1

Dearomatization of transition metal-­coordinated N-­heterocyclic

ligands and related chemistry

Rebeca Arévalo, Maialen Espinal-­Viguri, Miguel A. Huertos, Julio Pérez* and Lucía

Riera*

Departamento de Química Orgánica e Inorgánica. Julián Clavería, 8. Universidad de Oviedo.

33006 Oviedo (Spain). *Corresponding author e-­mail address: japm@uniovi.es

Centro de Investigación en Nanomateriales y Nanotecnología (CINN). CSIC-­Universidad de

Oviedo-­Principado de Asturias. Avenida de la Vega, 4-­6. 33940 El Entrego (Spain).

*Corresponding author e-­mail address: l.riera@cinn.es.

Contents

1. Introduction

2. Addition of Main Group Organometallic Reagents to Pyridines and Related Heteroaromatics

3. Reaction of Pyridines with Early Transition Metal Complexes

4. The Elusive Nucleophilic Attack on Transition Metal-­Coordinated 2,2’-­Bipyridine and 1,10-­

Phenanthroline

5. Reactivity of Carbonyl rhenium and Molybdenum Complexes

5.1 Reactions of the Phosphido Complex [Re(PPh2)(CO)3(phen)] with Activated

Acetylenes and Olefins

5.2 Dearomatization by Deprotonation of Complexes with N-­alkylimidazole Ligands

5.3 Couplings and Dearomatization Initiated by Deprotonation of C(sp3)-­H Bonds

5.4 Couplings Between Two Monodentate Hetericyclic Ligands

5.5 Ring Opening of Imidazole Rings

5.6 Couplings Between N-­Alkylimidazoles and Imine Ligands

5.7 Coupling Between N-­Alkylimidazoles and Nitriles or Isonitriles

2

5.8 Deprotonation of N-­Alkylimidazole Ligands in Phosphane-­Carbonyl Complexes

6 Metal-­Mediated tautomerization of N-­Heterocycles to NHC Complexes

6.1 Tautomerization of Pyridines

6.2 Tautomerization of Imidazoles

6.3 Tautomerization of Other Azoles

7 Metal-­Ligand Cooperation Based on Aromatization/Dearomatization Processes

8 Conclusions and Outlook

Acknowledgements

References

Abstract

This review focuses on chemistry published by the authors during the last decade, and relevant

chemistry from other areas is included to provide an appropriate context. 2,2’-­bipyridine (bipy)

and 1,10-­phenanthroline (phen), employed for a long time in all areas of coordination chemistry,

are archetypical auxiliary ligands that stabilize metal fragments but are not themselves the site

of the reactivity. Several examples of dearomatization of one of the pyridine rings of coordinated

bipy and phen are discussed, including one example of ring opening. The highly reactive species

resulting from deprotonation of coordinated N-­alkylimidazoles can result, besides of the

mentioned dearomatization, in other intramolecular C-­C coupling reactions involving

monodentate pyridines, other N-­alkylimidazoles, imine, nitrile, isonitrile and carbonyl ligands. In

some examples, the products of these couplings, and of those between two pyridines, can be

oxidatively rearomatized, affording pyridylimidazoles and bipyridines. Similar deprotonations

leading to C-­C couplings have been demonstrated for deprotonation of dimethylsulfide and

methylphosphane ligands. In some instances, the deprotonation of coordinated N-­

alkylimidazoles produces complexes with rare N-­alkylimidazol-­2-­yl ligands. The protonation or

alkylation of the non-­substituted nitrogen of the later affords coordinated N-­heterocyclic

carbenes.

3

1. Introduction.

This article aims to review the recent work by our group in new aspects of transition metal-­based

reactivity of pyridine and imidazole ligands, many of which involve dearomatization of those

heteroaromatic rings. Six member pyridines (1, Figure 1) and five member imidazoles (2, Figure

1) are some of the most important N-­heterocycles.1 There are several reasons for this relevance.

One is the prevalence of pyridine and imidazole rings in natural systems and in non-­natural

molecules with physiological activity. Imidazole groups of histidine residues are some of the

main donor groups toward metals in metalloproteins, including enzymes. This has been perhaps

the main reason why imidazoles or imidazole-­containing ligands have been the subject of many

studies in coordination chemistry.2 Despite this wealth of work, few studies dealt with the

reactivity of coordinated imidazoles beyond substitution reactions and proton transfer reaction

(including hydrogen bond formation) to and from a non-­coordinated imidazole nitrogen atom. N-­

alkylimidazolium salts (3, Figure 1) have been thoroughly studied materials;; for instance, as ionic

liquids.3 One of the ways to access such salts is by alkylation of free N-­alkylimidazoles. The

deprotonation at C2 of N-­alkylimidazolium cations is one of the most general ways to prepare

N-­heterocyclic carbenes (NHC, 4 in Figure 1), a type of ligands that are having a huge impact in

contemporary chemistry.4 In particular, NHCs are employed as ligands in many catalytic

processes, where their strong donor character, high steric profile, strong affinity for metal

centers, leading to the high thermal stability of their complexes, and tunability, make them useful

auxiliaries. Applications of NHC metal complexes outside the realm of catalysis are currently

being found as a result of intense research in this area.5 Despite the close relationship between

N-­alkylimidazoles and NHC ligands, few transformations linking the two types of compounds

were known. Recent contributions by our group are discussed in this paper, along with

appropriate mentions of previous and subsequent work by others.

Pyridines, being both good σ-­donor and π-­acceptor, are excellent ligands for all kinds of metal

fragments. The ability of pyridines to accept electron density in their low-­lying π-­symmetric empty

orbitals make them redox-­active ligands, and is also the basis of the rich photophysic behavior

of many metal complexes containing pyridine-­based ligands, in particular rhenium carbonyl

4

complexes. These properties have been particularly exploited for metal complexes of the

strongly chelating 2,2-­bipyridine (bipy, 5 in Figure 1) and 1,10-­phenanthroline (phen, 6 in Figure

1) and their derivatives, which have been employed as ligands for a long time.6,7 The complexes

of monodentate pyridines are often rather labile, a fact that considerably restricts their

applications and the study of the reactivity of the coordinated pyridines beyond their substitution.

In contrast, several types of pyridine-­based polydentate ligands, including the relatively simple

bipy and phen, form robust metal complexes that are very stable against substitution. Pyridyl-­

based ligands are typically resistant toward oxidation8 and very rarely have been found to

undergo chemical modification of the pyridyl ring. However, it must be noted that this is not the

result of an inert nature of pyridines. Pyridines are electron-­poor aromatic heterocycles in which

one of the CH groups of benzene has been replaced by the more electronegative nitrogen atom.1

Therefore, pyridines react with nucleophiles, which attack mainly the ortho and para positions,

those with a higher positive charge. The product of such nucleophilic additions is a non-­aromatic

amide with a high tendency to recover aromaticity, typically by a subsequent elimination step,

so that the overall addition-­elimination reaction is formally a substitution. Indeed, the tendency

to give substitution, as opposed to addition, products, is typical of aromatic substrates. If the

pyridine does not contain a good leaving group, such as a halide, the second step involves a

formal elimination of hydride, and the overall transformation is called an aromatic hydrogen

substitution.9 Alternatively, aromaticity can be regained by oxidation, formally a hydride

abstraction, often in fact a combination of electron transfer and proton abstraction steps.10 While

those reactions are well known of free pyridines, including bipy and phen, there was virtually no

precedent of nucleophilic attack to transition metal coordinated pyridines. For monodentate

pyridines, this can be attributed to their lability;; however, this cannot explain the lack of examples

of nucleophilic attack on coordinated bipy or phen ligands, especially given the vast number of

their transition metal complexes and how extensively they have been employed in every phase

of coordination chemistry. Neither can it be attributed to lack of interest;; in fact, there has been

a considerable interest in demonstrating nucleophilic attacks to transition metal-­coordinated bipy

and phen ligands following Gillard’s controversial suggestions that such attacks take place to

5

the bipy and phen ligands of some cationic metal complexes in basic aqueous solution, as it will

be discussed below.

Figure 1. Main types of N-­heterocyclic species dealt with in this work.

Metal-­mediated transformations of pyridines are thus mainly the realm of main group highly

electron-­rich compounds such as alkyl derivatives of lithium, magnesium and zinc, aluminum

hydrides, etc. This chemistry will be very succinctly covered with an emphasis on recent

developments, as it will the related alkyl migration to pyridines which have been found in a

number of f-­block derivatives, a topic which has been recently reviewed. In particular, rollover

cyclometalations, which are important processes that can be operative in bipy complexes, will

not be mentioned, and the interested reader is referred to a recent account of this chemistry.11

Most of this article will focus on our own chemistry, including several examples of

dearomatization of pyridyl rings of coordinated bipy and phen. Common features of all these

reactions are the very mild conditions under which they have been carried out, and their

intramolecular nature. In one instance, the reaction is initiated by the nucleophilic attack of a

terminal phosphanido ligand on electron-­poor alkenes and alkynes. In all the other examples, it

is the result of the deprotonation of one of the CH groups of a ligand. Metal-­coordinated N-­

alkylimidazoles, dimethylsulfide, trimethylphosphane and monodentate pyridines have been

demonstrated to generate, on deprotonation, internal nucleophiles, which then carry out the C-­

C coupling with proximal metal-­coordinated heteroaromatic rings. Deprotonated N-­

alkylimidazoles have been coupled also with nonaromatic ligands such as imines, nitriles,

N

R

1

NN R NNR'

+R NNR' R

2 3 4

N N N N

5 6

6

isonitriles and CO. Deprotonated monodentate pyridines have been coupled with other pyridine

ligands, affording 2,2’-­bipyridine chelates within the metal template. A key feature in designing

such coupling reactions is that the deprotonated ligand must be cis to the electrophilic ligand to

which the attack is planned to occur, so that the nucleophile resulting from the deprotonation

and its electrophilic counterpart are close in the space and can couple without leaving the metal

coordination sphere. Many dearomatized products have been characterized in solution;; in

several examples, in addition, they have been isolated as crystalline solids and structurally

characterized by single-­crystal X-­ray diffraction. A noteworthy feature of the C-­C coupling events

mentioned above is that they occur between partners that do not require functionalization other

than coordination to the metal, therefore constituting a modular, metal-­templated approach to

the direct synthesis of metal complexes containing elaborate polydentate ligands from

complexes of the monodentate ligands that serve as building blocks.

2. Addition of main group organometallic reagents to pyridines and related

heteroaromatics.

The addition of main group-­based organometallic or hydride reagents to pyridines and similar

systems takes place through coordination of the heterocyclic molecule to the Lewis acid metal

center followed by formation of dearomatized species, for which there is a small but growing

body of structural information.

The addition of nucleophiles to pyridines, pyridinium cations and other electron-­poor

heteroaromatic substrates has been known for a long time.12-­14 An example is the Chichibabin

amination, in which typically sodium amide adds to the 2 position of a pyridine.15-­17 Reactions of

this kind are thought to proceed through an initial step in which the pyridine coordinates the main

group metal cationic center, followed by the addition of the nucleophile (an alkyl or hydride) to

the 2-­position of the pyridine to afford a nonaromatic intermediate, the Meisenheimer adduct.

From this species, rearomatization to the 2-­substituted pyridine takes place through formal

hydride elimination, as showed in Scheme 1. This kind of mechanism is generally operative in

the chemistry of electron-­poor arenes.18 Note however, that the Chichibabin reaction has been

7

carried out in a variety of conditions, including homogeneous and heterogeneous media, so

different mechanisms can reasonably be expected. An elegant and synthetically useful

fluorination of pyridines and diazines, inspired by the Chichibabin reaction, has been recently

reported by Fier and Hartwig.19 Interestingly, in the (to our knowledge) only theoretical study of

the mechanism of the Chichibabin reaction, Dransfield and co-­workers found that the most

favorable mechanism involves the elimination of dihydrogen, rather than sodium hydride as it is

usually assumed.20

Scheme 1. Proposed mechanism of the Chichibabin reaction.

Alternative mechanisms involve heteroarynes or ring opening-­ring closure sequences.21,22 Main

group alkyl and, in some cases, hydride reagents, add to pyridines (the reaction is sometimes

called carbometalation, or pyridine insertion into the M-­C bond) affording either the dearomatized

N-­metalo-­1,2-­dihydropyridines or their 1,4-­isomers. Usually the 1,2-­isomers are produced under

kinetic control and the 1,4-­isomers, under thermodynamic control. Often mixtures of both

isomers are obtained, although regioselectivity has been achieved under certain conditions.

These main group complexes of dihydropyridines have been found to be the intermediates in

the reactions between pyridines and organometallic reagents to afford alkylpyridines. In some

instances, di-­ and tri-­alkylpyridines have been prepared employing an excess of the

organometallic reagent.23

Note that the classical syntheses of dihydropyridines (e.g. Hantzsch syntesis) employ de novo

construction of the rings by multicomponent reactions rather than starting from pyridines, and

that some of the pyridine reduction processes are actually reductions of pyridinium cations (e.

g. Fowler’s sodium borohydride reduction of the N-­acylpyridinium salts produced in situ by the

reaction of pyridines with chloroformate esters).

N

Na NH2

N

Na

NH2

H- NaH

N NH2

8

Neutral N-­H or N-­R dihydropyridines are employed both by nature (the NADH and NADPH

dinucleotide coenzymes) and by synthetic chemists as selective reducing agents in

transformations driven in large part by the tendency of dihydropyridines to achieve

rearomatization. In the field of transition metal organometallic chemistry, dihydropyridines have

been either formed on the coordination sphere of a metal to which they are bound through the

C=C double bonds, or used as substrates. Ishitani studied the formation of intermediate

complexes containing 1,4-­dihydropyridines η2-­coordinated to ruthenium fragments in the

reaction of pyridinium cations with ruthenium hydride complexes,24 Myers employed complexes

of a strongly π-­basic metal fragment with η2-­coordinated pyridinium cations to access metal-­

complexed dihydropyridines,25 Rudler found dihydropyridines to be useful reagents in the

chemistry of Fischer carbenes,26 and Liebeskind employed dihydropyridine π-­complexes as

intermediated in the synthesis of more reduced heterocycles, such as piperidines.27

The reaction of pyridines with organolithium reagents afforded mainly 2-­substituted pyridines

through alkyl addition to generate a dearomatized lithium complex of dihydropyridine. From this

species, it has been though that elimination of highly insoluble lithium hydride would yield the

final 2-­alkylpyridine product. Reaction mixtures usually contain some amount of the 4-­alkylated

isomer. Snaith and coworkers found that rather than undergoing an actual elimination of lithium

hydride, N-­lithium dihydropyridines hydrolize (e. g., with traces of moisture) to N-­H

dihydropyridines, which subsequently oxidize (e. g. on atmospheric exposure) to 2-­

alkylpyridines.28

Mulvey and co-­workers reported evidence pointing to intramolecular hydride transfer from a

dihydropyridide ligand to a pyridine ligand within a lithium complex (Scheme 2), and the crucial

role of the stoichiometry in the reactions between pyridines and organolithium reagents.29 These

results indicate the necessity of considering the entire coordination compound and to gain as

much knowledge as possible of its structure both to understand and to synthetically exploit the

reactivity of main group organometallics. Mulvey, Robertson and co-­workers recently isolated

and structurally characterized several N-­lithio-­2-­alkyl-­dihydropyridines.30

9

Scheme 2. Proposed hydride transfer between ligands in a lithium complex.

Methods consisting of nucleophilic addition followed by oxidative rearomatization are some of

the simpler and more expedient methods for pyridine functionalization. However, preactivation

of the pyridine by its transformation to a pyridine N-­oxide or an N-­alkyl-­ or N-­acyl pyridinium

cation is often required. In 2013 and 2014 Knochel and co-­workers reported nucleophilic

additions to pyridines mediated by BF3.31,32 They found that the formation of pyridine-­BF3 adducts

has a dramatic effect on the reaction course. Indeed, some reactions do not occur without the

presence of BF3 and, in other instances, the regioselectivity towards the product of addition to

the 4-­position is attributed to BF3 complexation. A similar effect of pyridine activation by its

complexation has been found by Urabe and co-­workers in the additions of benzyl Grignard

reagents.33

In the reactions between pyridines, in particular bipy and phen, and other electron-­poor N-­

heterocycles, and main group organometallic or hydride reagents, the formation of strongly

colored solutions have been noted a long time ago, and bipy and phen have been used as visual

indicators in the titrations of organolithium and Grignard reagents.34 However, attempts to isolate

stable metal complexes from these reactions failed. Kaim and others showed that, instead of the

previously assumed polar mechanism (carbanion transfer from the metal to the heterocycle),

many reactions between the metal reagent (alkyllithium, organomagnesium, organozinc,

aluminum hydride, etc.) and the heterocyclic substrate take place through a radical

mechanism.35-­37 Thus the initially formed adduct between the metal reagent and the heterocycle

(a charge transfer adduct) undergoes an intramolecular single electron transfer to form a radical

anion of the heterocyclic substrate and the radical cation of the metal reagent. One of the

possible pathways from that system leads to the diamagnetic product of alkyl or hydride transfer

NNLi

H HN nBu

LiN

HnBu

pypy

+py

py

10

to the heterocycle. Trapping of radicals and ESR spectroscopy provided evidence in support of

such a radical pathway. Note, however, that most studies of the reactivity of main group alkyl or

hydride reagents with electron-­poor heteroaromatics do not include the probing of the possible

intermediacy of radicals. Radical-­based reactions of electron-­poor heteroarenes can be

synthetically useful.38 Note also that radicals can display a considerable nucleophilic character

so that, for instance, radical addition to pyridines can be mainly directed to the 2 and 4 positions.

Maron, Okuda and co-­workers reported in 2010 that bis(η3-­allyl)calcium reacts with pyridine to

regioselectively afford a species with two anionic, dearomatized 1,4-­dihydropyridide ligands,

each resulting from the addition of an allyl group to a coordinated pyridine.39 In excess pyridine,

an octahedral complex could be isolated and structurally characterized by X-­ray diffraction,

which contains four intact pyridine ligands, and the two anionic ligands in trans positions. Its

reaction with E-­Cl electrophiles generates the neutral N-­protected 1,4-­dihydropyridines and

calcium chloride.

The mechanism of the dearomatization was studied by NMR and by computational methods. An

adduct between the diallylcalcium moiety and pyridine initially forms, followed by allyl migration

from calcium to the ortho position of two of the coordinated pyridines to afford the product of

double 1,2-­insertion. Next, the final double 1,4-­insertion product is formed by a rate determining

Cope rearrangement step.

The Lansbury reagent, formed as the product of the reaction between pyridines with lithium

tetrahydroaluminate (lithium alanate), has been employed as a useful reducing agent in organic

chemistry for a long time. Hensen and co-­workers demonstrated that Lansbury reagent has the

[Li(pyridine)4][Al(1,4-­dihydropyridide)4] composition and structurally determined its structure and

those of similar derivatives.40

Budzelaar et al. studied the reactions of a pyridylbis(imine) pincer ligand with aluminum alkyls.

Along with other species, they found products of alkyl addition to the pyridine ring. Radical and

ionic mechanisms were considered. Regarding the later, the authors found the best results in

their computational modeling for the alkyl transfer from an anionic R3AlCl-­ species to the pyridine

ring of the pincer ligand coordinated to the cationic RAlCl+ fragment.41

11

In 2011 Okuda and coworkers reported a study of the reactivity of tris(η1-­allyl)aluminum

complexes toward pyridines. In some cases, they found formation of dearomatized products of

the allyl addition to the ortho position of pyridine.42 Previous studies by other groups found either

no reaction or just formation of stable pyridine adducts in the reaction between pyridines and

other trialkylaluminum reagents. Okuda proposed a Claisen rearrangement in the case of allyl

addition to explain the especial behavior of this alkyl group. They encountered a dramatic solvent

effect in the reaction. Thus [Al(η1-­allyl)3(py)], quantitatively formed as the product of the reaction

between [Al(η1-­allyl)3(THF)] and pyridine, was found to be stable in pentane for weeks;; in

contrast, in THF solvent, the dearomatized product of allyl attack to the pyridine ortho position

was formed. Allyl attack is prevented by the presence of methyl groups not only at the ortho

(steric blocking), but also on the meta or para positions of the pyridine ring, indicating that

electron-­rich pyridines are not electrophilic enough for undergoing the nucleophilic attack of the

allyl group. Accordingly, 4-­dimethylaminopyridine does not react, whereas 4-­

trifluoromethylpyridine affords mainly the product of ortho-­allyl addition.

Addition of diorganozinc reagents, which are relatively mild nucleophiles, to pyridines have been

typically carried out employing transition metal catalysis. In 2015 Hevia and co-­workers reported

the regioselective addition of lithium arylzincate reagents [LiZnPh3] and [Li2ZnPh4] (prepared by

co-­complexation of the appropriate amounts of to LiPh and ZnPh2) to the 9-­position of acridine

under microwave irradiation.43 They found a much better performance of the heterometallic

reagents compared to simple diarylzinc reagents, which has been attributed to a combination of

the anionic activation of the organozinc reagent (by forming ZnPh3-­ or ZnPh42-­ species) and an

enhancement of the electrophilicity of the heterocycle by its coordination to the lithium centers.

Note the relation with the Budzelaar’s aluminum system mentioned above. Indeed, the authors

structurally characterized the dearomatized product of the addition to the 9-­position, in which the

nitrogen atom is coordinated to Li(THF)3+, as shown in Scheme 3.

12

Scheme 3. Dearomatization of acridine by reaction with lithium triphenyl zincate.

3. Reaction of pyridines with early transition metal complexes.

Early transition metal chemistry, including that of the f-­block elements, shares some features

with that of the main group metals due to a high polarity of the element-­metal bonds. Early

transition metal hydride and alkyl complexes, endowed with strongly electrophilic metal centers,

often react with the CH groups in the α position of N-­heterocyclic ligands. For pyridines, such

reaction produces κ2-­(C,N)-­pyridyl complex, depicted in Figure 2 (structure 7). Note that the

pyridyl ring of this type of complex maintains the aromaticity. These pyridyl complexes display a

rich reactivity such as insertions of unsaturated organic molecules (e.g., olefins) in the M-­C bond,

eventually initiating catalytic cycles. Alternatively, if a second molecule of an N-­heterocycle binds

the same metal center, interligand C-­C coupling can take place. For instance, the reaction of an

unsaturated alkyl complex with two equivalents of pyridine can generate a bipy ligand on the

metal coordination sphere. This chemistry has been excellently reviewed.44,45

Some early transition metal fragments are capable of binding pyridines in the very rare κ2-­(C,N)

mode. In contrast with the κ2-­(C,N)-­pyridyl complexes mentioned above, pyridine (as opposed

to pyridyl) ligands coordinated in the κ2-­(C,N) mode are dearomatized, and are considered to

possess metaloaziridine character (see structure 8 in Figure 2).

Figure 2. κ2-­(C,N)-­pyridyl (7) and κ2-­(C,N) pyridine (8) ligands.

N

NPhH

Li

THF

THFTHFLiZnPh3

7 8

NM

NM

H

13

Pyridine and its analogs are some of the main contaminants present in petroleum crudes, and

they should be removed to avoid the emission to the atmosphere of nitrogen oxides from fuel

combustion. To this end, large-­scale hydrodenitrogenation (HDN) of petroleum crudes is carried

out along with hydrodesulfurization (HDS) and hydrodeoxygenation (HDO) processes. These

hydrotreating processes employ sulfidized transition metal oxides as heterogeneous catalysts.

Since the sulfur-­containing organic pollutants would poison the catalysts of subsequent

processes to which the petroleum will be subjected, these processes operate under conditions

that have been optimized for HDS. Under these conditions, the HDN process, which is of obvious

economic and environmental relevance, is not very efficient. The mechanism of HDN is

incompletely understood and it has been hoped that homogeneous models could shed some

light on its nature and eventually lead to improvements in the efficiency of the process. Hence,

particular attention has been devoted to those few transition metal-­based homogeneous

systems that have been found to be able to mediate the ring opening of pyridines.46,47

In 1988, Wolczanski and co-­workers reported the first example of a metal complex containing a

pyridine ligand bonded in the κ2-­(C,N) mode.48 The key to obtain this previously unknown

coordination mode was the employment of the extremely reactive Ta(silox)3 (silox= OSitBu3)

complex, which was prepared by reduction of the previously known, stable complex TaCl2(silox)3

with excess sodium amalgam. Ta(silox)3 is a tricoordinated, highly reducing complex in which

the axial coordination of normal two electron donors is discouraged by the presence of a metal-­

centered, two-­electron filled molecular orbital perpendicular to the molecular plane. This feature

is of particular relevance for the reaction with pyridine, which is a potential two-­electron σ-­donor

when coordinated in the most common κ1-­(N) mode. The extraordinary reactivity of Ta(silox)3 is

illustrated by the result of its reaction with the equimolar amount of CO, reported in 1986 by the

same group: one could expect simply binding of carbon monoxide to afford a carbonyl complex,

since many carbonyl complexes effectively stabilize low oxidation state metal fragments as a

result of a significant back bonding. Instead, the reaction, an extreme form of an oxidative

addition, breaks down the very strong carbon-­oxygen bond of carbon monoxide, affording a

mixture of O=Ta(silox)3 and (silox)3Ta=C=C=Ta(silox)3, both Ta(V) species with

14

pseudotetrahedral geometries around the metal atoms.49 The presence of strong metal-­carbon

or metal-­nitrogen double bonds in the products must be a significant contribution to the driving

force of the reaction. The product of the reaction of Ta(silox)3 with pyridine is a metallaaziridine

complex in which the metal-­bonded C and N atoms display geometries consistent with sp3

hybridizations. The bond between these C and N atoms is a single bond;; therefore, the pyridine

has been potentially activated towards the subsequent C-­N bond breaking. In 1997, Wolczanski

and co-­workers reported that the thermolysis of a niobium complex analogous to the tantalum

species discussed above resulted in the ring-­opening of the κ2-­(C,N)-­coordinated pyridine,

affording products containing Nb-­nitrene and Nb-­alkylidene bonds, as shown in Scheme 4.50

Scheme 4. Pyridine ring-­opening mediated by a niobium complex reported by Wolczanski et

al.

In 1987, one year before the first κ2-­(C,N)-­coordinated pyridine was reported, Cordone and

Taube reported the first example of an η2-­(C,C)-­coordinated arene: 2,6-­lutidine.51 In this case,

the metal fragment was Os(NH3)5, with which Taube, Harman and co-­workers conducted an

extensive dearomatization chemistry.52 The pentaammineosmium fragment is strongly reducing;;

however, η2-­coordination of pyridines through a carbon-­carbon double bond is only observed

when the nitrogen is sterically blocked, as in 2,6-­lutidine, or quaternized (pyridinium cations).53

In general, when the aromatic substrate possesses functions capable of acting as two-­electron

donors, these are the ones that coordinate osmium, a fact attributed to the avoidance of the

(destabilizing) disruption of the aromatic system. Wigley and co-­workers reported the

preparation of a κ2-­(C,N)-­coordinated pyridine complex and its subsequent ring-­opening by

nucleophilic attack.54-­56 (Scheme 5). The complex does not result from the reaction of a metal

precursor with a free pyridine, but from the reaction of a nitrile with a tantallacyclopentadiene,

which in turn is formed as the product of the reduction of a Ta(V) precursor with sodium amalgam

2 (silox)3NbCl24 Na/Hg Δ, C6H6N

2 (silox)3Nb

H

py - py

HH

(silox)3Nb

H

H

N

HNb(silox)3

15

in the presence of two equivalents of a terminal acetylene. It must be noted, however, that the

same authors obtained related complexes featuring κ2-­(C,N)-­coordinated quinoline and 6-­

methylquinoline ligands. The compound containing the κ2-­(C,N)-­coordinated pyridine reacts with

nucleophiles such a hydride (its source being superhydride, LiBHEt3), Grignard, or organolithium

reagents. The attack of these nucleophiles occurs initially at the metal, where they replace a

chloride ligand, but subsequently, the hydride or alkyl group migrates to the metal-­bonded

carbon atom of the κ2-­(C,N)-­coordinated pyridine, affording a metallacyclic product in which the

ring opening of the ligated pyridine has taken place. In this product the pyridine nitrogen has

been incorporated into a metal-­bonded nitrene group (see Scheme 5);; as in the pyridine ring-­

opening reported by Wolczanski (see above) surely the formation of the strong Ta=N bond is a

significant contribution to the driving force of the reaction.

Scheme 5. Synthesis of a κ2-­(C,N)-­coordinated pyridine complex and its ring-­opening by

nucleophilic attack (Wigley et al.).

Mindiola and co-­workers, on the other hand, reported a completely different type of pyridine ring-­

opening reaction.57,58 The reaction of an unsaturated titanium alkylidine intermediate, generated

by alkane elimination from an (alkyl)alkylidene complex, with pyridines results in ring-­opening

TaCl(OAr)2

R

Ta(OEt2)(OAr)2Cl3 2 Na/Hg

Ar=2,6-diisopropylphenyl

CHtBuCexcess Δ

TaCl(OAr)2

R

R R

TaCl(OAr)2

R

R

NRCN

C

R

Δ

N

TaR

R

R

Cl OArOAr

LiX- LiCl

N

TaR

R

R

X OArOAr

X= Me, Et, nPr, nBu, H

NTa

RR

RX

ArOArO

16

metathesis of one of the pyridine C=N bonds across the Ti-­C triple bond, yielding the

metallaazabicyclic products depicted in Scheme 6.

Scheme 6. Titanium-­mediated pyridine ring-­opening developed by Mindiola et al.

The above discussed examples have been taken as a suggestion that the metal-­mediated ring

opening of pyridines under homogeneous mild conditions would require a complex with a κ2-­

(C,N)-­coordinated pyridine as precursor and, therefore, a very particular type of metal fragments.

The vast majority of metal complexes feature pyridines coordinated in the κ1-­(N) mode, in which

the pyridine ligand remains aromatic;; it was though that such species would not be able to

mediate pyridine ring opening.46

4. The elusive nucleophilic attack on transition metal-­coordinated 2,2’-­bipyridine

and 1,10-­phenanthroline.

Bipy and phen are some of the most prominent ligands in all areas of coordination chemistry.

Because of their combination of good σ-­donor and π-­acceptor properties, and their tendency to

form robust five-­member chelate rings, these aromatic diimines form stable complexes with all

metals in every oxidation state. In them, with very few exceptions, bipy and phen act as spectator

ligands, stabilizing the complex without being themselves the center of the reactivity. Some forty

years ago, while investigating the behavior of cationic bipy and phen transition metal complexes

in basic aqueous solution, Gillard and Lyons interpreted certain spectral features as due to

species (termed covalent hydrates) formed by hydroxide anion (or water) addition to the diimine

ligands.59 Gillard proposed that coordination to positively charged, Lewis-­acidic metal centers

activated the pyridine groups towards nucleophilic attack, and likened these complexes to the

pyridinium cations produced by nitrogen quaternization.60,61 This proposal sparked a long-­

py, 25 ºC12hrs.

- CH3tBuTi

HN

tBu

P

N

P

Ti

P

N

PCHtBu

CH2tBuTi

HN

tBu

P

N

P

17

standing controversy, and work by other groups satisfactorily explained the evidence presented

by Gillard in terms of hydroxide attack on the metal rather than on the bipy or phen ligands, thus

discrediting Gillard’s hypotesis.62-­66

In particular, Lay pointed out that, unlike alkyl cations, a transition metal fragment such as the

ones Gillard was considering (which were from mid to late transition metals with relatively high

electron counts) would be able to, besides withdrawing electron density via σ, release electron

density into the empty π orbitals of the heterocycle,67 and Blackman and co-­workers showed that

formation of pentacoordinated complexes by hydroxide attack to [Pt(bipy)2]2+ complexes

explained the early observations that prompted Gillard to propose attack to bipy.68 In 2002,

Zhang et al. demonstrated the hydroxide attack on bipy and phen in the presence of cupric ions,

suggesting that chemistry like that proposed by Gillard can be operative in certain systems.69

However, the fact that these reactions have needed to be carried out under hydrothermal

conditions can be taken as an indication of the difficulty of functionalizing the metal-­bonded

pyridine rings, a transformation that involves their dearomatization. The subsequent isolation of

an intermediate in these hydrothermal reactions containing both phen and OH ligands

coordinated to the same metal atom, led Latham et al. to suggest initial attack by OH-­ to the

metal, followed by a metal to phen migration.70 A perusal of the literature indicated that not only

the attack of the hydroxide anion, the one of the original Gillard’s proposal, to transition metal-­

bonded pyridines, but in fact any nucleophilic attack to these ligands, is extremely rare. A review

of the chemistry carried out by Gillard and co-­workers as well as by others following Gillard’s

seminal suggestions have been recently published by one of the major players in the field.71

5. Reactivity of carbonyl rhenium and molybdenum complexes.

5.1. Reactions of the phosphido complex [Re(PPh2)(CO)3(phen)] with activated

acetylenes and olefins.

In the past, our group has been concerned with the study of the reactivity towards electrophiles

of complexes containing basic ligands such as alkoxo,72,73 hydroxo,74-­76 amido,77-­81

alkylidenamido,82,83 etc. Alkoxo complexes [Re(OR)(CO)3(bipy)] reacted with

18

dimethylacetylendicarboxylate (DMAD) to afford the product of formal insertion of DMAD into

the Re-­O bond, presumably through nucleophilic attack of the coordinated alkoxo to one of the

acetylenic carbons.72 This would develop a negative charge at the other acetylenic carbon, which

then would attack the metal, from which the oxygen would be displaced, as shown in Scheme

7a. This displacement would be aided by the positive charge developed on the metal-­bonded

oxygen, which would make it a good leaving group. For the reactions of DMAD with hydroxo or

arylamido complexes, the target of the intramolecular nucleophilic attack is not the metal, but

one of the proximal CO ligands.76,80 H migration from the hydroxo or arylamido group to the

oxygen of the same carbonyl group helps to preserve the Re-­O or Re-­N bonds and to transform

the CO into a hydroxycarbene group, which is incorporated into a five-­member metallacycle, as

shown in Scheme 7b.

Scheme 7. Reactions of DMAD with alkoxo (a) or hydroxo (b) complexes.

We have synthesized the phosphido (phosphanido) complex [Re(PPh2)(CO)3(phen)] and carried

out preliminary studies of its reactivity.77 In contrast with the reactions of alkoxo, hydroxo or

arylamido complexes discussed above, the reactions of the phosphido complex with either

methyl propiolate or methyl acrylate afford products consistent with conjugated addition of the

phosphido ligand to the acetylene or olefin to afford a zwitterionic adduct84 (reminiscent of those

involved in several types of phosphane-­catalyzed coupling reactions),85 followed by

CC CO2MeMeO2C[M] CO

YR

[M] CO

YR C

C

CO2Me

CO2Me+-

[M] CO

CMeO2C C

YR

CO2Me

Y= OR= alkyl

Y

[M] C

C

CCO2Me

CO2Me

OR

Y= O, NArR= H

(a)

(b)

19

intramolecular attack of the other carbon to one of the ortho carbons of the phen ligand (Scheme

8).

Scheme 8. Reaction of [Re(PPh2)(CO)3(phen)] with methyl propiolate.

Evidence of attack to the phen ligand is found both in solution, where the NMR indicates a non-­

symmetric phen, and in the solid state. The structure of the product, determined by X-­ray

diffraction, confirms the formation of a carbon-­carbon bond and the non-­planarity of the phen

moiety. The comparison of the bonding distances N(1)-­C(11)= 1.452(11), C(11)-­C(12)=

1.540(14) and C(12)-­C(13)= 1.307(10) Å in the product with those in the phosphido precursor

(1.329 (11), 1.387(15) and 1.354(17) Å respectively) indicates the dearomatization of the

pyridine ring as a result of the intramolecular nucleophilic attack.

The reaction of the phosphido complex with DMAD proceeds similarly, affording complex 9.86

However, whereas the product of the reaction with methyl propiolate has been found to be

indefinitely stable in solution, the product of the analogous reaction with DMAD slowly evolves

to its tautomer 10 as shown in Scheme 9. Compounds 9 and 10 have been characterized by IR,

NMR and X-­ray diffraction. The transformation of 9 into 10 is at least partly driven by an increase

in the conjugation. The reaction of 9 with nBuLi (which, monitored by IR, showed the formation

of a species with low νCO bands, consistent with deprotonation to form an anionic complex)

followed by treatment with HOTf, instantaneously affords 10, suggesting that the hydrogen

migrates as a proton, rather than as a hydrogen atom or as a hydride.

N

NRe

OCOC

CO

N

NReOCOC

CO

HPPh2

H C C CO2Me

N

NRe

OCOC

CO

P

H

C C

CO2Me

PhPh

P

HC C

CO2Me

PhPh

1

11 1213

20

Scheme 9. Transformation of complex 9 into its tautomer 10.

The most striking feature of the reactions of the phosphido complex with the activated olefin and

acetylenes is the rapid dearomatization of the phen ligand under very mild conditions. It seems

likely that the reaction is somewhat facilitated by its intramolecular nature. Also noteworthy is

the stability of the dearomatized products, which have made possible to discover the

tautomerization discussed above and to crystallize the products by solvent slow diffusion.

Compared with the alkaline salts resulting from the addition of, for instance, RLi reagents to

pyridines, the dearomatized products of the reactions of the phosphido complex discussed

above are neutral complexes, without the possibility of eliminating an alkaline hydride (which,

having a large lattice energy, must contribute considerably to the driving force of the reaction).

Additionally, the presence of the metallacycle hampers the regaining of planarity that would be

required for rearomatization. It must be noted that the product of the attack to phen is the only

product of the reaction, and no product of attack to one of the two proximal CO ligands was

detected. This stands in contrast with the previously reported reactions of terminal phosphido

complexes with DMAD, where formation of five-­member metallacycles resulted from the

coupling of the phosphido ligand, DMAD and one CO ligand.87-­89 Note that our results in the

reactions of the hydroxo and amido complexes with DMAD discussed above indicate that the

proximal carbonyl ligands are susceptible to similar coupling reactions to form five-­member

metallacycles in pseudooctahedral rhenium tricarbonyl bipy complexes. Therefore, the

unprecedented observed coupling involving the coordinated phenanthroline is not only viable

under very mild conditions, but also preferred over the coupling involving one of the CO ligands.

N

NReOCOC

CO

HP

MeO2CC C

CO2Me

PhPh

N

NReOCOC

CO

P

HMeO2C CO2MePhPh

9 10

21

5.2. Dearomatization by deprotonation of complexes with N-­alkylimidazole ligands.

In 2008 we reported that the reaction of [Re(N-­MesIm)(CO)3(bipy)]OTf (11) (N-­MesIm= N-­

mesitylimidazole;; mesityl= 2,4,6-­trimethylphenyl) with the strong base KN(SiMe3)2 affords a

product consistent with deprotonation of the imidazole C2-­H group, followed by attack of that

carbon to the ortho (C6) carbon of the bipyridine ligand (complex 12, Scheme 10a).90 This

reaction stands in contrast with the transformation of an N-­alkylimidazole (N-­RIm) into an

anionic, C-­bonded imidazolyl ligand (trapped by protonation to afford a stable cationic NH,NHC

complex) by deprotonation of a [Mn(N-­RIm)(CO)3(bipy)]+ complex reported by Ruiz and

Perandones in 2007 (Scheme 10b).91 Note that imidazoles have been widely employed as

ligands in transition metal chemistry,2 and that metallation of free N-­alkylimidazoles at C2 was a

known reaction.92,93 However, the deprotonation of metal-­coordinated N-­alkylimidazoles has

been virtually unexplored before.

Scheme 10. Imidazole-­bipy C-­C coupling (a) or transformation of N-­RIm to NH-­NHC

complexes (b).

As in the reactions of the phosphido complex discussed above, the C-­C coupling reaction

resulting from the deprotonation of [Re(N-­MesIm)(CO)3(bipy)]OTf affords a product in which one

N

NRe

OCOC

CO

N

N

Mes

OTf

N

NRe

OCOC

CO

N

NMes

H

KN(SiMe3)2

[Mn] N NR (i) KOtBu

R= Me, Ph

(ii) NH4PF6

+

[Mn]

+

N

N

R

H

[Mn]= Mn(CO)3(bipy)

(a)

(b)

11 12

22

of the pyridine rings of the bipyridine ligands is dearomatized, and it takes place under very mild

conditions.

Reactions similar to the deprotonation of [Re(N-­MesIm)(CO)3(bipy)]OTf were carried out with its

N-­methylimidazole (N-­MeIm) analog as well as with the two similar compounds containing phen

instead of bipy. The stability of the products varied greatly. The neutral product of [Re(N-­

MesIm)(CO)3(bipy)]OTf deprotonation was sufficiently stable to permit isolation and full

characterization, including X-­ray crystallography. In solution the dearomatization of the attacked

ring is indicated by the upfield shift of several of the signals corresponding to its CH groups. The

solid-­state structure of this species confirms the formation of the new C-­C bond between the

central carbon (C2) of the imidazole ring and the C6 carbon atom of the bipyridine ligand, and

the dearomatization of the attacked pyridine ring, geometrically shown by its loss of planarity

(see Figure 3). Unlike in the C-­C coupling reactions of the phosphido complex discussed above,

where six-­member metalacycles were formed, now the product of the imidazole-­bipy coupling

features a five-­member ring. As a result of the C-­C forming reaction, the aromatic imine

functionality in the reactant is transformed into an amido group in the product.

Figure 3. Molecular structure of complex 12.

The combination of amido ligands, with a high tendency to act as π-­donors, with high oxidation

state metal fragments possessing empty orbitals of appropriate symmetry, usually leads to very

23

stable complexes.94 Although in principle, for an octahedral d6 complex, with the π-­symmetric t2g

orbitals completely filled, π-­donation from the amido ligand should not be possible, the electron

density from the amido lone pair can be donated to the strongly π-­acceptor CO ligands via the

π-­symmetric metal orbitals.95 Such donation, which would stabilize the complex, would lead to a

planar amido group. A planar at nitrogen geometry, characterized by a sum of the angles about

the nitrogen atom being 360°, has been encountered in most structurally characterized amido

complexes, including in arylamido rhenium tricarbonyl complexes, in which structural evidence

supports the delocalization of the amido lone pair through the aryl substituents.77 In contrast,

complex 12, the product of the deprotonation of [Re(N-­MesIm)(CO)3(bipy)]OTf, which is a rare

example of a stable amido complex of a low valent metal without aryl substituents at the amido

nitrogen, features a pyramidal amido group, the sum of the angles around the amido nitrogen

being 335°. This feature can be attributed to the constrained geometry resulting from the amido

group being part of a rigid tridentate ligand.

Besides of the structural evidence -­the geometries about both the carbon and the nitrogen are

consistent with sp3 hybridization in the product-­, this amido character is reflected in the reactivity.

Thus, the neutral products resulting from the deprotonation of the [Re(N-­RIm)(CO)3(N-­N)]OTf

(R= Me, Mes;; N-­N= bipy, phen) compounds react with MeOTf. For three of the compounds, the

reactions afford stable, cationic complexes featuring amino groups resulting from methylation at

nitrogen (Scheme 11). One of these derivatives (N-­MesIm, phen) was fully characterized,

including X-­ray diffraction. Comparing the two series of compounds, namely, the neutral amido

products with the cationic complexes that result from the methylation of the amido compounds,

the later have been found to be significantly more stable. This is attributed to the high

nucleophilic character of the amido ligand, a fact that has been previously noted in monodentate

amido rhenium tricarbonyl complexes.77,78,80

24

Scheme 11. Methylation of the amido group of the dearomatized, C-­C coupled products,

affording stable amino complexes or a ring-­opening product (13).

In the cationic amino complexes resulting from at-­nitrogen methylation of the amido complexes,

both NMR and X-­ray data indicate the presence of a dearomatized pyridyl ring as in the amido

precursor. The neutral species formed in the deprotonation of [Re(N-­MeIm)(CO)3(bipy)]OTf

reacts with excess methyl triflate under very mild conditions (15 minutes stirring at room

temperature) affording compound 13 (see Scheme 11 and Figure 4), which was characterized

spectroscopically and by X-­ray diffraction. The most interesting feature in the structure of 13 is

that it reveals, besides the double methylation of its nitrogen atom, that nitrogen extrusion

occurred in the pyridine ring to which the nucleophile attack took place. The product features a

tridentate ligand with pyridine, imidazole and dimethylamino donor groups, and a

cyclopentadienyl bridgehead group formed as the product of the mentioned nitrogen extrusion

from the attacked pyridine ring. The treatment of the neutral product of the initial deprotonation

with the stoichiometric amount of MeOTf failed to yield a monomethylated product akin to the

one resulting from methylation of 12;; however, taken collectively, the results outlined above

N

NRe

OCOC

CO

N

NR

H

MeOTfOTf

N

NRe

OCOC

CO

N

NR

H

Me

R= Mes; bipy, phenR= Me; phen

MeOTf (excess)R= Me; bipy

NReOC

OC

CO

N

N

N

Me

OTf

13

25

suggest that ring opening occurs via a second methylation of such a product. The fact that the

monomethylated phen complex does not react with excess MeOTf suggest that the additional

aromatic ring in the phen ligand somewhat hinders the rearrangement leading to nitrogen

extrusion.

Figure 4. Molecular structure of the cation of compound 13.

The overall transformation that starts with the deprotonation of the cationic N-­methylimidazole

bipyridine complex and ends in the pyridine ring opening shows that pyridine ring opening under

mild conditions can be achieved starting from a very stable metal complex in which the bipy

ligand, usually very inert, is coordinated in its normal mode, i.e., both pyridyl rings bind the metal

only through their nitrogen atoms, in contrast with previous examples of homogeneous metal-­

mediated pyridine ring-­opening, which necessitated highly reactive early transition metal

fragments capable of binding pyridines in the κ2-­(C,N) mode.

5.3. Couplings and dearomatization initiated by deprotonation of C(sp3)-­H bonds.

The C-­C coupling reactions discussed above have been initiated by the deprotonation of the

C(sp2)-­H bond of an N-­alkylimidazole ligand. We have found that similar C-­C couplings can be

carried out through the deprotonation of aliphatic CH groups such as those of coordinated

26

dimethylsulfide96 or trimethylphosphane,97 which triggers the C-­C coupling between the resulting

methylene group and one of the pyridyl groups of bipy and phen co-­ligands.

The product of the reaction of [Re(CO)3(bipy)(S(CH3)2)]OTf with a slight excess of KN(SiMe3)2

showed insufficient thermal stability to allow crystallization and thus was fully characterized only

in solution by means of NMR. To aid in this characterization the labeled analog

[Re(CO)3(bipy)(S(13CH3)2)]OTf was similarly synthesized and deprotonated. The results of the

NMR studies indicated that the methylene group resulting from the deprotonation of one of the

methyl groups of S(CH3)2 attacked the C2 position of bipy, in contrast with the attack at C6 found

in the C-­C coupling resulting from N-­alkylimidazole deprotonation.90 The product has been found

to be the mixture of the diasteromers showed in Scheme 12. The reaction of the mixture of

diasteromers with the equimolar amount of trimethylphosphane afforded a single compound,

resulting from the displacement (from the rhenium coordination sphere) of the sulfide donor

group group by the phosphane (Scheme 12). In an analogous fashion, the diasteromeric

mixtures reacted with bis(dimethylphosphino)methane (dmpm), affording a single product in

which the sulfide group has been replaced by a monodentate dmpm. No product containing a

bidentate dmpm ligand could be detected, despite the high nucleophilicity of this diphosphane,

showing that the low stability of the diasteromeric mixture resulting from the deprotonation and

C-­C coupling does not arise from lability of the ligands (e.g., decarbonylation).

Scheme 12. C-­C coupling and pyridine dearomatization initiated by the deprotonation of a

dimethylsulfide ligand.

N

NRe

OCOC

CO

+S

CH3H3C

N

NRe

OCOC

CO

H2CPMe3

S

H3C

KN(SiMe3)2

N

NRe

OCOC

CO

S

H3C H H

+

N

NRe

OCOC

CO

S

H3C H H

PMe3

27

This low stability was thus attributed to the dearomatization of one of the pyridyl rings, and thus

a similar C-­C coupling was sought which would involve a nonaromatic diimine in the hope that it

would afford a more stable product. Thus compound [Re(CO)3(2,6-­iPr-­BIAN)(S(CH3)2)]BAr’4

(2,6-­iPr-­BIAN= 1,2-­bis[(2,6-­diisopropylphenyl)imino]acenaphthene) was prepared and

characterized both spectroscopically and by X-­ray diffraction, and it was allowed to react with

KN(SiMe3)2. Indeed, the stable, single product of the reaction was found to be the neutral

complex resulting from the coupling between the methylene group of an H3CSCH2 fragment,

produced in the deprotonation of the coordinated dimethylsulfide, and one of the imine carbons

of the diimine chelate. A factor that can make the BIAN-­derived amido complexes more stable

compared with their bipy counterparts is the steric protection lent by the bulky aryl group in the

former.

The deprotonation of [Re(CO)3(bipy)(P(CH3)3)]OTf with KN(SiMe3)2 afforded a mixture of two

products (Scheme 13). One of them was the neutral cyano complex

[Re(CO)2(CN)(bipy)(P(CH3)3)], formed from attack of the amide on one of the CO ligands, a

known reaction that involves the elimination of hexamethyldisiloxane, O(SiMe3)2.98 The second,

minor product, was the expected result of the deprotonation of one of the phosphane methyl

groups and subsequent intramolecular attack on the bipy C6 position. Note the difference with

the similar reaction of the dimethylsulfide complex discussed above, in which the attack was to

the bipy C2 position instead.96

Scheme 13. Formation of cyano and dearomatized C-­C coupled products initiated by

deprotonation of a trimethylphosphane ligand.

N

NRe

OCOC

OTfCO

KN(SiMe3)2+

PH3C CH3

H3C

PH3C

H H

N

NRe

OCOC

CO

H

H3C

N

NRe

OCOC

CO

CN

28

As in the reaction of the sulfide complex just described, the product of C-­C coupling was found

to be too unstable for isolation, but could be characterized by NMR at low temperature. Stable

2,6-­iPr-­BIAN analogs were isolated and characterized, including by X-­ray diffraction, for P(CH3)3,

P(CH3)2Ph and P(CH3)Ph2 complexes (see Figure 5 for the P(CH3)3 derivative). The

deprotonation has been found to take place exclusively at the methyl -­not at the phenyl-­

substituents. The amido groups in the C-­C coupling products were found to be planar at nitrogen,

pointing to amido lone pair delocalization. At first sight such delocalization could be expected to

occur onto the aryl amido substituents. However, coplanarity would be the optimal orientation of

the aryl group with respect to the amido ligand in order to maximize the overlap between

π orbitals and allow the electronic delocalization onto the aryl group, and actually the amido

group was found to be very far from coplanar with the aryl substituent (the dihedral angle

between amido and aryl planes has been found to be 79° for the trimethylphosphane derivative).

Presumably this large deviation from coplanarity is due to the steric hindrance imposed by the

bulky isopropyl groups, as it is typical of BIAN complexes. Therefore, the planarity at the amido

nitrogen in the sulfide and phosphane derivatives results at least in part from π−donation from

the amido group to the strongly π−acceptors CO ligands via the metal π orbitals.95

Figure 5. Molecular structure of the BIAN C-­C coupled product obtained by deprotonation of a

trimethylphosphane ligand.

29

5.4. Coupling between two monodentate heterocyclic ligands.

Most small molecules, and certainly most metal-­complexing ligands, are constituted by a few

building blocks;; therefore, a modular synthesis employing cross-­coupling reactions between

appropriate precursors could serve as a general synthetic approach.99 However, those

appropriate precursors must be reactive enough, so conventional cross coupling procedures

require first the preparation of functionalized versions of the individual building blocks. For

instance, in Pd-­catalyzed C-­C coupling schemes, one of the partners must be an electron rich

compound, such as a main group organometallic, organoborane, etc., while the other must be

an electrophile possessing a good leaving group, such a triflate or iodide (Scheme 14).

Scheme 14. General scheme of most late-­metal catalyzed C-­C coupling reactions.

That adds further complication to the whole synthesis and generates unwanted byproducts.

Some subunits, notably the 2-­pyridyl group, are particularly problematic.99 Pyridyl groups are

prevalent motifs in several types on natural and unnatural products, and in particular in

polydentate ligands. Several families of coordination compounds, and in particular rhenium

tricarbonyl complexes, which have been the focus of most of our work, are potentially useful due

to their catalytic, luminescent or anticancer properties.100,101 The several examples of inter-­ligand

C-­C coupling within the metal coordination sphere discussed above suggested to us the

possibility of employing similar schemes to assemble monodentate ligands, including pyridines,

without the need of any previous functionalization other than metal coordination. The synthesis

of polydentate ligands, especially non-­symmetric ones, is often a challenging task. In currently

employed methodologies, the free ligand is first synthesized and purified employing conventional

organic synthesis procedures, which are frequently tedious, multistep methodologies affording

a low overall yield and require separation of byproducts. Then, the ligand is reacted with an

appropriate metal source to afford the targeted metal complex. We envisaged an alternative

scheme in which small, non-­functionalized building blocks, like pyridines, imidazoles, etc., are

first coordinated to a metal center by simple substitution reactions. Preassembly of those

HetAr1 M + X HetAr2 HetAr1 HetAr2

30

subunits would be taken care of by the geometric preferences of the metal fragment. For

instance, the strong preference for a fac disposition of the three CO ligands in octahedral metal

complexes ensures that any two of the remaining coordination sites are mutually cis and thus

optimally placed for a C-­C coupling. Additional advantages of the metal coordination are an

enhanced acidity of the CH groups to be deprotonated and an enhanced reactivity of the

electrophilic counterpart, both leading to more reactive systems and thus to milder conditions,

which in turn would provide more selective reactions.

Rhenium tricarbonyl complexes containing two N-­alkyimidazole ligands and one pyridine were

synthesized by the reaction of [Re(CO)3(N-­RIm)2(OTf)] (which in turn is easily prepared from the

reaction of [Re(CO)5(OTf)] and N-­alkylimidazoles) with either pyridine or 4-­picoline and the

equimolar amount of NaBAr’4.102,103 The new precursors [Re(CO)3(N-­RIm)2(py)]BAr’4 (R= Me,

Mes) are readily prepared in a half-­gram scale, are relatively stable and can be kept for several

weeks in Schlenk flasks under a nitrogen atmosphere. A key for the success of the reactions

discussed below is that in solution, [Re(CO)3(N-­RIm)2(py)]+ complexes -­and, in general,

rhenium(I) tricarbonyl octahedral complexes-­ do not undergo ligand scrambling. Their reactions

with KN(SiMe3)2 in THF at -­78°C immediately afford solutions with νCO bands at lower

wavenumber values, consistent with deprotonation. The addition of silver triflate afforded

cationic products (Scheme 15).

Scheme 15. Imidazole-­pyridine cross-­coupling at a rhenium center.

The solid state structures of two of these products were crystallographically determined,

confirming the presence of a fac-­Re(CO)3 fragment bonded to an intact N-­alkylimidazole ligand

NN

N

R

R'

ReOCOC

CO

N

N

R

BAr'4

ReOCOC

CO

N N

N

R

R'

BAr'4

(ii) AgOTf

(i) KN(SiMe3)2N N R

R= Me, MesR' H, Me

31

and to a bidentate ligand formed by the coupling between the C2 positions of an N-­alkylimidazole

ligand and the C2 carbon of pyridine (Figure 6). This is consistent with the deprotonation of the

C2-­H group of the N-­alkylimidazole, followed by the intramolecular nucleophilic attack of the

deprotonated group on the C2 carbon (the most electrophilic position) of the monodentate

pyridine. The resulting bidentate ligand initially formed as the product of the C-­C coupling would

feature a dearomatized pyridyl ring, like those formed in the nucleophilic attacks to the pyridine

rings of the bidentate bipy or phen ligands discussed above. Subsequently, that ring would be

rearomatized by reaction with the one electron oxidant silver triflate. Such rearomatizations could

not be carried out with the products of coupling between a deprotonated N-­alkylimidazole and a

bidentate bipy or phen ligand discussed above, the likely reason being that the rigid fac-­

tridentate ligand formed as the product of the C-­C coupling cannot become planar, as it would

be required for rearomatization.

Figure 6. Molecular structure of a pyridylimidazole complex obtained by C-­C coupling of

imidazole and pyridine ligands.

The fact that two equivalents of silver triflate are needed suggest the participation of two one-­

electron oxidation events, in agreement with formal hydride removal. In the absence of

mechanistic studies, it is proposed that the neutral, dearomatized product of C-­C coupling is

oxidized by one equivalent of silver triflate to afford a radical cation, a species that would be

deprotonated to afford a neutral radical;; this would then be oxidized by the second equivalent of

32

AgOTf yielding the observed cationic complex. Since only one equivalent of KN(SiMe3)2 was

employed, the putative radical cation would be deprotonated by hexamethyldisilazane,

HN(SiMe3)2, which would have been formed as the product of the initial deprotonation by

KN(SiMe3)2.

The course of the reaction has been found to be the same for the N-­methylimidazole and N-­

mesitylimidazole ligands. No other organometallic compounds could be detected as reaction

products. Note that free pyridylimidazoles, which are often employed as ligands, are usually

prepared by de novo construction of the pyrazole ring. Compounds containing [Re(CO)3(N-­

RIm)(dmap)2]BAr’4 (R= Me, Mes, dmap= 4-­dimethylaminopyridine) cationic complexes were

subjected to the same deprotonation/oxidation sequence, affording single products from

coupling between the C2 positions of the N-­alkylimidazole and the pyridine (Figure 7). These

reactions selectively afford the products of cross-­coupling between one imidazole and one

pyridine, without homocoupling (complexes containing biimidazole or bipyridine ligands)

products, regardless of the particular composition of the cationic precursors: two imidazoles and

one pyridine, or two pyridines and one imidazole. This is attributed to the higher acidity of the

C2-­H group of the N-­alkylimidazole ligand and the higher electrophilic character of the pyridine

ligand. Note that even the relatively electron-­rich dmap ligand is electrophilic enough to undergo

the C-­C coupling reaction.

Figure 7. Solid-­state structure of the complex obtained by the cross coupling of dmap and N-­

MesIm starting from [Re(CO)3(N-­MesIm)(dmap)2]BAr’4.

33

The presence of an intact N-­alkylimidazole ligand in the cationic complexes formed in the

reactions of pyridine-­imidazole coupling and rearomatization suggested to us the possibility of

its deprotonation. The internal nucleophile presumably resulting from deprotonation of the C2

position of the monodentate N-­RIm ligand could attack either the pyridine or the imidazole ring

of the non-­symmetric bidentate ligand. Thus, the reaction of tricarbonyl rhenium

(imidazole)(pyridylimidazole) compounds with KN(SiMe3)2 afforded neutral (IR) products too

unstable for isolation and even for NMR characterization. These species were in situ protonated

with HOTf, affording stable products, which could be fully characterized (Scheme 16).

Scheme 16. C-­C coupling between a monodentate N-­RIm ligand and the pyridine ring of a

pyridylimidazole chelate.

The determination of its solid-­state structure by X-­ray diffraction established the protonation at

the nitrogen of the dearomatized ring, and the presence of a fac-­capping tridentate ligand

resulting from the coupling between the C2 position of the N-­RIm ligand and the ortho position

of the pyridyl ring of the bidentate ligand. The metrical data of the pyridyl ring indicate its

dearomatization, in agreement with the NMR solution data. When an analogous reaction was

conducted starting with the precursor containing an N-­MesIm monodentate ligand, the product

of its deprotonation was not stable enough for isolation, but could be characterized in solution,

and its spectroscopic data suggested deprotonation of the monodentate N-­RIm ligand and attack

to the 2-­pyridyl ring, leading to its dearomatization. The reaction of this neutral species with triflic

acid afforded a stable product (which was also crystallized and fully characterized) resulting from

protonation at nitrogen similar to the one previously discussed. These results indicate that the

NN

N

RRe

OCOC

CO

N

N

R'

+

NReOC

OC

CO

N

NR'

H

NN R

NReOC

OC

CO

N

NR'

H

NN RH

+

KN(SiMe3)2 HOTf

34

intramolecular attack by the deprotonated N-­alkylimidazole takes place selectively on the

pyridine ring, as no product of attack to the imidazole ring could be detected. Note that the full

sequence of reactions leading to these products with a tridentate ligand from the starting

complexes containing three monodentate N-­heteroaromatic ligands (two N-­alkylimidazoles and

one pyridine) involve two consecutive C-­C coupling events between the C2 carbons of the two

N-­alkylimidazoles and the two ortho positions of the pyridine ring.

The C-­C coupling methodology outlined above was extended (in spite of the lower acidity of

pyridines compared with N-­alkylimidazoles) to the coupling between two pyridine ligands to

afford complexes containing a 2,2’-­bipyridine ligand. Thus, when [Re(CO)3(dmap)3]OTf (which

was readily prepared from [Re(OTf)(CO)5] and dmap) was treated with KN(SiMe3)2 and then with

AgOTf, the single organometallic product was found to be [Re(CO)3(2,2’-­bipy-­4,4’-­

NMe2)(dmap)]OTf, which was fully characterized, including X-­ray diffraction. Compounds

[Re(CO)3(py-­R)3]OTf (py-­R= pyridine or 4-­methoxypyridine), prepared by the reaction of the

appropriate pyridine with the labile [Re(CO)3(DMSO)3]OTf compound, afforded [Re(CO)3(bipy-­

R)(OTf)] products resulting from the coupling of two of the coordinated pyridines to afford a bipy

ligand when treated first with KN(SiMe3)2 and then with HOTf (which has been found to be a

cleaner oxidant in this case than AgOTf). The product containing the parent 2,2’-­bipyridine

ligand, a known complex, was identified by comparison (IR and NMR) with a authentic sample,

and the product of C-­C coupling between two 4-­methoxypyridine ligands was fully characterized,

including X-­ray diffraction.

These results demonstrated that deprotonation of a pyridine ligand coordinated in the by far

most commonly encountered κ1-­(N) mode is feasible. This methodology for inter-­pyridine

coupling could be successfully extended to two different pyridine ligands, affording complexes

with non-­symmetric bipy ligands. Thus [Re(CO)3(dmap)2(py)]BAr’4 and [Re(CO)3(dmap)2(py-­4-­

OMe)]BAr’4 were prepared from addition of either pyridine or 4-­methoxypyridine to

[Re(CO)3(dmap)2(OTf)] in the presence of the equimolar amount of NaBAr’4. The deprotonation

of these mixed pyridine compounds with KN(SiMe3)2 followed by oxidation with AgOTf afforded

[Re(CO)3(dmap)(N-­N’)]BAr’4 compound featuring non-­symmetric 2,2’-­bipyridines resulting from

35

cross-­coupling between different pyridine ligands (Scheme 17). As in the formation of

compounds with pyridylimidazole complexes (see above), no formation of symmetric,

homocoupled (from coupling of two equal pyridines) could be spectroscopically detected.

Scheme 17. Synthesis of a non-­symmetric bipy ligand by C-­C coupling followed by oxidation.

The formation of bipyridines by C-­C coupling between two pyridyl groups on the coordination

sphere of group III complexes has been reported by Diaconescu et al.104,105 A difference with our

system is that whereas Diaonescu starts with the metallation of one pyridine to afford a κ2(C,N)

pyridyl ligand (see Scheme 18), we coordinated two neutral pyridine ligands in the κ1(N) normal

coordination mode and then reacted the resulting stable cationic complex with an external base.

Scheme 18. Coupling between two pyridine ligands on a scandium complex by Diaconescu et

al.

5.5. Ring-­opening of imidazole rings.

The study of the deprotonation of coordinated N-­akylimidazoles was extended to cationic fac-­

Re(CO)3 complexes containing three such ligands.106,107 This reaction produces neutral

(ii) AgOTf

(i) KN(SiMe3)2

R= H, OMe

ReOCOC

CO

ReOCOC

CO

N

N

N R

N

N

BAr'4

N

NR

BAr'4

NN

N

THF

Ar

LScN

Ph

THF

LSc

N

Ph

NLSc

N

N

Ph

H

L= fc[NSitBuMe2]2, fc= ferrocene 1,1'-diamideAr= 3,5-dimethylphenyl

36

imidazolyl complexes as it will be discussed in Section 6.2 for [Re(CO)3(N-­MeIm)3]OTf. In

contrast, if at least one of the imidazole ligands is an N-­arylimidazole, neutral complexes

resulting from intramolecular attack of the deprotonated N-­RIm ligand to the C2 carbon of one

of the other N-­RIm ligands, which as a consequence undergoes ring opening, are produced (see

Scheme 19). In the products, the 1,3-­diaza fragment resulting from imidazole ring opening

display a cisoid geometry as a result of an intramolecular hydrogen bond, shown in dashed line

in Scheme 19. Protonation or methylation of these products occurs at the non coordinated

nitrogen of the ring opened moiety, affording transoid products.

Scheme 19. Imidazole C-­C coupling and ring-­opening at Re(I) complexes.

Carver and Diaconescu have reported the ring opening of N-­methylimidazole upon reaction of

scandium or yttrium benzyl complexes with three equivalents of MeIm for 5 hours at 70° C

(Scheme 20).108 The authors propose that the reaction occurs via C-­H activation of one of the

imidazoles (to afford an imidazole-­imidazolyl intermediate which could be characterized for an

yttrium analogue).

+

NN

HN

N

RRe

OCOC

CO

N

N

R

ReOCOC

CO

N

NR´

N

N

R

ReOC

OC

CO

N

N

R

NN

N

N´´R

+

R

KN(SiMe3)2

R= R'= MesR= Mes; R'= Me

HOTf or MeOTf

R''= H, Me

N N

37

Scheme 20. Proposed mechanism for scandium-­mediated imidazole coupling and ring-­

opening by Diaconescu et al.

Electrophilic addition at the imine-­type nitrogen to generate an imidazolium cation, followed by

the attack of a nucleophile (usually hydroxide anion) at C2 has been proposed as the mechanism

for a number of imidazole cleavage processes, from the venerable Bamberger reaction109 to the

recent tandem ring opening of imidazoles with electron-­deficient acetylenes and water.110 Of

these reactions, particularly mild conditions (45-­60° C) have been reported for the later. N-­

alkylimidazoles metalated (e.g., lithiated) at C2 have been found to display considerable stability

towards ring opening in comparison with other metalated N-­heterocyles, allowing their

employment in reactions with organic electrophiles.93 Is somewhat surprising that, although N-­

THF

Ar N N

C6D672 ˚C, 5h

N

N

N

LSc N

3

N N2

LSc

N

N

N

NAr

1Sc-(imidazole)2

N N

2Sc-imidazole-mesitylene

LSc

N

N

N

N

N

N

LSc

N

N

N

N

N

N

3Sc-imidazolex

x = 0, 1

N N- x

4Sc1Sc-THF

LSc

L= fc[NSitBuMe2]2, fc= ferrocene 1,1'-diamideAr= 3,5-dimethylphenyl

38

alkylimidazoles have been widely employed as ligands, deprotonation of metal-­coordinated N-­

alkylimidazoles and the reaction of metalated N-­alkylimidazoles with transition metal complexes

remain very little explored.111

5.6. Couplings between N-­alkylimidazoles and imine ligands.

In contrast with the reactivity displayed by the rhenium complexes discussed above, the

deprotonation of [Mo(η3-­methallyl)(CO)2(bipy)(N-­RIm)]+ complexes yielded the neutral

imidazolyl complexes, discussed on Section 6.2, and no product of C-­C coupling could be

detected. DFT calculations, however, indicated that the energy differences between the pathway

leading to the observed imidazolyl product and that leading to attack on bipy is only 3.5

kcal/mol.112 That led us to synthesize several compounds of the type [Mo(η3-­

methallyl)(CO)2(pyridylimino)(MeIm)]OTf and study their deprotonation with KN(SiMe3)2,

expecting that the nonaromatic imine function would be more reactive than bipy and hence could

be the target of the deprotonated imidazole.113 Indeed, attack by the deprotonated imidazole C2

carbon to the nonaromatic imine carbon, as shown in Scheme 21 has been found to be the sole

product.

Scheme 21. Imidazole-­imine C-­C coupling and protonation of the resulting amido group to

afford cationic amino complexes.

DFT calculations showed that the products of C-­C coupling were the favored ones both

kinetically (they were formed in a process without computable barrier) and thermodynamically.

KN(SiMe3)2

Ar= C6H5, C6H4-4-Me, C6H3-3,5-Me2

HOTf

N

NMo

OCOC

N

N

OTf

Ar

N

N

OCOC Mo

OTf

NN

H

HR

N

N

OCOC Mo

NN

HAr

39

Some of the neutral C-­C products were found to be stable enough to permit isolations;; for those

too unstable, protonation at the nitrogen originating from the nonaromatic imine with HOTf

yielded stable cationic complexes that were isolated as triflate salts and could be fully

characterized. Since allylmolbdenum dicarbonyl complexes are not as substitutionally inert as

the Re(I) complexes discussed above, possible intermolecular pathways involving the transfer

of the monodentate imidazole (or deprotonated imidazole) ligands between metal centers were

considered as a possibility (note that imidazolate bridges have been found by Braunstein,

Danopoulos and co-­workers).111 They, however, were ruled out by a crossover experiment in

which a mixture of two compounds having different pyridylimine and N-­alkylimidazole ligands

was treated with KN(SiMe3)2 afforded only the products of intramolecular C-­C coupling (Scheme

22).

Scheme 22. Crossover experiment showing the intramolecular nature of the N-­RIm-­imine

coupling reactions.

5.7. Coupling between N-­alkylimidazoles and nitriles or isonitriles.

Nucleophilic attacks on the sp-­hybridized carbon atom of nitrile and isonitrile ligands are well

known, so in principle the coupling between these unsaturated ligands and C2-­deprotonated N-­

alkylimidazole co-­ligands could offer a potential pathway to access new anisobidentate chelates

Ar= C6H4-4-MeR= iPr

N

NMo

OCOC

N

N

Me

OTf

+

(i) KN(SiMe3)2(ii) HOTf

N

N

OCOC Mo

OTf

NN

H

H

+

Not observed:

Ar

Me

Ar

N

NMo

OCOC

N

N

Et

OTf

R

N

N

OCOC Mo

OTf

NN

H

H

Et

RN

N

OCOC Mo

OTf

NN

H

H

Me

R

N

N

OCOC Mo

OTf

NN

H

H

Et

Ar

40

within the coordination sphere of a metal.114 Two possible difficulties were considered, one for

each type of monodentate unsaturated ligand: nitriles are labile;; therefore, attack to the metal

by either the base or the deprotonated N-­RIm ligand could compete with attack at the

coordinated nitrile;; as for isonitriles, the planned attack at the metal-­bonded carbon atom would

afford a four member ring, perhaps of limited stability;; note that such a product would be

comparable (carbonyl and isonitrile ligands are isoelectronic) to the computationally

encountered (but not stable enough for spectroscopic detection) intermediate in the reaction

leading to imidazolyl complexes, which is formed via C-­C coupling between a CO and the C2-­

deprotonated N-­RIm ligand.

Nitrile and isonitrile compounds were prepared by the reaction of complexes [Re(CO)3(N-­

RIm)2(OTf)] with pivalonitrile or tert-­butylisocyanide and the salt NaBAr’4 in dichloromethane.115

Employing the later as a triflate abstractor is based on the low solubility of sodium triflate in

dichloromethane, and is needed to achieve the displacement of triflate from the cationic complex

by the poor donor nitrile, or by the low-­nucleophilic isonitrile.

The [Re(CO)3(N-­RIm)2(tBuCN)]BAr’4 and [Re(CO)3(N-­RIm)2(tBuNC)]BAr’4 compounds, which

could be isolated and characterized, instantaneously reacted with KN(SiMe3)2 in THF at low

temperature to afford, as indicated by the change in the color and the IR spectrum of the solution.

For the nitrile complexes, the limited stability of the neutral (as judged by their νCO IR bands)

products precluded their isolation and even in situ NMR characterization. Reaction of these

neutral species with MeOTf or HOTf afforded cationic complexes, which were isolated and fully

characterized (see Scheme 23). Their NMR data are in agreement with the initial deprotonation

of the N-­alkylimidazole ligand at its C2-­H position and subsequent attack of the “internal

nucleophile” to the α carbon of the nitrile. The result of the C-­C coupling reaction would be the

formation a five-­member chelate ring featuring an alkylideneamido (N-­metaloimine,82

ketimide116) donor group. A rhenium tricarbonyl complex has been found to be one of the very

few highly reactive -­yet isolable-­ alkylideneamido complexes,82 in contrast with the chemical

inertness displayed by these ligands when coordinated to most other fragments.116 A similar high

reactivity may be the origin of the instability of the products of the deprotonation of [Re(CO)3(N-­

41

RIm)2(tBuCN)]BAr’4 (Scheme 23). Methylation of the alkylideneamido nitrogen would produce

stable, cationic imino complexes. Treatment of the solutions containing the neutral unstable

intermediate with triflic acid afforded similar products, resulting from protonation at nitrogen. The

structure of one these protonated derivatives, solved by X-­ray diffraction (see Figure 8), helped

to establish the reactivity pattern sketched above.

Scheme 23. Rhenium-­mediated couplings between imidazole and nitrile (top) or isonitrile

(bottom) ligands.

ReOCOC

CO

N

N

N

R

C

tBu

BAr´4

ReOCOC

CO

N

N

N

R

C

tBu

R'

KN(SiMe3)2R'OTf

BAr´4

ReOCOC

CO

LN

N

R

ReOCOC

CO

CN

NN

NR

RN

tBu

ReOCOC

CO

CN

NN

NR

RN

tBu

HOTf

H

OTf

KN(SiMe3)2

L= tBuCN

L= tBuNC

L= tBuCN, tBuNCR= Me, Mes

N N R

N N R N N R

R'= H, Me

42

Figure 8. Molecular structure of the protonated final C-­C coupling product between N-­MesIm

and tBuCN.

The products of the deprotonation of the isonitrile complexes were found to be stable both in

solution and in the solid state and could be completely characterized, including the X-­ray

structural determination of one of the derivatives (Figure 9). They result from the coupling

between C2(imidazole) and the isonitrile carbon, resulting in the formation of four member

chelates, consisting of an imidazole and a κ1(N)-­iminoacyl donor groups (Scheme 23). Note that

complexes with κ1(N)-­iminoacyl ligands are relatively rare, as most iminoacyls are κ2(N,C)-­

coordinated to early transition metals. Reaction of these complexes occurred at the iminoacyl

nitrogen, resulting in the formation of cationic aminocarbenes (see Scheme 23). It is interesting

to note that the conceptually simple synthesis of non-­heterocyclic carbenes by successive

additions of a nucleophile and an electrophile to isonitriles remains little explored. The discussed

results show that the intramolecular C-­C coupling initiated by C2-­deprotonation of N-­

alkylimidazole ligands can lead to the formation of four member rings and to the attack on usually

labile nitriles. In addition, the reactions are selective, affording the described products, and not

the foreseeable products of attack on CO ligands or N-­alkylimidazole co-­ligands.

43

Figure 9. Molecular structure of the C-­C coupling product resulting of the deprotonation of the

isocyanide compound [Re(CO)3(N-­MesIm)2(tBuNC)]BAr’4.

5.8. Deprotonationof N-­alkylimidazole ligands in phosphane-­carbonyl complexes

In view of the previously discussed results, which show that even notoriously inert co-­ligands

such as bipy and phen can be the target of deprotonated N-­alkylimidazole ligands, we set out to

explore the deprotonation of N-­alkylimidazole ligands in carbonyl complexes containing only

phosphane co-­ligands.117 Since the later cannot be the site of nucleophilic attack, we anticipated

the possibility of obtaining products of attack on the CO ligands. As mentioned above, such an

attack has been computationally found to yield intermediates in the formation of imidazolyl

complexes, but stable products of the intramolecular attack of deprotonated N-­RIm ligands on

carbonyl co-­ligands were not observed previously.

The deprotonation of a coordinated N-­methylimidazole ligand in cationic Re(I) tricarbonyl

phosphane complexes [Re(CO)3(MeIm)2(PR3)]BAr’4 employing the amide KN(SiMe3)2 showed a

dramatic dependence on the nature of the phosphane. Thus, whereas for trimethyphosphane

complexes, imidazolyl products were obtained, when the phosphane is either

triphenylphosphane or methyldiphenylphosphane, the deprotonation followed by methylation

with excess MeOTf reaction afforded the mixture of products shown in Scheme 24.

44

Scheme 24. Reactivity of [Re(CO)3(MeIm)2(PR3)]BAr’4 with the strong base KN(SiMe3)2.

Compound 15, which is the major product of the reaction, contains a binuclear cationic complex

resulting from a double activation of a N-­methylimidazole ligand. Its structure (Figure 10 shows

the X-­ray structure of the cation of the triphenylphosphane derivative) suggests that the C2

carbon of the deprotonated imidazole attacks one of the cis CO ligands, forming a four-­member

metallacycle. Methylation of the oxygen of the involved carbonyl generates a methoxycarbene

moiety. The same imidazolate ring binds the second rhenium fragment as an abnormal nitrogen-­

heterocyclic carbene through its C5 position, indicating a double imidazole deprotonation. This

second rhenium center completes its coordination sphere with one phosphane, two carbonyls

and an N, N’-­bidentate ligand that results from the formal coupling of a molecule of CO (from the

carbonyl ligand missing at this rhenium center), one imidazole and one imidazolyl ligand. The

oxygen atom of the CO molecule involved in this coupling has been methylated, so the carbon

atom originating from CO is now sp3-­hybridized. The minor product (16 in Scheme 24) contains

a cationic complex with two cis carbonyls, two trans phosphanes and a chelate bis(C-­

imidazolyl)ketone ligand similar to the one just described for the binuclear complex, but without

methylation at oxygen.

BAr´4

ReOCOC

CO

N N

NPRPh2

MeN

Me

(i) KN(SiMe3)2

(ii) MeOTf N

NN

N

Re

PRPh2

OC

OC

PRPh2

C O

Me

Me

Ph2RPRe

CO

C

CO

N

NN

N

Re

PRPh2

OC

OC CH

Me

OMeMe

N

N Me

OMeNNMe

+

BAr´4

BAr´4

R= Me, Ph14 15 16

45

Figure 10. Molecular structure of the cation present in compound 15.

When compound 14 was deprotonated using n-­butylllithium instead of KN(SiMe3)2, the product

was a neutral imidazolyl complex which turned out to be too unstable for isolation. Its reaction

with triflic acid afforded a stable, cationic complex featuring an NH-­NHC ligand (Scheme 25),

which could be crystallized as its triflate salt and characterized in the solid state by single-­crystal

X-­ray diffraction, and in solution by IR and NMR. This difference in reaction outcome as a

function of the base employed suggests a relative stabilization of the deprotonated N-­

methylimidazole as a result of the interaction of its C2 carbon atom with lithium, a smaller, more

polarizing cation than potassium.

Scheme 25. Transformation of a N-­MeIm ligand in a NH-­NHC by a deprotonation/protonation

sequence.

+

ReOCOC

CO

N N

NPPh3

MeN

Me

ReOCOC

CO

N

NPPh3

MeN NMe

+

ReOCOC

CO

N

NPh3

MeN NMe H

BuLi HOTf

46

The formation of the products 15 and 16 obviously involved complex, multistep reactions, and

proposing a meaningful mechanistic sequence would require additional work. Nevertheless, the

outlined results demonstrate several points, including the deprotonation of N-­alkylimidazole at

C5 and subsequent formation of “abnormal” nitrogen-­heterocyclic carbenes, the formation of

alkoxycarbenes via intramolecular attack of a C2-­deprotonated N-­alkylimidazole ligand to a CO

co-­ligand, the CO activation by the attack of two C2-­deprotonated N-­alkylimidazole ligands, and

the dramatic effect of the employed strong base on the nature of the products.

6. Metal-­mediated tautomerization of N-­heterocycles to NHC complexes.

As we have mentioned above, the coordination of organic molecules to transition metals can be

used as a pathway to activate them. In certain instances, a dramatic modification of its nature is

found to be the consequence of such coordination. A well established example of this concept

is the metal-­induced acetylene to vinylidene tautomerization (Figure 11). This process has been

studied, both theoretically and experimentally, and an activation barrier of 76 kcal·mol-­1 has been

found, the vinylidene species being 44 kcal·mol-­1 less stable than the acetylene isomer. 118 In the

presence of a number of metal fragments the process becomes thermodynamically favored and

kinetically available, affording the corresponding vinylidene metal complexes, the relative energy

of the two tautomers being inverted. 119

Figure 11. (a) Acetylene-­vinylidene isomerization. (b) Metal-­induced acetylene to vinylidene

tautomerization.

CC RH C CH

R

C

C

R

H

C CH

RLnM LnM

(a)

(b)

47

6.1. Tautomerization of pyridines.

The possible isomerization of pyridine to its 2-­carbene tautomer120 was first proposed by

Hammick as early as in 1937,121 but it took over 60 years to prove its existence. This type of

tautomerization is frequently the key step in important biological processes, where the

energetically less stable tautomer is often responsible for the biological activity.122 The extremely

unstable pyridyl-­2-­ylidene was generated in the gas phase by Schwarz et al, and characterized

by means of mass spectroscopy. 123 Pyridin-­2-­ylidines are more than 40 kcal·mol-­1 less stable

than pyridines, but coordination to transition metal fragments can strongly stabilize them. In 1987

Taube published the first pyridine carbene complex synthesized in solution, a 2,6-­lutidinium ylide

coordinated to Os(II) through the para carbon (Figure 12).51 In the last 10 years the number of

pyridylene complexes has increased considerably, probably due to the use of different strategies

to provide an additional stability to the carbenic species.

Figure 12. First metal-­pyridylene complex synthesized by Taube et al.

In 2006 Carmona, Poveda et al. achieved the tautomerization of 2-­substituted pyridines into the

carbene tautomers mediated by the [TpMe2Ir(C6H5)2N2](TpMe2= hydrotris(3,5-­

dimethylpyrazolyl)borate) fragment (Scheme 26).124 The steric hindrance provided by the

substituents at the 2-­position precluded the formation of the (κ1,N)-­coordinated pyridine

complexes while the formation of the N-­heterocyclic carbenes was not affected by this issue, as

the substituent in the 2-­position is away from the coordinated carbon atom.

Scheme 26. Formation of Ir(III) pyridylene complexes from 2-­substituted pyridines.

N[Os] H

[Os]= Os(NH3)4(NCMe)2+

[Ir]Ph

Ph N2+

N R [Ir]Ph

Ph N R

H

C6H6

[Ir]= TpMe2Ir R= Me, Ph, tBu, NMe2

60-90 ºC

48

Concurrently, in the research group of Esteruelas stable carbene tautomers of quinoline and 8-­

methylquinoline were synthesized by coordination to osmium-­ and ruthenium-­chloro

complexes.125 It is interesting to note that an increased stability of the resulting NHC complexes

is provided by an intramolecular NH···Cl interaction between the NH group and a chloride ligand

coordinated to the same metal atom (see Figure 13a). The bulkiness of the substituent and the

co-­ligands, along with an intramolecular hydrogen bond are also crucial in the formation of a

carbene tautomer of 2-­ethylpyridine bonded to a hydride osmium(II) complex (Figure 13b).126

Figure 13. Stabilization of N-­heterocyclic carbene complexes by intramolecular hydrogen

bonds.

There is just one example of a non-­substituted pyridylidene complex obtained as a 1:1 mixture

together with the N-­adduct (Scheme 27).127 This outstanding transformation was mediated by

an iridium complex featuring two Ir-­CH2 bonds that resulted from the metallation of two methyl

groups of mesityl substituents of the trispyrazolylborate ligand (TpMs= hydrotris(5-­

mesitylpyrazolyl)borate). The presence of an Ir-­CH2 bond within a chelate is essential for the

tautomerization process.

+

N

M= Ru, Os

(a)

[MH2Cl2(iPr3P)2]

R

N

[M]

R

HCl

(b)BF4

N

Os

HH

NCMe

MeCN

PiPr3

Pr3iP

49

Scheme 27. Tautomerization of non-­substittuted pyridine achieved by Carmona et al.

In contrast, there are some examples in which parent pyridylidenes have been implicated in the

functionalization of pyridines.128-­132 In this context Bergman, Ellman and coworkers found that

the formation of the Rh-­NHC complex 18 via C-­H bond activation of the heterocycle 17 (see

Scheme 28) was the key step in the Rh-­catalyzed coupling of N-­heterocycles and olefins.129 The

1,2-­hydrogen shift involved in this process was studied in detail, using experimental and

computational methods, and an intramolecular hydrogen transfer pathway through Rh-­H

intermediates was found to be the more plausible mechanism.

Scheme 28. C-­H activation of N-­heterocycle 17 by a Rh(I) complex.

Tautomerization of 2-­substituted pyridines to NH-­N-­heterocyclic carbenes induced by

TpMe2Ir(III) fragments (mentioned above) has been extended to the broadly used 2,2’-­bipyridine

and 1,10-­phenanthroline ligands.133 A new and unexpected coordination mode was found as

monohapto N-­heterocyclic carbenes, in which an intramolecular hydrogen bonding between the

NH unit of the coordinated ring and the imine-­type N atom of the other ring adds stability to these

species (Figure 14, complexes 19 and 20). A similar thermal activation was published for

terpyridine which is able to act as a mono-­ or bidentante NHC towards one or two metal atoms.134

A couple of examples have been published where chelation is the driving force to successfully

achieve the tautomerization of a pyridine moiety.135,136 An example of this strategy is shown in

TpMs''Ir(N2) +

NC6H6

TpMs''= dimetalated TpMs

60 ºC NTpMs''Ir

N

TpMs''Ir

H

+

TpMs= hydrotris(5-mesitylpyrazoly)lborate

+0.5 [RhCl(coe)2]2N

N

CH3

17

THF

75 ºC2 PCy3+

N

N

CH3

18

Rh

PCy3

PCy3 ClH

50

Figure 14 (complex 21) in which an Ir(I) fragment allows the formation of a stable metalacycle

upon α-­CH activation of 1,9-­phenanthroline.

Figure 14. Pyridylene tautomers of 2,2’-­bipyridine (complexes 19 and 20). Tautomerization of

1,9-­phenanthroline aided by the chelation effect (structure 21).

6.2. Tautomerization of imidazoles.

In spite of the higher stability of imidazole-­2-­ylidenes and their metal complexes, tautomerization

of imidazoles to the corresponding NHCs are also scarce processes. The relative stability of

imidazole N-­ or C-­metal bound isomers was computationally studied by Crabtree and Einsentein,

who found a strong dependence on the nature of the metal fragment. 137 Sundberg et al.

published in 1974 the first example of N-­ to C-­ tautomerization of an imidazole ligand mediated

by a Ru(II) complex (Scheme 29), but an acidic media was needed and very low yields were

obtained.138

Scheme 29. First example of a metal-­mediated imidazole to NH-­NHC tautomerization.

The only other example of tautomerization of a non-­chelated imidazole ligand to its NHC form

was proposed by Bergman and Ellman in their studies of Rh(I) catalyzed C-­C coupling between

alkenes and benzimidazole.139 The NHC is formed in situ via C-­H activation of the heterocycle

[Ir]

PhPh

N

N

H

[Ir]

N

N

H

N

N

[Ir]

H

[Ir]= TpMes2Ir [Ir]= Ir(COD)(PPh3)

19 20 21

NN H

R1 R2

[Ru] 2+

H+N

N

[Ru]

H

H

2+

R2

R1

[Ru]= Ru(NH3)5

51

(Scheme 30) being one of the first examples in which a NHC plays a non ancillary role in a

catalytic transformation.

Scheme 30. Isomerization of a benzimidazole derivative to its NHC isomer promoted by Rh(I).

The additional stability gained because of the formation of a bidentate chelate ligand has been

used to achieve imidazole to NHC tautomerization for a N-­phosphane-­functionalised imidazole

in the presence of iridium140 and ruthenium141 metal fragments (structure 22 in Figure 15). An

analogous activation occurred when 2-­pyridylbenzimidazole is refluxed in THF with [RuCp*Cl]4

to afford the 5-­membered chelate complex 23 depicted in Figure 15,142 or in the reaction of an

N-­arylimine-­functionalized imidazole with [Ir(cod)(µ-­Cl)]2 aided by a halogen abstractor to afford

complex 24 (Figure 15).143 The reverse tautomerization, i. e. from NH-­NHC to imidazole ligands

mediated by these two metals (Ir and Ru) have also been reported by Whittlesey144 and Li145.

Figure 15. Examples of tautomerization of N-­alkylimidazol derivatives to NH-­NHCs assisted by

chelation.

The groups of Siebert146 and Erker147 studied the reactivity towards a strong base of imidazole-­

borane adducts, showing that for the BH3 moiety the anionic 3-­boraneimidazol-­2-­ylidene could

be isolated (structure 25 in Scheme 31), whereas migration of BR3 (R=Et, C6F5) groups to the

PCy3

N

N

+ [RhCl(COE)2]2THF, 75 ºC

N

N

Rh PCy3

ClH

PPh2

Mn+

LCl

N

NH

tBu

22

M= Ru; L=Cp; n=0M= Ir; L= Cp*; n=1

Ru

Cl

Cp*

N

N

N

H

23

N N H

N [Ir]Ar

24

[Ir]= Ir(COD)Ar= 2,6-iPr2(C6H5)

+

52

carbene carbon atom was observed for trialkyl-­ or triarylborane reagents (complex 26 in Scheme

31).

Scheme 31. Reactivity of imidazole-­borane adducts studied by Siebert and Erker.

As we have mentioned above, in the last years our research interest has been focused on the

deprotonation of N-­alkylimidazole ligands coordinated to organometallic fragments. A cationic

metal complex bearing a N-­RIm ligand can be regarded as a N-­metallated imidazolium salt

(Figure 16), and therefore the deprotonation of the central imidazole CH group would afford a

NHC in an analogous manner to the most general method used to prepare imidazol-­2-­ylidenes

from imidazolium salts. Our results show that the species resulting from such deprotonation

reaction are very reactive, mainly because of their high nucleophilic behavior, and their evolution

strongly depends on the nature of the metal fragment and its coligands, as well as on the

substituent of the imidazole.

Figure 16. Analogy between an imidazolium salt (A) and a cationic imidazole metal complex

(B).

The reaction of [Re(CO)3(N-­MeIm)3]OTf (27) with the equimolar amount of KN(SiMe3) afforded

a neutral imidazol-­2-­yl product, 28 (Scheme 32).106,107 The formation of 28 implies, once the

deprotonation has occurred, the isomerization of the heterocyclic ligand from the N-­ to the C-­

rhenium bonded species. Examples of this type of complexes, which feature a C-­bonded

BuLi

R'

R'

N

N

BR3

R'

R'

N

N

BR3

Li

R'

R'

N

NR= Et, C6F5

BR3

R= H

25 26

N NR R'

+

N NR [M]

+

A B

53

imidazol-­2-­yl ligand with a non-­substituted nitrogen, are very rare.116,140-­142,146-­148 In addition,

these species tend to be elusive and have been previously proposed for the tautomerization of

N-­alkylimidazole to NHC ligands.91 Compound 28 reacts smoothly with electrophiles, such as

HOTf, to afford the product of protonation on the non-­coordinated nitrogen, compound 29

(Scheme 32). The overall transformation from compound 27 to 29 can be seen as a

tautomerization of an imidazole to a NH-­NHC ligand promoted by a strong base, complex 28

being a stable intermediate. This reaction sequence is reminiscent of the mechanism proposed

by Ruiz for the transformation of an imidazole into an NHC ligand at a Mn(I) center,91 although

in that case the authors could not isolate the neutral complex (analog to 28), probably due to its

lower stability.

Scheme 32. Tautomerization of a N-­methylimidazole ligand promoted by a

deprotonation/protonation sequence.

In compound 28 the heterocyclic ligand is an imidazol-­2-­yl, but its structural and spectroscopic

properties are very close to those of the rhenium N-­heterocyclic carbene compound 29 (see

Figure 17). Thus the Re-­C1 distances are undistinguishable (2.190(7) Å in 28, and 2.191(5) Å

in 29) and the 13C NMR chemical shifts for the Re-­bonded carbon are182.4 (28) and 178.7 ppm

(29). The rest of the metrical data for the N-­heterocyclic ligand show a high electronic

delocalization for both complexes. Also noteworthy is the similarly high trans influence, reflecting

the high donor ability of both C-­bonded N-­heterocyclic ligands as judged from the Re-­C11 bond

distances (1.958(7) Å for 28 and 1.945(6) Å for 29), compared with the other Re-­Ccarbonyl bond

distances (1.901(5) Å for 28, and 1.916(6) Å for 29). The presence of a hydrogen atom on N2 in

28 is the only difference between the metallic complexes present in 28and 29, and it was

OTf

ReOCOC

CO

N

N

N

NN

NRe

OCOC

CO

N

NN

N

N N

28

KN(SiMe3)2 ReOCOC

CO

N

NN

N

OTf

29

N N

27

H

HOTf

54

confirmed by a topological analysis of the Laplacian of the electron density (∇2ρ). This study

indicated the presence of an in-­plane lone pair at N2 in complex 28 and of an N-­H bond in 29,

as well as the electron delocalization mentioned above.

Figure 17. NMR and structural similarities between imidazole-­2-­yl and NH-­NHC ligands

coordinated to Re(CO)3(N-­MeIm)2 fragment.

In contrast, complexes [Re(CO)3(N-­MeIm)x(N-­MesIm)3-­x]+ (x= 1, 2), with at least one N-­

arylimidazole ligand, led, after deprotonation reaction, to the C-­C coupling and ring-­opening

products,106 as it has been mentioned in Section 1.3.

On the other hand, the related neutral complex [Re(OTf)(CO)3(N-­MeIm)2] (30) reacted

instantaneously with KN(SiMe3)3 to yield compound 31 (see Scheme 33).149

Scheme 33. Tautomerization of two N-­MeIm ligands promoted by a single equivalent of base.

The new complex contained a fac-­Re(CO)3 fragment bonded to one N-­MeIm ligand, one

imidazol-­2-­yl-­ligand and one NH-­NHC ligand, the last two resulting from N-­ to C-­coordination

change of two N-­MeIm ligands. The N-­H group of the NH-­NHC ligand acts as hydrogen bond

ReOCOC

CO

OTf N

NN

N NN

H

NN

ReOCOC

CO

N

N

KN(SiMe3)2N-MeIm

HOTfN

NHRe

OCOC

CO

N

N

N

HN

OTf

30 31 32

55

donor towards the non-­coordinated nitrogen of the imidazol-­2-­yl ligand, contributing to the

coplanarity of the two heterocyclic ligands (as shown in Figure 18 for the analogous mesityl

derivative). A molecular mirror plane is evident from the NMR spectra of 31, indicating the fast

(even at low temperature) H+ transfer between the two nitrogens, i.e., the complex can be

described as featuring two imidazol-­2-­yl ligands that share a proton. The Re-­bonded carbon of

these ligands occurs at 180.7 ppm in the 13C NMR spectrum, and the two Re-­C bond distances

are undistinguishable (Re-­C2 2.214(10) and Re-­C22 2.207(9) Å), showing the close similarity

between imidazol-­2-­yl and NH-­NHC ligands. The yield of 31 notably increased when its

preparation was conducted in the presence of the equimolar amount of N-­methylimidazole (N-­

MeIm), as expected since, in its absence, part of the bis(imidazole) precursor 30 must have

acted as a sacrificial source of N-­MeIm.

Figure 18. Molecular structure of the mesityl derivative analogous to compound 31.

Density functional theory (DFT) calculations about the reaction mechanism showed that the most

favorable one is that shown in Scheme 34. The Gibbs free energy in THF solution (in

parentheses) is referred to that of the deprotonated species [Re(OTf)(CO)3(N-­MeIm)2]-­ (structure

I, Scheme 34) and N-­MeIm. The reaction starts with loss of triflate from I to give intermediate IIa

in which the Re atom is simultaneously interacting with the non-­coordinated N atom and the C-­

2 atom of the imidazolyl ligand. Intermediate IIa undergoes a rotation of the imidazole ring

56

around the N-­Re bond through TS-­IIa/IIIa to give the intermediate IIIa. TS-­IIIa/IVa connects IIIa

with intermediate IVa wherein the two heterocyclic ligands are C-­bound to the Re atom. Finally,

addition of N-­MeIm to IVa leads to the formation of a rhenium imidazol-­2-­yl(carbene) complex

Va without any transition state. The formation of the rhenium imidazolyl-­carbene complex would

imply a Gibbs energy barrier in solution of 21.5 kcal/mol, consistent with the fast formation of the

product experimentally observed. A key feature of the proposed mechanism is the intermediacy

of η2-­N,C-­imidazolyl complexes, which make possible ligand dissociation without going through

high-­energy five-­coordinate species. Stable η2-­N,C-­imidazolyl complexes have been disclosed

by Diaconescu et. al.in scandium and uranium chemistry.150

Scheme 34. Proposed (based on DFT computations) mechanism for the formation of

imidazolyl-­NHC complex 32 from the neutral bis(imidazole) derivative 30.

The reaction of 31 with trifluoromethanesulfonic acid (HOTf) afforded 32, the triflate salt of the

bis(NH-­NHC) complex resulting from protonation at nitrogen (Scheme 33). The overall formation

of 32 from 30 involves, besides the substitution of OTf by the entering imidazole, the formation

of two new Re-­C bonds at the expense of the two Re-­N bonds. As we have discussed above,

deprotonation of a coordinated N-­MeIm ligand in [Re(CO)3(N-­MeIm)3]OTf followed by

protonation of the resulting imidazol-­2-­yl ligand affords a NHC complex (see Scheme 32). The

ReOCOC

CO

OTf N

N

I (0.0)

NN

- OTf

-

N

N

ReOCOC

CO

NN

TS-IIa/IIIa(-16.6)

N

N

ReOCOC

CO

NN

H

TS-IIIa/IVa(3.8)

N N

NN

H

ReOCOC

CON

NH

NN

ReOCOC

CO

N

N

N-MeIm

IIa (-17.2) IIIa (-17.7)

IVa (-10.5)Va (-21.8)

57

formation of the bis(carbene) complex from the bis(imidazole) precursor is not just twice that

process, because the addition of only one equivalent of base triggers the Re-­N to Re-­C

rearrangement of two imidazole ligands. It is also noteworthy that in the deprotonation reactions

of a) the tris(N-­MesIm) compound, or b) the triflato complex 30 in the presence of free N-­MesIm,

the components of the reactant mixture are the same, whereas different isomers are obtained

as products. The formation of the ring-­opening product in the former case or the imidazolyl-­

carbene in the later shows again the extreme sensitivity of the reaction course to the exact nature

and number of the ligands.

The wide variety of products obtained from the reactivity of the rhenium compounds prompted

us to extend our studies of deprotonation of N-­alkylimidazole ligands to molybdenum

organometallic species.112 The chosen cationic compounds of formula [Mo(η3-­

C4H7)(bipy)(CO)2(N-­RIm)]OTf feature, like those of rhenium, pseudooctahedral structures in

which the imidazole and each ring of the bipy ligand are in cis positions. The addition of a strong

base to [Mo(η3-­C4H7)(bipy)(CO)2(N-­RIm)]+ complexes, followed by protonation or alkylation of

the resulting neutral product, leads to the formation of Mo-­NHC compounds (Scheme 35). This

reactivity constitutes another example in which the addition of a strong base, followed by an acid

promotes the tautomerization of an N-­alkylimidazole ligand to NH-­NHC.

Scheme 35. Synthesis of imidazol-­2-­yl and NHC complexes from N-­alkylimidazole ligands

coordinated to Mo(η3-­C4H7)(bipy)(CO)2 fragment.

In agreement with the experimental results, a DFT study showed that the most favorable reaction

mechanism for the Mo(II) complexes consisted in an initial attack of the imidazole deprotonated

N

N

OCOC

OTf

Mo

N

N

R

THF, -78 ºC

KN(SiMe3)2

N

N

OCOC Mo

N NR

CH2Cl2

R'OTf

N

N

OCOC Mo

N NRR'

OTf

N = 2,2'-bipyridineNR= Me, MesR'= H, Me; Et

58

carbon atom onto a cis-­CO ligand, to afford in a second step imidazol-­2-­yl species (Figure 19).

This mechanism is reminiscent of the one found for [Mn(bipy)(CO)3(N-­RIm)]OTf compounds,151

suggesting that this new and unexpected ‘carbonyl mechanism’ can be quite general for related

transformations. As it is shown in Figure 19, pathway A, that led to the C-­C coupling product, is

favored over pathway B, which affords formation of the imidazole-­2-­yl complex, by only 3.5 kcal

mol-­‐1. In addition to this, the formation of Mo-­IIb (-­7.0 kcal mol-­1) implies a Gibbs energy barrier

of only 4.8 kcal mol-­1, which is clearly lower than the one required for obtaining Mo-­IIa (8.3 kcal

mol-­1). The better kinetic accessibility of Mo-­IIb in conjunction with the fact that its evolution to

Mo-­IIIb shows a Gibbs energy barrier in solution (11.8 kcal mol-­1) ) clearly lower than that for the

reversion to Mo-­IIa (15.3 kcal mol-­1) via Mo-­I, and that the Mo-­IIIb product is considerably stable

(13.4 kcal mol-­1), make B the most favorable pathway, affording the formation of imidazol-­2-­yl

products instead of the C-­C coupling species, as it is encountered experimentally.

Figure 19. Schematic view of the reaction mechanisms found for the deprotonation reaction of

[Mo(η3-­C4H7)(bipy)(CO)2(N-­MesIm)]+ at the B3LYP/6-­31G(d) (LANL2DZ for Mo) level of theory.

59

In 2013 Darensbourg evidenced the occurrence of a base-­promoted conversion of a N-­

alkylimidazole ligand to the corresponding NH-­NHC mediated by a dinitrosyl iron complex.152

6.3. Tautomerization of other azoles.

Compared with imidazol-­2-­ylidenes less attention has been paid to N,X-­heterocyclic carbenes

(X= O, S), mainly due to the instability of the free ligands which easily undergo dimerization

processes.153 A probably better alternative would be to force the tautomerization of the

coordinated azole ligand upon a deprotonation/protonation (or alkylation) sequence as that

described above for N-­alkyilimidazole ligands. This method is illustrated in Scheme 36 for

Mn(azole)(CO)3(bipy)+ (azole= oxazole, thiazole) complexes to afford the corresponding

heterocyclic carbenes.154 Prior to this work, deprotonation of 4-­methylthiazole155 or

benzothiazole156 ligands coordinated to Cr(CO)5 followed by methylation had led to the

formation of the carbene complexes, but lack of selectivity had been observed as the

dimethylated azole complexes were also obtained.

Scheme 36. Tautomerization of oxazole and thiazole to the corresponding carbene derivatives

at a Mn(I) fragment.

7. Metal-­ligand cooperation based on aromatization/dearomatization processes.

The chemical behavior of transition metal complexes is dramatically dependent on the steric and

electronic properties of the ligands coordinated to the metal center. Modification of the ligands

properties has been used as a tool to improve the desired properties of metal complexes

depending on the particular processes, i. e. increasing its electrophilic/nucleophilic, basic/acid

KOtBu

X

N

[Mn]

X

N

X

NNH4PF6

[Mn][Mn]

+H

+

[Mn]= Mn(CO)3(bipy)

X= O, S

60

character, etc. A particular area in which this concept has been broadly used is in homogeneous

catalysis. In the vast majority of reactions catalyzed by metal complexes, the catalytic activity is

primarily based on the metal while the ligands are considered as spectators, as they do not

participate in the chemical transformations directly. In the last decade the development of

bifunctional catalysts has gained interest showing that the metal center and its coordinated

ligands can jointly cooperate in the catalytic cycle.157 A particular case of this type of metal-­ligand

cooperation (MLC), studied by Milstein et al., is based on dearomatization/aromatization

processes on the ligand. These studies have been comprehensively covered in several recent

reviews,158-­160 but due to their relevance and fundamental importance they have been, although

briefly, also included herein. These authors found that pyridine-­based PNP and PNN (structures

33 and 34, Figure 20), and bipyridine-­based (structure 35, Figure 20) pincer ligands can stabilize

coordinatively unsaturated complexes.

Figure 20. PNP and PNN pincer ligands studied by Milstein et al.

The facile deprotonation of the pincer backbone at one of the methylene spacer groups affords

the dearomatization of the pyridine ring, which must be stabilized by being part of the pincer

ligand. The dearomatized complexes can activate various chemical bonds including H-­H, C-­H,

O-­H and N-­H bonds. These activations are carried out by cooperation between the metal and

the ligand, regaining aromatization of the ligand by protonation of the benzylic carbon atom

(Scheme 37).

N

NEt2

PR2

N

PR2

PR2

R= tBu, iPr

N

PR2

N

R= tBu, iPr, Ph

33 34 35

61

Scheme 37. Activation of H-­Y chemical bonds by cooperation of the metal and the ligand

through a dearomatization/rearomatization process.

Several pincer complexes of this type, mainly based on Ru158 and Fe,159 which are able of

participate in MLC processes, have been described showing their ability as versatile catalysts

for hydrogenation, dehydrogenation and related reactions. It has to be highlighted that the first

application of dearomatization-­reprotonation was the employment of complex 36 for the

dehydrogenation of alcohols, wherein the combined metal and dearomatized ligand act in

cooperative manner to convert, for example, primary alcohols to esters or secondary alcohols to

ketones, with concomitant extrusion of H2 (Scheme 38).161

Scheme 38. Dehydrogenation of alcohols to esters or ketones with a dearomatized pincer

complex.

N

L2

L1

MLn- H+

baseN

L2

L1

MLn N

L2

L1

MLn

H-Y

N

L2

L1

MLm

H

Y

Y= H, OH, OR, NH2, NR2

N

NEt2

PtBu2

Ru COH

36OH

R1R2

H R1 R2

O

+ H2

62

Milstein and co-­workers reported that, in a similar manner to aliphatic alcohols, water could also

be activated using complex 36 with the dearomatized PNN backbone (Scheme 39).162 Upon

reaction with water at room temperature, aromatization takes place to quantitatively form the

trans-­hydrido-­hydroxo complex 37. Thermal activation of a second molecule of water releases

molecular hydrogen and leads to the formation of cis-­hydroxo complex 38. DFT studies indicate

that this process involves H2 liberation from 37 by coupling of the hydride ligand with a proton

from the side arm, followed by addition of H2O to the generated dearomatized intermediate.

Significantly, irradiation of complex 38 led to the regeneration of compound 37 concomitant with

evolution of O2. This sequence would involve a photochemically induced reductive elimination

of H2O2 from dihydroxo complex 38, thereby generating a Ru(0) intermediate (39, not observed)

that undergoes intramolecular proton transfer to regenerate the starting compound. Therefore,

this is a new approach toward a complete cycle for the generation of dihydrogen and dioxygen

from water promoted by a soluble metal complex.

Scheme 39. Proposed reaction mechanism for the generation of O2 and H2 from H2O

mediated by a Ru(PNN) complex.

N

NEt2

PtBu2

Ru CO

36

37

H

N

NEt2

PtBu2

Ru COH

OH

38

N

NEt2

PtBu2

Ru OHOC

OH

39

N

NEt2

PtBu2

Ru CO

H2O H2

H2O + 0.5 O2 H2O2cat

hν

63

8. Conclusions and outlook.

Pyridines react with several types of main group organometallic compounds to give metal-­

pyridine adducts, proposed on the basis of computational studies or by extrapolation of the

behavior encountered in non-­reactive systems. They evolve to metal complexes of anionic

dihydropyridines, which have been isolated only in a few cases, and which finally yield

substituted pyridines. Only in the last few years some groups have started to employ N-­

coordination of the pyridine to an external Lewis acid (e.g., BF3) combined with nucleophilic

addition of an organometallic reagent, or the reaction of the pyridine with a bimetalic reagent

containing different Lewis acid and nucleophilic metal sites (e.g., lithiun aryl zincates), obtaining

selective, synthetically useful methodologies. In contrast, the pyridine rings in transition metal

complexes containing pyridyl-­based ligands -­which are among the most useful and widely

studied within coordination chemistry-­ are typically very inert. In the seventies this notion was

challenged by Gillard, who proposed that apparent anomalies in the behavior of cationic bipy

and phen transition metal complexes in basic aqueous media could be the result of hydroxide

attack to one of the pyridine carbon atoms. However, subsequent studies casted doubt on this

proposal. Our group demonstrated several instances of C-­C coupling via intramolecular

nucleophilic attack to the pyridyl rings on Re-­coordinated bipy and phen ligands under very mild

conditions, most of them initiated by deprotonation of C-­H groups of several types of commonly

employed monodentate ligands. The products of such reactions feature metal-­bonded,

dearomatized dihydropyridyl groups. The products of coupling between two monodentate N-­

alkylimidazole or pyridine ligands could be rearomatized by oxidation to afford pyridylimidazole

or bipyridine ligands, including non-­symmetric chelates. The reaction of one of the dearomatized

products of the bipy-­N-­alkylimidazole coupling with excess MeOTf led to pyridine ring opening,

a transformation previously limited to three examples of very reactive early transition metals. C-­

C coupling schemes were extended to ligands other than pyridines, allowing the modular

construction of non-­symmetric polydentate ligands on the metal coordination sphere.

In some cases the deprotonation of coordinated N-­alkylimidazoles afforded very rare imidazole-­

2-­yl ligands. Their reaction with electrophiles afford NHC ligands;; in particular, their reaction with

64

acids yield NH,NHC ligands. This kind of reaction can serve to directly access metal complexes

of NHC ligands directly from stable, easily accessible N-­alkylimidazole complexes.

Computational studies proved to be very useful in shedding light on the kinetics and

thermodynamics of the competing pathways that lead in some systems to C-­C coupling and in

others to imidazolyl formation. Most of these reactions have been carried out employing highly

stable, easily available rhenium tricarbonyl complexes, whose chemistry has been previously

almost exclusively dominated by substitution reactions.

A growing number of types of transition metal compounds are finding applications as catalysts,

materials, and drugs. Therefore, the synthesis of transition metal complexes is becoming a

proper goal beyond their classical employment as auxiliaries towards the synthesis of metal-­free

organic molecules. The traditional synthetic approach is based on the separate synthesis of the

ligands employing conventional organic procedures, which in the case of non-­symmetric,

polydentate ligands can be far from straightforward, followed by their binding to the metal

through substitution reactions. In some cases, this scheme could be advantageously replaced

by the modular synthesis of the polydentate ligands from easily available monodentate ligands,

which would be first coordinated to the metal and then coupled, taking advantage of the ligand

activation and geometric preorganization by their metal coordination.

9. References.

1. Balaban AT, Oniciu DC, Katritzky AR. Aromaticity as a cornerstone of heterocyclic chemistry.

Chem Rev. 2004;;104:2777-­2812.

2. Sundberg RJ, Martin RB. Interactions of histidine and other imidazole derivatives with

transition metal ions in chemical and biological systems. Chem Rev. 1974;;74:471-­517.

3. Welton T. Room-­temperature ionic liquids. Solvents for synthesis and catalysis. Chem Rev.

1999;;99:2071-­2083.

4. Hopkinson MN, Richter C, Schedler M, Glorius F. An overview of N-­heterocyclic carbenes.

Nature. 2014;;510:485-­496.

65

5. Zhao G, Lin H. Metal complexes with aromatic N-­containing ligands as potential agents in

cancer treatment. Curr Med Chem Anticancer Agents. 2005;;5:137-­147.

6. Kaes C, Katz A, Hosseini MW. Bipyridine: the most widely used ligand. A review of molecules

comprising at least two 2,2’-­bipyridine units. Chem Rev. 2000;;100:3553-­3590.

7. Sammes PG, Yahioglu G. 1,10-­Phenanthroline: A versatile ligand. Chem Soc Rev.

1994;;23:327-­334.

8. Shopov DY, Rudshteyn B, Campos J, Batista VS, Crabtree RH, Brudvig GW. Stable

iridium(IV) complexes of an oxidation-­resistant pyridine-­alkoxide ligand: highly divergent redox

properties depending on the isomeric form adopted. J Am Chem Soc. 2015;;137:7243-­7250.

9. Chupakhin ON, Charushin VN, van der Plas HC. Nucleophilic aromatic substitution of

hydrogen. 1st ed. California, United States: Academic Press Inc;; 1994.

10. Shaw AP, Ryland BL, Franklin MJ, Norton JR, Chen JY-­C, Hall ML. Using a two-­step hydride

transfer to achieve 1,4-­reduction in the catalytic hydrogenation of an acyl pyridinium cation. J

Org Chem. 2008;;73:9668-­9674.

11. Butschke B, Schwarz H. “Rollover” cyclometalation-­early history, recent developments,

mechanistic insights and application aspects. Chem Sci. 2012;;3:308-­326.

12. Mertel HE, Mizzoni RH, Shaw EN, Tenenbaum LE, Yale HL. Pyridine and its derivatives.

In: Weissberger A, Klingsberg E, eds. The chemistry of heterocyclic compounds. New York,

NY: Interscience Publishers Inc;; 1961.

13. Bull JA, Mousseau JJ, Pelletier G, Charette AB. Synthesis of pyridine and dihydropyridine

derivatives by regio-­ and stereoselective addition to N-­activated pyridines. Chem Rev.

2012;;112:2642-­2713.

14. Donohoe TJ, Connolly MJ, Walton L. Regioselective nucleophilic addition to pyridinium salts:

A new route to substituted dihydropyridones. Org Lett. 2009;;11:5562-­5565.

15. McGill CK, Rappa A. Advances in the Chichibabin reaction. Adv Heterocycl Chem.

1988;;44:1-­79.

66

16. Ma Y, Breslin S, Keresztes I, Lobkovsky E, Collum D. Synthesis of a 7-­Azaindole by

Chichibabin cyclization: Reversible base-­mediated dimerization of 3-­picolines. J Org Chem.

2008;;73:9610-­9618.

17. Mastalir M, Pittenauer E, Allmaier G, Kirchner K. 2,6-­Diamination of substituted pyridines via

heterogeneous Chichibabin reaction. Tetrahedron Lett. 2016;;57:333-­336.

18. Terrier F. Modern nucleophilic aromatic substitution. 1st ed. Weinheim, Germany: Wiley-­

VCH Verlag GmbH & Co.;; 2013.

19. Fier PS, Hartwig JF. Selective C-­H fluorination of pyridines and diazines inspired by a classic

amination reaction. Science 2013;;342:956-­960.

20. Rudnitskaya A, Török B, Dransfield T. A B3LYP/6-­31+G(d) study of the reaction pathways

and conformational preference in a model Chichibabin reaction. Comput Theor Chem.

2011;;963:191-­199.

21. Van der Plas HC. The SN(ANRORC) mechanism: A new mechanism for nucleophilic

substitution. Acc Chem Res. 1978;;11:462-­468.

22. Breuker K, Van der Plas HC. Occurrence of an SN(ANRORC) mechanism in the Chichibabin

amination of 4-­Phenylpyrimidine. J Org Chem. 1979;;44:4677-­4680.

23. Francis RF, Davis W, Wisener JT. Reaction intermediates in the alkylation of pyridine with

tert-­butyllithium. J Org Chem. 1974;;39:59-­62.

24. Matsubara Y, Kosaka T, Koga K, Nagasawa A, Kobayashi A, Konno H, Creutz C, Sakamoto,

Ishitani O. Formation of η2‑coordinated dihydropyridine−ruthenium(II) complexes by hydride

transfer from ruthenium(II) to pyridinium cations. Organometallics 2013;;32:6162−6165.

25. Harrison DP, Zottig VE, Kosturko GW, Welch KD, Sabat M, Myers WH, Harman WD. Stereo-­

and regioselective nucleophilic addition to dihapto-­coordinated

pyridine complexes. Organometallics 2009;;28: 5682–5690.

26. Rudler H, Martín-­Vaca B, Nicolas M, Audouin M, Vaissermann J. Formation and selective

trapping of 2,5-­dihydropyridine and its isopropylidene derivative by tungsten(0) alkylidene

complexes. X-­ray structure of the 5-­isopropylidene-­2,5-­dihydropyridine adduct. Organometallics

1998;;17:361-­366.

67

27. Moretto AF, Liebeskind LS. Stereo-­ and regiocontrolled construction of trisubstituted

piperidines using a TpMo(CO)2(Dihydropyridine) scaffold (Tp= hydridotrispyrazolylborate). J.

Org. Chem. 2000;;65:7445-­7455.

28. Barr D, Snaith R, Mulvey, RE, Reed, D. Characterization of the bis(pyridine) complex of the

butylllithium-­pyridine adduct, 2-­Bun(C5H5N)Li·(C5H5N)2;; its decomposition to 2-­butylpyridine via

a dihydropyridine. Polyhedron 1988;;7:665-­668.

29. Clegg W, Dunbar L, Horsburgh L, Mulvey RE. Stoichiometric dependence of the long-­

established reaction of butyllithium with pyridine: A hidden secondary reaction that produces a

pyridine adduct of a lithiodihydropyridine. Angew Chem Int Ed Engl. 1996;;35:753-­755.

30. Armstrong DR, Harris CMM, Kennedy AR, Liggat JJ, McLellan R, Mulvey RE, Urquhart MDT,

Robertson SD. Developing Lithium Chemistry of 1,2-­dihydropyridines: from kinetic intermediates

to isolable characterized compounds. Chem Eur J. 2015;; 21:14410-­14420.

31. Chen Q, du Jourdin M, Knochel P. Transition-­metal-­free BF3‑mediated regioselective direct

alkylation and arylation of functionalized pyridines using Grignard or organozinc reagents. J Am

Chem Soc. 2013;;135:4958-­4961.

32. Chen Q, León T, Knochel P. Transition-­metal-­free BF3-­Mediated oxidative and non-­oxidative

cross-­coupling of pyridines. Angew Chem Int Ed. 2014;;53:8746-­8750.

33. Mizumori T, Hata T, Urabe H. Alkylation of pyridines at their 4-­positions with styrenes plus

yttrium reagent or benzyl Grignard reagents. Chem Eur J. 2015;;21:422-­426.

34. Watson SC, Eastham JF. Colored indicators for simple direct titration of magnesium and

lithium reagents. J Organomet Chem. 1967;;9: 165-­168.

35. Kaim W. Radical-­forming electron-­transfer reactions involving main-­group organometallics.

Acc Chem Res. 1985;;18:160-­166.

36. Kaim W. Electron Transfer to Complex Ligands. Radical anions and organomagnesium

radical complexes of 2,2’-­bipyridines and 1,10-­phenanthrolines. J Am Chem Soc.

1982;;104:3833-­3837.

68

37. Ashby EC, Goel AB. Evidence for a single electron transfer mechanism in the reduction of

aromatic nitrogen heterocycles with main group metal hydrides and dihydropyridyl metal

complexes. Tetrahedron Lett. 1981;;22:4783-­4786.

38. O’Hara F, Blackmond DG, Baran PS. Radical-­based regioselective C−H functionalization of

electron-­deficient heteroarenes: Scope, tunability, and predictability. J Am Chem Soc.

2013;;135:12122-­12134.

39. Lichtenberg C, Spaniol TP, Okuda J. Reactivity of tris(allyl)aluminum toward pyridine:

coordination versus carbometalation. Organometallics. 2011;;30:4409-­4417.

40. Hensen K, Lemke A, Stumpf T. Synthesis and structural characterization of (1,4-­

dihydropyrid-­1-­yl)aluminum complexes. Inorg Chem. 1999;;38:4700-­4704.

41. Knijnenburg Q, Smits JMM, Budzelaar PHM. Reaction of the diimine pyridine ligand with

aluminum alkyls: An unexpectedly complex reaction. Organometallics. 2006;;25:1036-­1046.

42. Jochmann P, Dols TS, Spaniol TP, Perrin L, Maron L, Okuda J. Insertion of pyridine into the

calcium allyl bond: regioselective 1,4-­dihydropyridine formation and C-­H bond activation. Angew

Chem Int Ed. 2010;;49:7795-­7798.

43. Hernán-­Gómez A, Herd E, Uzelac M, Cadenbach T, Kennedy AR, Borilovic I, Aromí G, Hevia

E. Zincate-­mediated arylation reactions of acridine: pre-­ and postarylation structural insights.

Organometallics. 2015;;34:2614-­2623.

44. Diaconescu PL. Reactions of early transition metal-­carbon bonds with N-­heterocycles Curr

Org Chem. 2008;;12:1388-­1405.

45. Johnson KRD, Hayes PG. Cyclometalative C–H bond activation in rare earth and actinide

metal complexes. Chem Soc Rev. 2013;;42:1947-­1960.

46. Bianchini C, Meli A, Vizza F. Modelling the hydrodenitrogenation of aromatic N-­heterocycles

in the homogeneous phase. Eur J Inorg Chem. 2001;;43-­68.

47. Angelici RJ. An overview of modeling studies in HDS, HDN and HDO catalysis. Polyhedron.

1997;;16:3073-­3088.

69

48. Neithamer DR. Párkányi L, Mitchell JF, Wolczanski PT. η2-­(N,C)-­pyridine and µ-­η2(1,2):

η2(4,5)-­benzene complexes of (silox)3Ta (silox = t-­Bu3SiO-­). J Am Chem Soc. 1998;;110:4421-­

4423.

49. LaPointe RE, Wolczanski PT, Mitchell JF. Carbon monoxide cleavage by (silox)3Ta (silox =

t-­Bu3SiO-­). J Am Chem Soc. 1986;;108:6382-­6384.

50. Kleckley TS, Bennett JL, Wolczanski PT, Lobkovsky EB. Pyridine C=N bond cleavage

mediated by (silox)3Nb (silox = t-­Bu3SiO). J Am Chem Soc. 1997;;119:247-­248.

51. Cordone R, Taube H. Pentaammineosmium(II)-­η2-­2,6-­lutidine: An intermediate for C-­H

activation. J Am Chem Soc. 1987;;109:8101-­8102.

52. Harman WD. The activation of aromatic molecules with pentaammineosmium(II). Chem

Rev. 1997;;97:1953-­1978.

53. Cordone R, Harman WD, Taube H. Carbon-­hydrogen bond activation in novel η2-­bound

cationic heterocycle complexes of pentaammineosmium(II). J Am Chem Soc. 1989;;111:2896-­

2900.

54. Gray SD, Smith DP, Bruck MA, Wigley DE. Regioselective C-­N bond cleavage in an η2(N,C)-­

coordinated pyridine and an η1(N) → η2(N,C) bonding rearrangement in coordinated quinoline:

models for hydrodenitrogenation catalysis. J Am Chem Soc. 1992;;114:5462-­5463.

55. Gray SD, Weller KJ, Bruck MA, Briggs PM, Wigley DE. Carbon-­nitrogen bond cleavage in

an η2(N,C)-­pyridine complex induced by intramolecular metal-­to-­ligand alkyl migration: models

for hydrodenitrogenation catalysis. J Am Chem Soc. 1995;;117:10678-­10693.

56. Weller KJ, Filippov I, Briggs PM, Wigley DE. Pyridine degradation intermediates as models

for hydrodenitrogenation catalysis: Preparation and properties of a metallapyridine complex.

Organometallics. 1998;;17:322-­329.

57. Bailey BC, Fan H, Huffman JC, Baik M-­H, Mindiola DJ. Room temperature ring-­opening

metathesis of pyridines by a transient Ti≡C linkage. J Am Chem Soc. 2006;;128:6798-­6799.

58. Fout AR, Bailey BC, Tomaszewski J, Mindiola DJ. Cyclic denitrogenation of N-­heterocycles

applying a homogeneous titanium reagent. J Am Chem Soc. 2007;;129:12640-­12641.

70

59. Gillard RD, Lyons JR. Equilibria in complexes of heterocyclic ligands. J Chem Soc Chem

Commun. 1973;;585-­586.

60. Gillard RD. An explanation for anomalies among complexes of N-­heterocyclic ligands. Inorg

Chim Acta. 1974;;11:121-­122.

61. Gillard RD. Equilibria in complexes of N-­heterocyclic molecules. Part III (1, 2). An explanation

for classical anomalies among complexes of 1, 10-­phenanthrolines and 2, 2‘-­bipyridyls. Coord

Chem Rev. 1975;;16:67-­94.

62. Nord G. The base hydrolysis of bis(2,2’-­bipyridyl)platinum(II) perchlorate. Acta Chem Scand

A. 1975;;29:270-­272.

63. Nord G. Some properties of 2,2′-­bipyridine, 1,10-­phenanthroline and their metal complexes.

Comments Inorg Chem. 1985;;4:193-­212.

64. Constable EC. Nucleophilic attack upon coordinated heterocycles;; definitive evidence for the

enhanced electrophilicity of coordinated pyridines. Inorg Chim Acta. 1984;;82:53-­57.

65. Constable EC, Housecroft CE. Ligand reactivity in coordination compounds;; A molecular

orbital investigation of the quaternisation-­coordination analogy. Transition Met Chem.

1988;;13:19-­21.

66. Tzalis D, Tor Y. The organic chemistry of coordination compounds: unprecedented

substitution reactions of functionalized polypyridine complexes. Angew Chem Int Ed Engl.

1997;;36:2666-­2668.

67. Lay PA. Does coordination activate heterocycles toward nucleophilic attack? The importance

of π interactions between metal ion and ligand. Inorg Chem. 1984;;23:4775-­4777.

68. McInnes CS, Clare BR, Redmond WR, Clark CR, Blackman AG. The nature of the

[Pt(bipy)2]2+ ion in aqueous alkaline solution a new look at an old problem. Dalton Trans.

2003;;2215-­2218.

69. Zhang X-­M, Tong M-­L, Chen X-­M. Hydroxylation of N-­heterocycle ligands observed in two

unusual mixed-­valence CuI/CuII complexes. Angew Chem Int Ed. 2002;;41:1029-­1031.

70. Szpakolski KB, Latham K, Rix CJ, White JM, Moubaraki B, Murray KS. Synthetic and

structural studies on copper 1H-­[1,10]-­phenanthrolin-­2-­one coordination complexes: Isolation of

71

a novel intermediate during 1,10-­phenanthroline hydroxylation. Chem Eur J. 2010;;16:1691-­

1696.

71. Constable EC. Forty years on -­Covalent hydration of transition metal complexes revisited.

Polyhedron. 2016;;103:295-­306.

72. Hevia E, Pérez J, Riera L, Riera V. Reactive alkoxide complexes of groups 6 and 7 metals.

Organometallics. 2002;;21:1750-­1752.

73. Hevia E, Pérez J, Riera L, Riera V, del Río I, García-­Granda S, Miguel D. Insertion of

unsaturated organic electrophiles intyo molybdenum-­akoxide and rhenium-­alkoxide bonds of

neutral, stable carbonyl complexes. Chem. Eur. J. 2002;;8:4510-­4521.

74. Morales D, Navarro Clemente ME, Pérez J, Riera L, Riera V, Miguel D. The combination of

organometallic Mo(η3-­allyl)(CO)2(phen) fragments and aquo and hydroxo ligands: controlled

synthesis and structural characterization. Organometallics. 2002;; 21:4934-­4938.

75. Gerbino DC, Hevia E, Morales D, Navarro Clemente ME, Pérez J, Riera L, Riera V, Miguel

D. A new reactivity pattern of low-­valent transition metal hydroxo complexes: straightforward

synthesis of hydrosulfido complexes via reaction with carbon disulfide. Chem. Commun.

2003:328-­329.

76. Cuesta L, Gerbino DC, Hevia E, Morales D, Navarro Clemente ME, Pérez J, Riera L, Riera

V, Miguel D, del Río, García-­Granda S. Reactivity of molybdenum and rhenium hydroxo-­

carbonyl complexes toward organic electrophiles. Chem. Eur. J. 2004;;10:1765-­1777.

77. Hevia E, Pérez J, Riera V, Miguel D. New octahedral Re(I) tricarbonyl amido complexes.

Organometallics. 2002;;21:1966-­1974.

78. Hevia E, Pérez J, Riera V, Miguel D. Different sites of insertion in the reaction of isocyanates

with [Re(N(R)Ar)(CO)3(bipy)] (R= H or Me): N-­H vs. Re-­N. Chem. Commun. 2002:1814-­1815.

79. Morales D, Pérez J, Riera L, Riera V, Miguel D. Formation of a 1-­Azaallenylidene ligand by

reaction of an amido complex with tetracyanoethylene. Inorg. Chem. 2002;;41:4111-­4113.

80. Hevia E, Pérez J, Riera V, Miguel D. Reactivity of the amido complex

[Re(NHpTol)(CO)3(bipy)] toward neutral organic electrophiles. Organometallics. 2003;;22:257-­

263.

72

81. Morales D, Pérez J, Riera L, Riera V, Miguel D, Mosquera MEG, García-­Granda S.

Molybdenum amido complexes with single Mo-­N bonds: synthesis, structure and reactivity.

Chem. Eur. J. 2003;;9:4132-­4143.

82. Hevia E, Pérez J, Riera V, Miguel D. Insertion and cycloaddition reactivity of a transition-­

metal N-­metalloimine. Angew. Chem. Int. Ed. 2002;;41:3858-­3860.

83. Hevia E, Pérez J, Riera V, Miguel D, Campomanes, P, Menéndez MI, Sordo TL, García-­

Granda S. Synthesis of β−lactams from a N-­rhenaimine: effect of the transition metal on the

energetic profile of the Staudinger reaction. J. Am. Chem. Soc. 2003;;125:3706-­3707.

84. Cuesta L, Hevia E, Morales D, Pérez J, Riera V, Rodríguez E, Miguel D. Activation of a 1,10-­

phenanthroline ligand on a rhenium tricarbonyl complex. Chem. Commun. 2005:116-­117.

85. Methot JL, Roush WR. Nucleophilic phosphine organocatalysis. Adv Synth Catal.

2004;;346:1035-­1050.

86. Cuesta L, Hevia E, Morales D, Pérez J, Riera V, Seitz M, Miguel D. Activation of ancillary

ligands in the reactions of DMAD with phosphide and alkylidenamido rhenium complexes.

Organometallics 2005;;24:1772-­1775.

87. Adams H, Bailey NA, Blenkiron P, Morris MJ. Metallacycle formation through the linking of

an alkyne with phosphide and acetyl groups at an iron centre: X-­ray structure of

[CpFe(CO)Ph2PCH(CO2Me)C(CO2Me)=C(Me)O] (Cp= η-­C5H5). J Organomet Chem.

1993;;460:73-­81.

88. Ashby MT, Enemark JH, Cycloaddition of alkenes and alkynes to CpFe(CO)2PR2 to give

(R)2PFeC(=O)C=C heterometallacycles. Organometallics. 1986;;6:1323-­1327.

89. Serrano AL, Casado MA, Ciriano MA, de Bruin B, López JA, Tejel C. Nucleophilicity and

P−C bond formation reactions of a terminal phosphanido iridium complex. Inorg Chem.

2016;;55:828-­839.

90. Huertos MA, Pérez J, Riera L. Pyridine ring opening at room temperature at a rhenium

tricarbonyl bipyridine complex. J Am Chem Soc. 2008;;130:5662-­5663.

73

91. Ruiz J, Perandones BF. Base-­promoted tautomerization of imidazole ligands to N-­

heterocyclic carbenes and subsequent transmetalation reaction. J Am Chem Soc.

2007;;129:9298-­9299.

92. Hilf C, Bosold F, Harms K, Lohrenz JCW, Marsch M, Schimeczek M, Boche G. Carbene

structure of stable acyl (formyl) anion equivalents. Chem Ber/Recueil 1996;;130:1201-­1212.

93. Hilf C, Bosold F, Harms K, Marsch M, Boche G. The equilibrium between 2-­lithium-­

oxazole(thiazole, -­imidazole) derivatives and their acyclic isomers -­a structural investigation.

Chem Ber/Recueil 1996;;130:1213-­1221.

94. Gade LH. Transition metal complexes with polydentate amido ligands: novel structural

building blocks and chemical reagents. J Organomet Chem. 2002;;661: 85-­94.

95. Caulton KH. The influence of π-­stabilized unsaturation and filled/filled repulsions in transition

metal chemistry. New J Chem. 1994;;18:225-­241.

96. Arévalo R, Pérez J, Riera L. Intramolecular nucleophilic addition to the 2 position of

coordinated 2,2’-­bipyridine by a deprotonated dimethyl sulfide ligand. Inorg Chem.

2013;;52:6785-­6787.

97. Arévalo R, Pérez J, Riera L. Deprotonation of coordinated phosphanes in a rhenium

complex: C-­C coupling with diimine coligands. Chem Eur J. 2015;;21:3546-­3549.

98. Fehlhammer WP, Fritz M. Emergence of a CHN and cyano complex based organometallic

chemistry. Chem Rev. 1993;;93:1243-­1280.

99. Dick GR, Woerly EM, Burke MD. A General Solution for the 2-­Pyridyl Problem. Angew Chem

Int Ed. 2012;;51:2667 –2672

100. Sato S, Ishitani O. Photochemical reactions of fac-­rhenium(I) tricarbonyl complexes and

their application for synthesis. Coord Chem Rev. 2015;;282-­283:50-­59 and references therein.

101. Gasser G, Leonidova A. Undersestimated potential of organometallic rhenium complexes

as anticancer agents. ACS Chem Biol. 2014;;9:2180-­2193.

102. Espinal Viguri M, Huertos MA, Pérez J, Riera L, Ara I. Re-­mediated C-­C coupling of

pyridines and imidazoles. J Am Chem Soc. 2012;;134:20326-­20329.

74

103. Espinal Viguri M, Pérez J, Riera L. C-­C coupling of N-­heterocycles at the fac-­Re(CO)3

fragment: synthesis of pyridylimidazole and bipyridine ligands. Chem Eur J. 2014;;20:5732-­5740.

104. Miller KL, Williams BN, Benitez D, Carver CT, Ogilby KR, Tkatchouk E, Goddard III WA,

Diaconescu PL. Dearomatization reactions of N-­heterocycles mediated by group 3 complexes.

J Am Chem Soc. 2010;;132:342-­355.

105 Carver CT, Benitez D, Miller KL, Williams BN, Tkatchouk E, Goddard III WA, Diaconescu

PL. Reactions of group III biheterocycyclic complexes. J Am Chem Soc. 2009;;131:10269-­10278.

106. Huertos MA, Pérez J, Riera L, Menéndez-­Velázquez A. From N-­alkylimidazole ligands at a

rhenium center: ring opening or formation of NHC complexes. J Am Chem Soc. 2008;;130:13530-­

13531.

107. Huertos MA, Pérez J, Riera L, Díaz J, López R. Effect of the nature of the substituent in N-­

alkylimidazole ligands on the outcome of deprotonation: ring opening versus the formation of N-­

heterocyclic carbene complexes. Chem Eur J. 2010;;16:8495-­8507.

108. Carver CT, Diaconescu PL. Ring-­opening reactions of aromatic N-­heterocycles by

scandium and yttrium alkyl complexes. J Am Chem Soc. 2008;;130:7558-­7559.

109. Grace ME, Loosemore MJ, Semmel ML, Pratt RF. Kinetics and mechanism of the

Bamberger cleavage of imidazole and of histidine derivatives by diethyl pyrocarbonate in

aqueous solution. J Am Chem Soc. 1980;;102:6784-­6789.

110. Trofimov BA, Andriyankova LV, Nikitina LP, Belyaeva KV, Mal’kina AG, Sobenina LN,

Afonin AV, Ushakov IA. Stereoselective tandem ring opening of imidazoles with electron-­

deficient acetylenes and water: Synthesis of functionalized (Z,Z)-­1,4-­diaza-­2,5-­dienes. Org Lett.

2013;;15:2322-­2324.

111. He F, Ruhlmann L, Gisselbrech J-­P, Choua S, Orio M, Wesolek M, Danopoulos AA,

Braunstein P. Dinuclear iridium and rhodium complexes with bridging arylimidazolide-­N3,C2

ligands: synthetic, structural, reactivity, electrochemical and spectroscopic studies. Dalton

Trans. 2015;;44:17030-­17044.

75

112. Brill M, Díaz J, Huertos MA, López R, Pérez J, Riera L. Imidazole to NHC rearrangements

at molybdenum centers: an experimental and theoretical study. Chem Eur J. 2011;;17:8584-­

8595.

113. Cebollada A, Espinal Viguri M, Pérez J, Díaz J, López R, Riera L. Influence of the N-­N

coligand: C-­C coupling instead of formation of imidazole-­2-­yl complexes at Mo(η3-­allyl)(CO)2

fragments. Theoretical and experimental studies. Inorg Chem. 2015;;54:2580-­2590.

114. Espinal Viguri M, Huertos MA, Pérez J, Riera L. Imidazole-­nitrile or imidazole-­isonitrile C-­

C coupling on rhenium tricarbonyl complexes. Chem Eur J. 2013;;19:12975-­12977.

115. Hevia E, Pérez J, Riera V, Miguel D, Kassel S, Rheingold A. New synthetic routes to

cationic rhenium tricarbonyl bipyridine complexes with labile ligands. Inorg Chem.

2002;;41:4673-­4679.

116. Lu E, Lewis W, Blake AJ, Liddle ST. The ketimide ligand is not just an inert spectator:

Heteroallene insertion reactivity of an actinide–ketimide linkage in a thorium carbene amide

ketimide complex. Angew Chem Int Ed. 2014;;53:9356-­9359.

117. Huertos MA, Pérez J, Riera L. Double activation of an N-­alkylimidazole. Chem Eur J.

2012;;18:9530-­9533.

118. Gallo MM, Hamilton TP, Schaefer III HF. Vinylidene: the final chapter? J Am Chem Soc.

1990;;112:8714-­8719.

119. Bruce MI. Organometallic chemistry of vinylidene and related unsaturated carbenes. Chem

Rev. 1991;;91:197-­257.

120. Kunz D. Synthetic routes to N-­heterocyclic carbene complexes: pyridine-­carbene

tautomerizations. Angew Chem Int Ed. 2007;;46:3405-­3408.

121. Dyson P, Hammick PLl. Experiments on the mechanism of decarboxylation. Part I.

Decomposition of quinaldinic and isoquinaldinic acids in the presence of compounds containing

carbonyl groups. J Chem Soc. 1937;;1724-­1725.

122. Raczyńska ED, Kosińska W, Ośmialowski B, Gawinecki R. Tautomeric equilibria in relation

to pi-­electron delocalization. Chem Rev. 2005;;105:3561-­3612.

76

123. Lavorato D, Terlouw JK, Dargel TK, Koch W, McGibbon GA, Schwarz H. Observation of

the Hammick intermediate: reduction of the pyridine-­2-­ylid ion in the gas phase. J Am Chem

Soc. 1996;;118:11898-­11904.

124. Alvarez E, Conejero S, Paneque M., Petronilho A, Poveda ML, Serrano O, Carmona E.

Iridium(III)-­induced isomerization of 2-­substituted pyridines to N-­heterocyclic carbenes. J Am

Chem Soc. 2006;;128:13060-­13061.

125. Esteruelas MA, Fernández-­Álvarez FJ, Oñate E. Stabilization of NH tautomers of

quinolones by osmium and ruthenium. J Am Chem Soc. 2006;;128:13044-­13045.

126. Buil ML, Esteruelas MA, Garcés K, Oliván M, Oñate, E. Understanding the formation of N-­

H tautomers from a-­substituted pyridines: tautomerization of 2-­ethylpyridine promoted by

osmium. J Am Chem Soc. 2007;;129:10998-­10999.

127. Álvarez E, Conejero S, Lara P, López JA, Paneque M, Petronilho A, Poveda ML, del Río

D, Serrano O, Carmona E. Rearrangement of pyridine to its 2-­carbene tautomer mediated by

iridium. J Am Chem Soc. 2007;;129:14130-­14131.

128. Hayton TW, Boncella JM, Scott BL, Abboud, KA, Mills, RC. Coupling of an aldehyde or

ketone to pyridine mediated by a tungsten imido complex. Inorg Chem. 2005;;44:9506-­9517.

129. Wiedemann SH, Lewis JC, Ellman JA, Bergman RG. Experimental and computational

studies on the mechanism of N-­heterocycle C-­H activation by Rh(I). J Am Chem Soc.

2006;;128:2452-­2462.

130. Lewis JC, Bergman RG, Ellman JA. Rh(I)-­catalyzed alkylation of quinolones and pyridines

via C-­H bond activation. J Am Chem Soc. 2007;;129:5332-­5333.

131. Berman AM, Lewis JC, Bergman RG, Ellman JA. Rh(I)-­catalyzed direct arylation of

pyridines and quinolones. J Am Chem Soc. 2008;;130:14926-­14927.

132. Johnson DG, Lynam JM, Mistry NS, Slattery JM, Thatcher RJ, Whitwood AC. Ruthenium-­

mediated C-­H functionalization of pyridine: the role of vinylidene and pyridylidene ligands. J Am

Chem Soc. 2013;;135:2222-­2234.

77

133. Conejero S, Lara P, Paneque M, Petronilho A, Poveda ML, Serrano O, Vattier F, Álvarez

E, Maya C, Salazar V, Carmona E. Monodentate, N-­heterocyclic carbene-­type coordination of

2,2’-­bipyridine and 1,10-­phenanthroline to iridium. Angew Chem Int Ed. 2008;;47:4380-­4383.

134. Paneque M, Poveda ML, Vattier F, Álvarez E, Carmona E. Synthesis and structural

characterization of a binuclear iridium complex with bridging, bidentate N-­heterocyclic carbene

coordination of 2,2’:6’,2’’-­terpyridine. Chem Commun. 2009;;5561-­5563.

135. Song G, Li Y, Chen S, Li X. Hydrogen bonding-­assisted tautomerization of pyridine moieties

in the coordination sphere of an Ir(I) complex. Chem Commun. 2008;;3558-­3560.

136. Song G, Su Y, Periana RA, Crabtree RH, Han K, Zhang H, Li X. Anion-­exchange-­triggered

1,3-­shift of an NH proton to iridium in protic N-­heterocyclic carbenes: hydrogen-­bonding and ion-­

pairing effects. Angew Chem Int Ed. 2010;;49:912-­917.

137. Sini G, Eisenstein O, Crabtree H. Preferential C-­binding versus N-­binding in imidazole

depends on the metal fragment involved. Inorg Chem. 2002;;41:602-­604.

138. Sundberg RJ, Bryan RF, Taylor Jr IF, Taube H. Nitrogen-­bound and carbon-­bound

imidazole complexes of ruthenium ammines. J Am Chem Soc. 1974;;96:381-­392.

139. Tan KL, Bergman RG, Ellman JA. Intermediacy of an N-­heterocyclic carbene complex in

the catalytic C-­H activation of a substituted benzimidazole. J Am Chem Soc. 2002;;124:3202-­

3203.

140. Miranda-­Soto V, Grotjahn DB, DiPasquale AG, Rheingold AL. Imidazol-­2-­yl complexes of

Cp*Ir as bifunctional ambident reactants. J Am Chem Soc. 2008;;130:13200-­13201.

141. Miranda-­Soto V, Grotjahn DB, Cooksy AL, Golen JA, Moore CE, Rheingold AL. A labile

and catalytically active imidazole-­2-­yl fragment system. Angew Chem Int Ed. 2011;;50:631-­635.

142. Araki K, Kuwata S, Ikariya T. Isolation and Intercoversion of protic N-­heterocyclic carbene

and imidazolyl complexes: application to catalytic dehydrative condensation of N-­(2-­

pyridyl)benzimidazole and allyl alcohol. Organometallics 2008;;27:2176-­2178.

143. He F, Braunstein P, Wesolek M, Danopoulos AA, Imine-­functionalised protic NHC

complexes of Ir: direct formation by C-­H activation. Chem Commun. 2015;;51:2814-­2817.

78

144. Burling S, Mahon MF, Powell RE, Whittlesey MK, Williams JMJ. Ruthenium induced C-­N

bond activation of an N-­heterocyclic carbene: isolation of C-­ and N-­bound tautomers. J Am

Chem Soc. 2006;;128:13702-­13703.

145. Wang X, Chen H, Li X. Ir(III)-­induced C-­bound to N-­bound tautomerization of a N-­

heterocyclic carbene. Organometallics 2007;;26:4684-­4687.

146. Wacker A, Pritzkow H, Siebert W. Borane-­substituted imidazole-­2-­ylidenes: syntheses,

structures and reactivity. Eur J Inorg Chem. 1998:843-­849.

147. Vagedes D, Kehr G, König D, Wedeking K, Fröhlich R, Erker G, Mück-­Lichtenfeld C,

Grimme S. Formation of isomeric BAr3 adducts of 2-­lithio-­N-­methylimidazole. Eur J Inorg Chem.

2002:2015-­2021.

148. Kösterke T, Kösters J, Würthwein E-­U, Mück-­Lichtenfeld C, Schulte to Brinke C, Lahoz F,

Hahn FE. Synthesis of complexes containing an anionic NHC ligand with an unsubstituted ring

nitrogen atom. Chem Eur J. 2012;;18:14594-­14598.

149. Huertos MA, Pérez J, Riera L, Díaz J, López R. From bis(N-­alkylimidazole) to bis(NH-­NHC)

in rhenium carbonyl complexes. Angew Chem Int Ed. 2010;;49:6409-­6412.

150. Diaconescu PL. Reactions of aromatic N-­heterocycles with d0Fn-­metal alkyl complexes

supported by chelating diamide ligands. Acc Chem Res. 2010;;43:1352-­1363.

151. Ruiz J, Perandones BF, Van der Maelen JF, García-­Granda S. On the existence of an N-­

metalated N-­heterocyclic carbene: a theoretical study. Organometallics 2010;;29:4639-­4642.

152. Hsieh C-­H, Pulukkody R, Darensbourg MY. Dinitrosyl iron complex as a platform for metal-­

bound imidazole to N-­heterocyclic carbene conversion. Chem Commun. 2013;;49:9326-­9328.

153. Chien SW, Yen SK, Hor TSA. N,S-­Heterocyclic carbene complexes. Aust J Chem.

2010;;63:727-­741.

154. Ruiz J, Perandones BF. Metal-­induced tautomerization of oxazole and thiazole molecules

to heterocyclic carbenes. Chem Commun. 2009;;2741-­2743.

155. Raubenheimer HG, Stander Y, Marais EK, Thompson C, Kruger GJ, Cronje S, Deetlefs M.

Group 6 carbene complexes derived form lithiated azoles and the crystal structure of a

molybdenum thiazolinylidene complex. J Organomet Chem.1999;;590:158-­168.

79

156. Raubenheimer HG, Kruger GJ, Lombard AA, Linford L, Vijoen JC. Sulfur-­containing metal

complexes. 12. Reactions of α-­thio carbanions with carbene complexes of the type

[M(CO)5O(alkyl)Ar] and with the carbyne [(η5-­MeC5H4)Mn(CO)2(CPh)][BCl4]. Organometallics

1985;;4:275-­284.

157. Ikariya T, Masakatsu S. Topics in Organometallic Chemistry, Bifunctional Catalysis.

Springer: Berlin, Heidelberg 2011;; Vol.37.

158. Gunanathan C, Milstein D. Bond activation and catalysis by ruthenium pincer complexes.

Chem Rev. 2014;;114:12024-­12087.

159. Zell T, Milstein D. Hydrogenation and dehydrogenation iron pincer catalysts capable of

metal-­ligand cooperation by aromatization/dearomatization. Acc Chem Res. 2015;;48:1979-­

1994.

160. van der Vlugt, JI, Reek JNH. Neutral tridentate PNP ligands and their hybrid analogues:

versatile non-­innocent scaffolds for homogeneous catalysis. Angew Chem Int Ed. 2009;;48:8832-­

8846.

161. Zhang J, Leitus G, Ben-­David Y, Milstein D. Facile conversion of alcohols into esters and

dihydrogen catalyzed by new ruthenium complexes. J Am Chem Soc. 2005;;127:10840-­10841.

162. Kohl SW, Weiner L, Schwartsburd L, Konstantinovski L, Shimon LJW, Ben-­David Y, Iron

MA, Milstein D. Consecutive thermal H2 and light-­induced O2 evolution from water promoted by

a metal complex. Science 2009;;324:74-­77.

Keywords: dearomatization, C-­C coupling, imidazole-­2-­yl ligand, nitrogen-­heterocyclic

carbene, modular synthesis, nucleophilic attack to pyridine, dihydropyridine ligands, reactivity of

coordinated bipy and phen

Acknowledgements

Computational studies carried out by Dr. Ramón López (Universidad de Oviedo) and Dr. Jesús

Díaz (Universidad de Extremadura) have been instrumental to our incipient understanding of the

challenging mechanistic issues.

80

The authors gratefully acknowledge funding from Ministerio de Economía y Competitividad and

FEDER (grants CTQ2012-­37379-­C02-­01 and CTQ2012-­37379-­C02-­02, and FPI graduate

studentships to M.E.V. and M.A.H.) and Principado de Asturias (grant FC-­15-­GRUPIN14-­103,

administered by FICYT) and Ministerio de Educación Cultura y Deporte (FPU graduate

studentship to R.A.).