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Palladium(II)-Catalyzed Oxidative Cyclization Strategies Selective Formation of New C-C and C-N Bonds Andreas K. Å. Persson

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Page 1: Palladium(II)-Catalyzed Oxidative Cyclization Strategies516638/FULLTEXT01.pdf · the activation energy without undergoing any net-reaction itself. 2 The term “catalysis” was first

Palladium(II)-Catalyzed Oxidative Cyclization Strategies Selective Formation of New C-C and C-N Bonds

Andreas K. Å. Persson

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© Andreas Persson, Stockholm 2012

Cover picture by Johanna Persson

ISBN: 978-91-7447-495-4

Printed in Sweden by US-AB, Stockholm 2012

Distributor: Department of Organic Chemistry, Stockholm University

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Where is the rest? [Unknown]

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Abstract

The use of transition metal catalysts has proven to be one of the most diverse tools for the mild and selective formation of carbon-carbon bonds. In particular palladium-catalyzed cross-coupling reactions have revolutionized the field.

The main focus of this thesis has been directed towards preparation and oxidative carbocyclization of en-, dien- and aza-enallenes.

In the first part of this thesis, a stereoselective oxidative carbocyclization of dienallenes was realized. By employing cheap and readily available palladium trifluoroacetate we were able to efficiently cyclize a variety of dienallenes into hydroxylated carbocycles in high yield and high selectivity. This oxidative process was compatible with two different reoxidation protocols: one relying on p-benzoquinone (BQ) as the oxidant and the other employing molecular oxygen as the oxidant.

In the second part of the thesis the carbocyclization methodology was extended to include carbocyclization of aza-enallenes. This was achieved in two distinct steps. First, a copper-catalyzed coupling of allylic sulfonamides with bromoallenes was developed, giving access to the corresponding aza-enallenes. Subjecting these substrates to catalytic amounts of palladium acetate, along with BQ as the oxidant, rendered N-heterocycles in good yield. The reactivity of these N-heterocycles towards activated dienophiles was later exploited in a tandem (aerobic) oxidative carbocyclization/Diels-Alder reaction.

The third topic involves efficient oxidative arylative/borylative carbocyclization of enallenes. These reactions, catalyzed by palladium acetate, relies on transmetallation of a (σ-alkyl)palladium(II) intermediate with diboranes or arylboronic acids. With this novel methodology we were able to obtain an array of arylated or borylated carbocycles, as single diastereomers, in high yield.

Finally, we developed a palladium(II)-catalyzed cyclization of allylic carbamates. This mild, operationally, simple and scalable catalytic reaction opens up access to an array of oxazolidinones in high yield and excellent diastereoselectivity.

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List of Publications

This thesis is based on the following publications, referred to in the text by their Roman numerals I-VI. Reprints were made with the kind permission of the publisher (Appendix A).

I. Water As Nucleophile in Palladium-Catalyzed Oxidative

Carbohydroxylation of Allene-Substituted Conjugated Dienes Piera, J.; Persson, A.; Caldentey, X.; Bäckvall, J. -E. J. Am. Chem. Soc. 2007, 129, 14120-14121

II. Copper Catalyzed N-Allenylation of Allylic Sulfonamides Persson, A. K. Å.; Johnston, E. V.; Bäckvall, J. -E. Org. Lett. 2009, 11, 3814-3817

III. Palladium(II)-Catalyzed Oxidative Carbocyclization of Aza-

Enallenes Persson, A. K Å.; Bäckvall, J. -E. Angew. Chem. Int. Ed. 2010, 49, 4624-4627

IV. Palladium-Catalyzed Oxidative Borylative Carbocyclization of

Enallenes Persson, A. K. Å.; Jiang, T.; Johnson, M. T.; Bäckvall, J. -E. Angew. Chem. Int. Ed. 2011, 50, 6155-6159

V. Palladium-Catalyzed Oxidative Carbocyclization/Arylation of

Enallenes Jiang, T.; Persson, A. K. Å.; Bäckvall, J. -E. Org. Lett. 2011, 13, 5838-5841

VI. Palladium(II)-Catalyzed Oxidative Cyclization of Allylic

Tosylcarbamates – Scope, Derivatization and Mechanistic

Aspects Joosten, A. Y.; Persson, A. K. Å.; Millet, R.; Johnson, M. T.; Bäckvall, J. -E. Submitted for publication.

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Related papers by the author, but not included as part of this thesis:

Palladium-Catalyzed Oxidative Arylating Carbocyclization of

Allenynes

Deng, Y.; Bartholomeyzik, T.; Persson, A. K. Å.; Sun, J.; Bäckvall, J. -E. Angew. Chem. Int. Ed. 2012, 51, 2703-2707

Enantioselective Synthesis of a-Methyl Carboxylic

Acids via Chemoenzymatic Dynamic Kinetic Resolution Thalén, L. K.; Sumic, A.; Bogár, K.; Norinder, J.; Persson, A. K. Å.; Bäckvall, J. -E. J. Org. Chem. 2010, 75, 6842–6847 Palladium-Catalyzed Oxidative Carbocyclization –

Diversity in Carbon-Carbon Bond formation

Deng, Y†.; Persson, A. K. ņ.; Bäckvall, J. -E. Review Article, Submitted for publication.

† Authors contributed equally to this work

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Table of Contents

Abstract ....................................................................................................................... v

List of Publications .................................................................................................. vii

Table of Contents ........................................................................................................ x

Abbreviations .......................................................................................................... xiii

1. Introduction ............................................................................................................. 1 1.1 Catalysis ........................................................................................................... 1 1.2 Transition Metal Catalysis ............................................................................... 1 1.3 Palladium Catalysis - Background ................................................................... 2

1.3.1 Palladium Catalysis – Fundamental Reactions ........................................ 3 1.4 Palladium(II)-Catalyzed Oxidations Not Involving Carbon-Carbon Bond Formation ............................................................................................................... 3

1.4.1 Reoxidation of Palladium(0) Using Different Oxidation Systems ........... 5 1.4.2 Aerobic Reoxidation of Palladium(0) ...................................................... 5

1.5 Palladium(II)-Catalyzed Oxidations Involving Carbon-Carbon Bond Formation ............................................................................................................... 7

1.5.1 Palladium(II-IV)-Catalyzed Oxidative Carbocyclizations ....................... 8 1.5.2 Palladium(II)-Catalyzed Oxidative Carbocyclizations Involving Allenes ........................................................................................................................ 10

2. Preparation of Starting Materials .......................................................................... 13 2.1 Representative Materials Prepared for Paper I ............................................... 13 2.2 Representative Materials Prepared for Paper II ............................................. 13 2.3 Representative Materials Prepared for Paper IV-V........................................ 14

3. Thesis Aim and Objectives ................................................................................... 15

4.Water As Nucleophile in Palladium(II)-Catalyzed Oxidative Carbocyclizations (Paper I) .................................................................................................................... 16

4.1 Results and Discussion .................................................................................. 17 4.1.1 Attempts to Use Amide Nucleophiles .................................................... 17 4.1.2 Water as Nucleophile ............................................................................. 18 4.1.3 Reaction Scope ...................................................................................... 18 4.1.4 Mechanistic Discussion ......................................................................... 20 4.1.5 The Hydrolysis Dilemma ....................................................................... 22

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4.2 Conclusions .................................................................................................... 23

5. Copper(I)-Catalyzed N-Allenylation of Allylic Sulfonamides (Paper II) ............. 24 5.1 Results and Discussion .................................................................................. 26

5.1.1 Identifying a Model Substrate and Initial Optimization ....................... 26 5.1.2 Allenylation of Allylic Sulfonamides .................................................... 27 5.1.3 Structural Limitations ............................................................................ 29 5.1.4 Allenylation of Non-Allylic Sulfonamides ............................................ 29 5.1.5 Stability of the Aza-Enallenes ............................................................... 30 5.1.6 Mechanistic Discussion ......................................................................... 31

5.2 Conclusions .................................................................................................... 32

6. Palladium(II)-Catalyzed Oxidative Carbocyclization of Aza-Enallenes (Paper III) .................................................................................................................................. 33

6.1. Results and Discussion ................................................................................. 34 6.1.1 Optimization of the Reaction Conditions .............................................. 34 6.1.2 In situ 1H NMR Experiments ................................................................. 35 6.1.3 Scope and Limitations ........................................................................... 36 6.1.4 Aerobic Reoxidation and Tandem Diels-Alder Reaction ...................... 38 6.1.5 Stereochemical Assignment ................................................................... 40 6.1.6 Mechanistic Discussion ......................................................................... 40

6.2 Conclusions .................................................................................................... 42

7. Palladium(II)-catalyzed Oxidative Carboborylation/Carboarylation of Enallenes (Paper IV-V) ............................................................................................................. 43

7.1 Palladium(II)-Catalyzed Oxidative Carbocyclization/Borylation of Enallenes. ............................................................................................................................. 45

7.1.1 Development of a Catalytic System for Oxidative Carbocyclization/Borylation of Enallenes ...................................................... 45 7.1.2 Investigation of the Scope and Limitations ............................................ 47 7.1.3 Stereochemical Assignment of the Borylated Carbocycles ................... 50 7.1.4 Mechanistic Discussion ......................................................................... 51

7.2 Palladium(II)-Catalyzed Oxidative Carbocyclization/Arylation of Enallenes. ............................................................................................................................. 54

7.2.1 Arylboronic acids as Transmetallation Reagent. ................................... 54 7.2.2 Scope and Limitations ........................................................................... 55 7.2.3 Mechanistic Discussion ......................................................................... 59

7.3 Conclusions on the Oxidative Arylative/Borylative Carbocyclization of Enallenes. ............................................................................................................. 60

8. Palladium(II)-Catalyzed Formation of Oxazolidinones Through Cyclization of Allylic Tosylcarbamates – Scope, Mechanistic Aspects and Further Derivatization. (Paper -VI) ................................................................................................................ 61

8.1 Results and Discussion .................................................................................. 63 8.1.1 Finding Efficient Reaction Conditions .................................................. 63

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8.1.2 Scope and Limitations ........................................................................... 65 8.1.3 Biomimetic Reoxidation and Scale Up .................................................. 67 8.1.4 Further Transformations of the Oxazolidinones .................................... 68 8.1.5 Stereochemical Analysis and X-ray Structures ...................................... 70 8.1.6 Deuterium Labeling and Mechanistic Discussion.................................. 71

8.2 Conclusions .................................................................................................... 74

10 Concluding Remarks ............................................................................................ 75

Reprint Permissions (Appendix A) ........................................................................... 77

Acknowledgements ................................................................................................... 78

References ................................................................................................................. 81

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Abbreviations

Abbreviations and acronyms are used in agreement with the standard of the subject.1 Only nonstandard and unconventional ones that appear in the thesis are listed here. Acac Acetylacetone

B2pin2 Bis(pinacolato)diboron

BQ 1,4-Benzoquinone

Cu(OTf)2 Copper(II)-trifluoromethylsulfonate

CuTc Copper(I)-thiophene 2-carboxylate

DCM Dichloromethane

DEEDA N,N'-Diethylethylenediamine

DIBAL-H Diisobutylaluminium hydride

DMBQ 2,6-Dimethylbenzoquinone

DMEDA N,N'-Dimethylethylenediamine

dppe 1,2-Bis(diphenylphosphino)ethane

ETM Electron transfer mediator

EtOAc Ethyl acetate

FePc Iron(II)-phthalocyanine

HOAc Acetic acid

HQ 1,4-Hydroquinone

NHC N-heterocyclic carbene

OAc Acetate

PIDA Iodobenzene I,I-bis(diacetate)

PhBQ 2-Phenylbenzo-1,4-quinone

PIFA Iodobenzene I,I-bis(trifluoroacetate)

TBAF Tetrabutylammonium fluoride

TBDMSCl tert-Butyldimethylsilyl chloride

TBDPS tert-Butyldiphenylsilyl

TEMPO 2,2,6,6-Tetramethyl-1-piperidinyloxy

TIPS-EBX 1-[(Triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one

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1. Introduction

1.1 Catalysis

A catalyst is a substance that accelerates a chemical reaction by lowering the activation energy without undergoing any net-reaction itself.2 The term “catalysis” was first introduced by the Swedish chemist J. J Berzelius already in 1836.3 Under ideal conditions, the catalyst is not consumed during the reaction and theoretically it can be reused in an infinite number of cycles. As a result, catalytic processes have the potential to become environmentally friendly as well as very cost effective. Although there are numerous industrial catalytic processes currently in operating such as the Monsanto-4 and Cativa-5 acetic acid processes, there is still a demand for more environmentally friendly chemical processes employing sustainable and robust catalysts. Owing to this demand, the field of catalysis has received massive attention across all fields of chemistry.

Catalysis can be roughly divided into several different subgroups depending on the nature of the actual catalyst. Some of the major individual areas are biocatalysis, Lewis-acid/base catalysis, organocatalysis and transition metal catalysis6. All four catalytic areas may be further categorized depending on if they act as homogeneous or heterogeneous catalysts.7

1.2 Transition Metal Catalysis

The use of transition metals in catalysis has received considerable attention during the past century. It all started with a discovery made by Humphry Davy in 1817; he discovered that a preheated platinum wire became red hot when exposed to an atmosphere of a combustible gas and air. What he had discovered was the first example of a heterogeneous catalytic oxidation.8

Many of the properties of the transitions metals that make them useful in catalysis arise from their ability to exist in different oxidation states, allowing the metal to interact in a specific manner with a substrate depending on electron configuration.

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One particular group of transition metals has been of special interest to chemists, namely the platinum group: ruthenium (Ru), rhodium (Rh), palladium (Pd), osmium (Os), iridium (Ir) and platinum (Pt). The platinum group metals have shown outstanding catalytic activities in a broad range of chemical reactions ranging from oxidations, reductions, carbon-carbon couplings, carbon-heteroatom couplings, and isomerizations.6,9

1.3 Palladium Catalysis - Background

Although Kolbe10 reported the first palladium mediated catalytic hydrogenation back in 1871, the major breakthrough in palladium catalysis is generally considered to be the development of the Wacker-process in 1959 (Scheme 1, Eq 1).11 This industrially important process allows for selective oxidation of ethylene to acetaldehyde in the presence of catalytic amounts of PdCl2 and CuCl2 together with molecular oxygen.12 The discovery of this reaction initiated an era of intense research, resulting in the development of some very versatile palladium-catalyzed processes, such as the palladium-catalyzed cross-coupling reactions13 developed by Heck,14,15 Negishi16 and Suzuki17 for which they obtained the 2010 Nobel Prize (Scheme 1, Eq 2).

Scheme 1. Wacker oxidation (Eq. 1) and the Suzuki-Miyaura cross-coupling (Eq. 2)

The versatility of palladium catalysts is directly related to some of its unique physical properties. First, palladium interconverts between the 0 and +II oxidation state with relative ease (d10and d8, respectively). As a rule of thumb, palladium in oxidation state 0 is considered nucleophilic while the +II oxidation state is considered electrophilic. Until recently, the majority of research conducted on palladium catalysis has involved palladium in the 0 and +II oxidation state. Nevertheless, species having oxidation states +I, +III18 and +IV do exist, and have recently found application in catalysis.19,20 Palladium is moderately electronegative (2.2) and has a rather “soft” character. Properties like these make the metal center less prone to interact with electronegative hard groups (such as alcohols). Instead it has a higher affinity towards “soft” σ- and π-donors. Consequently, alkenes, alkynes and allenes readily form π-complexes with palladium.21

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In addition, palladium is prone to form complexes with for example amines, N-heterocyclic carbenes (NHC`s) and phosphines, to mention a few. Variation of the ligand on palladium can completely alter the reactivity or be used to tune the catalyst for each process, regardless of the oxidation state involved. Consequently, chemists have been able to develop very robust catalytic systems as well as achieving asymmetric transformations with chiral ligands.22,23

1.3.1 Palladium Catalysis – Fundamental Reactions

All transition metal-catalyzed processes can be divided into several fundamental organometallic reactions.21 Out of these, 7 are depicted in Figure 1 as they are directly or indirectly involved in further chapters of this thesis.

Figure 1. Fundamental reactions occurring on a palladium metal center.

1.4 Palladium(II)-Catalyzed Oxidations Not Involving

Carbon-Carbon Bond Formation

In palladium-catalyzed oxidation chemistry, a lot of effort has been addressed towards developing systems that allow for selective oxidation of alcohols to ketones using molecular oxygen as terminal oxidant.24,25,26 In this class of transformations a few of the more successful catalytic protocols employ Pd/pyridine/O2 (Uemura),27 Pd-NHC/O2 (Sigman),28 Pd/DMSO/O2 (Larock)29 and Pd/bathophenanthroline/O2 (Sheldon).30 As mentioned earlier,

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palladium(II) readily forms π-complexes with a wide range of unsaturated hydrocarbons such as alkynes, alkenes and allenes. The coordination to palladium renders these fragments susceptible towards nucleophilic attack and/or migratory insertion. Many palladium(II)-catalyzed oxidative processes, such as the Wacker-oxidation,26,31,32 allylic acetoxylations,33,34,35 aminations,26,36,37 functionalizations of 1,3-dienes38 and allenes39 are based on derivatization of olefins.

One very recent contribution to the field of palladium(II)-catalyzed aerobic amination has been reported by Stahl.40 They developed an aerobic palladium(II)/NHC-catalyzed (L1) aza-Wacker type cyclization of olefin-substituted sulfonamides (Scheme 2). The process renders hydroindoles (2) in good to high yield using only molecular oxygen as the terminal oxidant.

Scheme 2. Stahl´s aza-wacker cyclization of olefin substituted sulfonamides.

The properties of any incoming nucleophile play a key role in determining whether trans- or cis-nucleopalladation is predominant, and it is generally quite troublesome to prove the actual mechanistic pathway. On many occasions, both mechanistic processes proceed in parallel and subtle solvent or ligand alterations can affect the reaction mechanism.37a One example which beautifully illustrates this phenomenon is how an acetate can be directed to undergo either trans-attack or cis-migratory insertion in the 1,4-diacetoxylation of 1,3-cyclohexadiene (3) (Scheme 3).38

Scheme 3. Palladium(II)-catalyzed cis/trans 1,4-diacetoxylation of 1,3-dienes.

The selectivity observed arises from the fact that chloride coordinates stronger to palladium than acetate. Consequently, cis-migratory insertion of

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(π-allyl)palladium(II)-complex 5b is blocked in the presence of chloride, and the acetate is forced to attack externally (trans) to give cis-6. On the other hand, the reactivity of (π-allyl)palladium(II) complex 4b is different (no chlorides) and it undergoes cis-migratory insertion to give trans-6. In both cases, p-benzoquinone (BQ) was required in at least catalytic amounts to obtain an efficient catalytic reaction.

1.4.1 Reoxidation of Palladium(0) Using Different Oxidation Systems

The net-reaction of a palladium(II)-catalyzed oxidation produces palladium(0). Efficient reoxidation is necessary in order to achieve catalytic turnover as well as to prevent precipitation of palladium black. Early palladium-catalyzed protocols employed stoichiometric amounts of palladium but this is for obvious reasons not ideal. To circumvent this problem a variety of oxidants have been employed to achieve catalytic selective oxidation. The most commonly used oxidants in this field include copper-salts, MnO2, quinones,41 TEMPO,42 various peroxides,43 and PIDA/PIFA20. Of particular importance to this thesis is the use of BQ and its analogues, and the suggested BQ promoted pathway for oxidation of palladium(0) to palladium(II) is depicted in Scheme 4 (M1 to M3).

Scheme 4. Schematic mechanism for the BQ-mediated reoxidation of Pd(0).

Unfortunately, many of the above listed oxidants, except hydrogen peroxide, contribute to decreased atom efficiency and production of large amounts of waste. Replacement of the stoichiometric organic or metal oxidant with molecular oxygen is generally not straightforward because stoichiometric oxidants can be essential as cofactors and/or ligands in many transformations.

1.4.2 Aerobic Reoxidation of Palladium(0)

To circumvent the use of stoichiometric amounts of organic or metal-based oxidants, much research has been devoted to find catalytic systems allowing for air or molecular oxygen to be used as the terminal oxidant.42 In this field, Stahl,44 Sigman,45,32 Stoltz46 and Goddard47 have all made significant contributions with respect to both the mechanistic understanding of aerobic reoxidation as well as developing new synthetic methods. Most of the

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progress in aerobic oxidation has been done with Wacker/aza-Wacker type reactions or in the field of alcohol oxidation. There are of course many exceptions. For example, Sigman recently reported an efficient aerobic Pd(IPr)(OTs)2/Cu(OTf)2-catalyzed oxidative Heck-reaction between electronically non-biased olefins (7) and phenylboronic esters (8).48 The arylation proceeded smoothly at 35 °C giving styrenes (9) with high E/Z-selectivity and chemical yield under an atmosphere of oxygen (Scheme 5).

Scheme 5. Sigman´s palladium(II)-catalyzed oxidative Heck-reaction of non-biased olefins.

Finding a reoxidation system compatible with both the substrate and the product is one of the major hurdles in oxidation chemistry. Occasionally, addition of stabilizing ligands (ligand modulation) or co-catalysts (co-factor modulation) shuts down, or severely inhibits the intended reaction. One successful and well documented approach that rely on co-factor modulated oxidation has been pioneered by Bäckvall. This particular approach was developed as solution to the problem of reoxidizing palladium(0) to palladium(II) directly using molecular oxygen.42,49 The authors achieved this oxidation by mimicking the cell´s respiratory chain i.e. relying on several coupled redox-catalysts as electron transfer mediators (ETM’s). With this strategy, the relatively high energy barrier for direct oxidation of palladium(0) by molecular oxygen was broken down into several steps, all with relatively low energy barriers (Scheme 6).

Scheme 6. Bäckvall´s triple-catalytic (biomimetic) aerobic oxidation.

This approach is based on introduction of an oxygen activating metal complex (Scheme, 6, M(ox) + M(red)), which readily gets oxidized by molecular oxygen. The oxidized metal complex M(ox) then oxidizes 1,4-

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hydroquinone (HQ) to BQ, and BQ in turn oxidizes palladium(0) to palladium(II). To this date there are many different metal complexes, serving as ETM’s, capable of activating molecular oxygen. Some of the most commonly employed complexes are FePc,50 Cobalt-salophen,51 FePc-AMPS (10)52 and more recently, a hybrid HQ-tethered-cobalt(II)-catalyst (11).53 In the latter, BQ has been tethered directly to the oxygen-activating metal complex, thus fusing two of the components of the triple catalytic system into one (Figure 2).

Figure 2. Structure of the oxygen activating complexes FePcAMPS (10) and Co(II)-hybrid (11).

Implementation of such a “biomimetic” triple-catalytic system has been successfully achieved in a variety of palladium(II)-catalyzed processes, such as carbocyclization of en- and dienallenes52,54 1,4-oxidation of dienes55 as well as ruthenium-catalyzed oxidation of alcohols to ketones and lactones.56,57

1.5 Palladium(II)-Catalyzed Oxidations Involving

Carbon-Carbon Bond Formation

The formation of new carbon-carbon bonds is absolutely central to organic chemists. Palladium(0)-catalyzed reactions, relying on oxidative addition of organo halides, has dominated the field and provided chemists with a plethora of efficient methods for carbon-carbon bond formation such as the Suzuki-, Heck-, Negishi- and Tsuji-Trost-reactions.58 On the contrary, there are rather few examples of oxidative palladium(II)-catalyzed carbon-carbon bond forming reactions. This concept has proven especially difficult when a carbon nucleophile, such as an enolate, is used to attack a π-ligand.59 Several problems arise when using carbon nucleophiles. First of all, even stabilized nucleophiles are relatively easy to oxidize leading to potential radical formation and/or side reactions. Secondly, palladium(II) can easily be

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reduced to palladium(0) by the carbon nucleophile itself. Because of this, reports on palladium(II)-catalyzed oxidative olefin alkylation are scarce. However, there are still a few very efficient and well documented reactions involving carbon-carbon bond formation under oxidative conditions, mainly in the area of oxidative Heck-type reactions,48,60 allylic C-H alkylation61,62 and various carbocyclizations (See Chapter 1.5.1).63

One of the more recent contributions to this field was reported by White et al.64 They disclosed an intermolecular oxidative palladium(II)-catalyzed alkylation of allylbenzene derivatives (12) using stabilized carbon nucleophiles (13). Formation of the linear alkylated product 14 predominated and the overall process proceeds in good yield (Scheme 7).

Scheme 7. White´s approach to palladium(II)-catalyzed oxidative allylic alkylation.

Furthermore, they determined that the reaction proceeds through C-H activation of the allyl benzene followed by a subsequent nucleophilic attack by the nitroacetate on the (π-allyl)palladium(II) intermediate.

In addition to the more classical palladium(II)-catalyzed processes, palladium(IV) catalyzed carbon-carbon bond forming reactions have been reported recently.20,65

1.5.1 Palladium(II-IV)-Catalyzed Oxidative Carbocyclizations

Carbocyclization involving palladium(0)-catalysts has received considerable attention. However, further elaboration on this field is beyond the scope of this thesis.66 Additionally, several non-oxidative palladium(II)-catalyzed, approaches (cycloisomerizations) have also been reported by Trost67, Hitamo68 and others.69

Palladium(II)-catalyzed oxidative carbocyclizations have received considerably less attention, mainly due to the previously mentioned incompatibility between oxidants and carbon nucleophiles.70,71 Successful examples include reports by Bäckvall et al. They reported an intramolecular alkylation (carbocyclization) of various cyclic 1,3-dienes, substituted with stabilized carbon-nucleophiles, catalyzed by Pd(OAc)2.

72 Furthermore, Widenhoefer70b,73 and others74 reported palladium(II)-catalyzed oxidative carbocyclization protocols involving olefin-substituted diketones (Scheme 8). In the latter case CuCl2 was used as co-oxidant in combination with molecular oxygen, and it was suggested that the enol-form (M4) undergoes

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trans nucleophilic attack on a (π-olefin)palladium(II)-complex, to form the new carbon-carbon bond (17).

Scheme 8. Widenhoefer´s palladium(II)-catalyzed oxidative carbocyclization of diketones.

A related, ligand-modulated approach to aerobic carbocyclization has been developed by Stoltz for the cyclization of olefin substituted indoles (Scheme 9, 18).75 This elegant reaction uses ethyl nicotinate (L2) as ligand in combination with Pd(OAc)2 and molecular oxygen to provide tricyclic heterocycles (19) in high yields under relatively mild conditions. Mechanistically, this reaction proved much different from Widenhoefers methodology as it most likely involves C-H-activation of the indole followed by cis-insertion. Since the initial discovery of this reaction several additional contributions to this particular field have been made.76

Scheme 9. Stoltz´s palladium(II)-catalyzed oxidative carbocyclization of olefin-substituted indoles.

Carbocyclizations via palladium(IV) intermediates have emerged as interesting alternatives to palladium(II)-catalysis.19,20 One such example is the oxidative carbocyclization of 1,6-enynes (20), in which a hypervalent iodine compound, PhI(OAc)2 (PIDA), was used as oxidant (Scheme 10).77

Scheme 10. Bellers´s Pd(OAc)2/PIDA-mediated cyclopropanation of 1,6-enynes.

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The main feature of this approach is the one pot formation of two new carbon-carbon bonds including one cyclopropyl ring in high yield and stereoselectivity (21).

Finally, there are protocols that employ nontraditional carbon nucleophiles, more specifically π-nucleophiles. In these instances, the π-system acts as a nucleophile instead of a “free” electron pair. The most well established method utilizing this approach is the reaction of allylsilane-substituted 1,3-dienes, leading to products formed through an overall trans-carbopalladation.78

1.5.2 Palladium(II)-Catalyzed Oxidative Carbocyclizations Involving

Allenes

Over the past 10 years, preparation and subsequent palladium(II)-catalyzed carbocyclization of en-52,54,79 and dienallenes80 has been extensively studied by the Bäckvall-group (Scheme 11).81

Scheme 11. Palladium(II)-catalyzed oxidative carbocyclization of en- and dienallenes.

The main feature of these protocols has proven to be its high stereoselectivity and formation of new carbon-carbon bonds under oxidative conditions.82 Oxidative cyclization of allene-substituted olefin (enallene) 22 has been efficiently carried out with stoichiometric amounts of organic oxidants (Table 1, entry 4),79 as well as with molecular oxygen via electron transfer mediators (Table 1, entries 1-3).52,54 Some representative data, with regards to different reoxidation systems, for the conversion of 22 into 23 is presented in Table 1 for comparison.

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Table 1. Comparison of different oxidation systems in the palladium(II)-catalyzed oxidative carbocyclization of enallene 22 to give 23.

Entry Co-catalyst Pd-cat. (mol%) Solvent Time

(h)

Temp

(°C)

Yield of 23

(%)

1 Co-Hybrid (11), O2 1% Pd(OAc)2 EtOH 1 75 97

2 FePc, BQ, O2 5% Pd(O2CCF3)2 Toluene 4 95 99

3 FePc-AMPS (10), BQ, O2 5% Pd(O2CCF3)2 Toluene 16 95 89

4 1.5 equiv. of BQ 1% Pd(O2CCF3)2 THF 4 75 94

The mechanism for this carbocyclization has been suggested to proceed

through activation of the allene (M5), possibly through an allenylic C-H activation, forming an initial (σ-vinyl)palladium(II) intermediate (M6). This complex undergoes exclusive cis-carbopalladation (M7) followed by β-hydride elimination to form 23 (Scheme 12)

Scheme 12. Postulated mechanistic cycle for the palladium(II)-catalyzed oxidative carbocyclization of enallenes.

An alternative mechanism considered for this transformation goes via an initiation of the reaction through a syn-C-H abstraction of the allylic side chain, rendering a (π-allyl)palladium(II) intermediate. However, previous investigators probed and deemed this pathway less likely through deuterium labeling studies and by subjecting compound 26 to carbocyclization conditions (Scheme 13).79

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Scheme 13. Results disfavoring formation of π-allyl intermediates in the palladium(II)-catalyzed oxidative carbocyclization of enallenes.

For allene-substituted 1,3-dienes the mechanism shares several key features with that of enallenes (22). The major difference is that the cyclization step is followed by the formation of a (π-allyl)palladium(II) intermediate, susceptible to attack by a nucleophile. These transformations have been studied in great detail both under stoichiometric and catalytic conditions using HOAc/acetate as the external nucleophile.80 Other nucleophiles such as benzoic acid or pentafluorophenol also proved compatible. However, increased steric bulk on the nucleophile resulted in low yields, exemplified by the comparison between acetic acid (79%) and isobutyric acid (15%).80c

Overall, palladium(II)-catalyzed oxidative carbocyclization of en- and dienallenes is an effective way to achieve selective carbon-carbon bond formation under oxidative conditions and provide potentially useful synthetic intermediates.

Although this thesis is dedicated to the formation of new carbon-carbon bonds via palladium(II)-catalyzed oxidative cyclization of allenes, many other transition metal catalyzed allene cyclizations have been described. In this class, the majority of transformations belong to the non-oxidative category.83

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2. Preparation of Starting Materials

Most of the required starting materials for this thesis have been reported previously (vide infra). The following section broadly outlines the synthesis of these materials for additional clarity.

2.1 Representative Materials Prepared for Paper I

Allene-substituted 1,3-dienes (dienallenes) and bromoallenes were prepared in accordance with literature procedures (Scheme 14).38b,80a Notably, cyclic dienallenes with unsymmetrical allenic alkyl-groups were obtained as 1:1 mixture of diastereomers.

Scheme 14. Overview of the synthesis of allene-substituted 1,3-dienes (dienallenes).

2.2 Representative Materials Prepared for Paper II

Synthesis of N-tosyl protected allylic amines were conducted according to published procedures (Scheme 15).84 For the preparation of alkyl substituted allylic sulfonamides, the isomerization of allylic carbamates was preferred over alkylation of allylic bromides due to matters involving purification.

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Scheme 15. Synthesis of allylic sulfonamides.

2.3 Representative Materials Prepared for Paper IV-V

Preparation of enallenes was performed as previously described (Scheme 16).79

Scheme 16. Synthesis of allene-substituted olefins (enallenes).

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3. Thesis Aim and Objectives

The aim of this thesis has been to extend the scope, generality and knowledge of our previously developed methodologies on palladium(II)-catalyzed oxidative carbocyclization of en- and dienallenes. In addition to investigating the possibilities and limitations of incoming nucleophiles in the dienallene carbocyclization, our primary focus was to evaluate a palladium(II)-catalyzed oxidative carbocyclization of aza-enallenes. To achieve this, we intended to identify and develop novel synthetic methods to gain access to suitable nitrogen containing precursors (aza-enallenes) and study their subsequent palladium(II)-catalyzed oxidative carbocylization.

Furthermore, previous mechanistic data and DFT-calculations conducted on the palladium(II)-catalyzed carbocyclization reaction have suggested that interception of a palladium(II) intermediate could be possible. We wanted to illuminate this possibility and investigate if an expansion of the scope of our carbocyclization methodology was possible through classical trapping methodologies.

Finally, as a response to the rather limited substrate tolerance observed in the preparation of aza-enallenes, we intended to launch a project where oxazolidinones are efficiently synthesized via palladium catalysis. Ideally, these substrates would serve as precursors for aza-enallenes.

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4.Water As Nucleophile in Palladium(II)-Catalyzed Oxidative Carbocyclizations (Paper I)

Previous members of our group have reported that dienallenes undergo carbocyclization when subjected to catalytic amounts of palladium(II) in combination with certain oxygen nucleophiles and an oxidant (Scheme 17).80 The highlights of these protocols are: formation of a new carbon-carbon bond, as well as a carbon-oxygen bond, under oxidative palladium(II)-catalysis. The overall reaction across the 1,3-diene can be denoted “1,4-carboacetoxylation” and proceeds with high stereoselectivity (>99% trans-1,4-addition). For some time, acetate was the only efficient nucleophile, simply because acetic acid was necessary as solvent. Later developments allowed for other carboxylic acids as well as some alcohols to be used as nucleophiles.80c Related oxidative palladium(II)-catalyzed carbocyclizations of 1,3-diene substituted allylsilanes78 and dienynes85 have also been reported.

Scheme 17. Palladium(II)-catalyzed 1,4-carboacetoxylation of dienallenes.

In order to further broaden the scope and knowledge regarding this transformation, we decided to investigate whether amides were accepted as nucleophiles. Also, because biomimetic reoxidations have successfully been integrated in several related palladium(II)-catalyzed processes42, we argued that a similar approach could be applicable in this case.

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4.1 Results and Discussion

4.1.1 Attempts to Use Amide Nucleophiles

As we initially set out trying to find new classes of nucleophiles for the carbocyclization reaction, a number of amides (Figure 3, 29-33) with varying pKa values were selected for this study.

Figure 3. Amide nucleophiles evaluated in the palladium(II)-catalyzed oxidative carbocyclization.

Reactions were conducted using 1 equiv. of 24, 10 mol% of Pd(OAc)2 or 10 mol% Pd(O2CCF3)2, 2 equiv. of BQ and 3 equiv. of the respective amide (29-33). All reactions were conducted for 24 hours at 45 ºC in three different solvents: acetone, THF and EtOAc. These specific solvents were selected as they have previously been highly efficient in related oxidative reactions.50a Unfortunately, the desired amidated carbocycle was not observed in any of the reactions described above. Instead, a small amount (~10%) of an unexpected carbocyclization product was detected. Isolation and characterization of this species (34) revealed that, instead of attack by the added amide, nucleophilic attack by 1,4-hydroquinone (HQ) had occurred (Scheme 18). The presence of the latter side product implies that some form of background oxidation is occurring forming small amounts of HQ. Addition of a weak external base (1-5 equiv. LiOAc or NaOAc) or addition of free amines (e.g. Et3N) did not promote amide attack.

Scheme 18. Detected product from attempted use of amide nucleophiles in the oxidative carbocyclization of dienallene 24.

One additional product was observed when the reaction was performed in acetone (not anhydrous), and after some experimentation it was determined to be the hydroxylated carbocycle 35 (Scheme 19). Excited by this result excess water was added to a reaction in THF, and the same product from

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water attack could be observed in improved yield. Although our initial goal of using amides as nucleophiles was unsuccessful we believed that the water attack was worth looking into in more detail.

4.1.2 Water as Nucleophile

Treatment of 24 with 10 mol% of Pd(O2CCF3)2, 2 equiv. of BQ in a water/THF mixture (1:10) for 20 hours at room temperature produced hydroxylated product 35 in 66% yield. Analysis of product 35, through derivatization with Ac2O and comparison with the NMR-data of the known acetate,80a revealed that the product had been formed via an overall trans-1,4-carbohydroxylation (>99% trans), with formation of a cis-fused ring-junction. Encouraged by these results the H2O/THF ratio together with the palladium(II)-loading was studied. We disclosed that 1 mol% of Pd(O2CCF3)2 together with 2 equiv. of BQ in a H2O/THF mixture (4:1) rendered the desired product 35 in 85% isolated yield after a 9 hour reaction time (Scheme 19).

Scheme 19. Palladium(II)-catalyzed oxidative 1,4-carbohydroxylation of dienallenes.

Comparable results were obtained with Pd(OAc)2, but introduction of halides to the palladium catalyst (Li2PdCl4 or PdCl2(CH3CN)2) completely inhibited this transformation. Attempts were also made to conduct this reaction in a purely aqueous medium; unfortunately this only provided 16% of cyclized product, even after use of more harsh conditions.

4.1.3 Reaction Scope

To investigate the substrate scope of this carbohydroxylation, a series of dienallenes were synthesized as previously described.80 Gratifyingly, all investigated dienallenes reacted smoothly with 1-5 mol% Pd(O2CCF3)2 and 2 equiv. of BQ to give carbocycles 35-41 in 74-92% isolated yield (Table 2, Method A). With 1 mol% Pd(O2CCF3)2 the desired carbohydroxylated products were obtained within 12-24 hours. With 5 mol% of catalyst, higher yields were achieved with much shorter reaction times (5 hours), hence a more practical procedure.

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Substrates with non-symmetrical allenic side chains (Table 2, entries 3-5, 37-39) provided hydroxylated carbocycles with the more substituted double bond as the major isomer (thermodynamic product).

Table 2. Scope of the 1,4-carbohydroxylation of dienallenes (E = CO2Me).

Entry Product Yield (%)

Method A (a,c)

Yield (%)

Method B (b,c)

1

HOE E

35

85

90(d)

88

2

83

89(d)

81

3

80

37/37’

2:1

82(e)

37/37’

2:1

4

84(d)

38/38’

8:1

82(e)

38/38’

7:1

5

85(d)

39/39’

7:1

84(e)

39/39’

6:1

6

90

92(d)

91

94(e)

7

74(d) 71(e)

(a) Method A (Stoichiometric BQ): Dienallene (1.0 equiv.), Pd(O2CCF3)2 (1 mol%) and BQ (2 equiv.), H2O/THF (4:1), r. t., 9-12 h (b) Method B (Aerobic): Dienallene (1.0 equiv.), Pd(O2CCF3)2 (1 mol%), BQ (5 mol%), and FePc (1 mol%) under O2 atmosphere (balloon), H2O/THF (4:1), r. t. 24-48 h. (c) Isolated yields. (d) 5 mol% of Pd(O2CCF3)2, 4-6 h. (e) With 5 mol% of Pd(O2CCF3)2, 20 mol% of BQ, and 5 mol% of FePc in H2O/THF (2:1) at r.t. for 24 h.

The dienallene bearing an 8-membered cyclic olefin proved least efficient, producing the desired hydroxylated carbocycle 41 in 74% isolated yield (Table 2, entry 7). For this specific carbocycle, as well as for 35, the configuration of the ring-junction was determined to be cis. On the contrary, carbocyclization of the 7-membered dienallene gave the trans-fused ring

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product 40 but still through trans-1,4-carbohydroxylation, all in accordance with previous studies (Table 2, entry 6).80

The results discussed so far have involved the use of stoichiometric amounts of BQ as the terminal oxidant. To make this process catalytic in BQ, a triple catalytic aerobic oxidation system based on iron(II)phthalocyanine (FePc, 42) and catalytic amounts of BQ was introduced (Scheme 20).

Scheme 20. Triple catalytic (biomimetic) palladium(II)-catalyzed 1,4-carbohydroxylation of dienallenes.

Subjecting 24 to 1 mol% of Pd(O2CCF3)2, 5 mol% BQ and 1 mol% FePc under an atmospheric pressure of molecular oxygen (balloon), resulted in an effective oxidation protocol (Table 2, entry 1, Method B). At room temperature carbocycle 35 was isolated in 88% yield after 36 hours. A few cyclizations were slower; carbocyles 37 and 37’ (Table 2, entry 3) required 48 hours to fully consume the starting dienallene. To reduce the reaction time, the catalytic protocol was modified to 5 mol% of Pd(O2CCF3)2, 20 mol% of BQ and 5 mol% of FePc in a 2:1 H2O/THF-mixture. This adjustment allowed for full conversion within 24 hours. With these data in hand we applied this catalytic system to the remaining substrates (Table 2, Method B). Comparison between the triple catalytic system and the stoichiometric BQ-mediated version showed that they were comparable with respect to chemical yield.

4.1.4 Mechanistic Discussion

Mechanistic studies have previously been performed on oxidative 1,4-carboacetoxylation of dienallenes,80a and several aspects of the previous studies has been taken into consideration in our suggested mechanism for the 1,4-carbohydroxylation. To begin with, this process requires overall trans-1,4-carbohydroxylation to occur across the 1,3-diene. We suggest that the

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reaction is initiated by activation of the pendant allene (M12) to form (σ-vinyl)palladium(II)-complex M13 by loss of CF3CO2H (TFA) or HOAc, depending on the palladium source. This initial process has been in part supported by monitoring the reaction by 1H NMR spectroscopy. When conducting this reaction with stoichiometric amounts of Pd(OAc)2 in THF-d8, without any BQ, we only observed rapid disappearance of the allenic methyl groups. No cyclized product was observed without the addition of at least catalytic amounts of BQ. Based on this we believe that the reaction probably starts with something resembling an allenylic C-H activation (Scheme 21, M9-M11).

Scheme 21. Possible pathway for the “allene attack on palladium” in the oxidative carbocyclization of en- and dienallenes.

After “allene attack on palladium”, cis-migratory insertion of the 1,3-diene into the vinyl palladium bond in M13 would form the new carbon-carbon bond together with the (π-allyl)palladium(II)-complex M14 (Scheme 22). The final step raises the question why water can act as a nucleophile in this specific case, as this observation is relatively unique in palladium-diene chemistry (M14-M15).86 Our explanation is based on that the adjacent olefin on the prenyl side chain coordinates to the palladium(II)-center. This will increase the bond length of the palladium-carbon bond furthest away from the prenyl side chain in M14. The effect of this “chelate” increases the electrophilicity of M14, thus making it more susceptible towards nucleophilic attack (by water). This proposal has been supported by a recent DFT-calculation (Scheme 22, M14DFT).87 Finally, decoordination of M15 followed by BQ-mediated reoxidation closes the catalytic cycle (Scheme 22).

Another mechanism a priori possible and can explain the reaction outcome of the catalytic reaction. In this mechanism, (η4-π-1,3-diene)palladium(II) coordination from the same face as the already existing substituent, followed by a trans-Wacker addition of water, could give rise to a hydroxylated (π-allyl)palladium(II) intermediate (not shown). Insertion of the pending allene, and subsequent β-hydride elimination would produce the carbocycle with the correct stereochemistry. Although this is a possible pathway it was considered less likely based on the results obtained from the stoichiometric Pd(OAc)2 reaction discussed earlier.

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Scheme 22. Proposed mechanism for the palladium(II)-catalyzed 1,4-carbohydroxylation of dienallenes.

4.1.5 The Hydrolysis Dilemma

In principle, the carbocyclization reaction could proceed through a simple trifluoroacetoxylation/hydrolysis pathway, only having the formal appearance of a hydroxylation. To evaluate this possible pathway Pd(O2CCF3)2 was replaced with Pd(OAc)2. With the latter catalyst, the expected 1,4-carbohydroxylated product 35 was obtained in 80% isolated yield from 24, without any further modification to the catalytic protocol. Next, a mixture of dienallene 24 and acetoxylated carbocycle 25 was subjected to the carbocyclization protocol using Pd(OAc)2 as catalyst. In this experiment we observed that 25 remained intact after the reaction and that the desired hydroxylated carbocycle formed as expected in 76% isolated yield (Scheme 23).

Scheme 23. Probing the possibility of an acetoxylation/hydrolysis pathway in the palladium(II)-catalyzed oxidative carbocyclization of dienallene 24.

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4.2 Conclusions

Allene-substituted 1,3-dienes (dienallenes) have been shown to undergo a palladium(II)-catalyzed stereoselective carbocyclization (1,4-carbo-hydroxylation) at room temperature upon treatment with 1-5 mol% of Pd(O2CCF3)2 and 2 equiv. of BQ in H2O/THF solvent mixtures. This catalytic system allows for the selective formation of new carbon-carbon bonds under oxidative conditions in an aqueous medium. The transformation relies on attack by water on a (π-allyl)palladium(II)-complex to produce trans-1,4-carbohydroxylated carbocycles as the only observed isomer in high yield. The present methodology was further extended by the implementation of a FePc-based biomimetic reoxidation system, using molecular oxygen as the terminal oxidant. Comparison between the two reoxidation methods showed that they were equally efficient with respect to yield.

A mechanism for this transformation was also suggested. It is likely that the external attack by water is made possible due to formation of a (π-allyl)palladium(II)-olefin complex (chelate). This “chelate” would make the carbon atom furthest away from the palladium(II)-center more electrophilic and susceptible to nucleophilic attack.

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5. Copper(I)-Catalyzed N-Allenylation of Allylic Sulfonamides (Paper II)

As we are interested in investigating the possibility of a palladium(II)-catalyzed oxidative carbocyclization of aza-enallenes we sought a method for the preparation of this substrate class. We envisioned that a transition metal catalyzed coupling reaction could potentially be the key step in their preparation.

Transition metal-catalyzed cross-couplings have emerged as one of the most diverse procedures for selective construction of new carbon-carbon bonds. Notably, these protocols are not limited to formation of carbon-carbon bonds. Vast numbers of selective carbon heteroatom (N, O, S) bond formation, catalyzed by transition metals have been disclosed over the years.88 One very effective, and currently dominating reaction for carbon-nitrogen bond formation, was originally developed by Buchwald and Hartwig.89 A common feature of these protocols is that they employ palladium(0) as the catalyst, in combination with phosphine- and, more recently, NHC-ligands.90 This particular catalytic approach has been studied in great detail, and even coupling reactions between amines/amides and deactivated aryl chlorides have recently been realized through exhaustive ligand modification.91 Apart from palladium(0)-catalyzed couplings, the use of copper(I) has been reported as a cheap and almost as efficient alternative.92

Copper(I)-based systems have their origin in the carbon-carbon bond forming Ullmann-protocol, reported by Fritz Ullmann in 1901.93 Originally, the coupling was used to form of new aromatic carbon-carbon bonds, but later developments have made it equally useful in carbon-heteroatom bond formation.92 The advantage of the Ullmann protocol is mainly that the price of copper is much lower than that of palladium, hence, low catalytic loadings are less crucial. In general, copper(I)-based protocols require harsher conditions to facilitate coupling of amines and amides with organohalides.

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Scheme 24. Examples of carbon-nitrogen bond formation using the Ullmann- and Buchwald-Harwig-reactions.

Two representative carbon-nitrogen bond-forming reactions based on the Buchwald-Hartwig94- and Ullmann-protocols95 are given in Scheme 24.

The Ullmann-type reaction has proven effective in a range of carbon-nitrogen bond forming reactions. Despite this, we were only able to find two representative protocols demonstrating coupling of haloallenes with nitrogen nucleophiles. These two protocols, developed by Trost96 and Hsung97, respectively, both described the copper(I)-catalyzed coupling of carbamates (43) and ureas with bromoallenes and iodoallenes (44a and 44b) to give N-allenylated products (45) in high yields (Scheme 25).

A few other interesting alternatives to prepare N-allenylated compounds have been reported previously. Most of these reactions involve base-catalyzed isomerization of propargylic amines and amides, opening up access to monosubstituted N-allenyl amides/carbamates with ease.98 Unfortunately, synthesis of disubstituted N-allenyl amides has proven very difficult using this approach.99

Based on the results reported by Trost, we set out to investigate if a copper(I)-catalyzed coupling between allylic sulfonamides and haloallenes was a viable method to produce aza-enallenes.

Scheme 25. Trost´s copper(I)-catalyzed N-allenylation of oxazolidinones.

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5.1 Results and Discussion

5.1.1 Identifying a Model Substrate and Initial Optimization

The choice of model substrate finally fell on cyclic tosyl-protected allylic amide 47, and initial couplings were attempted using iodoallene 44b. Coupling using 1 equiv. of 47 with 2.5 equiv. of iodoallene 44b (or bromoallene 44a), together with 10 mol% of CuI, 20 mol% of N,N -dimethylethylenediamine (DMEDA, Figure 4, L4), and 2 equiv. of Cs2CO3 in refluxing toluene did not give rise to any detectable amount of the coupled product 48. After several attempts, varying copper sources (Cu2O, CuI, CuCN, CuBr, CuTC, CuOAc), bases, solvents, temperature and various ligands (mainly phosphines and amines), it was decided to abandon 47 as model substrate (Scheme 26). Instead we focused on reevaluating the reaction using a less sterically demanding allylic sulfonamide.

Scheme 26. Unsuccessful Cu(I)-catalyzed coupling of 47 with haloallenes.

Our attention turned towards the simplest tosyl-protected allylic sulfonamide 49 (Scheme 27). Treatment of 1.0 equiv. 49 with 2.5 equiv. of bromallene (44a), 10 mol% of CuI, 20 mol% of DMEDA (Figure 4, L4) and 2.0 equiv. of Cs2CO3 in toluene (90 °C) afforded the N-allenylated product 50 in a modest isolated yield of 49% after 16 hours. Encouraged by these results, several copper sources were evaluated again. Copper(I)-thiophene-2-carboxylate (CuTC) distinguished itself as the superior catalyst (64% isolated yield) followed by CuI, resulting in approximately 15% lower conversion. Throughout this study, DMEDA (L4) was used as ligand. A Comparison between a few other nitrogen-based ligands revealed that only structurally related DEEDA (L5) provided coupled product in moderate yield under the conditions described above in Figure 4.

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Figure 4. Ligands evaluated for the copper(I)-catalyzed coupling of allylic sulfonamide 49 with bromoallene 44a.

The influence of various bases in addition to Cs2CO3 was also briefly investigated. Powdered K3PO4 did in fact give the desired product in 38% isolated yield but K2CO3 and Na2CO3 were completely ineffective. Other bases such as; KOtBu or amines (DBU, DBN and Et3N) failed to improve the reaction

An interesting phenomenon caught our attention when the temperature was increased. In refluxing toluene N-allenylation did proceed, but was accompanied by large amounts of a side product derived from an intramolecular Alder-ene reaction of the product (50AE).100 Already at 90 °C, small amounts of this product were detected. Hence, it was decided to conduct the coupling at 80 °C to avoid this problem (Scheme 27).

Scheme 27. Optimized conditions for the Cu(I)-catalyzed N-allenylation of allylic sulfonamides.

At an early stage we noticed that the aquired aza-enallenes were very sensitive towards acidic conditions. Purification over silica gel proved impossible, even after deactivation with Et3N. Isolation was instead performed using basic aluminum oxide (Al2O3, basic, Brockmann I). After overcoming these initial problems we set out to investigate the limitations of the catalytic reaction.

5.1.2 Allenylation of Allylic Sulfonamides

Coupling of various alkyl-substituted allylic sulfonamides is presented in Table 3. Monosubstituted olefins reacted smoothly with bromoallene 44a, affording aza-enallene 50 in high yield (Table 3, entry 1). An additional (E)-methyl substituent at the allylic moiety did not affect the reaction to any considerable extent (Table 3, entry 2). When the size of this substituent was

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further increased from methyl to butyl, a slight drop in isolated yield (Table 3, entry 7) to 72% was observed. N-Allenylation of disubstituted allylic sulfonamides proceeded with comparable yields regardless of the substituents on the bromoallene (Table 3, entries 3, 5 and 6).

Table 3. Scope of the copper(I)-catalyzed N-allenylation of allylic sulfonamides.(a)

(a) Reaction conditions: Allylic sulfonamide (1.0 equiv.), 15 mol% CuTC (46), 30 mol% DMEDA (L4), Cs2CO3 (2.0 equiv.), bromoallene (2.5 equiv.), toluene, 80 °C, 24 h. (b) Isolated yield. (c) Conducted at 40 °C.

Surprisingly, N-allenylation of 53 using a monosubstituted bromoallene displayed a dramatic decrease in yield (Table 3, entry 4). We speculate that the initially formed aza-enallene undergo a base-catalyzed isomerization to form the corresponding propargylic isomer (not shown).

Somewhat surprising results were also obtained with (E)-aryl substituted allylic substrates 60, 62 and 64 (Table 3, entries 8-10). In all these instances, the starting material was completely consumed, but decomposed into an

Entry Sulfonamide Aza-enallene Yield (%)a, b

1

89

2

82

3

74

4

35

5

65

6

67

7

72

8

53c

9

20c

10

52c

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unknown mixture of products in toluene at 80 °C. Lowering the temperature to 40 °C generated the desired aza-enallenes, 61 and 65 in approximately 50% yield, accompanied by around 25% of a byproduct originating from an intramolecular [2+2]-cycloaddition.100,101 Unfortunately, N-allenylation of 62 did not yield more than 20% of the desired N-allenylated product (63) even after several repeated attempts (Table 3, entry 9).

5.1.3 Structural Limitations

A logical extension of this coupling protocol would be to simply exchange the amine protecting group from p-toluenesulfonyl (Ts) to for instance acetyl. For this purpose, a few analogues of 49, where the tosyl-group had been replaced with Cbz, Boc, benzyl, acetyl and trifluoroacetyl were prepared. Unfortunately all of the amides, except trifluoroacetamide, failed to give the desired product. In the case of trifluoroacetamide, around 20% conversion was observed and the product proved equally unstable on silica gel as the corresponding tosyl-protected derivatives. A likely explanation for the failed coupling of these substrates is that a sufficiently acidic amide N-H is crucial for reactivity. In our series of amides, the tosyl and trifluoroacetylamides have the lowest pKa.

A few other potentially useful allylic sulfonamides were prepared and evaluated in the coupling with bromoallenes. Introduction of a methyl group on the internal carbon of the allylic bond inhibited the reaction (Figure 5, 66). Replacement of the allylic side chain with a simple ethyl group (Figure 5, 67) resulted in only 10% conversion, and the same observation was made for homoallylic sulfonamides (not shown). Furthermore, the catalytic system does not accept substrates where a substituent has been introduced in the α-position with respect to the amide nitrogen (Figure 5, 68-70)

Figure 5. Allylic sulfonamides incompatible with the developed copper(I)-catalyzed N-allenylation.

5.1.4 Allenylation of Non-Allylic Sulfonamides

Although the developed catalytic reaction had some limitations, some additional compound classes proved applicable in the N-allenylation reaction without further optimization (Table 4). For example, Ts-protected anilides (71 and 73) could be allenylated in moderate yields, even with a substituent

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in the ortho-position (Table 4, entry 2). Ditosylated 1,2-anilides formed an interesting cyclized product when subjected to the coupling protocol (Table 4, entry 3).

Table 4. Copper(I)-catalyzed cross-coupling between sulfonyl amides and bromoallene 44a.(a)

(a) Reaction conditions: Sulfonamide (1.0 equiv.), 15 mol% CuTC (46), 30 mol% DMEDA (L4), Cs2CO3

(2.0 equiv.), 44a (2.5 equiv.), dioxane (reflux), 24 h. (b) Isolated yields. (c) Refluxing THF.

Presumably, after coupling, a subsequent 5-exo-trig-cyclization step (catalyzed or non-catalyzed) occurs, rendering the cyclic protected “aminal” 76 in moderate yield. Finally, tosyl-protected amino acid 77 also underwent N-allenylation in a modest isolated yield of 41%.

5.1.5 Stability of the Aza-Enallenes

The majority of the prepared aza-enallenes had to be handled with great care. Even when stored under argon at -20 °C their lifetime was generally limited to weeks. After approximately 2 weeks, the isolated products could contain up to 10% of various byproducts, of which 1,3-dienes were the major ones. Stirring the aza-enallene in THF together with 20 mol% of AcOH did not induce immediate decomposition. However, the same mixture underwent partial hydrolysis of the N-allenyl bond when heated (50 °C), to give N-allyl-4-methylbenzenesulfonamide (83) and 3-methyl-2-butenal (84) (Scheme 31, Chapter 6.1.1).

Entry Substrate Product Yield (%)a, b

1

NTs

72

56

2

O

NTs

74

44

3

63c

4

41

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5.1.6 Mechanistic Discussion

The actual mechanism in operation in these Ullmann-type couplings is still subject to debate and multiple catalytic pathways have been put forward.102 In this study, no direct investigation of the mechanism was conducted. Instead, experimental data have been the basis of the schematic mechanism suggested in Scheme 28. Our proposal is based on a copper(I)-copper(III) cycle. The cycle is initiated by an overall oxidative addition of a DMEDA/CuTC-complex to the bromoallene, forming the d8-square-planar (σ-allenyl)copper(III) complex M16 (Scheme 28). It is not clear whether the sulfonamide is replacing the thiophene-2-carboxylate(TC)-ligand on copper prior to, or after oxidative addition (Scheme 28, central pathway). Next, we suggest that the pending olefin can act as a ligand giving rise to complex M17-M18 (in equilibrium). Reductive elimination of M18 would then give the aza-enallene as well as regenerating the active catalyst. This hypothesis is based on the fact that removal of the allylic olefin, or addition of a substituent in the α-position, resulted in an inactive catalytic reaction. Also, bulkier substituents on the olefin provided lower yields of coupling product.

Br

•Cu(I)

TsN

NH

HN

TC

35

Br

Cu(III)NH

HNBr

+

NTs

Cs

-CsBrCu(III)NH

HN•

NTs

Cu(III)

N Ts

NH

N

H

oxidative addition

ligand exchangereductive elimination

Cu(I)

HN

TCHN

decoordination

TsN

oxidativeaddition

Cu(I)NH

HN

NTs

NTs

Cs

-CsTC

M16

M17M18

M19

Scheme 28. Possible pathway for the copper(I)-catalyzed formation of aza-enallenes.

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5.2 Conclusions

As the first stage towards the carbocyclization of aza-enallenes we have developed a copper(I)-catalyzed N-allenylation of allylic sulfonamides. Our coupling reaction between allylic sulfonamides and bromoallenes renders aza-enallenes in moderate yields using 15 mol% of CuTC as catalyst and 30 mol% of DMEDA as the privileged ligand. The substrate scope is currently limited to allylic tosyl-protected sulfonamides together with a few non-allylic tosyl-amides/anilides.

This study has provided us with valuable information on the stability, purification, and storage of this new substrate category. This information will be truly helpful when studying future catalytic reactions. We were intrigued to see that the developed protocol could supply us with substantial quantities of aza-enallenes, suitable for palladium(II)-catalyzed oxidative carbocyclizations.

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6. Palladium(II)-Catalyzed Oxidative Carbocyclization of Aza-Enallenes (Paper III)

Many biologically interesting molecules have at least one heterocyclic ring in its basic backbone. Consequently, synthetic methods that provide access to structurally diverse nitrogen containing heterocycles have always been greatly appreciated by the synthetic community.103 A few representative examples of naturally occurring compounds with N-heterocylic cores are presented in Figure 6 (79-81).104

Figure 6. Examples of naturally occurring substances having a N-heterocyclic backbone.

Our research group has had a long lasting interest in palladium-catalyzed cyclizations of enallenes105 especially oxidative variants (Scheme 29).54,79 This category of catalytic transformations has facilitated selective formation of carbon-carbon bonds, but the substrate scope has so far been limited to fully carbocyclic structures.

Scheme 29. Features and limitations of the palladium(II)-catalyzed oxidative carbocyclization of enallenes.

Introduction of a heteroatom into the core of the enallene would significantly increase the substrate scope. The first step to achieve this goal was presented in chapter 5, outlining a copper(I)-catalyzed cross-coupling protocol between allylic sulfonamides and bromoallenes that open up access to aza-enallenes

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in moderate yields. With these substrates in hand, we aimed to investigate whether an oxidative carbocyclization was a viable method for also the preparation of pyrrole/pyrrolidine-type N-heterocycles (Scheme 30). Evaluation of this novel reaction is not just interesting from an academic point of view as the formed N-heterocycles are potential precursors to natural products and pharmaceuticals.104

Scheme 30 Outline towards N-heterocycles using palladium(II)-catalyzed oxidative carbocyclization of aza-enallenes.

6.1. Results and Discussion

6.1.1 Optimization of the Reaction Conditions

When aza-enallene 52 was allowed to react with 5 mol% of Pd(OAc)2, 1.05 equiv. of BQ in THF at 50 °C for 5 hours, the desired product 82 was formed in approximately 80% yield (Table 5, entry 1).

Table 5. Investigation of different palladium(II)-sources in the oxidative carbocyclization of aza-enallene 52.(a)

Entry Pd(II)-source

Conv.

(%)(b)

Prod (82:83:84:85)

Ratio (%)(b)

Yield of 82

(%)(c)

1 Pd(OAc)2 100 90:0:0:10 80 2 PdCl2(CH3CN)2 100 5:45:45:5 <5 3 Pd(O2CCF3)2 95 1:49:49:0 <1 4 Pd(acac)2 0 s.m 0 5 Pd(OAc)2 + Phen(d) 0 s.m 0 6 none 0 s.m 0

(a) Reaction conditions: Aza-Enallene (1.0 equiv.), Pd(II)-source (5 mol%), BQ (1.05 equiv.), THF, 50 °C, 5 h. (b) Product distribution and conversion determined using 1H NMR analysis. (c) Yield based on internal standard (anisole). (d) Phen = 1,10-phenantroline (L9)

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In addition to the expected product (82) we also detected around 10% of a by-product (85), arising from a subsequent Diels-Alder reaction between the cyclized product 82 and BQ.

Switching palladium(II)-source from Pd(OAc)2 to PdCl2(CH3CN)2 had a profound negative effect on the outcome of the reaction. Instead of selective cyclization, only trace amounts of the product, accompanied by an approximate 1:1 mixture of N-allyl-4-methylbenzenesulfonamide 83 and 3-methyl-2-butenal 84 (Table 5, entry 2) was observed. We believe that this was a result of an acid-catalyzed hydrolysis of the N-allenyl bond (Scheme 31, M20-M22). The same characteristics was observed during the preparation of aza-enallenes.

Scheme 31. Acid-catalyzed hydrolysis of aza-enallenes (P. S = proton shift).

Pd(acac)2 or Pd(OAc)2 + 1,10-phenantroline (1:1) did not catalyze the reaction and the majority of the starting material was recovered. Background reactions (without any palladium(II)-catalyst) rendered no reaction a part from some slight background decomposition of the starting aza-enallene.

It has previously been demonstrated that oxidative carbocyclizations are most effective in THF or ethanol.54,79 When catalysis was performed in ethanol, the reaction proceeded smoothly, albeit with formation of an unidentified byproduct (~5%), which proved impossible to separate from the carbocycle using chromatographic methods. Owing to this, the best solvent was finally decided to be reagent grade THF (~100 ppm H2O). Some further experimentation using THF as solvent revealed that the transformation was not sensitive towards moisture or air, and that a few different quinones (napthoquinone, 2,6-dimethylbenzoquinone (DMBQ)) were suitable as oxidants.

6.1.2 In situ 1H NMR Experiments

Formation of the Diels-Alder adduct has an eroding effect on the overall yield, consuming both the aza-enallene and the oxidant. To obtain further insight into the formation of 82 and 85, monitoring of the reaction using 1H NMR spectroscopy in THF-d8 (48 °C) using 2 mol% of Pd(OAc)2, 1.05 equiv. of BQ and 1.00 equiv. of anisole (internal standard) was undertaken (Figure 7). From this experiment it became apparent that the reaction was complete within approximately 2.5 hours, furnishing 82 in 82% yield based on the internal standard.

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0

10

20

30

40

50

60

70

80

90

100

0 50 100 150 200

Time (min)

Co

nvers

ion

(%

)

♦= Starting material (52), ■= Product (82)▲= Diels-Alder adduct (85)

Figure 7. NMR study on the formation of 82 and Diels-Alder adduct 85.

The Diels-Alder-adduct (85) started to become measurable at around 40% conversion, and the total amount was around 10% after full conversion. Some further interesting observations were made when studying the data from Figure 7. Formation of 82 displayed a sigmoidal curve. The probable explanation to this phenomenon is that commercially available Pd(OAc)2 (being trimeric) requires some form of activation or dissociation to produce a catalytic active monomeric species.106 Another plausible explanation could be that the unwanted Diels-Alder adduct (85) participates as a ligand in the reaction. A similar observation was recently described in the stereoselective 1,4-diacetoxylation of 1,3-dienes.107

6.1.3 Scope and Limitations

The scope and limitations of this transformation were evaluated with 2 mol% of Pd(OAc)2 and 1.05 equiv. of BQ in THF at 50 °C for 4 hours. The results are summarized in Table 6. In general, aza-enallenes were oxidatively cyclized to give N-heterocycles in good to high yields. Methyl substituted substrate 52 afforded pyrroline 82 in 74% isolated yield after 4 hours.

Aza-enallene 50 (Table 6, entry 2) somewhat surprisingly afforded the N-tosyl protected pyrrole 86 in 64% yield after extending the reaction time to 24 hours. This aromatic product was probably formed through syn-β-hydride elimination (after bond rotation) to form the N-heterocycle with the exocyclic double (Table 6, entry 2, 86b). Studying this reaction using 1H-NMR spectroscopy revealed that this was indeed the case. 86b formed first but was almost completely isomerized during the course of the catalytic reaction to the corresponding aromatic derivative 86. (Scheme 36, M30).

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An interesting observation was made when a phenyl group was introduced on the allylic side chain (Table 6, entry 3). Aza-enallene 61 was smoothly cyclized to give (Z)-87 in 95% yield without any detectable amount of [2+2]-cycloaddition, aromatized, or Diels-Alder by-products.

Table 6. Substrate scope of the palladium(II)-catalyzed carbocyclization of aza-enallenes.(a)

Entry Aza-enallene Product Yield (%)(b)

1

74

2

64(c)

3

TsN

•61

95 (Z)

4

71

5

84

6

TsN

•57

70 90/90’

1:3

7

TsN

91

81

8

No reaction. 0d

(a) Reaction conditions: Aza-Enallene (1.0 equiv.), Pd(OAc)2 (2 mol%), BQ (1.05 equiv.), THF, 50 °C, 4 h. (b) Isolated yields. (c) 24 h reaction time. (d) S.m. was recovered.

The absence of the latter two products was explained by the extended conjugation added by the phenyl group, making the structure less prone to undergo Diels-Alder reactions and/or isomerization.

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Disubstituted olefins 55-57 provided good yields of carbocyclization products regardless of the substituent on the allenic side chain (Table 6, entries 4-7). As anticipated, aza-enallenes with an internal substituent on the double bond failed to give any carbocyclized product, even at elevated temperatures (Table 6, entry 8). This reactivity can be explained by the absence of β-hydrogens in the presumed palladium(II) intermediate (Scheme 36, M29).

The Diels-Alder adduct could be formed selectively by subjecting 52 to slightly modified reaction conditions (2.1 equiv. BQ), This modification resulted in almost quantitative formation of 85 with excellent selectivity (Scheme 32, 99% endo, trans/cis 97:3).

Scheme 32. Selective formation of tricyclic Diels-Alder adduct 85.

6.1.4 Aerobic Reoxidation and Tandem Diels-Alder Reaction

Inspired by the success of the stoichiometric BQ-mediated oxidation procedure, we decided to further broaden the synthetic utility of the transformation by investigating a biomimetic triple catalytic oxidation system. Our choice fell on a catalytic system previously developed in our laboratories.53 This specific system utilizes an oxygen-activating catalyst tethered to BQ (11), thus making it possible to perform the biomimetic oxidation without addition of catalytic amounts of BQ (Scheme 33, M23). Removal of the BQ will have one other positive effect. Perhaps it will be possible to perform the particular carbocyclization in the presence of other dienophiles in a tandem carbocyclization/Diels-Alder sequence. In addition to a more practical and operationally simple procedure, tethering of BQ to the metal macrocycle has also been shown to accelerate the reoxidation system.54

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Scheme 33. Biomimetic oxidation of palladium(0) using Co-hybrid-catalyst 11.

With 11 as the only co-catalyst, a higher yield of cyclized product was expected because secondary Diels-Alder reactions between BQ and 82 are minimized. After some initial experimentation employing different oxygen-activating catalysts and solvents we found good conditions for the biomimetic reoxidation. Subjecting 52 or 56 to 5 mol% of Pd(OAc)2, 5 mol% of 11 in THF at 50 °C under 1 atm of O2 (balloon) provided the desired dihydropyrroles, 82 and 91, in 94% and 86% isolated yield (Scheme 34). As postulated, formation of Diels-Alder adducts was not detected in the crude mixtures.

TsN

• THF, 50 °C

O2, 6 h

TsN

5 mol% Pd(OAc)2

5 mol% Co-cat (11)

TsN

TsN

5 mol% Pd(OAc)2

5 mol% Co-cat (11)

94% isol. yield 86% isol. yield

THF, 50 °C

O2, 6 h

52 82 56 91

Scheme 34. Biomimetic palladium(II)-catalyzed oxidative carbocyclization of aza-enallenes 52 and 56.

We considered it quite surprising that the reactions proceeded without substantial decomposition of the starting aza-enallene or formation of over-oxidized side-products. The absences of large amount of side- and over- oxidized products once again confirm that the biomimetic reoxidation approach is a mild and very selective reoxidation system.

Apart from providing a more environmentally friendly reoxidation, biomimetic reoxidation systems using Co-hybrid catalyst 11 opened up the possibility to use a variety of dienophiles in a tandem

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carbocyclization/Diels-Alder reaction (Scheme 35). For example, the oxidative cyclization of 52, conducted with the addition of 1 equiv. of maleimide, resulted in the formation of tricyclic N-heterocycle 92 in 93% isolated yield. In this case, both the endo- and cis/trans-selectivity was lower than the analogous reaction with BQ. Less activated dienophiles, such as acrylates, displayed disappointing results and by-products started to form before acceptable conversions could be obtained. So far, the carbocyclization/Diels-Alder sequence is limited to activated dienophiles such as maleic acid and maleimide.

Scheme 35. Tandem palladium(II)-catalyzed oxidative carbocyclization/Diels-Alder sequence using maleimide as dienophile.

6.1.5 Stereochemical Assignment

The stereochemical relation in 85 and 92 were determined using 2D-NOESY experiments (Figure 8) The crucial NOE-interactions are indicated on an energy-minimized 3D-model structure of 85. NOE-interactions between the internal, olefinic-C-Ha and the TsN-C-Hb indicated that they were indeed on the same side of the 5,6-fused ring system. In addition, TsN-C-Hb displayed a clear NOE with the two adjacent α-carbonyl protons Hc and Hd (Hd not shown) consistent only with the endo-isomer.

Figure 8. Selected 2D-NOESY interactions observed in tricyclic compound 85. Most hydrogens are omitted for clarity.

6.1.6 Mechanistic Discussion

We believe that the mechanism of the oxidative carbocyclization of aza-enallenes has much in common with the carbocyclization of enallenes

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(Chapter 1.5.2). Attack of the allene on the palladium(II)-source would initially form M28, which can undergo a cis-carbopalladation of the olefin to give M29. β-Hydride elimination of this species (after bond rotation) forms the exocyclic terminal olefin M30 (R = H). Under our reaction conditions this species isomerizes (86b), possibly via hydro/dehydropalladation, to the N-tosyl-protected pyrrole 86. In cases where the intermediate (σ-alkyl)palladium(II)-complex (M29) can form different β-hydride elimination products, elimination occurs at the most easily accessible hydride oriented syn to the palladium(II)-center (R = Me).

Scheme 36. Proposed mechanistic pathway for the palladium(II)-catalyzed oxidative carbocyclization of aza-enallenes.

The above suggested mechanism has been based on cyclization of aza-enallene 50 as this substrate lacked a substituent on the allylic moiety. The absence of this substituent excludes formation of an initial (π-allyl)palladium(II) intermediate, through syn C-H abstraction. Hence, the latter mechanistic pathway can be considered highly unlikely.79

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6.2 Conclusions

We have been able to considerably extend the palladium(II)-catalyzed carbocyclization methodology to include a new substrate class. Aza-enallenes underwent efficient oxidative carbocyclization to provide 5-membered N-heterocycles when treated with catalytic amounts of Pd(OAc)2 and stoichiometric amounts of BQ. In most cases the aza-enallenes were cyclized in high yield under mild conditions.

Low concentrations of BQ were found to be essential due to the presence of an active 1,3-diene in the formed N-heterocycles. When the oxidation was conducted with stoichiometric quantities of BQ, small amounts of the undesired Diels-Alder product was observed in essentially all cases. If excess amounts of BQ were used, a tricyclic Diels-Alder adduct could be obtained in essentially quantitative yield.

Implementation of a biomimetic reoxidation system, based on BQ-tethered Co-catalyst (11) was also realized. This strategy has the advantage of being a more environmentally friendly reaction because the use of “free” BQ could be completely avoided. Furthermore, this catalytic system minimizes the formation of the undesired Diels-Alder adduct and maximizes the yield of N-heterocycles. Additionally, using the biomimetic reoxidation, the carbocyclization of aza-enallenes could be performed with the addition of activated dienophiles to render a tandem carbocyclization/Diels-Alder reaction. This approach rendered tricyclic heterocycles in high yield and good selectivity. Unfortunately, due to substrate-limitations, the diastereoselectivty of the reaction could not been studied. We are currently evaluating the possibility to use the pyrrole/hydropyrrole-type products in the total synthesis of kainic acid.108

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7. Palladium(II)-catalyzed Oxidative Carboborylation/Carboarylation of Enallenes (Paper IV-V)

Our group has previously been involved in palladium(II)-catalyzed oxidative carbocyclizations of en-79 and dienallenes,80 both using stoichiometric amounts of BQ or aerobic reoxidation protocols.42 We have shown earlier that fully carbocyclic structures as well as N-heterocycles can be constructed using this powerful methodology (Chapter 5 and 6). The main feature of this methodology has been the selective formation of carbon-carbon bonds under oxidative conditions, a process commented on in earlier parts of this thesis (Chapter 1.5). Carbocycles obtained from the oxidative carbocyclization, especially the 5,6- and 5,7-fused ring systems, are common motifs in numerous interesting naturally occurring substances. A few of the more representative examples are cyanthiwigin B109 and aphanamol101 (Figure 9).

OO

HH

cyanthiwigin B enallene carbocyclization core

R

R RMe

H

O

OH

aphanamol

Figure 9. Structures of cyanthiwigin B and aphanamol along with the core skeleton obtained after palladium(II)-catalyzed oxidative carbocyclization of enallenes.

Our previous contributions to the field of oxidative carbocyclizations have all involved catalytic cycles terminated with β-hydride elimination to give the unsaturated carbo/heterocycle (Scheme 37, B) This fact should not be considered a limitation, as the newly formed olefin can act as a diverse chemical handle, opening up for further selective transformations.

Functionalization of the proposed (σ-alkyl)palladium(II) intermediate, (Scheme 37, A) could potentially be achieved by promoting transmetallation with a suitable transmetallation reagent. To the best of our knowledge, such an oxidative approach has previously not been reported. However, a closely related reaction has recently been disclosed by Cárdenas. In summary, Cárdenas reported that enynes (93) and enallenes reacted under palladium-

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catalysis together with bis-(pinacolato)diboron (B2pin2) and methanol to give borylated carbocycles (95) in good yields with high chemoselectivity (Scheme 38).110

Scheme 37. Rationalization of the palladium(II)-catalyzed oxidative carbocyclization-transmetallation of enallenes.

Another source of inspiration to this trapping approach originates from a previous DFT-calculation conducted by our group regarding the palladium(II)-catalyzed 1,4-carbohydroxylation of dienallenes (Chapter 4).87 In this study, the DFT-calculations suggested that the formed (π-allyl)palladium(II) intermediate was coordinating to the pending (exocyclic) alkene, making it more electron deficient and susceptible to nucleophilic attack (Scheme 37, D).

Scheme 38. Cárdenas Palladium-catalyzed borylative carbocyclization of enynes.

Based on this interaction we reasoned that a similar palladium(II)-olefin interaction could be present when the substrate is changed from dienallene to enallene. Stabilization of the (σ-alkyl)palladium(II) intermediate could potentially divert the reaction to undergo transmetallation in favor of syn-β-hydride elimination (Scheme 37, C). If indeed possible, one could quickly gain access to diverse borylated or arylated carbocycles, depending on the choice of reagent, in one pot under oxidative conditions.

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7.1 Palladium(II)-Catalyzed Oxidative

Carbocyclization/Borylation of Enallenes.

7.1.1 Development of a Catalytic System for Oxidative

Carbocyclization/Borylation of Enallenes

We first settled for enallene 22 as the model substrate as it was relatively easy to synthesize. In our first cyclization attempt, we found that treatment of 22 with 5 mol% of Pd(OAc)2, 1 equiv. of B2pin2 and 1.5 equiv. of BQ in THF at 40 °C for 4 hours gave rise to 40% of the desired overall cis-borylated carbocycle 96 along with 8% of the β-hydride eliminated product 23 (Scheme 39). Remarkably, the borylated carbocyle was obtained as one single diastereomer.

Scheme 39. Initial attempt of a palladium(II)-catalyzed oxidative borylative carbocyclization of enallene 22.

Encouraged by these results, optimization of the overall reaction parameters was undertaken, starting with the role of the solvent (Table 7). Clearly, the choice of solvent played a crucial role for the selectivity between 96 and 23, and toluene proved to be by far the most effective solvent (Table 7, entry 7). In toluene, at 40 °C, 70% of 96 and only 5% of 23 was observed by1H NMR analysis of the crude reaction mixture. Other solvents such as acetone and acetonitrile showed overall poor selectivity between the two species (Table 7, entries 3 and 6). As anticipated, a range of solvents did provide relatively good conversions, but with fluctuating selectivity between 96 and 23. Once toluene had been established as the most effective solvent, the influence of the palladium source was investigated. Previous studies on the carbocyclization of en- and dienallenes have shown that Pd(OAc)2 and Pd(O2CCF3)2 were the most suitable catalysts. This proved to be true in this case aswell, as Pd(OAc)2 displayed the most promising conversion and selectivity. Most other common Pd(II)-salts such as: PdCl2, PdCl2(CH3CN)2, PdCl2(PPh3)2, Pd[(nacnac)(OAc)], Pd(acac)2 performed poorly.

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Table 7. Solvent effects in the palladium(II)-catalyzed oxidative carbocyclization of enallene 22.(a)

Entry Solvent Yield of 96 (%)(b) Yield of 23 (%) (b)

1 THF 40 8

2 DCM 45 34

3 CH3CN 20 46

4 EtOH 56 13

5 EtOAc 55 12

6 Acetone 60 30

7 Toluene 70 5 (a) Reaction conditions (unless otherwise noted): Enallene 22 (1.0 equiv.), Pd(OAc)2 (5 mol%), B2pin2 (1.0 equiv.) and BQ (1.5 equiv.) in the indicated solvent at 40 °C for 4 h. (b) Yields were determined by 1H NMR analysis of crude mixtures using anisole as the internal standard.

Next, our focus turned towards minimizing the catalyst loading. Fortunately, the amount of catalyst could be lowered down to 1 mol% (at 40 °C) simply by extending the reaction time from 4 to 10 hours. Attempts were also made to suppress the formation of the β-hydride elimination product 23 by modification of the protocol. First, different temperatures were evaluated (Table 8), using 1 mol% Pd(OAc)2, and the ratio between borylated/eliminated product (96/23) was determined from the crude mixture by 1H NMR analysis. Elevated temperatures resulted in significantly higher amounts of the undesired product 23 (Table 8, entries 3-4).

Table 8. Product distribution in the palladium(II)-catalyzed oxidative carbocyclization of enallene 22 at various temperatures.(a)

Entry T (°C) Yield of 96 (%) Yield of 23 (%) (b)

1 r.t 54 6(c)

2 40 79 7

3 60 62 14

4 80 43 50 (a) Reaction conditions (unless otherwise noted): Enallene 22 (1.0 equiv.), Pd(OAc)2 (1 mol%), B2pin2 (1.0 equiv.) and BQ (1.2 equiv.) in the indicated solvent, 10 h (b) Yields were determined by 1H NMR analysis of crude mixtures using anisole as the internal standard. (c) Full conversion could not be obtained after 24 h.

After some further optimization we found that excess BQ (1.5 equiv.) and/or excess B2pin2 (1.5 equiv.) did not improve the yield nor the selectivity.

A range of commonly used oxidants are potentially capable of reoxidizing Pd(0) back to Pd(II) in these reactions, but it has been observed on previous occasions that quinones are the only class of oxidants that are truly effective for the oxidative carbocyclization methodology. Owing to this, further investigation of alternative oxidants was not attempted.111

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Some common additives such as NaOAc, HOAc and H2O were introduced to determine if the acidity of the medium, or the amount of water present affected the reaction outcome. Of these additives, a slight increase in rate was observed when water was introduced; however, the effect was rather small and not investigated further. Nevertheless, it proved that the reaction was not very sensitive to water, which in turn makes this transformation robust and easy to perform (Scheme 40).

Scheme 40. Optimized conditions for the palladium(II)-catalyzed oxidative borylative carbocyclization of enallenes.

7.1.2 Investigation of the Scope and Limitations

After having established an efficient catalytic protocol for the model substrate 22 an investigation regarding the substrate scope was initiated (Table 9). Overall this transformation displayed rather consistent results, providing borylated carbocycles in good yields (Table 9).

Table 9. Scope of the palladium(II)-catalyzed oxidative borylative carbocyclization of enallenes.(a)

Entry Enallene Carbocycle Yield (%) (b)

1

77

2 •

97

E E

78

3

68

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Table 9 contd. Scope of the palladium(II)-catalyzed oxidative borylative carbocyclization of enallenes.(a)

Entry Enallene Carbocycle Yield (%) (b)

4

60

102/102’ (3:1)

5

58

6 •

105

E E

5c, d

7

86

8

64e

9

89

10

63f

11

62f

(a) Reaction conditions (unless otherwise noted): Enallene (1.0 equiv.), Pd(OAc)2 (1 mol%), B2pin2 (1.0 equiv.), BQ (1.2 equiv.), toluene, 40 °C, 10 hours. (b) Isolated yield after column chromatography (c) Full conversion could not be achieved within 36 hours. (d) Determined from crude reaction mixture. (e) 109 consisted of an inseparable mixture of allene/alkyne (1:1.6) where the alkyne does not react during catalysis. (f) 20 h reaction time.

However, there are a few observations that require some further comments. In most cases products originating from β-hydride elimination were detected. The quantity of this product was always below 10%, and easily separated from the desired product using chromatographic methods. It is also worth mentioning that we could not detect any other side products arising from palladium(0)-catalysis. Related palladium(0)-catalyzed reactions have been reported previously by both Morken112 and Cárdenas110.

Terminally disubstituted olefin 105 displayed very poor compatibility with our catalytic system, and only 25% conversion of the starting material was observed after 36 hours (Table 9, entry 6). The major product turned out

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to be the β-hydride elimination product and only around 5% of the desired borylated compound was detected in the crude reaction mixture. This result discouraged us to further pursue terminally disubstituted olefins in this study.

Cyclic enallenes (Table 9, entries 1 and 9-11) performed much better and the products were obtained with an overall stereospecific cis-addition of the elements of carbon and boron to the double bond. Notably, the 5-, 6- and 8-membered cyclic enallenes (111, 22 and 115) formed borylated carbocycles with overall cis-stereochemistry (Table 9, entries 1, 9 and 11) while the 7-membered enallenes (113) formed the borylated carbocycle with a trans-fused ring junction (Table 9, entry 10). Another clearly detectable trend with regard to ring size, was a drop in yield for 7- and 8-membered rings (63% and 62% respectively), whereas the 5- and 6-membered rings allowed for formation of borylated carbocycles in much higher yield (89% and 77% respectively). We do believe this behavior can be traced back to the stabilizing effect of the exocyclic olefin on the (σ-alkyl)palladium(II) intermediate (Scheme 42, M34). Through modeling we reasoned that the 5,5-fused ring-system should have the strongest chelating properties, and the larger rings the weakest, all in accordance with our observed chemical yields. This trend was also supported by the amounts of β-hydride elimination products observed in each case. Enallenes 113 and 115 produced significantly more side products than 22 and 111.

Acyclic, monosubstituted olefins cyclized as expected to give primary alkylboronates in moderate yields (Table 9, entries 2-4). Introduction of substituents on the internal carbon efficiently rendered the borylated carbocycle with one new quaternary stereocenter (Table 9, entry 7). Clearly, this substrate class was one of the most efficient, giving the desired product 108 in 86% isolated yield. We rationalize this result by the fact that the (σ-alkyl)palladium(II) intermediate lacks the presence of a β-hydrogen, i.e. transmetallation can proceed smoothly without this eroding pathway.

Enallenes substituted on the olefin (E) with alkyl (103) or aryl groups (109) rendered carbocycles 104 and 110 in moderate yield (Table 9, entries 5 and 8). These specific borylated carbocycles were obtained as sticky oils, which made X-ray analysis impossible. The stereochemical relationship was instead determined with the aid of 1H/13C NMR techniques (COSY, HSQC, HMBC, 2D-NOESY and NOE-diff) together with molecular modeling.

Finally, we decided to investigate whether the previously developed aza-enallenes (Chapters 5 and 6) could potentially undergo this novel transformation. Surprisingly, treatment of 117 under the conditions developed for the carbocyclic reaction (1 mol% of Pd(OAc)2, 1.0 equiv. of B2pin2, 1.2 equiv. of BQ, toluene, 40 °C) rendered the borylated hydropyrrole 119 in acceptable yield, albeit accompanied by large amounts of the Diels-Alder adduct 119b (Scheme 41). Minor adjustments to the catalytic protocol, mainly reduction of the amount of BQ to 1.05 equivalents,

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allowed access to borylated dihydropyrrole in 71% isolated yield. In the same manner aza-enallene 118 afforded 120 as one single isomer in 60% isolated yield.

Scheme 41. Palladium(II)-catalyzed oxidative borylative carbocyclization of aza-enallenes 117 and 118.

7.1.3 Stereochemical Assignment of the Borylated Carbocycles

The stereochemical relation of the carbocyclized products 96, 112 and 116 was determined by careful 1H NMR analysis. 2D-NOESY along with NOE-diff (3.5-10% NOE) experiments clearly revealed that the two bridgehead protons, along with the pinB-C-Ha were situated on the same side (cis) (Figure 10, 96, Hb and Hc).

Bpin

E

E

HbHa

HcHa

Bpin

HcHb

E

E

E = CO2Me96 112

Selected J -couplings for 112

Ha: δ 1.30-1.24 ppm poorly resolved multiplet

Hb: δ 3.03 ppm (ddd), J= 11.2, 6.5, 5.3 Hz

Hc: δ 3.54 ppm (ddd), J= ~6.4 (*2), 2.5 Hz

Figure 10. Schematic representation of the bridgehead protons in the borylated carbocycles 96 and 112.

Eventually, we managed to obtain crystals of compound 96 suitable for X-ray analysis, which confirmed our stereochemical assignment (Figure 11, left). In contrast to the 5,6-fused carbocycle, the 5,7-fused product 114 did not at all show the same NOE-characteristics. Instead, interactions indicative of a trans-ring junction and overall cis-carboborylation was observed. The configuration of 114 was later confirmed by an X-ray structure obtained after the original publication (Figure 11, right).113

The stereochemistry of the monocyclic borylated compounds 104, 110 and 120 were established by matching 2D-NOESY interactions with energy minimized 3D-models along with J-couplings of the requisite compound, as exemplified by the study of compound 110 (Figure 12).

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Figure 11. X-ray structures for the borylated carbocycles 96 (left) and 114 (right).

Figure 12. Observed NOE-interactions for borylated carbocycle 110, indicated on an energy minimized model (some hydrogens are omitted for clarity).

7.1.4 Mechanistic Discussion

Our proposed mechanism is derived from previous studies on the palladium-catalyzed carbocyclizations of enallenes79 together with data disclosed in the current study. We suggest that after π-coordination of Pd(OAc)2 cis to the already present stereocenter (Scheme 42, M32), the metal undergoes an allenylic C-H abstraction, denoted “allene attack” on palladium. This step would produce the relatively stable (σ-vinyl)palladium(II) intermediate M33. From M33, the olefin exclusively undergoes cis-insertion, most likely mediated by coordination of one molecule of BQ. After insertion, a (σ-alkyl)palladium(II) intermediate M34 is formed. Normally, this intermediate undergoes facile syn-ß-hydride elimination. However, our results strongly indicate that the pending (exocyclic) olefin stabilizes this intermediate in a way that allows for transmetallation with B2pin2. Notably, the cyclopentyl enallene 111 provided the highest yield of the corresponding carbocycle. We believe that this outcome can be explained by the relative stability of the

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palladium intermediate (M34), where the 5,5-fused carbocycle have the most stabilization and the 5,8-fused the least favored one.

Scheme 42. Suggested mechanism for the palladium(II)-catalyzed oxidative borylative carbocyclization of enallenes.

Regardless of chelation, M34 undergoes transmetallation and subsequent reductive elimination (with retention of configuration) to produce the carboborylated products. Expelled palladium(0) is finally reoxidized by BQ in the presence of catalytic amounts of HOAc to complete the catalytic cycle.

One matter of controversy regarding this mechanistic pathway has been whether transmetallation was occurring much earlier, for example already in M32. Transmetallation at this stage would completely avoid having to pass through transmetallation of a highly sensitive (σ-alkyl)palladium(II) intermediate (M34). Although this pathway has been considered, our hypothesis is that a more electrophilic catalyst, Pd(OAc)2 as opposed to (pin)BPdOAc, is essential for the initial allene attack on palladium.

A second possible, but less likely pathway involves initial transmetallation of Pd(OAc)2 to give (pin)BPdOAc (Scheme 43, M37). Insertion of the cyclic olefin could occur, providing intermediate M38. Another insertion, this time of the allene, (M39) followed by ß-hydride elimination would then render the product. In our opinion the experimental data does not support this mechanistic pathway, as we would expect (some) borylation of the allene moiety, without formation of carbocycles. Also, this

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particular mechanism does not account for the formation of the observed ß-eliminated products.

In addition to the above discussed mechanisms, we have considered two other pathways, one involving a Pd(IV) intermediate and one starting from oxidative addition on B2pin2 by a palladium(0)-source. The high oxidation pathway was judged highly unlikely using BQ as the oxidant. The second alternative was ruled out as the expected borylated product was not observed under palladium(0)-catalysis.

Scheme 43. Alternative pathway explaining the palladium(II)-catalyzed borylative carbobocyclization of enallenes.

We should point out that the detailed mode of transmetallation has not been investigated for this novel transformation. However, our belief is that transmetallation is mediated by acetate, as previously described in the Miyaura borylation.114

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7.2 Palladium(II)-Catalyzed Oxidative

Carbocyclization/Arylation of Enallenes.

7.2.1 Arylboronic acids as Transmetallation Reagent.

After having realized the catalytic oxidative borylative carbocylization of enallenes we turned our focus towards an arylative carbocyclization sequence (Scheme 44). This attractive process could substantially widen the substrate scope, and supply us with further knowledge regarding the carbocyclization. Starting from the borylation protocol described in Chapter 7.1, simple re-optimization using arylboronic acids (ArB(OH)2) was anticipated to give arylation instead of borylation. Our choice of model substrate fell on enallene 97 as we expected that this substrate was least prone to undergo ß-hydride elimination.

In preliminary experiments, using the same conditions as in the borylation case, treatment of 97 with 5 mol% of Pd(OAc)2, 1.2 equiv. of BQ and 1 equiv. of PhB(OH)2 in toluene at 40 oC afforded the desired phenylated carbocycle 121a in 53% yield. In this instance 121a was accompanied by some unreacted starting material together with trace amount of the expected by-product 122 (Scheme 44).

Scheme 44. First attempt on the palladium(II)-catalyzed arylative carbocylization of enallene 97.

A look at different solvents quickly revealed that the transformation proceeded in most solvents, except strongly coordinating acetonitrile. Notably, very little ß-hydride eliminated product (122) was formed in all cases. The conversion differed substantially for each case (Table 10). The best solvent proved to be THF, rendering the desired product in 92% yield after 16 hours together with 4% of 122 (Table 10, entry 6). During this optimization, products arising from homo-coupling of PhB(OH)2 (biphenyls) were indeed observed, albeit in a low yield of around 2-5% in each separate catalytic reaction. Additional attempts to improve the performance of this transformation were based on interchanging the boronic acid derivative. Unfortunately, almost all other boronic acid derivatives such as boronic esters and potassium trifluoroborates were all completely inactive for this

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transformation, and only trace amounts of the desired arylated carbocycles were detected.

Table 10. Solvent effects in the palladium(II)-catalyzed oxidative arylative carbocyclization of enallene 97.(a)

Entry Solvent Yield of 121a (%)(b) Yield of 122 (%)(b)

1 Acetone 90 7

2 Acetonitrile 0 0

3 DCM 67 4

4 DCE 64 5

5 1,4-Dioxane 86 2

6 THF 92 4

7 Toluene 53 1 (a) Reaction conditions (unless otherwise noted): Pd(OAc)2 (5 mol%), PhB(OH)2 (1.0 equiv.) and BQ (1.2 equiv.) in the indicated solvent at 40 oC for 16 h (b) Yields were determined by 1H NMR analysis of crude mixtures using anisole as the internal standard.

Most of the commercially available arylboronic acids are delivered as mixtures of the “free” arylboronic acid (124) and the boroxine (123). Fortunately no significant difference was observed when the reaction was conducted with one or the other (Scheme 45).

Scheme 45. Optimized conditons for the palladium(II)-catalyzed oxidative arylative carbocylization of enallenes.

7.2.2 Scope and Limitations

The reaction conditions in Scheme 45 were used to explore the scope of the palladium(II)-catalyzed oxidative arylative carbocyclization. Both electron-rich and electron-deficient arylboronic acids were evaluated and the results are summarized in Table 11. Overall, monosubstituted enallene 97 was cyclized efficiently independent of the electronic properties of the arylboronic acid (61-95% isolated yield).

Electron-rich boronic acids displayed marginally lower yields compared to the electron-deficient variants. The least effective arylboronic acid, p-hydroxyphenylboronic acid, also being the most electron rich, did not reach full conversion after 24 hours and the isolated yield was only 68%. In

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addition to the effect of electron-rich substrates, a possible (small) meta-effect was noticed. Comparison of 2-Me- (121ab), 3-Me- (121ac), and 4-Me-C6H4B(OH)2 (121ad) showed that the 2-Me boronic acid performed worst (79%) followed by the para-substituted (84%) and finally by the meta-substituted (88%). 2-OMe-substituted boronic acid (Table 11, entry 5) delivered the overall least efficient reaction in our series. Whether this is due to the electron rich character and/or because of steric demands (meta-effect) is not clear.

Table 11. Scope of arylboronic acids in the palladium(II)-catalyzed oxidative arylative carbocylization of enallene 97.(a)

Entry ArB(OH)2 Carbocycle Time (h) Yieldb (%)

1 C6H5 121aa 2 83

2 2-Me-C6H4 121ab 4 79

3 3-Me-C6H4 121ac 4 88

4 4-Me-C6H4 121ad 4 84

5 2-OMe-C6H4 121ae 4 61

6 3-OMe-C6H4 121af 4 87

7 4-OMe-C6H4 121ag 4 75

8 4-tBu-C6H4 121ah 5 82

9 4-TMS-C6H4 121ai 5 88

10 4-vinyl-C6H4 121aj 5 90

11 4-F-C6H4 121ak 5 90

12 4-Cl-C6H4 121al 5 82

13 4-Br-C6H4 121am 5 92

14 4-CF3-C6H4 121an 5 73

15 4-acetyl-C6H4 121ao 5 86

16 4-formyl-C6H4 112ap 5 95

17 3-NO2-C6H4 121aq 5 86

18 4-OH-C6H4 121ar 21 68c

(a) Reaction conditions: 97 (1.0 equiv.), Pd(OAc)2 (1 mol% ) BQ (1.1 equiv.), ArB(OH)2 (1.0 equiv.) THF, 60 oC. (b) Isolated yield after column chromatography. (c) 1.3 equiv. ArB(OH)2 was used.

Electron-deficient boronic acids (Table 11, entries 15-17) did not influence the reaction to any great extent apart from the slightly longer reaction times required to reach full conversion. We were also pleased to find that 4-formyl- (121ap) and 4-acetyl-substituted boronic acids (121ao)

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performed well, as these functional groups might serve as useful chemical handles in subsequent reactions (Table 11, entries 15-16).

Carbocyclizations employing halogenated boronic acids 121ak-121am gave the desired carbocyles without any further optimization (Table 5, entries 11-13,). Unfortunately, 4-I-C6H4B(OH)2, completely failed to produce the desired product, and the starting material could be recovered (not shown). Two other synthetically useful aryl boronic acids; 4-TMS (Table 11, entry 9) and 4-vinyl (Table 11, entry 10) also provided the desired arylated carbocycle in high yield without formation of side products arising from secondary catalytic reactions of these functional groups.

After realizing that most arylboronic acids seemed compatible with our protocol we wanted to investigate the limitations of the starting enallene. As depicted in Table 12, chemical yields were noticeably lower when steric bulk on the allene (Table 12, entry 6) or additional substituents on the olefin were introduced. Internal olefin 107 produced the desired carbocycle, having one new quaternary carbon, in good yield after extending the reaction time to 7 hours. A much longer reaction time (24 hours) was necessary to transform the E-phenyl substituted enallene 109, and even after an extended reaction time the corresponding carbocycle could be isolated in only 55% yield.

In previous studies regarding the oxidative borylation, we were searching for products being borylated on the allene-moiety (Chapter 7.1.2). However, such products were never observed in our crude reaction mixtures. In the arylative catalytic variant such arylated side-products were observed for the first time when enallene 109 was subjected to the catalytic reaction (Scheme 46, 126b). This type of by-product is of special interest when considering various mechanistic pathways.

Cyclic enallenes (22 and 111) underwent the carbocyclization/arylation sequence to give products with stereospecific cis-addition of the central carbon of the allene and the phenyl (from phenylboronic acid) to the olefin (Table 12, entries 4 and 5). For these instances a slight excess (1.3 equiv.) of phenylboronic acid clearly improved the transformation.

Increasing the steric demand on the allenic side chain completely shut down any catalytic activity (Table 12, entry 6). This was in sharp contrast to our previous studies on the borylative carbocyclization (Chapter 7.1.2) as well as the carbocyclization of aza-enallenes (Chapter 6.1.3), where this lack of activity was not as profound. The only reasonable explanation we have for this behavior is that in the arylation case, transmetallation might occur prior to coordination of the enallene. Formation of a Ar-PdOAc complex will probably suppress the “allene attack on palladium” (M40-M41), thus derailing the catalytic reaction.

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Table 12. Scope of different enallenes in the palladium(II)-catalyzed oxidative arylative carbocyclization.(a)

Entry Enallene Carbocycle Time (h) Yieldb (%)

1

2 83

2

7 76

3

24 55

4

2 61

5

4 63

6

24 N.R.c

(a) Reaction conditions: Enallene (1.0 equiv.), Pd(OAc)2,(1 mol%), BQ (1.1 equiv.), PhB(OH)2 (1.0 equiv., entries 1 and 2), (1.3 equiv., entries 3 to 6), THF, 60 oC. (b) Isolated yield after column chromatography. (c) No reaction based on 1H NMR analysis of the crude mixture, N. R = no reaction.

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7.2.3 Mechanistic Discussion

We believe that the mechanism in operation for the oxidative arylative carbocyclization (Scheme 46) is essentially the same as that suggested for the carbocyclization/borylation case. There are however some observations that require some comments. After initial coordination (M40) and subsequent allene attack on Pd(OAc)2 a (σ-vinyl)palladium(II) intermediate is obtained (M41). Probably, with certain substrates, this intermediate undergoes transmetallation (slow) followed by reductive elimination to give a new arylated-1,3-diene (126b).

Pd(II)

E E

E E

Pd(OAc)2

-HOAc

Pd(II)

E E

Pd(II)

EE

Pd(II)

Ph

EE

Ph

EE

EE

cis insertion

allene attack

coordination

transmetallation

BQ-coordination

red. elim.- Pd(0)

AcOB(OH)2

E E

Ph

1) transmetallation2) red. elim.

-H elimination

Observed Observed

M40

M41M42

M43

126b

Pd(II)/Pd(0)

catalytic cycle

additional ligands omitted for clarity

Pd(0)reoxidation

(BQ + HOAc)

AcO

AcO

E = CO2Me

ArB(OH)2

AcO

Scheme 46. Possible mechanism for the palladium(II)-catalyzed oxidative arylative carbocyclization of enallenes.

Despite this side product, the usual reaction pathway is still in operation. After insertion of the olefinic side-chain (M41) the crucial π-olefin-chelated (σ-alkyl)palladium(II) intermediate M42 is formed. This intermediate undergoes facile transmetallation, eliminating AcOB(OH)2 followed by reductive elimination to give the arylated carbocyle. Products from β-hydride elimination were also observed during this catalytic reaction and we believe they are being formed in the same manner as in the carbocyclization/borylation reaction, hence through ß-hydride elimination of M42.

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7.3 Conclusions on the Oxidative Arylative/Borylative

Carbocyclization of Enallenes.

In conclusion, we have developed two new powerful protocols evolved from our previous studies on palladium(II)-catalyzed oxidative carbocyclization of en- and dienallenes. Initially, we developed an oxidative borylative carbocyclization of enallenes. The overall catalytic protocol employs minimal amounts of the catalyst, Pd(OAc)2, as well as minimal amounts of both B2pin2 and BQ. Secondly, with minor adjustments of the reaction parameters, mainly replacing B2pin2 with ArB(OH)2, the reaction could be directed to produce arylated carbocycles. Gratifyingly, a range of structurally and electronically diverse arylboronic acids proved effective for this reaction.

Both procedures accepted a range of cyclic and acyclic enallenes. Generally, carbocycles were formed in moderate to high yield, including products with new quaternary carbon centers. In all cases the carbocycles are formed as one single diastereomer. We have determined that both the borylative and arylative carbocyclization proceeds exclusively through cis-carboborylation (or cis-carboarylation) of the olefin. This was done by examining the stereochemistry of the products using NMR- and X-ray techniques. Furthermore, a plausible mechanism for both the borylation- and arylation-processes, based on the observed product distribution was proposed.

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8. Palladium(II)-Catalyzed Formation of Oxazolidinones Through Cyclization of Allylic Tosylcarbamates – Scope, Mechanistic Aspects and Further Derivatization. (Paper -VI)

Oxazolidinones are common precursors to 1,2-aminoalcohols, a functionality present in many pharmaceuticals and natural products, as well as in the fundamental backbone of many asymmetric ligands.115 Owing to the abundance of this functionality, there are many efficient catalytic methods available leading these structural motifs.115,116 One very popular approach towards the oxazolidinone backbone involves the use of a palladium catalyst in combination with allylic tosylcarbamates (130). This particular methodology has been demonstrated to be highly modular, and catalytic reactions involving Pd(0), Pd(II) and Pd(IV) are efficient for this cyclization. A few recent representative examples of these processes are: amino-carbonylation117, amino-acetoxylation118 and amino-alkynylation119 (Scheme 47).

Scheme 47. Palladium-catalyzed formation of oxazolidinones from allylic tosylcarbamates.

In the majority of the above-mentioned catalytic protocols, cheap and readily available allylic alcohols are used as starting materials. However, this methodology is not strictly limited to this class of alcohols. Several

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examples involving palladium-catalyzed cyclization of carbamates bearing alkynes120 and allenes121 are represented in the literature.122

A closer look at these previous protocols revealed that one fundamental type of palladium(II)-catalyzed oxidative cyclization of allylic carbamates was not yet described, namely formation of vinyl substituted oxazolidinones. White37,123 recently published a range of cyclizations leading to the formation of oxazolidinones, albeit using homoallylic carbamates (134) as starting materials. For these examples, the cyclization proceeded via a (π-allyl)palladium(II) intermediate (M44), formed by a palladium(II)-bis-sulfoxide (White catalyst, 15) mediated allylic C-H activation (Scheme 48).123a

Scheme 48. White's approach to vinyl-oxazolidinones through palladium(II)-catalyzed C-H activation of homoallylic carbamates.

Our initial interest in the oxazolidinone skeleton emerged from previous projects on the preparation and oxidative carbocyclization of aza-enallenes (Chapters 5 and 6). More specifically, Trost96 and Hsung97 reported that bromoallenes could be coupled to oxazolidinones in high yield using copper(I)-catalysis., Unfortunately, neither Hsung´s nor Trost´s approach included vinyl-oxazolidinones. With this in mind we initiated a project, based on palladium(II)-catalyzed oxidation chemistry, which could potentially give us access to a variety of vinyl-substituted oxazolidinones. This would represent the first step towards a possible new substrate-class suitable for palladium(II)-catalyzed carbocyclizations (Scheme 49).

Scheme 49. Palladium(II)-catalyzed formation of oxazolidinones and anticipated further derivatizations.

Although this was the primary objective, we were also puzzled over the fact that the oxidative approach, relying on β-hydride elimination to furnish the oxazolidinone, appeared to be overlooked in the literature. We argue that the

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development of a reaction terminated by ß-elimination would be a useful addition to the already existing synthetic methodologies.

8.1 Results and Discussion

8.1.1 Finding Efficient Reaction Conditions

Crotyl carbamate 136 (E/Z = 12:1) was selected as the model substrate due to its availability and low cost. Treatment of crotyl alcohol (1.0 equiv.) with p-toluenesulfonyl isocyanate (TsNCO, 1.0 equiv.) in THF at room temperature produced the target allylic tosylcarbamate as a white solid in nearly quantitative yield. After considerable experimentation, reaction conditions rendering measurable amounts of vinyl-oxazolidinone 137 were found. The yields were at first very low, but solvent mixtures of THF and DMSO along with addition of a weak base, in the form of NaOAc, improved the efficiency.

At an early stage, a more detailed analysis of the formed by-products was undertaken. This revealed that in addition to the desired 5-exo-trig cyclization delivering the oxazolidinone, an allylic sulfonamide (138) was also formed in almost equimolar amounts (Table 13).

Table 13. Finding working conditions for the Pd(OAc)2-catalyzed oxidative cyclization of allylic carbamate 136.(a)

Entry

HOAc

(equiv.)

NaOAc

(equiv.)

Conversion

(%)(b)

Distribution

(137:138:139)(b)

1 0.5 none 100% 45:5:50

2 none 0.5 100% 40:20:40

3 2 1 100% 75:20:5

4 1 2 65% 55:35:10

5 7 1 100% 80:10:10

6 7 0.5 100% 85:10:5

7 3.5 0.5 100% 85:10:5 (a) Reaction conditions (unless otherwise noted): Allylic tosylcarbamate 136 (1.0 equiv.), 1 mol% Pd(OAc)2, 1.5 equiv. BQ, HOAc/NaOAc, THF/DMSO (9:1), 50 °C, 12 h.(b) Determined by NMR spectroscopy

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Selective formation of this rearranged product had been previously reported under Pd(OAc)2/LiBr catalysis by Lei84b, and seems to occur through a decarboxylative (6-endo-trig, Aza-Claisen) Overman-type rearrangement.124 It was also observed that the starting tosylcarbamate appeared to undergo hydrolysis under certain conditions to give the starting allylic alcohol 139. In order to minimize formation of the Overman- and hydrolysis-products an investigation of various reaction parameters was initiated. A short summary is presented in Table 13. The results could be concluded as follows: If catalytic amounts of NaOAc or HOAc were used separately (Table 13, entries 1-2) high conversions and low amounts of the Overman-product 138 were observed together with large amounts of the starting allylic alcohol 139. The most positive effect was observed when mixtures of HOAc and NaOAc were used (Table 13, entries 3-7). For example, a 2:1 mixture of HOAc/NaOAc (equivalents, with respect to allylic tosylcarbamate) gave full conversion of the carbamate with good selectivity for the oxazolidinone. The optimal ratio between HOAc and NaOAc was eventually found to be around 3.5-7:0.5 (equiv.). Regarding the solvent, mixtures of THF/DMSO (9:1) proved optimal. When less DMSO was used, lower conversions together with formation of palladium black were observed. On the contrary, addition of more DMSO had no further beneficial effect. Optimal reaction conditions were found to be 1 mol% of Pd(OAc)2, 1.5 equiv. of BQ, HOAc/NaOAc (7 equiv./0.5 equiv.) in THF/DMSO (9:1) at 50 °C. Using this set of parameters, full conversion was achieved within 12 hours, and further extending the reaction time did not seem to erode the yield to any measurable extent (Scheme 50).

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Scheme 50. Optimal conditions for the palladium(II)-catalyzed cyclization of allylic tosylcarbamate 136.

After having found efficient reaction conditions for the cyclization of crotyl carbamate 136 (E/Z = 12:1) to give the oxazolidinone 137, the influence of the stereochemistry of the double bond was investigated (Scheme 51).

Scheme 51. Behaviour of E- and Z-140 in the palladium(II)-catalyzed cyclization of allylic tosylcarbamates.

Z-140 was smoothly cyclized to give the oxazolidinone 141 in 95% yield together with only trace amounts of the Overman-product (142). This was in sharp contrast to the reactivity displayed by E-140 where 59% of the oxazolidinone 141 was obtained, accompanied by 20% of the Overman-product 142. This behavior was explained through a 6-membered transition state (Scheme 51), in which the Z-olefin suffers from 1,3-pseudo-diaxial strain, hence, disfavoring the 6-endo-trig type Overman-isomerization. This observation led us to use Z-substituted allylic alcohols for the subsequent investigation regarding the scope and limitations. Finally, at this stage of the investigation the initial 2-step procedure was replaced by a one-pot protocol by avoiding isolation of the allyl tosylcarbamate.

8.1.2 Scope and Limitations

Confident that an efficient catalytic protocol had been developed, a customary investigation of the scope and limitations was conducted (Table 14). Simple Z-substituted allylic alcohols 144 and (Z)-146 were smoothly transformed into the target oxazolidinones in excellent yield and high E/Z-selectivity (>20:1) using the one pot, two step procedure (Table 14, entry 2 and 4). Prenyl alcohol 147 was however considerably less reactive, and full conversion could not be achieved even after prolonged reaction times or

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increased catalytic loading (10 mol%) (Table 14, entry 5). Despite these much more forcing conditions the expected oxazolidinone 148 was isolated in only 40% yield.

Next the stereoselectivity of this transformation was probed using different secondary (Z)-allylic alcohols (Table 14, entries 6-11). In all cases tested, the reaction proceeded with excellent diastereoselectivity (>20:1) rendering trans-oxazolidinones in 62-95% isolated yield. The high degree of diastereoselectivity is a clear advantage of this approach, compared to the less diastereoselective protocol described by White.123 In the array of allylic carbamates evaluated, phenyl-substituted allylic alcohol 149 performed the worst (62%). In this case we were not able to separate the phenyl-oxazolidinone derivative from the Overman-product.

Table 14. Investigation of the scope and limitations for the palladium(II)-catalyzed cyclization of allylic tosylcarbamates.(a)

Entry Alcohol Oxazolidinone d.r. Yield

(%) Entry Alcohol Oxazolidinone d.r.

Yield

(%)

1

- 83 7

20:1 79(d)

2

- 81 8

ONTs

O

TBDMSO

154

20:1 78(d)

3

- 59 9

20:1 83(d)

4

- 95 10

20:1 81(b)

5

- 41(b) 11

46(b,c)

6

20:1

61(c,d)

(a) Carbamate formation: Allylic alcohol (1.0 equiv), TsNCO (1.05 equiv.), THF, r.t. 1 h. (b) Cyclization conditions: Allylic tosylcarbamate (1.0 equiv.), 1 mol% of Pd(OAc)2, 1.5 equiv. BQ, 7 equiv. AcOH, 0.5 equiv. NaOAc, THF/DMSO (9:1), 50 ºC, 12 h. (b) 10 mol% Pd(OAc)2, 48 h. (c) Hydrolysis of the crude oxazolidinone was undertaken to facilitate purification of the product. (d) Same conditions as (a) but 5 mol% Pd(OAc)2 and 48 h reaction time.

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Instead, the crude oxazolidinone was immediately hydrolyzed to give the 1,2-amidoalcohol 150 as a crystalline solid.

Cyclic allylic alcohol 157 proved slightly less efficient (Table 14, entry 10). Increasing the catalytic loading from 1 mol% to 5 mol% of Pd(OAc)2 was enough to regain acceptable conversions. Although an extensive study on the effect of peripheral functional groups were not undertaken, TMS-protected alcohol 153 was indeed compatible with the reaction conditions (Tabe 14, entry 8), producing TMS-functionalized oxazolidinone 154 in high yield and diastereoselectivity.

One attempt was made to cyclize homoallylic alcohols (159). Under our catalytic conditions, without any further modification, the desired 6-membered product could be obtained in moderate yield after prolonged reaction times and increased catalytic loading (Table 14, entry 11). Unfortunately, isolation of the cyclic carbamate proved impossible because of partial hydrolysis during both extraction and purification on silica gel. Instead, the analogous 1,3-amidoalcohol 160 was isolated after one hydrolysis step in 46% yield. Nonetheless, this indicated that the catalytic protocol was capable of forming 1,3-amido-alcohols, albeit in a rather modest yield.

8.1.3 Biomimetic Reoxidation and Scale Up

To probe the possibility of an aerobic, i.e. green(er) catalytic process, reaction conditions using molecular oxygen as the terminal oxidant was briefly evaluated. Without any co-catalysts large amounts of hydrolyzed, over-oxidized and rearranged products were observed in pure DMSO under an atmosphere of oxygen.

Instead our focus turned to a biomimetic approach using a cobalt-based metal macrocycle as electron transfer mediator. Replacing stoichiometric amounts of BQ with catalytic amounts (10 mol%), together with 5 mol% of Co(II)-salophen (161) under an atmospheric pressure of molecular oxygen rendered the desired oxazolidinones in acceptable yields (Scheme 52). Without essentially any further modification to the catalytic system, allylic alcohols 139 and (Z)-146 provided oxazolidinone 137 and 141 in 60% and 75% yield, respectively, after 72 hours. The yields for the aerobic version were slightly lower than that with stoichiometric amounts of BQ.

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Scheme 52. Palladium(II)-catalyzed cyclization of allylic tosylcarbamates using an aerobic (biomimetic) reoxidation system.

As we were aiming to use the substrates for further functionalization within various other projects, we decided to scale up this process. Linear scale up of our small scale reaction proved reasonably effective, with one minor modification: Formation of the starting allylic tosylcarbamate was conducted at 0 °C instead of room temperature. Two different substrates were used for this scale up 139 (27.7 mmol) and 144 (34.8 mmol). The corresponding oxazolidinones were isolated in 75% and 78% yield, respectively (Scheme 53). The desired products were collected by simple precipitation from ethyl acetate (after extraction), hence no further chromatographic purification was necessary.

Scheme 53. Scale up of the palladium(II)-catalyzed cyclization of allylic tosylcarbamates 139 and 144.

8.1.4 Further Transformations of the Oxazolidinones

To further extend the synthetic utility of the developed oxidative cyclization, a range of subsequent transformations was developed. First an enzymatic kinetic resolution (KR) protocol was investigated for substrate 137 (Scheme 54). Our approach can be outlined as follows: Hydrolysis of oxazolidinone 137 under standard conditions rendered the 1,2-amidoalcohol (rac-162), which was then subjected to Lipase AK (Amano 20) along with an acyldonor (164) in toluene at room temperature for 20 hours. At 51% conversion the amidoacetate (R)-163 was isolated in 42% yield with 89% ee. The remaining unreacted amidoalcohol (S)-162 was isolated in 48% yield

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and 93% ee. The E-value for this kinetic resolution was determined to be around 60.

Scheme 54. Hydrolysis and kinetic resolution of oxazolidinone 137 using Lipase AK (Amano 20).

A few oxazolidinones were also subjected to a few other synthetically interesting transformations. First a Wacker-type oxidation (Scheme 55, A) was developed using conditions previously reported by Feringa.125 Indeed this gave rise to the expected methyl ketone 165 in 75% isolated yield. Selectivity for the ketone (vs. aldehyde) was high (95:5) and the reaction was complete within 16 hours.

Scheme 55. Further transformations of tosyl-protected oxazolidinones.

Oxazolidinone 137 was also subjected to a cross-metathesis (Scheme 55, B) reaction with methyl acrylate. Addition of 5 mol% Hoveyda-Grubbs 2nd generation catalyst in two portions (2.5 mol% each time), together with 137 (1 equiv.) and methylacrylate (3 equiv.) in DCM produced the desired α-ß-unsaturated compound 166 in an acceptable yield of 69% with a 10:1 selectivity for the E-isomer. This particular starting material is currently

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being evaluated further in the total synthesis of (+/-)-Kainic acid (Scheme 55, 79).126

Inspired by recent achievements in oxidative Heck-chemistry, 137 was subjected to an oxidative Heck-type reaction (Scheme 55, C) using BQ as oxidant and phenylboronic acids as the arylsource.127,48,60 This transformation was originally intended to be conducted as a one-pot reaction coupled to the cyclization, however we were unable to obtain acceptable yields using this approach. Instead a two-step sequence was developed. Treatment of 137 with 5 mol% of Pd(OAc)2, 10 mol% of 1,10-phenanthroline (L9), 1.3 equiv. of ArB(OH)2 and 1.5 equiv. of BQ in a THF/DMSO mixture (1:1) at room temperature gave rise to (E)-arylated oxazolidinones (167a-e) in high yields (87-96%) with E/Z-selectivites around 15:1. An array of diverse arylboronic acids, including TMS-groups and chlorides, proved compatible with this transformation.

Finally, and most importantly, an easy and reliable procedure for the removal of the p-toluenesulfonyl (Ts) group was investigated. The classical deprotection strategy using sodium/napthalene at low temperatures is generally rather time consuming and impractical.128 Ragnarsson et. al. reported that magnesium in MeOH under ultrasonic conditions was capable of cleaving various tosyl-carbamates.129 When oxazolidinone 145 was subjected to magnesium powder in MeOH at room temperature, cleavage along with large amounts of the tosyl protected 1,2-amidoalcohol (169) was observed (Scheme 56). Gratifyingly, the undesired hydrolysis product could be almost completely suppressed when the reaction was conducted at 0 °C in dry MeOH. Using these conditions the deprotected oxazolidinone 168 was obtained in 82% isolated yield as a colorless solid.

Scheme 56. Deprotection of tosyl-oxazolidinone 145 under ultrasonic conditions.

8.1.5 Stereochemical Analysis and X-ray Structures

Most of the oxazolidinones described in this study are known in the literature and good spectrometric data is available for either identical compounds or structurally related derivatives. Although compound 158 is known and has appeared in a series of publications, the NMR-shifts reported were not of satisfactory quality to be compared with our results. Instead of relying on previous data, crystals were grown and subjected to X-ray

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analysis. Indeed this confirmed the cis stereochemistry of 158, as already indicated by NMR spectroscopy (Figure 13, left).130 The trans-relationship of the remaining oxazolidinones was assigned based on the X-ray structure of 156

131 together with known 1H NMR coupling constants (Figure 13, right).123b

Figure 13. X-ray structure of 158 (left) and 156 (right).

8.1.6 Deuterium Labeling and Mechanistic Discussion

Palladium is known to undergo both cis- and trans-amino/amidopalladation depending on the characteristics of the amide and reaction parameters. We set out to investigate which mechanistic pathway was in operation for this novel cyclization. To illuminate this aspect, trans-deuterated cyclic allylic alcohol trans-175-d1 was synthesized as outlined in Scheme 57.132

Scheme 57. Synthesis of trans-175-d1 form 1,3-cyclohexadiene.

The synthesis was achieved through cis-1,4-acetoxychlorination38c of 1,3-cyclohexadiene to give 171 followed by DIBAL-H mediated cleavage of the acetyl-group to give cis-1,4-chloroalcohol cis-172. Protection of the alcohol with TBDMSCl and imidazole then gave cis-173. Finally, SN2 type nucleophilic substitution of the chloride with a deuterium and subsequent deprotection of the TBDMS-group was achieved using LiAlD4 and TBAF to give trans-175-d1.

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The trans-deuterated allylic alcohol (trans- 175-d1) was then subjected to the standard cyclization conditions described in Scheme 58. Analysis of 158 after the reaction revealed that the deuterium atom had been completely removed.

Scheme 58. Investigation of the mechanism for palladium(II)-catalyzed cyclization of trans-176-d1.

It has been shown that the stereochemistry of true aminopalladations are always trans.133 On the contrary, in the case of amidopalladations such as sulfonamidopalladation and sulfoacetamidopalladation the addition to the double bond can occur with either cis37a,134 or trans135,118 stereochemistry. Stahl and coworkers conducted an elegant and systematic study (similar to the work by Stoltz for oxypalladation46d) on the aza-Wacker addition of different sulfonamides to double bonds. Their work concluded that many different parameters guide the stereochemistry of the aminopalladation step.136

Having performed the cyclization of trans-176-d1 and observed complete removal of the deuterium we can only argue that the mechanism has to occur through either trans-amidopalladation (Scheme 59, upper pathway) or via some form of π-allyl intermediate (Scheme 59, middle). This conclusion rely on the simple fact that the final step, ß-elimination, occurs with a hydride/deuteride aligned syn to the palladium(II)-center. As indicated in the cis-amidopalladation pathway (Scheme 59, M49 + M50), the palladium metal center cannot align syn to the deuterium, hence they are anti, and ß-elimination will occur with the hydride.

For trans-amidopalladation, coordination of palladium(II) to the olefin occurs prior to external attack (trans) by the tosyl-carbamate. In this case the deuterium and the metal center will end up on the same side (syn) and the deuterium is expected to be removed through ß-deuteride elimination (Scheme 59, M45-M46). The intermediate π-allyl pathway (Scheme 59, middle) could possibly give rise to 158 from trans-176-d1, however control experiments using the homoallylic carbamate 177, instead of the allylic derivative, lead us to the conclusion that this pathway was probably not in operation (Scheme 60).

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Scheme 59. Possible mechanistic pathways for the palladium(II)-catalyzed cyclization of allylic tosylcarbamate trans-176-d1.

Some additional evidence strengthening the trans-amidopalladation reaction pathway was indirectly obtained. Clearly, the developed process displayed high diastereoselectivity (>20:1), which is in sharp contrast to the related protocol developed by White. In the latter case, diastereoselectivity was generally around 6:1. This might indicate a different mechanistic pathway between the two different reactions. White has shown that their catalytic reaction is operating through C-H activation, forming a (π-allyl)palladium(II) intermediate.

Scheme 60. Attempted palladium(II)-catalyzed cyclization of homoallylic tosylcarbamate 177.

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Taking all of our experimental data into account we conclude that the reported palladium(II)-catalyzed aza-Wacker cyclization proceeds through trans-amidopalladation followed by β-H elimination.

8.2 Conclusions

Starting from readily available allylic alcohols and tosyl isocyanate (TsNCO) a highly efficient cyclization protocol employing as little as 1 mol% Pd(OAc)2 has been developed. Overall, the protocol leads oxazolidinones in isolated yields ranging from 40-95% with excellent diastereoselectivity (>20:1). This particular catalytic process was easily scaled up to 35 mmol (of the starting allylic alcohol) without any substantial loss in efficiency.

In addition to the study of the cyclization of allylic tosyl carbamates, a variety of subsequent transformations of the acquired oxazolidinones have been investigated. For example, a palladium(II)-catalyzed ketone-selective Wacker-oxidation and a palladium(II)-catalyzed oxidative Heck-type reaction were successfully realized. A mild and operationally simple tosyl deprotection strategy using only magnesium in MeOH under ultrasonic irradiation was also developed.

In order to determine the actual sterical mode of amidopalladation (trans vs. cis.), the mechanism was studied through deuterium labeling experiments. The requisite deuterated compound was synthesized and characterized. Results from the deuterium-labeling study strongly indicate that the reaction occurs via an overall trans-amidopalladation.

We are currently testing whether the deprotected oxazolidinones will undergo coupling with bromoallenes to give well-defined aza-enallenes, suitable for subsequent palladium(II)-catalyzed oxidative carbocyclizations.

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10 Concluding Remarks

To begin with, we have developed a stereoselective palladium(II)-catalyzed oxidative 1,4-carbohydroxylation of allene-substituted 1,3-dienes (dienallenes). This novel catalytic carbocyclization rendered hydroxylated carbocycles in high yield. Two different reoxidation-protocols were evaluated, one relying on stoichiometric amounts of BQ, and the other using molecular oxygen as terminal oxidant. Remarkably, both reoxidation-systems proved equally efficient with respect to conversion and chemical yield. Most importantly, the developed protocol showcases that water can act as a nucleophile on (π-allyl)palladium-complexes, a process which is rarely observed.

The second and third chapter involved development of new synthetic methodology towards a palladium(II)-catalyzed carbocyclization of aza-enallenes. In order to obtain the starting aza-enallenes, we first successfully developed a copper(I)-catalyzed coupling of allylic sulfonamides with bromoallenes. In addition to the study of the scope and limitations of this process, the stability of the acquired aza-enallenes was determined. The requisite aza-enallenes were then used in a palladium(II)-catalyzed oxidative carbocyclization. After considerable experimentation, catalytic conditions rendering hydropyrroles in good yield were found. An array of aza-enallenes proved compatible with the developed protocol. In a similar fashion as discussed above, reoxidation was achieved by the use of either stoichiometric quantities of BQ or a biomimetic reoxidation system utilizing O2. After realizing an efficient biomimetic reoxidation, employing a BQ-tethered metal macrocycle, we also developed a tandem oxidative carbocyclization/Diels-Alder reaction using activated dienophiles.

By combining information from all our previous enallene carbocyclizations, and conclusions drawn from a DFT-study, an oxidative arylative/borylative carbocyclization of enallenes was successfully developed. This transformation was achieved by introducing transmetallation reagents such as B2pin2 or arylboronic acids to the oxidative carbocyclization reaction. The reaction proved highly stereoselective and allowed for formation of new carbon-carbon and carbon-boron bonds. The mechanism behind this novel reactivity has been suggested to involve a (σ-alkyl)palladium(II) intermediate being stabilized by a pending olefin. This interaction probably opens up a path to achieve transmetallation.

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In the final chapter a new cyclization methodology was developed for the formation of vinyl substituted oxazolidinones. This Pd(OAc)2-catalyzed process proved efficient and readily scalable. It was demonstrated that the reaction proceeds through trans-amidopalladation.

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Reprint Permissions (Appendix A)

Paper I - Reprinted with permission from: Water as Nucleophile in Palladium-Catalyzed Oxidative

Carbohydroxylation of Allene-Substituted Conjugated Dienes

Julio Piera, Andreas Persson, Xisco Caldentey, and Jan-E. Bäckvall J. Am. Chem. Soc., 2007, 129 (46), pp 14120–14121 Copyright (2007) American Chemical Society. Paper II - Reprinted with permission from: Copper-Catalyzed N-Allenylation of Allylic Sulfonamides

Andreas K. Å. Persson, Eric V. Johnston and Jan-E. Ba ̈ckvall Org. Lett., 2009, 11 (17), pp 3814–3817 Copyright (2009) American Chemical Society. Paper III - Reprinted with permission from: Palladium(II)-Catalyzed Oxidative Carbocyclization of Aza-Enallenes

Andreas K. Å. Persson and Jan-E. Bäckvall Angew. Chem. Int. Ed. 2010, 49, 4624–4627 Copyright (2010) John Wiley and Sons.

Paper IV - Reprinted with permission from: Palladium-Catalyzed Oxidative Carbocyclization/Arylation of Enallenes

Tuo Jiang, Andreas K. Å. Persson, and Jan-E. Bäckvall Org. Lett., 2011, 13 (21), pp 5838–5841 Copyright (2011) American Chemical Society.

Paper V - Reprinted with permission from: Palladium-Catalyzed Oxidative Borylative Carbocyclization of

Enallenes Andreas K. Å. Persson, Tuo Jiang, Magnus T. Johnson and Jan-E. Bäckvall Angew. Chem. Int. Ed. 2011, 50, 6155 –6159 Copyright (2011) John Wiley and Sons.

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Acknowledgements

I would like to express my sincerest gratitude to the following people: My supervisor, Prof. Jan-Erling Bäckvall for accepting me as a Ph. D.

candidate in your group. Thanks for all the inspiration, motivation, support, and for letting me work on challenging and interesting projects. My collaborators and friends

Jan Deska, what would I have done without you? Thanks for the massive support you have given me during these years. I would be much less of a chemist without your wise words. Also, thanks for taking such good care of me during my 3 month stay at Uni. Cologne, unforgettable! Wish you the best in the future and I am looking forward to future discussions. “allenes on top of the world!”

Julio Piera Balaguer, for being the number one diploma-work supervisor

and friend. My time at Stockholm University would not have been the same without you and your epic quote (one out of many): “relax your long body”. It has been a true pleasure to have met and worked with you.

Tuo Jiang, for the collaboration on the allene-projects, and for being an

exceptionally good diploma student! I was very lonely with my allenes before you came and cheered me up…

Annika Träff, for all the nice discussions, lunches, “spex” etc (long list!).

Most importantly, thanks for providing me with a tiny bit of your “monster” organization skills, they have been much needed! I am pretty sure we will see more of each other in the future…

Reanud Millet, for being a good friend both inside and outside the lab.

Chemistry was good, fondue was great, and the rest was excellent! Magnus Johnson, for supplying X-ray structures with such enthusiasm!

Our conference trips have been great and I hope our paths will cross again both on a personal and professional level.

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My co-workers for good collaborations on various projects: Tuo Jiang, Teresa Bartholomeyzik, Antoine Joosten, Julio Piera Balaguer, Xisco Caldentey, Lisa K. Thalén, Eric Johnston, Magnus Johnson and Youqian Deng.

My friends and colleagues who have improved and commented on this

thesis: Jan Deska, Teresa Bartholomeyzik(!), Nanna Ahlsten, Tuo Jiang, Johanna Persson and Renaud Millet. Your help has been priceless!

My diploma workers and Erasmus-students Tuo Jiang, Lidya Aho Soysal,

Paula Martirez, and last but definitely not least: Natascha “spatz” Bruckner. It has been a pleasure working with each and every one of you.

All the people at the Department (past and present), for making my time

here at Stockholm University very enjoyable! All the people who made my stay at Uni. Cologne such a great time: Jan,

Chicco, Axel, Philip, David, Thomas, Sabrina, Lars, Daniel, Benedikt and Matthias. Best of luck to all of you!

Financial support from K & A Wallenberg´s travel scholarship, C. F.

Liljevalch travel scholarship, The Swedish Chemical Society travel scholarship, Ångpanneföreningens (ÅF) scholarship, Astra Zeneca travel scholarship in memory of Nils Löfgren and finally the Berzelii Center EXSELENT for traveling grants.

All past and present members of the JEB-group: Jan, Madde, Krisztián,

Patrik, Katrin , Christine, Dirk, Julio, Lisa, Linnéa, Jenny, Karin L., Annika, Karin E., Tuo, Teresa, Sasha, Maria, Jonas, Anuja, Tony, Anders, Deng, Min, Baneesh, Ibrar, Jean-Baptiste, Renaud, Antione, Alex, Ylva, Richard, Micke, Byron, Hoa, Bao-Lin, Markus, Oscar, Eric, Xisco, Erik, Yoshi, Mozaffar, Xu, Thanks for making my time at the department great! (I hope I didn´t miss anyone!)

The TA-staff: Martin, Britt, Louise, Christina, Kristina, Joakim, Pia and

Olle. A special thanks goes out to: Martin Roxengren for making the aluminum heating blocks, and to Britt Eriksson for always keeping track of the administrative things that I don’t understand.

My lecturers at MdH: Simon Dunne and Sarah Angus-Dunne for giving

me the best education in organic chemistry.

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All the other MdH-people who made my time there so enjoyable: Jocke a.k.a. “Bosse”, Jonas a.k.a. “Bosse”, Linda, Martina, Kristofer, Henrik and Therese.

The “French dinner mafia” Richard Lihammar, Renaud Millet, Antoine

Joosten. The monthly (pseudo-scientific?) Akkurat beer gang: Alex Kasrayan,

Patrik Krumlinde, Gaston Lavén and Julio Piera Balaguer. We continue, right?

All the members of ÅGC: Kalle, Johan, Tälje, Hage, Jens, Macke and

Svenne for being the best friends in the world, period! All the Östlund family (and affiliates) Perra, Annika, Magda, Staffan,

Marita and Fredrik. for nice dinners and gatherings: My mother (Carina Mårtensson), father (Åke Persson) and sister (Lina

Persson) for your unconditional love, mental support and believing in me from day one. It is always a pleasure travelling “back south” to let go of some steam and chat about life in general. Finally…

To my wife: Johanna Thank you for all the support, love, tears and laughs. My 8 years with you have been the best of my life and I’m sure it will only become better…Älskar dig!

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