, among others. DES
(Deep Eutectic Solvent) is an environmentally benign alternative to hazardous
(organic) solvents and, in many cases, might replace them. DESs are liquid
systems formed from a eutectic mixture of a solid Lewis or Brønsted acids and
bases which can contain a variety of anionic and/or cationic species.166
These two
components are capable of self-association, often through a strong bond
interaction, to form a eutectic mixture with a melting or phase transition point
lower than that of each individual component.167
The properties of a solvent, such as conductivity, viscosity, vapour
pressure and thermal stability can be fine-tuned by the choosing appropriately the
mixture components, with the large-scale preparation being feasible. Besides
these interesting advantages, the application of DES in organic synthesis is in its
infancy,168
with the related metal-catalysed process being nearly unknown.169
Only, very recently, the superparamagnetic CuFeO2 has been used as catalyst for
the multicomponent synthesis of imidazo[1,2-a]pyridines in DMU-citric acid
165 a) A. S.-K. Tsang, P. Jensen, J. M. Hook, A. S. K. Hashmi, M. H. Todd, Pure Appl. Chem.
2011, 83, 655-665; b) W. Fu, W. Guo, G. Zou, C. Xu, J. Fluorine Chem. 2012, 140, 88-94; c) J.
Dhineshkumar, M. Lamani, K. Alagiri, K. R. Prabhu, Org. Lett. 2013, 15, 1092-1095; d) G.
Zhang, Y. Ma, S. Wang, W. Kong, R. Wang, Chem. Sci. 2013, 4, 2645-2651; e) A. Tanoue,
W.-J. Yoo, S. Kobayashi, Org. Lett. 2014, 16, 2346-2349; f) L. Huang, J. Zhao, RSC Adv.
2013, 3, 23377-23388; g) H.-M. Huang, Y.-J. Li, Q. Ye, W.-B. Yu, L. Han, J.-H. Jia, J.-R. Gao,
J. Org. Chem. 2014, 79, 1084-1092; h) J. F. Franz, W. B. Kraus, K. Zeitler, Chem. Commun.
2015, 51, 8280-8283. 166 E. L. Smith, A. P. Abbot, K. S. Ryder, Chem. Rev. 2014, 114, 11060-11082. 167 a) C. Ruβ, B. König, Green Chem. 2012, 14, 2969-2982; b) Q. Zhang, K. D. O. Vigier, S.
Royer, F. Jérôme, Chem. Soc. Rev. 2012, 41, 7108-7146; c) Y. Dai, J. van Spronsen, G.-J.
Witkamp, R. Verpoorte, Y. H. Choi, Anal. Chim. Acta 2013, 766, 61-68; d) M. Francisco, A.
van den Bruinhorst, M. C. Kroon, Angew. Chem. Int. Ed. 2013, 52, 3074-3085; e) B. Tang, K.
H. Row, Monatsh Chem. 2013, 144, 1427-1454; f) A. Paiva, R. Craveiro, I. Aroso, M. Martins,
R. L. Reis, A. R. C. Duarte, ACS Sustainable Chem. Eng, 2014, 2, 1063-1071. 168 a) P. Liu, J.-W. Hao, L.-P. Mo, Z.-H. Zhang, RSC Adv. 2015, 5, 48675-48705; b) D. A. Alonso,
A. Baeza, R. Chinchilla, G. Guillena, I. M. Pastor, D. J. Ramón, Eur. J. Org. Chem. 2016, 612-
632. 169 a) J. García-Alvarez in Green Technologies for the Environment, (Ed.: R. Luqie, O. Obre),
ACS Books, New York, 2015, pp. 37-53; b) J. García-Alvarez, Eur. J. Inorg. Chem. 2015, 31,
5147-5157.
Chapter II. Reactions performed by nanoparticles of Copper 86
medium.170
With this in hand, we thought that impregnated copper on magnetite
could be an interesting catalyst for this transformation.
3.2 RESULTS
To start with this study, 2-(4-fluorophenyl)-1,2,3,4-
tetrahydroisoquinoline (15a) and phenylacetylene (5a) using impregnated copper
on magnetite as catalyst was selected as the model reaction for the optimization
of the conditions (Table 13).
Initially, the reaction was performed using different DES (entries 1-6),
obtaining the best result (entry 4) with the mixture choline chloride
(ChCl):ethylene glycol (1:2), with the only by-product observed being the
corresponding lactam 17a. Then, the influence of the amount of catalyst was
evaluated, obtaining similar results when the catalyst loading decreased (entry 7).
However, a further decrease of catalyst loading to 0.37 mol% (entry 8) led to
lower yield. Increasing the amount of copper to 3.64 mol% (entry 9), the yield
could be improved. It should be pointed out that even this high amount of copper
catalyst is one of the lowest metal catalyst loadings reported so far in the
literature for this type of transformations.
The addition of only one equivalent of alkyne led to a decrease of the
reaction yield (entry 10), and the addition of an excess of alkyne did not improve
it (entry 11). The study of the temperature of the reaction was carried out
obtaining, after seven days of reaction at room temperature, a full conversion of
the starting material (entry 12). Increasing the temperature up to 100 ºC,
decreased the yield (entry 13). The reaction was carried out under an argon
atmosphere (entry 14) obtaining a very low yield, highlighting the capital role of
oxygen in the air as the final oxidising agent. To finish with the optimization of
the reaction conditions, the reaction was tested using LED irradiation
(photoredox conditions), microwave irradiation and an ultrasound bath (entries
15-17), but the yield did not improved. Finally, the reaction was repeated in only
ethylene glycol obtaining a modest result (entry 18).
170 J. Lu, X.-T. Li, E.-Q. Ma, L.-P. Mo, Z.-H. Zhang, ChemCatChem 2014, 6, 2854-2859.
87 Chapter II. Reactions performed by nanoparticles of Copper
Table 13. Optimization of the reaction conditions.a
Entry Catalyst (mol%) DES (molar ratio) T
(ºC) 16a (%)
b
17a (%)
b
1 CuO-Fe3O4 (1.82) ChCl:urea (1:2) 50 55 29
2 CuO-Fe3O4 (1.82) AcChCl:urea (1:2) 50 50 13
3 CuO-Fe3O4 (1.82) ChCl:glycerol (1:2) 50 59 11
4 CuO-Fe3O4 (1.82) ChCl:ethylene glycol (1:2) 50 83 2
5 CuO-Fe3O4 (1.82) Ph3P+MeBr
-:glycerol (1:2) 50 60 11
6 CuO-Fe3O4 (1.82) ChCl:resorcinol (1:1) 50 10 21
7 CuO-Fe3O4 (0.91) ChCl:ethylene glycol (1:2) 50 83 3
8 CuO-Fe3O4 (0.37) ChCl:ethylene glycol (1:2) 50 56 21
9 CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) 50 95 3
10c CuO-Fe3O4 (1.82) ChCl:ethylene glycol (1:2) 50 75 2
11d
CuO-Fe3O4 (1.82) ChCl:ethylene glycol (1:2) 50 92 2
12 CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) RT 57e 0
13 CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) 100 38 0
14f
CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) 50 42 0
15g
CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) 50 49 9
16h
CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) 50 32 6
17i
CuO-Fe3O4 (3.64) ChCl:ethylene glycol (1:2) 53 17 0
18 CuO-Fe3O4 (3.64) Ethylene glycol 50 40 9 a
Reaction carried out using compounds 15a (0.5 mmol), and 5a (1 mmol) in 1mL of
DES. b Conversion determined by
1H-NMR.
c Reaction carried out using compounds 15a (0.5 mmol), and 5a (0.5 mmol) in 1mL of
DES. d Reaction carried out using 15a (0.5 mmol), and 5a (2.5 mmol) in 1mL of DES.
e 99 % of conversion after 7 days of reaction.
f Reaction carried out under an Argon atmosphere.
g Reaction carried out using visible LED light irradiation.
h Reaction carried out under microwave irradiation during 10 h at 80W.
i Reaction carried out under ultrasound bath during 8 h.
Chapter II. Reactions performed by nanoparticles of Copper 88
To prove the essential role of DES [ChCl:ethylene glycol], other VOC
solvents were tested as reaction medium (Figure 22). In all cases, a mixture of
products 16a and 17a were obtained in a ratio close to 1:1, highlighting the role
of DES to minimise the lactam formation. It should be pointed out that when the
reaction was performed in 1,4-dioxane as solvent the main product was 17a.
0
50
100
Yie
ld (
%)
16a
17a
Figure 22. Yield obtained yield in different volatile organic solvents.
We also found an interesting correlation between DES conductivity and
the yield of the desired product (Figure 23), in such a way that a higher
conductivity affords a better yield. Since an iminium intermediate is generated in
the reaction media, a better conductivity means an easier movement of ions that
could explain the increase in the yield. Nevertheless, the correlation between
obtained yields and conductivities of VOC solvents and of water did not fit with
the aforementioned plot. It should be pointed out that the reaction using
ChCl:1,2-propanediol:water (1:1:1, conductivity 12.09 mS/cm) or
ChCl:glycerol:water (1:2:1, conductivity 13.78 mS/cm) gave the product 16a in
46 and 53 % yield respectively. Although these two mixtures have higher
conductivity than the previous DES used, the presence of water changed the
direct proportion between yield and conductivity, probably due to the highly
nucleophilic character of water.
89 Chapter II. Reactions performed by nanoparticles of Copper
0
10
20
30
40
50
60
70
80
90
0 2 4 6 8
Yie
ld 1
6a
(%
)
Conductivity (mS/cm)
Yield (%) = 4,0·Conductivity + 52,6
R2 = 0,9915
H2O
ChCl:urea
(1:2)
ChCl:(CH2OH)2
(1:2)
ChCl:glycerol (1:2)
Ph3PMeBr:glycerol
(1:2)
Figure 23. Relationship between solvent conductivity and yield.
Once the optimal conditions were determined, the reaction was repeated
with a variety of catalysts prepared by the simple impregnation protocol85a
(Table
14). The reaction without a catalyst gave a poor yield (entry 2). Then, the activity
of the support was evaluated using magnetite as the unique catalyst.
Microparticles and nanoparticles of magnetite (entries 3 and 4) were used with
the results showing the inactivity of the support, reaching a low conversion of
product and highest amount of compound 17a, as the only by-product detected
by CG-MS. Once the activity of magnetite was tested, different metal oxides
impregnated on magnetite (entries 5-17) were evaluated as catalysts, observing
that none of them gave better results than the copper catalyst (entry 1). After that,
different copper salts were tested (entries 18-20), obtaining from moderate to
good results, but poorer results than the one obtained by the heterogeneous
copper oxide impregnated on magnetite.
After, that, the addition of a mixture of CuO and Fe3O4 was evaluated
(entry 21), obtaining a decrease in the conversion compared to the impregnated
catalyst, which seems to be related with a synergic effect between the metal
oxide and support in the catalyst.
Chapter II. Reactions performed by nanoparticles of Copper 90
Table 14. Optimization of the catalyst.a
Entry Catalyst (mol%) 16a (%)
b 17a (%)
b
1 CuO-Fe3O4 (3.64) 95 3
2 - 6 20
3 Micro-Fe3O4 (259.15) 15 48
4 Nano-Fe3O4 (259.15) 0 34
5 CoO-Fe3O4 (2.83) 4 31
6 NiO-Fe3O4 (2.06) 30 30
7 Ru2O3-Fe3O4 (2.64) 8 28
8 Rh2O3-Fe3O4 (0.84) 0 45
9 PdO-Fe3O4 (2.43) 46 7
10 Ag2O/Ag-Fe3O4 (2.5) 13 0
11 OsO2-Fe3O4 (1.03) 5 21
12 IrO2-Fe3O4 (0.26) 33 47
13 PtO/PtO2-Fe3O4 (1.08) 33 7
14 Au2O3/Au-Fe3O4 (0.28) 13 4
15 PdO/Cu-Fe3O4 (3.05/1.79) 35 28
16 NiO/Cu-Fe3O4 (1.82/1.76) 78 2
17 WO3-Fe3O4 (1.13) 37 8
18 CuCl2 (8.5) 88 5
19 CuO (4.04) 46 10
20 Cu(OAc)2 (3.64) 80 6
21 CuO (3.64) + Fe3O4 (255.26) 51 9 a
Reaction carried out using compounds 15a (0.5 mmol), and 5a (1 mmol) in 1mL of
DES. b Conversion determined by
1H-NMR.
Once the best conditions were established, the scope of the reaction was
evaluated. First of all, different pro-electrophiles were tested by modifying the
nitrogen substituent at the tetrahydroisoquinoline ring (Table 15). The reaction
was carried out with different N-substituted substrates. When the substituent was
an aryl group, bearing both, electron-withdrawing or electron-donating groups
(entries 1 and 3), the results were excellent. In the case of phenyl derivatives, the
91 Chapter II. Reactions performed by nanoparticles of Copper
yield was moderate. On the other hand, when the reaction was carried out with
the free amine or with a strong electron-withdrawing group such as tosyl, the
reaction did not take place at all (entries 4 and 5), recovering the starting material
unchanged.
Table 15. Scope of the reaction with different pro-electrophiles.a
Entry R Product Yield (%)
b
1 4-FC6H4 16a 94
2 Ph 16b 63
3 4-MeOC6H4 16c 90
4 Ts 16d 0/0c
5 H 16e 0 a
Reaction carried out using compounds 15 (0.5 mmol), and 5a (1 mmol) in 1mL of
DES. b Isolated yield after bulb-to-bulb distillation.
c Yield obtained after 7 days of reaction at room temperature.
Having studied the scope of pro-electrophiles, we tested a variety of
alkynes as pro-nucleophiles (Table 16). Once again, the reaction took place
obtaining from moderate to good yields when the alkyne had an electron-rich
(entry 1) or electron-poor (entries 2-5) aryl substituents. Not only aryl
substituents were tested, but also olefinic and aliphatic ones (entries 6-9) and the
reaction still worked smoothly. It has to be pointed out that, in the case of using a
dialkyne, the reaction was selective in such a way that only one of the two
alkynes reacted (entry 8).
Chapter II. Reactions performed by nanoparticles of Copper 92
Table 16. Scope of the reaction using different alkynes.a
Entry R
2 Product Yield (%)
b
1 4-MeOC6H4 16f 57
2 4-BrC6H4 16g 61
3 4-CF3C6H4 16h 68
4 3-ClC6H4 16i 58
5 2-BrC6H4 16j 64
6 1-C6H9 16k 37
7 C6H11 16l 83
8 HC≡CC5H10 16m 71
9 THPOCH2c
16n 65 a
Reaction carried out using compounds 15a (0.5 mmol), and 5 (1 mmol) in 1mL of
DES. b Isolated yield after distillation.
c THPO stands for 2-(tetrahydro-2H-pyran-2-yl)oxy.
After the study of alkynes as pro-nucleophiles was completed, we
decided to check other types of reagents (Table 17), such as nitroalkanes (entry
1), heterocycles (entry 2), phosphonates (entry 3), silyl enol ethers (entry 4),
ketones (entries 5 and 6) and fluoroborates (entry 7), proving that this
methodology can be applied to a wide range of substrates with very different
properties and obtaining similar results. It should be noted that both, silyl enol
ether and ketone (entries 4 and 5) afford the same product 16r but with different
diastereomeric ratios. Only the starting material alongside a small amount of by-
product 17a was detected from the crude of the reaction, when a moderate or low
yield of product was obtained.
93 Chapter II. Reactions performed by nanoparticles of Copper
Table 17. Scope of the reaction with different pro-nucleophiles.a
Entry Nu-H Product Yield (%)
b
1 MeNO2 16o 95/15c
2
16p 84
3
16q 45
4
16r 50d
5
16r 38e
6
16s 24
7 16t 51 a
Reaction carried out using compounds 15a (0.5 mmol), and 18 (1 mmol) in 1mL of
DES. b Isolated yield after bulb-to-bulb distillation.
c Yield after 7 days at room temperature.
d Mixture of isomers syn:anti (1:1.25).
e Mixture of isomers syn:anti (1.4:1).
In order to stablish the reusability of the catalyst and DES, the reaction
with nitromethane (Table 17, entry 1) was repeated under standard conditions
(Figure 24). When the reaction was completed, the mixture was extracted with
cyclopentyl methyl ether, recently reported as a potential green alternative
Chapter II. Reactions performed by nanoparticles of Copper 94
solvent.171
All organic compounds were removed and the mixture of DES and
catalyst, lower phase in the decantation, was reused under the same reaction
conditions. This catalytic mixture could be recycled up to ten times without any
decrease of the yield.
When only the catalyst was recovered by magnetic decantation, and fresh
solvent was used, the obtained yield showed an important decrease, pointing out
the sharp decrease of the catalyst after four reaction cycles. In fact, the ICP-MS
analysis of crude reaction solution showed the leaching of a small amount of
copper (14.2 ppm; 3.6 % of the initial amount) and iron (0.30 ppm; 0.001 % of
the initial amount), these values were completely different from the reported
solubility of these metal oxides in this DES (3.68 ppm for CuO and 10.85 ppm
for Fe3O4).172
The higher solubility in DES of copper species seems to show that
the heterogeneous catalyst is only a reservoir of highly active copper clusters.
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10
Yie
ld 1
6o
(%)
Cycle
CuO-Fe3O4
CuO-Fe3O4 + DES
Figure 24. Recycling of the CuO-Fe3O4 catalyst and CuO-Fe3O4 + DES.
171 a) K. Watanabe, N. Yamagiwa, Y. Torisawa, Org. Processs Res. Dev. 2007, 11, 251; b) A.
Kadam, M. Nguyen, M. Kopach, P. Richardson, F. Gallou, Z.-K. Wan, Green Chem. 2013, 15,
1880. 172 A. P. Abbot, G. Gapper, D. L. Davies, K. J. McKenzie, S. U. Obi, J. Chem. Eng. Data 2006,
51, 1280-1282.
95 Chapter II. Reactions performed by nanoparticles of Copper
To try to understand more this effect, the standard reaction was
performed as usual (Table 14, entry 1) and, after 36 h, only the catalyst was
removed by magnetic decantation, with the yield of 16a being estimated in 40 %
by CG-MS. The mixture was heated again for 36 h, and after the usual work up
the yield of compound 16a increased up to 65 %, with the oxidised by-product
17a reaching 25 %. This fact seems to indicate that a partial copper catalyst
specie solubilisation took place during the reaction. However, at the end of the
first cycle, the catalyst was removed, by magnetic decantation, as well as the
organics by cyclopentyl methyl ether extraction (yield of compound 16a 93 %).
Then, the used DES medium was employed alone in other cycles (without
catalyst) and the final product 16a was obtained in 52 % (29 % for by-product
17a). These two experiments showed that there was a partial leaching of active
species, capable of performing the oxidative step. However, and due to the great
amount of by-product, these leached species seemed to be less effective to
catalyse the final nucleophilic addition.
In order to study the effect of the reaction conditions on the copper
heterogeneous catalyst, TEM images of the catalyst were analysed to obtain the
nanosize distribution of the copper nanoparticles before and after one reaction
cycle (Figure 25). A uniform size distribution was found, 60 % of nanoparticles
have an average size between 2-4 nm on the recycled catalyst. In the fresh
catalyst, 63 % of nanoparticles have an average size between 2-6 nm, showing a
small overall decrease in the particle size with the reaction cycles which is in
concordance with a partial solubilization-readsoption of copper species.
Chapter II. Reactions performed by nanoparticles of Copper 96
0
20
40
60
80
Par
ticl
es
Particle size (nm)
Recycled catalyst
Initial catalyst
Figure 25. a) TEM image of fresh CuO-Fe3O4 catalyst. b) TEM image of
recycled CuO-Fe3O4 catalyst. c) Particle size distribution of fresh and recycled
catalyst.
a) b)
c)
97 Chapter II. Reactions performed by nanoparticles of Copper
The XPS and Auger Electron Spectroscopy (AES) studies of the catalyst
showed the transformation of the initial Cu(0) (Figure 15), onto the
corresponding copper(I) oxide and Cu(OH)2 in the recycled catalyst (Figure 26)
with CuO being the main species in both cases. These changes in particle size as
well as in the initial oxidation state did not seem to affect the activity of the
catalyst, since it could be reused ten times without losing its activity.
-50
450
950
1450
1950
2450
2950
3450
926 931 936 941 946
Inte
nsi
ty/a
rb. unit
s
Binding energy (eV)
After reactionFit
Cu2O 2p3/2
CuO 2p3/2
Cu(OH)2 2p3/2
CuO 2p3/2 sat.
CuO 2p3/2 sat.
11400
11600
11800
12000
12200
12400
12600
12800
13000
13200
13400
899 904 909 914 919 924
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu3LVV
Figure 26. a) XPS of recycled copper catalyst. b) AES of recycled copper
catalyst.
a) b)
Chapter II. Reactions performed by nanoparticles of Copper 98
4. SYNTHESIS OF BENZO[b]FURANS FROM ALKYNES AND 2-
HYDROXYARYLCARBONYL DERIVATIVES
4.1 INTRODUCTION
Heterocycles are important structural motifs of a wide range of natural
substrates, compounds of pharmaceutical interest and commodity chemicals.
Benzo[b]furan173
core is present in a large number of natural products and has
attracted a great deal of interest due to its biological activity like anticancer,
antimicrobial, antiviral or anti-inflammatory activity among others, and its
potential applications as pharmacological agents.174
These compounds are
important intermediates for the synthesis of a variety of useful and novel
heterocyclic systems that are otherwise difficult to obtain synthetically.175
The synthesis of these heterocyclic compounds has attracted enormously
the attention of synthetic organic chemists, which has been developed through
different methodologies,176
but the most common route used is the cyclization
through different mechanism starting from phenols.177
An interesting alternative,
involves the formation of a C-C bond through a Sonogashira type process using
2-iodophenol derivatives and the subsequent cyclization to give the
corresponding benzo[b]furan.90,178
173 R. Benassi in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.05, (Eds.: A. R.
Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 259-295. 174 a) B. A. Keay in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.08, (Eds.: A. R.
Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 395-435; b) A.
Radadiya, A. Shah Eur. J. Med. Chem. 2015, 97, 356-376; c) H. Khanam, Shamsuzzaman, Eur.
J. Med. Chem. 2015, 97, 483-504. 175 a) H. Heaney, J. S. Ahn in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.06, (Eds.: A.
R. Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 297-348; b) A.
A. Abu-Hashem, H. A. R. Hussein, A. S. Aly, M. A. Gouda, Synth. Commun. 2014, 44, 2899-
2920. 176 a) W. Friedrichsen in Comprehensive Heterocyclic Chemistry II, Vol. 2, ch. 2.07, (Eds.: A. R.
Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 352-392; b) C. P.
Dell in Science of Synthesis, Vol. 10, ch. 1, (Eds.: E. J. Thomas), Georg Thieme Verlag,
Stuttgart, 2002, 1. pp. 11-86; c) A. A. Abu-Hashem, H. A. R. Hussein, A. S. Aly, M. A. Gouda,
Synth. Commun. 2014, 44, 2285-2312; d) S. Cacchi, G. Fabrizi, A. Goggiamani, Org. Biomol.
Chem. 2011, 9, 641-652. 177 a) E. J. Guthrie, J. Macritchie, R. C. Hartley, Tetrahedron Lett. 2000, 41, 4987-4990; b) T. Pei,
C.-Y. Chen, L. CiMichele, I. W. Davies, Org. Lett. 2010, 12, 4972-4975; c) S. Ghosh, J. Das,
Tetrahedron Lett. 2011, 52, 1112-1116; d) J. Liu, Z. Liu, P. Liao, X. Bi, Org. Lett. 2014, 16,
6204-6207. 178 a) C. G. Bates, P. Saejueng, J. M. Murphy, D. Venkataraman, Org. Chem. 2002, 4, 4727-4729;
b) M. Nagamochi, Y.-Q. Fang, M. Lautens, Org. Lett. 2007, 9, 2955-2958; c) C. Rossy, E.
Fouquet, F.-X. Felpin, Beilstein J. Org. Chem. 2013, 9, 1426-1431.
99 Chapter II. Reactions performed by nanoparticles of Copper
Alternatively, it has been demonstrated that the addition of ortho-
hydroxy arylalkynes to N-tosylhydrazones179
catalysed by copper salts gave
directly the corresponding benzo[b]furans. An alternative route, was designed
avoiding the high cost of the ortho-functionalised arylalkynes, starting from the
corresponding N-tosylhydrazone, using terminal alkynes, acetonitrile as solvent
and the homogeneous CuBr (10 mol%) as catalyst.180
We anticipated that our copper catalyst could be the promoter in the
heterogeneous approach to their synthesis. Moreover, we expected that using this
catalyst the mandatory hydrazone synthesis could be overcome.
4.2 RESULTS
The coupling of 2-hydroxybenzaldehyde (19a) with phenylacetylene (5a)
using impregnated copper(II) oxide on magnetite, in the presence of 4-
methylbenzenesulfonohydrazide, was selected as the model for the optimization
of the reaction conditions (Table 18). Initially, the reaction was studied with
different solvents (entries 1-8) and in its absence (entry 9), obtaining only good
yield when EtOH was used.
Some organic and inorganic bases were examined (entries 10-18)
obtaining traces of the product with organic bases and moderate yields when
some inorganic hydroxide salts were used. The reaction failed in the absence of
base (entry 19). Furthermore, the decrease of the temperature on the reaction was
tested (entries 20 and 21) obtaining lower yields. The reaction with only one
equivalent of base (entry 22) was tested obtaining a decrease in the reaction
yield. Moderate results were obtained using three equivalents of terminal alkyne
(entry 23) or using different amounts of solvent (entries 24 and 25).
179 T. Xiao, X. Dong, L. Zhou, Org. Biomol. Chem. 2013, 11, 1490-1497. 180 L. Zhou, Y. Shi, Q. Xiao, Y. Liu, F. Ye, Y. Zhang, J. Wang, Org. Lett. 2011, 13, 968-971.
Chapter II. Reactions performed by nanoparticles of Copper 100
Table 18. Optimization of the reaction conditions.a
Entry Solvent Base T (ºC) Yield (%)
b
1 THF Cs2CO3 100 26
2 PhMe Cs2CO3 100 0
3 CH3CN Cs2CO3 100 0
4 1,4-Dioxane Cs2CO3 100 3
5 DMF Cs2CO3 100 0
6 H2O Cs2CO3 100 0
7 DMSO Cs2CO3 100 0
8 EtOH Cs2CO3 100 91
9 - Cs2CO3 100 0
10 EtOH KOAc 100 0
11 EtOH MeONa 100 3
12 EtOH Et3N 100 0
13 EtOH DABCO 100 0
14 EtOH KOH 100 56
15 EtOH NaOH 100 43
16 EtOH CsOH·H2O 100 58
17 EtOH t-BuOK 100 34
18 EtOH K2CO3 100 0
19 EtOH - 100 0
20 EtOH Cs2CO3 50 28
21 EtOH Cs2CO3 25 37
22c
EtOH Cs2CO3 100 35
23d
EtOH Cs2CO3 100 63
24e
EtOH Cs2CO3 100 58
25f
EtOH Cs2CO3 100 44 a
Reaction carried out using compounds 19a (0.4 mmol), 5a (0.5 mmol), and 1.2 mmol
of base in 2 mL of the corresponding solvent. b Yield calculated by GC using tridecane as an internal standard.
c Reaction carried out using 19a (0.4 mmol), 5a (0.5 mmol), and 0.4 mmol of base in 2
mL of the corresponding solvent. d
Reaction carried out using 19a (0.4 mmol), 5a (1.2 mmol), and 1.2 mmol of base in 2
mL of the corresponding solvent. e
Reaction carried out using 19a (0.4 mmol), 5a (0.5 mmol), and 1.2 mmol of base in 1
mL of the corresponding solvent.
101 Chapter II. Reactions performed by nanoparticles of Copper
Table 18. Continuation.
f Reaction carried out using 19a (0.4 mmol), 5a (0.5 mmol), and 1.2 mmol of base in 6
mL of the corresponding solvent.
Having stablished the optimal reaction conditions, different catalysts
prepared by simple impregnation protocol were tested on the reaction (Table
19).85a
First of all, the reaction was tested without catalyst (entry 1) and only with
the support of the catalyst (entries 2 and 3), but failed. After that, different
supported metal catalysts were tested (entries 4-16), obtaining traces of the
product with some of them. In the case of the palladium catalyst, the reaction
took place with moderate results. Having stablished that the impregnated
copper(II) oxide on magnetite was the best catalyst to perform this reaction (entry
6), different amounts of them were used (entries 17 and 18). Trying to decrease
the metal loading led to moderate results. Then, a variety of copper(I) and
copper(II) salts were used obtaining moderate yields (entries 19-25), and
confirming the higher activity of the supported catalyst.
Chapter II. Reactions performed by nanoparticles of Copper 102
Table 19. Optimization of the catalyst.a
Entry Catalyst (mol%) Yield (%)
b
1 - 5
2 Micro-Fe3O4 (162) 4
3 Nano-Fe3O4 (162) 4
4 CoO-Fe3O4 (3.54) 4
5 NiO-Fe3O4 (2.58) 3
6 CuO-Fe3O4 (2.40) 91
7 Ru2O3-Fe3O4 (3.30) 4
8 Rh2O3-Fe3O4 (1.05) 4
9 PdO-Fe3O4 (3.04) 32
10 Ag2O/Ag-Fe3O4 (3.13) 0
11 OsO2-Fe3O4 (1.28) 3
12 PtO/PtO2-Fe3O4 (1.34) 4
13 Au2O3/Au-Fe3O4 (0.35) 4
14 PdO/Cu-Fe3O4 (3.82/2.24) 6
15 NiO/Cu-Fe3O4 (2.28/2.20) 2
16 WO3-Fe3O4 (1.41) 2
17 CuO-Fe3O4 (1.2) 56
18 CuO-Fe3O4 (0.50) 44
19 CuO (2.40) 46
20 Cu(OAc)2 (2.40) 43
21 CuBr2 (2.4) 46
22 Cu2O (2.40) 36
23 CuCN (2.40) 49
24 CuBr (2.40) 61
25 Cu (powder) (2.40) 9 a Reaction carried out using 19a (0.4 mmol), and 5a (0.5 mmol).
b Yield calculated by GC using tridecane as an internal standard.
Once the optimal conditions were obtained, the problem of recycling was
examined. When the catalyst was recovered from the reaction mixture by using a
magnet, washed with ethanol and reused under the same reaction conditions only
traces (12 %) of the expected product 20a were obtained (Figure 27).
103 Chapter II. Reactions performed by nanoparticles of Copper
0
20
40
60
80
100
01
2
Yie
ld 2
0a
(%)
Cycle
Normal
recycling
Recycling by
bubbling up O2
Recycling using
t-BuOOH
Figure 27. Catalyst recycling.
To explain these phenomena some studies were carried out. First of all,
XPS and AES analysis before and after reaction (Figure 15 and 28), showing that
before the reaction the catalyst was formed by a mixture 4:1 of Cu(II):Cu(0)
nanoparticles, and after the reaction only Cu(0) was detected in the catalyst.
-100
400
900
1400
1900
2400
2900
3400
3900
4400
925 930 935 940 945 950 955 960 965
Inte
nsi
ty/a
rb. u
nit
s
Binding energy (eV)
Fit
Cu 2p3/2
Cu 2p1/2
5400
5500
5600
5700
5800
5900
6000
6100
6200
6300
6400
900 905 910 915 920 925
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Cu L3VV
Figure 28. a) XPS of recycled catalyst. b) AES of recycled catalyst.
TEM images were analysed before and after the reaction completion.
Before the reaction, 73 % of the copper oxide nanoparticles had an average size
between 2-6 nm, while after completion of the reaction, nanoparticles were not
detected and only a sheet of copper(0) were observed (Figure 29).
a) b)
Chapter II. Reactions performed by nanoparticles of Copper 104
0
10
20
30
40
50
0-1
1-2
2-3
3-4
4-5
5-6
6-7
7-8
8-9
9-1
0
10
-11
11
-12
12
-13
13
-14
14
-15
15-2
0
20
-25
25
-30
30
-35
Par
ticl
es
Particle size (nm)
Figure 29. a) TEM image of fresh copper catalyst. b) TEM image of recycled
copper catalyst. c) Particle size distribution of fresh copper catalyst.
The ICP-MS analysis of the reaction solution showed the presence of
copper (20.5 % of the initial amount). With these results in hand we could
speculate that the heterogeneous CuO-Fe3O4 catalyst could serve as a reservoir of
copper and when the copper goes to the reaction solution181
catalyses the
reaction, after that it is reduced by ethanol to give a Cu(0) sheet. In fact, the
obtained result using Cu(0) powder (entry 25, Table 19) was the same as the one
using the recycled catalyst.
181 For an example were recyclable impregnated cobalt oxide on magnetite acts as heterogeneous
reservoir for the homogeneous reaction see results from Chapter I.
a) b)
c)
105 Chapter II. Reactions performed by nanoparticles of Copper
The hot filtration experiment was performed to confirm that
nanoparticles of copper were leached to the homogeneous solution. After
completion of the standard reaction, the catalyst was removed and the reaction
was performed using 1-ethynyl-4-methoxybenzene as a substrate. After 6 h, the
reaction was quenched and only traces of the corresponding product 20j were
observed by 1H-NMR, recovering the starting alkyne unchanged.
Due to the inability of the catalyst to be reused after completion of the
reaction, re-oxidation was tried using different methodologies. In order to re-
oxidise the Cu(0) sheet formed, O2 was bubbled up during 4 h using THF as
solvent. However, only 22 % of yield of the product 20a was obtained when the
reaction was repeated . Another method used to re-oxidise the catalyst was to add
t-BuOOH in decane to the catalyst, which was previously washed with ethanol to
remove the reaction products. When the reaction was carried out using this re-
oxidised catalyst, heating the reaction at 70 ºC overnight, higher yield of product
20a compared to the aforementioned protocol, was achieved. However, the yield
was not good enough to consider this protocol the appropriate method for the
catalyst recycling (see Figure 27).
The mechanism for the formation of the final product are similar to the
previously introduced,180
as shown in Scheme 24. First of all, 2-
hydroxybenzaldehyde reacts with 4-methylbenzenesulfonohydrazide to give the
corresponding hydrazone, which in turn reacts with the base (Cs2CO3) to form 2-
(diazomethyl)phenol derivative. At the same time, phenylacetylene reacts with
the base giving copper phenyl acetylide. Having formed these two species, they
react with each other through a dediazotization reaction giving a copper carbene
intermediate that through a migratory insertion forms [1-(2-hydroxyphenyl)-3-
phenylprop-2-yn-1-yl]copper intermediate. The subsequent protonation of this
intermediate gives the corresponding allene, and finally it cycles generating the
corresponding benzo[b]furan.
To check if the reaction took place through the formation of the N-
tosylhidrazone, the reaction was performed starting from the previously prepared
4-methylbenzenesulfonohydrazine obtaining the product 20a with the same yield
than under standard reaction conditions. Moreover, when only 30 mol% of
TsNHNH2 was used in the reaction, only 29 % of conversion to product 20a was
obtained. These results seem to indicate that the formation of hydrazone is
fundamental in the reaction pathway.
Chapter II. Reactions performed by nanoparticles of Copper 106
Scheme 24. Proposed mechanism for the synthesis of benzo[b]furan.
107 Chapter II. Reactions performed by nanoparticles of Copper
The optimised reaction conditions were applied to other substrates (Table
20). Different substituted o-hydroxybenzaldehydes were used (entries 2 and 3)
obtaining good results. After that, some arylalkynes with electron-withdrawing
substituents in different positions at the aromatic ring were tested (entries 4-7),
obtaining good results.
Table 20. Scope of the reaction.a
Entry R
1 R
2 R
3 Product Yield (%)
b
1 H H Ph 20a 91 (58)c
2 t-Bu t-Bu Ph 20b 71
3 Br OMe Ph 20c 75
4 H H 2-BrC6H4 20d 70
5 H H 3-ClC6H4 20e 82
6 H H 4-BrC6H4 20f 90
7 H H 4-CF3C6H4 20g 92
8 H H 2-MeC6H4 20h 67
9 H H 3-MeC6H4 20i 67
10 H H 4-MeOC6H4 20j 68
11 H H CH3(CH2)4 20k 54
12 H H C6H11 20l 39
13 H H Cl(CH2)3 20m 70
14 H H CH2OC5H10O 20n 90
15 H H 3-(CH≡C)C6H4 20o 17
16 t-Bu t-Bu 4-BrC6H4 20p 69 a Reaction carried out using 19 (0.4 mmol), and 5 (0.5 mmol).
b Isolated yield after column chromatography.
c Reaction carried out using 19a (8 mmol), and 5a (10 mmol).
Slightly lower yields were obtained when the reaction was performed
using arylalkynes with electron-donating groups at the aromatic ring (entries 8-
10). Then, some aliphatic alkynes were tested (entries 11-14) obtaining moderate
to good yields. The reaction could be performed selectively using a diyne, giving
the mono-benzofuran 20o in low yield (entry 15). To finish with the reaction
scope a combination of substituted o-hydroxybenzaldehyde and a substituted
Chapter II. Reactions performed by nanoparticles of Copper 108
alkyne was used to obtain compound 20p with good yield (entry 16). The
reaction could be scaled up to 20 fold obtaining product 20a in good yield (entry
1, footnote c).
The same reaction could be carried out with different o-
hydroxybenzofenones, reaching good yields of the corresponding substituted
benzo[b]furan in both cases, showing the great versatility of the reaction (Scheme
25).
Scheme 25. Reaction with o-hydroxyacetophenone.
CHAPTER III
Reactions performed using the
impregnated bimetallic Nickel(II)
Oxide/Copper(0) on Magnetite
111 Chapter III. Reactions performed by nanoparticles of Nickel and Copper
1. MULTICOMPONENT AZIDE-ALKYNE CYCLOADDITION
REACTION
1.1 INTRODUCTION
Although the 1,3-dipolar cycloaddition of azide derivatives and alkynes
dates back to the nineteenth century,182
the pioneer and seminal works of the
Medal183
and Sharpless184
groups on the copper-catalysed process were the
definitive push for the blossoming of this process.
The process allowed access to different 1,2,3-triazoles of great interest to
different areas of chemistry and pharmacy, in short reaction times, under mild
conditions, and as only one regioisomer.185
The tremendous success of the homogeneous copper(I) complexes as
catalysts has eclipsed the activity of others, such as those derived from
ruthenium, platinum, palladium,186
silver,187
or nickel,188
as well as the use of
other heterogeneous catalysts.
182 A. Michael, J. Prakt. Chem. 1893, 48, 94-95. 183 C. W. Tornøe, C. Christensen, M. Medal, J. Org. Chem. 2002, 67, 3057-3064. 184 V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. Int. Ed. 2002, 41,
2596-2599. 185 a) V. D. Bock, H. Hiemstra, J. H. van Maarseveen, Eur. J. Org. Chem. 2006, 51-68; b) M.
Medal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952-3015; c) F. Amblard, J. H. Cho, R. F.
Schinazi, Chem. Rev. 2009, 109, 4207-4220; d) J. E. Hein, V. V. Fokin, Chem. Soc. Rev. 2010,
39, 1302-1315; e) L. Liang, D. Astruc, Coord. Chem. Rev. 2011, 255, 2933-2945; f) S. Díez-
González, Catal. Sci. Technol 2011, 1, 166-178; g) T. Jin, M. Yan, Y. Yamamoto,
ChemCatChem 2012, 4, 1217-1229. 186 C. Schilling, N. Jung, S. Bräse, in Organic Azides: Syntheses and Applications; Eds.: S. Bräse,
K. Banert, Wiley-VCH, Weinheim, 2010, pp 269-284. 187 a) J. McNulty, K. Keskar, R. Vemula, Chem. Eur. J. 2011, 17, 14727-14730; b) J. McNulty, K.
Keskar, Eur. J. Org. Chem. 2012, 5462-5470. 188 a) P. Paul, K. Nag, Inorg. Chem. 1987, 26, 2969-2974; b) R. Nasani, M. Saha, S. M. Mobin, S.
Mukhopadhyay, Polyhedron 2013, 55, 24-36.
Chapter III. Reactions performed by nanoparticles of Nickel and Copper 112
However, very recently some heterogeneous catalysts have emerged as
an alternative. Thus, the particles of copper,189
or its oxide derivatives,190
different copper salts supported on charcoal,191
on organic materials,192
as well as
on inorganic supports193
have been tested for this transformation, with copper
loading of these catalysts ranging from 0.5 to 12 mol%. Interestingly, some of the
inorganic supports were based on iron, permitted the development of magnetic
catalyst and separation, as it was for the case of copper supported iron (5
mol%),194
copperferrite (5 mol%),195
or ligand-grafted copper on magnetite (2
mol%).196
189 a) F. Alonso, Y. Moglie, G. Radivoy, M. Yus, Tetrahedron Lett. 2009, 50, 2358-2362; b) F.
Alonso, Y. Moglie, G. Radivoy, M. Yus, Eur. J. Org. Chem. 2010, 1875-1884; c) T. Jin, M.
Yan, Menggernbateer, T. Minato, M. Bao, Y. Yamamoto, Adv. Synth. Catal. 2011, 353, 3095-
3100; d) T. L. Cook, J. A. Walker, J. Mack, Green Chem. 2013, 15, 617-619. 190 a) J. Y. Kim, J. C. Park, H. Kang, H. Song, K. H. Park, Chem. Commun. 2010, 46, 439-441; b)
C. Shao, R. Zhu, S. Luo, Q. Zhang, X. Wang, Y. Hu, Tetrahedron Lett. 2011, 52, 3782-3785; c)
F. Alonso, Y. Moglie, G. Radivoy, M. Yus, Synlett 2012, 23, 2179-2182; d) H. Woo, H. Kang,
A. Kim, S. Jang, J. C. Park, S. Park, B.-S. Kim, H. Song, K. H. Park, Molecules 2012, 17,
13235-13252. 191 a) B. H. Lipshutz, B. R. Taft, Angew. Chem. Int. Ed. 2006, 45, 8235-8238; b) C-T. Lee, S.
Huang, B. H. Lipshutz, Adv. Synth. Catal. 2009, 351, 3139-3142; c) M. Fuchs, W. Goessler, C.
Pilger, C. O. Kappe, Adv. Synth. Catal. 2010, 352, 323-328; d) F. Alonso, Y. Moglie, G.
Radivoy, M. Yus, Adv. Synth. Catal. 2010, 352, 3208-3214; e) F. Alonso, Y. Moglie, G.
Radivoy, M. Yus, Org. Biomol. Chem. 2011, 9, 6385-6395; f) F. Alonso, Y. Moglie, G.
Radivoy, M. Yus, J. Org. Chem. 2011, 76, 8394-8405. 192 a) U. Sirion, Y. J. Bae, B. S. Lee, D. Y. Chi, Synlett 2008, 2326-2330; b) L. Bonami, W. van
Camp, D. van Rijckegem, F. E. Du Prez, Macromol. Rapid Commun. 2009, 30, 34-38; c) H.
Hagiwara, H. Sasaki, T. Hoshi, T. Suzuki, Synlett 2009, 643-647; d) Y. Wang, J. Liu, C. Xia,
Adv. Synth. Catal. 2011, 353, 1534-1542; e) M. Liu, O. Reiser, Org. Lett. 2011, 13, 1102-1105;
f) B. Kaboudin, Y. Abedi, T. Yokomatsu, Org. Biomol. Chem. 2012, 10, 4543-4548; g) A.
Kumar, S. Aerry, A. Saxena, A. de, S. Mozumdar, Green Chem. 2012, 14, 1298-1301; h) Y. M.
A. Yamada, S. M. Sarkar, Y. Ouzumi, J. Am. Chem. Soc. 2012, 134, 9285-9290. 193 a) S. Chassaing, M. Kumarraja, A. S. S. Sido, P. Pale, J. Sommer, Org. Lett. 2007, 9, 883-886;
b) S. Chassaing, A. S. S. Sido, A. Alix, M. Kumarraja, P. Pale, J. Sommer, Chem. Eur. J. 2008,
14, 6713-6721; c) K. Namitharan, M. Kumarraja, K. Pitchumani, Chem. Eur. J. 2009, 15, 2755-
2758; d) P. Veerkumar, M. Velayudham, K.-L. Lu, S. Rajogopal, Catal. Sci. Technol. 2011, 1,
1512-1525; e) J. C. Park, A. Y. Kim, J. Y. Kim, S. Park, K. H. Park, H. Song, Chem. Commun.
2012, 48, 8484-8486; f) M. N. S. Rad, S. Behrouz, M. M. Doroodmand, A. Movahediyan,
Tetrahedron 2012, 68, 7812-7821; g) S. Mohammed, A. K. Padala, B. A. Dar, B. Singh, B.
Sreedhar, R. A. Vishwakarma, S. B. Bharate, Tetrahedron 2012, 68, 8156-8162; h) L. Wan, C.
Cai, Catal. Lett. 2012, 142, 1134-1140. i) J. M. Collinson, J. D. E. T. Wilton-Ely, S. Díez-
González, Chem. Commun. 2013, 49, 11358-11360. 194 a) S. Kovács, K. Zih-Perényi, Á. Révész, Z. Novák, Synthesis 2012, 44, 3722-3730; b) R.
Hudson, C.-J. Li, A. Moores, Green Chem. 2012, 14, 622-624. 195 B. S. P. A. Kumar, H. V. Reddy, B. Madhav, K. Ramesh, Y. V. D. Nageswar, Tetrahedron Lett
2012, 53, 4595-4599. 196 a) A. Megía-Fernández, M. Ortega-Muñoz, J. López-Jaramillo, F. Hernández-Mateo, F.
Santoyo-González, Adv. Synth. Catal. 2010, 352, 3306-3320; b) R. B. N. Baig, R. S. Varma,
Green Chem. 2012, 14, 625-632.
113 Chapter III. Reactions performed by nanoparticles of Nickel and Copper
The intrinsic instability of organic azides, mainly those of low molecular
weight, has been an important drawback in the generalization of this approach for
the synthesis of interesting polyvalent structures. However, the use of a
multicomponent approach, generating the azide derivative in situ by reaction of
sodium azide and the corresponding organic reagent,190c,191b,d-f,192d,f,h,193h,195,196b,197
has permitted us to overcome this problem. With these antecedents in hands, we
thought that impregnated copper on magnetite could be a good catalyst for this
click process.
1.2 RESULTS
Although our ultimate goal was to get a heterogeneous and recyclable
catalyst for the multicomponent version of azide-alkyne cycloaddition, the study
was started with the standard two-component reaction between ethynylbenzene
(5a) and (azidomethyl)benzene (23a) catalysed by impregnated copper on
magnetite (Table 21).
The initial reaction was conducted in absence of catalyst at 110 ºC in
water, obtaining after 7 days a 1:1 mixture of both possible isomers. Then, the
reaction was repeated in the presence of copper catalyst in toluene at 70 ºC
giving exclusively 1-benzyl-4-phenyl-1H-1,2,3-triazole (24a) in modest yield
(entry 2). Both, the decrease and the increase of temperature, led to the formation
of a mixture of regioisomers (entries 3 and 4).
Then, the influence of solvent was examined (entries 5-11), finding that
the highest yield was reached in water (entry 10). Under these conditions, the
role of magnetite support was studied and high activity of the supposed inert
material was found (entry 12).
197 a) A. K. Feldman, B. Colasson, V. V. Fokin, Org. Lett. 2004, 6, 3897-3899; b) P. Appukkuttan,
W. Dehaen, V. V. Fokin, E. van der Eycken, Org. Lett. 2004, 6, 4223-4225; c) Z.-X. Wang, A.-
G. Zhao, J. Heterocycl. Chem. 2007, 44, 89-92; d) J. T. Fletcher, J. E. Reilly, Tetrahedron Lett.
2011, 52, 5512-5515; e) R. B. N. Baig, R. S. Varma, Chem. Commun. 2012, 48, 5853-5855; f)
S. Koguchi, K. Izawa, Synthesis 2012, 44, 3603-3608.
Chapter III. Reactions performed by nanoparticles of Nickel and Copper 114
Table 21. Optimization of cycloaddition reaction conditions.a
Entry Solvent T (ºC) t (d) Yield 24a (%)
b Yield 25a (%)
b
1c H2O 110 7 46 49
2 PhMe 70 2 58 0
3 PhMe 25 2 35 7
4 PhMe 110 2 73 25
5 THF 70 2 43 7
6 CHCl3 70 2 52 6
7 MeCN 70 2 15 6
8 DMSO 70 2 33 8
9 MeOH 70 2 50 0
10 H2O 70 1 94 0
11 - 70 2 73 12
12d
H2O 70 1 82 1 a Reaction carried out using compounds 5a (1 mmol), and 23a (1 mmol) in 2 mL of
solvent. b Isolated yield after column chromatography.
c Reaction carried out in absence of catalyst.
d Reaction performed using only nanomagnetite (21 mol%).
Once the activity of copper catalyst was examined, its recycling was
studied. After the first trial, the magnetite was collected with a magnet, washed
with toluene and ethanol, and dried. The recycled catalyst could be re-used three
fold with similar results (82-78 %). However, the yield dropped to 35 % in the
fourth use, keeping this level of results during the following five cycles (Figure
30).
115 Chapter III. Reactions performed by nanoparticles of Nickel and Copper
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10
Yie
ld 2
4a (%
)
Cycle
Figure 30. Recycling of CuO-Fe3O4 catalyst for the cycloaddition.
The phenomenon of leaching was studied by ICP-MS analysis of the
resulting reaction solution mixture, and 1.1 % of the initial amount of copper was
detected (0.007 % of iron), explaining the loss of activity. Moreover, the TEM
images of the recycled catalyst showed a small change in the copper particle size
from 7.1 ± 6.5 nm of the fresh prepared catalyst to 6.4 ± 5.2 nm for the recycled
one, which would not affect the reactivity of the recycled catalyst. Finally, it
should be pointed out that the BET surface area did not suffer a great change,
from 6.2 m2g
-1 for the initial catalyst to 8.4 m
2g
-1 for the used one, being is
practically the same specific area.
After finding that copper catalyst was effective in the cycloaddition
between azides and terminal alkynes, the problem of the multicomponent
version,190c,191d,e,192d,h,193h,195,196b,c
using benzyl bromide (26a), sodium azide (27)
and ethynylbenzene (5a) as reaction model (Table 22) was faced. The reaction in
water gave a mixture of the expected heterocycle 24a together with its
regioisomer 25a (compare entry 1 in Table 22 and entry 9 in Table 21). This
initial trial showed that the change from simple cycloaddition to the
multicomponent reaction one was not so straightforward. Thus, a new
optimization process on this multicomponent reaction was carried out, starting by
studying the effect of solvent (entries 1-8 in Table 22).
Chapter III. Reactions performed by nanoparticles of Nickel and Copper 116
The best result was obtained in absence of solvent, but a small amount
of the product arising from homocoupling of terminal alkyne was found (see
Chapter II.1). The optimal temperature seemed to be 50 ºC (entries 8-11), since at
higher temperatures different by-products were formed, while lower temperatures
gave a modest yield for product 24a.
Table 22. Optimization of multicomponent cycloaddition process.a
Entry Solvent T (ºC) t (d) Yield 24a (%)
b Yield 25a (%)
b
1 H2O 70 3 57 13
2 PhMe 70 3 33 0
3 THF 70 3 21 4
4 CHCl3 70 3 19 1
5 MeCN 70 3 16 0
6 DMSO 70 3 25 3
7 MeOH 70 3 32 25
8 - 70 3 69c 0
9 - 50 2 71 0
10 - 25 3 38 0
11 - 110 2 53c 6
a Reaction carried out using compounds 5a (1 mmol), 26a (2 mmol), and 27 (2 mmol) in
2 mL of solvent. b Isolated yield after column chromatography.
c 1,4-Diphenylbuta-1,3-diyne was isolated in a 10 % yield.
Although copper catalysts have been the most used, other metal
catalysts have also shown some activity for this reaction. For this reason, a series
of impregnated metal catalyst in this multicomponent version were tested (Table
23), studying also the uncatalysed reaction (entry 1).
117 Chapter III. Reactions performed by nanoparticles of Nickel and Copper
Table 23. Optimization of catalyst for multicomponent cycloaddition.a
Entry Catalyst (mol%) Yield (%)
b
1 - 0
2 Micro-Fe3O4 (21) 0
3 Nano-Fe3O4 (21) 0
4 CoO-Fe3O4 (1.4) 0
5 NiO-Fe3O4 (1.0) 5
6 CuO-Fe3O4 (0.9) 83
7 Ru2O3-Fe3O4 (1.3) 0
8 Rh2O3-Fe3O4 (0.4) 0
9 PdO-Fe3O4 (1.2) 0
10 Ag2O/Ag-Fe3O4 (1.3) 0
11 OsO2-Fe3O4 (0.5) 0
12 IrO2-Fe3O4 (0.1) 0
13 PtO/PtO2-Fe3O4 (0.5) 0
14 Au2O3/Au-Fe3O4 (0.1) 0
15 PdO/Cu-Fe3O4 (1.5/0.9) 42
16 NiO/Cu-Fe3O4 (0.9/0.9) 98
17 NiO/Cu-Fe3O4 (0.2/0.2) 15
18 NiO/Cu-Fe3O4 (1.8/1.8) <99e
19 NiO-Fe3O4 (1.0) + CuO-Fe3O4 (0.9) 87
20 CuO (0.9) 78
21 NiO (0.9) 12
22 Cu(OH)2 (0.9) 58
23 Ni(OH)2 (0.9) 11
24 NiO (0.9) + CuO (0.9) 76
25 Ni(OH)2 (0.9) + Cu(OH)2 (0.9) 62 a Reaction carried out using compounds 5a (1 mmol), 26a (2 mmol), and 27 (2 mmol).
b Isolated yield after column chromatography.
e Reaction performed during 24 h.
Chapter III. Reactions performed by nanoparticles of Nickel and Copper 118
From all ductile metal oxide, only nickel and copper catalysts showed
activity (Table 23, entries 2-14). Then, a series of bimetallic derivatives were
studied, finding that Pd/Cu system90
could render the expected product 24a (entry
15). Very recently, different bimetallic Ni-Cu/C composite catalysts198
have been
tested in the simple cycloaddition of azides and terminal alkynes and these results
prompted us to prepare the corresponding impregnated bimetallic catalyst. Its
reaction gave the expected product with an excellent result (entry 16). The
decrease of the amount of Ni-Cu catalyst had an important detrimental effect,
meanwhile its increase had a marginal benefitial effect (compare entries 16-18).
Faced with the excellent result obtained with the bimetallic nickel-
copper catalyst, we wondered if the yield was the result of the simple addition of
two independent catalytic sites or if there was some type of synergic effect. To
answer that question, the reaction was repeated using both catalysts (the copper
and the nickel one) with almost the same loading. The achieved results seemed to
be due to the addition of the activity of both catalysts (compare entries 5 and 6
with entry 19 in Table 23). Therefore, we believe that the bimetallic catalyst
(entry 16) develops a synergetic effect that makes it superior to the addition of
both parts, although the nature of this positive interaction is unknown.
Finally, the unsupported metal catalysts were tested. Thus, the reaction
using CuO alone gave the expected product 24a with a good result (Table 23,
entry 20), meanwhile the related nickel oxide gave a worse result (entry 21).
When the reaction was repeated with the corresponding metal hydroxide
derivatives the yields were slightly lower (entries 22 and 23).
The equimolecular mixture of both metallic catalysts did not show any
improvement of the result obtained by the copper derivative (compare entries 20,
22 and 24, 24, respectively).
198 a) B. H. Lipshutz, D. M. Nihan, E. Vinogradova, B. R. Taft, Ž. V. Bošković, Org. Lett. 2008,
10, 4279-4282; b) J. Gong, J. Liu, L. M. Ma, X. Wen, X. Chen, D. Wan, H. Yu, Z. Jiang, E.
Borowiak-Palen, T. Tang, Appl. Catal.,B 2012, 117-118, 185-193.
119 Chapter III. Reactions performed by nanoparticles of Nickel and Copper
The bimetallic Ni-Cu catalyst could be recycled and reused ten-fold,
just by collection of the catalyst with a magnet, washing with toluene and
ethanol, and drying, without any depletion in its activity (Figure 31).
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9 10
Yie
ld2
4a
(%
)
Cycles
Figure 31. Recycling of NiO/Cu-Fe3O4 catalyst for the multicomponent reaction.
The phenomenon of leaching was studied by ICP-MS analysis of the
resulting reaction solution mixture, and 1.1 and 0.2 % of the initial amount of
copper, and nickel, respectively, was detected (0.006 % of iron). The TEM
images of the recycled catalyst showed a small change in the particle size from
3.1 ± 1.7 nm of the freshly prepared catalyst to 4.7 ± 2.4 nm for the recycled one
(Figure 32).
Chapter III. Reactions performed by nanoparticles of Nickel and Copper 120
0
20
40
60
80
Par
ticl
es
Particle size (nm)
before reaction
after reaction
Figure 32. TEM images: a) before and b) after recycling bimetallic
nickel/copper catalyst. c) Nickel/Copper particle size distribution before and
after reaction.
Moreover, XPS data analysis of bimetallic catalyst showed only NiO,
CuO and Cu2O species, which was confirmed by Auger spectroscopy (Figure
33). However, the recycled one showed the presence of Ni(OH)2 as well as
Cu(OH)2. These small changes, in particle size and the nickel species seemed not
to affect the activity of the bimetallic catalyst, since it could be reused several
times with similar activity.
a) b)
c)
121 Chapter III. Reactions performed by nanoparticles of Nickel and Copper
-100
900
1900
2900
3900
4900
5900
928 933 938 943 948
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
fit
Cu 2p3/2
CuO 2p3/2
-100
400
900
1400
1900
2400
2900
3400
3900
4400
847 852 857 862 867
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Fit
NiO 2p3/2
NiO 2p3/2
-100
100
300
500
700
900
1100
1300
926 931 936 941 946 951
Inte
nsi
ty/a
rb. u
nit
s
Binding Energy (eV)
Fit
Cu(OH)2 2p3/2
Cu(OH)2 2p3/2 sat.
-100
400
900
1400
1900
2400
2900
3400
3900
4400
845 850 855 860 865 870
Inte
nsi
ty/a
rb. unit
s
Binding Energy (eV)
Fit
Ni(OH)2 2p3/2
Ni(OH)2 2p3/2
Figure 33. XPS of the a) fresh and b) recycled NiO/Cu-Fe3O4 catalyst.
To know if the reaction took place by the leached copper or nickel
species to the organic medium, the standard multicomponent reaction was
performed (Table 23, entry 16). After that, the catalyst was removed carefully by
a magnet at high temperature, and washed with toluene. The solvents of the
above solution, without catalyst, were removed under low pressure and alkyne
5a, sodium azide (27) and 4-bromobenzyl bromide were added to the above
residue. The resulting mixture was heated again at 50 ºC for 24 h. The analysis of
crude mixture, after hydrolysis, revealed the formation of compound 24a in 95 %
(catalysed process) and product 24b in less than 1 % yield by GC-analysis
(compare with entry 2 in Table 24). Therefore, we could exclude that the final
leached copper-nickel species were responsible for the reaction results under the
standard conditions.
Once the catalytic activity and the recyclability of bimetallic catalyst
were proved, the scope of the reaction was tested (Table 24). The reaction gave
excellent results independently of the substituent at the aromatic ring. Also the
position of the substituent at the aromatic ring of the bromide 26 seemed not to
have influence on the results (compare entries 1-7). The reaction with 2-
(bromomethyl)isoindoline-1,3-dione gave the expected compound 24h in modest
yield (entry 8). Also, the reaction was accomplished with alkynes 5 with different
groups at the aromatic ring, with no clear correlation of the reached yields with
the electronic nature of the substituents (entries 9-17). However, it should be
pointed out that the reactions using less electrophilic reagents such as aliphatic
a)
b)
Chapter III. Reactions performed by nanoparticles of Nickel and Copper 122
bromide (1-bromododecane) or benzyl chloride, failed after seven days under
standard conditions, recovering unchanged the starting alkyne, as well as in the
case of using an aliphatic substituted alkyne (oct-1-yne).
Table 24. Multicomponent cycloaddition.a
Entry R
1 R
2 Nº Yield (%)
b
1 Ph Ph 24a 98
2 Ph 4-BrC6H4 24b <99
3 Ph 3-BrC6H4 24c <99
4 Ph 2-BrC6H4 24d <99c
5 Ph 2-MeC6H4 24e 59c
6 Ph 3-MeC6H4 24f 50
7 Ph 3,5-(MeO)2C6H4 24g 89
8 Ph C6H4(CO)2N 24h 37c
9 4-ClC6H4 Ph 24i 80c
10 4-ClC6H4 4-BrC6H4 24j <99
11 2-ClC6H4 Ph 24k 45c
12 4-BrC6H4 Ph 24l 42c
13 4-BrC6H4 3-MeC6H4 24m 90
14 4-MeOC6H4 Ph 24n 42c
15 3-MeC6H4 Ph 24o 55b
16 3-MeC6H4 3-BrC6H4 24p 86
17 3-MeC6H4 3-MeC6H4 24q 49 a Reaction carried out using compounds 5 (1 mmol), 26 (2 mmol), and 27 (2 mmol).
b Isolated yield after column chromatography.
c Reaction performed during 4 days.
Then, the initial source of benzyl azide was tested (Scheme 26). The
reaction with benzylic alcohols failed after 6 days, recovering unchanged the
initial alkyne. The reaction also failed using the silyl ether 28b. However, the
reaction using benzyl mesylate gave a modest yield (35 %) after 2 days reaction
time. When the reaction time was increased up to 6 days a reasonable yield was
isolated (75 %). When the reaction was performed with benzyl tosylate (28d) the
result was very modest.
123 Chapter III. Reactions performed by nanoparticles of Nickel and Copper
Scheme 26. Multicomponent cycloaddition with benzyl derivatives.
The multicomponent reaction with symmetrical internal alkynes 29
gave the expected compound 30 with very modest yield (Scheme 27). This result
highlighted the possible selectivity of the catalyst. In order to confirm this, the
reaction of benzyl bromide (26a, 2 eq.), sodium azide (27, 2 eq.), ethynylbenzene
(5a, 1 eq.) and 1,2-diphenylethylene (29a, 1 eq.) was performed under standard
conditions, finding exclusively the compound 24a (94 %) from the analysis of
crude mixture, and the internal alkyne unchanged.
Scheme 27. Multicomponent cycloaddition with internal alkynes.
Once the scope of the reaction was studied, we faced the problem of
reaction sequentiality was faced. For this proposal, we carried out the reaction
with the dibromide derivative 31, and a double amount of sodium azide (27),
obtaining after six days the azide 32 with a moderate yield (Scheme 28).
Chapter III. Reactions performed by nanoparticles of Nickel and Copper 124
Scheme 28. Sequential multicycloaddition process.
The CG-MS analysis of crude mixture did not show the presence of the
symmetrical bis-triazole, with the relate bis-azide derivative being the main by-
product. The isolated azide 32 was re-submitted to another cycloaddition process,
yielding the unsymmetrical bis-triazole derivative 33 in good yield. This
approach highlights the possibilities of the catalyst in the synthesis of different
substituted triazoles.
CHAPTER IV†
Reactions performed using
nanoparticles of impregnated
Palladium(II) Oxide on Magnetite
† The results presented in this Chapter were performed in collaboration with the
research group of Prof. Dr. McGlacken from the University of Cork in Ireland
127 Chapter IV. Reactions performed by nanoparticles of Palladium
1. DIRECT ARYLATION OF HETEROCYCLES
1.1 INTRODUCTION
The formation of aryl-aryl (Ar-Ar’) bonds and heteroaryl (Ar-Het and
Het-Het') analogues is an important transformation in compounds used in in
Organic Synthesis due to number of compounds containing these moieties in the
pharmaceutical and other industries.199
Traditional methods200
for the
introduction of the Ar-Ar' bond (e.g. Suzuki-Miyaura, Stille, Negishi and other
named reactions) suffer from drawbacks, as they require the installation of
activating groups on both coupling partners. The associated waste (B, Sn, Zn-
based) is also a major problem in the pharmaceutical and other industries. A
modern, efficient and environmentally friendly alternative is termed Direct
Arylation (DA).201
Through catalytic C–H activation,154,202
DA avoids the
preactivation steps, establishing a convenient pathway for the synthesis of
arylated compounds in terms of atom economy and environmental impact.41a,f,203
In the last decade a broad number of catalytic systems have been used
for the DA of heterocycles.204
However, most of these methodologies are based
on homogeneous catalysis and needed harsh reaction conditions. Homogeneous
catalysis suffers from a number of drawbacks. Deactivation due to metal
aggregation and precipitation205
and separation of the catalyst from the API
product206
seriously impede scale-up of many potentially useful transformations.
199 D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev. 2003, 103, 893-930. 200 E. Negishi in Handbook of Organopalladium Chemistry for Organic Synthesis, Wiley, New
York, 2003. 201 a) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174-238; b) L. Ackermann, R.
Vicente, A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792-9826; c) G. P. McGlacken, L. M.
Bateman, Chem. Soc. Rev. 2009, 38, 2447-2464. 202 K. Godula, D. Sames, Science 2006, 312, 67-72. 203 a) B. M. Trost, Science 1991, 254, 1471-1477; b) Green Chemistry: Designing Chemistry for
the Environment; (Eds.: P. T. Anastas, T. C. Williamson), American Chemical Society:,
Washington DC, 1996; c) B. M. Trost, Acc. Chem. Res. 2002, 35, 695-705; d) R. A. Sheldon, I.
Arends, U. Hanefeld, Green Chemistry and Catalysis, Wiley–VCH, Weinheim, Germany,
2007. 204 For recent reviews see: a) J. J. Mousseau, A. B. Charette, Acc. Chem. Res. 2013, 45, 412-424;
b) F. Shibahara, T. Murai, Asian J. Org. Chem. 2013, 8, 624-636; c) K. Yuan, H. Doucet,
ChemCatChem 2013, 5, 3495-3496; d) R. Rossi, F. Bellina, M. Lessi, C. Manzini, Adv. Synth.
Catal. 2014, 356, 17-117; e) R. Rossi, F. Bellina, M. Lessi, C. Manzini, L. A. Perego, Synthesis
2014, 46, 2833-2883; f) S. El Kazzouli, J. Koubachi, N. El Brahmi, G. Guillaumet, RSC Adv.
2015, 5, 15292-15327; g) Y. Liang, S. F. Wnuk, Molecules 2015, 20, 4874-4901. 205 J. G. de Vries, Dalton Trans. 2006, 421-429. 206 C. E. Garret, K. Prasad, Adv. Synth. Catal. 2004, 346, 889-900.
Chapter IV. Reactions performed by nanoparticles of Palladium 128
Heterogeneous catalysis,207
on the other hand, offers a more attractive approach.
Heterogeneous catalysts possess good thermal stability and can usually be
removed from the reaction media and can, in principle, be recycled.
Recently notable progress has been made in the search of
heterogeneous systems for DA.208
Palladium has been the most employed
transition-metal to accomplish this transformation. Examples include Pd
supported on zeolite,209
modified silica,210
metal organic frameworks,211
carbon212
and mesocellular foam.213
Palladium has been incorporated within a bimetallic
heterodimer with magnetite using thermal decomposition.214
Discerning whether
the catalyst behaves in a homogeneous or heterogeneous manner is difficult and
complex.208
In many cases, heterogeneous catalyst precursors are used, but
leaching to homogeneous species215
(e.g. soluble nanoparticles) is likely,
although both in some cases212b,213
have good evidence for a heterogeneous
pathway in Pd-catalysed DA reactions. However, in both cases, recycling of the
catalyst was not possible (Pd/C and PD/mesocellular foam respectively). Other
heterogeneous systems used are based on copper,216
nickel217
and TiO2.218
Even a
transition-metal-free arylation methodology has been reported with similar
overall objectives.219
We thought that impregnated palladium on magnetite
catalyst fitted all requirements.
207 J. Ross in Heterogeneous Catalysis Fundamentals and Applications, Elsevier, Amsterdam,
2012. 208 R. Cano, A. F. Schmidt, G. P. McGlacken, Chem. Sci. 2015, 6, 5338-5346. 209 a) L. Djakovitch, V. Dufaud, R. Zaidi, Adv. Synth. Catal. 2006, 348, 715-724; b) G. Cusati, L.
Djakovitch, Tetrahedron Lett. 2008, 49, 2499-2502. 210 a) L. Wang, W.-B. Yi, C. Cai, Chem. Commun. 2011, 47, 806-808.; b) J. Areephong, A. D.
Hendsbee, G. C. Welch, New J. Chem. 2015, 39, 6714-6717. 211 Y. Huang, Z. Lin, R. Cao, Chem. Eur. J. 2011, 17, 12706-12712. 212 a) D.-T. D. Tang, K. D. Collins, F. Glorius, J. Am. Chem. Soc. 2013, 135, 7450-7453; b) D.-T.
D. Tang, K. D. Collins, J. B. Ernst, F. Glorius, Angew. Chem. Int. Ed. 2014, 53, 1809-1813; c)
K. D. Collins, R. Honeker, S. Vásquez-Céspedes, D.-T. D. Tang, F. Glorius, Chem. Sci. 2015,
6, 1816-1824; d) S. Hayashi, Y. Kojima, T. Koizumi, Polym. Chem. 2015, 6, 881-885. 213 J. Malmgren, A. Nagendiran, C.-W. Tai, J.-E. Bäckvall, B. Olofsson, Chem. Eur. J. 2014, 20,
13531-13535. 214 J. Lee, J. Chung, S. Moon Byun, B. Moon Kim, C. Lee, Tetrahedron 2013, 69, 5660-5664. 215 C. G. Baumann, S. De Ornellas, J. P. Reeds, T. E. Storr, T. J. Williams, I. J. S. Fairlamb,
Tetrahedron 2014, 70, 6174-6187. 216 a) W. Zhang, Q. Zeng, X. Zhang, Y. Tian, Y. Yue, Y. Guo, Z. Wang, J. Org. Chem. 2011, 76,
4741-4745. b) W. Zhang, Y. Tian, N. Zhao, Y. Wang, J. Li, Z. Wang, Tetrahedron 2014, 70,
6120-6126; c) S. Keshipour, A. Shaabani, Appl. Organometal. Chem. 2014, 28, 116-119; d) H.
T. N. Le, T. T. Nguyen, P. H. L. Vu, T. Truong, N. T. S. Phan, J. Mol. Catal. A: Chem. 2014,
391, 74-82. 217 N. T. S. Phan, C. K. Nguyen, T. T. Nguyen, T. Truong, Catal. Sci. Technol. 2014, 4, 369-377. 218 J. Zoeller, D. C. Fabry, M. Rueping, ACS Catal. 2015, 5, 3900-3904. 219 H. Liu, B. Yin, Z. Gao, Y. Li, H. Jiang, Chem. Commun. 2012, 48, 2033-2035.
129 Chapter IV. Reactions performed by nanoparticles of Palladium
1.2 RESULTS
1.2.1 DIRECT ARYLATION OF HETEROCYCLES
To start with the arylation study, benzothiophene (34a) and diphenyliodonium
tetrafluoroborate (35a) in bio-renewable ethanol as solvent was chosen as a
model for the optimization of the reaction conditions (Table 25). Our first
attempt gave the corresponding arylated heterocycle (36a) after 24 h, and
arylation occurred selectively at C3-position but in low yield (entry 1). Increasing
the equivalents of 35a, gave a small increase in yield (entries 2 and 3). A
reduction of palladium loading (3 mol%), led to a lower conversion (entry 4) and
an increase of catalyst (10 mol%) improved the yield (entry 5).
Table 25. Optimization of the reaction conditions.a
Entry 35a (mol%) Solvent T (ºC) Pd (mol%) Yield (%)
b
1 110 EtOH 80 6 22
2 220 EtOH 80 6 45
3 300 EtOH 80 6 31
4 220 EtOH 80 3 11
5 220 EtOH 80 10 59
6 300 EtOH 80 10 62
7 300 EtOH 100 10 65
8 300 EtOH 60 10 71
9 300 EtOH 40 10 39
10 300 EtOH 25 10 0
11 300 1,4-Dioxane 60 10 0
12 300 H2O 60 10 0
13 300 PhMe 60 10 0
14c
300 EtOH 60 0 0 a
Reaction carried out using compound 34a (0.5 mmol), 35a (0.6 mmol), in 1.5 mL of
solvent, unless otherwise stated. b Isolated yield after column chromatography.
c Reaction performed in absence of catalyst.
With the optimised catalyst loading in hand, the amount of iodonium salt was
modified (entry 6). The yield of 36a was increased to 62 % with the addition of 3
Chapter IV. Reactions performed by nanoparticles of Palladium 130
equivalents of the salt. The temperature effect was evaluated at this point.
Increasing the temperature to 100 ºC only gave a slightly higher yield (entry 7).
However, the best yield was obtained at 60 ºC (entry 8). Unfortunately, it was not
possible to reduce the temperature without a significant reduction in yield
(entries 9 and 10). The impact of the solvent was evaluated (entries 11-13). The
reaction failed in 1,4-dioxane, water and toluene. Finally, with the best
conditions in hand, the reaction was performed in the absence of catalyst (entry
14). Only starting material was recovered, confirming the catalytic role of the
palladium on magnetite.
Once the best reaction conditions for this process were found, a number of
impregnated metal catalysts were tested (Table 26). Only the palladium on
magnetite showed high activity. However, the bimetallic palladium-copper
catalyst did give a small amount of arylated product (entry 10). Finally, the
reaction was also performed using Pd-free magnetite nanoparticles to confirm the
role of Pd, and no product was observed.
Table 26. Optimization of catalyst.a
Entry Catalyst (mol%) Yield (%)
b
1 Micro-Fe3O4 (259) 0
2 Nano-Fe3O4 (259) 0
3 CoO-Fe3O4 (5.7) 0
4 NiO-Fe3O4(4.1) 0
5 CuO-Fe3O4 (3.5) 0
6 Rh2O3-Fe3O4 (1.7) 0
7 Ag2O/Ag-Fe3O4 (5.0) 0
8 OsO2-Fe3O4 (2.1) 0
9 Au2O3/Au-Fe3O4 (0.6) 0
10 PdO/Cu-Fe3O4 (6.1/3.5) 8
11 NiO/Cu-Fe3O4 (3.6/3.5) 0
12 WO3-Fe3O4(2.3) 0 a Reaction carried out using 34a (0.5 mmol), and 35a (1.5 mmol).
b Isolated yield after column chromatography.
The optimised protocol was then applied to other prominent heterocycles
(Table 27). When benzofuran was used as substrate, the arylated product was
131 Chapter IV. Reactions performed by nanoparticles of Palladium
isolated in an excellent yield (99 %, entry 1). The reaction was completely
regioselective at the C2 position. Indoles containing electron-withdrawing
substituents coupled well (entries 2-4), affording the arylated products in yields
from 58 to 83 % and there was no problems associated with the presence of free
NH groups in this compounds. For all the indoles tried, the arylation took place at
the C-2 position selectively.
Table 27. Substrate scope: arylation of different heterocycles.a
Entry X R Product Yield (%)
b
1 O H 36b 99
2 NH 7-CO2Me 36c 83
3 NH 5-F 36d 79
4 NH 4-Br 36e 58 a
Reaction carried out using the corresponding heterocycle 34 (0.5 mmol), and 35a (1.5
mmol). b Isolated yield after column chromatography.
The use of other iodonium salts was also studied (Table 28). Chemoselective
arylation could be performed by introducing a non-transferable aryl group such
as 2,3,5-triisopropylphenyl (TRIP).212b,213
Table 28. Substrate scope: use of different diaryliodonium salts.a
Entry X Ar
1 Ar
2 Ar
2 position Product Yield (%)
b
1 S TRIP 4-MeC6H4 C3 36f 38
2 O TRIP 4-MeC6H4 C2 36g 71
3 O TRIP 2-MeC6H4 C2 36h 66
4 O TRIP 4-ClC6H4 C2 36i 55
5 O 4-MeOC6H4 4-MeOC6H4 C2 36j 84 a
Reaction carried out using the corresponding heterocycle 34 (0.5 mmol), and 35 (1.5
mmol). b Isolated yield after column chromatography.
Chapter IV. Reactions performed by nanoparticles of Palladium 132
Using this approach, an arylated benzothiophene was isolated in low yield
(entry 1). Better yields were obtained using benzofuran and methyl phenyl
groups (entries 2 and 3). An electron-poor aryl group was also shown to be a
suitable substrate (entry 4). Finally, and electron-rich aryl moiety was
transferred, this time using a symmetrical iodonium salt (entry 5). The catalyst
gave excellent regioselectivity in all the cases (arylation of benzofuran at C2-
position and thiophene at C3-position).
The protocol was then extended to the arylation of simple thiophenes under
the same reaction conditions (Table 29). Using thiophenes, the process was not as
high yielding or selective as with previous substrates and a mixture of the mono-
and di-arylated heterocycles was obtained in 39 % overall yield (entry 1).
Table 29. Substrate scope: arylation of thiophenes.a
Entry R Product Yield (%)
b
1 H 38a 39
2 2-Cl 38b 34
3 2-Br 38c 18
4 3-Br 38d 51
5
38e 48
a Reaction carried out using the corresponding heterocycle 37 (0.5 mmol), 35a (1.5
mmol). b Isolated yield after column chromatography.
Using 2-chlorothiophene the reaction reached 34 % of the mono-arylated
product (entry 2, Table 29). With 2-bromothiophene, only 18 % of the mono-
arylated heterocycle was recovered, (entry 3). Better yield was obtained with the
3-bromothiophene (entry 4). In both cases the bromine remained intact, allowing
for further functionalisation. Finally, 2,2’-bithiophene gave the corresponding
monoarylated product selectively in 48 % yield (entry 5).
Once the substrate scope was evaluated, the recyclability of the catalyst was
tested. After a standard reaction using benzofuran as heterocycle, the catalyst was
retained in the reaction vessel using a magnet and washed several times with
133 Chapter IV. Reactions performed by nanoparticles of Palladium
ethanol. The vessel was then charged with a new set of reagents and the standard
conditions applied. The corresponding product 36b was obtained in 49 % yield
after the second cycle, and 18 % after third. These results show deactivation of
the catalyst. While others have shown that heterogeneous catalysis and
recyclability can prove mutually exclusive, no examinations of the reasons for
deactivation have been proposed in these systems. We sought to examine the
catalyst structure before and after the reaction. TEM analysis showed that fresh
(Figure 34a) and recycled (Figure 35a) particles displayed a similar appearance.
Also no sinterization of the particles could be observed after the reaction.
Additionally, both fresh and recycled catalyst particles showed an identical
particle-size distribution (Figures 34b and 35b).
0
5
10
15
20
25
30
Par
ticl
es
Particle size (nm)
Figure 34. a) TEM image of fresh palladium catalyst. b) Palladium particle size
distribution of fresh catalysts.
a)
b)
Chapter IV. Reactions performed by nanoparticles of Palladium 134
0
50
100
Par
ticl
es
Particle size (nm)
Figure 35. a) TEM image of recycled palladium catalyst. b) Palladium particle
size distribution of recycled catalysts.
XPS analysis of the catalyst did not show any change in the oxidation state of
the palladium on the magnetite surface. The XPS spectra of the recycled catalyst
showed, after deconvolution, two peaks at 337.0 and 342.1 eV, which correspond
to the binding energies of PdO 3d5/2 and PdO 3d3/2, respectively. The spectra
were identical to that taken from the catalyst before reaction (Figure 36). Thus
we cannot attribute deactivation of the catalyst to an oxidation change at the
surface.220
220 G. Collins, M. Schmidt, C. O’Dwyer, J. D. Holmes, G. P. McGlacken, Angew. Chem. Int. Ed.
2014, 53, 4142-4145.
a)
b)
135 Chapter IV. Reactions performed by nanoparticles of Palladium
-100
1900
3900
5900
7900
9900
11900
330 335 340 345
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Fit
3d 5/2 PdO
3d 3/2 PdO
-100
900
1900
2900
3900
4900
5900
6900
7900
8900
330 332 334 336 338 340 342 344 346 348
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Fit
PdO 3d 5/2
PdO 3d 3/2
Figure 36. XPS of a) fresh catalyst and b) recycled catalyst.
We then hypothesised that leaching of the Pd from the support might be
occurring, rendering the insoluble catalyst framework inactive, when reused. The
phenomenon of leaching was studied by ICP-MS. Here, the reaction mixture was
filtered hot after the reaction and the homogeneous solution was tested by
dissolved Pd. Only 1.95 % of the initial amount of palladium was detected. This
amount seems insufficient to explain the deactivation given the lower turnover
numbers observed when lower Pd loading was used (Table 25). The inability of
the solution phase to catalyse the arylation of benzofuran was confirmed by
observation of the reaction progress after filtration. Thus, after two hours, the
catalyst was filtered hot. No reaction progress was observed after this point
confirming that no active species were solubilised under the reaction conditions.
The above tests point strongly to heterogeneous catalysis, in line with the
conclusion previously reported in the arylation of 2-butylthiophene.212b
Clearly, if leaching is ruled out, some change, which deactivates the catalyst,
must occur at the surface.221
XRF was then used to gain further insight at the
catalyst surface. More specifically, 5.4 % of iodine was detected at the catalyst
surface. The adsorbance of halides on the surface of Pd catalysts has previously
been shown to affect the activity of heterogeneous catalysts and we believe this
to be this case here also.222
221 J. Pal, T. Pal, Nanoscale 2015, 7, 14159-14190. 222 a) E. J. A. X. van de Sandt, A. Wiersma, M. Makkee, H. van Bekkum, J. A. Moulijn, Appl.
Catal. A Gen. 1998, 173, 161-173; b) F. J. Urbano, J. M. Marinas, J. Mol. Catal. A Chem. 2001,
173, 329-345; c) P. Kar, B. G. Mishra, J. Clust. Sci. 2014, 25, 1463-1478.
a) b)
Chapter IV. Reactions performed by nanoparticles of Palladium 136
1.2.2 INTRAMOLECULAR DIRECT ARYLATION
Encouraged by the success that obtained in the direct arylation of
heterocycles, we decided to apply palladium on magnetite to an intramolecular
arylation.204d,223
A different mechanism is operative here and thus application to
this reaction would give a good indication of the broad utility of the catalyst. The
intramolecular arylation of haloether 39a to obtain the corresponding chromene
40a (Table 30) as a suitable reaction was chosen for this study.
Table 30. Optimization of the reaction conditions.a
Entry Base (mol%) Solvent T (ºC) Pd (mol%) Yield (%)
b
1 KOAc (200) DMA 140 0.1 5
2 KOAc (200) DMA 140 1 9
3 KOAc (200) DMA 140 2 20
4 KOAc (200) DMA 140 5 61
5 KOAc (200) DMA 140 10 85
6 KOAc (200) DMA 140 15 77
7 KOAc (100) DMA 140 10 64
8 KOAc (300) DMA 140 10 71
9 KOH (200) DMA 140 10 5
10 NaOH (200) DMA 140 10 0
11 NaOAc (200) DMA 140 10 56
12 K2CO3 (200) DMA 140 10 0
13 KOAc (200) PhMe 140 10 0
14 KOAc (200) DMF 140 10 74
15 KOAc (200) t-BuOK 140 10 25
16 KOAc (200) DMA 160 10 75
17 KOAc (200) DMA 120 10 63
18c
KOAc (200) DMA 140 0 0 a
Reaction carried out using compounds 39a (0.5 mmol), and KOAc (1 mmol), in 2 mL
of solvent, unless otherwise stated. b Isolated yield after column chromatography.
c Reaction performed in absence of catalyst.
223 L. Campeau, K. Fagnou, Chem. Commun. 2006, 1253-1264.
137 Chapter IV. Reactions performed by nanoparticles of Palladium
Firstly, the optimum catalyst loading was established (entry 1-6). Again 10
mol% of Pd was needed to obtain the best chemical yield (entry 5). Then the
effect of the base was tested (entries 7-12). When one equivalent of base was
used the yield of 40a was reduced (entry 7). The addition of 3 equivalents was
not beneficial for the cyclisation process (entry 8). Different bases were tried, but
none were as efficient as KOAc (entries 9-12). The impact of the solvent was
studied (entries 13-15). Only DMF gave a comparable yield, but was slightly
lower to the one obtained with N,N-dimethylacetamide (DMA). Finally, the
temperature was modified. Neither a higher, nor lower temperature gave better
yields (entries 16 and 17). As a control test, the reaction was performed in the
absence of catalyst under the optimised conditions (entry 18). Only starting
material was recovered confirming the role of palladium in this process.
The best reaction conditions were then applied to different substrates to
evaluate the reaction scope (Table 31). First we studied the tolerance of
substituents on the phenoxy group. The presence of a methoxy group was
tolerated with only a small detriment in yield (entry 2).
Table 31. Scope of the reaction.a
Entry R
1 R
2 R
3 Product Yield (%)
b
1 H H H 40a 85
2 H H 4-MeO 40b 75
3 H H 4-Me 40c 86
4 H H 4-Cl 40d 93
5 H H 4-F 40e 92
6 H H 3-F 40f 89c
7 H H 2-F 40g 87
8 H CF3 H 40h 84
9 F H H 40i 77 a Reaction carried out using compounds 39 (0.5 mmol), KOAc (1 mmol).
b Isolated yield after column chromatography.
c A mixture of isomers was obtained: 1-Fluoro-6H-benzo[c]chromene (40f) and 3-
Fluoro-6H-benzo[c]chromene (40f’) (45:55).
Good yield was obtained with methyl substituent at the 4-position of the ring
(entry 3). The introduction of electron-withdrawing groups had a beneficial effect
Chapter IV. Reactions performed by nanoparticles of Palladium 138
on the process, and excellent yields were achieved (entries 4 and 5). Then, the
effect of substitution on the benzyloxy group was evaluated. Similarly good
results were obtained using electron-withdrawing groups (entries 5-7), although a
mixture of regioisomers was obtained when a F substituent at the meta-position
was presented. Little impact on the yield was observed on substitution on the
halo-aryl either, and very good yields were observed (entries 8 and 9).
The recyclability of the catalyst was also investigated in this case. In a similar
way to the intermolecular reaction, the catalyst was removed using a magnet and
reused using the standard reaction conditions (see Table 30, entry 5). Again
deactivation of the catalyst was observed. This time no product was detected
after the second cycle of reaction. ICP-MS analysis of the reaction solution
showed 3.3 % of the initial palladium was leached.
XPS analysis also showed a distinctive change and four peaks were observed
(Figure 37). Two peaks at 336.9 and 342.2 eV, correspond to the binding
energies of PdO 3d5/2 and PdO 3d3/2, respectively. The two other peaks at 334.9
and 340.1 eV, correspond to the binding energies of PdO 3d5/2 and PdO 3d3/2,
respectively. The ratio between the two oxidation states was Pd:PdO 2:1. Clearly
some reduction of the PdO species had occurred perhaps forming inactive Pd-
black aggregates.
-100
400
900
1400
1900
2400
330 332 334 336 338 340 342 344 346
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Fit
Pd 3d 5/2
PdO 3d 5/2
Pd 3d 3/2
PdO 3d 3/2
Figure 37. XPS of recycled catalyst.
139 Chapter IV. Reactions performed by nanoparticles of Palladium
Recycled TEM analysis revealed that a substantial sintering of palladium
nanoparticles had occurred (compare Figure 34 and Figure 38).
0
20
40
60
Par
ticl
es
Particle size (nm)
Figure 38. a) TEM image of recycled palladium catalyst. b) Palladium particle
size distribution of recycled catalysts.
The hot filtration test determined that no reaction progress occurred after
filtration. Thus, we believe that changes in the oxidation state of Pd during the
reaction renders the recovered Pd/magnetite unable to catalyse subsequent
reactions. Thus in an attempt to recycle the catalyst, recycled particles of
palladium were subjected to oxygen (bubbling O2). Using this protocol, the re-
generation of the palladium(II) oxide nanoparticles was impossible. Other
oxidants like I2 or t-BuOOH were tested giving the same result.
a)
b)
Chapter IV. Reactions performed by nanoparticles of Palladium 140
2. SYNTHESIS OF 4-ARYLCOUMARINS THROUGH THE HECK-
ARYLATION/CYCLIZATION REACTION
2.1 INTRODUCTION
The Heck reaction224
is a powerful and general synthetic method used in
Organic Chemistry to construct compounds by C-C bond formation. Its synthetic
flexibility and compatibility with most organic functional groups makes it one of
the most explored reaction promoted by palladium.225
Some efforts have been
devoted to improve the efficiency of this reaction, and recently, iodonium salts226
have been extensively studied as arylation agent to replace aryl halides or triflates
in the Heck reaction. They are appealing coupling partners as they display
different reactivity profiles to halides, are highly reactive yet air- and moisture-
stable, and can be easily prepared in one step from commercially available
starting materials.227
Coumarins228
are important structural motifs in natural compounds and
exhibit broad biological activity. Particularly, 4-aryl derivatives constitute a
subgroup of flavonoids that have received considerable attention, as they display
important biological activities such as anti-HIV, antimalarial, antibacterial and
cytotoxic properties. Classical synthetic approaches for the synthesis of 4-
arylcoumarins are based on Knoevenagel condensation,229
cross-coupling
reactions,230
C-H bond activation,154,208,231
von Pechman condensation,232
among
224 a) R. F. Heck, Acc. Chem. Res. 1979, 12, 146-151; b) A.-L. Lee, Org. Biomol. Chem. 2016,
DOI: 10.1039/c5ob01984b. 225 a) P. Prediger, A. R. da Silva, C. R. D. Correia, Tetrahedron Lett. 2014, 70, 3333-3341; b) D.
H. Ortgies, A. Hassanpour, F. Chen, S. Woo, P. Forgione, Eur. J. Org. Chem. 2016, 408-425. 226 a) R. M. Moriarty, W. R. Epa, A. K. Awasthi, J. Am. Chem. Soc. 1991, 113, 6315-6317; b) M.
Zhu, Y. Song, Y. Cao, Synthesis 2007, 853-856; c) J. Aydin, J. M. Larsson, N. Selander, K. J.
Szabó, Org. Lett. 2009, 11, 2852-2854; d) R. J. Phipps, L. McMurray, S. Ritter, H. A. Duong,
M. J. Gaunt, J. Am. Chem. Soc. 2012, 134, 10773-10776; e) J. Li, L. Liu, Y.-Y. Zhou, S.-N. Xu,
RSC Adv. 2012, 2, 3207-3209; f) N. Gigant, L. Chausset-Boissarie, M.-C. Belhomme, T.
Poisson, X. Pannecoucke, I. Gillaizeau, Org. Lett. 2013, 15, 278-281. 227 a) R. J. Phipps, N. P. Grimster, M. J. Gaunt, J. Am. Chem. Soc. 2008, 130, 8172-8174; b) R. J.
Phipps, M. J. Gaunt, Science 2009, 323, 1593-1597; c) M. Bielawski, M. Zhu, B. Olofsson,
Adv. Synth. Catal. 2007, 349, 2610-2618; d) M. Bielawski, D. Aili, B. Olofsson, J. Org. Chem.
2008, 73, 4602-4607; e) E. A. Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48, 9052-
9070. 228 F. Boeck, M. Blazejak, M. R. Anneser, L. Hintermann, Beilstein J. Org. Chem. 2012, 8, 1630-
1636. 229 J. Crecente-Campo, M. P. Vázquez-Tato, J. A. Seijas, Eur. J. Org. Chem. 2010, 4130-4135. 230 W. Gao, Y. Luo, Q. Ding, Y. Peng, J. Wu, Tetrahedron Lett. 2010, 51, 136-138. 231 Y. Li, Z. Qi, H. Wang, X. Fu, C. Duan, J. Org. Chem. 2012, 77, 2053-2057. 232 H. Wang, Monatsch Chem. 2013, 144, 411-414.
141 Chapter IV. Reactions performed by nanoparticles of Palladium
others.233
In many cases, the reactions were performed under harsh reaction
conditions and high temperatures. The loading of transition metal was, in many
cases, very high (5-20 mol%).
Another methodology to obtain 4-arylcoumarins, that has been less
studied, is the arylation/cyclization of o-hydroxylcinnamates. Initially, this
approach was reported in 2005 using aryl halides in a molten n-Bu4NOAc/n-
Bu4NBr mixture.234
Later on, the approach was modified by the use of aryl
diazonium salts in methanol.235
Finally, diaryliodonium(III) salts have been
successfully used to perform this transformation using dimethylformamide as
solvent.236
In all cases the reaction was performed with the help of high amounts
of the homogeneous Pd(OAc)2 catalyst (5-10 mol%), giving moderate to good
yields. For this reason we thought that impregnated palladium catalyst could be a
promising candidate for the heterogeneous version of the aforementioned
approach.
2.2 RESULTS
To start the study, (E)-ethyl 3-(2-hydroxyphenyl)acrylate (41a) and
diphenyliodonium tetrafluoroborate (35a), using impregnated palladium on
magnetite as catalyst, was selected as the reaction model for the optimization
(Table 32). Initially, the reaction was performed using different equivalents of
compound 35a (entries 1-3). Full conversion of the starting material was
observed after 5 hours when 2 equivalents of the salt were used. This result could
not be improved by increasing the amount of iodonium salt. After that, different
loadings of palladium catalyst were tested (entries 4-7). Good yields were
obtained with 2.5 mol% Pd, with the yield being slightly improved using higher
233 a) B. M. Trost, F. D. Toste, K. Greenman, J. Am. Chem. Soc. 2003, 125, 4518-4526; b) J.
Ferguson, F. Zeng, H. Alper, Org. Lett. 2012, 14, 5602-5605; c) K. Sasano, J. Takaya, N.
Iwasawa, J. Am. Chem. Soc. 2013, 135, 10954-10957; d) P. Shah, M. D. Santana, J. García, J.
L. Serrano, M. Naik, S. Pednekar, A. R. Kapdi, Tetrahedron 2013, 69, 1446-1453; e) M.
Khoobi, F. Molaverdi, M. Alipour, F. Jafarpour, A. Foroumadi, A. Shafiee, Tetrahedron 2013,
69, 11164-11168; f) J. Li, H. Chen, D. Zhang-Negrerie, Y. Du, K. Zhao, RSC Adv. 2013, 3,
4311-4320; g) M. L. N. Rao, A. Kumar, Tetrahedron 2014, 70, 6995-7005; h) P. Niharika, B.
V. Ramulu, G. Satyanarayana, Org. Biomol. Chem. 2014, 12, 4347-4360; i) S. K. Gadekh, S.
Dey, A. Sudalai, J. Org. Chem. 2015, 80, 11544-11550; j) A. M. Escobar, D. M. Ruiz, J. C.
Autino, G. P. Romanelli, Res. Chem. Intermed. 2015, 41, 10109-10123. 234 G. Battistuzzi, S. Cacchi, I. D. Salve, G. Fabrizi, L. M. Parisi, Adv. Synth. Catal. 2005, 347,
308-312. 235 D. A. Barancelli, A. G. Salles Jr., J. G. Taylor, C. R. C. Correia, Org. Lett. 2012, 14, 6036-
6039. 236 Y. Yang, J. Han, X. Wu, S. Xu, L. Wang, Tetrahedron Lett. 2015, 56, 3809-3812.
Chapter IV. Reactions performed by nanoparticles of Palladium 142
amounts of metal. Then, a study of the solvent was performed (entries 8-15). A
moderate yield was obtained in H2O, but best results were observed in bio-
renewable ethanol (entry 5). When the reaction was performed without solvent
(entry 16) only traces of the product could be detected. To complete the
optimization, different temperatures were tried (entries 17 and 18). Only traces of
product were detected at room temperature and full conversion of the starting
material was observed at 80 ºC.
Table 32. Optimization of the reaction conditions.a
Entry Pd (mol%) Solvent T (ºC) Yield (%)
b
1 10 EtOH 60 99
2c
10 EtOH 60 54
3d
10 EtOH 60 99
4 1 EtOH 60 46
5 2.5 EtOH 60 86
6 5 EtOH 60 90
7 7.5 EtOH 60 99
8 2.5 PhMe 60 0
9 2.5 THF 60 0
10 2.5 H2O 60 64
11 2.5 1,4-Dioxane 60 0
12 2.5 DCM 60 0
13 2.5 CH3CN 60 34
14 2.5 DMF 60 48
15 2.5 DMSO 60 10
16 2.5 - 60 15
17 2.5 EtOH 25 7
18 2.5 EtOH 80 99 a Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.5 mmol).
b Yield determined by GC using 0.25 mmol of tridecane as internal standard.
c Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.25 mmol).
c Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.75 mmol).
Once the optimal conditions were determined, the reaction was submitted
to a variety of catalysts, prepared by a simple impregnation protocol85
(Table 33).
The reaction without catalyst did not give any product (entry 2). The partial
143 Chapter IV. Reactions performed by nanoparticles of Palladium
inactivity of the support was confirmed (entries 3 and 4), the role of magnetite is
only to facilitate the easy separation of the reaction media through magnetic
decantation. The inactivity of the support was confirmed (entries 3 and 4). Then,
different metal oxides impregnated on magnetite (entries 5-17) were evaluated as
catalyst, but the high activity displayed by the palladium catalyst could not be
surpassed. With these results in hand, the reaction was carried out using different
sources of palladium, (entries 18-20). All catalysts tested (homogeneous, as well
as heterogeneous) failed to give similar or improved activities relative to
palladium on magnetite (entry 1).
Table 33. Optimization of the catalyst.a
Entry Catalyst (mol %) Yield (%)
b
1 PdO-Fe3O4 (2.5) 99
2 - 0
3 Micro-Fe3O4 (129.9) 10
4 Nano-Fe3O4 (129.9) 11
5 CoO-Fe3O4 (2.8) 17
6 NiO-Fe3O4 (2.1) 0
7 CuO-Fe3O4 (2.3) 0
8 Ru2O3-Fe3O4 (2.6) 25
9 Rh2O3-Fe3O4 (2.5) 25
10 Ag2O/Ag-Fe3O4 (2.5) 4
11 OsO2-Fe3O4 (2.1) 8
12 IrO2-Fe3O4 (2.1) 10
13 PtO/PtO2-Fe3O4 (2.2) 17
14 Au2O3/Au-Fe3O4 (2.3) 0
15 PdO/Cu-Fe3O4 (3.1/1.8) 18
16 NiO/Cu-Fe3O4 (1.8/1.8) 7
17 WO3-Fe3O4 (2.3) 25
18 PdO (2.5) 79
19 PdCl2 (2.5) 83
20 Pd(OAc)2 (2.5) 76 a Reaction carried out using compounds 41a (0.25 mmol), and 35a (0.5 mmol).
b Yield determined by GC using 0.25 mmol of tridecane as internal standard.
Chapter IV. Reactions performed by nanoparticles of Palladium 144
In order to stablish the reusability of the catalyst, the standard reaction
was repeated (Figure 39). When the reaction was completed, the catalyst was
retained in the reaction vessel using a magnet and washed several times with
ethanol. The vessel was then charged with a new set of reagents and the standard
conditions were applied. The corresponding product was obtained with a 39 %
yield after the first cycle indicating that the catalytic activity of the catalyst has
been affected by the first reaction.
0
50
100
01
2
Yiel
d 4
2a
(%)
Cycle
Normal recycling
Re-used catalystafter regenerationby O2 treatment
Figure 39. Recycling of the PdO-Fe3O4 catalyst.
As a consequence of the non-recyclability of the catalyst, some studies
were performed. XPS analysis of the catalyst showed a change in the oxidation
state [Pd(II) to Pd(0)] after completion of the reaction. The XPS spectra of the
recycled catalyst showed, after deconvolution, four peaks at 334.9, 335.7, 340.3
and 341.3 eV, which correspond to the binding energies of Pd 3d5/2 and Pd 3d3/2,
and two more peaks, that have the same binding energy as the starting PdO
nanoparticles, with a relative area of 4 % (Figure 40).
145 Chapter IV. Reactions performed by nanoparticles of Palladium
-50
450
950
1450
1950
2450
2950
330 335 340 345
Inte
nsi
ty/a
rb. U
nit
s
Binding energy (eV)
Fit
Pd 3d 5/2
Pd 3d 5/2
PdO 3d 5/2
Pd 3d 3/2
Pd 3d 3/2
PdO 3d 3/2
Figure 40. XPS of recycled catalyst.
TEM analyses were carried out. A high sinterization of the palladium
nanoparticles as well as dissociation of the palladium particles from the support
after completion of the reaction was observed (Figure 41). The initial size range
of the starting PdO nanoparticles was 2-4 nm but increased to 14-16 nm after the
reaction.
Figure 41. TEM images of recycled palladium catalyst.
The phenomenon of leaching was studied by ICP-MS. Here, the reaction
mixture was filtered at high temperature after completion of the reaction and the
catalytic activity of the homogeneous solution was tested. Only 3.64 % of the
Chapter IV. Reactions performed by nanoparticles of Palladium 146
initial palladium was present in solution. More importantly, no progress of the
reaction was observed in the filtrate after the filtration, providing further
evidence of the heterogeneous nature of the reaction.
Finally, a modified hot filtration test was performed. Thus, after the
standard reaction, the mixture was decanted with the aid of a magnet, while hot,
and a mixture of 41c (0.25 mmol) and 35a (0.5 mmol) dissolved in 0.75 mL of
ethanol, was added to the filtrate. After five hours at 80 ºC, the product 42a
(heterogeneous catalysed system), as well as the aforementioned starting
reagents, were detected.
The TPR and TPO analyses of Fe3O4, fresh and recycled catalyst
were carried out (Figure 42). Previously to analyses, the samples were pre-treated by heating at 200 ºC under Argon atmosphere to be sure that all the organic material was removed. Then, the samples were heated to 900 ºC at 10 ºC/min in the corresponding atmosphere [TPR was performed with a mixture Ar/H2 (1.8 %), and TPO with a mixture Ar/O2 (3%)].
Figure 42. a) TPR and b) TPO analysis. In the case of differential thermogravimetric analysis under
reductive atmosphere (Figure 43a), when the temperature reached 100 ºC only the fresh catalyst sample showed a consumption of hydrogen and an emergence of H2O (Figure 44), what it could be assigned to the reduction from PdO to Pd(0). At 300 ºC a new consumption of H2 could be observed and it seems to be due to the reduction of superficial magnetite. In the case of both magnetite support and recycled catalyst, only this last consumption of hydrogen was detected. It should be pointed out that in the case of the supported catalyst the reduction of superficial magnetite took places at lower temperatures, probably by the influence of the supported palladium.
0 200 400 600 800 1000
%
T (ºC)
Fe3O4
Fresh PdO-Fe3O4
Recycled PdO-
Fe3O4
a) b)
147 Chapter IV. Reactions performed by nanoparticles of Palladium
Figure 43. a) DTPR and b) DTPO analysis. From the data of differential thermogravimetric analysis under
reductive atmosphere it could be calculated the expected weight losing due to a PdO to Pd(0) transformation, with this figure being slightly higher than the nominal palladium. This could be due to the reduction through a spill-over of hydrogen to the support of magnetite units that are in intimate contact with palladium.
Figure 44. MS analysis on fresh catalyst under reductive conditions.
In the case of differential thermogravimetric analysis under oxidative
atmosphere (Figure 43b), only the recycled sample showed a weight losing at
about 400 ºC. The analysis showed the loss of CO2 and then iodine in the case of
recycled catalyst (Figure 45). The emergence of CO2 should be associated to
organic compounds strongly bounded to the catalyst surface; meanwhile the
emergence of iodine could be a hindered proof of the poisoning of palladium
species by this element.
-0,00005
0,00045
0,00095
0,00145
0,00195
0,00245
0 200 400 600 800 1000
mg·s
-1
T (ºC)
Fe3O4
Fresh PdO-Fe3O4
Recycled PdO-Fe3O4
-9,00E-04
-6,00E-04
-3,00E-04
0,00E+00
3,00E-04
6,00E-04
0 200 400 600 800
mg·s
-1
T (ºC)
Fe3O4
Fresh PdO-Fe3O4
Recycled PdO-Fe3O4
0 50 100 150 200 250 300 350
Ms
sign
al (
arb
. U
nit
s)
T (ºC)
H2O
0 50 100 150 200 250 300 350
MS
sig
nal
(ar
b. U
nit
s)
T (ºC)
H2
a) b)
Chapter IV. Reactions performed by nanoparticles of Palladium 148
Figure 45. MS analysis on recycled catalyst under oxidative conditions.
Guided by the previously mentioned XPS, as well as TPR and TPO
analysis, we attribute the deactivation of the catalyst to an almost complete
reduction of the nanoparticles of palladium(II) oxide to palladium(0), and/or the
associated morphologic changes and the poisoning by iodine species. Thus, in an
attempt to recycle the catalyst, the recycled catalyst was subjected to oxygen
(bubbling O2, see Figure 39). Using this protocol, the results obtained for the
recycling of the catalyst were improved but did not reach the initial catalyst
activity. Other oxidants tested (e.g. t-BUOOH or I2) gave poorer results.
Once the best conditions were established, the scope of the reaction was
evaluated (Table 34). Moderate yields could be obtained using symmetrical
bis(4-fluorophenyl)iodonium tetrafluoroborate (entry 2). Better results were
observed, with symmetrical bis(4-methoxyphenyl)iodonium tetrafluoroborate
giving 77 % yield (entry 3). Chemoselective Heck-arylation/cyclization reactions
were performed by introducing a non-transferable aryl group such as 1,3,5-
triisopropylphenyl (TRIP). Good results were observed with substrates bearing
electron-withdrawing and sterically hindered electron-donating groups (entries 4
and 5).
Then various substituted o-hydroxyphenylacrylates were tested (entries
6-8). Better results were found with the sterically hindered (E)-ethyl 3-(3,5-di-
tert-butyl-2-hydroxyphenyl)acrylate. The presence of electron-withdrawing
groups at the 5-position in the aromatic ring of the acrylate seemed to affect
negatively the reaction. The use of substituted acrylates and diaryliodonium
tetrafluoroborates gave very good yields in all cases (entries 9-11). To finish with
the study, different diaryliodonium trifluoromethanesulfonates were tested,
which gave moderate to good results (entries 12-14). In the case of phenyl(2,4,6-
triisopropylphenyl)iodonium trifluoromethanesulfonate (entry 12), the expected
product 42a was obtained with lower yield than that obtained with the previously
0 200 400 600 800 1000
MS
sig
nal
(ar
b. U
nit
s)
T (ºC)
Iodine
0 200 400 600 800 1000
MS
sig
nal
(ar
b. U
nit
s)
T (ºC)
CO2
149 Chapter IV. Reactions performed by nanoparticles of Palladium
tested diphenyliodonium tetrafluoroborate (entry 1). Others aryl sources were
ineffective under similar reaction conditions.237
Table 34. Scope of the reaction.a
Entry R
1 R
2 X Ar
1 Ar
2 Product Yield (%)
b
1 H H BF4 Ph Ph 42a 98
2 H H BF4 4-FC6H4 4-FC6H4 42b 40
3 H H BF4 4-MeOC6H4 4-MeOC6H4 42c 77
4 H H BF4 4-ClC6H4 TRIP 42d 64
5 H H BF4 2-MeC6H4 TRIP 42e 55
6 F H BF4 Ph Ph 42f 72
7 t-Bu t-Bu BF4 Ph Ph 42g 97
8 Br OMe BF4 Ph Ph 42h 56
9 F H BF4 4-MeOC6H4 4-MeOC6H4 42i 70
10 t-Bu t-Bu BF4 4-FC6H4 4-FC6H4 42j 79
11 Br OMe BF4 4-FC6H4 4-FC6H4 42k 95
12 H H OTf Ph TRIP 42a 66
13 H H OTf 4-MeC6H4 4-MeC6H4 42l 52
14 Br OMe OTf 4-MeC6H4 4-MeC6H4 42m 91 a Reaction carried out using compounds 41 (0.25 mmol), and 35 (0.5 mmol).
bIsolated yield after column chromatography.
Once the scope of the reaction was evaluated, the possible pathway of the
process was studied. The reaction could occur through a cyclization reaction
followed by an arylation238
or through a Heck-arylation reaction and a subsequent
cyclization. To check if the reaction took place following the first process, the
cyclization reaction of (E)-ethyl 3-(2-hydroxyphenyl)acrylate (41a) using ethanol
at 80 °C was tested. Here, the starting material was recovered unchanged. We
237 Reaction performed using 2 equivalents of other arylation agents (phenyl boronic acid, 4-
bromoanisole, 4-methoxybenzenediazonium tetrafluoroborate) under the standard conditions
failed to give the corresponding product. 238 a) M.-T. Nolan, J. T. W. Bray, K. Eccles, M. S. Cheung, Z. Lin, S. E. Lawrence, A. C.
Whitwood, I. J. S. Fairlamb, G. P. McGlacken, Tetrahedron 2014, 70, 7120-7127; b) M.-T.
Nolan, L. M. Pardo, A. M. Prendergast, G. P. McGlacken, J. Org. Chem. 2015, 80, 10904-
10913; c) L. M. Pardo, A. M. Prendergast, M.-T. Nolan, E. Ó. Muimhneacháin, G. P.
McGlacken, Eur. J. Org. Chem. 2015, 3450-3550.
Chapter IV. Reactions performed by nanoparticles of Palladium 150
gained access to the cyclised product using an n-Bu3P mediated reaction.228
When the resulting 2H-chromen-2-one was treated with salt 35a and PdO-Fe3O4
under standard conditions, only starting chromenone was recovered. These
results suggest that the cyclization/arylation pathway is unlikely. To further study
if the Heck-arylation reaction took place first, followed by cyclization (Scheme
29), some acrylates 43, no longer possessing the required hydroxyl group needed
for cyclization, were tested under the optimal reaction conditions (Table 35).
Scheme 29. Possible mechanism of the reaction.
Using two equivalents of 35a, a 3:1 mixture of the mono- and di-
substituted products 44 were obtained in good yield (entry 1). With these results
in hand, the reaction was repeated with only one equivalent of the salt 35a. A
lower amount of the di-substituted product 44b was obtained, along with
concomitant improvement in the yield of 44a (entry 2). Then, methyl cinnamate
(43b) was tested and 68 % yield of 44c was obtained (entry 3). To finish with the
study of the Heck-arylation, different substituents at the 4-possition of the
aromatic ring of starting cinnamate were used, obtaining a ca. mixture 1:1 of Z/E
isomers in good yields (entries 4 and 5).
151 Chapter IV. Reactions performed by nanoparticles of Palladium
Table 35. Heck-arylation reaction.a
Entry R
1 R
2 Product Yield (%)
b
1 H Et 44a 76 (23)c
2d
H Et 44a 86 (13)c
3 Ph Et 44b 68
4 4-MeC6H4 Me 44c 71 (Z/E 0.95/1)
5 4-MeOC6H4 Me 44d 69 (Z/E 1/0.8) a Reaction carried out using compounds 43 (0.25 mmol), and 35a (0.5 mmol).
b Isolated yield after bulb-to-bulb distillation.
c Isolated yield of compound 44b.
d Reaction carried out using compounds 43 (0.25 mmol), and 35a (0.25 mmol).
All these findings seem to suggest that the mechanism follows the
pathway described in Scheme 29. Thus, the initial Heck reaction favors the final
cyclization process.
CHAPTER V
Reactions without catalyst
155 Chapter V. Reactions without catalyst
1. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLES AND
ISOXAZOLINES IN DEEP EUTECTIC SOLVENTS
1.1 INTRODUCTION
Isoxazoles and related 4,5-dihydroisoxazoles are a valuable and well
established239
class of heterocyclic compounds240
with broad applications,241
as
pharmaceutical and agricultural compounds due to their activities.242
Numerous synthetic approaches for the construction of the isoxazole
and 4,5-dihydroisoxazole framework have been reported. There are two main
methodologies: the first approach involves the condensation of hydroxylamine
with 1,3-dicarbonyl compounds or their three-carbon 1,2-electrophilic variants,
such as α,β-unsaturated ketones, enamino ketones, β-alkylthioenones, and
ynones. The second one is the 1,3-dipolar cycloaddition reaction between alkynes
or alkenes with nitrile oxides, generated in situ from aldoximes or nitroalkanes.243
239 a) A. Padwa in Comprehensive Organic Synthesis, ch. 4.9; Vol. 4 (Eds.: B. M. Trost, I.
Fleming), Pergamon Press, Oxford, 1991, pp. 1069-1105; b) M. Sutharchanadevi, R. Murugan
in Comprehensive Heterocyclic Chemistry II, ch. 3.03; Vol. 4 (Eds.: A. R. Katritzky, C.
W.Rees, E. F. V. Scriven), Pergamon Press, Oxford, 1996, pp. 221-234; c) B. J. Wakefield in
Science of Synthesis, ch. 9; Vol. 11 (Eds.: E. Schaumann), Georg Thieme Verlag, Stuttgart,
2002, pp. 229-288; d) T. M. V. D. Pinho e Melo, Curr. Org. Chem. 2005, 9, 925-958. 240 A. I. Kotyatkina, V. N. Zhabinsky, V. A. Khripach, Russ. Chem. Rev. 2001, 70, 641-653. 241 a) G. Lopopolo, F. Fiorella, M. de Candia, O. Nicolotti, S. Martel, P.-A. Carrupt, C. Altomare,
Eur. J. Pharm. Sci. 2011, 42, 180-191; b) S. Levent, B. Çalişkan, M. Çiftçi, Y. Özkan, I.
Yenicesu, H. Ünver, E. Banoglu, Eur. J. Med. Chem., 2013, 64, 42-53. 242 a) S. Castellano, D. Kuck, M. Viviano, J. Yoo, F. López-Vallejo, P. Conti, L. Tamborini, A.
Pinto, J. L. Medina-Franco, G. Sbardella, J. Med. Chem. 2011, 54, 7663-7677; b) M. Ruthu, Y.
Pradeepkumar, C. M. Chetty, G. Prasanthi, V. J. S. Reddy, J. Global Trend Pharm. Sci. 2011,
2, 55-62; c) K. A. Kumar, P. Jayaroopa, Int. J. Pharm. Chem. Biol. Sci. 2013, 3, 294-304; d)
K.-Y. Dong, H.-T. Qin, X.-X. Bao, F. Liu, C. Zhu, Org. Lett. 2014, 16, 5266-5268. 243 a) T. Sugiyama, Appl. Organomet. Chem. 1995, 9, 399-411; b) Y. Basel, A. Hassner, Synthesis
1997, 3, 309-312; c) G. Giacomelli, L. De Luca, A. Porcheddu, Tetrahedron 2003, 59, 5437-
5440; d) L. Cecchi, F. De Sarlo, F. Machetti, Tetrahedron Lett. 2005, 46, 7877-7879; e) L.
Cecchi, F. De Sarlo, C. Faggi, F. Machetti, Eur. J. Org. Chem. 2006, 3016-3020; f) L. Cecchi,
F. De Sarlo, F. Machetti, Eur. J. Org. Chem. 2006, 4852-4860; g) F. Machetti, L. Cecchi, E.
Trogu, F. De Sarlo, Eur. J. Org. Chem. 2007, 4352-4359; g) L. Cecchi, F. De Sarlo, F.
Machetti, Chem. Eur. J. 2008, 14, 7903-7912; h) J. A. Burkhard, B. H. Tchitchanov, E. M.
Carreira, Angew. Chem. Int. Ed. 2011, 123, 5491-5494; i) K.-I. Itoh, T. Aoyama, H. Satoh, Y.
Fujii, H. Sakamaki, T. Takido, Tetrahedron Lett. 2011, 52, 6892-6895; j) E. Trogu, C.
Vinattieri, F. De Sarlo, F. Machetti, Chem. Eur. J. 2012, 18, 2081-2093; k) S. Mohammed, R.
A. Vishwakarma, S. B. Bharate, RSC Adv. 2015, 5, 3470-3473.
Chapter V. Reactions without catalyst 156
In turn, these heterocycles can be transformed into β-functionalised carbonylic
compounds,244
by cleavage of the labile N-O heterocyclic bond.
Different metallic derivatives have been used to perform the
regioselective cycloaddition reaction, including aluminium,245
magtrieve
(CrO2),246
cobalt247
and copper248
complexes, AgBF4,249
SnPh4,250
triscetylpyridiniumtetrakis(oxodiperoxotungsto)phosphate,251
gold compounds,252
and Pb(OAc)2.253
Conversely, in the case of cyclopentadienyl ruthenium
derivatives,254
the regioselective formation of the related 4,5-disubstituted
heterocycles was observed.
It should be pointed out that for many applications the use of toxic
transition metals is undesirable, if not prohibited. Therefore, there is a clear
necessity for metal-free protocols. This green approach has been conducted by
different oxidative reagents such as oxone,255
iodine,256
iodobenzene
244 B. Raghava, G. Parameshwarappa, A. Acharya, T. R. Swaroop, K. S. Rangappa, H. Ila, Eur. J.
Org. Chem, 2014, 1882-1892. 245 O. Jackowski, T. Lecourt, L. Micouin, Org. Lett. 2011, 13, 5664-5667. 246 a) S. Bhosale, S. Kurhade, U. V. Prasad, V. P. Palle, D. Bhuniya, Tetrahedron Lett. 2009, 50,
3948-3951; b) S. Bhosale, S. Kurhade, S. Vyas, V. P. Palle, D. Bhuniya, Tetrahedron 2010, 66,
9582-9588. 247 X. Wei, J. Fang, Y. Hu, H. Hu, Synthesis 1992, 12, 1205-1206. 248 a) T. V. Hansen, P. Wu, V. V. Fokin, J. Org. Chem. 2005, 70, 7761-7764; b) M. Koufaki, T.
Fotopoulou, G. A. Heropoulos, Ultrason. Sonochem. 2014, 21, 35-39; c) F. Himo, T. Lovell, R.
Hilgraf, V. V. Rostovtsev, L. Noodleman, K. B. Sharples, V. V. Fokin, J. Am. Chem. Soc.
2005, 127, 210-216; d) B. Willy, W. Frank, F. Rominger, T. J. J. Müller, J. Organomet. Chem.
2009, 694, 942-949; e) A. A. Vieira, F. R. Bryk, G. Conte, A. J. Bortoluzzi, H. Gallardo,
Tetrahedron Lett. 2009, 50, 905-908; f) S. B. Bharate, A. K. Padala, B. A. Dar, R. R. Yadav, B.
Singh, R. A. Vishwakarma, Tetrahedron Lett. 2013, 54, 3558-3561; g) S. Kovács, Z. Novák,
Tetrahedron 2013, 69, 8987-8993; h) K. Chanda, S. Rej, M. H. Huang, Nanoscale 2013, 5,
12494-12501. 249 M. Ueda, Y. Ikeda, A. Sato, Y. Ito, M. Kakiuchi, H. Shono, T. Miyoshi, T. Naito, O. Miyata,
Tetrahedron 2011, 67, 4612-4615. 250 O. Moriya, Y. Urata, T. Endo, J. Chem. Soc., Chem. Commun. 1991, 17-18. 251 F. P. Ballistreri, U. Chiacchio, A. Rescifina, G. Tomaselli, R. M. Toscano, Molecules 2008, 13,
1230-1237. 252 K. K.-Y. Kung, V. K.-Y. Lo, H.-M. Ko, G.-L. Li, P.-Y. Chan, K.-C. Leung, Z. Zhou, M.-Z.
Wang, C.-M. Che, M.-K. Wong, Adv. Synth. Catal. 2013, 355, 2055-2070. 253 T. C. Sharma, S. Rojindar, D. D. Berge, A. V. Kale, Indian J. Chem. B 1986, 25B, 437. 254 S. Grecian, V. V. Fokin, Angew. Chem. Int. Ed. 2008, 47, 8285-8287. 255 a) A. Yoshimura, K. R. Middleton, A. D. Todora, B. J. Kastern, S. R. Koski, A. V. Maskaev, V.
V. Zhdankin, Org. Lett. 2013, 15, 4010-4013; b) L. Han, B. Zhang, M. Zhu, J. Yan,
Tetrahedron Lett. 2014, 55, 2308-2311. 256 a) A. V. Ingle, A. G. Doshi, A. W. Raut, N. S. Kadu, Orient. J. Chem. 2011, 27, 1815-1818; b)
S. Akbar, K. A. Srinivasan, Eur. J. Org. Chem. 2013, 1663-1666; c) R. Harigae, K. Moriyama,
H. Togo, J. Org. Chem. 2014, 79, 2049-2058.
157 Chapter V. Reactions without catalyst
trifluoroacetate,257
iodobenzene diacetate,258
tert-butyl hypoiodite,259
or
chloramine-T.260
However, these new protocols have several inconveniencies
such as stability, price, and manipulation of reagents. The importance of the
solvents used as reaction media has been recently addressed by the use of
aqueous biphasic protocols,261
ionic liquid,262
and aqueous polyethylene glycol.263
Within the framework of green chemistry, solvents occupy a strategic place. To
be qualified as a green medium, the components of this solvent have to meet
different criteria such as availability, non-toxicity, biodegradability, recyclability,
inflammability, renewability, and low price, among others.
Deep eutectic solvents167b,c,e,264
(DES), as it has been previously
reported (Chapter II), are an environmentally benign alternative to hazardous
(organic) solvents and, in many cases, might replace them. DESs are liquid
systems formed from an eutectic mixture of solid Lewis or Brønsted acids and
bases, which can contain a variety of anionic and/or cationic species.166
These
two components are capable of self-association, often through a strong bond
interaction, to form an eutectic mixture with a melting point lower167a,d,265
than
that of each individual component. The typical green characteristic properties of
a solvent, such as conductivity, viscosity, vapour pressure and thermal stability
can be fine-tuned by the appropriate choosing of the mixture components, with
the large-scale preparation being feasible.
The applications of DES in organic synthesis have notable advantages.
As most of the components are soluble in water, addition of water to the reaction
257 A. M. Jawalckar, E. Reubsaet, F. P. J. T. Rutjes, F. L. van Delft, Chem. Commun. 2011, 47,
3198-3200. 258 a) B. A. Mendelsohn, S. Lee, S. Kim, F. Teyssier, V. S. Aulakh, M. A. Ciufolini, Org. Lett.
2009, 11, 1539-1542; b) B. C. Sanders, F. Friscourt, P. A. Ledin, N. E. Mbua, S. Arumugam, J.
Guo, T. J. Boltje, V. V. Popik, G.-J. Boons, J. Am. Chem. Soc. 2011, 133, 949-957; c) R. S. B.
Gonçalves, M. D. Santos, G. Bernadat, D. Bonnet-Delpon, B. A. Crousse, Beilstein J. Org.
Chem. 2013, 9, 2387-2394. 259 S. Minakata, S. Okumura, T. Nagamachi, Y. Takeda, Org. Lett. 2011, 13, 2966-2969. 260 M. Koufaki, T. Fotopoulou, M. Kapetanou, G. A. Heropoulos, E. S. Gonos, N. Chondrogianni,
Eur. J. Med. Chem. 2014, 83, 508-515. 261 a) A. P. Kozikowski, M. Adamczyk, J. Org. Chem. 1983, 48, 366-372; b) Y. Koyama, M.
Yonekawa, T. Takata, Chem. Lett. 2008, 37, 918-919. 262 H. Valizadeh, M. Amiri, H. Gholipur, J. Heterocyclic Chem. 2009, 46, 108-110. 263 R. G. Chary, G. R. Reddy, Y. S. S. Ganesh, K. V. Prasad, A. Raghunadh, T. Krishna, S.
Mukherjee, M. Pal, Adv. Synth. Catal. 2014, 356, 160-164. 264 A. P. Abbott, R. C. Harris, K. S. Ryder, C. D’Agostino, L. F. Gladden, M. D. Mantle, Green
Chem. 2011, 13, 82-90. 265 a) A. P. Abbott, G. Capper, D. L. Davies, R. K. Rasheed, V. Tambyrajah, Chem. Commun.
2003, 70-71; b) M. A. Kareem, F. S. Mjalli, M. A. Hashim, I. M. AlNashel, J. Chem. Eng. Data
2010, 55, 4632-4637.
Chapter V. Reactions without catalyst 158
mixture dissolves the reaction medium, and the organic products either form a
separate layer or precipitate. Moreover, the solvent and the catalyst may be
recycled by the adequate quenching of the reaction.
DES have been used as an ideal medium in biocatalysed,266
organocatalysed267
reactions as well as in reactions using homogeneous268
and
heterogeneous170
catalysts. Although there are several misconceptions about their
uses in organic synthesis due to the high reactivity of the intermediate, this kind
of eutectic mixture has a promising future.
1.2 RESULTS
To start our study we decided to examine the three step one pot synthesis
of 3,5-disubstituted isoxazoles, similar to those previously reported,248f
using
benzaldehyde (2a) and phenylacetylene (5a) as the starting materials, and our
impregnated copper(II) oxide on magnetite as catalyst. After dissolving reagents
in DMF (1 mL) at room temperature, hydroxylammonium chloride and solid
NaOH were added, which should lead to the formation of the corresponding
oxime after 1 h of reaction. Then NCS was added to the basic reaction mixture,
which should result in the formation of hydroxyiminoyl chloride derivative after
3 h at room temperature. To obtain the corresponding isoxazole 45a in 60 %
yield, the addition of phenylacetylene (5a) and 0.44 mol% of CuO-Fe3O4 at 100
ºC was needed. Once the protocol was checked using our catalyst, the reaction
was repeated changing the solvent by the same amount of slightly basic eutectic
mixture ChCl:urea (1:2), obtaining better results (72 % yield). After that, the
reaction was repeated without the addition of CuO-Fe3O4 catalyst, surprisingly,
reaching a similar yield.
With these results in hand, the reaction was performed in a similar way
but changing the common organic volatile solvent by different DES in absence of
catalyst (Table 36). The reaction conditions were modified slightly, performing
all the steps at 50 ºC. Initially, the effect of DES in the reaction was examined
(entries 1-6). In first place, the reaction was performed in the DES formed by
ChCl:glycerol (1:2) and although the yield was not satisfactory, it proved that the
concept may work (entry 1). Then, other DESs were examined as medium for the
266 Z. Maugeri, P. Domínguez de María, ChemCatChem. 2014, 6, 1535-1537. 267 a) C. R. Müller, I. Meiners, P. Domínguez de María, RSC Adv. 2014, 4, 46097-46101; b) R.
Martínez, L. Berbegal, G. Guillena, D. J. Ramón, Green Chem. 2016,
DOI:10.1039/C5GC02526E. 268 L. Gu, W. Huang, S. Tang, S. Tian, X. Zhang, Chem. Eng. J. 2015, 259, 647-652.
159 Chapter V. Reactions without catalyst
reaction, finding that DES containing urea gave better results. The initial mixture
ChCl:urea (1:2) led to the best yield (entry 6).
Table 36. Optimization of the reaction conditions.a
Entry DES (molar ratio) t (h) Yield (%)
b
1 ChCl:glycerol (1:2) 8 20
2 ChCl:trifluoroacetamide (1:2.5) 8 0
3 ChCl:ethylene glycol (1:2) 8 0
4 Ph3P+MeBr
-:glycerol (1:2) 8 0
5 AcChCl:urea (1:2) 8 40
6 ChCl:urea (1:2) 8 71
7 ChCl:urea (1:2) 1 46
8 ChCl:urea (1:2) 2 64
9 ChCl:urea (1:2) 4 73 (70)c
10d
THF 8 4
11d
THF (urea)e
8 13
12d
THF (ChCl)e
8 11
13 ureaf
8 34
14 ChClf
8 15 a
Reaction carried out using compounds 2a (203 μL, 2mmol), NH2OH·HCl (138 mg, 2
mmol), NaOH (80 mg, 2 mmol), NCS (400 mg, 3 mmol) and 5a (110 μL, 2 mmol) in
1mL of DES. b Isolated yield after column chromatography.
c Reaction carried out using compounds 2a (2.03 mL, 20 mmol), NH2OH·HCl (1,38 g, 20
mmol), NaOH (800 mg, 20 mmol), NCS (4g, 30 mmol) and 5a (2.2 mL, 20 mmol) in 10
mL of DES. d Reaction carried out using 1 mL of THF.
e 2 equivalents of additive was added.
f Reaction carried out in the absence of solvent using 2 equivalents of additive.
It should be pointed out that this renewable solvent is a good medium for
different reactions, including the deprotonation of aromatic hydroxylammonium
chloride with solid sodium hydroxide, condensation of amine derivative with
benzaldehyde, and chlorination of the formed oxime with N-chlorosuccinimide to
give the corresponding hydroximinoyl chloride, which is stable enough into the
Chapter V. Reactions without catalyst 160
highly functionalized medium, to allow the final [3+2] cycloaddition by slow
HCl elimination.
Then, the reaction time was evaluated for the last cycloaddition step
(entries 6-9), finding that after 4 h the increase of the yield was marginal. The
reaction was scaled up to grams using 10 mL of DES (entry 9, footnote c), and
after completion of the reaction 10 mL of NaOH 1 M and 10 mL of hexane were
added. The resulting mixture was stirred during 30 minutes and after that, the
obtained solid was filtered off, obtaining the corresponding pure product with
good yield. This purification protocol is easier and greener than that employed in
the milligram scale.
In order to clarify the role of different components or the solvent, the
reaction was performed in THF adding 2 equivalents of urea or chlorine chloride
(Table 36, entries 10-12), obtaining slightly better results using these additives.
When the reaction was repeated in absence of solvent but in the presence of the
aforementioned additives (Table 36, entries 13 and 14), the best result was
obtained in the presence of urea. These facts highlight the beneficial role of urea
in the reaction mechanism, probably by stabilising the ionic intermediates
through hydrogen bonds.
With the best conditions in hand, the scope of the reaction was evaluated
(Table 37). The reaction gave excellent results for substituted benzaldehydes
independently of the nature of the substituent at the aromatic ring of the aldehyde
(entries 1-3) as well as of the relative position (compares entries 3 and 4). The
reaction was tested using aliphatic (entry 5) and heterocyclic (entries 6 and 7)
aldehydes, obtaining good yields.
The reaction was also accomplished with different substituted
ethynylbenzenes, using electron-donating substituents as well as electron-
withdrawing groups, obtaining good yields (entries 8 and 9). Heterocyclic (entry
10) and aliphatic (entry 11) alkynes were also tested leading to good results. The
combination of substituted aldehydes and alkynes was not problematic, obtaining
the corresponding product with a similar good yield (entry 12).
161 Chapter V. Reactions without catalyst
Table 37. Preparation of Isoxazoles.a
Entry R
1 R
2 Product Yield (%)
b
1 Ph Ph 45a 73
2 4-ClC6H4 Ph 45b 83
3 4-MeC6H4 Ph 45c 96
4 2-MeC6H4 Ph 45d 81
5 C6H11 Ph 45e 86
6 2-Quinolyl Ph 45f 82
7 2-Thienyl Ph 45g 86
8 Ph 3-ClC6H4 45h 80
9 Ph 4-MeOC6H4 45i 76
10 Ph 2-Pyridyl 45j 63
11 Ph C6H11 45k 84
12 4-MeC6H4 4-MeOC6H4 45l 70 a
Reaction carried out using compounds 2 (2mmol), NH2OH·HCl (138 mg, 2 mmol),
NaOH (80 mg, 2 mmol), NCS (400 mg, 3 mmol) and 5 (2 mmol) in 1mL of ChCl:urea
(1:2). b Isolated yield after column chromatography.
The recycling of ChCl:urea medium was evaluated once the compound
45a was obtained. The simple decantation of DES mixture with toluene permitted
the partial isolation of all organic products and by-products. The lower DES layer
was reused in a second cycle, but the yield decreased from 73 to 32 %. The high
solubility of initial reagents (NH2OH·HCl, NaOH, NCS), as well as the
stoichiometric by-product formed (H2O and succinimide) presented in the second
cycle might modify the initial DES structure, decreasing the initial beneficial
solvent effect.
Once the study of this reaction was finished, a similar process was
performed but using alkenes269
(Table 38). The yields were similar to the
previously obtained with alkynes allowing either the use of aromatic (entries 1-3)
and heterocyclic (entry 4) aldehydes or the use of aromatic (entry 5), heterocyclic
(entry 6), and aliphatic (entries 7 and 8) alkenes. The combination of aromatic
269 L. Han, B. Zhang, C. Xiang, J. Yan, Synthesis 2014, 46, 503-509.
Chapter V. Reactions without catalyst 162
aldehydes and aliphatic alkenes gave the corresponding product with moderate
yield (entry 9).
Table 38. Preparation of Isoxazolines.a
Entry R
1 R
2 Product Yield (%)
b
1 Ph Ph 47a 54
2 4-ClC6H4 Ph 47b 91
3 4-MeC6H4 Ph 47c 51
4 2-Thienyl Ph 47d 79
5 Ph 4-ClC6H4 47e 70
6 Ph 2-Pyridyl 47f 84
7 Ph C6H13 47g 74
8 Ph 4-MeOC6H4CH2 47h 47
9 4-NO2C6H4 CH2Br 47i 42 a
Reaction carried out using compounds 2 (2mmol), NH2OH·HCl (138 mg, 2 mmol),
NaOH (80 mg, 2 mmol), NCS (400 mg, 3 mmol) and 46 (2 mmol) in 1mL of DES. b Isolated yield after column chromatography.
Once the scope of the reaction was studied, a ring opening reaction270
was carried out using 0.5 equivalents of Mo(CO)6 and starting from the
previously obtained isoxazoles 45 (Table 39). The reaction took place with good
yields when the substituents of the isoxazole were aromatic, independently of the
electronic nature of the substituents at the rings (entries 1-3). However, when the
reaction was performed with aliphatic substituents, the yield decreased (entry 4).
270 a) C. Kashima, S. Tobe, N. Sugiyama, M. Yamamoto, Bull. Chem. Soc. Jpn. 1973, 46, 310-313;
b) C. Kashima, J. Org. Chem. 1975, 40, 526-527; c) D. P. Curran, J. Am. Chem. Soc. 1983,
105, 5826-5833; d) M. Nitta, T. Kobayashi, J. Chem. Soc., Perkin Trans. 1985, 1, 1401-1406;
e) C.-S. Li, E. Lacasse, Tetrahedron Lett. 2002, 43, 3565-3568; f) R. Saxena, V. Singh, S.
Batra, Tetrahedron 2004, 60, 10311-10320; g) S. I. Sviridov, A. A. Vasil’ev, S. V. Shorshnev,
Tetrahedron 2007, 63, 12195-12201; h) L. Zhu, G. Wang, Q. Guo, Z. Xu, D. Zhang, R. Wang,
Org. Lett. 2014, 16, 5390-5393.
163 Chapter V. Reactions without catalyst
Table 39. Synthesis of β-amino enones.a
Entry R
1 R
2 Product Yield (%)
b
1 Ph Ph 48a 90
2 4-ClC6H4 Ph 48b 92
3 Ph 4-MeOC6H4 48c 89
4 Ph C6H13 48d 55 a
Reaction carried out using compounds 45 (1 mmol), H2O (1 mmol), Mo(CO)6 (0.5
mmol) in 20 mL of CH3CN. b Isolated yield after column chromatography.
Our next goal was to examine if a similar dipolar cycloaddition is
feasible also with activated nitroalkenes. So, the simple approach for the
synthesis of ethyl 5-substituted isoxazole-3-carboxylates by reaction of the
corresponding nitrocompounds using DES was tested (Table 40). Ethyl 2-
nitroacetate (49) and phenylacetylene (5a) were selected as the model for the
optimization of the reaction conditions. Initially, the effect of different DES was
examined (entries 1-5). The reaction was performed in some of the previously
tested DES, with only those containing urea giving the expected product 50a.
With these results in hand, the reaction was repeated increasing the
temperature (entries 6 and 7) observing that, in the mixture acetyl choline
chloride (AcChCl):urea the reaction took place with good yield after 24 h. The
reaction was tested using 2 equivalents of compound 49, obtaining good yield
after only 4 h of reaction (entry 8), with the yield not being improved by an
increasing the reaction time. To prove the beneficial effect of the DES media, the
reaction was repeated in absence of solvent, under the best reaction conditions,
and the starting material was recovered unchanged (entry 9).
Chapter V. Reactions without catalyst 164
Table 40. Optimization of the reaction conditions.a
Entry DES (molar ratio) T (ºC) t (h) Yield (%)
b
1 ChCl:glycerol (1:2) 50 48 0
2 ChCl:ethylene glycol (1:2) 50 48 0
3 Ph3P+MeBr
-:glycerol (1:2) 50 48 0
4 AcChCl:urea (1:2) 50 48 42
5 ChCl:urea (1:2) 50 48 35
6 ChCl:urea (1:2) 100 24 40
7 AcChCl:urea (1:2) 100 24 85
8c AcChCl:urea (1:2) 100 4 79 (80)
d
9 - 100 24 0 a
Reaction carried out using compounds 49 (0.5 mmol) and 5a (0.5 mmol) in 1mL of
DES. b Isolated yield after column chromatography.
c Reaction carried out using compounds 49 (1 mmol) and 5a (0.5 mmol) in 1mL of DES.
d After 8 h of reaction.
Once the optimization was performed and with the best conditions in
hand, the scope of the reaction was evaluated using AcChCl:urea (1:2) at 100 ºC
(Table 41).
Table 41. Scope of the reaction.a
Entry R Product Yield (%)
b
1 Ph 50a 79
2 3-ClC6H4 50b 91
3 3-MeC6H4 50c 85
4 4-MeOC6H4 50d 78
5 C6H13 50e 63 a Reaction carried out using compounds 49 (1 mmol) and 5 (0.5 mmol) in 1mL of DES.
b Isolated yield after column chromatography.
165 Chapter V. Reactions without catalyst
The reaction gave excellent results with different substituted
ethynylbenzenes 5, independently of the relative position or the electron nature of
the substituent. However, the reaction with a related aliphatic alkyne gave the
expected product 50e with a slight decrease in yield (entry 5).
Once the positive effect of the DES on the reaction was proved, the
recycling of the media was evaluated. After performing the reaction and
generating compound 50a in AcChCl:urea (1:2), the product was isolated by
extraction with toluene and the DES media was reused for the next process
(Figure 46). The DES solvent could be reused five times obtaining similar yields
compared to the freshly prepared one.
0
10
20
30
40
50
60
70
80
90
100
12
34
5
Yie
ld 5
0a
(%)
Cycle
Figure 46. Yields obtained with recycled DES (AcChCl:urea).
Finally, a possible picture of the hypothetic mechanism is described in
Scheme 30. In both protocols, only DES containing urea gave the expected
product in a reasonable yield. This fact might be due to the high hydrogen-bond
donating character of this component. In the first approach, we believe that urea
favours the release of chloride from the imidoyl chloride compound. In fact, this
interaction is the responsible for the formation of DES. In the second approach, a
similar interaction would favour the nitrotautomerization. Finally, the nitrile
oxide intermediate formed in both cases could be stabilised by both component
of DES, through hydrogen bonding with urea and through electronic interaction
with the choline derivative.
Chapter V. Reactions without catalyst 166
Scheme 30. Possible mechanism pathway.
EXPERIMENTAL PART
169 Experimental Part
1. GENERAL
1.1. SOLVENTS AND SUBSTRATES
All reagents listed in the present research work, whose preparation has
not been described, were purchase with the best commercial grade and were used
without purification (Acros, Aldrich, Alfa Aesar, Fluka, Fluorochem, Merck).
The solvents used in the reactions that required anhydrous conditions were dried
under standard conditions before the use. Other solvents employed (hexane, ethyl
acetate, diethyl ether, methanol, ethanol) were the best grade commercially
available.
1.2. INSTRUMENTATION
The X-ray fluorescence analyses (XRF) were carried out on the units of
Technical Services Research at the University of Alicante on a PHILIPS MAGIX
PRO (PW2400) X-ray spectrometer equipped with a rhodium X-ray tube and a
beryllium window.
The gas adsorption analysis were carried out on the units of Technical
Services Research at the University of Alicante with an automatic volumetric
equipment of physical adsoption gas and degassing AUTOSORB-6 and
AUTOSORB DEGASSER, both from Quantachrome. N2 was used as gas.
The X-ray photoelectron spectroscopy (XPS) analyses were carried out
on the units of the Technical Services of Investigation at the University of
Alicante in a VG-Microtech Multilab 3000 equipped with a hemispheric electron
analyser with 9 channeltrons (pass energy between 2 and 200 eV) and an X-ray
tube with Mg and Al anodes.
The transmission electron microscopy (TEM) analyses were carried out
on the units of the Technical Services of Investigation at the University of
Alicante on a JEOL JEM-2010 microscope, equipped with a X-ray detector
OXFORD INCA Energy TEM 100 for microanalysis EDS.
TG-DTA analysis were carried out on a METTLER TOLEDO
equipment, model TGA/SDTA851e/LF/1600, and EM analysis on a PFEIFFER
VACUUM, model THERMOSTAR GSD301T.
Melting points were obtained with a Reichert Thermovar apparatus.
Experimental Part 170
The purity of volatile compounds and the chromatographic analysis
(GLC) was performed with a Younglin 6100GC equipped with a flame ionization
detector (FID) and a capillary column HP-5 (5 % crosslinking PH ME siloxane)
30 m length, 0.25 mm internal diameter and 0.25 μm thick sheet, using nitrogen
(2 mL/min) as carrier gas, 10 psi pressure in the injector block temperature 270
°C injection volume 0.75 μL sample injected and 5 mm/min speed recording. The
selected program was 60 °C initial temperature for 3 minutes 15 °C/min heating
rate to 270 °C, where the temperature is held for ten minutes. The retention times
(tr) are given in minutes under these conditions.
Thin layer chromatography (TLC) was carried out on Schleicher &
Schuell F1400/LS 254 plates coated with a 0.2mm layer of silica gel; detection
by UV254 light, staining with phosphomolybdic acid [25 g phosphomolybdic acid,
10 g Ce(SO4)2·4H2O, 60 mL of concentrated H2SO4 and 940 mL H2O].
IR spectra (cm-1
) were obtained with a spectrophotometer Nicolet Impact
400 D-FT spectrophotometer or with a spectrophotometer attenuated total
reflectance (ATR) JASCO 4100LE (Pike Miracle). Samples were prepared on
glass capillary film on sodium chloride in the case of oils. For solid samples, the
corresponding potassium bromide pellets were prepared, in a proportion of 0.5-1
% by mass. In the case of ATR spectrometer, the samples were analyzed directly.
Proton nuclear magnetic resonance spectra (1H-NMR), carbon (
13C-
NMR) and fluorine (19
F-NMR) were performed in the unit of Nuclear Magnetic
Resonance of the Technical Services Research at the University of Alicante with
a Bruker AC-300 or Bruker Avance-400, using deuterated chloroform as solvent
(unless otherwise is indicated) and tetramethylsilane (TMS) as an internal
standard (if not indicated otherwise). The spectra of proton nuclear magnetic
resonance were performed at 300 or 400 MHz, while the carbon became 75 or
100 MHz and 282 MHz for fluorine. Chemical shifts (δ) are given in parts per
million (ppm) and coupling constants (J) in Hz.
The mass spectrometric analysis was performed using a spectrometer
Agilent GC / MS-5973N, performing studies in the form of electron impact (EI) at
70 eV ionization source and helium as the mobile phase. Samples were
introduced by injection through a gas chromatograph Hewlett-Packard HP-6890,
equipped with a HP-5MS column 30 m length, 0.25 mm internal diameter and
0.25 μm film thickness (crosslinking 5 % PH ME siloxane). Ions derived from
the breaks are given as m/z with brackets relative percent intensities.
171 Experimental Part
The mass spectrometry analyses of high resolution (HRMS) were
performed in units Mass Spectrometry of the Technical Services Research at the
University of Alicante with a spectrometer Finnigan MAT95-S.
Elemental analyses were carried out on the units of the Technical
Services of Investigation at the University of Alicante with an elemental
microanalyser Thermo Finningan Flash 1112.
Column chromatography was performed on pre-packed columns (12 mm
7.5 to 15 cm) using a pump chromatography type Büchi Pump (C-610
Controller Module C-601). The sample was introduced into the column prior
preparation of slurry with the apolar eluent, eluting with mixtures of the solvents
indicated in the purification of each particular compound and increasing in
polarity (hexane, ethyl acetate and methanol). They were also made with glass
columns, using as stationary phase silica gel Merck 60, with a particle size of
0.040 to 0.063 mm (flash silica), or 0.063 to 0.2 mm. This was introduced into
the column prior preparation of slurry with the initial eluent, eluting with
mixtures of hexane and ethyl acetate of increasing polarity, unless otherwise
specified.
The analysis of mass spectrometry with inductively coupled plasma
(ICP-MS) were performed in units of Technical Services Research at the
University of Alicante with a mass spectrometer with inductively coupled plasma
THERMO ELEMENTAL, model VG PQ.ExCell.
2. PREPARATION OF CATALYSTS
To a stirred solution of the metal salt MClx (1 mmol) in deionized water
(120 mL) was added commercially available Fe3O4 (17 mmols, 4g, powder
<5μm, BET area: 9.86 m2/g). After 10 min at room temperature, the mixture was
slowly basified with NaOH (1M) until pH around 13. The mixture was stirred
during one day at room temperature in air. After that, the catalyst was filtered and
washed several times with deionized water (3 x 10 mL). The solid was dried at
100 ºC during 24 h in a standard glassware oven, obtaining the expected catalyst.
In the case of the palladium catalysts, 13 mmol of KCl were added
initially to increase the solubility of the palladium salt (PdCl2) and the usual
procedure was followed.
For the preparation of the bimetallic catalysts, 1 mmol of each metallic
salt was dissolved in 120 mL and the usual procedure was carried out.
Experimental Part 172
3. REACTIONS CATALYSED BY NANOPARTICLES OF
IMPREGNATED COBALT(II) OXIDE ON MAGNETITE
3.1. HYDROACYLATION OF AZODICARBOXYLATE COMPOUNDS
General Procedure: To a stirred solution of the corresponding aldehyde
(2, 1.2 mmol) in trichloroethylene (1 mL) were added the catalyst (50 mg) and
the corresponding substituted azodicarboxylate (1, 1 mmol). The resulting
mixture was stirred at 60 ºC until the end of the reaction. The catalyst was
removed by a magnet and the resulting mixture was quenched with water and
extracted with AcOEt (3 x 5 mL). The organic phases were dried over MgSO4,
followed by evaporation under reduced pressure to remove the solvent. The
product was usually purified by chromatography on silica gel (hexane/ethyl
acetate) to give the corresponding products 3:
Diisopropyl 1-benzoylhydrazine-1,2-
dicarboxylate (3a):113
white solid; m.p. = 120-121
ºC (hexane); tr = 15.8; Rf = 0.1 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.69
(m, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.40-7.45 (m,
2H), 6.87 (s, br, 1H), 4.85-5.10 (2m, 1 and 1H,
respectively), 1.30 (d, J = 6.0 Hz, 6H), 1.07 (d, J =
5.4 Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ 171.1,
155.2, 152.8, 135.1, 131.8, 128.0 (4C), 72.3, 70.5, 21.8 (2C), 21.2 (2C); IR
(ATR): ν 3275, 1756, 1740, 1684, 1251, 1047 cm-1
; MS (EI) m/z (%): 222 (8),
105 (100), 77 (17).
Diisopropyl 1-(2-methylbenzoyl)hydrazine-1,2-
dicarboxylate (3b): pale yellow solid; m.p. = 64-66
ºC (hexane); tr = 15.9; Rf = 0.53 (hexane/ethyl
acetate: 3/2); 1H NMR (300 MHz, CDCl3): δ 7.30-
7.40 (m, 2H), 7.15-7.30 (m, 2H), 6.97 (s, br, 1H),
5.03 (heptet, J = 6.2 Hz, 1H), 4.84 (heptet, J = 6.2
Hz, 1H), 2.39 (s, 3H), 1.30 (d, J = 6.2 Hz, 6H), 1.00
(d, J = 6.2 Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ
170.4, 155.1, 152.2, 136.1, 135.2, 130.2, 129.9, 126.2, 125.3, 72.3, 70.6, 21.9
(2C), 21.1 (2C), 19.1; IR (ATR): ν 3294, 2984, 1754, 1734, 1687, 1252, 1505
cm-1
; MS (EI) m/z (%): 322 (M+, 0.1), 120 (9), 119 (100), 91 (17); Elemental
analysis calcd. for C16H22N2O5: C = 59.61, H = 6.88, N = 8.69; found: C = 59.65,
H = 6.93, N = 8.59.
173 Experimental Part
Diisopropyl 1-(3-methylbenzoyl)hydrazine-1,2-
dicarboxylate (3c): white solid; m.p. = 96-98 ºC
(hexane); tr = 16.3; Rf = 0.7 (hexane/ethyl acetate:
3/2); 1H NMR (300 MHz, CDCl3): δ 7.50 (s, br,
2H), 7.25-7.35 (m, 2H), 6.96 (s, br, 1H), 5.01
(heptet, J = 6.2 Hz, 1H), 4.89 (heptet, J = 6.2 Hz,
1H), 2.38 (s, 3H), 1.29 (d, J = 6.2 Hz, 6H), 1.07 (d,
J = 6.2 Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ
171.3, 155.2, 152.9, 137.9, 135.1, 132.6, 128.9, 128.0, 125.2, 72.3, 70.6, 21.9
(2C), 21.3 (2C), 21.2; IR (ATR): ν 3273, 2985, 1741, 1689, 1519, 1252; MS (EI)
m/z (%): 236 (8), 120 (9), 119 (100), 91 (18) cm-1
; Elemental analysis calcd. for
C16H22N2O5: C = 59.61, H = 6.88, N = 8.69; found: C = 59.68, H = 7.01, N =
8.75.
Diisopropyl 1-(p-tolyl)hydrazine-1,2-
dicarboxylate (3d):113
white solid; m.p. = 100-102
ºC (hexane); tr = 16.4; Rf = 0.7 (hexane/ethyl
acetate: 3/2); 1H NMR (300 MHz, CDCl3): δ 7.61
(s, br, 2H), 7.22 (d, J = 7.9 Hz, 2H), 6.86 (s, br,
1H), 4.90-5.10 (2m, 1 and 1H, respectively), 2.40
(s, 3H), 1.29 (d, J = 5.6 Hz, 6H), 1.11 (d, J = 5.6
Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ 171.1, 155.2, 153.0, 142.7, 132.1, 128.7
(2C), 128.4 (2C), 72.3, 70.6, 21.9 (2C), 21.6, 21.3 (2C); IR (ATR): ν 3281, 1753,
1736, 1685, 1250, 1044 cm-1
; MS (EI) m/z (%): 236 (9), 120 (14), 119 (100), 91
(22).
Diisopropyl 1-(4-methoxyphenyl)hydrazine-
1,2-dicarboxylate (3e): white solid; m.p. = 85-
87 ºC (hexane); tr = 17.4; Rf = 0.57
(hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,
CDCl3): δ 7.73 (m, 2H), 7.05 (s, br, 1H), 6.91
(d, J = 8.8 Hz, 2H), 4.85-5.05 (m, 2H), 3.85 (s,
3H), 1.28 (d, J = 6.0 Hz, 6H), 1.13 (d, J = 6.0
Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ 170.6, 163.9, 163.0, 153.4, 153.2, 132.3,
131.0, 113.4 (2C), 72.2, 70.5, 55.4, 21.9 (2C), 21.4 (2C); IR (ATR): ν 3258,
1748, 1719, 1698, 1251, 1024 cm-1
; MS (EI) m/z (%): 136 (10), 135 (100).
Experimental Part 174
Diisopropyl 1-(3,4,5-
trimethoxybenzoyl)hydrazine-1,2-
dicarboxylate (3f):113
white solid; m.p.= 92-
94 ºC (hexane); tr = 18.9; Rf = 0.3
(hexane/ethyl acetate: 3/2); 1H NMR (300
MHz, CDCl3): δ 7.01 (s, 2H), 6.93 (s, br, 1H),
4.85-5.05 (m, 2H), 3.89 (s, 3H), 3.88 (s, 6H),
1.30 (d, J = 6.3 Hz, 6H), 1.14 (d, J = 6.3 Hz,
6H); 13
C NMR (75 MHz, CDCl3): δ 170.8, 155.3, 153.0, 152.9 (2C), 141.7,
129.9, 106.0 (2C), 72.4, 70.6, 60.9, 56.2 (2C), 21.9 (2C), 21.4 (2C); IR (ATR): ν
3283, 2979, 1746, 1719, 1699, 1587, 1248 cm-1
; MS (EI) m/z (%): 398 (M+, 5%),
196 (11), 195 (100).
Diisopropyl 1-(4-fluorobenzoyl)hydrazine-1,2-
dicarboxylate (3g):109b
white solid; m.p. = 98-99 ºC
(hexane); tr = 15.5; Rf = 0.8 (hexane/ethyl acetate:
1/1); 1H NMR (300 MHz, CDCl3): δ 7.70-7.75 (m,
2H), 7.12 (t, J = 7.1 Hz, 2H), 6.95-7.00 (m, 1H),
4.90-5.05 (m, 2H), 1.31 (d, J = 5.9 Hz, 6H), 1.14 (d,
J = 5.9 Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ
170.2, 164.9 (d, 1JC-F = 253.3 Hz), 152.8, 152.2,
131.1, 130.8 (d, 3JC-F = 6.8 Hz, 2C), 115.3 (d,
2JC-F = 22 Hz, 2C), 72.6, 70.7, 21.9
(2C), 21.4 (2C); IR (ATR): ν 3282, 1745, 1723, 1698, 1283 cm-1
: MS (EI) m/z
(%): 240 (10), 154 (10), 124 (12), 123 (100), 95 (20).
Diisopropyl 1-(2-chlorobenzoyl)hydrazine-1,2-
dicarboxylate (3h): yellow oil; tr = 16.4; Rf = 0.63
(hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,
CDCl3): δ 7.30-7.50 (m, 4H), 6.99 (s, 1H), 4.85-
5.05 (2m, 1 and 1H, respectively), 1.05-1.35 (2m, 6
and 6H, respectively); 13
C NMR (75 MHz, CDCl3):
δ 167.5, 154.9, 151.6, 136.1, 130.8, 130.2, 129.3,
127.9, 126.6, 72.6, 70.6, 21.8 (2C), 21.2 (2C); IR (ATR) ν 3312, 2983, 2937,
1739, 1257 cm-1
; MS (EI) m/z (%): 256 (10), 141 (34), 139 (100), 111 (12);
Elemental analysis calcd. for C15H19ClN2O5: C = 52.56, H = 5.59, N = 8.17;
found: C = 52.42, H = 5.49, N = 8.23.
175 Experimental Part
Diisopropyl 1-(3-chlorobenzoyl)hydrazine-1,2-
dicarboxylate (3i): white solid; m.p. = 108-110
ºC (hexane); tr = 16.5; Rf = 0.7 (hexane/ethyl
acetate: 3/2); 1H NMR (300 MHz, CDCl3): δ 7.45-
7.65 (m, 3H), 7.30-7.40 (m, 1H), 7.04 (s, br, 1H),
4.90-5.10 (m, 2H), 1.30 (d, J = 6.2 Hz, 6H), 1.11
(d, J = 5.9 Hz, 6H); 13
C NMR (75 MHz, CDCl3):
δ 169.8, 155.1, 152.5, 136.8, 134.2, 131.7, 129.5, 128.0, 126.1, 72.8, 70.8, 21.9
(2C), 21.3 (2C); IR (ATR): ν 3286, 2985, 2940, 1744, 1757, 1527, 1518, 1254
cm-1
: MS (EI) m/z (%): 256 (12), 214 (11), 170 (17), 141 (39), 139 (100), 111
(20); Elemental analysis calcd. for C15H19ClN2O5: C = 52.56, H = 5.59, N = 8.17;
found: C = 52.59, H = 5.48, N = 8.08.
Diisopropyl 1-(4-chlorobenzoyl)hydrazine-1,2-
dicarboxylate (3j):110a
white solid; m.p. = 82-84
ºC (hexane); tr = 16.6; Rf = 0.7 (hexane/ethyl
acetate: 3/2); 1H NMR (300 MHz, CDCl3): δ
7.65-7.70 (m, 2H), 7.30-7.40 (m, 2H), 6.95 (s, br,
1H), 4.90-5.05 (m, 2H), 1.30 (d, J = 5.2 Hz, 6H),
1.13 (d, J = 5.2 Hz, 6H); 13
C NMR (75 MHz,
CDCl3): δ 170.2, 155.1, 152.7, 138.2, 133.4, 129.6 (2C), 128.4 (2C), 72.7, 70.8,
21.9 (2C), 21.4 (2C); IR (ATR): ν 3310, 2989, 1735, 1712, 1596, 1486, 1264 cm-
1; MS (EI) m/z (%): 256 (8), 141 (33), 139 (100), 111 (14).
Diisopropyl 1-(1-naphthoyl)hydrazine-1,2-
dicarboxylate (3k): white solid; m.p. = 102-104 ºC
(hexane); tr = 19.0; Rf = 0.4 (hexane/ethyl acetate:
3/2); 1H NMR (300 MHz, CDCl3): δ 8.15-8.20 (m,
1H), 7.93 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 7.9 Hz,
1H), 7.60-7.65 (m, 1H), 7.45-7.55 (m, 3H), 7.10 (s,
1H), 5.05-5.10 (m, 1H), 4.65-4.70 (m, 1H), 1.34 (d,
J = 6.2 Hz, 6H), 0.65-0.75 (m, 6H); 13
C NMR (75
MHz, CDCl3): δ 170.4, 155.3, 152.0, 134.1, 133.1, 130.5, 129.9, 128.2, 127.3,
126.4, 124.7, 124.6 (2C), 72.3, 70.7, 21.9 (2C), 20.8 (2C); IR (ATR): ν 3278,
1760, 1743, 1514, 1251 cm-1
; MS (EI) m/z (%): 358 (M+, 6), 156 (26), 155 (100),
127 (61); Elemental analysis calcd. for C19H22N2O5: C = 63.67, H = 6.19, N =
7.82; found: C = 63.8, H = 6.25, N = 7.9.
Experimental Part 176
Diisopropyl 1-(thiophene-2-carbonyl)hydrazine-
1,2-dicarboxylate (3l):111
colorless oil; tr = 16.0; Rf
= 0.47 (hexane/ethyl acetate: 3/2); 1H NMR (300
MHz, CDCl3): δ 7.89 (dd, J = 3.9, 1.3 Hz, 1H), 7.60
(dd, J = 5.0, 1.3 Hz, 1H), 7.22 (s, br, 1H), 7.09 (dd, J
= 5.0, 3.9 Hz, 1H), 4.95-5.10 (m, 2H), 1.25-1.35 (m,
12H); 13
C NMR (75 MHz, CDCl3): δ 162.6, 155.3, 154.8, 152.6, 135.5, 133.5,
127.1, 72.6, 70.8, 21.8 (2C), 21.5 (2C); IR (ATR): ν 3299, 1736, 1234 cm-1
; MS
(EI) m/z (%): 228 (12), 186 (8), 142 (10), 111 (100).
Diisopropyl 1-cinnamoylhydrazine-1,2-
dicarboxylate (3m):111
colorless oil; tr = 17.9; Rf
= 0.53 (hexane/ethyl acetate: 3/2); 1H NMR (300
MHz, CDCl3): δ 7.72 (d, J = 15.7 Hz, 1H), 7.45-
7.50 (m, 3H), 7.25-7.30 (m, 3H), 6.81 (s, br, 1H),
5.01 (heptet, J = 6.3 Hz, 1H), 4.93 (heptet, J = 6.3
Hz, 1H), 1.27 (d, J = 6.3 Hz, 6H), 1.15-1.25 (m, 6H); 13
C NMR (75 MHz,
CDCl3): δ 166.5, 155.1, 152.8, 145.8, 134.6, 130.4, 128.8 (2C), 128.4 (2C),
118.8, 72.3, 70.4, 21.8 (2C), 21.7 (2C); IR (ATR): ν 3311, 1732, 1236 cm-1
; MS
(EI) m/z (%): 132 (10), 131 (100), 103 (16).
Diisopropyl 1-butyrylhydrazine-1,2-
dicarboxylate (3n):109b
colorless oil; tr = 13.01; Rf =
0.6 (hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,
CDCl3): δ 6.84 (s, br, 1H), 4.85-5.00 (m, 2H), 2.80-
2.85 (m, 2H), 1.62 (m, 2H), 1.20-1.25 (m, 12H),
0.90 (t, J = 7.4 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 173.7, 155.1, 152.6, 71.9,
70.2, 38.7, 21.8 (2C), 21.6 (2C), 18.0, 13.5; IR (ATR): ν 3311, 1719, 1235 cm-1
;
MS (EI) m/z (%): 204 (48), 173 (10), 162 (28), 146 (13), 120 (33), 118 (46), 103
(13), 102 (20), 76 (51), 71 (100), 59 (11).
Diisopropyl 1-nonanoylhydrazine-1,2-
dicarboxylate (3o):109a
colorless oil; tr = 16.2. Rf =
0.7 (hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,
CDCl3): δ 6.66 (s, br, 1H), 4.90-5.10 (m, 2H), 2.85-
2.90 (m, 2H), 1.60-1.70 (m, 2H), 1.2-1.35 (m, 22H),
0.87 (t, J = 6.7 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 173.9, 155.1, 152.6, 71.9,
70.2, 36.9, 31.7, 29.2, 29.0 (2C), 24.6, 22.5, 21.8 (2C), 21.6 (2C), 14.0; IR
(ATR): ν 3314, 2981, 2925, 1720, 1244 cm-1
; MS (EI) m/z (%): 205 (12), 204
177 Experimental Part
(100), 162 (44), 160 (12), 141 (52), 120 (24), 118 (70), 76 (32), 71 (26), 57 (28),
55 (13).
Diisopropyl 1-(2-ethylbutanoyl)hydrazine-1,2-
dicarboxylate (3p): colorless oil; tr = 13.6; Rf =
0.73 (hexane/ethyl acetate: 3/2); 1H NMR (300
MHz, CDCl3): δ 7.01 (s, br, 1H), 4.95-5.10 (2m, 1
and 1H, respectively), 3.45-3.50 (m, 1H), 1.65-1.80
(m, 2H), 1.50-1.60 (m, 2H), 1.32 (d, J = 6.3 Hz,
6H), 1.25-1.30 (m, 6H), 0.91 (t, J = 7.4 Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ 177.0, 155.1, 152.6, 71.8, 70.0, 47.3, 24.7 (2C),
21.7 (2C), 21.5 (2C), 11.4 (2C); IR (ATR): ν 3311, 2970, 2937, 2878, 1719, 1230
cm-1
; MS (EI) m/z (%): 302 (M+, <0.1%), 204 (16), 162 (9), 120 (15), 99 (46), 98
(22), 76 (11), 71 (100); Elemental analysis calcd. for C14H26N2O5: C = 55.61, H =
8.67, N = 9.26; found: C = 55.57, H = 8.60, N = 9.19.
Diisopropyl 1-pivaloylhydrazine-1,2-
dicarboxylate (3q):109b
colorless oil; tr = 12.7; Rf =
0.73 (hexane/ethyl acetate: 3/2); 1H NMR (300
MHz, CDCl3): δ 6.81 (s, br, 1H), 4.95-5.10 (m, 2H),
1.20-1.35 (m, 21H); 13
C NMR (75 MHz, CDCl3): δ
179.6, 155.7, 153.2, 72.1, 70.5, 42.0, 27.4 (3C),
21.8 (2C), 21.6 (2C); IR (ATR): ν 3295, 2981, 1720, 1227 cm-1
; MS (EI) m/z
(%): 204 (37), 162 (30), 120 (43), 118 (15), 103 (11), 85 (17), 76 (31), 57 (100).
(Z)-Diisopropyl 1-(dec-7-enoyl)hydrazine-
1,2-dicarboxylate (3r):
colorless oil; tr =
16.7; Rf = 0.47 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 6.72 (s, br,
1H), 5.25-5.40 (m, 2H), 4.90-5.10 (m, 2H),
2.90 (t, J = 6.8 Hz, 2H), 1.95-2.05 (m, 4H),
1.60-1.70 (m, 2H), 1.20-1.40 (m, 16H), 0.95 (t, J = 7.5 Hz, 3H); 13
C NMR (75
MHz, CDCl3): δ 173.0, 155.1, 152.6, 131.7, 128.9, 72.0, 70.3, 36.9, 29.4, 28.7,
26.9, 24.5, 21.8 (2C), 21.6 (2C), 20.4, 14.3; IR (ATR): ν 3313, 1736, 1502, 1237
cm-1
; MS (EI) m/z (%): 356 (M+, 0.08), 205 (14), 204 (100), 163 (11), 162 (49),
153 (54), 152 (32), 135 (13), 123 816), 121 (13), 120 (27), 118 (74), 109 (11), 83
(15), 76 (43), 71 (10), 69 (37), 67 (16), 55 (31); Elemental analysis calcd. for
C18H32N2O5: C = 60.65, H = 9.05, N = 7.86; found: C = 60.67, H = 9.03, N =
7.87.
Experimental Part 178
Diethyl 1-benzoylhydrazine-1,2-dicarboxylate (3s):
271 colorless oil; tr = 15.5; Rf = 0.5
(hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,
CDCl3): δ 7.68 (d, J = 7.1 Hz, 2H), 7.35-7.55 (m,
3H), 7.24 (s, br, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.15
(q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.07 (t,
J = 7.1 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 172.1, 155.7, 153.4, 133.7, 132.0,
130.1, 128.4, 128.1, 64.0 (2C), 14.3 (2C); IR (ATR): ν 3312, 2921, 1705, 1222
cm-1
; MS (EI) m/z (%): 106 (8), 105 (100), 77 (21).
Di-tert-butyl 1-benzoylhydrazine-1,2-
dicarboxylate (3t): white solid; m.p. = 118-120 ºC
(hexane); tr = 14.9; Rf = 0.67 (hexane/ethyl acetate:
3/2); 1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 7.7
Hz, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.4
Hz, 2H), 6.84 (s, br, 1H), 1.50 (s, 9H), 1.23 (s, 9H); 13
C NMR (75 MHz, CDCl3): δ 171.6, 154.5, 151.7, 135.8, 131.7, 128.1 (4C),
84.4, 82.2, 28.1 (3C), 27.4 (3C); IR (ATR): ν 3336, 1760, 1721, 1703, 1280,
1063 cm-1
; MS (EI) m/z (%): 180 (13), 163 (22), 136 (37), 105 (100), 77 (47), 59
(10), 57 (94), 51 (15); Elemental analysis calcd. for C17H24N2O5: C = 60.7, H =
7.19, N = 8.33; found: C = 60.65, H = 7.23, N = 8.32.
4. REACTIONS CATALYSED BY NANOPARTICLES OF
IMPREGNATED COPPER(II) OXIDE ON MAGNETITE
4.1. SYNTHESIS OF 1,3-DIYNES
General Procedure: t-BuOK (224 mg, 2 mmol) and CuO-Fe3O4 (10 mg,
0.26 mol%) or NiO/Cu-Fe3O4 were added to a stirred solution of the appropiate
alkyne 5 (2 mmol) under air, and the mixture was vigorously stirred at 60 ºC until
the reaction was complete. The catalyst was collected by using a magnet and
washed successively with EtOAc (2 x 5 mL) and H2O (2 x 5 mL). The collected
organic phases were dried over MgSO4 and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica gel
(hexane/ethyl acetate) to give the corresponding products 6.
271 T. Osikawa, M. Yamashita, Rep. Fac. Eng. Shizuoka Univ. 1984, 35, 37-40.
179 Experimental Part
1,1’-Buta-1,3-diyne-1,4-diyldibenzene
(6a):126b
white solid; m.p. = 83-85 °C (hexane);
tr = 15.8 min; Rf = 0.67 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50 (m, 4 H), 7.25-7.30 (m, 6 H);
13C
NMR (75 MHz, CDCl3): δ 132.5 (4C), 129.2 (2C), 128.4 (4C), 121.8 (2C), 81.5
(2C), 73.9 (2C); IR (ATR): ν 3050, 1593, 1485 cm-1
; MS (EI) m/z (%): (M+
+ 1,
17), 202 (M+, 100), 201 (11), 200 (22), 101 (8).
4,4’-(Buta-1,3-diyne-1,4-
diyl)bis(N,N-dimethylaniline)
(6b):122b
pale brown solid; m.p.
= 215-217 ºC (hexane); tr = 13.4
min; Rf = 0.43 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.35-
7.40 (d, J = 8.8 Hz, 4H), 6.65-6.70 (d, J = 8.8 Hz, 4H), 3.00 (s, 12H); 13
C NMR
(75 MHz, CDCl3): δ 150.4 (2C), 133.2 (4C), 111.7 (4C), 108.8 (2C), 84.8 (2C),
74.7 (2C), 40.2 (4C); IR (ATR): ν 1598, 1358, 1225 cm-1
; MS (EI) m/z (%): 298
(M+, 10), 269 (10), 229 (19), 208 (14), 207 (60), 203 (22), 202 (100), 201 (70),
183 (12), 155 (19), 78 (11), 77 (40), 51 (15).
1,4-Bis(4-methoxyphenyl)buta-
1,3-diyne (6c):272
pale yellow
solid; m.p. = 131-133 ºC
(hexane); tr = 20.7 min; Rf = 0.37
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50 (d, J = 8.8
Hz, 4H), 6.80-6.85 (d, J = 8.8 Hz, 4H), 3.82 (s, 6H); 13
C NMR (75 MHz, CDCl3):
δ 160.2 (2C), 134.0 (4C), 114.1 (4C), 113.9 (2C), 81.2 (2C), 72.9 (2C), 55.3
(2C); IR (ATR): ν 3004, 2939, 2837, 1598, 1502 cm-1
; MS (EI) m/z (%): 263 (M+
+ 1, 19), 262 (M+, 100), 248 (11), 247 (58), 219 (14), 176 (15), 131 (13).
1,4-Di-p-tolylbuta-1,3-diyne (6d):128
pale yellow solid; m.p. = 118-120 ºC
(hexane); tr = 17.5 min; Rf = 0.8
(hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.35-7.40 (d, J = 8.0 Hz, 4H), 7.10-7.15 (d, J = 8.0 Hz,
4H), 2.34 (s, 6H); 13
C NMR (75 MHz, CDCl3): δ 139.5 (2C), 132.4 (4C), 129.2
(4C), 118.8 (2C), 81.5 (2C), 73.4 (2C), 21.6 (2C); IR (ATR): ν 3032, 1501 cm-1
;
272 X. Feng, Z. Zhao, F. Yang, T. Jin, Y. Ma, M. Bao, J. Org. Chem. 2011, 696, 1479-1482.
Experimental Part 180
MS (EI) m/z (%): 231 (M+
+ 1, 19), 230 (M+, 100), 229 (22), 228 (12), 226 (13),
215 (17).
1,4-Bis(4-chlorophenyl)buta-1,3-
diyne (6e): 128
pale yellow solid; m.p.
= 165-167 ºC (hexane); tr = 18.0 min;
Rf = 0.77 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50 (d, J = 8.7 Hz, 4H), 7.30-7.35 (d, J =
8.7 Hz, 4H); 13
C NMR (75 MHz, CDCl3): δ 134.0 (2C), 133.7 (4C), 128.9 (4C),
119.3 (2C), 80.8 (2C), 76.6 (2C); IR (ATR): ν 1483, 1395, 1092 cm-1
; MS (EI)
m/z (%): 274 (M++4, 11), 273 (M
++3, 11), 272 (M
++2, 65), 271 (M
++1, 18), 270
(M+, 100), 200 (28).
1,4-Bis(2-chlorophenyl)buta-1,3-diyne
(6f):122c
white solid; m.p. = 135-138 ºC
(hexane); tr = 18.4 min; Rf = 0.5 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
7.55-7.60 (dd, J = 7.6, 1.7 Hz, 2H), 7.40-7.45
(dd, J = 8.0, 1.2 Hz, 2H), 7.30-7.35 (td, J =
7.5, 1.7 Hz, 2H), 7.20-7.25 (td, J = 7.5, 1.2 Hz, 2H); 13
C NMR (75 MHz, CDCl3):
δ 136.9 (2C), 134.4 (2C), 130.3 (2C), 129.4 (2C), 126.5 (2C), 121.8 (2C), 79.4
(2C), 78.3 (2C); IR (ATR): ν 3068, 1463, 1433, 1053 cm-1
; MS (EI) m/z (%): 274
(M+
+ 4, 12), 273 (M+
+ 3, 12), 272 (M+
+ 2, 64), 271 (M+
+ 1, 18), 270 (M+, 100),
200 (34).
1,4-Bis((4-
trifluoromethyl)phenyl)buta-1,3-
diyne (6g):273
pale yellow solid;
m.p. = 165-168 ºC (hexane); tr =
15.0 min; Rf = 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
7.60-7.65 (m, 8H); 13
C NMR (75 MHz, CDCl3): δ 132.8 (4C), 131.1 (q, 2JC-F = 33
Hz, 2C), 125.4 (q, 3JC-F = 3.8 Hz, 4C), 125.3 (2C), 123.7 (q,
1JC-F = 272.4 Hz,
2C), 80.9 (2C), 75.6 (2C); IR (ATR): ν 1610, 1407 cm-1
; MS (EI) m/z (%): 339
(M+
+ 1, 22), 338 (M+, 100), 319 (17).
273 K. Kude, S. Hayase, m. Kawatsura, T. Itoh, Heteroat. Chem. 2011, 22, 397-404.
181 Experimental Part
1,4-Bis(4-bromophenyl)buta-1,3-
diyne (6h):274
pale yellow solid; m.p.
= 140-141 ºC; tr = 20.7 min; Rf = 0.73
(hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.45-7.50 (d, J = 8.5 Hz, 4H), 7.35-7.40 (d, J = 8.5 Hz,
4H); 13
C NMR (75 MHz, CDCl3): δ 133.8 (4C), 131.8 (4C), 131.7 (2C), 120.6
(2C), 81.0 (2C), 77.2 (2C); IR (ATR): ν 1480, 1066 cm-1
; MS (EI) m/z (%): 361
(M+
+ 1, 18), 360 (M+, 100), 358 (52), 281 (12), 207 (19), 200 (34), 199 (11), 174
(10).
1,4-Di-m-tolylbuta-1,3-diyne (6i):128
pale
yellow solid; m.p. = 65-67 ºC (hexane); tr =
17.3 min; Rf = 0.67 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.30-
7.35 (m, 4H), 7.15-7.25 (m, 4H), 2.33 (s,
6H); 13
C NMR (75 MHz, CDCl3): δ 138.1
(2C), 132.9 (2C), 130.1 (2C), 129.6 (2C), 128.3 (2C), 121.6 (2C), 81.6 (2C), 73.6
(2C), 21.1 (2C); IR (ATR): ν 3035, 1479 cm-1
; MS (EI) m/z (%): 231 (M+
+ 1,
19), 230 (M+, 100), 229 (10), 228 (10).
1,4-Dicyclohexylbuta-1,3-diyne (6j):126b
pale
yellow solid; m.p. = 77-82 ºC (hexane); tr =
15.1 min; Rf = 0.97 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 2.35-2.40
(m, 2H,), 1.60-1.75 (m, 8H), 1.35-1.45 (m, 6H), 1.15-1.25 (m, 6H); 13
C NMR (75
MHz, CDCl3): δ 81.9 (2C), 65.1 (2C), 32.3 (4C), 29.5 (2C), 25.7 (2C), 24.8 (4C);
IR (ATR): ν 2925, 2852, 1447 cm-1
; MS (EI) m/z (%): 215 (M+
+ 1, 15), 214 (M+,
84), 207 (18), 185 (16), 171 (35), 158 (11), 157 (21), 145 (27), 144 (14), 143
(39), 141 (14), 133 (11), 132 (15), 131 (62), 130 (20), 129 (63), 128 (47), 127
(14), 119 (17), 118 (28), 117 (82), 116 816), 115 (55), 105 (33), 104 (32), 103
(16), 102 (11), 95 (17), 93 (15), 92 (23), 91 (100), 89 (15), 80 (26), 79 (43), 78
(17), 77 (33), 76 (14), 75 (10), 67 (39).
Hexadeca-7,9-diyne (6k):272
colorless oil; tr =
14.1 min; Rf = 0 .87 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 2.20-2.25 (t, J =
274 N. Mizuno, K. Kamata, Y. Nakagawa, T. Oishi, K. Yamaguchi, Catal. Today 2010, 157, 359-
363.
Experimental Part 182
6.8 Hz, 4H), 1.45-1.55 (m, 4H), 1.25-1.45 (m, 12H), 0.85-0.95 (m, 6H); 13
C
NMR (75 MHz, CDCl3): δ 77.5 (2C), 65.2 (2C), 31.3 (2C), 28.5 (2C), 28.3 (2C),
22.5 (2C), 19.2 (2C), 14.0 (2C); IR (ATR): ν 1465, 1459, 1378, 724 cm-1
; MS
(EI) m/z (%): 218 (M+, 0.3), 161 (10), 147 (16), 133 (25), 121 (12), 119 (43), 117
(15), 107 (26), 106 (12), 105 (63), 95 (26), 93 (43), 92 (20), 91 (100), 81 (41), 80
(12), 79 (56), 78 (31), 77 (37), 76 (10), 69 (14), 67 (46), 65 (17), 63 (11), 55 (37),
51 (13).
Icosa-9,11-diyne (6l):272
colorless oil; tr =
16.6 min; Rf = 0.8 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 2.20-
2.25 (t, J = 6.9 Hz, 4H), 1.45-1.55 (m, 4H),
1.25-1.40 (m, 20H), 0.85-0.90 (t, J = 6.5 Hz, 6H); 13
C NMR (75 MHz, CDCl3): δ
77.5 (2C), 65.2 (2C), 31.8 (2C), 29.1 (2C), 29.0 (2C), 28.8 (2C), 28.4 (2C), 22.6
(2C), 19.2 (2C), 14.1 (2C); IR (ATR): ν 2924, 2854, 1464, 722 cm-1
; MS (EI) m/z
(%): 274 (M+, 0), 175 (14), 161 (25), 149 (12), 148 (10), 147 (32), 135 (20), 134
(12), 133 (45), 131 (10), 121 (41), 120 (15), 119 (55), 117 (21), 115 (13), 109
(15), 108 (10), 107 (41), 106 (14), 105 (60), 103 (12), 95 (38), 94 (17), 93 (52),
92 (22), 91 (100), 82 (12), 81 (57), 80 (15), 79 (61), 78 (25), 77 (32), 69 (19), 67
(50), 65 (13), 57 (14), 55 (38).
Tetracosa-11,13-diyne (6m):275
pale yellow
oil; tr = 19.5 min; Rf = 0.8 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
2.20-2.25 (t, J = 7.1 Hz, 4H), 1.45-1.55 (m,
4H), 1.25-1.30 (m, 28H), 0.85-0.90 (m, 6H); 13
C NMR (75 MHz, CDCl3): δ 77.5
(2C), 65.2 (2C), 31.9 (2C), 29.6 (2C), 29.5 (2C), 29.3 (2C), 29.1 (2C), 28.8 (2C),
28.3 (2C), 22.7 (2C), 19.2 (2C), 14.1 (2C); IR (ATR): ν 2953, 2923, 2853, 1464,
721 cm-1
; MS (EI) m/z (%): 330 (M+, 0), 189 (15), 175 (21), 163 (11), 162 (11),
161 (35), 149 (15), 148 (17), 147 (38), 135 (30), 134 (21), 133 (54), 131 (14),
123 (11), 122 (16), 121 (67), 120 (19), 119 (60), 117 (25), 115 (12), 109 (25),
108 (15), 107 (48), 106 (17), 105 (59), 103 (11), 96 (12), 95 (57), 94 (24), 93
(55), 92 (25), 91 (100), 83 (20), 82 (20), 81 (71), 80 (21), 79 (66), 78 (24), 77
(27), 69 (33), 67 (65), 65 (11), 57 (27), 55 (50).
275 T.-P. Cheng, B.-S. Liao, Y.-H. Liu, S.-M. Peng, S.-T. Liu, Dalton Trans. 2012, 41, 3468-3473.
183 Experimental Part
1,10-Dichlorodeca-4,6-diyne (6n):272
pale
yellow oil; tr = 13.5 min; Rf = 0.67
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 3.60-3.65 (t, J = 6.3 Hz, 4H), 2.45-2.50 (t, J = 6.8 Hz, 4H), 1.95-
2.00 (p, J = 6.5 Hz, 4H); 13
C NMR (75 MHz, CDCl3): δ 75.8 (2C), 66.0 (2C),
43.4 (2C), 31.0 (2C), 16.6 (2C); IR (ATR): ν 2960, 2927, 1288 cm-1
; MS (EI) m/z
(%): 206 (M+
+ 4, 10), 204 (M+
+ 2, 61), 202 (M+, 88), 176 (16), 174 (20), 167
(20), 141 (15), 139 (42), 131 (39), 130 (10), 129 (20), 128 (10), 127 (20), 125
(47), 117 (45), 116 (38), 114 (61), 112 (26), 111 (11), 105 (33), 104 (33), 103
(93), 102 (14), 91 (100), 89 (29), 79 (12), 78 (25), 77 (86), 76 (25), 74 (16), 65
(22), 64 (12), 63 (36), 62 (10), 53 (11), 51 (29).
4.2. HYDRATION OF 1,3-DIYNES TO AFFORD 2,5-DISUBSTITUTED
FURANS
General Procedure: CuO-Fe3O4 (5 mg, 0.26 mol%) and t-BuOK (112
mg, 1 mmol) were added to a stirred solution of the appropiate alkyne 5 (1 mmol)
and the resulting mixture was stirred at 60 ºC until the reaction was complete.
The catalyst was then removed by using a magnet and washed with DMSO (5
mL). The DMSO washings were combined with the original reaction solution,
and KOH (280 mg, 5 mmol, 500 mol%) and H2O (4 mmol, 400 mol%) were
added under air. The resulting solution was stirred at 80 ºC for 1 day, then the
reaction was quenched by addition of H2O (5 mL). The resulting mixture was
extracted with EtOAc (2 x 5 mL) and the combined organic phases were dried
with MgSO4 and concentrated under reduced pressure. The residue was purified
by column chromatography to give the corresponding products 7.
2,5-Diphenylfuran (7a):134
pale yellow solid; m.p.
= 47-52 ºC (hexane); tr = 15.8 min; Rf = 0.73
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.70-7.75 (m, 4H), 7.40-7.45 (m, 4H),
7.25-7.30 (m, 2H), 6.75 (s, 2H); 13
C NMR (75
MHz, CDCl3): δ 153.3 (2C), 130.7 (2C), 128.7 (4C), 127.3 (2C), 123.7 (4C),
107.2 (2C); IR (ATR): ν 3022, 1259, 1023, 927 cm-1
; MS (EI) m/z (%): 221 (M+
+ 1, 18), 220 (M+, 100), 191 (20), 115 (32), 105 (16), 77 (29), 51 (10).
Experimental Part 184
2,5-Bis(4-methoxyphenyl)furan
(7b):276
white solid; m.p. = 189-192 ºC
(hexane); tr = 17.5; Rf = 0.20
(hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.65-7.70 (d, J =
9.0 Hz, 4H), 6.90-6.95 (d, J = 9.0 Hz, 4H), 6.58 (s, 2H), 3.85 (s, 6H); 13
C NMR
(75 MHz, CDCl3): δ 158.8 (2C), 152.8 (2C), 124.0 (2C), 125.0 (4C), 114.1 (4C),
105.5 (2C), 55.3 (2C); IR (ATR): ν 2839, 1600, 1509, 1018 cm-1
; MS (EI) m/z
(%): 281 (M+
+ 1, 20), 280 (M+, 100), 266 (16), 265 (87), 140 (14).
2,5-Di-p-tolylfuran (7c):276
white solid; m.p. =
114-117 ºC (hexane); tr = 17.9 min; Rf = 0.73
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.60-7.65 (d, J = 8.1 Hz, 4H), 7.20-
7.25 (d, J = 8.1 Hz, 4H), 6.70 (s, 2H), 2.40 (s,
6H); 13
C NMR (75 MHz, CDCl3): δ 153.0 (2C), 136.9 (2C), 129.2 (4C), 128.0
(2C), 123.4 (4C), 106.3 (2C), 21.2 (2C); IR (ATR): ν 3020, 2914, 2856, 1605,
1503, 1021 cm-1
; MS (EI) m/z (%): 249 (M+
+ 1, 20), 248 (M+, 10), 129 (9).
2,5-Bis(4-(trifluoromethyl)phenyl)furan
(7d):134
pale yellow solid; m.p. = 139-141
ºC (hexane); tr = 15.5; Rf = 0.57
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.85-7.90 (d, J = 8.1 Hz,
4H), 7.65-7.70 (d, J = 8.1 Hz, 4H), 6.9 (s, 2H); 13
C NMR (75 MHz, CDCl3): δ
152.8 (2C), 133.4 (2C), 129.4 (q, 2JC-F = 33.2 Hz, 2C), 125.8 (q,
3JC-F = 3.7 Hz,
4C), 124.1 (q, 1JC-F = 271.8 Hz, 2C), 123.9 (4C), 109.4 (2C); IR (ATR): ν 1617
cm-1
; MS (EI) m/z (%): 357 (M+
+ 1, 20), 356 (M+, 100), 337 (10), 183 (21), 173
(11), 145 (17).
4.3. DECARBOXYLATIVE COUPLING OF 3-PHENYLPROP-2-YONIC
ACID
General Procedure: Et3N (0.07 mL, 138 mol%), DMF (1.5 mL), and
CuO-Fe3O4 (50 mg, 2.1 mol%) or NiO/Cu-Fe3O4 (50 mg, 1.5/1.83 mol%) were
added to a stirred solution of alkynoic acid 8 (0.6 mmol) under air, and the
276 P. Nun, S. Dupuy, S. Gaillard, A. Poater, L. Cavallo, S. P. Nolan, Catal. Sci. Technol. 2011, 1,
58-61.
185 Experimental Part
resulting mixture was stirred at 130 ºC for 2 days. The catalyst was removed by
using a magnet and washed with EtOAc (2 x 5 mL) and H2O (2 x 5 mL). The
collected organic phases were dried with MgSO4 and concentrated under reduced
pressure. The residue was purified by column chromatography giving the
corresponding product 6a.
4.4. SYNTHESIS OF ARYL IMINES DERIVATIVES FROM ALCOHOLS
AND AMINES
General Procedure: To a stirred solution of the corresponding alcohol (9,
1 mmol) in toluene (3 mL) under an Ar atmosphere was added CuO-Fe3O4 (50
mg, 1.3 mol%), NaOH (56 mg, 1.4 mmol) and the corresponding amine (10, 2
mmol). The resulting mixture was stirred at 100 ºC for 4 days. The catalyst was
removed by a magnet and washed with EtOAc (2 x 5 mL). The collected organic
phases were dried with MgSO4, and the solvents were removed under reduced
pressure. The product was purified either by bulb-to-bulb distillation or
crystallization to give the corresponding pure products 11.
(E)-N-Benzylideneaniline (11a):277
pale yellow oil; tr =
13.3; Rf = 0.37 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 8.46 (s, 1H), 7.90-7.95 (m, 2H),
7.2-7.5 (m, 8H); 13
C NMR (75 MHz, CDCl3): 160.4,
152.0, 136.2, 131.4, 129.1 (2C), 128.8 (4C), 125.9,
120.9 (2C); IR (ATR): ν 1621, 1597 cm-1
; MS (EI) m/z (%): 182 (M+
+ 1, 11),
181 (M+, 100), 104 (8), 77 (35), 51 (12).
(E)-N-Benzylidene-3-chloroaniline (11b):278
pale
yellow oil; tr = 14.8; Rf = 0.87 (hexane/ethyl acetate:
4/1); 1
H NMR (300 MHz, CDCl3): δ 8.4 (s, 1H),
7.85-7.90, 7.40-7.50, 7.30-7.35, 7.15-7.20, 7.05-7.10
(5m, 1, 2, 1, 3 and 2H, respectively); 13
C NMR (75
MHz, CDCl3): δ 161.3, 153.3, 135.8, 134.7, 131.7, 130.0, 128.9 (2C), 128.8 (2C),
125.8, 120.9, 119.4; IR (ATR): ν 1622, 1582, 1067 cm-1
; MS (EI) m/z (%): 217
(M+
+ 1, 31), 216 (M+, 45), 215 (93), 214 (100), 111 (26), 89 (10), 75 (15).
277 L. C. da Silva-Filho, V. L. Júnior, M. G. Constantino, G. V. J. da Silva, Synthesis 2008, 16,
2527-2536. 278 H. Naeimi, H. Sharghi, F. Salimi, K. Rabiei, Heteroat. Chem. 2008, 19, 43-47.
Experimental Part 186
(E)-N-Benzylidene-4-methoxyaniline (11c):139c
white solid; m.p. = 66-68 ºC (hexane); tr = 15.4; Rf
= 0.53 (hexane/ethyl acetate: 4/1); 1
H NMR (300
MHz, CDCl3): δ 8.51 (s, 1H), 7.90-7.95 (m, 2H),
7.45-7.50 (m, 3H), 7.25-7.30 (m, 2H), 6.95-7.00
(m, 2H), 3.85 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 158.3, 158.2, 144.8, 136.4,
131.0, 128.7 (2C), 128.5 (2C), 122.1 (2C), 114.3 (2C), 55.4; IR (ATR): ν 1609,
1581, 1247 cm-1
; MS (EI) m/z (%): 212 (M+
+ 1, 14), 211 (M+, 88), 210 (15), 197
(15), 196 (100), 167 (22).
(E)-N-Benzylidene-2,5-dimethylaniline (11d):279
orange solid; m.p. = 86-90 ºC (hexne); tr = 14.5; Rf =
1.5 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 8.36 (s, 1H), 7.90-7.95 (m, 2H), 7.45-7.50
(m, 3H), 7.11 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6
Hz, 1H), 6.75 (s, 1H), 2.34 (s, 3H), 2.31 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ
159.4, 151.1 (2C), 136.7, 136.4, 131.3, 130.2, 128.8 (4C), 126.4, 118.5, 21.2,
17.5; IR (ATR): ν 3019, 1629, 1573 cm-1
; MS (EI) m/z (%): 210 (M+
+ 1, 19),
209 (M+, 100), 208 (96), 194 (13), 193 (33), 132 (100), 131 (12), 130 (13), 117
(16), 105 (12), 103 (16), 79 (14), 77 (27).
(E)-N-Benzylidenebutan-1-amine (11e):142c
brown
oil; tr = 10.1; Rf = 0.56 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 8.30 (s, 1H), 7.40-7.70
(m, 5H), 3.60 (t, J = 6.4 Hz, 2H), 1.35-1.70 (2m, 4H),
0.95 (t, J = 6.6 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 160.9, 136.4, 130.6,
128.7 (2C), 128.1 (2C), 61.6, 33.1, 20.6, 14.0; IR (ATR): ν 3026, 1645, 1451 cm-
1; MS (EI) m/z (%): 161.1 (M
+, 8) 160.1 (21), 132 (31), 119 (29), 118 (100), 117
(10), 105 (10), 104 (30), 91 (93), 90 (9), 89 (13), 84 (19), 83 (14), 77 (15).
(E)-N-Benzylidene-2,2-dimethylpropan-1-amine
(11f):280
yellow oil; tr = 9.9; Rf = 0.63 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 8.23 (s,
1H), 7.75-7.80 (m, 2H), 7.35-7.45 (m, 3H), 3.37 (s,
2H), 0.98 (s, 9H); 13
C NMR (75 MHz, CDCl3): δ 160.9, 136.6, 130.5, 128.7 (2C),
128.2 (2C), 74.1, 32.8, 28.1 (3C); IR (ATR): ν 3027, 1742, 1645 cm-1
; MS (EI)
279 R. Nagarajan, P. T. Perumal, Synth. Commun. 2001, 31, 1733-1736. 280 W. D. Jones, E. T. Hessell, Organometallics 1990, 9, 718-727.
187 Experimental Part
m/z (%): 175 (M+, 9) 174 (21), 160 (16), 119 (37), 118 (100), 117 (10), 91 (100),
90 (9), 89 (10).
(E)-N-Benzylidenedodecan-1-amine (11g):143
yellow
oil; tr = 16.4; Rf = 0.6 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 8.26 (s, 1H), 7.70-7.75,
7.25-7.40 (2m, 3 and 2H, respectively), 3.60 (t, J = 6.7
Hz, 2H), 1.65-1.75 (m, 2H), 1.20-1.50 (m, 18H), 0.88 (t, J = 5.4 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): δ 160.6, 136.3, 130.3, 128.5 (2C), 128.0 (2C), 61.8,
31.9, 30.9, 29.6 (3C), 29.5, 29.4, 29.3, 27.3, 22.6, 14.0; IR (ATR): ν 3021, 1647,
1466 cm-1
; MS (EI) m/z (%): 273 (M+, 2), 174 (16), 161 (12), 160 (100), 132
(25), 119 (16), 118 (35), 104 (11), 91 (29).
(E)-N-(4-Chlorobenzylidene)aniline (11h):146a
yellow solid; m.p. = 51-54 ºC (hexane); tr = 14.8; Rf
= 0.7 (hexane/ethyl acetate: 4/1); 1
H NMR (300
MHz, CDCl3): δ 8.37 (s, 1H), 7.75-7.85, 7.35-7.40,
7.15-7.20 (3m, 3, 4 and 2H, respectively); 13
C NMR
(75 MHz, CDCl3): δ 158.6, 151.5, 137.2, 134.6, 129.8 (2C), 129.3, 129.1 (2C),
128.9 (2C), 120.8 (2C); IR (ATR): ν 1621, 1578, 1092 cm-1
; MS (EI) m/z (%):
217 (M+
+ 1, 32), 216 (M+, 46), 215 (95), 214 (100), 104 (10), 77 (43), 51 (13).
(E)-3-Chloro-N-(4-
chlorobenzylidene)aniline (11i):281
brown
oil; tr = 16.1; Rf = 0.67 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 8.39 (s,
1H), 7.82 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5
Hz, 2H), 7.20-7.35 (m, 4H); 13
C NMR (75
MHz, CDCl3): δ 159.9, 152.9, 137.8, 134.8, 134.3, 130.2, 130.1 (2C), 129.2 (2C),
126.1, 120.9, 119.4; IR (ATR): ν 3060, 1596, 1485 cm-1
; MS (EI) m/z (%): 253
(M+
+ 4, 10), 252 (M+
+ 3, 18), 251 (M+
+ 2, 64), 250 (M+
+ 1, 74), 249 (M+, 100),
248 (99), 138 (19), 113 (20), 112 (13), 111 (63), 89 (26), 77 (10), 76 (12), 75
(45), 51 (10).
281 S. S. Karki, S. R. Butle, R. M. Shaikh, P. K. Zubaidha, G. S. Pedgaonkar, G. S. Shendarkar, C.
G. Raiput, Res. J. Pharm. Biol. Chem. Sci. 2010, 1, 707-717.
Experimental Part 188
(E)-N-(4-Methylbenzylidene)aniline (11j):277
yellow oil; tr = 14.3; Rf = 0.67 (hexane/ethyl acetate:
4/1); 1
H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H),
7.78 (d, J = 8.0 Hz, 2H), 7.10-7.25 (m, 7H), 2.40 (s,
3H); 13
C NMR (75 MHz, CDCl3): δ 160.4, 145.3,
141.8, 133.5, 129.5 (2C), 128.7 (2C), 120.8, 118.4 (2C), 115.0 (2C), 21.6; IR
(ATR): ν 3027, 1602, 1498 cm-1
; MS (EI) m/z (%): 196 (M+
+ 1, 20), 195 (M+,
100), 194 (100), 91 (19), 77 (58), 51 (16).
(E)-N-(4-Methoxybenzylidene)aniline (11k):139c
yellow solid; m.p. = 45-48 ºC (hexane); tr = 15.4;
Rf = 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 8.32 (s, 1H), 7.75-7.85, 7.30-
7.35, 7.15-7.20, 6.90-6.95 (4m, 2, 3, 2 and 2H,
respectively), 3.78 (s, 3H); 13
C NMR (75 MHz,
CDCl3): δ 161.7, 159.1, 151.8, 130.0, 128.7 (2C), 128.6 (2C), 125.0, 120.4 (2C),
113.6 (2C), 54.8; IR (ATR): ν 1679, 1600, 1245 cm-1
; MS (EI) m/z (%): 213 (M+,
1), 212 (13), 211 (88), 210 (100), 167 (12), 77 (20).
(E)-3-Chloro-N-(4-
methoxybenzylidene)aniline (11l):282
brown oil; tr = 16.7; Rf = 0.57 (hexane/ethyl
acetate: 4/1); 1
H NMR (300 MHz, CDCl3): δ
8.33 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.15-
7.30 (m, 6H), 3.86 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 162.4, 160.6, 159.5, 153.5, 134.7, 130.2, 130.1 (2C), 118.3,
114.2, 113.8 (2C), 113.1, 55.2; IR (ATR): ν 1621, 1597, 1243, 1027 cm-1
; MS
(EI) m/z (%): 247 (M+
+ 2, 32), 246 (M+
+ 1, 45), 245 (M+, 96), 244 (100), 111
(23), 77 (10), 75 (17).
(E)-N-(3-Methylbenzylidene)aniline (11m):277
brown oil; tr = 14.3; Rf = 0.7 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 7.75
(s, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.20-7.40 (m, 7H),
2.41 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 160.6,
152.1, 138.5, 136.1, 132.2, 129.1 (2C), 128.9, 128.6,
126.4, 125.8, 120.8 (2C), 21.3; IR (ATR): ν 3030,
282 S. Oumar, M. Righezza, Anal. Chim. Acta 1997, 356, 187-193.
189 Experimental Part
1627, 1584 cm-1
; MS (EI) m/z (%): 196 (M+
+ 1, 15), 195 (M+, 100), 194 (100),
104 (11), 91 (14), 77 (52), 51 (15).
(E)-N-(3-Methoxybenzylidene)aniline (11n):277
yellow oil; tr = 15.2; Rf = 0.6 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 8.40 (s, 1H), 7.40
(s, 1H), 7.20-7.35 (m, 8H), 3.83 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 160.3, 159.8, 151.8, 137.4, 129.5,
129.1 (2C), 125.9, 122.3, 120.8 (2C), 118.3, 111.6,
55.1; IR (ATR): ν 3005, 1601, 1584, 1265, 1037 cm-1
;
MS (EI) m/z (%): 212 (M+
+ 1, 24), 211 (M+, 100), 210 (100), 182 (11), 181 (26),
180 (13), 168 (10), 167 (24), 104 (18), 77 (63), 51 (16).
(E)-N-(3,5-Dimethylbenzylidene)aniline (11o):283
brown oil; tr = 14.9; Rf = 0.67 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.5
(s, 2H), 7.35-7.40 (m, 2H), 7.15-7.25 (m, 4H), 2.40
(s, 6H); 13
C NMR (75 MHz, CDCl3): 161.0, 152.3,
138.1 (2C), 136.2, 133.3, 129.2 (2C), 126.7 (2C),
125.9, 124.9 (2C), 21.3 (2C); IR (ATR): ν 3014, 1625, 1588 cm-1
; MS (EI) m/z
(%): 210 (M+
+ 1, 44), 209 (M+, 100), 208 (100), 194 (14), 193 (13), 165 (12),
105 (11), 104 (25), 103 (13), 91 (26), 78 (13), 77 (100), 51 (25).
(E)-3-Chloro-N-(3,5-
dimethylbenzylidene)aniline (11p): brown oil; tr
= 16.1. Rf = 0.7 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 8.33 (s, 1H), 7.84 (d, J
= 8.6 Hz, 2H), 6.95-7.10 (m, 5H), 3.80 (s, 6H); 13
C
NMR (75 MHz, CDCl3): δ 161.9, 147.6, 138.1
(2C), 135.6, 134.7, 130.2, 129.8, 126.0 (2C), 118.2, 114.8, 113.0, 21.1 (2C); IR
(ATR): ν 3019, 1597, 1485 cm-1
; MS (EI) m/z (%): 245 (M+
+ 2, 31), 244 (M+
+
1, 48), 243 (M+, 96), 242 (100), 109 (23), 91 (12), 76 (11), 75 (13); HRMS calcd.
(%) for C15H14ClN: 243.0815; found: 243.0800.
283 A. M. Voutchkova, R. H. Crabtree, J. Mol. Catal. A 2009, 312, 1-6.
Experimental Part 190
(E)-N-(3,5-Dimethoxybenzylidene)aniline
(11q):284
brown oil; tr = 16.7; Rf = 0.5
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): 8.40 (s, 1H), 7.35-7.40 (m, 2H), 7.20-
7.25 (m, 3H), 7.05 (d, J = 2.3 Hz, 2H), 6.58 (t, J
= 2.3 Hz, 1H), 3.84 (s, 6H); 13
C NMR (75 MHz,
CDCl3): 161.1 (2C), 160.4, 152.0, 138.3, 129.2 (2C), 126.1, 121.0 (2C), 106.5
(2C), 104.3, 55.6 (2C); IR (ATR): ν 3004, 1627, 1587, 1151 cm-1
; MS (EI) m/z
(%): 242 (M+
+ 1, 37), 241 (M+, 100), 240 (100), 226 (10), 212 (23), 211 (56),
210 (19), 196 (12), 183 (10), 182 (18), 167 (12), 154 (12), 104 (24), 78 (10), 77
(78), 51 (18).
(E)-3-Chloro-N-(3,5-
dimethoxybenzylidene)aniline (11r): red oil;
tr = 17.9; Rf = 0.5 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 8.31 (s, 1H),
7.20-7.30 (m, 3H), 7.05-7.10 (m, 4H), 3.84 (s,
6H); 13
C NMR (75 MHz, CDCl3): δ 161.2,
160.9 (2C), 153.0, 147.6, 137.7, 130.2 (2C),
130.1, 125.8, 120.8, 119.3, 104.4, 55.6 (2C); IR (ATR): ν 3004, 1593, 1484,
1204, 1064 cm-1
; MS (EI) m/z (%): 277 (M+
+ 2, 32), 276 (M+
+ 1, 47), 275 (M+,
100), 274 (99), 246 (12), 245 (21), 138 (11), 111 (20); HRMS calcd. (%) for
C15H14ClNO2: 275.0713; found: 275.0730.
4.5. SYNTHESIS OF ARENECARBALDEHYDES
General Procedure: To a stirred solution of the corresponding alcohol (9,
1 mmol) in toluene (3 mL) under an Ar atmosphere was added CuO-Fe3O4 (50
mg, 1.3 mol%), NaOH (56 mg, 1.4 mmol) and the corresponding aniline (10a,
0.18 mL, 2 mmol). The resulting mixture was stirred at 100 ºC for 4 days. The
catalyst was removed by a magnet and then HCl (2 mL) and ether (2 mL) were
added. The resulting mixture was stirred for 2 h at room temperature, and then it
was quenched with water (2 mL) and extracted with EtOAc (3 x 5 mL). The
organic phases were dried with MgSO4, followed by evaporation under reduced
pressure to remove the solvent. The product was purified by vacuum distillation
at 120 ºC to give the corresponding products 2.
284 D. Blanco-Ania, P. H. H. Hermkers, L. A. J. M. Sliedregt, H. W. Scheeren, F. P. J. T. Rutjes,
Tetrahedron 2009, 65, 5393-5401.
191 Experimental Part
Benzaldehyde (2a):285
colorless oil; tr = 6.1; Rf = 0.6
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
10.01 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.50-7.65 (m, 3H); 13
C
NMR (75 MHz, CDCl3): δ 192.2, 136.5, 134.3, 129.6 (2C),
128.8 (2C); IR (ATR): ν 3060, 1697 cm-1
; MS (EI) m/z (%): 106
(M+, 100), 105 (96), 78 (17), 77 (98), 51 (37).
4-Chlorobenzaldehyde (2j):286
white solid; m.p. = 46-48
ºC (hexane); tr = 8.3; Rf = 0.53 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 9.99 (s, 1H), 7.83
(d, J = 7.9 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H); 13
C NMR
(75 MHz, CDCl3): δ 190.9, 141.0, 134.7, 130.9 (2C),
129.5 (2C); IR (ATR): ν 1687, 1574 cm-1
; MS (EI) m/z (%): 142 (M+
+ 2, 35),
141 (M+
+ 1, 56), 140 (M+, 100), 139 (100), 113 (27), 112 (13), 111 (87), 77 (22),
76 (11), 75 (39), 74 (21), 51 (16).
4-Methylbenzaldehyde (2d):285
colorless oil; tr = 7.8; Rf =
0.53 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3):
δ 9.94 (s, 1H), 7.75-7.80 (m, 2H), 7.30-7.35 (m, 2H), 2.40 (s,
3H); 13
C NMR (75 MHz, CDCl3): δ 191.8, 145.3, 133.9,
129.6 (2C), 129.5 (2C), 21.6; IR (ATR): ν 1700, 1603 cm-1
;
MS (EI) m/z (%): 121 (M+
+ 1, 12), 120 (M+, 100), 119 (100),
92 (16), 91 (100), 89 (16), 65 (38), 63 (20), 51 (11).
4-Methoxybenzaldehyde (2e):285
yellow oil; tr = 9.7; Rf
= 0.37 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 9.87 (s, 1H), 7.80-7.85 (m, 2H), 7.00-7.05 (m,
2H), 3.87 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 190.5,
164.3, 131.7 (2C), 129.6, 114.0 (2C), 55.3; IR (ATR): ν
1681, 1509, 1255, 1022 cm-1
; MS (EI) m/z (%): 137 (M+
+ 1, 14), 136 (M+, 100), 135 (100), 107 (34), 92 (35), 77 (59), 65 (17), 64 (16),
63 (19), 51 (11).
285 P. Paraskevopoulu, N. Psaroudakis, S. Koinis, P. Stavropoulos, K. Mertis, J. Mol. Catal. A
2005, 240, 27-32. 286 K. Fujita, T. Yoshiba, Y. Imori, R. Yamaguchi, Org. Lett. 2011, 13, 2278-2281.
Experimental Part 192
3-Methylbenzaldehyde (2c):285
brown oil; tr = 7.6; Rf = 0.57
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.95
(s, 1H), 7.65 (s, 2H), 7.40 (s, 2H), 2.40 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 192.3, 138.7, 136.3, 135.0, 129.7, 128.6,
127.0, 20.9; IR (ATR): ν 1699, 1587 cm-1
; MS (EI) m/z (%):
121 (M+
+ 1, 14), 120 (M+, 100), 119 (100), 92 (19), 91 (100),
89 (17), 65 (42), 63 (22), 51 (11).
3-Methoxybenzaldehyde (2s):285
yellow oil; tr = 9.1; Rf = 0.57
(hexane/ethyl acetate: 4/1); 1
H NMR (300 MHz, CDCl3): δ 9.98
(s, 1H), 7.40-7.45 (m, 3H), 7.15-7.20 (m, 1H), 3.87 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 192.0, 160.1, 137.8, 130.0, 123.5,
121.4, 112.0, 55.4; IR (ATR): ν 1699, 1585, 1260, 1037 cm-1
;
MS (EI) m/z (%): 136 (M+, 100), 135 (96), 107 (35), 92 (16), 77
(35), 65 (18), 64 (11), 63 (14).
2,6-Dichlorobenzaldehyde (2t):287
white solid; m.p. = 69-71
ºC (hexane); tr = 10.5; Rf = 0.6 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 10.50 (s, 1H), 7.40 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 188.8, 136.8 (3C), 133.6, 129.7
(2C); IR (ATR): ν 3092, 1697, 1576 cm-1
; MS (EI) m/z (%): 178 (M
+ + 4, 8), 177 (M
+ + 3, 16), 176 (M
+ + 2, 49), 175 (M
+ + 1, 85), 174 (M
+,
76), 173 (100), 147 (20), 146 (12), 145 (29), 111 (21), 110 (20), 109 (15), 75
(38), 74 (26).
3,4-Dichlorobenzaldehyde (2u):288
white solid; m.p. = 39-
41 ºC (hexane); tr = 10.1; Rf = 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.95 (s, 1H), 7.96 (d, J = 1.8
Hz, 1H), 7.73 (dd, J = 8.2, 1.8 Hz, 1H), 7.64 (d, J = 8.2 Hz,
1H); 13
C NMR (75 MHz, CDCl3): δ 189.6, 139.1, 135.8,
133.9, 131.2, 131.1, 128.3; IR (ATR): ν 3063, 1698, 1561
cm-1
; MS (EI) m/z (%): 178 (M+
+ 4, 6), 177 (M+
+ 3, 13),
176 (M+
+ 2, 41), 175 (M+
+ 1, 69), 174 (M+, 64), 173 (100), 147 (27), 145 (41),
111 (19), 109 (18), 75 (34), 74 (30), 73 (11).
287 P. Zheng, L. Yan, X. Ji, X. Duan, Synth. Commun. 2011, 41, 16-19. 288 S. Rani, B. R. Bhat, Tetrahedron Lett. 2010, 51, 6403-6405.
193 Experimental Part
3,5-Dimethylbenzaldehyde (2v):289
yellow oil; tr = 8.78; Rf =
0.63 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3):
δ 9.94 (s, 1H), 7.48 (s, 2H), 7.25 (s, 1H), 2.38 (s, 6H); 13
C
NMR (75 MHz, CDCl3): δ 192.7, 138.7 (2C), 136.5, 136.1,
127.5 (2C), 21.0 (2C); IR (ATR): ν 1696, 1608 cm-1
; MS (EI)
m/z (%): 135 (M+
+ 1, 12), 134 (M+, 100), 133 (100), 106 (11),
105 (100), 103 (20), 91 (28), 79 (23), 78 (10), 77 (34), 63 (11), 51 (12).
3,5-Dimethoxybenzaldehyde (2w):
286 white solid; m.p.
= 46-48 ºC (hexane); tr = 11.3; Rf = 0.43 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.91 (s,
1H), 7.01 (d, J = 2.5 Hz, 2H), 6.71 (t, J = 2.5 Hz, 1H),
3.85 (s, 6H); 13
C NMR (75 MHz, CDCl3): δ 192.0, 161.2
(2C), 138.3, 107.2, 107.1 (2C), 55.6 (2C); IR (ATR): ν
3060, 1697, 1590, 1206, 1064 cm-1
; MS (EI) m/z (%): 167 (M+
+ 1, 17), 166 (M+,
100), 165 (68), 137 (30), 135 (46), 122(28), 109 (21), 107 (22), 95 (14), 79 (13),
77 (17), 63 (19), 51 (10).
3,4,5-Trimethoxybenzaldehyde (2f):290
white solid; m.p.
= 71-73 ºC (hexane); tr = 12.7; Rf = 0.20 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 9.88 (s, 1H),
7.14 (s, 2H), 3.95 (s, 3H), 3.94 (s, 6H); 13
C NMR (75
MHz, CDCl3): δ 191.1, 153.6 (2C), 131.6 (2C), 106.6
(2C), 61.0, 56.2 (2C); IR (ATR): ν 1682, 1585, 1123, 990 cm
-1; MS (EI) m/z (%): 197 (M
+ + 1, 11), 196 (M
+, 100), 181 (41), 125 (22), 110
(17), 95 (11), 93 (10).
4.6. SYNTHESIS OF ARYL IMINES DERIVATIVES FROM PRIMARY
AMINES
General Procedure: To a stirred solution of the corresponding amine (13,
2 mmol) in toluene (3 mL) under air was added CuO-Fe3O4 (50 mg, 2.6 mol%)
and NaOH (120 mg, 2 mmol). The resulting mixture was stirred at 100 ºC for 3
days. The catalyst was removed by a magnet and washed with EtOAc (2 x 5 mL).
The collected organics phases were dried with MgSO4, and the solvents were
289 M. Zahmakiran, S. Akbayrak, T. Kodaira, S. Özkar, Dalton Trans. 2010, 39, 7521-7527. 290 L. J. Gooβen, B. A. Khan, T. Fett, M. Tren, Adv. Synth Catal. 2010, 352, 2166-2170.
Experimental Part 194
removed under reduced pressure. The product was purified either by bulb-to-bulb
distillation or crystallization to give the corresponding pure products 14.
(E)-N-Benzylidene-1-phenylmethanamine (14a):137g
brown oil; tr = 13.9; Rf = 0.56 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): 8.39 (s, 1H),
7.78 (d, J = 3.3 Hz, 2H), 7.20-7.50 (m, 8H), 4.82 (s,
2H); 13
C NMR (75 MHz, CDCl3): 162.0, 139.2, 136.1, 130.7, 128.6 (2C), 128.5
(2C), 128.2 (2C), 127.9 (2C), 126.9, 65.0; IR (ATR): ν 3061, 3027, 1643, 1579
cm-1
; MS (EI) m/z (%): 196 (M+
+ 1, 7), 195 (M+, 45), 194 (44), 117 (12), 92
(33), 91 (100), 89 (15), 65 (14).
(E)-N-(4-Methylbenzylidene)-1-(p-
tolyl)methanamine (14b):137g
white solid; m.p.
= 51-53ºC (hexane); tr = 15.4; Rf = 0.6
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3); 8.34 (s, 1H), 7.66 (d, J = 7.8 Hz, 2H),
7.10-7.25 (m, 6H), 4.77 (s, 2H), 2.34 (s, 6H); 13
C NMR (75 MHz, CDCl3);
161.7, 140.9, 136.5, 136.3, 133.6, 129.3 (2C), 129.1 (2C), 128.2 (2C), 127.9
(2C), 64.8, 21.5, 21.1; IR (ATR): ν 3015, 1646, 1558 cm-1
; MS (EI) m/z (%): 223
(M+, 27), 222 (12), 106 (20), 105 (100), 77 (12).
(E)-N-(3-Methylbenzylidene)-1-(m-
tolyl)methanamine (14c):291
yellow oil; tr = 15.2;
Rf = 0.5 (hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3); 8.35 (s, 1H), 7.64 (s, 2H), 7.25-
7.60 (m, 6H), 4.77 (s, 2H), 2.37 (s, 3H), 2.33 (s,
3H); 13
C NMR (75 MHz, CDCl3): 162.1, 139.1, 138.4, 138.3, 138.0, 132.6,
131.5, 128.7, 128.1, 127.7, 125.8, 125.0, 124.2, 65.1, 21.3, 21.2; IR (ATR): ν
1652, 1568 cm-1
; MS (EI) m/z (%): 223 (M+, 35), 222 (22), 208 (15), 106 (54),
105 (100), 103 (15), 91 (14), 79 (13), 77 (19).
291 S. M. Landge, V. Atanassova, M. Thimmaiah, B. Torök, Tetrahedron Lett. 2007, 48, 5161-
5164.
195 Experimental Part
4.7. SYNTHESIS OF N-ARYLATED 1,2,3,4-
TETRAHYDROISOQUINOLINES.
General Procedure: Copper(I) iodide (200 mg, 1.0 mmol) and potassium
phosphate (4.25 g, 20.0 mmol) were placed into a 50 mL two-neck flask. The
flask was evacuated and back filled with Ar. 2-Propanol (10.0 mL), ethylene
glycol (1.11 mL), 1,2,3,4-tetrahydroisoquinoline (2.0 mL, 15 mmol) and the
corresponding iodoaryl (10.0 mmol) were added successively by syringe at room
temperature. The reaction mixture was heated at 90 °C for 24 h and then allowed
to cool to room temperature. Et2O (20 mL) and water (20 mL) were then added to
the reaction mixture. The organic layer was extracted with diethyl ether (2 × 20
mL). The combined organic phases were washed with brine and dried over
sodium sulphate. The solvent was removed and the residue was purified by
column chromatography on silica gel using hexane/ethyl acetate (20:1) as an
eluent giving the corresponding products 15.
2-(4-Fluorophenyl)-1,2,3,4-
tetrahydroisoquinoline (15a):292
white solid;
m.p. = 69-71 ºC (ethanol); tr= 15.3; Rf= 0.6
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.10-7.20 (m, 4H), 6.90-7.00 (m, 4H),
4.33 (s, 2H), 3.48 (t, J = 5.9 Hz, 2H), 2.98 (t, J =
5.9 Hz, 2H); 13
C NMR (75 MHz, CDCl3): δ 156.7 (d, 1JC-F = 238.0 Hz), 147.4
(d, 4JC-F = 1.5 Hz), 134.5, 134.3, 128.6, 126.5, 126.4, 126.0, 117.1 (d,
3JC-F
= 7.5 Hz, 2C), 115.5 (d, 2JC-F = 22.0 Hz, 2C), 51.9, 47.8, 29.0; IR (ATR): ν
1505, 1205 cm-1
; MS (EI) m/z (%): 228 (M+
+ 1, 14), 227 (M+, 95), 226 (100),
104 (72), 103 (15), 95 (12), 78 (12).
2-Phenyl-1,2,3,4-tetrahydroisoquinoline (15b):165a
pale yellow solid; m.p. = 45-47 ºC (ethanol); tr = 15.4;
Rf = 0.8 (hexane/ethyl acetate : 4/1); 1H NMR (300
MHz, CDCl3): δ 7.25-7.30 (m, 2H), 7.10-7.20 (m,
4H), 6.96 (d, J = 8.0 Hz, 2H), 6.82 (t, J = 7.3 Hz,
1H), 4.39 (s, 2H), 3.53 (t, J = 5.8 Hz, 2H), 2.96 (t,
J = 5.8 Hz, 2H); 13
C NMR (75 MHz, CDCl3): δ 150.5, 134.8, 134.4, 130.2 (2C),
129.2, 126.5, 126.3, 126.0, 118.6, 115.1 (2C), 50.7, 46.5, 29.1; IR (ATR): ν
292 J.-J. Zhang, Q.-Y. Meng, G.-X. Wang, Q. Liu, B. Chen, K. Feng, C.-H. Tung, L.-Z. Wu, Chem.
Eur. J. 2013, 19, 6443-6450.
Experimental Part 196
3058, 3023, 1598, 1500, 1386 cm-1
; MS (EI) m/z (%): 210 (M+
+ 1, 10), 209 (M+,
82), 208 (M+-1, 100), 104 (56), 78 (10), 77 (17).
2-(4-Methoxyphenyl)-1,2,3,4-
tetrahydroisoquinoline (15c):293
pale orange
solid; m.p. 92-94 ºC (ethanol); tr = 18.6; Rf = 0.5
(hexane/ethyl acetate : 4/1); 1H NMR (300
MHz, CDCl3): δ 7.10-7.20 (m, 4H), 6.95-7.00
(m, 2H), 6.80-6.90 (m, 2H), 4.29 (s, 2H), 3.77
(s, 3H), 3.44 (t, J = 5.8 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H); 13
C NMR (75
MHz, CDCl3): δ 153.6, 145.5, 134.7 (2C), 128.8, 126.6, 126.4, 126.0, 118.1 (2C),
114.7 (2C), 55.8, 52.8, 48.6, 29.2; IR (ATR): ν 2808, 1509, 1239, 1036 cm-1
; MS
(EI) m/z (%): 240 (M+
+ 1, 16), 239 (M+, 100), 238 (M
+ - 1, 93), 224 (22), 135
(27), 120 (20), 104 (24).
General Procedure for the preparation of 2-Tosyl-1,2,3,4-
tetrahydroisoquinoline (15d):294
To a mixture of 1,2,3,4-tetrahydroisoquinoline
(0.2663 g, 2 mmol) and pyridine (0.5 mL), p-toluenesulfonyl chloride (0.46 g,
2.4 mmol) in dry dichloromethane (5 mL) was added slowly and stirred at room
temperature for 1 h. The reaction mixture was then washed with aqueous 1N HCl
(10 mL) and extracted with diethyl ether (2 x 10 mL). The combined organic
phases were washed with water (10 mL), brine solution (10 mL) and dried over
anhydrous sodium sulphate. The filtered solution was concentrated and purified
by column chromatography. Pale yellow solid;
m.p. 132-134 ºC (ethanol); tr = 15.6; Rf = 0.4
(hexane/ethyl acetate : 4/1); 1
H NMR (300
MHz, CDCl3): δ 7.70-7.75 (m, 2H), 7.30-7.40
(m, 2H), 7.14 (dd, J = 5.6, 3.5 Hz, 2H), 7.00-
7.10 (m, 2H), 4.24 (s, 2H), 3.35 (t, J = 5.9 Hz,
2H), 2.93 (t, J = 5.9 Hz, 2H), 2.42 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 143.8,
133.3, 133.1, 131.7, 129.8 (2C), 129.0, 128.9, 127.8 (2C), 126.8, 126.4, 47.6,
43.8, 28.9, 21.6; IR (ATR): ν 3064, 1489, 1338, 1163 cm-1
; MS (EI) m/z (%): 287
(M+, 5), 286 (M
+ - 1, 14), 132 (100), 131 (29), 130 (32), 105 (26), 104 (53), 103
(15), 91 (29), 77 (16).
293 M. Brzozowski, J. A. Forni, P. G. Savage, A. Polyzos, Chem. Commun. 2015, 51, 334-337. 294 S. O’Sullivan, E. Doni, T. Tuttle, J. A. Murphy, Angew. Chem. Int. Ed. 2014, 53, 474-478.
197 Experimental Part
4.8. SYNTHESIS OF 1-SUBSTITUTED-N-ARYLATED 1,2,3,4-
TETRAHYDROISOQUINOLINES.
General Procedure: To a stirred solution of the corresponding
tetrahydroisoquinoline 15 (0.5 mmol) and catalyst (100 mg, 3.64 mol%) in 1 mL
of DES were added and the corresponding nucleophiles 5 or 18 (1 mmol). The
resulting mixture was stirred at 50 ºC during 3 days until the end of the reaction.
The mixture was quenched with water and extracted with AcOEt (3 x 5 mL). The
organic phases were dried over MgSO4, followed by evaporation under reduced
pressure to remove the solvent. The product was usually purified by
chromatography on silica gel (hexane/ethyl acetate) and/or distillation to give the
corresponding product 16.
2-(4-Fluorophenyl)-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (16a): brown oil; tr = 21.0;
Rf = 0.6 (hexane/ethyl acetate : 4/1); 1
H NMR (300
MHz, CDCl3): δ 7.35-7.40 (m, 1H), 7.20-7.30
(m, 8H), 7.05-7.10 (m, 2H), 7.00-7.05 (m, 2H),
5.54 (s, 1H), 3.60-3.65 (m, 2H), 3.10-3.20 (m,
1H), 2.96 (dt, J = 16.3, 3.6 Hz, 1H); 13
C NMR
(75 MHz, CDCl3): δ 157.4 (d, 1JC-F = 239.3 Hz),
146.4, 135.1, 134.0, 131.7 (2C), 129.0, 128.1 (3C), 127.4, 127.2, 126.2, 122.8,
119.4 (d, 3JC-F = 7.7 Hz, 2C), 115.5 (d,
2JC-F = 22.2 Hz, 2C), 88.1, 85.3, 53.7,
44.0, 29.0; IR (ATR): ν 3056, 3026, 1506, 1489 cm-1
; MS (EI) m/z (%): 328 (M+
+ 1, 9), 327 (M+, 50), 326 (M
+-1, 100), 222 (10), 207 (14), 204 (27), 203 (33),
202 (36), 102 (22); HRMS calcd. (%) for C23H18FN: 327.1423; found: 327.1412.
2-Phenyl-1-(phenylethynyl)-1,2,3,4-
tetrahydroisoquinoline (16b):158i
yellow oil; tr = 21.4;
Rf = 0.6 (hexane/ethyl acetate : 4/1); 1
H NMR (300
MHz, CDCl3): δ 7.35-7.40 (m, 1H), 7.25-7.35 (m,
4H), 7.20-7.25 (m, 6H), 7.12 (dd, J = 8.7, 0.9 Hz,
2H), 6.88 (dd, J = 7.7, 6.8 Hz, 1H), 5.64 (s, 1H),
3.8-3.9 (m, 1H), 3.67 (ddd, J = 12.4, 10.2, 4.0 Hz,
1H), 3.14 (ddd, J = 16.1, 10.2, 6.1 Hz, 1H), 2.97
(dt, J = 16.1, 4.0 Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 149.5, 135.4, 134.4,
131.7 (2C), 129.1 (2C), 128.9, 128.0 (2C), 128.0, 127.4, 127.2, 126.2, 123.0,
119.6, 116.7 (2C), 88.6, 84.7, 52.3, 43.4, 28.9; IR (ATR): ν 3059, 3024, 1596,
1501, 1490 cm-1
; MS (EI) m/z (%): 310 (M+
+ 1, 13), 309 (M+, 63), 308 (100),
204 (27), 203 (21), 202 (27), 77 (8).
Experimental Part 198
2-(4-Methoxyphenyl)-1-(phenylethynyl)-
1,2,3,4-tetrahydroisoquinoline (16c):158i
brown
oil; tr = 25.1; Rf = 0.5 (hexane/ethyl acetate : 4/1);
1H NMR (300 MHz, CDCl3): δ 7.35 (dd, J =
5.0, 3.9 Hz, 1H), 7.15-7.35 (m, 8H), 7.05-7.15
(m, 2H), 6.85-6.95 (m, 2H), 5.51 (s, 1H), 3.78
(s, 3H), 3.45-3.70 (m, 2H), 3.15 (ddd, J =
16.4, 6.2, 3.4 Hz, 1H), 2.93 (dt, J = 16.4, 3.4
Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 154.3, 144.1, 135.4, 134.0, 131.7 (2C),
129.0, 128.0 (2C), 127.9, 127.5, 127.1, 126.1, 123.1, 120.2 (2C), 114.4 (2C),
88.4, 85.5, 54.6, 54.4, 44.2, 29.0; IR (ATR): ν 1509, 1242, 1035 cm-1
; MS (EI)
m/z (%): 339 (M+, 82), 338 (M
+ - 1, 100), 291 (29), 283 (35), 281 (51), 218 (28),
208 (47), 207 (95), 204 (31), 203 (33), 202 (31), 133 (28), 115 (28), 102 (40), 92
(31), 78 (33), 61 (36).
2-(4-Fluorophenyl)-1-((4-
methoxyphenyl)ethynyl)-1,2,3,4-
tetrahydroisoquinoline (16f): pale yellow oil; tr =
26.4; Rf = 0.4 (hexane/ethyl acetate : 4/1); 1
H
NMR (300 MHz, CDCl3): δ 7.30-7.35 (m, 1H),
7.20-7.25 (m, 3H), 7.15-7.20 (m, 2H), 7.05-
7.10 (m, 2H), 7.00-7.05 (m, 2H), 6.70-6.75 (m,
2H), 5.52 (s, 1H), 3.75 (s, 3H), 3.55-3.65 (m,
2H), 3.10-3.20 (m, 1H), 2.94 (dt, J = 16.2, 3.6
Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 159.4,
157.4 (d, 1JC-F = 238.8 Hz), 146.4, 135.4, 133.9,
133.1 (2C), 128.9, 127.4, 127.2, 126.2, 119.3 (d, 3JC-F = 7.6 Hz), 115.4 (d,
2JC-F =
22.1 Hz, 2C), 114.9, 113.7 (2C), 86.6, 85.2, 55.2, 53.7, 44.0, 28.9; IR (ATR): ν
3050, 1604, 1506 cm-1
; MS (EI) m/z (%): 357 (M+, 82), 356 (M
+ - 1, 100), 283
(10), 208 (11), 207 (54), 191 (19), 190 (10), 189 (29), 133 (15), 73 (12), 65 (10);
HRMS calcd. (%) for C24H20FNO: 357.1529; found: 357.1517.
199 Experimental Part
1-((4-Bromophenyl)ethynyl)-2-(4-fluorophenyl)-
1,2,3,4-tetrahydroisoquinoline (16g): brown oil;
tr = 26.5; Rf = 0.6 (hexane/ethyl acetate : 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.30-7.40 (m, 3H),
7.15-7.25 (m, 3H), 6.95-7.15 (m, 6H), 5.52 (s, 1H),
3.60 (dd, J = 8.6, 3.7 Hz, 2H), 3.13 (dt, J = 16.3,
8.6 Hz, 1H), 2.95 (dt, J = 16.3, 3.7 Hz, 1H); 13
C
NMR (75 MHz, CDCl3): δ 157.6 (d, 1JC-F = 239.3
Hz), 146.6, 135.0, 134.1, 133.2, 131.5, 129.2,
127.5 (2C), 126.4, 122.4, 121.9, 119.5 (d, 3JC-F =
7.7 Hz, 2C), 115.7 (d, 2JC-F = 22.2 Hz, 2C), 89.5,
84.4, 53.9, 44.2, 29.1; IR (ATR): ν 3058, 3025, 1657, 1507 cm-1
; MS (EI) m/z
(%): 408 (M+
+ 2, 11), 407 (M+
+ 1, 54), 406 (M+, 100), 404 (M
+-2, 94), 284 (26),
282 (27), 350 (15), 226 (10), 224 (25), 207 (10), 203 (23), 202 (83), 201 (16),
200 (12), 122 (15), 95 (17); HRMS calcd. (%) for (C23H17BrFN - H): 404.0450;
found: 404.0437.
2-(4-Fluorophenyl)-1-((4-
(trifluoromethyl)phenyl)ethynyl)-1,2,3,4-
tetrahydroisoquinoline (16h). orange oil, tr = 20.2;
Rf = 0.5 (hexane/ethyl acetate : 4/1); 1
H NMR (300
MHz, CDCl3): δ 7.45-7.50 (m, 2H), 7.30-7.40
(m, 3H), 7.20-7.25 (m, 3H), 6.95-7.15 (m, 4H),
5.56 (s, 1H), 3.61 (dd, J = 8.5, 3.6 Hz, 2H), 3.10-
3.20 (m, 1H), 2.96 (dt, J = 16.2, 3.6 Hz, 1H); 13
C
NMR (75 MHz, CDCl3): δ 157.5 (d, 1JC-F = 239.5
Hz), 146.2, 134.6, 134.0, 131.9 (2C), 129.8 (q, 2JC-F
= 32.6 Hz), 129.0, 127.4 (2C), 126.6, 126.3, 125.0
(q, 3JC-F = 3.6 Hz, 2C), 123.8 (q,
1JC-F = 271.1 Hz), 119.4 (d,
3JC-F = 7.7 Hz, 2C),
115.6 (d, 2JC-F = 22.1 Hz, 2C), 90.8, 84.0, 53.8, 44.0, 28.9; IR (ATR): ν 3065,
1614, 1507 cm-1
; MS (EI) m/z (%): 396 (M+
+ 1, 12), 395 (M+, 64), 394 (M
+-1,
100), 272 (46), 203 (10), 202 (31), 95 (12); HRMS calcd. (%) for C24H17F4N:
395.1297; found: 395.1287.
Experimental Part 200
1-((3-Chlorophenyl)ethynyl)-2-(4-fluorophenyl)-
1,2,3,4-tetrahydroisoquinoline (16i): yellow oil; tr
= 23.6; Rf = 0.7 (hexane/ethyl acetate : 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.30-7.35 (m, 1H),
7.20-7.30 (m, 5H), 7.10-7.15 (m, 2H), 6.95-7.10
(m, 4H), 5.52 (s, 1H), 3.60 (dd, J = 8.3, 3.6 Hz,
2H), 3.05-3.20 (m, 1H), 2.95 (dt, J = 16.2, 3.4 Hz,
1H); 13
C NMR (75 MHz, CDCl3): δ 157.7 (d, 1JC-F
= 239.3 Hz), 146.4, 134.9, 134.1 (2C), 131.7, 130.0,
129.5, 129.2, 128.5, 127.5 (2C), 126.5, 124.7, 119.5
(d, 3JC-F = 7.6 Hz, 2C), 115.7 (d,
2JC-F = 22.2 Hz, 2C), 89.6, 84.1, 53.8, 44.2, 29.1;
IR (ATR): ν 3061, 2924, 2832, 1591, 1507 cm-1
; MS (EI) m/z (%): 362 (M+
+ 1,
42), 361 (M+, 67), 360 (M
+ - 1, 100), 238 (35), 208 (13), 207 (56), 203 (21), 202
(52), 136 (13); HRMS calcd. (%) for (C23H17ClFN - H): 360.0955; found:
360.0966.
1-((2-Bromophenyl)ethynyl)-2-(4-fluorophenyl)-
1,2,3,4-tetrahydroisoquinoline (16j): brown oil; tr =
25.4; Rf = 0.4 (hexane/ethyl acetate : 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.48 (dd, J = 7.9, 1.3 Hz, 1H),
7.35-7.40 (m, 1H), 7.29 (dd, J = 7.6, 1.8 Hz, 1H),
7.15-7.25 (m, 3H), 6.95-7.15 (m, 6H), 5.59 (s, 1H),
3.55-3.75 (m, 2H), 3.15 (m, 1H), 2.97 (dt, J = 16.3,
3.7 Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 157.6 (d, 1JC-F = 239.1 Hz), 146.4, 134.9, 134.2, 133.5, 132.4,
129.4, 129.1, 127.7, 127.5, 126.9, 126.4, 125.7, 125.1, 119.6 (d, 3JC-F = 7.6 Hz,
2C), 115.7 (d, 2JC-F = 22.1 Hz, 2C), 93.1, 84.1, 53.9, 44.3, 29.2; IR (ATR): ν
3063, 2920, 1507, 1468 cm-1
; MS (EI) m/z (%): 407 (M+
+ 1, 5), 406 (M+, 12),
405 (M+
- 1, 5), 404 (M+-2, 12), 281 (20), 209 (36), 207 (100), 202 (11); HRMS
calcd. (%) for (C23H17BrFN - H): 404.0450; found: 404.0451.
201 Experimental Part
1-(Cyclohex-1-en-1-ylethynyl)-2-(4-fluorophenyl)-
1,2,3,4-tetrahydroisoquinoline (16k): brown oil; tr
= 21.0; Rf = 0.6 (hexane/ethyl acetate : 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.25-7.30 (m, 1H),
7.15-7.20 (m, 4H), 6.95-7.05 (m, 3H), 5.90-5.95
(m, 1H), 5.42 (s, 1H), 3.50-3.60 (m, 2H), 3.05-
3.15 (m, 1H), 2.91 (dt, J = 16.2, 3.6 Hz, 1H),
1.95-2.00 (m, 4H), 1.50-1.55 (m, 4H); 13
C NMR
(75 MHz, CDCl3): δ 157.3 (d, 1JC-F = 238.7 Hz),
146.4, 135.6, 134.6, 133.8, 128.9, 127.4, 127.0, 126.1, 120.2, 119.2 (d, 3JC-F = 7.6
Hz, 2C), 115.4 (d, 2JC-F = 22.1 Hz, 2C), 87.1, 85.2, 53.5, 43.9, 29.2, 28.9, 25.5,
22.2, 21.4; IR (ATR): ν 3050, 3023, 2927, 2857, 1507 cm-1
; MS (EI) m/z (%):
331 (M+, 18), 330 (M
+ - 1, 34), 281 (15), 208 (14), 207 (100); HRMS calcd. (%)
for C23H22FN: 331.1736; found: 331.1719.
1-(Cyclohexylethynyl)-2-(4-fluorophenyl)-1,2,3,4-
tetrahydroisoquinoline (16l): yellow oil; tr = 19.9;
Rf = 0.3 (hexane/ethyl acetate 9/1); 1
H NMR (300
MHz, CDCl3): δ 7.25-7.30 (m, 1H), 7.10-7.20 (m,
3H), 6.95-7.05 (m, 4H), 5.32 (s, 1H), 3.52 (dd, J
= 8.5, 3.6 Hz, 2H), 3.05-3.10 (m, 1H), 2.89 (dt, J
= 16.2, 3.6 Hz, 1H), 2.25-2.30 (m, 1H), 1.50-1.65
(m, 4H), 1.40-1.45 (m, 1H), 1.15-1.30 (m, 5H); 13
C NMR (75 MHz, CDCl3): δ 157.3 (d, 1JC-F = 238.6
Hz), 146.6, 136.0, 133.7, 128.8, 127.3, 126.9, 126.0, 119.3 (d, 3JC-F = 7.6 Hz,
2C), 115.3 (d, 2JC-F = 22.1 Hz, 2C), 89.9, 78.6, 53.2, 43.8, 32.5 (2C), 29.0, 28.8
(2C), 25.8, 24.4; IR (ATR): ν 3061, 3024, 2927, 2852, 1507 cm-1
; MS (EI) m/z
(%): 334 (M+
+ 1, 11), 333 (M+, 74), 332 (M
+ - 1, 100), 250 (30), 224 (12), 167
(16), 165 (13), 153 (11), 141 (13), 128 (17), 115 (12), 95 (13); HRMS calcd. (%)
for C23H24FN: 333.1893; found: 333.1885.
2-(4-Fluorophenyl)-1-(nona-1,8-diyn-1-yl)-1,2,3,4-
tetrahydroisoquinoline (16m): pale yellow oil; tr =
20.5; Rf = 0.5 (hexane/ethyl acetate : 4/1); 1
H NMR
(300 MHz, CDCl3): δ 7.25-7.30 (m, 1H), 7-10-7.20
(m, 3H), 6.95-7.05 (m, 4H), 5.31 (s, 1H), 3.50-3.60
(m, 2H), 3.09 (dt, J = 16.4, 8.3 Hz, 1H), 2.90 (dt, J =
16.4, 3.6 Hz, 1H), 2.15-2.00 (m, 4H), 1.92 (t, J = 2.6
Hz, 1H), 1.15-1.50 (m, 6H); 13
C NMR (75 MHz,
CDCl3): δ 157.4 (d, 1JC-F = 238.8 Hz), 146.6, 136.1,
Experimental Part 202
133.9, 129.0, 127.5, 127.2, 126.3, 119.2 (d, 3JC-F = 7.6 Hz, 2C), 115.5 (d,
2JC-F =
22.1 Hz, 2C), 85.7, 84.6, 79.1, 68.4, 53.8, 43.9, 29.1, 28.3, 28.1, 27.9, 18.7, 18.4;
IR (ATR): ν 3303, 2937, 2859, 1508 cm-1
; MS (EI) m/z (%): 345 (M+, 38), 344
(M+
- 1, 100), 302 (12), 276 (27), 264 (13), 262 (31), 250 (27), 226 (12), 224
(19), 207 (18), 155 (13), 153 (13), 142 (11), 141 (23), 95 (13); HRMS calcd. (%)
for C24H24FN: 345.1893; found: 345.1877.
2-(4-Fluorophenyl)-1-(3-((tetrahydro-2H-
pyran-2-yl)oxy)prop-1-yn-1-yl)-1,2,3,4-
tetrahydroisoquinoline (16n): colourless oil; tr =
22.3; Rf = 0.4 (hexane/ethyl acetate : 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.15-7.30 (m, 4H),
6.95-7.05 (m, 4H), 5.39 (s, 1H), 4.56 (t, J = 3.2
Hz, 1H), 4.18 (d, J = 1.9 Hz, 2H), 3.65-3.80 (m,
1H), 3.50-3.60 (m, 2H), 3.35-3.45 (m, 1H), 3.10
(ddd, J = 16.3, 9.7, 7.0 Hz, 1H), 2.90 (dt, J = 16.3, 3.5 Hz, 1H), 1.70-1.80 (m,
1H), 1.40-1.65 (m, 5H); 13
C NMR (75 MHz, CDCl3): δ 157.5 (d, 1JC-F = 239.2
Hz), 146.5, 135.0, 134.0, 129.1, 127.5, 127.4, 126.3, 119.3 (d, 3JC-F = 7.7 Hz,
2C), 115.6 (d, 2JC-F = 22.1 Hz, 2C), 96.4, 84.8, 81.2, 62.1, 54.3, 53.3, 43.9, 30.3,
29.0, 25.5, 19.2; IR (ATR): ν 2923, 2849, 1230, 1021 cm-1
; MS (EI) m/z (%): 365
(M+, 16), 364 (M
+ - 1), 281 (16), 280 (16), 264 (56), 263 (37), 262 (100), 250
(19), 248 (29), 235 (12), 226 (22), 224 (21), 207 (27), 141 (21), 140 (12), 139
(13), 129 (14), 128 (14), 122 (15), 115 (26), 95 (18), 85 (17), 84 (46), 83 (24), 57
(12), 56 (25), 55 (60), 54 (12); HRMS calcd. (%) for C23H24FNO2: 365.1791;
found: 365.1781.
2-(4-Fluorophenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (16o):293
yellow oil; tr = 17.5;
Rf = 0.3 (hexane/ethyl acetate : 4/1); 1
H NMR (300
MHz, CDCl3): δ 7.05-7.30 (m, 4H), 6.85-6.95 (m,
4H), 5.42 (dd, J = 8.6, 5.9 Hz, 1H), 4.82 (dd, J = 12.0,
8.6 Hz, 1H), 4.55 (dd, J = 12.0, 5.9 Hz, 1H), 3.55-
3.60 (m, 2H), 2.95-3.05 (m, 1H), 2.70 (dt, J = 16.5, 4.2 Hz, 1H); 13
C NMR (75
MHz, CDCl3): δ 157.1 (d, 1JC-F = 239.1 Hz), 145.3, 135.2, 132.5, 129.4, 128.0,
126.9, 126.7, 117.8 (d, 3JC-F = 7.6 Hz, 2C), 115.8 (d,
2JC-F = 22.2 Hz, 2C), , 78.7,
58.6, 42.7, 25.7. IR (ATR): ν 2913, 2843, 1547, 1506 cm-1
; MS (EI) m/z (%): 286
(M+, 5), 227 (23), 226 (100), 225 (29), 224 (68), 128 (10), 104 (13), 95 (12).
203 Experimental Part
2-(4-Fluorophenyl)-1-(1-methyl-1H-indol-3-yl)-
1,2,3,4-tetrahydroisoquinoline (16p): white solid;
m.p. 137-139 ºC (ethanol); tr = 24.6; Rf = 0.5
(hexane/ethyl acetate : 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.42 (dt, J = 8.0, 0.9 Hz, 1H), 7.10-7.25
(m, 6H), 7.0 (ddd, J = 8.0, 6.8, 1.3 Hz, 1H), 6.85-6.95
(m, 4H), 6.43 (s, 1H), 6.00 (s, 1H), 3.61 (s, 3H), 3.40-
3.60 (m, 2H), 3.02 (ddd, J = 16.1, 9.8, 5.8 Hz, 1H),
2.79 (dd, J = 16.1, 4.3 Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 156.7 (d, 1JC-F =
237.7 Hz), 146.9, 137.6, 137.4, 135.4, 129.0 (2C), 128.3, 127.2, 126.7, 125.9,
121.8, 120.2, 119.3, 118.6 (d, 3JC-F =7.5 Hz, 2C), 117.5, 115.6 (d,
2JC-F = 22.0 Hz,
2C), 109.3, 57.7, 43.4, 32.8, 26.9; IR (ATR): ν 3047, 2957, 1505 cm-1
; MS (EI)
m/z (%): 355 (M+
- 1, 1%), 262 (20), 186 (13), 170 (37), 169 (14), 168 (23), 142
(10), 141 (26), 115 (12), 104 (12), 94 (66), 78 (100), 77 (43), 76 (16), 66 (16), 65
(16), 52 (13), 51 (22), 50 (17); HRMS calcd. (%) for C24H21FN2: 356.1689;
found: 356.1692.
(Diethyl(2-(4-fluorophenyl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)phosphonate
(16q):295
pale pink oil; tr = 17.52; Rf = 0.3
(hexane/ethyl acetate : 4/1); 1
H NMR (300 MHz,
CDCl3): δ 7.30-7.40 (m, 1H), 7.10-7.25 (m, 3H),
6.85-7.00 (m, 4H), 5.06 (d, J = 20.2 Hz, 1H), 3.8-
4.3, 3.45-3.60 (2m, 1 and 5H, respectively), 2.85-3.10 (m, 2H), 1.24 (t, J = 7.07,
3H), 1.14 (td, J = 7.07, 0.28, 3H); 13
C NMR (75 MHz, CDCl3): δ 156.5 (d, 1JC-F =
237.7 Hz), 146.3 (dd, JC-P = 6.4, 1.9 Hz), 136.4 (d, 4JC-F = 5.5 Hz), 130.5, 128.9
(2C), 127.6, 126.0, 116.7 (d, 3JC-F = 7.4 Hz, 2C), 115.6 (d,
2JC-F = 22.1 Hz, 2C),
63.4 (d, 2JC-P = 7.3 Hz), 62.4 (d,
2JC-P = 7.7 Hz), 59.4 (d,
1JC-P = 158.4 Hz), 44.4,
26.6, 16.5 (d, 3JC-P = 5.9 Hz), 16.4 (d,
3JC-P = 5.9 Hz); IR (ATR): ν 1508, 1234,
1018 cm-1
; MS (EI) m/z (%): 363 (M+, 1), 227 (21), 226 (100), 224 (13).
2-(2-(4-Fluorophenyl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)cyclohexanone
(16r):165d
yellow oil; tr = 19.73; Rf = 0.4
(hexane/ethyl acetate : 4/1); 1H NMR (300 MHz,
CDCl3): δ 6.75-7.25 (4m, 1, 7, 7 y 1H,
respectively), 5.56 (d, J = 8.5 Hz, 1H, anti), 5.47
(d, J = 5.2 Hz, 1H, syn), 3.50-3.70 (2m, 2 y 2H,
295 M. Rueping, S. Zhu, R. M. Koenigs, Chem. Commun. 2011, 47, 8679-8681.
Experimental Part 204
respectively), 2.80-2.90 (m, 6H), 2.15-2.45 (2m, 2 y 2H, respectively), 1.25-1.90
(m, 12H); 13
C NMR (75 MHz, CDCl3): δ 212.1 (anti), 211.9 (syn), 156.3 (d, 1JC-F
= 237.5 Hz, syn), 155.2 (d, 1JC-F = 235.3 Hz, anti), 146.2 (2C, anti, syn), 140.1
(anti), 135.8 (syn), 135.0 (syn), 134.5 (anti), 128.9 (syn), 128.1 (anti), 128.0
(syn), 127.3 (anti), 126.8 (2C, anti, syn), 126.4 (anti), 125.8 (syn), 117.1 (d, 3JC-F
= 7.3 Hz, syn, 2C), 115.5 (d, 2JC-F = 22.0 Hz, syn, 2C), 115.4 (d,
2JC-F = 22.0 Hz,
anti, 2C ), 113.6 (d, 3JC-F = 7.3 Hz, anti, 2C), 59.4 (anti), 56.5 (syn), 55.8 (syn),
54.7 (anti), 44.1 (anti), 43.5 (syn), 43.2 (anti), 41.4 (syn), 32.8 (anti), 30.5 (syn),
28.8 (anti), 27.5 (syn), 27.4 (anti), 26.8 (syn), 25.7 (anti), 23.8 (syn); IR (ATR): ν
2938, 2862, 1703, 1507 cm-1
; MS (EI) m/z (%): 323 (M+, 0.5%), 227 (19), 226
(100), 55 (14).
1-(2-(4-Fluorophenyl)-1,2,3,4-
tetrahydroisoquinolin-1-yl)but-3-en-2-one
(16s): yellow oil; tr = 17.51; Rf = 0.4 (hexane/ethyl
acetate : 4/1); 1H NMR (300 MHz, CDCl3): δ 7.10-
7.20 (m, 4H), 6.80-7.00 (m, 4H), 6.29 (dd, J =
17.6, 10.5 Hz, 1H), 6.10 (dd, J = 17.6, 1.1 Hz,
1H), 5.76 (dd, J = 10.5 Hz, 1.1 Hz, 1H), 5.37 (t, J
= 6.3 Hz, 1H), 3.45-3.65 (m, 2H), 3.19 (dd, J = 16.1, 6.3 Hz, 1H), 3.04 (m, 1H),
2.94 (dd, J = 16.1, 6.3 Hz, 1H), 2.80 (dt, J = 16.2, 4.5 Hz, 1H); 13
C NMR (75
MHz, CDCl3): δ 199.1, 156.5 (d, 1JC-F = 237.3 Hz), 145.8, 138.2, 136.9, 134.3,
128.9, 128.7, 127.1, 127.0, 126.4, 116.9 (d, 3JC-F = 7.4 Hz, 2C), 115.8 (d,
2JC-F =
22.1 Hz, 2C), 55.9, 46.1, 42.6, 27.1; IR (ATR): ν 3052, 1676, 987, 956 cm-1
; MS
(EI) m/z (%): 295 (M+, 6), 227 (19), 226 (100), 225 (11), 207 (17), 55 (11);
HRMS calcd. (%) for C19H18FNO: 295.1862; found: 295.1845.
(E)-2-(4-Fluorophenyl)-1-styryl-1,2,3,4-
tetrahydroisoquinoline (16t): orange oil; tr =
21.48; Rf = 0.6 (hexane/ethyl acetate : 4/1); 1
H
NMR (300 MHz, CDCl3): δ 7.10-7.45 (m, 9H),
6.75-7.05 (m, 4H), 6.40 (d, J = 15.9 Hz, 1H), 6.30
(dd, J = 15.9, 4.7 Hz, 1H), 5.25 (d, J = 4.7 Hz 1H),
3.63 (ddd, J = 12.2, 7.3, 5.1 Hz, 1H), 3.45-3.55 (m,
1H), 2.85-3.10 (m, 2H); 13
C NMR (75 MHz,
CDCl3): δ 156.4 (d, 1JC-F = 237.0 Hz), 146.5 (2C),
136.9, 136.5, 135.4, 131.0, 130.4, 128.6 (2C),
127.8, 127.6, 127.0, 126.6 (2C), 126.4, 116.6 (d, 3JC-F = 7.4 Hz, 2C), 115.7 (d,
2JC-F = 22.1 Hz, 2C), 62.4, 43.9, 28.4; IR (ATR): ν 3025, 2904, 2834, 1735, 1507
cm-1
; MS (EI) m/z (%): 329 (M+, 52), 328 (M
+ - 1, 38), 252 (10), 238 (30), 237
205 Experimental Part
(20), 226 (100), 224 (17), 128 (12), 115 (14), 95 (11), 91 (24); HRMS calcd. (%)
for C23H20FN: 329.1580; found: 329.1577.
2-(4-Fluorophenyl)-3,4-dihydroisoquinolin-
1(2H)-one (17a): yellow solid; m.p. 112-114 ºC
(ethanol); tr = 16.56; Rf = 0.5 (hexane/ethyl acetate
: 3/2); 1H NMR (300 MHz, CDCl3): δ 8.14 (dd, J =
7.7, 1.2 Hz, 1H), 7.47 (td, J = 7.4, 1.5 Hz, 1H),
7.30-7.40 (m, 3H), 7.20-7.30 (m, 1H), 7.00-7.15
(m, 2H), 3.95 (t, J = 6.5 Hz, 2H), 3.14 (t, J = 6.5 Hz, 2H); 13
C NMR (75 MHz,
CDCl3): δ 164.5, 160.8 (d, 1JC-F = 245.6 Hz), 139.2, 138.3, 132.3, 130.1, 129.6,
128.8, 127.3 (d, 3JC-F = 6.7 Hz, 2C), 127.1, 115.8 (d,
2JC-F = 22.6, 2C), 49.7, 28.7;
IR (ATR): ν 1650, 1500 cm-1
; MS (EI) m/z (%): 242 (M+
+ 1, 16), 241 (M+, 91),
240 (M+
- 1, 25), 122 (20), 119 (13), 118 (100), 95 (18), 90 (46), 89 (24); HRMS
calcd. (%) for C15H12FNO: 241.0903; found: 241.0907.
4.9. SYNTHESIS OF BENZO[b]FURANS.
General Procedure: To a stirred solution of the corresponding aldehyde
19 (0.4 mmol) in EtOH (2 mL), was added 4-methylbenzenesulfonohydrazine
(74 mg, 0.4 mmol) and the reaction was stirred at 100 ºC during 1 h. After that
time, Cs2CO3 (390 mg, 1.2 mmol), tridecane (73.7 mg, 0.4 mmol as an internal
standard), CuO-Fe3O4 (50 mg, 2.4 mol%) were added to the reaction solution
followed by the corresponding terminal alkyne 5 (0.5 mmol). The resulting
mixture was stirred at 100 ºC during 5 h. The catalyst was removed by magnetic
decantation and the solvent was removed under reduce pressure. The resulting
mixture was quenched with deionised water and extracted with AcOEt (3 x 5
mL). The organic phases were dried over MgSO4, followed by evaporation under
reduced pressure to remove the solvent. The product was usually purified by
column chromatography on silica gel (hexane/ethyl acetate) to give the
corresponding product 20.
2-Benzylbenzofuran (20a):180
colorless oil; tr= 14.2;
Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.40-7.45 (m, 1H), 7.35-7.40 (m, 1H),
7.15-7.30 (m, 7H), 6.33 (s, 1H), 4.06 (s, 2H); 13
C
NMR (75 MHz, CDCl3): δ 157.8, 154.9, 137.2, 128.9
(2C), 128.8, 128.6 (2C), 126.7, 123.4, 122.5, 120.4,
Experimental Part 206
110.9, 103.3, 35.0; IR (ATR): ν 3029, 1454, 1252, 952 cm-1
; MS (EI) m/z (%):
208 (M+, 88), 207 (M
+ - 1, 100), 178 (22), 131 (36), 77 (8).
2-Benzyl-5,7-di-tert-butylbenzofuran (20b):
colorless oil; tr= 17.0; Rf= 0.7 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.31
(d, J = 1.9 Hz, 1H), 7.20-7.30 (m, 5H), 7.17 (d, J =
1.9 Hz, 1H), 6.31 (s, 1H), 4.10 (s, 2H), 1.47 (s,
9H), 1.35 (s, 9H); 13
C NMR (75 MHz, CDCl3): δ
156.8, 151.3, 145.2, 137.7, 133.4, 128.8 (3C),
128.4 (2C), 126.5, 118.0, 114.5, 103.1, 35.1, 34.8, 34.4, 31.9 (3C), 29.9 (3C); IR
(ATR): ν 2955, 2905, 1603, 1479, 1242, 1030 cm-1
;. MS (EI) m/z (%): 321 (M+
+
1, 11), 320 (M+, 49), 306 (31), 305 (100), 153 (9), 91 (17), 57 (12); HRMS calcd.
(%) for C23H28O: 320.21402; found: 320.2137.
2-Benzyl-5-bromo-7-methoxybenzofuran (20c):
yellow solid; m.p. = 52-54ºC (Hexane); tr= 17.6;
Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.20-7.35 (m, 5H), 7.18 (d, J =
1.7 Hz, 1H), 6.83 (d, J = 1.7 Hz, 1H), 6.24 (t, J =
0.94 Hz, 1H), 4.09 (s, 2H), 3.95 (s, 3H); 13
C NMR
(75 MHz, CDCl3): δ 159.3, 145.2, 142.9, 136.7, 131.6, 128.9 (2C), 128.6 (2C),
126.8, 115.6 (2C), 109.3, 103.2, 56.2, 34.8; IR (ATR): ν 1597, 1472, 1207 cm-1
;
MS (EI) m/z (%): 319 (M+
+ 3, 17), 318 (M+
+ 2, 96), 317 (M+
+ 1, 57), 316 (M+,
100), 315 (21), 281 (19), 241 (10), 237 (19), 222 (16), 209 (11), 208 (19), 207
(41), 206 (91), 194 (19), 181 (37), 166 (19), 165 (64), 89 (14), 82 (12), 78 (44);
HRMS calcd. (%) for C16H13BrO2: 316.0099; found: 316.0109.
2-(2-Bromobenzyl)benzofuran (20d): pale yellow
oil; tr= 16.0; Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.55-7.60 (m, 1H), 7.45-
7.50 (m, 1H), 7.40-7.45 (m, 1H), 7.10-7.30 (m, 5H),
6.38 (s, 1H), 4.24 (s, 2H); 13
C NMR (75 MHz,
CDCl3): δ 156.0, 154.9, 136.8, 132.9, 130.9, 128.7,
128.5, 127.6, 124.6, 123.5, 122.6, 120.5, 110.9, 104.0, 35.2; IR (ATR): ν 1601,
1585, 1453, 1251, 1025 cm-1
; MS (EI) m/z (%): 289 (M+
+ 3, 15), 288 (M+
+ 2,
98), 287 (M+
+ 1, 54), 286 (M+, 100), 285 (M
+-1, 39), 208 (11), 207 (63), 206
(17), 105 (41), 178 (73), 177 (16), 176 (24), 152 (16), 151 (12), 131 (82), 89
207 Experimental Part
(33), 88 (11), 77 (14), 76 (26), 63 (12); HRMS calcd. (%) for C15H11BrO:
285.9993; found: 285.9985.
2-(3-Chlorobenzyl)benzofuran (20e):179
pale yellow
oil; tr= 15.5; Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.45-7.50 (m, 1H), 7.35-
7.40 (m, 1H), 7.29 (br s, 1H), 7.15-7.25 (m, 5H), 6.40
(s, 1H), 4.06 (s, 2H); 13
C NMR (75 MHz, CDCl3): δ
156.7, 155.0, 139.2, 134.4, 129.8, 129.0, 128.6, 127.0
(2C), 123.6, 122.6, 120.5, 110.9, 103.7, 34.6; IR
(ATR): ν 1596, 1585, 1574, 1453, 1252, 1008 cm-1
; MS (EI) m/z (%): 244 (M+
+
2, 34), 243 (M+
+ 1, 37), 242 (M+, 100), 241 (M
+-1, 69), 208 (10), 207 (77), 205
(13), 179 (22), 178 (44), 131 (67), 77 (13), 76 (14).
2-(4-Bromobenzyl)benzofuran (20f):296
white solid;
m.p. = 47-49 ºC (Hexane); tr= 16.2; Rf= 0.7
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.40-7.50 (m, 4H), 7.10-7.20 (m, 4H), 6.36
(dd, J = 1.1, 0.9 Hz, 1H), 4.03 (s, 2H); 13
C NMR (75
MHz, CDCl3): δ 156.9, 154.9, 136.2, 131.7 (2C),
130.6 (2C), 128.6, 123.6, 122.6, 120.7, 120.5, 110.9,
103.6, 34.4; IR (ATR): ν 1599, 1584, 1488, 1452, 1250, 1010 cm-1
; MS (EI) m/z
(%): 289 (M+
+ 3, 19), 288 (M+
+ 2, 78), 287 (M+
+ 1, 69), 286 (M+, 75), 285
(M+-1, 66), 208 (19), 207 (100), 205 (24), 179 (25), 178 (56), 177 (16), 176 (14),
152 (14), 151 (11), 131 (52), 103 (12), 102 (13), 89 (25), 77 (17), 76 (32), 63
(12).
2-(4-Trifluoromethyl)benzyl)benzofuran (20g):180
pale yellow oil; tr= 14.0; Rf= 0.6 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.58
(d, J = 7.8 Hz, 2H), 7.45-7.50 (m, 1H), 7.40-7.45
(m, 3H), 7.15-7.25 (m, 2H), 6.41 (s, 1H), 4.16 (s,
2H); 13
C NMR (75 MHz, CDCl3): δ 156.4, 155.0,
141.3, 129.2 (2C), 129.2 (q, 2JC-F = 32.3 Hz), 128.1,
126.0 (q, 1JC-F = 272.4 Hz), 125.5 (q,
3JC-F = 3.8 Hz, 2C), 123.7, 122.7, 120.5,
110.9, 103.8, 34.8; IR (ATR): ν 1454, 1322, 1252 cm-1
; MS (EI) m/z (%): 277
296 J. Barluenga, M. Tomás-Gamasa, F. Aznar, C. Valdés, Nat. Chem. 2009, 1, 494-499.
Experimental Part 208
(M+
+ 1, 16), 276 (M+, 100), 275 (M
+-1, 84), 207 (59), 179 (11), 178 (26), 131
(57).
2-(2-Methylbenzyl)benzofuran (20h):179
pale yellow
oil; tr= 14.8; Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.42 (ddd, J = 8.2, 1.8, 0.7
Hz, 2H), 7.10-7.25 (m, 6H), 6.23 (d, J = 0.9 Hz, 1H),
4.09 (s, 2H), 2.34 (s, 3H); 13
C NMR (75 MHz,
CDCl3): δ 157.5, 154.9, 136.6, 135.4, 130.4, 129.8,
128.8, 127.1, 126.2, 123.3, 122.5, 120.3, 110.9, 103.2, 32.7, 19.4; IR (ATR): ν
1599, 1585, 1454, 1253, 1008 cm-1
; MS (EI) m/z (%): 223 (M+
+ 1, 18), 222 (M+,
100), 221 (M+
- 1, 31), 207 (37), 178 (23), 131 (27), 116 (11), 115 (10), 110 (10),
107 (48), 104 (22), 77 (11).
2-(3-Methylbenzyl)benzofuran (20i):180
colorless oil;
tr= 14.7; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.45-7.50 (m, 1H), 7.40-7.45
(m, 1H), 7.15-7.25 (m, 3H), 7.05-7.10 (m, 3H), 6.37
(s, 1H), 4.06 (s, 2H), 2.33 (s, 3H); 13
C NMR (75 MHz,
CDCl3): δ 157.9, 154.9, 138.2, 137.1, 129.6, 128.8,
128.5, 127.5, 125.9, 123.3, 122.5, 120.4, 110.9, 103.3, 34.9, 21.4; IR (ATR): ν
3065, 3026, 1601, 1586, 1454, 1251, 954 cm-1
; MS (EI) m/z (%): 222 (M+, 100),
221 (M+
- 1, 81), 207 (54), 179 (11), 178 (25), 131 (34).
2-(4-Methoxybenzyl)benzofuran (20j):180
colorless oil; tr= 15.9; Rf= 0.5 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-
7.50 (m, 1H), 7.35-7.40 (m, 1H), 7.15-7.25 (m,
4H), 6.85-6.90 (m, 2H), 6.34 (dd, J = 1.9, 0.9 Hz,
1H), 4.04 (s, 2H), 3.79 (s, 3H); 13
C NMR (75 MHz,
CDCl3): δ 158.5, 158.3, 154.9, 129.9 (2C), 129.3,
128.8, 123.3, 122.5, 120.4, 114.0 (2C), 110.9, 103.1, 55.3, 34.1; IR (ATR): ν
1612, 1584, 1509, 1245 cm-1
; MS (EI) m/z (%): 238 (M+, 59), 237 (M
+ - 1, 56),
207 (100), 131 (13).
209 Experimental Part
2-Hexylbenzofuran (20k):90
colorless oil; tr= 12.6;
Rf= 0.9 (hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.35-7.40, 7.45-7.50 (2m, 1H and
1H respectively), 7.10-7.20 (m, 2H), 6.34 (s, 1H),
2.74 (t, J = 7.5 Hz, 2H), 1.73 (quin-, J = 7.5 Hz,
2H), 1.25-1.40 (m, 6H), 0.89 (t, J = 7.14 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 159.8, 154.7, 129.1, 123.0, 122.4, 120.2, 110.7,
101.8, 31.6, 28.9, 28.5, 27.7, 22.6, 14.1; IR (ATR): ν 1600, 1587, 1252, 1009,
738 cm-1
; MS (EI) m/z (%): 202 (M+, 24), 132 (29), 131 (100), 95 (13), 77 (13).
2-(Cyclohexylmethyl)benzofuran (20l): colorless oil;
tr= 13.9; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.35-7.50 (m, 2H), 7.10-7.20 (m,
2H), 6.35 (s, 1H), 2.63 (d, J = 6.8 Hz, 2H), 1.60-1.80
(m, 6H), 1.10-1.30 (m, 3H), 0.90-1.05 (m, 2H); 13
C
NMR (75 MHz, CDCl3): δ 158.5, 154.7, 129.0, 122.9,
122.3, 120.1, 110.7, 102.8, 37.0, 36.3, 33.2 (2C), 26.4, 26.2 (2C); IR (ATR): ν
2921, 2850, 1601, 1586, 1453, 1253, 1008 cm-1
; MS (EI) m/z (%): 214 (M+, 50),
133 (12), 132 (90), 131 (100), 83 (10), 77 (10); HRMS calcd. (%) for C15H18O:
214.1357; found: 214.1351.
2-(4-Chlorobutyl)benzofuran (20m):297
colorless oil; tr= 13.2; Rf= 0.7 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
7.45-7.50 (m, 1H), 7.40-7.45 (m, 1H), 7.15-7.25
(m, 2H), 6.40 (s, 1H), 3.58 (t, J = 6.2 Hz, 2H),
2.81 (t, J = 7.1 Hz, 2H), 1.85-1.95 (m, 4H); 13
C NMR (75 MHz, CDCl3): δ
158.6, 154.6, 128.8, 123.2, 122.5, 120.2, 110.7, 102.2, 44.6, 31.9, 27.7, 25.0; IR
(ATR): ν 2922, 2853, 1603, 1584, 1455, 1252, 948 cm-1
; MS (EI) m/z (%): 208
(M+, 18), 132 (15), 131 (100), 77 (10).
2-(2-(Tetrahydro-2H-pyran-2-
yl)oxy)ethyl)benzofuran (20n): colorless oil;
tr= 15.0; Rf= 0.5 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.45-7.50 (m, 1H),
7.35-7.40 (m, 1H), 7.15-7.25 (m, 2H), 6.47 (d, J
= 0.9 Hz, 1H), 4.60-4.65 (m, 1H), 4.09 (dt, J =
297 M. Yamaguchi, H. Katsumata, K. Manabe, J. Org. Chem. 2013, 78, 9270-9281.
Experimental Part 210
9.8, 6.8 Hz, 1H), 3.75-3.85 (m, 2H), 3.45-3.55 (m, 1H), 3.08 (td, J = 6.8, 0.8 Hz,
2H), 1.45-1.85 (m, 6H); 13
C NMR (75 MHz, CDCl3): δ 156.4, 154.6, 128.9,
123.2, 122.4, 120.3, 110.7, 103.0, 98.8, 65.0, 62.2, 30.6, 29.3, 25.4, 19.4; IR
(ATR): ν 2941, 2871, 1602, 1587, 1455, 1252, 1030 cm-1
; MS (EI) m/z (%): 246
(M+, 1), 162 (28), 145 813), 144 (50), 132 (16), 131 (100), 85 (26), 77 (14), 55
(12); HRMS calcd. (%) for C15H18O3: 246.1256; found: 246.1264.
2-(3-Ethylbenzyl)benzofuran (20o): pale yellow oil;
tr= 15.4; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.35-7.50 (m, 4H), 7.25-7.30 (m,
2H), 7.15-7.20 (m, 2H), 6.39 (d, J = 0.9 Hz, 1H), 4.08
(s, 2H), 3.06 (s, 1H); 13
C NMR (75 MHz, CDCl3): δ
157.0, 155.0, 144.9, 137.5, 132.5, 130.6, 129.5, 128.6,
123.6, 122.6, 120.5, 110.9, 103.6, 83.5, 77.3, 34.7; IR
(ATR): ν 3291, 1599, 1584, 1454, 1251, 1008 cm-1
; MS (EI) m/z (%): 233 (M+
+
1, 18), 232 (M+, 100), 231 (M
+-1, 87), 203 (14), 202 (31), 131 (36), 101 (11);
HRMS calcd. (%) for C17H12O: 232.0888; found: 232.0886.
2-(4-Bromobenzyl)-5,7-di-tert-
butylbenzofuran (20p): white solid; m.p. =
104-106 ºC (Hexane); tr= 15.0; Rf= 0.8
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.40-7.45 (m, 2H), 7.32 (d, J =
1.9 Hz, 1H), 7.15-7.20 (m, 3H), 6.32 (s, 1H),
4.05 (s, 2H), 1.46 (s, 9H), 1.35 (s, 9H); 13
C
NMR (75 MHz, CDCl3): δ 155.9, 151.4, 145.4,
136.7, 133.5, 131.5 (2C), 130.5 (2C), 126.7,
120.4, 118.2, 114.6, 103.4, 34.8, 34.5, 34.4, 31.9 (3C), 29.9 (3C); IR (ATR): ν
2959, 2950, 1607, 1478 cm-1
; MS (EI) m/z (%): 401 (M+
+ 2, 39), 400 (M+
+ 1,
10), 399 (M+, 39), 386 (22), 385 (99), 384 (24), 383 (100), 281 (10), 227 (12),
207 (28), 169 (16), 152 (10), 138 (56), 57 (46); HRMS calcd. (%) for C23H27BrO:
398.1245; found: 398.1251.
General Procedure: To a stirred solution of the corresponding
acetophenone 21 (0.4 mmol) in EtOH (2 mL) was added 4-
methybenzenesulfonohydrazine (74 mg, 0.4 mmol) and the reaction was stirred at
100 ºC during 1 h. After that time, Cs2CO3 (390 mg, 1.2 mmol), CuO-Fe3O4 (50
mg, 2.4 mol%) were added to the reaction solution followed by the
corresponding terminal alkyne 5 (0.5 mmol). The resulting mixture was stirred at
211 Experimental Part
ºC during 5 h. The catalyst was removed by magnetic decantation and the solvent
was removed under reduce pressure. The resulting mixture was quenched with
deionised water and extracted with AcOEt (3 x 5 mL). The organic phases were
dried over MgSO4, followed by evaporation under reduced pressure to remove
the solvent. The product was usually purified by column chromatography on
silica gel (hexane/ethyl acetate) to give the corresponding product 22.
2-Benzyl-3-methylbenzofuran (22a):298
colorless oil;
tr= 14.4; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.45-7.50 (m, 1H), 7.20-7.40
(m, 8H), 4.09 (s, 2H), 2.23 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 154.0, 152.1, 138.0, 130.2, 128.6
(2C), 128.5 (2C), 126.5, 123.4, 122.0, 118.9, 110.8,
32.6, 8.0; IR (ATR): ν 1494, 1454, 1088, 744 cm-1
; MS (EI) m/z (%): 223 (M+
+
1, 19), 222 (M+, 94), 221 (M
+ - 1, 49), 208 (23), 207 (100), 178 (20), 145 (48),
131 (10), 115 (19).
2-Benzyl-3-methylbenzofuran (22b): colorless
oil; tr= 16.5; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.56 (d, J = 1.9
Hz, 1H), 7.25-7.30 (m, 3H), 7.20-7.25 (m, 4H),
4.07 (s, 2H), 2.18 (s, 3H); 13
C NMR (75 MHz,
CDCl3): δ 153.6, 152.8, 137.5, 132.3, 128.6
(2C), 128.4 (2C), 126.6, 126.2, 121.7, 115.2,
112.2, 110.5, 32.6, 7.9; IR (ATR): ν 1602, 1494, 1445, 1262, 1089, 799 cm-1
; MS
(EI) m/z (%): 302 (M+
+ 2, 72), 301 (M+
+ 1, 38), 300 (M+, 80), 299 (M
+ - 1, 28),
287 (85), 285 (100), 281 (33), 225 (37), 223 (27), 207 (99), 205 (27), 193 (29),
191 (18), 115 (28), 110 (18), 103 (27), 89 (21), 88 (16), 78 (17), 74 (17), 73 (16),
63 (19), 61 (23). HRMS calcd. (%) for C16H13BrO: 300.0150; found: 300.0143.
298 R. Stoermer, R. Wehln, Ber. Dtsch. Chem. Ges. 1902, 35, 3549-3560.
Experimental Part 212
5. REACTIONS CATALYSED BY NANOPARTICLES OF
BIMETALLIC IMPREGNATED NICKEL(II) OXIDE AND
COPPER(0) ON MAGNETITE
5.1. SYNTHESIS OF 1,4-DISUBSTITUTED-1H-1,2,3-TRIAZOLES
General Procedure: To a stirred solution of sodium azide (27, 2 mmol)
and benzyl halide 26 (2 mmol) were added NiO/Cu-Fe3O4 (50 mg, 0.9 mol% of
Ni and 0.9 mol% of Cu) and the corresponding alkyne 5 or 29 (1 mmol). The
resulting mixture was stirred at 50 ºC until the end of the reaaction. The catalyst
was removed by magnetic decantation and the resulting mixture was quenched
with deionized water and extracted with AcOEt (3 x 5 mL). The organic phases
were dried over MgSO4, followed by evaporation under reduced pressure to
remove the solvent. The product was usually purified by chromatography on
silica gel (hexane/ethyl acetate) to give the corresponding produts 24 and 30.
1-Benzyl-4-phenyl-1H-1,2,3-triazole (24a):191e
white
solid; m.p. 104-108 °C (hexane/ethyl acetate); tr=
17.9; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.75-7.80 (m, 2H), 7.66 (s, 1H),
7.30-7.45 (m, 8H), 5.57 (s, 2H); 13
C NMR (75 MHz,
CDCl3): δ 148.2, 134.7, 130.5, 129.1 (2C), 128.8
(3C), 128.1, 128.0 (2C), 125.7 (2C), 119.4, 54.2; IR (ATR): ν 3021, 2920, 1450,
1223 cm-1
; MS (EI) m/z (%): 235 (M+, 22%), 207 (14), 206 (71), 180 (13), 179
(11), 116 (100), 104 (21), 91 (84), 89 (29), 65 (20), 63 (11).
1-(4-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (24b):
299 white solid; m.p. 150-152 °C (hexane/
ethyl acetate); tr= 21.2; Rf= 0.2 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-
7.85 (m, 2H), 7.70 (s, 1H), 7.52 (d, J = 8.4 Hz, 2H),
7.40-7.45 (m, 2H), 7.30-7.35 (m, 1H), 7.17 (d, J =
8.4 Hz, 2H), 5.50 (s, 2H); 13
C NMR (75 MHz,
CDCl3): δ 148.4, 133.6, 132.3 (2C), 130.3, 129.6
(2C), 128.8 (2C), 128.3, 125.7 (2C), 122.9, 119.4, 53.5; IR (ATR): ν 3082, 1489,
1221, 1073 cm-1
; MS (EI) m/z (%): 315 (M+
+ 2, 9%), 313 (M+, 10%), 286 (16),
284 (17), 206 (20), 171 (24), 169 (25), 116 (100), 90 (19), 89 (28).
299 J. Albadi, M. Keshavarz, M. Abedini, M. Vafaie-Nezhad, Chinese Chem. Lett. 2012, 23, 797-
800.
213 Experimental Part
1-(3-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (24c):
195 white solid; m.p. 85-87 °C (hexane/ethyl
acetate); tr= 21.0; Rf= 0.1 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 2H),
7.71 (s, 1H), 7.45-7.50 (m, 2H), 7.40-7.45 (m, 2H),
7.30-7.35 (m, 1H), 7.20-7.25 (m, 2H), 5.54 (s, 2H); 13
C NMR (75 MHz, CDCl3): δ 148.3, 136.8, 131.9,
130.9, 130.7, 130.2, 128.8 (2C), 128.3, 126.5, 125.7 (2C), 123.1, 119.5, 53.4; IR
(ATR): ν 3084, 1460, 1432, 1222, 1046 cm-1
; MS (EI) m/z (%): 315 (M+
+ 2,
8%), 313 (M+, 8%), 286 (14), 284 (14), 206 (21), 171 (22), 169 (23), 116 (100),
90 (20), 89 (29).
1-(2-Bromobenzyl)-4-phenyl-1H-1,2,3-triazole (24d):
195 white solid; m.p. 101-103 °C (hexane/ethyl
acetate); tr= 21.3; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.82 (d, J = 7.3 Hz,
2H), 7.78 (s, 1H), 7.62 (dd, J = 7.9, 1.0 Hz, 1H), 7.40-
7.45 (m, 2H), 7.30-7.35 (m, 2H), 7.15-7.25 (m, 2H),
5.70 (s, 2H); 13
C NMR (75 MHz, CDCl3): δ 148.1,
134.2, 133.2, 130.4, 130.2, 130.1, 128.8 (2C), 128.2 (2C), 125.7 (2C), 123.4,
119.8, 53.8; IR (ATR): ν 3051, 1459, 1430, 1220, 1043 cm-1
; MS (EI) m/z (%):
315 (M+
+ 2, 12%), 313 (M+, 11%), 208 (12), 207 (59), 206 (93), 184 (11), 171
(31), 169 (32), 117 (11), 116 (100), 103 (13), 91 (21), 90 (24), 89 (34), 63 (10).
1-(2-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (24e):
193h white solid; m.p. 98-99 °C (hexane/ethyl
acetate); tr= 18.6; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.75-7.80 (m, 2H),
7.54 (s, 1H), 7.35-7.45 (m, 2H), 7.30-7.35 (m, 2H),
7.20-7.25 (m, 3H), 5.60 (s, 2H), 2.31 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 148.0, 137.0, 132.5, 131.1,
130.5, 129.4, 129.2, 128.8 (2C), 128.1, 126.7, 125.6 (2C), 119.2, 52.5, 19.0; IR
(ATR): ν 3096, 1462, 1216 cm-1
; MS (EI) m/z (%): 249 (M+, 22%), 220 (35), 207
(17), 206 (11), 118(31), 117 (39), 116 (100), 105 (63), 104 (10), 103 (15), 89
(23), 79 (14), 77 (21).
Experimental Part 214
1-(3-Methylbenzyl)-4-phenyl-1H-1,2,3-triazole (24f):
299 white solid; m.p. 95-96 °C (hexane/ethyl
acetate); tr= 15.9; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 2H),
7.66 (s, 1H), 7.25-7.45 (m, 4H), 7.10-7.20 (m, 3H),
5.52 (s, 2H), 2.34 (s, 3H); 13
C NMR (75 MHz,
CDCl3): δ 148.1, 139.0, 134.5, 130.5, 129.5, 129.0, 128.8 (2C), 128.7, 128.1,
125.6 (2C), 125.1, 119.5, 54.2, 21.3; IR (ATR): ν 3089, 1464, 1222 cm-1
; MS
(EI) m/z (%): 249 (M+, 29%), 221 (13), 220 (61), 206 (36), 179 (20), 118 (14),
117 (17), 116 (100), 105 (66), 103 (14), 89 (24), 79 (13), 77 (20).
1-(3,5-Dimethoxybenzyl)-4-phenyl-1H-1,2,3-
triazole (24g): 193h
white solid; m.p. 90-92 °C
(hexane/ethyl acetate); tr= 22.8; Rf= 0.4
(hexane/ethyl acetate: 3/2); 1H NMR (300
MHz, CDCl3): δ 7.75-7.80 (m, 2H), 7.68 (s,
1H), 7.35-7.40 (m, 2H), 7.30-7.35 (m, 1H),
6.44 (s, 3H), 5.49 (s, 2H), 3.76 (s, 6H); 13
C
NMR (75 MHz, CDCl3): δ 161.2 (2C), 148.2, 136.7, 130.5, 128.8 (2C), 128.1,
125.6 (2C), 119.5, 106.0 (2C), 100.4, 55.4 (2C), 54.2; IR (ATR): ν 3086, 1610,
1197 cm-1
; MS (EI) m/z (%): 296 (M+
+ 1, 13%), 295 (M+, 74%), 281 (14), 266
(41), 252 (10), 239 (32), 236 (19), 209 (21), 208 (15), 207 (61), 164 (36), 152
(13), 151 (100), 117 (12), 116 (100), 91 (19), 89 (21), 78 (11), 77 (18), 65 (11).
2-((4-Phenyl-1H-1,2,3-triazol-1-
yl)methyl)isoindoline-1,3-dione (24h): white
solid; m.p. 186-188 °C (hexane/ethyl acetate);
tr= 15.4; Rf= 0.4 (hexane/ethyl acetate: 1/1); 1H
NMR (300 MHz, CDCl3): δ 8.11 (s, 1H), 7.90-
7.95 (m, 2H), 7.75-7.85 (m, 4H), 7.25-7.40 (m,
3H), 6.26 (s, 2H); 13
C NMR (75 MHz, CDCl3):
δ 166.5 (2C), 148.4, 134.9 (2C), 131.4 (2C), 130.1, 128.8 (2C), 128.3, 125.8
(2C), 124.1 (2C), 120.5, 49.7; IR (ATR): ν 1715 cm-1
; MS (EI) m/z (%): 304 (M+,
31%), 281 (11), 248 (10), 208 (10), 207 (40), 161 (11), 160 (100), 133 (15), 116
(31), 104 (16), 77 (15), 76 (14); Elemental analysis calcd. for C17H12N4O2: C =
67.10; H = 3.97; N = 18.41; found: C = 67.11; H = 3.96; N = 18.42.
215 Experimental Part
1-Benzyl-4-(4-chlorophenyl)-1H-1,2,3-triazole (24i):
196b white solid; m.p. 125-127 °C
(hexane/ethyl acetate); ); tr= 19.6; Rf= 0.1
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.72 (d, J = 8.7 Hz, 2H), 7.65 (s, 1H),
7.30-7.40 (m, 7H), 5.57 (s, 2H); 13
C NMR (75
MHz, CDCl3): δ 147.1, 134.5, 133.9, 129.2 (2C),
129.0 (2C), 128.8, 128.1 (2C), 126.9 (2C), 119.5, 60.4, 54.3; IR (ATR): ν 3060,
1481, 1222, 1069 cm-1
; MS (EI) m/z (%): 271 (M+
+ 2, 9%), 269 (M+, 26%), 242
(23), 241 (15), 240 (70), 207 (14), 206 (27), 179 (29), 152 (36), 151 (10), 150
(100), 125 (10), 123 (25), 104 (20), 102 (11), 91 (93), 65 (22).
1-(4-Bromobenzyl)-4-(4-chlorophenyl)-1H-
1,2,3-triazole (24j): white solid; m.p. 146-150
°C (hexane/ethyl acetate); tr= 24.9; Rf= 0.2
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.72 (d, J = 8.5 Hz, 2H), 7.66
(s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.36 (d, J =
8.5 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 5.53 (s,
2H); 13
C NMR (75 MHz, CDCl3): δ 147.3, 133.9, 133.5, 132.3 (2C), 129.6 (2C),
129.0 (2C), 128.8, 126.9 (2C), 123.0, 119.5, 53.5; IR (ATR): ν 1487, 1456, 1227,
1092, 1072 cm-1
; MS (EI) m/z (%): 349 (M+
+ 2, 17%), 347 (M+, 13%), 320 (19),
318 (14), 240 (26), 207 (10), 171 (27), 169 (29), 152 (33), 151 (10), 150 (100),
123 (16), 90 (19), 89 (16); HRMS (ESI): m/z calcd for C15H11BrClN3: 346.9825;
found: 346.9828.
1-Benzyl-4-(2-chlorophenyl)-1H-1,2,3-triazole (24k):
300 white solid; m.p. 77-78 °C (hexane/ethyl
acetate); tr= 18.7; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 8.22 (dd, J = 7.8, 1.8
Hz, 2H), 8.12 (s, 1H), 7.20-7.45 (m, 7H), 5.61 (s,
2H); 13
C NMR (75 MHz, CDCl3): δ 144.4, 134.6,
131.1, 130.1, 129.8, 129.2, 129.1 (2C), 129.0, 128.7,
127.9 (2C), 127.1, 123.1, 54.2; IR (ATR): ν 3083, 1461, 1227, 1056 cm-1
; MS
(EI) m/z (%): 271 (M+
+ 2, 6%), 269 (M+, 17%), 242 (12), 240 (36), 206 (40),
179 (30), 152 (28), 150 (87), 123 (14), 104 (26), 102 (10), 91 (100), 65 (19).
300 X. Meng, X. Xu, T. Gao, B. Chen, Eur. J. Org. Chem. 2010, 5409-5414.
Experimental Part 216
1-Benzyl-4-(4-bromophenyl)-1H-1,2,3-
triazole (24l):187b
white solid; m.p. 143-145 °C
(hexane/ethyl acetate); tr= 20.9; Rf= 0.1
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.65-7.70 (m, 3H), 7.50-7.55
(m, 2H), 7.30-7.40 (m, 5H), 5.56 (s, 2H); 13
C
NMR (75 MHz, CDCl3): δ 147.1, 134.4, 131.9 (2C), 129.4, 129.1 (2C), 128.8,
128.1 (2C), 127.2 (2C), 122.0, 119.5, 54.3; IR (ATR): ν 3070, 1477, 1449, 1222,
1050 cm-1
; MS (EI) m/z (%): 315 (M+
+ 2, 23%), 313 (M+, 24%), 287 (10), 286
(54), 285 (11), 284 (53), 207 (12), 206 (40), 204 (11), 196 (73), 194 (75), 179
(32), 178 (12), 169 (13), 167 (13), 115 (11), 104 (18), 102 (12), 91 (100), 88
(14), 65 (19).
4-(4-Bromophenyl)-1-(3-methylbenzyl)-
1H-1,2,3-triazole (24m): white solid; m.p.
127-128 °C (hexane/ethyl acetate); tr= 22.4;
Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.67 (d, J = 8.6 Hz,
2H), 7.65 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H),
7.28 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.11 (d, J = 7.3 Hz, 2H), 5.53
(s, 2H), 2.35 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 147.1, 139.1, 134.3, 131.9
(2C), 129.6, 129.5, 129.0, 128.8, 127.2 (2C), 125.2, 122.0, 119.5, 54.3, 21.3; IR
(ATR): ν 3016, 1450, 1225, 1069 cm-1
; MS (EI) m/z (%): 329 (M+
+ 2, 24%), 327
(M+, 22%), 300 (34), 298 (36), 286 (27), 284 (26), 220 (21), 207 (22), 196 (70),
194 (76), 193 (27), 178 (12), 169 (12), 167 (12), 118 (18), 117 (11), 115 (15),
105 (100), 103 (20), 102 (14), 88 (15), 79; Elemental analysis calcd. for
C16H14BrN3: C = 58.55; H = 4.30; N = 12.80; found: C = 58.50; H = 4.29; N =
12.69.
1-Benzyl-4-(4-methoxyphenyl)-1H-1,2,3-
triazole (24n):196b
white solid; m.p. 135-136 °C
(hexane/ethyl acetate); tr= 20.6; Rf= 0.4
(hexane/ethyl acetate: 3/2); 1H NMR (300
MHz, CDCl3): δ 7.72 (d, J = 8.9 Hz, 2H), 7.58
(s, 1H), 7.25-7.40 (m, 5H), 6.93 (d, J = 8.9 Hz,
2H), 5.55 (s, 2H), 3.82 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 159.5, 148.0, 134.7, 129.1 (2C), 128.7, 128.0 (2C), 127.0 (2C),
123.2, 118.6, 114.2 (2C), 55.3, 54.1; IR (ATR): ν 1455, 1250 cm-1
; MS (EI) m/z
(%): 266 (M+
+ 1, 6%), 265 (M+, 35%), 237 (21), 236 (100), 222 (17), 210 (10),
217 Experimental Part
209 (20), 206 (19), 194 (10), 193 (10), 179 (16), 160 (11), 146 (82), 119 (29), 91
(63), 89 (15), 76 (13), 65 (24).
1-Benzyl-4-(m-tolyl)-1H-1,2,3-triazole (24o):300
white solid; m.p. 145-146 °C (hexane/ethyl acetate);
tr= 18.7; Rf= 0.6 (hexane/ethyl acetate: 3/2); 1H
NMR (300 MHz, CDCl3): δ 7.65-7.70 (m, 2H), 7.58
(d, J = 7.6 Hz, 1H), 7.25-7.45 (m, 6H), 7.12 (d, J =
7.6 Hz, 1H), 5.58 (s, 2H), 2.38 (s, 3H); 13
C NMR
(75 MHz, CDCl3): δ 148.3, 138.5, 134.7, 130.3,
129.1 (2C), 128.9, 128.8, 128.7, 128.0 (2C), 126.3, 122.8, 119.4, 54.2, 21.4; IR
(ATR): ν 3031, 1454, 1220 cm-1
; MS (EI) m/z (%): 249 (M+, 25%), 221 (13), 220
(58), 206 (10), 179 (12), 131 (11), 130 (100), 104 (13), 103 (14), 91 (70), 77
(14), 65 (14).
1-(3-Bromobenzyl)-4-(m-tolyl)-1H-1,2,3-triazole (24p):
187a white solid; m.p. 90-93 °C (hexane/ethyl
acetate); tr= 22.3; Rf= 0.3 (hexane/ethyl acetate:
3/2); 1H NMR (300 MHz, CDCl3): δ 7.70 (s, 1H),
7.65 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.40-7.45 (m,
2H), 7.10-7.30 (m, 4H), 5.48 (s, 2H), 2.35 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 148.3, 138.4, 136.8,
131.7, 130.7, 130.5, 130.1, 128.9, 128.6, 126.4, 126.2, 122.9, 122.6, 119.5, 53.2,
21.3; IR (ATR): ν 3036, 1429, 1223, 1084 cm-1
; MS (EI) m/z (%): 329 (M+
+ 2,
11%), 327 (M+, 12%), 300 (18), 298 (17), 220 (18), 207 (39), 171 (24), 169 (22),
131 (11), 130 (100), 103 814), 90 (14), 89 (13).
1-(3-Methylbenzyl)-4-(m-tolyl)-1H-1,2,3-triazole (24q): white solid; m.p. 127-128 °C (hexane/ethyl
acetate); tr= 19.5; Rf= 0.2 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.66 (s, 1H),
7.64 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.25-7.30 (m,
2H), 7.10-7.20 (m, 4H), 5.52 (s, 2H), 2.37 (s, 3H),
2.34 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 148.2,
139.0, 138.4, 134.6, 130.4, 129.5, 129.0, 128.8, 128.7, 128.6, 126.3, 125.1,
122.7, 119.4, 54.2, 21.4, 21.3; IR (ATR): ν 3017, 1446, 1220 cm-1
; MS (EI) m/z
(%): 264 (M+
+ 1, 7%), 263 (M+, 35%), 235 (14), 234 (62), 220 (41), 207 (18),
193 (18), 131 (10), 130 (100), 118 (15), 105 (62), 103 (22), 79 (10), 77 (25);
HRMS (ESI): m/z calcd for C17H17N3 263.1422; found: 263.1414.
Experimental Part 218
1-Benzyl-4,5-diphenyl-1H-1,2,3-triazole (30a):
301 white solid; m.p. 109-110 °C
(hexane/ethyl acetate); tr= 22.3; Rf= 0.2
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.55-7.60 (m, 2H), 7.40-7.50
(m, 3H), 7.20-7.30 (m, 6H), 7.10-7.15 (m, 2H),
7.00-7.05 (m, 2H), 5.41 (s, 2H); 13
C NMR (75
MHz, CDCl3): δ 144.5, 135.3, 133.9, 130.9,
130.1 (2C), 129.6, 129.1 (2C), 128.7 (2C), 128.4 (2C), 128.1, 127.8, 127.7, 127.5
(2C), 126.7 (2C), 52.0; IR (ATR): ν 3058, 1449, 1246 cm-1
; MS (EI) m/z (%):
311 (M+, 17%), 193 (16), 192 (100), 165 (23), 91 (75), 89 (16).
1-Benzyl-4,5-bis(4-butylphenyl)-1H-
1,2,3-triazole (30b): pale yellow oil; tr=
19.3; Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.45-7.50
(m, 2H), 7.20-7.25 (m, 5H), 7.00-7.10 (m,
6H), 5.39 (s, 2H), 2.67 (t, J = 7.6 Hz, 2H),
2.55 (t, J = 7.6 Hz, 2H), 1.50-1.70 (m,
4H), 1.25-1.45 (m, 4H), 0.97 (t, J = 7.3
Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): δ 144.5, 144.4,
142.4, 135.5, 133.6, 129.9 (2C), 129.1
(2C), 128.6 (2C), 128.4 (2C), 128.0, 127.5 (2C), 126.5 (2C), 125.1, 51.9, 35.5,
35.3, 33.4, 33.3, 22.3 (2C), 14.0, 13.9; IR (ATR): ν 3030, 1455, 1245 cm-1
; MS
(EI) m/z (%): 423 (M+, 0%), 361 (16), 360 (69), 359 (24), 328 (13), 283 (18), 282
(20), 281 (72), 209 (13), 208 (18), 207 (100); Elemental analysis calcd. for
C29H33N3: C = 82.23; H = 7.85; N = 9.92; found: C = 82.26; H = 7.75; N = 9.89.
1-(3-Bromobenzyl)-4,5-diphenyl-1H-1,2,3-
triazole (30c): white solid; m.p. 70-73 °C
(hexane/ethyl acetate); tr= 19.9; Rf= 0.2
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.35-7.60 (m, 6H), 7.20-7.30
(m, 3H), 7.10-7.15 (m, 4H), 6.97 (d, J = 7.7 Hz,
1H), 5.37 (s, 2H); 13
C NMR (75 MHz, CDCl3):
δ 144.6, 137.3, 133.8, 131.4, 130.7, 130.3,
130.0 (2C), 129.9, 129.3 (2C), 128.4 (2C),
301 D.-R. Hou, T.-C. Kuan, Y.-K. Li, R. Lee, K.-W. Huang, Tetrahedron 2010, 66, 9415-9420.
219 Experimental Part
127.8, 127.6 (2C), 126.6 (2C), 126.2, 122.7, 51.4; IR (ATR): ν 3054, 1572, 1241
cm-1
; MS (EI) m/z (%): 391 (M+
+ 2, 6%), 389 (M+, 6%), 193 (15), 192 (100),
165 (28), 89 (15); Elemental analysis calcd. for C21H16BrN3: C = 64.63; H = 4.13;
N = 10.77; found: C = 64.65; H = 4.17; N = 10.69.
1-((2’-(Azidomethyl)-[1,1’-biphenyl]-2-yl)-4-
phenyl-1H-1,2,3-triazole (32): colorless oil; tr=
14.8; Rf= 0.7 (hexane/ethyl acetate: 1/1); 1H
NMR (300 MHz, CDCl3): δ 7.70-7.80 (m, 2H),
7.35-7.50 (m, 8H), 7.20-7.30 (m, 3H), 7.15-7.20
(m, 1H), 5.25-5.35 (m, 2H), 3.95-4.05 (m, 2H); 13
C NMR (75 MHz, CDCl3): δ 147.5, 139.1 (2C),
133.5, 132.9, 130.1, 129.9, 129.6, 128.9, 128.7
(2C), 128.6, 128.5, 128.4 (2C), 128.0, 125.5 (2C),
119.7, 52.3, 51.7; IR (ATR): ν 2092, 1242 cm-1
;
MS (EI) m/z (%): 194 (M+
- 172, 16%), 193 (100), 192 (28), 166 (14), 165 (56),
164 (10), 163 (10); Elemental analysis calcd. for C22H18N6: C = 72.11; H = 4.95;
N = 22.94; found: C = 72.12; H = 4.98; N = 22.98.
4-(4-Methoxyphenyl)-1-((2’-((4-phenyl-1H-
1,2,3-triazol-1-yl)methyl)-[1,1’-biphenyl]-2-
yl)methyl)- 1H-1,2,3-triazole (33): pale yellow
oil; Rf= 0.6 (hexane/ethyl acetate: 1/1); 1H NMR
(300 MHz, CDCl3): δ 7.70-7.75 (m, 2H), 7.60-
7.65 (m, 2H), 7.47 (s, 1H), 7.30-7.45 (m, 9H),
7.25-7.30 (m, 3H), 6.90-6.95 (m, 2H), 5.30-5.35
(m, 2H), 5.10-5.25 (m, 2H), 3.83 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 159.6, 147.4 (2C),
138.6 (2C), 133.3 (2C), 130.3, 130.1, 130.0,
129.9, 129.1, 128.8, 128.7 (2C), 128.6 (2C),
128.1, 126.9 (2C), 125.6 (2C), 123.0, 120.4,
119.5, 114.5, 114.2 (2C), 60.3, 55.3, 51.8; IR
(ATR): ν 1245 cm-1
; MS (EI) m/z (%): 499 (M+
+
1, 5%), 498 (M+, 14%), 339 (11), 325 (15), 324
(13), 309 (11), 295 (16), 294 (15), 292 (10), 283 (14), 282 (62), 180 (27), 179
(100), 178 (61), 166 (10), 165 (36), 146 (16), 133 (12), 132 (11), 116 (19), 89
(10); Elemental analysis calcd. for C31H26N6O: C = 74.68; H = 5.26; N = 16.86;
found: C = 74.69; H = 5.28; N = 16.87.
Experimental Part 220
6. REACTIONS CATALYSED BY NANOPARTICLES OF PALLADIUM
6.1. SYNTHESIS OF DIARYLIODONIUM SALTS
Diphenyliodonium tetrafluoroborate (35a):227d
m-CPBA (5.120 g, 24 mmol)
was dissolved in CH2Cl2 (80 mL). To the solution was added iodobenzene (2.48
mL, 21.6 mmol) followed by slow addition of BF3·OEt2 (6.8 mL, 54.4 mmol) at
room temperature. The resulting yellow solution was stirred at room temperature
for 30 min and then cooled to 0 ºC and PhB(OH)2 (2.960 g, 24 mmol) was added.
After 15 min of stirring at room temperature, the crude mixture was applied on a
silica plug (20 g) and eluted with CH2Cl2 (2 x 100 mL) followed by
CH2Cl2/MeOH (2 x 100 mL). The latter solution was concentrated and diethyl
ether (40 mL) was added to the residue to induce precipitation. The solution was
allowed to stir for 15 min, and then the solid was filtered and washed several
times with diethyl ether and then dried in vacuo. White
solid; m.p. = 133-135 ºC (Et2O); 1H NMR (300 MHz,
DMSO-d6): δ 8.25 (d, J = 7.3 Hz, 4H), 7.68 (t, J = 7.4
Hz, 2H), 7.54 (t, J = 7.6 Hz, 4H); 13
C NMR (75 MHz,
DMSO-d6): δ 135.1 (4C), 132.0 (2C), 131.7 (4C), 116.4
(2C); 19
F NMR (282 MHz, DMSO-d6): δ -148.3 (dd, J =
2.3, 1.2 Hz), -148.2 (br. s); IR (KBr): ν 1559, 1471, 1443, 1287, 1167, 1053, 740
cm-1
.
The appropriate iodoarene (5 mmol) was added to a stirred solution of m-
CPBA (1.6 g, 7.5 mmol) in acetic anhydride (10 mL) and the solution was stirred
for 1 h at room temperature after which 1,3,5-triisopropyl benzene (1.32 mL, 6.5
mmol) was added and the solution cooled to 0 ºC. Tetrafluoroboric acid (50 %
aqueous, 1.25 mL, 10 mmol) was added over 15 min via syringe pump and the
solution stirred at 0 ºC for 30 min before being allowed to warm to rt. After 6 h
the solution was recooled to 0 ºC and water (100 mL) was slowly added with fast
stirring. The solution was extracted with CH2Cl2 (2 x 50 mL) and the combined
organic extracts dried (MgSO4) and evaporated. The pure iodonium
tetrafluoroborate salts were precipitated with Et2O from a concentrated solution
of hot CH2Cl2 and obtained by filtration followed by washed with generous
amounts of Et2O on the filter
221 Experimental Part
p-Tolyl(2,4,6-trisopropylphenyl)iodonium
tetrafluoroborate (35b): white solid; m.p. =
189-191 ºC (Et2O); 1H NMR (300 MHz,
DMSO-d6): δ 7.82 (d, J = 8.4 Hz, 2H), 7.35 (d,
J = 8.2 Hz, 2H), 7.30 (s, 2H), 3.40 (heptet, J =
6.8 Hz, 2H), 2.97 (heptet, J = 6.8 Hz, 1H), 2.33
(s, 3H), 1.22 (app. t, J = 6.8 Hz, 18H); 13
C
NMR (75 MHz, DMSO-d6): δ 154.1, 151.1
(2C), 142.2, 134.0 (2C), 132.5 (2C), 124.5 (2C), 123.2, 111.3, 38.6 (2C), 33.3,
24.0 (4C), 23.5 (2C), 20.7; 19
F NMR (282 MHz, DMSO-d6): δ -148.3 (dd, J =
2.3, 1.2 Hz), -148.3 (br. s); IR (KBr): ν 1585, 1571, 1480, 1463, 1057, 1023, 998,
985 cm-1
; HRMS calcd. (%) for C22H30I: 421.1387; found: 421.1368.
o-Tolyl(2,4,6-trisiopropylphenyl)iodonium
tetrafluoroborate (35c): white solid; m.p. = 154-
155 ºC (Et2O); 1H NMR (300 MHz, DMSO-d6): δ
7.77 (d, J = 7.9 Hz, 1H), 7.50-7.60 (m, 2H), 7.25-
7.35 (m, 3H), 3.31 (heptet, J = 6.9 Hz, 2H), 2.98
(heptet, J = 6.9 Hz, 1H), 2.63 (s, 3H), 1.21 (2 x d,
J = 6.7 and 6.9 Hz respectively, 18H); 13
C NMR
(75 MHz, DMSO-d6): δ 154.2, 151.1 (2C), 140.4,
135.4, 132.3, 132.0, 129.6, 124.8 (2C), 123.0, 119.4, 38.9 (2C), 33.3, 24.4, 24.0
(4C), 23.5 (2C); 19
F NMR (282 MHz, DMSO-d6): δ -148.3 (br. s), -148.3 (dd, J =
2.3, 1.1 Hz); IR (KBr): ν 1586, 1572, 1560, 1467, 1426, 1058, 979 cm-1
; HRMS
calcd. (%) for C22H30I: 421.1387; found: 421.1368.
(4-Chlorophenyl)(2,4,6-
triisopropylphenyl)iodonium
tetrafluoroborate (35d):212b
white solid;
m.p. = 180-181 ºC (Et2O); 1H NMR (300
MHz, CDCl3): δ 7.64 (d, J = 8.9 Hz, 2H),
7.42 (d, J = 8.9 Hz, 2H), 7.20 (s, 2H), 3.26
(heptet, J = 6.7 Hz, 2H), 2.79 (heptet, J = 6.9
Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H), 1.26 (d, J = 6.8 Hz, 12H); 13
C NMR (75 MHz,
CDCl3): δ 156.1, 152.7 (2C), 139.0, 133.9 (2C), 132.6 (2C), 125.5 (2C), 119.7,
108.6, 39.7 (2C), 32.4, 24.3 (4C), 23.6 (2C); 19
F NMR (282 MHz, CDCl3): δ -
146.8 (dd, J = 3.3, 1.6 Hz), -146.7 (br. s); IR (KBr): ν 1585, 1570, 1471, 1427,
1389, 1369, 1087, 1055, 1011, 817 cm-1
.
Experimental Part 222
Bis(4-methoxyphenyl)iodonium tetrafluoroborate (35e): 227d
. m-CPBA (1.280
g, 6 mmol) was dissolved in CH2Cl2 (20 mL). To the solution was added 1-iodo-
4-methoxybenzene (1.264 g, 5.4 mmol). The mixture was placed then on a pre-
heated oil bath at 80 ºC and stirred for 10 min. The mixture was cooled at -78 ºC.
A 0 ºC cooled mixture of BF3·OEt2 (1.7 mL, 13.6 mmol) and 4-
methoxybenzeneboronic acid (912 mg, 6 mmol) in 20 mL of CH2Cl2 was added
dropwise. The resulting solution was stirred at -78 ºC for 30 min Then was
allowed to warm to room temperature and was applied on a silica plug (12 g) and
eluted with CH2Cl2 (2 x 50 mL) followed by CH2Cl2/MeOH (2 x 50 mL). The
latter solution was concentrated and diethyl ether (40 mL) was added to the
residue to induce precipitation. The solution was allowed to stir for 15 min, and
then the solid was filtered and washed several times with diethyl ether and then
dried in vacuo. Grey solid; m.p. = 177-180 ºC (Et2O); 1H NMR (300 MHz,
DMSO-d6): δ 8.13 (d, J = 9.1 Hz, 4H), 7.07
(d, J = 9.2 Hz, 4H), 3.80 (s, 6H); 13
C NMR
(75 MHz, DMSO-d6): δ 161.8 (2C), 136.8
(4C), 117.3 (4C), 105.9 (2C), 55.7 (2C); 19
F
NMR (282 MHz, DMSO-d6): δ -148.3 (dd, J
= 2.3, 1.1 Hz), -148.2 (br. s); IR (KBr): ν
1572, 1487, 1441, 1406, 1302, 1258, 1177, 1062, 1022, 825 cm-1
.
Phenyl(2,4,6-triisopropylphenyl)iodonium trifluoromethanesulfonate (35f):
227a 1,3,5-triisopropylbenzene (2.38 mL, 10 mmol) was added to a solution
of iodobenzene (1 mL ,9 mmol) and m-CPBA (2.64 g, 10 mmol) in CH2Cl2 (40
mL). The solution was cooled to 0ºC. Trifluoromethanesulfonic acid (1.31 mL,
15 mmol) was added dropwise over 5 min and the mixture allowed to slowly
warm to room temperature over 2 hours. The latter solution was concentrated and
diethyl ether (40 mL) was added to the residue to induce precipitation. The
solution was allowed to stir for 15 min, and then the solid was filtered and
washed several times with diethyl ether and then dried in vacuo. White solid;
m.p. = 169-170 ºC (Et2O); 1H NMR (300 MHz,
DMSO-d6): δ 7.93 (d, J = 7.3 Hz, 2H), 7.64 (t, J
= 7.4 Hz, 1H), 7.54 (t, J = 7.5 Hz, 2H), 7.32 (s,
2H), 3.35-3.45 (m, 2H), 2.90-3.05 (m, 1H), 1.15-
1.25 (m, 18H); 13
C NMR (75 MHz, DMSO-d6): δ
154.2, 151.2 (2C), 133.9 (2C), 131.9 (2C), 131.7,
124.6 (2C), 123.0, 114.9, 38.6 (2C), 33.3, 23.9
(4C), 23.4 (2C); 19
F NMR (282 MHz, DMSO-d6):
δ -148.3 (dd, J = 2.3, 1.2 Hz), -77.8 (br. s); IR (KBr): ν 1580, 1588, 1566, 1465,
1279, 1240, 1162, 1029, 881, 756 cm-1
.
223 Experimental Part
Di-p-tolyliodonium trifluoromethanesulfonate (35g):227c
m-CPBA (285 mg,
1.65 mmol) and 1-iodo-4-methylbenzene (327 mg, 1.5 mmol) were dissolved in
CH2Cl2 (7 mL). Toluene (176 μL, 1.65 mmol) was added to the solution at room
temperature followed by dropwise addition of TfOH (2 equiv.). The reaction
mixture was stirred at room temperature during 10 minutes and subsequently
concentrated under vacuum. Et2O was added and the mixture was stirred at room
temperature for 10 minutes to precipitate out an off-white solid. To ensure
complete precipitation, the flask was stored in the freezer for at least 30 minutes
before the solid was filtered off, washed with Et2O
and dried under vacuum. Grey solid; m.p. = 121-
123 ºC (Et2O); 1H NMR (300 MHz, DMSO-d6): δ
8.05-8.10 (m, 4H), 7.30-7.35 (m, 4H), 2.33 (s,
6H); 13
C NMR (75 MHz, DMSO-d6): δ 142.4 (2C),
135.0 (4C), 132.3 (4C), 113.0 (2C), 20.8 (2C); IR
(ATR): ν 1481, 1242, 1156, 1024, 812, 796 cm-1
.
Bis(4-fluorophenyl)iodonium tetrafluoroborate (35h):236
m-CPBA (610 mg,
2.9 mmol) was dissolved in CH2Cl2 (10 mL). To the solution was added 1-fluoro-
4-iodobenzene (300 μL, 2.6 mmol) followed by slow addition of BF3·OEt2 (802
μL, 6.5 mmol) at room temperature. The resulting solution was stirred at room
temperature for 30 minutes and then cooled at 0 ºC, and 4-(fluorophenyl)boronic
acid (406 mg, 2.9 mmol) was added. After 15 min of stirring at room
temperature, the crude mixture was applied on a silica plug (20 g) and eluted
with CH2Cl2 (2 x 100 mL) followed by CH2Cl2/MeOH (2 x 100 mL). The latter
solution was concentrated and diethyl ether (40 mL) was added to the residue to
induce precipitation. The solution was allowed to stir for 15 min, and then the
solid was filtered and washed several times with diethyl ether and then dried in
vacuo. White solid; m.p. = 97-98 ºC (Et2O); 1H
NMR (300 MHz, DMSO-d6): δ 8.30-8.35 (m, 4H),
7.40-7.45 (m, 4H); 13
C NMR (75 MHz, DMSO-
d6): δ 164.0 (d, 1JC-F = 251.4 Hz, 2C), 138.0 (d,
3JC-
F = 9.0 Hz, 4C), 119.4 (d, 2JC-F = 22.8 Hz, 4C),
111.2 (2C); IR (ATR): ν 1576, 1479, 1232, 1034,
996, 827 cm-1
.
Experimental Part 224
6.2. SYNTHESIS OF ARYLATED HETEROCYCLES
General Procedure: To a stirred solution of the corresponding
heterocycle 34 or 37 (0.5 mmol) in ethanol (1.5 mL) were added the
corresponding diaryliodonium tetrafluoroborate 35 (1.5 mmol) and PdO-Fe3O4
(180 mg, 10 mol% Pd). The mixture was stirred at 60 ºC for 24 h. The catalyst
was removed by a magnet and the solvent evaporated under reduced pressure.
The corresponding products 36 or 38 were usually purified by column
chromatography on silica gel (hexane/ethyl acetate).
3-Phenylbenzo[b]thiophene (36a):212b
colorless oil; 1H
NMR (300 MHz, CDCl3): δ 7.90-8.00 (m, 2H), 7.60-7.65
(m, 2H), 7.50-7.55 (m, 2H), 7.40-7.50 (m, 4H); 13
C NMR
(75 MHz, CDCl3): δ 140.7, 138.1, 137.9, 136.0, 128.7
(4C), 127.5, 124.4, 124.3, 123.4, 122.90, 122.90, IR (KBr):
ν 1600, 1524, 1484, 1442, 1425, 1348, 834 cm-1
; HRMS
calcd. (%) for C14H11S: 211.0581; found: 211.0573.
2-Phenylbenzofuran (36b):212b
white solid; m.p. =
122-124 ºC (hexane/ethyl acetate); 1H NMR (300
MHz, CDCl3): δ 7.85-7.90 (m, 2H), 7.55-7.60 (m,
1H), 7.52 (d, J = 8.1 Hz, 1H), 7.40-7.50 (m, 2H),
7.15-7.40 (m, 3H), 7.02 (d, J = 0.7 Hz, 1H); 13
C
NMR (75 MHz, CDCl3): δ 155.9, 154.9, 130.4, 129.2, 128.8 (2C), 128.5, 124.9
(2C), 124.2, 122.9, 120.9, 111.2, 101.3; IR (KBr): ν 1605, 1562, 1491, 1471,
1455, 1259, 1020 cm-1
.
Methyl 2-phenyl-1H-indole-7-carboxylate (36c):
white solid; m.p. = 72-74 ºC (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 10.11 (br s, 1H),
7.80-7.90 (m, 2H), 7.70-7.75 (m, 2H), 7.40-7.50
(m, 2H), 7.30-7.35 (m, 1H), 7.14 (t, J = 7.7 Hz,
1H), 6.85 (d, J = 2.4 Hz, 1H), 3.99 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 168.0, 139.0, 136.9,
131.9, 130.3, 129.0 (2C), 128.0, 126.1, 125.3 (2C), 124.2, 119.4, 112.2, 99.5,
51.9; IR (ATR): ν 3435, 1699, 1438, 1268 cm-1
; HRMS calcd. (%) for
C16H13NO2: 251.0946; found: 251.0951.
225 Experimental Part
5-Fluoro-2-phenyl-1H-indole (36d):302
white
solid; m.p. = 175-177 ºC (hexane/ethyl acetate); 1H
NMR (300 MHz, CDCl3): δ 8.30 (br s, 1H), 7.60-
7.65 (m, 2H), 7.40-7.45 (m, 2H), 7.25-7.40 (m,
3H), 6.93 (m, 1H), 6.77 (dd, J = 2.0, 0.6 Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 158.2 (d, 1JC-F = 235.0 Hz), 139.6, 133.3, 132.0,
129.6 (d, 3JC-F = 10.4 Hz), 129.1 (2C), 128.0, 125.2 (2C), 111.5 (d,
3JC-F = 9.7
Hz), 110.6 (d, 2JC-F = 26.4 Hz), 105.4 (d,
2JC-F = 23.6 Hz), 100.0 (d,
4JC-F = 4.7
Hz); IR (ATR): ν 3434, 1624, 1586, 1472, 1457 cm-1
.
4-Bromo-2-phenyl-1H-indole (36e):303
white solid;
m.p. = 100-102 ºC (hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3): δ 8.40 (br s, 1H), 7.60-7.65 (m,
2H), 7.40-7.45 (m, 2H), 7.25-7.50 (m, 3H), 7.01 (t, J =
7.9 Hz, 1H), 6.85 (d, J = 1.8 Hz, 1H); 13
C NMR (75
MHz, CDCl3): δ 138.4, 136.8, 131.6, 130.0, 129.0
(2C), 128.1, 125.2 (2C), 123.1 (2C), 114.5, 110.0, 100.1; IR (ATR): ν 3443,
1597, 1568, 1456, 1452 cm-1
.
3-(p-Tolyl)benzo[b]thiophene (36f):212a
colourless oil; 1H
NMR (300 MHz, CDCl3): δ 7.85-8.95 (m, 2H), 7.48 (d, J =
8.0 Hz, 2H), 7.35-7.40 (m, 3H), 7.29 (d, J = 7.8 Hz, 2H),
2.43 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 140.7, 138.1,
138.0, 137.3, 133.1, 129.4 (2C), 128.6 (2C), 124.3, 124.2,
123.0, 122.94, 122.89, 21.2; IR (NaCl): ν 1532, 1495, 1456,
1425, 1344, 1060, 1021, 819 cm-1
.
2-(p-Tolyl)benzofuran (36g):304
white solid; m.p.
= 115-117 ºC (hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3): δ 7.75 (d, J = 7.9 Hz, 2H),
7.55 (d, J = 7.0 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H),
7.15-7.30 (4H, m), 6.94 (1H, s), 2.38 (3H, s); 13
C NMR (75 MHz, CDCl3): δ
156.2, 154.8, 138.6, 129.5 (2C), 129.3, 127.8, 124.9 (2C), 124.0, 122.8, 120.7,
111.1, 100.5, 21.4; IR (KBr): ν 1613, 1587, 1504, 1451, 1257, 1033, 801 cm-1
.
302 K. Funaki, T. Sato, S. Oi, Org. Lett. 2012, 14, 6186-6189. 303 V. Guilarte, M. P. Castroviejo, P. García-García, M. A. Fernández-Rodríguez, R. Sanz, J. Org.
Chem. 2011, 76, 3416-3437. 304 M. L. N. Rao, D. N. Jadhav, P. Dasgupta, Eur. J. Org. Chem. 2013, 781-788.
Experimental Part 226
2-(o-Tolyl)benzofuran (36h):305
colorless oil; 1H
NMR (300 MHz, CDCl3): δ 7.75-7.90 (m, 1H), 7.58
(d, J = 6.7 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.15-
7.35 (m, 5H), 6.87 (s, 1H), 2.56 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 155.7, 154.4, 135.8, 131.2, 129.9,
129.2, 128.5, 128.2, 126.1, 124.2, 122.8, 120.9, 111.1, 105.1, 21.9; IR (NaCl): ν
1605, 1575, 1489, 1473, 1454, 1259, 1019, 921, 805 cm-1.
2-(4-Chlorophenyl)benzofuran (36i):304
white
solid; m.p. = 135-138 ºC (hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 7.77 (d, J = 8.7
Hz, 2H), 7.55-7.60 (m, 1H), 7.45-7.50 (m, 1H),
7.40 (d, J = 8.8 Hz, 2H), 7.29 (td, J = 7.7, 1.6 Hz,
1H), 7.22 (td, J = 7.4, 1.2 Hz, 1H), 6.99 (d, J = 0.8 Hz, 1H); 13
C NMR (75 MHz,
CDCl3): δ 154.9, 154.8, 134.3, 129.05, 129.02 (2C), 128.98, 126.1 (2C), 124.5,
123.1, 121.0, 111.2, 101.7; IR (KBr): ν 1602, 1581, 1487, 1450, 1404, 1256,
1104, 1094, 1031, 1010, 836, 804 cm-1
.
2-(4-Methoxyphenyl)benzofuran (36j): 304
white solid; m.p. = 147-148 ºC (hexane/ethyl
acetate); 1H NMR (300 MHz, CDCl3): δ 7.78
(d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.1 Hz, 1H),
7.49 (d, J = 7.6 Hz, 1H), 7.15-7.30 (m, 2H), 6.95 (d, J = 8.5 Hz, 2H), 6.85 (s,
1H), 3.82 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 160.0, 156.0, 154.7, 129.5,
126.4 (2C), 123.7, 123.3, 122.8, 120.5, 114.2 (2C), 111.0, 99.7, 55.3; IR (KBr): ν
1610, 1593, 1505, 1453, 1440, 1248, 1180, 1023, 835, 799 cm-1
.
3-Phenylthiophene (38a):212b
white solid; m.p. = 91-92 ºC
(hexane/ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 7.60-
7.65 (m, 2H), 7.40-7.50 (m, 4H), 7.25-7.40 (m, 2H); 13
C
NMR (75 MHz, CDCl3): δ 142.4, 135.9, 128.8 (2C), 127.2,
126.4 (2C), 126.3, 126.2, 120.3; IR (ATR): ν 3059, 3033,
1597, 1530, 1493 cm-1
.
305 S. E. Denmark, R. C. Smith, W.-T. T. Chang, J. M. Muhuhi, J. Am. Chem. Soc. 2009, 131,
3104-3118.
227 Experimental Part
3,4-Diphenylthiophene (38a’):212b
white solid; m.p. =
112-114 ºC (hexane/ethyl acetate); 1H NMR (300 MHz,
CDCl3): δ 7.31 (s, 2H), 7.15-7.25 (m, 10H); 13
C NMR
(75 MHz, CDCl3): δ 141.7 (2C), 136.5 (2C), 129.0 (4C),
128.1 (4C), 126.9 (2C), 124.0 (2C); IR (ATR): ν 3049,
3023, 1670, 1598, 1508 cm-1
.
2-Chloro-4-phenylthiopehene (38b): white solid; m.p. =
49-51 ºC (hexane/ethyl acetate); 1H NMR (300 MHz,
CDCl3): δ 7.50-7.55 (m, 2H), 7.35-7.45 (m, 2H), 7.30-7.35
(m, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 141.7, 135.1, 130.7, 128.9
(2C), 127.6, 126.1 (2C), 125.5, 118.5; IR (ATR): ν 3065,
3038, 1598, 1493 cm-1
; MS (EI) m/z (%): 196 (M+
+ 2, 37),
194 (M+, 100), 158 (9), 115 (39), 79 (9).
2-Bromo-4-phenylthiophene (38c):302
white solid; m.p. =
48-50 ºC (hexane/ethyl acetate); 1H NMR (300 MHz,
CDCl3): δ 7.50-7.55 (m, 2H), 7.35-7.40 (m, 2H), 7.30-7.35
(m, 3H); 13
C NMR (75 MHz, CDCl3): δ 142.8, 134.9,
129.2, 128.9 (2C), 127.6, 126.2 (2C), 121.4, 112.9; IR
(ATR): ν 3082, 3057, 1596, 1492, 1446 cm-1
.
3-Bromo-4-phenylthiophene (38d):306
white solid; m.p. =
57-59 ºC (hexane/ethyl acetate); 1H NMR (300 MHz,
CDCl3): δ 7.45-7.50 (m, 2H), 7.40-7.45 (m, 3H), 7.35 (d, J
= 3.5 Hz, 1H), 7.24 (d, J = 3.5 Hz, 1H); 13
C NMR (75 MHz,
CDCl3): δ 142.0, 135.1, 129.0 (2C), 128.2 (2C), 127.8,
124.0, 123.4, 111.0; IR (ATR): ν 3058, 3030, 1600, 1523,
1482 cm-1
.
306 I. Schnapperelle, T. Bach, ChemCatChem 2013, 5, 3232-3236.
Experimental Part 228
4-Phenyl-2,2’-bithiophene (38e):307
pale brown solid;
m.p. = 72-74 ºC (hexane/ethyl acetate); 1H NMR (300
MHz, CDCl3): δ 7.55-7.65 (m, 2H), 7.44 (d, J = 1.4
Hz, 1H), 7.35-7.40 (m, 2H), 7.30-7.35 (m, 2H), 7.20-
7.25 (m, 2H), 7.02 (dd, J = 5.0, 3.7 Hz, 1H); 13
C NMR
(75 MHz, CDCl3): δ 142.9, 138.0, 137.3, 135.5, 128.8
(2C), 127.8, 127.3, 126.3 (2C), 124.5, 123.9, 122.9, 119.1; IR (ATR): ν 3063,
3029, 1596, 1491 cm-1
.
6.3. SYNTHESIS OF HALOETHERS
General Procedure: To a mixture of potassium carbonate (690 mg, 5
mmol) and the apropriate phenol (5 mmol), was added acetone (5 mL). To the
stirring mixture was added the required benzyl bromide (2.5 mmol) followed by
heating to 50 ºC overnight. The reaction mixture was then cooled to room
temperature, poured into a solution of NaOH (2M), and extracted three times
with ether. The organic extracts were dried over MgSO4 and concentrated under
reduced pressure. Purification was done by column chromatography using
hexane/ethyl acetate (9:1) mixtures to afford the haloethers 39.
1-Bromo-2-(phenoxymethyl)benzene (39a):308
white
solid; m.p. = 39-40 ºC (hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3): δ 7.55-7.60 (m, 2H), 7.25-7.35 (m,
3H), 7.15-7.20 (m, 1H), 6.95-7.00 (m, 3H), 5.14 (s,
2H); 13
C NMR (75 MHz, CDCl3): δ 158.4, 136.4,
132.6, 129.5 (2C), 129.1, 128.8, 127.5, 122.2, 121.2,
114.9 (2C), 69.3; IR (KBr): ν 1597, 1585, 1570, 1497, 1482, 1447, 1437, 1379,
1303, 1245, 1171, 1154, 1056, 1044, 1024, 750 cm-1
.
1-Bromo-2-((4-
methoxyphenoxy)methyl)benzene (39b):309
colorless oil; 1H NMR (300 MHz, CDCl3): δ
7.56 (app. t, J = 7.3 Hz, 2H), 7.32 (dd, J = 7.5,
1.2 Hz, 1H), 7.17 (dd, J = 7.9, 1.7 Hz, 1H), 6.92
(d, J = 9.3 Hz, 2H), 6.84 (d, J = 9.3 Hz, 2H),
307 S. Varello, S. T. Handy, Synthesis 2009, 1, 138-142. 308 C.-L. Sun, Y.-F. Gu, W.-P. Huang, Z.-J. Shi, Chem. Commun. 2011, 47, 9813-9815. 309 L.-C. Campeau, M. Parisien, A. Jean, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 581-590.
229 Experimental Part
5.08 (s, 2H), 3.76 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 154.2, 152.6, 136.6,
132.6, 129.1, 128.9, 127.5, 122.3, 115.9 (2C), 114.7 (2C), 70.1, 55.7; IR (NaCl):
ν 1593, 1570, 1506, 1465, 1455, 1441, 1381, 1230, 1108, 1042, 823, 749 cm-1
.
1-Bromo-2-((p-tolyloxy)methyl)benzene (39c):308
colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.50-
7.60 (m, 2H), 7.30 (dd, J = 7.6, 0.8 Hz, 1H), 7.15
(dd, J = 7.7, 1.5 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H),
6.87 (d, J = 8.5 Hz, 2H), 5.09 (s, 2H), 2.28 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 156.3, 136.6, 132.5,
130.4, 129.9 (2C), 129.1, 128.8, 127.5, 122.2, 114.7 (2C), 69.5, 20.5; IR (NaCl):
ν 1586, 1570, 1510, 1441, 1380, 1297, 1239, 1044, 1025, 817, 747 cm-1
.
1-Bromo-2-((4-chlorophenoxy)methyl)benzene (39d):
308 colorless oil;
1H NMR (300 MHz, CDCl3):
δ 7.58 (dd, J = 7.9, 1.1 Hz, 1H), 7.51 (1H, d, J = 7.7
Hz, 1H), 7.32 (td, J = 7.6, 1.1 Hz, 1H), 7.24 (d, J =
9.1 Hz, 2H), 7.18 (td, J = 7.9, 1.7 Hz, 1H), 6.90 (d,
J = 9.0 Hz, 2H), 5.10 (s, 2H); 13
C NMR (75 MHz,
CDCl3): δ 157.0, 135.9, 132.7, 129.41 (2C), 129.36, 128.8, 127.6, 126.1, 122.3,
116.2 (2C), 69.7; IR (NaCl): ν 1599, 1493, 1439, 1291, 1249, 1174, 1096, 1044
cm-1
.
1-Bromo-2-((4-fluorophenoxy)methyl)benzene (39e):
308 pale yellow oil;
1H NMR (300 MHz,
CDCl3): δ 7.57 (dd, J = 7.9, 1.1 Hz, 1H), 7.52 (d, J
= 7.7 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.18
(td, J = 7.9, 1.7 Hz, 1H), 6.85-7.05 (m, 4H), 5.09 (s,
2H); 13
C NMR (75 MHz, CDCl3): δ 157.5 (d, 1JC-F =
238.8 Hz), 154.6 (d, 4JC-F = 2.1 Hz), 136.1, 132.6, 129.3, 128.9, 127.6, 122.3,
116.0 (d, 3JC-F = 10.0 Hz, 2C), 115.9 (d,
2JC-F = 21.2 Hz, 2C), 70.1; IR (NaCl): ν
1602, 1571, 1505, 1469, 1440, 1381, 1298, 1247, 1220, 1097, 1044, 1025, 827
cm-1
; 19
F NMR (282 MHz, CDCl3): -123.3 (tt, 3JH-F = 8.0 Hz,
4JH-F = 4.5 Hz).
1-Bromo-2-((3-fluorophenoxy)methyl)benzene (39f):
309 pale yellow oil;
1H NMR (300 MHz,
CDCl3): δ 7.55-7.65 (m, 2H), 7.32 (td, J = 7.6, 1.2
Hz, 1H), 7.17 (td, J = 7.9, 1.7 Hz, 1H), 6.85-7.15
Experimental Part 230
(m, 4H), 5.18 (s, 2H); 13
C NMR (75 MHz, CDCl3): δ 152.9 (d, 1JC-F = 246.0 Hz),
146.5 (d, 3JC-F = 10.6 Hz), 135.9, 132.5, 129.3, 128.8, 127.6, 124.3 (d,
3JC-F = 3.9
Hz), 122.1, 121.7 (d, 2JC-F = 6.9 Hz), 116.3 (d,
2JC-F = 18.2 Hz), 115.7 (d,
4JC-F =
1.6 Hz), 70.6; IR (NaCl): ν 1611, 1595, 1490, 1440, 1280, 1263, 1166, 1136,
1027, 748 cm-1
; 19
F NMR (282 MHz, CDCl3): -133.9 (m).
1-Bromo-2-((2-fluorophenoxy)methyl)benzene (39g):
310 colorless oil;
1H NMR (300 MHz, CDCl3): δ
7.58 (dd, J = 7.9, 1.1 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H),
7.33 (td, J = 7.6, 1.2 Hz, 1H), 7.15-7.25 (m, 2H), 6.60-
6.80 (m, 3H), 5.11 (s, 2H); 13
C NMR (75 MHz, CDCl3):
δ 163.6 (d, 1JC-F = 245.5 Hz), 159.8 (d,
2JC-F = 10.9 Hz),
135.8, 132.7, 130.3 (d, 3JC-F = 10.0 Hz), 129.4, 128.9, 127.6, 122.3, 110.6 (d,
4JC-
F = 2.9 Hz), 108.1 (d, 3JC-F = 21.4 Hz), 102.8 (d,
2JC-F = 24.9 Hz), 69.6;
19F NMR
(282 MHz, CDCl3): -111.4 (m); IR (NaCl): ν 1591, 1571, 1504, 1456, 1442,
1380, 1313, 1284, 1260, 1206, 1110, 1024, 745 cm-1
.
1-Bromo-2-(phenoxymethyl)-4-
(trifluoromethyl)benzene (39h): white solid; m.p.
= 70-72 ºC (hexane/ethyl acetate); 1H NMR (300
MHz, CDCl3): δ 7.86 (s, 1H), 7.67 (d, J = 8.3 Hz,
1H), 7.41 (d, J = 8.3 Hz, 1H), 7.31 (t, J = 7.8 Hz,
2H), 6.95-7.05 (m, 3H), 5.10 (s, 2H); 13
C NMR (75
MHz, CDCl3): δ 158.1, 137.7, 133.1, 130.2 (q, 2JC-F = 33.0 Hz), 129.6 (2C),
125.74 (q, 3JC-F = 3.8 Hz), 125.73, 125.5 (q,
3JC-F = 3.8 Hz), 123.8 (q,
1JC-F =
272.4 Hz), 121.6, 114.9 (2C), 68.8; 19
F NMR (282 MHz, CDCl3): -62.6 (s); IR
(KBr): ν 1600, 1586, 1498, 1484, 1459, 1449, 1417, 1342, 1304, 1248, 1173,
1154, 1128, 1060, 1022, 904, 831 cm-1
.
2-Bromo-4-fluoro-1-(phenoxymethyl)benzene (39i): colorless oil;
1H NMR (300 MHz, CDCl3): δ
7.52 (dd, J = 8.6, 6.0 Hz, 1H), 7.25-7.35 (m, 3H),
6.90-7.10 (m, 4H), 5.08 (s, 2H); 13
C NMR (75 MHz,
CDCl3): δ 161.9 (d, 1JC-F = 250.6 Hz), 158.3, 132.3
(d, 4JC-F = 3.5 Hz), 130.0 (d,
3JC-F = 8.5 Hz), 129.6
310 J. Barluenga, F. J. Fañanás, R. Sanz, Y. Fernández, Chem. Eur. J. 2002, 8, 2034-2046.
231 Experimental Part
(2C), 122.4 (d, 3JC-F = 9.6 Hz), 121.3, 119.9 (d,
2JC-F = 24.6 Hz), 114.9 (2C),
114.7 (d, 2JC-F = 21.0 Hz), 68.8;
19F NMR (282 MHz, CDCl3): -112.5 (m); IR
(NaCl): ν 1601, 1496, 1457, 1304, 1238, 1171, 1054, 1032, 812, 752 cm-1
.
6.4. SYNTHESIS OF SUBSTITUTED BENZO[c]CHROMENE
DERIVATIVES
General Procedure: To a stirred solution of the corresponding arene 39
(0.5 mmol) in N,N-dimethylacetamide (2 mL) were added KOAc (98 mg, 1
mmol) and PdO-Fe3O4 (180 mg, 10 mol% Pd). The mixture was stirred at 140 ºC
for 48 h. The catalyst was removed by a magnet and the mixture was quenched
with water and extracted with AcOEt (3 x 10 mL). The organic phases were dried
over MgSO4, followed by evaporation under reduced pressure to remove the
solvent. The corresponding products 40 were usually purified by column
chromatography on silica gel (hexane/ethyl acetate).
6H-Benzo[c]chromene (40a):311
colorless oil; 1H NMR (300
MHz, CDCl3): δ 7.71 (dd, J = 7.7, 1.6 Hz, 1H), 7.67 (d, J =
7.5 Hz, 1H), 7.34 (td, J = 7.6, 1.4 Hz, 1H), 7.20-7.25 (m, 2H),
7.11 (d, J = 7.4 Hz, 1H), 7.03 (td, J = 7.5, 1.3 Hz, 1H), 6.98
(dd, J = 8.1, 1.2 Hz, 1H), 5.09 (s, 2H); 13
C NMR (75 MHz,
CDCl3): δ 154.8, 131.4, 130.1, 129.4, 128.4, 127.6, 124.6,
123.3, 122.9, 122.1, 122.0, 117.3, 68.4; IR (NaCl): ν 2842, 1607, 1594, 1487,
1440, 1245, 1198, 1018, 755 cm-1
.
2-Methoxy-6H-benzo[c]chromene (40b):309
colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 7.5 Hz, 1H),
7.38 (td, J = 7.6, 1.3 Hz, 1H), 7.25-7.30 (m with td at 7.30, J
= 7.4, 1.2 Hz, 2H), 7.16 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 8.8
Hz, 1H), 6.81 (dd, J = 8.8, 2.9 Hz, 1H), 5.07 (s, 2H), 3.84 (s,
3H); 13
C NMR (75 MHz, CDCl3): δ 154.8, 148.9, 131.9,
130.2, 128.4, 127.8, 124.7, 123.6, 122.1, 118.0, 115.0,
108.3, 68.6, 55.8; IR (NaCl): ν 2835, 1614, 1572, 1496, 1450, 1219, 1194, 1049,
1037 cm-1
.
311 M. Parisien, D. Valette, K. Fagnou, J. Org. Chem. 2005, 70, 7578-7584.
Experimental Part 232
2-Methyl-6H-benzo[c]chromene (40c):308
colorless oil; 1H
NMR (300 MHz, CDCl3): δ 7.68 (d, J = 7.6 Hz, 1H), 7.53
(d, J = 1.7 Hz, 1H), 7.36 (td, J = 7.6, 1.1 Hz, 1H), 7.26 (td, J
= 7.4, 1.2 Hz, 1H), 7.13 (d, J = 7.4 Hz, 1H), 7.03 (dd, J =
8.2, 2.0 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.08 (s, 2H), 2.36
(s, 3H); 13
C NMR (75 MHz, CDCl3): δ 152.6, 131.6, 131.3,
130.3, 130.1, 128.3, 127.5, 124.6, 123.6, 122.6, 121.9, 117.1, 68.5, 20.9; IR
(NaCl): ν 2840, 1607, 1593, 1573, 1498, 1449, 1246, 1199, 1021 cm-1
.
2-Chloro-6H-benzo[c]chromene (40d):308
colorless oil; 1H
NMR (300 MHz, CDCl3): δ 7.67 (d, J = 2.5 Hz, 1H), 7.64
(d, J = 7.5 Hz, 1H), 7.38 (td, J = 7.6, 1.4 Hz, 1H), 7.30 (td, J
= 7.4, 1.3 Hz, 1H), 7.17 (dd, J = 8.6, 2.5 Hz, 1H), 7.14 (d, J
= 7.5 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H), 5.10 (s, 2H); 13
C
NMR (75 MHz, CDCl3): δ 153.3, 131.3 (2C), 129.1, 128.6,
128.3, 127.1, 124.7, 124.3, 123.1, 122.1, 118.7, 68.5; IR
(NaCl): ν 2842, 1591, 1487, 1445, 1408, 1249, 1259, 1247, 1200, 1093, 1020,
815 cm-1
.
2-Fluoro-6H-benzo[c]chromene (40e): 308
colorless oil; 1H
NMR (300 MHz, CDCl3): δ 7.60 (d, J = 7.7 Hz, 1H), 7.35-
7.40 (m, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.3 Hz,
1H), 6.85-6.95 (m, 2H), 5.08 (s, 2H); 13
C NMR (75 MHz,
CDCl3): δ 158.2 (d, 1JC-F = 238.9 Hz), 150.7 (d,
4JC-F = 2.0
Hz), 131.5, 129.4 (d, 4JC-F = 2.2 Hz), 128.5, 128.3, 124.7,
124.1 (d, 3JC-F = 8.1 Hz), 122.2, 118.4 (d,
3JC-F = 8.3 Hz),
115.8 (d, 2JC-F = 23.5 Hz), 109.6 (d,
2JC-F = 24.2 Hz), 68.5;
19F NMR (282 MHz,
CDCl3): -121.5; IR (NaCl): ν 2842, 1619, 1577, 1495, 1448, 1426, 1285, 1247,
1173, 1021, 902, 867, 815 cm-1
.
1-Fluoro-6H-benzo[c]chromene (40f)
and 3-Fluoro-6H-benzo[c]chromene
(40f’) (45:55): colorless oil; 1H NMR
(300 MHz, CDCl3): δ 8.04 (d, J = 7.8
Hz, 1H), 7.67 (dd, J = 8.6, 6.4 H, 1H),
7.63 (d, J = 7.8 Hz, 1H), 7.25-7.45 (m,
4H), 7.10-7.20 (m, 3H), 6.65-6.85 (m,
4H), 5.12 (s, 2H), 5.07 (s, 2H); 13
C NMR (75 MHz, CDCl3): δ 163.3 (d, 1JC-F =
247.3 Hz), 160.7 (d, 1JC-F = 250.7 Hz), 156.6 (d,
3JC-F = 6.6 Hz), 156.0 (d,
3JC-F =
233 Experimental Part
12.1 Hz), 131.5, 130.4, 129.5, 129.0 (d, 3JC-F = 11.1 Hz), 128.5, 127.9 (d,
4JC-F =
1.1 Hz), 127.5, 127.0 (d, 4JC-F = 3.0 Hz), 126.3, 126.2, 124.7, 124.6, 124.4 (d,
3JC-
F = 10.0 Hz), 121.7, 119.2 (d, 4JC-F = 3.2 Hz), 113.1 (d,
4JC-F = 3.2 Hz), 112.3 (d,
3JC-F = 13.7 Hz), 109.7 (d,
2JC-F = 23.3 Hz), 109.3 (d,
2JC-F = 22.0 Hz), 104.8 (d,
2JC-F = 24.3 Hz), 68.8, 68.7;
19F NMR (282 MHz, CDCl3): 115.1 (m), -111.5
(m); IR (NaCl): ν 2842, 1618, 1591, 1508, 1486, 1459, 1440, 1262, 1144, 1039,
1025, 966, 793, 763 cm-1
;HRMS calcd. (%) for C13H8FO: 199.0559; found:
199.0551.
4-Fluoro-6H-benzo[c]chromene (40g): colorless oil; 1H
NMR (300 MHz, CDCl3): δ 7.68 (d, 3JH-H = 7.5 Hz, 1H),
7.49 (dt, 3JH-H = 7.8 Hz,
5JH-F = 1.3 Hz, 1H), 7.39 (td,
3JH-H
= 7.4 Hz, 4JH-H = 1.3 Hz, 1H), 7.31 (td,
3JH-H = 7.4 Hz,
4JH-H
= 1.3 Hz, 1H), 7.17 (d, 3JH-H = 7.4 Hz, 1H), 7.04 (ddd,
3JH-F
= 10.1 Hz, 3JH-H = 8.1 Hz,
4JH-H = 1.6 Hz, 1H), 6.97 (td,
3JH-H = 8.0 Hz,
4JH-F = 5.1 Hz, 1H), 5.19 (s, 2H);
13C NMR
(75 MHz, CDCl3): δ 152.1 (d, 1JC-F = 245.5 Hz), 142.6 (d,
2JC-F = 11.5 Hz), 131.1,
129.3 (d, 3JC-F = 3.2 Hz), 128.6, 128.2, 125.4 (d,
4JC-F = 2.1 Hz), 124.8, 122.3,
121.6 (d, 3JC-F = 7.2 Hz), 118.4 (d,
4JC-F = 3.5 Hz), 115.9 (d,
2JC-F = 18.2 Hz),
68.7; 19
F NMR (282 MHz, CDCl3): -136.0 (ddd, 3JH-F = 10.2 Hz,
4JH-F = 5.2 Hz,
5JH-F = 1.1 Hz); IR (NaCl): ν 2843, 1617, 1593, 1575, 1488, 1467, 1438, 1299,
1279, 1258, 1221, 1014, 900, 753 cm-1
. HRMS calcd. (%) for C13H8FO:
199.0559; found: 199.0559.
8-(Trifluoromethyl)-6H-benzo[c]chromene (40h):312
white solid; m.p. = 68-70 ºC (hexane/ethyl acetate); 1H
NMR (300 MHz, CDCl3): δ 7.77 (d, J = 9.0 Hz, 1H),
7.74 (dd, J = 8.0, 1.5 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H),
7.41 (s, 1H), 7.30 (td, J = 7.8, 1.5 Hz, 1H), 7.08 (td, J =
7.6, 1.2 Hz, 1H), 7.02 (dd, J = 8.1, 0.9 Hz, 1H), 5.14 (s,
2H); 13
C NMR (75 MHz, CDCl3): δ 155.1, 133.7, 131.8, 130.7, 129.5 (q, 2JC-F =
32.6 Hz), 125.3 (q, 3JC-F = 3.8 Hz), 124.1 (q,
1JC-F = 272.1 Hz), 123.8, 122.4,
122.3, 121.7 (q, 3JC-F = 3.8 Hz), 121.6, 117.6, 68.0;
19F NMR (282 MHz, CDCl3):
-62.5; IR (NaCl): ν 2851, 1607, 1483, 1424, 1333, 1246, 1164, 1076, 757 cm-1
.
312 D. W. Manley, R. T. McBurney, P. Miller, J. C. Walton, J. Org. Chem. 2014, 79, 1386-1398.
Experimental Part 234
9-Fluoro-6H-benzo[c]chromene (40i):313
colorless oil; 1H NMR (300 MHz, CDCl3): δ 7.63 (dd,
3J = 7.7 Hz,
4J
= 1.5 Hz, 1H), 7.35 (dd, 3JH-F = 9.9 Hz,
4J = 2.5 Hz,
1H), 7.20-7.30 (m, 1H), 6.90-7.15 (m, 4H), 5.07 (s, 2H); 13
C NMR (75 MHz, CDCl3): δ 163.1 (d, 1JC-F = 244.8
Hz), 154.7, 132.3 (d, 3JC-F = 8.3 Hz), 130.1, 127.0 (d,
4JC-F = 2.9 Hz), 126.2 (d,
3JC-F = 8.5 Hz), 123.5, 122.3, 122.1 (d,
4JC-F = 2.5 Hz),
117.5, 114.3 (d, 2JC-F = 22.1 Hz), 109.0 (d,
2JC-F = 23.2 Hz), 67.9;
19F NMR (282
MHz, CDCl3): δ -113.5 (m); IR (NaCl): ν 2846, 1598, 1574, 1504, 1455, 1422,
1246, 1180, 1040, 1015, 757 cm-1
.
6.5. SYNTHESIS OF ACRYLATES
General Procedure: To a solution of the corresponding 2-
hydroxybenzaldehyde (5 mmol) in THF (30 mL) was added ethyl 2-
(diethoxyphosphoryl)acetate (1.03 mL, 5.2 mmol) and DBU (0.77 mL, 5.1
mmol). The solution was stirred at room temperature overnight. The resulting
mixture was quenched with water and extracted with AcOEt (3 × 5 mL). The
organic phases were dried over MgSO4, followed by evaporation under reduced
pressure to remove the solvent. The corresponding products 41 were usually
purified by column chromatography on silica gel (hexane/ethyl acetate).
(E)-Ethyl 3-(2-hydroxyphenyl)acrylate (41a):235
white
solid; m.p. = 83-86 ºC (hexane/ethyl acetate); tr= 13.9;
Rf= 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 8.02 (d, J = 16.2 Hz, 1H), 7.45-7.50 (m, 1H),
7.20-7.25 (m, 1H), 6.85-6.95 (m, 3H), 6.62 (d, J = 16.2
Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13
C NMR (75 MHz,
CDCl3): δ 168.0, 155.6, 140.9, 131.4, 129.2, 121.6, 120.5, 118.1, 116.4, 60.8,
14.3; IR (ATR): ν 3375, 1675, 1601, 1459, 1249, 1036 cm-1
; MS (EI) m/z (%):
192 (M+, 7), 147 (15), 146 (69), 118 (100), 91 (20), 90 (18), 89 (21).
(E)-Ethyl 3-(5-fluoro-2-hydroxyphenyl)acrylate (41b): white solid; m.p. = 114-115 ºC (hexane/ethyl
acetate); 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J =
15.7 Hz, 1H), 7.10-7.20 (m, 2H), 6.94 (ddd, 3JH-H =
8.8 Hz, 3JH-F = 7.8 Hz,
4JH-H = 8.8 Hz, 1H), 6.82 (dd,
313 H. Xie, F. Lin, Q. Lei, W. Fang, Organometallics 2013, 32, 6957-6868.
235 Experimental Part
3JH-H = 8.9 Hz,
4JH-F = 4.6 Hz, 1H), 6.59 (d, J = 16.2 Hz, 1H), 4.30 (q, J = 7.1 Hz,
2H), 1.35 (t, J = 7.1 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 168.5, 156.7 (d, 1JC-F
= 238.4 Hz), 151.7 (d, 4JC-F = 1.9 Hz), 139.8 (d,
4JC,F = 2.2 Hz), 122.6 (d,
3JC-F =
7.5 Hz), 119.1, 118.1 (d, 2JC-F = 23.5 Hz), 117.4 (d,
3JC-F = 8.0 Hz), 114.3 (d,
2JC-F
= 23.3 Hz), 61.0, 14.2; 19
F NMR (282 MHz, CDCl3): -123.9 (m); IR (KBr): ν
3431, 1685, 1629, 1508, 1445, 1372, 1335, 1264, 1199 cm-1
.
(E)-Ethyl 3-(3,5-di-tert-butyl-2-
hydroxyphenyl)acrylate (41c):236
pale yellow
solid; m.p. = 120-122 ºC (hexane/ethyl acetate); Rf=
0.4 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 8.09 (d, J = 15.8 Hz, 1H), 7.36 (d, J = 2.4
Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 6.44 (d, J = 15.8
Hz, 1H), 5.84 (br s, 1H), 4.27 (q, J = 7.1 Hz, 2H),
1.44 (s, 9H), 1.33 (t, J = 7.1 Hz, 3H), 1.30 (s, 9H); 13
C NMR (75 MHz, CDCl3): δ
167.5, 151.4, 142.7, 140.6, 136.5, 126.6, 122.3, 121.8, 118.7, 60.7, 34.8, 34.3,
31.4 (3C), 29.9 (3C), 14.3; IR (ATR): ν 1684, 1621, 1471, 1441, 1289, 1186 cm-
1; MS (EI) m/z (%): 304 (M
+, 7), 244 (16), 243 (100).
(E)-Ethyl 3-(5-bromo-2-hydroxy-3-
methoxyphenyl)acrylate (41d): white solid; m.p. =
97-99 ºC (hexane/ethyl acetate); tr= 16.5; Rf= 0.3
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.85 (d, J = 16.2 Hz, 1H), 7.22 (d, J = 2.2
Hz, 1H), 6.95 (d, J = 2.2 Hz, 1H), 6.55 (d, J = 16.2
Hz, 1H), 6.11 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.91
(s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 167.1, 147.4,
144.3, 137.9, 123.0, 122.2, 120.3, 114.8, 111.5, 60.5, 56.4, 14.3; IR (ATR): ν
1734, 1701, 1630, 1359, 1260, 1172 cm-1
; MS (EI) m/z (%): 302 (M+
+ 2, 18),
300 (M+, 21), 281 (18), 257 (17), 256 (100), 255 (24), 254 (98), 226 (16), 208
(69), 148 (16), 133 (13), 105 (27), 77 (15), 76 (11); HRMS calcd. (%) for
C12H13BrO4: 299.9997; found: 299.9990.
6.6. SYNTHESIS OF 2H-CHROMEN-2-ONE DERIVATIVES
General Procedure: To a stirred solution of the corresponding acrylate
41 (0.25 mmol) in ethanol (0.75 mL) were added the corresponding
diaryliodonium salt 35 (2 equiv) and PdO-Fe3O4 (25 mg, 2.5 mol% Pd). The
mixture was stirred at 80 ºC for 5 h. The catalyst was removed by a magnet and
Experimental Part 236
the solvent was evaporated under reduced pressure. The corresponding products
42 were usually purified by column chromatography on silica gel (hexane/ethyl
acetate).
4-Phenyl-2H-chromen-2-one (42a):236
white solid; m.p.
= 98-100 ºC (hexane/ethyl acetate); tr= 16.1; Rf= 0.4
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3):
δ 7.35-7.60 (m, 8H), 7.20-7.30 (m, 1H), 6.38 (s, 1H); 13
C
NMR (75 MHz, CDCl3): δ 160.7, 155.6, 154.2, 135.2,
131.9, 129.6, 128.8 (2C), 128.4 (2C), 127.0, 124.1, 118.9,
117.3, 115.1; IR (KBr): ν 1737, 1607, 1558, 1444, 1367,
1247, 1181, 1115, 941, 884, 773, 744, 699 cm-1
; MS (EI)
m/z (%): 222 (M+, 100), 221 (M
+ - 1, 50), 194 (89), 166 (11), 165 (69), 164 (13),
163 (10), 139 (11); HRMS calcd. (%) for C15H11O2: 223.0759; found: 223.0762.
4-(4-Fluorophenyl)-2H-chromen-2-one (42b):236
white
solid; m.p. = 128-130 ºC (hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3): δ 7.57 (ddd, J = 8.6, 7.3, 1.6 Hz, 1H),
7.40-7.50 (m, 4H), 7.20-7.30 (m, 3H), 6.37 (s, 1H); 13
C
NMR (75 MHz, CDCl3): δ 163.5 (d, 1JC-F = 250.2 Hz),
160.5, 154.6, 154.1, 132.0, 131.2 (d, 4JC-F = 3.5 Hz), 130.4
(d, 3JC-F = 8.4 Hz, 2C), 126.7, 124.2, 118.9, 117.4, 116.1
(d, 2JC-F = 21.8 Hz, 2C), 115.3; IR (ATR): ν 1724, 1605,
1507, 1190, 1158, 943, 840, 830 cm-1
; MS (EI) m/z (%):
241 (M+
+ 1, 11), 240 (M+, 72), 239 (10), 213 (15), 212 (100), 207 (27), 184 (13),
183 (82).
4-(4-Methoxyphenyl)-2H-chromen-2-one (42c):236
white solid; m.p. = 123-126 ºC (hexane/ethyl acetate); 1H
NMR (300 MHz, CDCl3): δ 7.50-7.60 (m, 2H), 7.35-7.45
(m, 3H), 7.20-7.30 (m, 1H), 7.00-7.05 (m, 2H), 6.35 (s,
1H), 3.90 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 160.9,
160.8, 155.3, 154.2, 131.8, 129.9 (2C), 127.5, 127.0,
124.1, 119.2, 117.3, 114.6, 114.3 (2C), 55.4; IR (KBr): ν
1731, 1605, 1509, 1451, 1367, 1296, 1245, 1176, 1030,
929, 831, 752 cm-1
; HRMS calcd. (%) for C16H13O3:
253.0865; found: 253.0863.
237 Experimental Part
4-(4-Chlorophenyl)-2H-chromen-2-one (42d):236
white
solid; m.p. = 180-182 ºC (hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3): δ 7.50-7.60 (m, 3H), 7.35-7.45 (m, 4H),
7.15-7.30 (m, 1H), 6.36 (s, 1H); 13
C NMR (75 MHz,
CDCl3): δ 160.4, 154.4, 154.2, 136.0, 133.6, 132.1, 129.8
(2C), 129.2 (2C), 126.7, 124.3, 118.7, 117.4, 115.4; IR
(KBr): ν 1733, 1606, 1557, 1482, 1445, 1404, 1365, 1253,
1191, 1093, 945, 842, 750 cm-1
; HRMS calcd. (%) for
C15H10O2Cl: 257.0369; found: 257.0371.
4-(o-Tolyl)-2H-chromen-2-one (42e):236
colorless oil; 1H
NMR (300 MHz, CDCl3): δ 7.53 (ddd, J = 8.6, 7.2, 1.6 Hz,
1H), 7.35-7.45 (m, 2H), 7.30-7.35 (m, 2H), 7.15-7.20 (m,
2H), 7.07 (dd, J = 7.9, 1.6 Hz, 1H), 6.32 (s, 1H), 2.16 (s,
3H); 13
C NMR (75 MHz, CDCl3): δ 160.8, 156.1, 153.8,
135.3, 134.7, 131.9, 130.5, 129.2, 128.4, 126.9, 126.1,
124.3, 119.4, 117.1, 115.7, 19.7; IR (KBr): ν 1731, 1604,
1564, 1483, 1451, 1365, 1276, 1254, 929 cm-1
; HRMS
calcd. (%) for C16H13O2: 237.0916; found: 237.0908.
6-Fluoro-4-phenyl-2H-chromen-2-one (42f):314
white
solid; m.p. = 127-129 ºC (hexane/ethyl acetate); 1H NMR
(300 MHz, CDCl3): δ 7.50-7.60 (m, 3H), 7.35-7.50 (m, 3H),
7.20-7.30 (m, 1H), 7.10-7.20 (m, 1H), 6.42 (s, 1H); 13
C
NMR (75 MHz, CDCl3): δ 160.2, 158.6 (d, 1JC-F = 243.9
Hz), 154.7 (d, 4JC-F = 2.7 Hz), 150.3 (d,
4JC-F = 2.0 Hz),
134.6, 129.9, 129.0 (2C), 128.2 (2C), 119.9 (d, 3JC-F = 8.6
Hz), 119.3 (d, 2JC-F = 24.5 Hz), 118.8 (d,
3JC-F = 8.4 Hz),
116.0, 112.5 (d, 2JC-F = 25.2 Hz);
19F NMR (282 MHz, CDCl3): δ -116.9 (m); IR
(KBr): ν 1732, 1564, 1481, 1446, 1428, 1360, 1263, 1247, 1179, 971, 826 cm-1
;
HRMS calcd. (%) for C15H10O2F: 241.0665; found: 241.0668.
314 J. Wu, L. Zhang, Y. Luo, Tetrahedron Lett. 2006, 47, 6747-6750.
Experimental Part 238
6,8-Di-tert-butyl-4-phenyl-2H-chromen-2-one (42g):
236 white solid; m.p. = 181-183 ºC (hexane/ethyl
acetate); Rf= 0.4 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.61 (d, J = 2.3 Hz, 1H), 7.50-
7.55 (m, 3H), 7.40-7.45 (m, 2H), 7.32 (d, J = 2.3 Hz,
1H), 6.35 (s, 1H), 1.56 (s, 9H), 1.26 (s, 9H); 13
C NMR
(75 MHz, CDCl3): δ 160.6, 156.8, 150.9, 146.1, 137.5,
136.1, 129.4, 128.7 (2C), 128.4 (2C), 127.1, 121.5,
118.6, 114.4, 35.2, 34.7, 31.3 (3C), 30.0 (3C); IR
(ATR): ν 1720, 1568, 1362, 1250, 869, 766, 704 cm-1
; MS (EI) m/z (%): 334
(M+, 22), 320 (23), 319 (100), 207 (55).
6-Bromo-8-methoxy-4-phenyl-2H-chromen-2-one (42h): white solid; m.p. = 181-183 ºC (hexane/ethyl
acetate); tr= 19.3; Rf= 0.3 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.50-7.55 (m, 3H),
7.40-7.45 (m, 2H), 7.20 (d, J = 2.3 Hz, 1H), 7.16 (d, J =
2.3 Hz, 1H), 6.40 (s, 1H), 3.98 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 159.4, 154.8, 148.3, 143.1, 134.8,
129.9, 129.0 (2C), 128.3 (2C), 120.7, 120.6, 116.8,
116.5, 116.4, 56.6; IR (ATR): ν 1726, 1554, 1461,
1443, 1358, 1259, 1209, 1167, 1085, 865, 699 cm-1
; MS (EI) m/z (%): 332 (M+
+
2, 91), 331 (M+
+ 1, 19), 330 (M+, 92), 304 (32), 302 (35), 281 (29), 208 (22),
207 (100), 163 (12), 152 (83), 151 (24), 150 (15), 102 (17), 76 (23), 73 (10);
HRMS calcd. (%) for C16H11BrO3: 329.9892; found: 329.9883.
6-Fluoro-4-(4-methoxyphenyl)-2H-chromen-2-one (42i):
315 white solid; m.p. = 162-164 ºC (hexane/ethyl
acetate); 1H NMR (300 MHz, CDCl3): δ 7.35-7.45 (m
with d at 7.40, J = 8.8 Hz, 3H), 7.20-7.30 (m, 2H), 7.06
(d, J = 8.8 Hz, 2H), 6.39 (s, 1H), 3.90 (s, 3H); 13
C NMR
(75 MHz, CDCl3): δ 161.0, 160.5, 158.6 (d, 1JC-F =
243.4 Hz), 154.5 (d, 4JC-F = 2.7 Hz), 150.3 (d,
4JC-F = 2.0
Hz), 129.8 (2C), 126.9, 120.1 (d, 3JC-F = 8.5 Hz), 119.2
(d, 2JC-F = 24.5 Hz), 118.8 (d,
3JC-F = 8.4 Hz), 115.5,
114.5 (2C), 112.6 (d, 2JC-F = 25.2 Hz), 55.4;
19F NMR (282 MHz, CDCl3): δ -
117.1 (m); IR (KBr): ν 1718, 1610, 1565, 1510, 1478, 1431, 1361, 1253, 1176,
315 Y. Luo, J. Wu, Tetrahedron Lett. 2009, 50, 2103-2105.
239 Experimental Part
1120, 1036, 824 cm-1
; HRMS calcd. (%) for C16H12O3F: 271.0770; found:
271.0758.
6,8-Di-tert-butyl-4-(4-fluorophenyl)-2H-chromen-2-
one (42j): white solid; m.p. = 112-114 ºC (hexane/ethyl
acetate); tr= 18.0; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 2.3 Hz, 1H),
7.40-7.50 (m, 2H), 7.20-7.30 (m, 3H), 6.33 (s, 1H), 1.56
(s, 9H), 1.26 (s, 9H); 13
C NMR (75 MHz, CDCl3): δ
163.3 (d, 1JC-F = 250.0 Hz), 160.4, 155.7, 150.9, 146.2,
137.7, 132.1 (d, 4JC-F = 3.1 Hz), 130.4 (d,
3JC-F = 8.3 Hz,
2C), 127.3, 121.2, 118.6, 115.9 (d, 2JC-F = 21.8 Hz, 2C),
114.6, 35.3, 34.8, 31.3 (3C), 30.0 (3C); IR (ATR): ν
1727, 1601, 1507, 1223 cm-1
; MS (EI) m/z (%): 330
(M+, 23), 338 (23), 337 (100); HRMS calcd. (%) for C23H25FO2: 352.1839;
found: 352.1830.
6-Bromo-4-(4-fluorophenyl)-8-methoxy-2H-
chromen-2-one (42k): white solid; m.p. = 178-180 ºC
(hexane/ethyl acetate); tr= 19.1; Rf= 0.3 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.40-7.45
(m, 2H), 7.25-7.30 (m, 2H), 7.21 (d, J = 2.0 Hz, 1H),
7.11 (d, J = 2.0 Hz, 1H), 6.39 (s, 1H), 3.98 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 163.6 (d, 1JC-F = 250.7 Hz),
159.2, 153.7, 148.3, 143.1, 130.7 (d, 4JC-F = 3.5 Hz),
130.3 (d, 3JC-F = 8.4 Hz, 2C), 120.6, 120.3, 116.9, 116.6,
116.5, 116.2 (2C, d, 2JC-F = 21.9 Hz), 56.6; IR (ATR): ν
1719, 1601, 1558, 1507, 1262, 1091, 835 cm-1
; MS (EI) m/z (%): 351 (M+
+ 3,
18), 350 (M+
+ 2, 100), 349 (M+
+ 1, 21), 348 (M+, 99), 323 (10), 322 (45), 321
(10), 320 (43), 279 (10), 277 (12), 184 (14), 181 (11), 171 (11), 170 (94), 169
(22), 120 (21), 85 (19); HRMS calcd. (%) for C16H10BrFO3: 347.9797; found:
347.9786.
Experimental Part 240
4-(p-Tolyl)-2H-chromen-2-one (42l):236
pale yellow solid;
m.p. = 108-110 ºC (hexane/ethyl acetate); tr= 16.8; Rf= 0.4
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
7.50-7.60 (m, 2H), 7.35-7.45 (m, 5H), 7.20-7.25 (m, 1H),
6.36 (s, 1H), 2.46 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ
160.8, 155.7, 154.1, 139.9, 132.2, 131.8, 129.5 (2C), 128.4
(2C), 127.0, 124.0, 119.0, 117.3, 114.8, 21.3; IR (ATR): ν
3068, 1727, 1605, 1189, 940 cm-1
; MS (EI) m/z (%): 237
(M+
+ 1, 10), 236 (M+, 92), 235 (M
+ - 1, 26), 221 (54), 209
(17), 208 (100), 207 (25), 179 (14), 178 (30), 176 (10), 165 (35), 152 (13), 89
(11), 76 (10), 63 (10).
6-Bromo-8-methoxy-4-(p-tolyl)-2H-chromen-2-one (42m): white solid; m.p. = 186-188 ºC (hexane/ethyl
acetate); tr= 20.5; Rf= 0.3 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.30-7.35 (m, 4H),
7.15-7.30 (m, 2H), 6.38 (s, 1H), 3.98 (s, 3H), 2.46 (s,
3H); 13
C NMR (75 MHz, CDCl3): δ 159.5, 154.9,
148.3, 143.1, 140.1, 131.9, 129.7 (2C), 128.3 (2C),
120.9, 120.7, 116.8, 116.4, 116.1, 56.6, 21.4; IR (ATR):
ν 1726, 1558, 1460, 1261, 1091 cm-1
; MS (EI) m/z (%):
347 (M+
+ 3, 24), 346 (M+
+ 2, 100), 345 (M+
+ 1, 17),
344 (M+, 95), 329 (13), 318 (32), 316 (36), 222 (12), 207 (22), 194 (10), 166
(35), 165 (56), 164 (13), 163 (10), 139 (10), 115 (16); HRMS calcd. (%) for
C17H13BrO3: 344.0048; found: 344.0029.
6.7. SYNTHESIS OF CINNAMATE DERIVATIVES
General Procedure: To a stirred solution of the corresponding α,β-
unsaturated ester 43 (0.25 mmol) in ethanol (0.75 mL), was added the
corresponding diaryliodonium salt 35 (2 equiv) and PdO-Fe3O4 (25 mg, 2.5
mol% Pd). The mixture was stirred at 80 ºC for 5 h. The catalyst was removed by
a magnet and the solvent was evaporated under reduced pressure. The
corresponding products 44 were usually purified by bulb-to-bulb distillation.
241 Experimental Part
Ethyl cinnamate (44a):316
colorless oil; tr= 11.2; Rf= 0.3
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
7.69 (d, J = 16.0 Hz, 1H), 7.50-7.55 (m, 2H), 7.35-7.40 (m,
3H), 6.43 (d, J = 16.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H),
1.33 (t, J = 7.1 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 166.9, 144.5, 134.4,
130.1, 128.8 (2C), 127.9 (2C), 118.2, 60.4, 14.2; IR (ATR): ν 1707, 1637, 1450,
1165, 1036, 765 cm-1
; MS (EI) m/z (%): 176 (M+, 31), 148 (13), 147 (16), 132
(11), 131 (100), 103 (44), 102 (12), 77 (28), 51 (10).
Ethyl 3,3-diphenylacrylate (44b):317
brown oil; tr= 14.5;
Rf= 0.6 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.20-7.40 (2m, 2H and 8H respectively), 6.36 (s,
1H), 4.05 (q, J = 7.1 Hz, 2H), 1.11 (t, J = 7.1 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): δ 166.1, 156.4, 140.8, 139.0, 129.3, 129.1 (2C), 128.3
(2C), 128.2 (2C), 128.0, 127.8 (2C), 117.5, 60.0, 13.9; IR (ATR): ν 1719, 1617,
1574 cm-1
; MS (EI) m/z (%): 253 (M+
+ 1, 15), 252 (M+, 83), 251 (M
+ - 1, 18),
223 (15), 211 (28), 208 (12), 207 (73), 180 (45), 179 (60), 178 (100), 177 (16),
176 (21), 165 (20), 152 (27), 151 (13), 105 (18), 77 (18).
(E/Z)-Methyl 3-phenyl-3-(p-tolyl)acrylate (44c):225
pale yellow oil; tr= 15.0/15.1; Rf= 0.6 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.10-
7.40 (m, 18H), 6.35 (s, 1H), 6.32 (s, 1H), 3.63 (s,
3H), 3.60 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 166, 157.4, 157.1, 141.1, 139.7, 139.0, 138.1, 137.9,
135.7, 129.4, 129.1 (2C), 129.0 (4C), 128.6 (2C), 128.4 (2C), 128.3 (2C), 128.8
(2C), 128.1, 128.0, 127.8 (2C), 116.4, 115.8, 51.2 (2C), 21.3, 21.2; IR (ATR): ν
1721, 1608, 1509, 1492, 1263, 1160, 1150, 815 cm-1
; MS (EI) m/z (%): 253 (M+
+ 1, 17), 252 (M+, 100), 251 (M
+ - 1, 35), 222 (16), 221 (97), 194 (13), 193 (29),
192 (14), 191 (19), 189 (15), 179 (16), 178 (57), 165 (17), 115 (23).
316 B. Zhang, C. Lu, W. Li, Z. Cui, D. Chen, F. Cao, F. Miao, L. Zhou, Chem. Pharm. Bull. 2015,
63, 255-262. 317 S. K. Guchhait, G. Priyadarshani, J. Org. Chem. 2015, 80, 6342-6349.
Experimental Part 242
(E/Z)-Methyl 3-(4-methoxyphenyl)-3-
phenylacrylate (44d):318
pale yellow oil; tr=
16.0/16.2; Rf= 0.5 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.15-7.40 (m, 14H),
6.91 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H),
6.32 (s, 1H), 6.28 (s, 1H), 3.85 (s, 3H), 3.81 (s,
3H), 3.64 (s, 3H), 3.60 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 166.6 (2C), 160.8,
159.8, 157.1, 156.9, 153.9, 141.5, 139.0, 133.1, 130.9 (2C), 129.8 (2C), 129.4
(2C), 129.0 (2C), 128.6 (2C), 128.3 (2C), 128.1 (2C), 127.9 (2C), 116.2, 114.6,
113.8, 113.2, 55.4, 55.2, 51.2 (2C); IR (ATR): ν 2843, 1719, 1601, 1509, 1247,
1160, 1147, 1031, 831 cm-1
; MS (EI) m/z (%): 269 (M+
+ 1, 12), 268 (M+, 100),
267 (M+
- 1, 13), 238 (13), 237 (71), 210 (16), 209 (15), 195 (11), 194 (16), 178
(10), 166 (16), 165 (50), 135 (21).
7. REACTIONS WITHOUT CATALYST
7.1. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLES
General Procedure: To a stirred solution of the corresponding aldehyde 2
(2 mmol) in ChCl:urea (1:2) (1 mL) were added hydroxylamine hydrochloride
(138 mg, 2 mmol) and sodium hydroxide (80 mg, 2 mmol). The resulting mixture
was stirred at 50 ºC during one hour. After that N-chlorosuccinimide (400 mg, 3
mmol) was added to the mixture and it reacted during three hours at 50ºC. Then,
the corresponding alkyne 5 (2 mmol) was added, and the mixture reacted during
four hours at 50ºC, after this time the reaction was quenched with water and
extracted with AcOEt (3 x 5 mL). The organic phases were dried over MgSO4,
followed by evaporation under reduced pressure to remove the solvent. The
product 45 was usually purified by column chromatography on silica gel
(hexane/ethyl acetate).
3,5-Diphenylisoxazole (45a):248g
white solid; m.p. =
117-120 ºC (hexane/ethyl acetate); tr= 16.4; Rf= 0.5
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.80-7.90 (m, 4H), 7.45-7.50 (m, 6H),
6.83 (s, 1H); 13
C NMR (75 MHz, CDCl3): δ 170.4,
163.0, 130.2, 130.0, 129.1, 129.0 (2C), 128.9 (2C),
318 Z. She, Y. Shi, Y. Huang, Y. Cheng, F. Song, J. You, Chem. Commun. 2014, 50, 13914-13916.
243 Experimental Part
127.4, 126.8 (2C), 125.8 (2C), 97.5; IR (ATR): ν 3050, 1593, 1572 cm-1
; MS (EI)
m/z (%): 222 (M+
+ 1, 10), 221 (M+, 61), 220 (16), 144 (15), 105 (100), 89 (10),
77 (51), 51 (13).
3-(4-Chlorophenyl)-5-phenylisoxazole (45b):
248f pale yellow solid; m.p. = 112-113 ºC
(hexane/ethyl acetate); tr= 17.4; Rf= 0.5
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.80-7.90 (m, 4H), 7.45-7.55 (m, 5H),
6.83 (s, 1H); 13
C NMR (75 MHz, CDCl3): δ
170.7, 162.0, 136.0, 130.4, 129.2 (2C), 129.0 (2C), 128.1 (2C), 127.6, 127.3,
125.8 (2C), 97.3; IR (ATR): ν 1488, 1092 cm-1
. MS (EI) m/z (%): 257 (M+
+ 2,
17), 256 (M+
+ 1, 10), 255 (M+, 53), 105 (100), 77 (35).
5-Phenyl-3-(p-tolyl)isoxazole (45c):252
white
solid; m.p. = 130-132 ºC (hexane/ethyl acetate);
tr= 16.9; Rf= 0.5 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 2H),
7.76 (d, J = 8.0 Hz, 2H), 7.45-7.50 (m, 3H), 7.29
(d, J = 8.0 Hz, 2H), 6.81 (s, 1H), 2.41 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 170.2, 162.9, 140.1, 130.1, 129.6 (2C), 129.0 (2C),
127.5, 126.7 (2C), 126.2, 125.8 (2C), 97.4, 21.4; IR (ATR): ν 1568, 1494 cm-1
.
MS (EI) m/z (%): 236 (M+
+ 1, 16), 235 (M+, 90), 234 (14), 220 (16), 207 (10),
158 (23), 105 (100), 77 (43).
5-Phenyl-3-(o-tolyl)isoxazole (45d):319
pale orange
oil; tr= 16.5; Rf= 0.7 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 2H),
7.50-7.55 (m, 1H), 7.40-7.50 (m, 3H), 7.20-7.35 (m,
3H), 6.67 (s, 1H), 2.51 (s, 3H); 13
C NMR (75 MHz,
CDCl3): δ 169.4, 163.6, 136.8, 131.0, 130.1, 129.4,
129.3, 128.9 (2C), 128.7, 127.4, 125.9, 125.7 (2C), 100.1, 21.0; IR (ATR): ν
3061, 1614 cm-1
; MS (EI) m/z (%): 236 (M+
+ 1, 13), 235 (M+, 83), 234 (M
+ - 1,
94), 209 (13), 208 (22), 207 (100), 206 (11), 191 (14), 158 (35), 130 (34), 117
(12), 105 (48), 103 (10), 90 (10), 89 (12), 77 (48), 51 (11).
319 R. L. N. Harris, J. L. Huppatz, Aust. J. Chem. 1977, 30, 2225-2240.
Experimental Part 244
3-Cyclohexyl-5-phenylisoxazole (45e):248a
pale
yellow solid; m.p. = 52-54 ºC (hexane/ethyl
acetate); tr = 16.0; Rf = 0.5 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.75-7.80 (m,
2H), 7.40-7.45 (m, 3H), 6.4 (s, 1H), 2.75-2.85 (m,
1H), 2.00-2.05 (m, 2H), 1.75-1.85 (m, 3H), 1.25-
1.55 (m, 5H); 13
C NMR (75 MHz, CDCl3): δ 169.3, 169.0, 129.9, 128.9 (2C),
127.8, 125.7 (2C), 97.8, 36.0, 32.1 (2C), 26.0 (2C), 25.9; IR (ATR): ν 2927,
2852, 1447 cm-1
; MS (EI) m/z (%): 227 (M+, 37), 226 (77), 208 (11), 207 (15),
199 (16), 198 (36), 186 (16), 185 (10), 173 (11), 172 (100), 159 (41), 150 (17),
122 (16), 105 (52), 94 (11), 91 (10), 82 (11), 81 (14), 80 (10), 77 (45), 67 (14),
56 (13), 55 (18), 54 (20), 51 (11).
5-Phenyl-3-(quinolin-2-yl)isoxazole (45f):
white solid; m.p. = 109-110 ºC (hexane/ethyl
acetate); tr = 20.9; Rf = 0.6 (hexane/ethyl
acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ
8.25-8.30 (m, 2H), 8.15-8.20 (m, 1H), 7.90-
7.95 (m, 2H), 7.85 (m, 1H), 7.75-7.80 (m, 1H),
7.60-7.65 (m, 1H), 7.45-7.55 (m, 3H), 7.40 (s, 1H); 13
C NMR (75 MHz, CDCl3):
δ 170.6, 164.2, 148.7, 148.0, 136.9, 130.3, 129.9, 129.7, 129.0 (2C), 128.4,
127.7, 127.5, 127.3, 125.9 (2C), 119.1, 98.6. IR (ATR): ν 1591, 1573, 1562 cm-1
;
MS (EI) m/z (%): 273 (M+
+ 1, 18), 272 (M+, 100), 271 (18), 246 (19), 244 (21),
154 (14), 128 (53), 105 (31), 101 (11), 77 (19); HRMS calcd. (%) for C18H12N2O:
272.0950; found: 272.0941.
5-Phenyl-3-(thiophen-2-yl)isoxazole (45g):256a
pale orange solid; m.p. = 84-86 ºC (hexane/ethyl
acetate); tr = 16.4; Rf = 0.5 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.85 (m,
2H), 7.52 (dd, J = 3.6, 1.1 Hz, 1H), 7.45-7.50 (m,
3H), 7.43 (dd, J =5.1, 3.6 Hz, 1H), 7.14 (dd, J = 5.1, 3.6 Hz, 1H), 6.76 (s, 1H); 13
C NMR (75 MHz, CDCl3): δ 170.3, 158.1, 130.8, 130.3, 129.0 (2C), 127.6
(2C), 127.4, 127.2, 125.8 (2C), 97.5; IR (ATR): ν 3050, 1593, 1572 cm-1
; MS
(EI) m/z (%): 228 (M+
+ 1, 12), 227 (M+, 76), 105 (100), 77 (42).
245 Experimental Part
5-(3-Chlorophenyl)-3-phenylisoxazole (45h):247
white solid; m.p. = 110-112 ºC (hexane/ethyl
acetate); tr = 17.6; Rf = 0.5 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.90 (m,
3H), 7.70-7.75 (m, 1H), 7.40-7.50 (m, 5H), 6.86 (s,
1H); 13
C NMR (75 MHz, CDCl3): δ 168.9, 163.1, 135.1, 130.4, 130.2 (2C),
129.0, 129.0 (2C), 128.8, 126.8 (2C), 125.9, 123.9, 98.3; IR (ATR): ν 1561, 1079
cm-1
. MS (EI) m/z (%): 257 (M+
+ 2, 30), 256 (M+
+ 1, 20), 255 (M+, 78), 254
(28), 207 (11), 144 (35), 141 (20), 139 (100), 113 (13), 111 (30), 103 (34), 89
(10), 77 (20), 76 (10), 75 (18).
5-(4-Methoxyphenyl)-3-phenylisoxazole
(45i):252
white solid; m.p. = 117-118 ºC
(hexane/ethyl acetate); tr = 18.3; Rf = 0.5
(hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.85-7.90 (m, 2H), 7.75-7.80
(m, 2H), 7.45-7.50 (m, 3H), 6.95-7.05 (m, 2H), 6.71 (s, 1H), 3.87 (s, 3H); 13
C
NMR (75 MHz, CDCl3): δ 170.4, 162.9, 161.1, 129.9, 129.3, 128.9 (2C), 127.4
(2C), 126.8 (2C), 120.3, 114.4 (2C), 96.1, 55.4; IR (ATR): ν 2839, 1613, 1465,
1248 cm-1
; MS (EI) m/z (%): 251 (M+, 82), 207 (21), 136 (12), 135 (100), 103
(26), 77 (14).
3-Phenyl-5-(pyridin-2-yl)isoxazole (45j):257
white
solid; m.p. = 78-80 ºC (hexane/ethyl acetate); tr =
15.9; Rf = 0.3 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 8.70-8.75 (m, 1H), 7.80-8.00
(2m, 3H and 1H respectively), 7.45-7.50 (m, 3H),
7.35-7.40 (m, 1H), 7.28 (s, 1H); 13
C NMR (75 MHz, CDCl3): δ 169.9, 163.2,
150.0, 146.5, 137.2, 130.1, 128.9 (2C), 128.4, 126.8 (2C), 125.4, 120.9, 100.3; IR
(ATR): ν 3059, 1699, 1576, 1560 cm-1
; MS (EI) m/z (%): 223 (M+
+ 1, 14), 222
(M+, 100), 221 (M
+ - 1, 36), 194 (12), 193 (16), 145 (11), 144 (94), 116 (22), 103
(67), 78 (20), 77 (32), 76 (15), 51 (17).
5-Cyclohexyl-3-phenylisoxazole (45k):256c
pale
yellow oil; tr = 15.8; Rf = 0.6 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.75-7.80 (m,
2H), 7.40-7.45 (m, 3H), 6.25 (d, J = 0.8 Hz, 1H),
2.70-2.85 (m, 1H), 2.10-2.15 (m, 2H), 1.80-1.85 (m,
2H), 1.25-1.55 (m, 6H); 13
C NMR (75 MHz, CDCl3): δ 178.4, 162.1, 129.7,
Experimental Part 246
129.5, 128.8 (2C), 126.7 (2C), 97.0, 36.4, 31.2 (2C), 25.8, 25.7 (2C); IR (ATR):
ν 2928, 2853, 1596, 1577 cm-1
; MS (EI) m/z (%): 199 (M+
- 28, 30), 197 (99),
195 (100), 124 (16), 97 (10).
5-(4-Methoxyphenyl)-3-(p-
tolyl)isoxazole (45l):248h
white solid; m.p.
= 130-131 ºC (hexane/ethyl acetate); tr =
19.2; Rf = 0.3 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.75-7.80
(m, 4H), 7.28 (d, J = 7.9 Hz, 2H), 6.95-7.05 (m, 2H), 6.68 (s, 1H), 3.87 (s, 3H),
2.41 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 170.2, 162.9, 161.1, 140.0, 129.6
(2C), 127.4 (2C), 126.7 (2C), 126.4, 120.4, 114.4 (2C), 96.1, 55.4, 21.4; IR
(ATR): ν 1614, 1568, 1505, 1250, 1047 cm-1
; MS (EI) m/z (%): 266 (M+
+ 1, 11),
265 (M+, 53), 135 (100), 117 (14), 116 (10), 77 (8).
7.2. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLINES
General Procedure: To a stirred solution of the corresponding aldehyde
2 (2 mmol) in ChCl:urea (1:2) (1 mL) were added hydroxylamine hydrochloride
(138 mg, 2 mmol) and sodium hydroxide (80 mg, 2 mmol). The resulting mixture
was stirred at 50 ºC during one hour. After that N-chlorosuccinimide (400 mg, 3
mmol) was added to the mixture and it reacted during three hours at 50ºC. Then,
the corresponding alkene 46 (2 mmol) was added, and the mixture reacted during
four hours at 50ºC, after this time the reaction was quenched with water and
extracted with AcOEt (3 x 5 mL). The organic phases were dried over MgSO4,
followed by evaporation under reduced pressure to remove the solvent. The
product 47 was usually purified by column chromatography on silica gel
(hexane/ethyl acetate).
3,5-Diphenyl-4,5-dihydroisoxazole (47a):255a
pale
yellow solid; m.p. = 67-69 ºC (hexane/ethyl
acetate); tr = 16.3; Rf = 0.4 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.65-7.70 (m,
2H), 7.30-7.45 (m, 8H), 5.74 (dd, J = 11.0, 8.3 Hz,
1H), 3.78 (dd, J = 16.7, 11.0 Hz, 1H), 3.35 (dd, J = 16.7, 8.3 Hz, 1H); 13
C NMR
(75 MHz, CDCl3): δ 156.1, 140.9, 130.1, 129.4, 128.7 (4C), 128.2, 126.7 (2C),
125.8 (2C), 82.5, 43.2; IR (ATR): ν 3027, 1492, 1446 cm-1
; MS (EI) m/z (%):
224 (M+
+ 1, 13), 223 (M+, 40), 222 (11), 117 (12), 115 (17), 106 (70), 105 (87),
104 (67), 103 (37), 91 (12), 78 (23), 77 (100), 75 (13), 52 (13), 51 (42).
247 Experimental Part
3-(4-Chlorophenyl)-5-phenyl-4,5-
dihydroisoxazole (47b):255a
white solid; m.p. =
117-119 ºC (hexane/ethyl acetate); tr = 17.6; Rf =
0.4 (hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.60-7.65 (m, 2H), 7.30-7.40
(m, 7H), 5.75 (dd, J = 11.0, 8.4 Hz, 1H), 3.75 (dd, J = 16.6, 11.0 Hz, 1H), 3.31
(dd, J = 16.6, 8.4 Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 155.2, 140.6, 136.1,
129.0 (2C), 128.8 (2C), 128.3, 128.0, 127.9 (2C), 125.8 (2C), 82.8, 43.0; IR
(ATR): ν 1589, 1491 cm-1
; MS (EI) m/z (%): 259 (M+
+ 2, 27), 258 (M+
+ 1, 22),
257 (M+, 81), 256 (27), 240 (15), 192 (18), 153 (10), 151 (22), 137 (11), 115
(11), 111 (11), 106 (13), 105 (26), 104 (100), 103 (17), 91 (12), 78 (17), 77 (25),
75 (13), 51 (12).
5-Phenyl-3-(p-tolyl)-4,5-dihydroisoxazole
(47c):255a
white solid; m.p. = 88-90 ºC
(hexane/ethyl acetate); tr = 17.4; Rf = 0.4
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.58 (d, J = 8.1 Hz, 2H), 7.30-7.40
(m, 5H), 7.21 (d, J =8.1 Hz, 2H), 5.72 (dd, J = 10.9, 8.2 Hz, 1H), 3.77 (dd, J =
16.6, 10.9 Hz, 1H), 3.33 (dd, J = 16.6, 8.2 Hz, 1H), 2.38 (s, 3H); 13
C NMR (75
MHz, CDCl3): δ 156.0, 141.0, 140.4, 129.4 (2C), 128.7 (2C), 128.2, 126.7 (2C),
126.6, 125.9 (2C), 82.4, 43.3, 21.4; IR (ATR): ν 3035, 1560, 1515 cm-1
; MS (EI)
m/z (%): 237 (M+, 73), 236 (20), 220 (11), 207 (29), 133 (13), 132 (17), 131 (13),
119 (15), 117 (45), 116 (20), 115 (18), 106 (100), 105 (98), 104 (50), 103 (17),
91 (31), 78 (36), 77 (99), 74 (20), 65 (13), 52 (12), 51 (44), 50 (24).
5-Phenyl-3-(thiophen-2-yl)-4,5-dihydroisoxazole
(47d):256a
yellow oil; tr = 16.3; Rf = 0.4
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.30-7.40 (m, 6H), 7.18 (d, J = 3.6 Hz,
1H), 7.00-7.05 (m, 1H), 5.72 (dd, J = 10.8, 8.4 Hz,
1H), 3.77 (dd, J = 16.5, 10.8 Hz, 1H), 3.33 (dd, J = 16.5, 8.4 Hz, 1H); 13
C NMR
(75 MHz, CDCl3): δ 151.9, 140.5, 131.9, 128.7 (2C), 128.4, 128.2 (2C), 127.3,
125.8 (2C), 82.7, 43.9; IR (ATR): ν 1671, 1438 cm-1
; MS (EI) m/z (%): 230 (M+
+ 1, 12), 229 (M+, 87), 212 (29), 166 (10), 165 (28), 125 (13), 123 (10), 115 (26),
109 (24), 107 (10), 106 (99), 105 (100), 104 (56), 103 (12), 78 (33), 77 (92), 74
(15), 52 (10), 51 (45).
Experimental Part 248
5-(4-Chlorophenyl)-3-phenyl-4,5-
dihydroisoxazole (47e):255a
white solid; m.p. =
97-99 ºC (hexane/ethyl acetate); tr = 17.6; Rf =
0.3 (hexane/ethyl acetate: 4/1); 1H NMR (300
MHz, CDCl3): δ 7.7-7.65 (m, 2H), 7.45-7.4 (m,
3H), 7.30-7.35 (m, 4H), 5.72 (dd, J = 11.0, 8.0 Hz, 1H), 3.79 (dd, J = 16.7, 11.0
Hz, 1H), 3.3 (dd, J = 16.7, 8.0 Hz, 1H); 13
C NMR (75 MHz, CDCl3): δ 156.0,
139.5, 134.0, 130.3, 129.2, 128.9 (2C), 128.8 (2C), 127.2 (2C), 126.8 (2C), 81.8,
43.2; IR (ATR): ν 3056, 1599, 1491, 1091 cm-1
; MS (EI) m/z (%): 259 (M+
+ 2,
14), 257 (M+, 38), 256 (15), 192 (10), 142 (21), 141 (37), 140 (95), 139 (100),
138 (88), 125 (10), 117 (16), 13 (18), 112 (14), 111 (52), 104 (13), 103 (41), 89
(10), 77 (40), 76 (16), 75 (38), 74 (19), 51 (23), 50 (27).
3-Phenyl-5-(pyridin-yl)-4,5-dihydroisoxazole
(47f):320
brown oil; tr = 16.2; Rf = 0.3 (hexane/ethyl
acetate: 3/2); 1H NMR (300 MHz, CDCl3): δ 8.55-
8.60 (m, 1H), 7.65-7.75 (m, 3H), 7.55-7.60 (m, 1H),
7.35-7.40 (m, 3H), 7.20-7.30 (m, 1H), 5.88 (dd, J =
11.1, 6.8 Hz, 1H), 3.86 (dd, J = 16.8, 11.1 Hz, 1H), 3.69 (dd, J = 16.8, 6.8 Hz,
1H); 13
C NMR (75 MHz, CDCl3): δ 159.6, 156.3, 149.1, 136.8, 129.9, 129.0,
128.5 (2C), 126.6 (2C), 122.7, 120.4, 82.2, 41.2; IR (ATR): ν 3057, 1590, 1570
cm-1
; MS (EI) m/z (%): 224 (M+, 5), 195 (21), 194 (86), 193 (100), 192 (12), 146
(13), 79 (15), 77 (11), 51 (10).
5-Pentyl-3-phenyl-4,5-dihydroisoxazole
(47g):321
yellow solid; m.p. = 36-38 ºC
(hexane/ethyl acetate); tr = 14.9; Rf = 0.6
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.65-7.70 (m, 2H), 7.35-7.45 (m, 3H),
4.73 (dddd, J = 10.3, 8.2, 6.9, 6.0 Hz, 1H), 3.39
(dd, J = 16.4, 10.3 Hz, 1H), 2.96 (dd, J = 16.4, 8.2 Hz, 1H), 1.55-1.85 (m, 2H),
1.25-1.55 (m, 6H), 0.85-0.95 (m, 3H); 13
C NMR (75 MHz, CDCl3): δ 156.4,
129.9, 129.8, 128.6 (2C), 126.5 (2C), 81.5, 39.9, 35.3, 31.6, 25.2, 22.5, 13.4; IR
(ATR): ν 3051, 2920, 2854, 1446 cm-1
; MS (EI) m/z (%): 217 (M+, 17), 147 (13),
146 (100), 144 (11), 119 (16), 118 (58), 117 (20), 104 (26), 103 (36), 91 (17), 77
(45), 76 (18), 57 (26), 56 (22), 55 (14), 51 (14).
320 D. Maiti, P. K. Bhattacharya, Synlett 1998, 4, 385-386. 321 S. Auricchio, A. Ricca, Heterocycles 1988, 27, 2395-2402.
249 Experimental Part
5-(4-Methoxybenzyl)-3-phenyl-4,5-
dihydroisoxazole (47h): white solid; m.p.
= 69-71 ºC (hexane/ethyl acetate); tr =
18.5; Rf = 0.3 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.65-7.70
(m, 2H), 7.40-7.45 (m, 3H), 7.20-7.25 (m, 2H), 6.85-6.90 (m, 2H), 4.90-5.05 (m,
1H), 3.82 (s, 3H), 3.33 (dd, J = 16.6, 10.2 Hz, 1H), 3.11 (dd, J = 13.9, 6.1 Hz,
1H), 3.06 (dd, J = 16.6, 7.8 Hz, 1H), 2.86 (dd, J = 13.9, 7.2 Hz, 1H); 13
C NMR
(75 MHz, CDCl3): δ 158.4, 156.4, 130.3 (2C), 129.9, 128.9, 128.6 (2C), 126.6
(2C), 114.0 (2C), 82.1, 55.3, 40.1, 39.3; IR (ATR): ν 3035, 2839, 1609, 1582,
1242, 1034 cm-1
; MS (EI) m/z (%): 267 (M+, 7), 122 (19), 121 (100), 91 (10), 78
(11), 77 (18). HRMS calcd. (%) for C17H17NO2: 267.1249; found: 267.1247.
5-(Bromomethyl)-3-(4-nitrophenyl)-4,5-
dihydroisoxazole (47i):322
pale yellow solid;
m.p. = 166-168 ºC (hexane/ethyl acetate); tr =
16.6; Rf = 0.2 (hexane/ethyl acetate: 4/1); 1H
NMR (300 MHz, CDCl3): δ 8.29 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H),
5.05-5.15 (m, 1H), 3.60-3.80 (m, 2H), 3.45-3.60 (m, 1H), 3.30-3.45 (m, 1H); 13
C
NMR (75 MHz, CDCl3): δ 154.7, 148.6, 135.0, 127.5 (2C), 124.0 (2C), 80.7,
44.7, 37.9; IR (ATR): ν 1574, 1515, 1336, 853, 693 cm-1
; MS (EI) m/z (%): 286
(M+
+ 2, 1), 284 (M+, 5), 207 (17), 148 (16), 128 (33), 117 (100), 105 (10), 77
(11), 76 (51), 64 (12).
7.3. SYNTHESIS OF β-AMINO ENONES
General Procedure: To a stirred solution of the corresponding isoxazole
45 (1 mmol) in CH3CN (20 mL), were added H2O (1 mmol) and Mo(CO)6 (0.5
mmol). The resulting mixture was stirred at 81 ºC during four hours. After this
time, the reaction was quenched with water and extracted with AcOEt (3 x 5
mL). The organic phases were dried over MgSO4, followed by evaporation under
reduced pressure to remove the solvent. The product 48 was usually purified by
column chromatography on silica gel (hexane/ethyl acetate).
322 N. Dorostkar-Ahmadi, M. Bakavoli, F. Moeinpour, A. Davoodnia, Spectrochim Acta A 2011,
79, 1375-1380.
Experimental Part 250
(Z)-3-Amino-1,3-diphenylprop-2-en-1-one
(48a):270d
yellow oil; tr = 17.2; Rf = 0.5
(hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,
CDCl3): δ 10.43 (br s, 1H), 7.80-7.90 (m, 2H),
7.60-7.65 (m, 2H), 7.45-7.50 (m, 6H), 6.15 (s, 1H),
5.48 (br s, 1H); 13
C NMR (75 MHz, CDCl3): δ 190.1, 162.9, 140.3, 137.6, 131.0,
130.7, 129.0 (2C), 128.3 (2C), 127.2 (2C), 126.3 (2C), 91.8; IR (ATR): ν 3453,
3348, 1598, 1563 cm-1
; MS (EI) m/z (%): 223 (M+, 29), 222 (M
+ - 1, 100), 209
(11), 208 (10), 207 (68), 191 (11), 146 (22), 117 (11), 104 (11), 103 (16), 89
(11), 79 (10), 78 (27), 77 (15), 50 (12).
(Z)-3-Amino-3-(4-chlorodiphenyl)-1-
phenylprop-2-en-1-one (48b):248g
yellow oil;
tr = 18.7; Rf = 0.2 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 10.38 (br s,
1H), 7.90-7.95 (m, 2H), 7.55-7.60 (m, 2H),
7.40-7.50 (m, 5H), 6.11 (s, 1H), 5.42 (br s,
1H); 13
C NMR (75 MHz, CDCl3): δ 190.3, 161.4, 140.1, 136.7, 136.0, 131.2,
129.3 (2C), 128.3 (2C), 127.7 (2C), 127.2 (2C), 92.0; IR (ATR): ν 3454, 3342,
1595, 1557, 1523, 1475 cm-1
; MS (EI) m/z (%): 258 (M+
+ 2, 43), 257 (M+
+ 1,
49), 256 (M+, 100), 207 (20), 180 (27), 77 (13).
(Z)-3-Amino-1-(4-methoxyphenyl)-3-
phenylprop-2-en-1-one (6c):323
yellow oil; tr =
19.6; Rf = 0.4 (hexane/ethyl acetate: 1/1); 1H
NMR (300 MHz, CDCl3): δ 10.34 (br s, 1H),
7.90-7.95 (m, 2H), 7.60-7.65 (m, 2H), 7.45-
7.50 (m, 3H), 6.90-6.95 (m, 2H), 6.12 (s, 1H),
5.36 (br s, 1H), 3.86 (s, 3H); 13
C NMR (75 MHz, CDCl3): δ 189.2, 162.3, 162.0,
137.8, 133.0, 130.6, 129.1 (2C), 129.0 (2C), 126.3 (2C), 113.4 (2C), 91.5, 55.3;
IR (ATR): ν 3463, 3354, 2837, 1593, 1560, 1524, 1507 cm-1
; MS (EI) m/z (%):
253 (M+, 26), 252 (M
+ - 1, 100), 209 (10), 207(25).
323 X. Yu, L. Wang, M. Bao, Y. Yamamoto, Chem. Commun. 2013, 49, 2885-2887.
251 Experimental Part
(Z)-3-Amino-1-cyclohexyl-3-phenylprop-2-en-1-
one (48d): yellow oil; tr = 16.5; Rf = 0.5
(hexane/ethyl acetate: 3/2); 1H NMR (300 MHz,
CDCl3): δ 9.98 (br s, 1H), 7.55-7.60 (m, 2H), 7.40-
7.45 (m, 3H), 5.47 (s, 1H), 5.20 (br s, 1H), 2.31 (tt,
J = 11.6, 3.4 Hz, 1H), 1.65-1.90 (m, 5H), 1.15-1.50 (m, 5H); 13
C NMR (75 MHz,
CDCl3): δ 203.8, 161.3, 137.6, 130.4, 128.9 (2C), 126.2 (2C), 93.6, 50.8, 29.8
(2C), 26.1 (2C); IR (ATR): ν 3342, 3171, 2924, 2850, 1603, 1572, 1524, 1485
cm-1
; MS (EI) m/z (%): 229 (M+, 12), 207 (60), 146 (100), 104 (20); HRMS
calcd. (%) for C15H19NO: 229.1466; found: 229.1473.
7.4. SYNTHESIS OF ISOXAZOLES FROM ETHYL 2-NITROACETATE
General Procedure: To a stirred solution of the corresponding ethyl 2-
nitroacetate (49, 0.5 mmol) in 1 mL of AcChCl:urea (1:2), was added the
corresponding alkyne 5 (0.5 mmol). The mixture was stirred at 81 ºC during four
hours. After this time, the reaction was quenched with water and extracted with
AcOEt (3 x 5 mL). The organic phases were dried over MgSO4, followed by
evaporation under reduced pressure to remove the solvent. The product 50 was
usually purified by column chromatography on silica gel (hexane/ethyl acetate).
Ethyl 5-phenylisoxazole-3-carboxylate (50a):263
pale
yellow solid; m.p. = 50-52 ºC (hexane/ethyl acetate); tr
= 14.1; Rf = 0.5 (hexane/ethyl acetate: 4/1); 1H NMR
(300 MHz, CDCl3): δ 7.80-7.85 (m, 2H), 7.45-7.50
(m, 3H), 6.93 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 1.45 (t,
J = 7.1 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ 171.7,
160.0, 156.9 130.8, 129.1 (2C), 126.6, 125.9 (2C), 99.9, 62.2, 14.1; IR (ATR): ν
1728, 1480 cm-1
; MS (EI) m/z (%): 218 (M+
+ 1, 10), 217 (M+, 68), 172 (24), 145
(36), 105 (100), 78 (11), 77 (36), 51 (16).
Ethyl 5-(3-chlorophenyl)isoxazole-3-carboxylate
(50b):241a
white solid; m.p. = 80-82 ºC (hexane/ethyl
acetate); tr = 12.1; Rf = 0.4 (hexane/ethyl acetate: 4/1); 1H NMR (300 MHz, CDCl3): δ 7.80-7.85 (m, 1H),
7.65-7.70 (m, 1H), 7.40-7.45 (m, 2H), 6.96 (s, 1H),
4.48 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): δ 170.2, 159.8, 157.0, 135.3, 130.8, 130.5, 128.2, 126.0,
124.0, 100.7, 62.3, 14.1; IR (ATR): ν 1721, 1247, 1081, 1020 cm-1
; MS (EI) m/z
Experimental Part 252
(%): 253 (M+
+ 2, 28), 251 (M+, 69), 207 (25), 206 (31), 181 (11), 179 (29), 141
(29), 139 (100), 114 (12), 113 (17), 111 (23), 75 (24).
Ethyl 5-(m-tolyl)isoxazole-3-carboxylate (50c):
colorless oil; tr = 15.0; Rf = 0.4 (hexane/ethyl acetate:
4/1); 1H NMR (300 MHz, CDCl3): δ 7.60-7.65 (m,
1H), 7.61 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H),
7.29 (d, J = 7.6 Hz, 1H), 6.91 (s, 1H), 4.47 (q, J = 7.1
Hz, 2H), 2.43 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H); 13
C NMR (75 MHz, CDCl3): δ
171.9, 160.1, 156.9, 139.0, 131.6, 129.0, 126.5 (2C), 123.1, 99.8, 62.2, 21.4,
14.2; IR (ATR): ν 1725, 1579, 1249, 1049 cm-1
; MS (EI) m/z (%): 232 (M+
+ 1,
14), 231 (M+, 91), 186 (21), 159 (14), 119 (100), 92 (12), 91 (32); HRMS calcd.
(%) for C13H13NO3: 231.0895; found: 231.0882.
Ethyl 5-(4-methoxyphenyl)isoxazole-3-
carboxylate (50d):241b
white solid; m.p. = 78-80
ºC (hexane/ethyl acetate); tr = 16.2; Rf = 0.3
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 7.70-7.75 (m, 2H), 6.95-7.00 (m, 2H),
6.8 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.87 (s. 3H), 1.44 (t, J = 7.1 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): δ 171.7, 161.5, 160.1, 156.9, 127.6 (2C), 119.4, 114.5
(2C), 98.5, 62.1, 55.4, 14.1; IR (ATR): ν 2839, 1726, 1609, 1508, 1243, 1024 cm-
1; MS (EI) m/z (%): 248 (M
+ + 1, 12), 247 (M
+, 78), 202 (14), 136 (10), 135
(100).
Ethyl 5-cyclohexylisoxazole-3-carboxylate
(50e):324
pale yellow oil; tr = 10.8; Rf = 0.5
(hexane/ethyl acetate: 4/1); 1H NMR (300 MHz,
CDCl3): δ 6.37 (d, J = 0.7 Hz, 1H), 4.43 (q, J = 7.1
Hz, 2H), 2.80-2.85 (m, 1H), 2.05-2.10 (m, 2H), 1.65-
1.85 (m, 4H), 1.35-1.50 (m, 7H); 13
C NMR (75 MHz, CDCl3): δ 179.7, 160.3,
156.1, 99.8, 62.0, 36.3, 31.0 (2C), 25.6, 25.5 (2C), 14.1; IR (ATR): ν 2929, 2855,
1730, 1588, 1229, 1020 cm-1
; MS (EI) m/z (%): 223 (M+, 20), 179 (12), 178 (76),
150 (37), 125 (18), 124 (95), 122 (14), 110 (16), 109 (20), 108 (19), 97 (17), 96
(69), 95 (16), 83 (32), 82 (10), 91 (30), 90 (19), 79 (11), 78 (10), 69 (18), 68
(100), 67 (17), 55 (48), 54 (15), 53 (13).
324 C. Mioskowski, S. D. L. Marin, M. Maruani, M. Gill, US Pat. 0199853A1, 2006.
CONCLUSIONS
255 Conclusions
From the results of these studies, we can conclude that magnetite can be
used as an adequate support showing reasonable stability and it can be easily
remove from the reaction media throught a magnetic decantation.
Furthermore, magnetite is a good support for the anchoring metal oxides,
including cobalt, copper, nickel and palladium. The protocol for the preparation
of these impregnated catalysts is very easy and reproducible.
Also, depending on the reaction conditions the catalyst could be recycled
several times without lose of their initial catalytic activity.
The applicability of these heterogeneous catalysts in reactions previously
reported with similar homogeneous catalysts seems to be factible in most cases,
without major changes.
BIOGRAPHY
259 Biography
I was born in Baza (Granada) on 15th March 1988.
I conducted my primary studies at school "Salesianos" and secundary
ones at I. E. S. "Barrachina" in Ibi (Alicante).
During 2006-2011, I realized the degree in Chemistry on the Science
Faculty at the University of Alicante.
In September 2011 I joined the research group of Prof. Ramón at the
Organic Chemistry Department of the University of Alicante, where I performed
the Máster in Medicinal Chemistry.
Since 2012 to the present, I have been working in my Doctoral Thesis.
Part of results are presented this manuscript.
Since December 2012, I hold a FPI grant from the Spanish Ministerio de
Economía y Competitividad (MICINN).
From 1st June 2014 to 1
st September 2014, I performed an internship at
presitigious research group of Prof. Dr. Silvia Díez-González, at the Imperial
College of London, working in click chemistry.
ACKNOWLEDGMENTS
263 Acknowledgments
I would like to thank all people and institutuions which helped and
permitted to reach the current situation, including the Spanish Ministerio de
Economía y Competitividad (MICINN, CTQ2011-24151 and fellowship) and
University of Alicante for their continuous economical support.
I would like to express my gratitude to all people who kindly welcomed
and helped me during my stay at the Imperial College in London. In particular,
Prof. Dr. Silvia Díez-González, thank you for your hospitality and the perfect
working atmosphere in the lab.
I am also very grateful to Dr. Rafael Cano, thank you for transmitting
your knowledge during my first time in the lab, when I was an absolut beginner,
for your patient and for all your advices.
Last but not least, I do not want to forget my family, my ‘little kid’, Xavi,
and my lab partners. Thank you for your patient and for all the good moments we
have lived together in the lab.
INDEX
PROLOGUE 1
RESUMEN/SUMMARY/RESUM 5
PREFACE 11
GENERAL INTRODUCTION 15
1. MAGNETITE 17
1.1 SYNTHETIC METHODS 19
1.2 APPLICATIONS 20
2. MAGNETITE AS CATALYST SUPPORT 27
2.1 COATED CATALYST 27
2.2 GRAFTED CATALYST 29
2.3 COATED-GRAFTED CATALYST 30
2.4 CO-PRECIPITATION AND DUMBELL-LIKE
COMPOSITES
32
2.5 IMPREGNATED CATALYST 34
2.5.1 COBALT CATALYST 35
2.5.2 NICKEL CATALYST 36
2.5.3 COPPER CATALYST 37
2.5.4 PALLADIUM CATALYST 39
RESULTS 43
CHAPTER I. Reactions performed using nanoparticles of
impregnated Cobalt(II) Oxide on Magnetite
45
1. HYDROACYLATION REACTION OF
AZODICARBOXYLATES
47
1.1 INTRODUCTION 47
1.2 RESULTS 50
CHAPTER II. Reactions performed using nanoparticles of
impregnated Copper(II) Oxide on Magnetite
59
1. HOMOCOUPLING OF TERMINAL ALKYNES 61
1.1 INTRODUCTION 61
1.2 RESULTS 63
2. SYNTHESIS OF AROMATIC IMINES FROM
ALCOHOLS AND AMINES OR NITROARENES
71
2.1 INTRODUCTION 71
2.2 RESULTS 73
3. CROSS-DEHYDROGENATIVE COUPLING
REACTION IN DEEP EUTECTIC SOLVENTS
83
3.1 INTRODUCTION 83
3.2 RESULTS 86
4. SYNTHESIS OF BENZO[b]FURANS FROM ALKYNES
AND 2-HYDROXYARYLCARBONYL DERIVATIVES
98
4.1 INTRODUCTION 98
4.2 RESULTS 99
CHAPTER III. Reactions performed using the impregnated
bimetallic Nickel(II) Oxide/Copper(0) on
Magnetite
109
1. MULTICOMPONENT AZIDE-ALKYNE
CYCLOADDITION REACTION
111
1.1 INTRODUCTION 111
1.2 RESULTS 113
CHAPTER IV. Reactions performed using nanoparticles of
impregnated Palladium(II) Oxide on Magnetite
125
1. DIRECT ARYLATION OF HETEROCYCLES 127
1.1 INTRODUCTION 127
1.2 RESULTS 129
1.2.1 DIRECT ARYLATION OF HETEROCYCLES 129
1.2.1 INTRAMOLECULAR DIRECT ARYLATION 136
2. SYNTHESIS OF 4-ARYLCOUMARINS THROUGH
THE HECK-ARYLATION/CYCLIZATION REACTION
140
2.1 INTRODUCTION 140
2.2 RESULTS 141
CHAPTER V. Rections without catalyst 153
1. SYNTHESIS OF 3,5-DISUBSTITUTED ISOXAZOLES
AND ISOXAZOLINES IN DEEP EUTECTIC
SOLVENTS
155
1.1 INTRODUCTION 155
1.2 RESULTS 158
EXPERIMENTAL PART 167
1. GENERAL 169
1.1 SOLVENTS AND SUBSTRATES 169
1.2 INSTRUMENTATION 169
2. PREPARATION OF CATALYSTS
171
3. REACTIONS CATALYSED BY NANOPARTICLES OF
IMPREGNATED COBALT(II) OXIDE ON
MAGNETITE
172
3.1 HYDROACYLATION OF AZODICARBOXYLATE
COMPOUNDS
172
4. REACTION CATALYSED BY NANOPARTICLES OF
IMPREGNATED COPPER(II) OXIDE ON
MAGNETITE
178
4.1 SYNTHESIS OF 1,3-DIYNES 178
4.2 HYDRATION OF 1,3-DIYNES TO AFFORD 2,5-
DISUBSTITUTED FURANS
183
4.3 DECARBOXYLATIVE COUPLING OF 3-
PHENYLPROP-2-YONIC ACID
184
4.4 SYNTHESIS OF ARYL IMINES DERIVATIVES
FROM ALCOHOLS AND AMINES
185
4.5 SYNTHESIS OF ARENECARBALDEHYDES 190
4.6 SYNTHESIS OF ARYL IMINES DERIVATIVES
FROM PRIMARY AMINES
193
4.7 SYNTHESIS OF N-ARYLATED 1,2,3,4-
TETRAHYDROISOQUINOLINES
195
4.8 SYNTHESIS OF 1-SUBSTITUTED-N-ARYLATED
1,2,3,4-TETRAHYDROISOQUINOLINES
197
4.9 SYNTHESIS OF BENZO[b]FURANS 205
5. REACTIONS CATALYSED BY NANOPARTICLES OF
BIMETALLIC IMPREGNATED NICKEL(II) OXIDE
AND COPPER(0) ON MAGNETITE
212
5.1 SYNTHESIS OF 1,4-DISUBSTITUTED-1H-1,2,3-
TRIAZOLES
212
6. REACTIONS CATALYSED BY NANOPARTICLES OF
PALLADIUM
220
6.1 SYNTHESIS OF DIARYLIODONIUM SALTS 220
6.2 SYNTHESIS OF ARYLATED HETEROCYCLES 224
6.3 SYNTHESIS OF HALOETHERS 228
6.4 SYNTHESIS OF SUBSTITUTED 231
BENZO[b]CHROMENE DERIVATIVES
6.5 SYNTHESIS OF ACRYLATES 234
6.6 SYNTHESIS OF 2H-CHROMEN-2-ONE
DERIVATIVES
235
6.7 SYNTHESIS OF CINNAMATE DERIVATIVES 240
7. REACTIONS WITHOUT CATALYST 242
7.1 SYNTHESIS OF 3,5-DISUBSTITUTED
ISOXAZOLES
242
7.2 SYNTHESIS OF 3,5-DISUBSTITUTED
ISOXAZOLINES
246
7.3 SYNTHESIS OF β-AMINO ENONES 249
7.4 SYNTHESIS OF ISOXAZOLES FROM ETHYL 2-
NITROACETATE
251
CONCLUSIONS 253
BIOGRAPHY 257
ACKNOWLEDGMENT 261
EPILOGUE
273 Epilogue
La magnetita, Fe3O4, es un óxido mixto de Fe(II) y Fe(III), que posee una
estructura cúbica de espinela inversa, en la que los átomos de oxígeno se
encuentran formando una celdilla unidad cúbica centrada en las caras y los
cationes de hierro ocupan los huecos intersticiales. Más concretamente, los
huecos tetraédricos están ocupados por iones de Fe(III) y los octaédricos por
iones de Fe(II) y Fe(III) por igual.
El interés de la magnetita en el campo de la Química Orgánica ha
aumentado en los últimos años gracias a las propiedades peculiares que presenta,
ya que puede ser fácilmente separada del medio de reacción mediante la
aplicación de un campo magnético externo, facilitando así su reutilización.
Debido a lo anteriormente expuesto, el número de aplicaciones de la
magnetita en los últimos años ha ido en aumento en campos como la catálisis.
Recientemente, la impregnación con metales de transición en su superficie, ha
sido considerada como una metodología muy poderosa y alternativa para la
preparación de nuevos catalizadores.
El protocolo de impregnación de prácticamente todos los metales de
transición en la superficie de la magnetita, ha dado lugar a una primera
generación de catalizadores. Estos catalizadores han sido usados en un gran
rango de transformaciones orgánicas, incluyendo reacciones conocidas como la
simple formación de derivados de iminas, oxidación, adición, autotransferencia
de hidrogeno y reacciones multicomponentes, o reacciones desconocidas como la
β-alquilación cruzada directa de alcoholes primarios mediante deshidrogenación.
En muchos de los casos, el estudio de la superficie del catalizador por
medio de diferentes técnicas superficiales ha permitido determinar las especies
involucradas en el proceso y los cambios estructurales por culpa de los ciclos de
reacción. Además, la posterior modificación de los catalizadores mediante
reducción u oxidación de los metales inmovilizados en la superficie, o mediante
la adición de ligandos, ha engrandecido la aplicabilidad de este tipo de
catalizadores.
En la presente memoria, se han desarrollado algunas de las reacciones
que han sido llevadas a cabo con este tipo de catalizadores durante los últimos
años, y que han sido incluidas como trabajo experimental de mi tesis doctoral.
Los catalizadores de óxido de cobalto(II) y óxido de niquel(II)
impregnados en magnetita fueron preparados, caracterizados y usados en la
Epilogue 274
reacción de hidroacilación de diferentes azodicarboxilatos con aldehídos, usando
para ello cantidades casi equimoleculares de ambos reactivos y en solo tres horas
de reacción. Además, esta reacción fue realizada con la menor cantidad de
catalizador jamás reportada. Los correspondientes productos de reacción fueron
obtenidos generalmente con buenos rendimientos, incluso cuando se usaron
aldehídos alifáticos. El catalizador de cobalto fue lo suficientemente estable
como para poder ser reciclado hasta diez veces sin pérdida de actividad catalítica.
Tras realizar el estudio del catalizador mediante XPS y TEM se pudo comprobar
que las nanopartículas de óxido de cobalto(II) iniciales se transformaron en
hidróxido de cobalto(II) y que hubo un pequeña sinterización de las mismas tras
los diez ciclos de reacción, pero sin ningún efecto en la actividad del catalizador.
Hidroacilación de azodicarboxylatos.
El catalizador de óxido de cobre(II) impregnado en magnetita fue usado
para llevar a cabo diferentes reacciones en síntesis orgánica como:
1) La síntesis de 1,3-diinos mediante el homoacoplamiento de alquinos
terminales. En este caso, no fue necesario el uso de oxigeno presurizado como
oxidante, así como de disolvente o condiciones enérgicas de reacción para llevar
a cabo la misma. Además, la reacción tuvo lugar con la menor cantidad de
catalizador jamás comunicada con catalizadores heterogéneos, pudiéndose
eliminar el mismo del medio de reacción con el simple uso de un imán. Además,
la síntesis 2,5,-furanos tras la formación de dichos 1,3-diinos, pudo ser llevada a
cabo obteniendo muy buenos resultados con los sustratos aromáticos.
275 Epilogue
Homoacoplamiento de alquinos terminales usando CuO-Fe3O4.
2) La síntesis de iminas partiendo de alcoholes y aminas, o nitroarenos,
también pudo ser llevada a cabo usando el catalizador de óxido de cobre(II)
impregnado en magnetita. Dicho catalizador no requiere el uso de ligandos
orgánicos caros o difíciles de manipular, obteniendo rendimientos buenos con
condiciones suaves de reacción. El reciclado del catalizador se intentó llevar a
cabo sin éxito debido a la siterización de las nanopartículas de cobre facilitada
por la presencia de especies nitrogenadas en el medio de reacción. La reacción de
deshidrogenación de alcoholes en presencia de anilina en un solo recipiente,
seguido de hidrólisis acuosa, dio los aldehídos puros con excelentes
rendimientos. También pudieron ser usados nitroarenos como reactivos que
contienen átomos de nitrógeno, para la formación de las correspondientes iminas.
Por último, se llevó a cabo la reacción con aminas primarias, obteniéndose con
éxito las correspondientes iminas y usando condiciones de reacción similares.
Síntesis de iminas partiendo de alcoholes y aminas.
Epilogue 276
3) La síntesis de diferentes tetrahidroisoquinolinas pudo ser llevada a
cabo con éxito usando la mezcla cloruro de colina:etilenglicol (1:2), evitando así
la presencia de disolventes orgánicos volátiles, junto con el catalizador de óxido
de cobre(II) impregnado en magnetita, siendo la cantidad de cobre utilizada la
más baja comunicada hasta el momento. La presencia de DES fue esencial
debido a que la reacción en ausencia del mismo no tuvo lugar. Una relación
directamente proporcional fue encontrada entre la conductividad del medio
eutéctico y el rendimiento obtenido. La recuperación del catalizador se llevó a
cabo usando dos metodologías diferentes. Por una parte, la mezcla de DES y
catalizador pudieron ser reutilizados mediante simple extracción y posterior
decantación, hasta diez veces sin un descenso en el rendimiento de la reacción.
Las condiciones estrictamente aeróbicas de la reacción hacen que el protocolo
sea sostenible debido a que el único residuo generado es agua. Sin embargo,
cuando solo el catalizador fue recuperado del medio de reacción, mediante
decantación magnética, se produjo un descenso importante en el rendimiento de
la reacción después del cuarto ciclo. Esta diferencia puede ser atribuida a la alta
disolución irreversible de las nanopartículas de cobre en la mezcla eutéctica. De
hecho, la mezcla eutéctica reciclada pudo ser usada para llevar a cabo el
acoplamiento deshidrogenante después de haber eliminado el catalizador, que
permanecía sobre la magnetita
Reacción de acoplamiento cruzado deshidrogenante.
4) La síntesis de benzo[b]furanos a través de un proceso de
acoplamiento-alenilación-ciclación entre alquinos y derivados de 2-
hidroxiarilcarbonilo en presencia de hidracida de p-toluenosulfonilo, fue llevada
a cabo usando el catalizador de óxido de cobre(II) impregnado en magnetita y
etanol como disolvente no tóxico y biorenovable. La cantidad de cobre utilizada
en este caso fue muy pequeña y el catalizador pudo ser eliminado del medio de
reacción mediante el simple uso de un imán. La reutilización del catalizador se
intentó llevar a cabo sin éxito debido a la reducción del cobre(II) inicial a
cobre(0), lo cual fue comprobado mediante estudios del catalizador con técnicas
277 Epilogue
como XPS o TEM. Posteriormente, se intentó llevar a cabo la re-oxidación de
dichas nanopartículas mediante burbujeo del catalizador con oxígeno, o usando
oxidantes como t-BuOOH, pero ninguno de los procedimientos utilizados fue
efectivo para la regeneración de las nanopartículas de cobre(II).
Síntesis de benzo[b]furanos usando CuO-Fe3O4.
El catalizador bimetálico de nanopartículas de óxido de niquel(II) y
cobre(0) impregnadas sobre magnetita pudo ser preparado, caracterizado y usado
en la reacción multicomponente entre alquinos terminales, azida de sodio y
bromuro de bencilo (Esquema 36). Tras probar diferentes condiciones de
reacción, el producto deseado fue obtenido con un 83 % de rendimiento, sin el
uso de disolvente. Con este catalizador, se pudieron sintetizar diferentes triazoles
con rendimientos que oscilaban entre buenos y moderados. La presencia de
ambas especies metálicas en la superficie de la magnetita mostró tener un efecto
positivo y sinérgico en la reacción, pudiéndose reciclar el mismo hasta en diez
ocasiones sin pérdida de actividad catalítica. Tal y como cabría esperar, tras
llevar a cabo el reciclado del catalizador, la disolución irreversible de las
nanopartículas metálicas de cobre y níquel que forman el catalizador fue
despreciable. Tras el estudio del mismo, mediante XPS y TEM, se pudo
comprobar una pequeña sinterización de las nanopartículas, así como una
transformación de las especies metálicas iniciales en los correspondientes
hidróxidos, los cuales parecen no afectar en la actividad catalítica del catalizador.
Epilogue 278
Reacción multicomponente catalizada por NiO/Cu-Fe3O4.
El catalizador de óxido de paladio(II) impregnado sobre magnetita pudo
ser usado en diferentes reacciones como:
1) La arilación directa de compuestos heterocíclicos usando el
catalizador de paladio mencionado con anterioridad. Dicha reacción fue llevada a
cabo usando etanol como disolvente no tóxico y renovable, bajo condiciones de
reacción relativamente suaves. Una gran variedad de sustratos pudieron ser
utilizados obteniendo rendimientos de moderados a buenos. En la gran mayoría
de los casos, el catalizador se mostró selectivo obteniendo los productos arilados
en la posiciones 2 ó 3 dependiendo del heterociclo utilizado. Dicha metodología
se extendió a la síntesis de cromenos a través de una reacción de arilación directa
intramolecular. En ambas reacciones el catalizador es desactivado tras llevar a
cabo la reacción siendo imposible la reutilización del mismo. Tras llevar a cabo
diferentes estudios del catalizador reciclado, se descartó la disolución irreversible
de las especies de paladio en el medio, así como la sinterización de las mismas o
el cambio de estado de oxidación, ya que el catalizador permanecía igual tras la
reacción. Tras llevas a cabo el estudio del catalizador mediante fluorescencia de
rayos X pudimos comprobar que lo que parece inactiva el catalizador es la
presencia de haluros en la superficie del mismo.
Arilación directa de heterociclos con PdO-Fe3O4.
2) La síntesis de 4-arilcumarinas, a través de una reacción de arilación
tipo Heck seguida de una ciclación, pudo ser llevada a cabo usando un
catalizador de óxido de paladio(II) impregnado sobre magnetita y etanol como
disolvente no tóxico y biorenovable. La reacción pudo ser aplicada a una gran
279 Epilogue
variedad de sustratos obteniendo buenos resultados. El reciclado del catalizador
no pudo llevarse a cabo con gran éxito debido a la prácticamente total reducción
del paladio(II) inicial a paladio(0). Dicha reducción fue comprobada realizando
estudios del catalizador, como XPS o TEM, observando una gran sinterización de
dichas nanopartículas al igual que una disociación del metal del soporte tras
completar la reacción. Habiendo observado dicha reducción, se intentó llevar a
cabo la oxidación del paladio(0) generado, a través de diferentes técnicas como el
burbujeo del catalizador con oxígeno o la adición de oxidantes como el t-BuOOH
o I2, siendo imposible la regeneración de la actividad inicial del catalizador.
Síntesis de 4-arilcumarinas.
Por último, la síntesis de isoxazoles 3,5-disustituidos, así como las
correspondientes isoxazolinas relacionadas, usando cloruro de colina:urea (1:2)
como medio de reacción, en un solo recipiente y mediante tres pasos de reacción,
pudo ser llevada a cabo con éxito (Esquema 39). El uso de mezclas eutécticas
(DES) nucleofílicas altamente funcionalizadas no afectó en el proceso donde
reactivos altamente electrofílicos, o intermedios estaban involucrados. La
presencia de DES parece ser esencial debido a que la reacción sin este medio de
reacción no tuvo lugar. El DES pudo ser reciclado hasta en cinco ocasiones sin
obtener un descenso en el rendimiento de la reacción. Dicha reacción fue
escalada para la obtención de gramos del correspondiente producto sin ningún
problema. Para finalizar, diferentes isoxazoles fueron fácilmente transformados
en β–amino enonas con buenos rendimientos mediante el uso de Mo(CO)6 como
catalizador.
Epilogue 280
Síntesis de isoxazoles e isoxazolinas usando DES.