N-Heterocyclic Carbenes in the Alkyl-Alkyl Negishi Cross-Coupling Reaction and Its Application Toward the Synthesis of Rhizochalin

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N-Heterocyclic Carbenes in the Alkyl-Alkyl Negishi Cross-Coupling Reaction and its Application toward the Synthesis of Rhizochalin

Niloufar Hadei

A Dissertation Submitted to the Faculty of Graduate Studies in Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy

Graduate Program in Chemistry York University Toronto, Ontario

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••I Canada N-Heterocyclic Carbenes in the alkyl-alkyl Negishi cross-coupling reaction and its application toward the synthesis of Rhizochalin

By Niloufar Hadei

a dissertation submitted to the Faculty of Graduate Studies of York University in partial fulfillment of the requirements for the degree of

DOCTOR OP PHILOSOPHY

Permission has been granted to: a) YORK UNIVERSITY LIBRARIES to lend or sell copies of this dissertation in paper, microform or electronic formats, and b) LIBRARY AND ARCHIVES CANADA to reproduce, lend, distribute, or sell copies of this dissertation anywhere in the world in microform, paper or electronic formats and to authorize or procure the reproduction, loan, distribution or sale of copies of this dissertation anywhere in the world in micro form, paper or electronic formats.

The author reserves other publication rights, and neither the dissertation nor extensive extracts from it may be printed or otherwise reproduced without the author's written permission. ABSTRACT

An efficient method for the alkyl-alkyl Negishi cross-coupling reaction of unactivated primary alkyl halides with alkyl organozinc reagents using an N-heterocyclic carbene- based Pd catalyst has been developed. A number of N-heterocyclic carbenes (NHCs) were prepared and evaluated as ligands for a range of cross-couplings. Among these, 1,3- bis (2,6-diisopropylphenyl) imidazolium chloride (IPrHCl) demonstrated the highest reactivity when used in combination with Pd2(dba)3. This initial work eventually led to the development of an air- and moisture-stable NHC-Pd pre-catalyst, Pd-PEPPSI-IPr

(Pyridine-Enhanced Precatalyst Preparation, Stabilization, and Initiation) which was shown to be superior to the in-situ generated catalyst in terms of improved reproducibility and catalyst turn-over number. The optimized protocol using Pd-PEPPSI-IPr allowed for the coupling of a variety of alkyl- and aryl- halides, and pseudohalides with organozinc reagents providing the corresponding products in some of the highest isolated yields reported to date for this chemical transformation. Moreover, the developed protocol is generally applicable and tolerant of a variety of functional groups including esters, nitriles, and amides. Further investigations confirmed similar reactivity of Pd-PEPPSI-IPr in aryl-aryl Kumada-Tamao-Corriu cross-coupling reaction. The developed methodology was then applied to the synthesis of the naturally occurring sphingolipid rhizochalin, using the Pd-PEPPSI-IPr catalyzed alkyl-alkyl Negishi cross-coupling reaction as a key- step.

iv ACKNOWLEDGMENT

/ would like to thank all those who have helped and inspired me during my doctoral study. I especially want to thank my supervisor, Prof. Michael G. Organ, for his detailed and constructive comments, and for his continuous support throughout this work. Prof. P.

G. Potvin, Prof. E. Lee-Ruff, Prof A. Orellana, Prof. B. Loughton, and Prof. J. E.

Backvall deserve special thanks as my thesis committee members and advisors. I would also like to thank all my lab colleagues in Prof. Organ's group for their friendship and support, especially Dr. Chistopher O 'Brien and Dr. Erik Kantchev. Special thanks to Dr.

Howard Hunter for his help with NMR spectroscopy. I would also like to thank Dr. Cory

Valente and George Achonduh for proofreading my thesis and their helpful comments. I owe my loving thanks to my husband and my beautiful daughter Nadia. Without their encouragement and understanding, it would have been impossible for me to finish this work. My special gratitude is due to my parents, my sister, and brothers, and their families, for their loving support.

v TABLE OF CONTENTS Page

Abstract iv Acknowledgment v Table of Contents vi List of Figures ix List of Tables xii List of Abbreviations xiv

Chapter One: Introduction 1. Alkyl-Alkyl cross-coupling reactions 2 1.1 Background 2 1.2 The mechanism of the cross-coupling reaction 4 1.3 Common metals used in cross-coupling reactions 6 1.4 Leaving group effect 7 1.5 Palladium in cross-coupling reactions 8 1.6 The role of the ligand on the metal catalyst in the catalytic cycle 9 1.6.1 Organophosphines 10 1.6.2 Phosphines as ligands in cross-coupling reactions 12 1.6.3 N-Heterocyclic Carbenes (NHCs) 16 1.6.4 Electronic Features of NHCs versus phosphine ligands 18 1.6.5 Complex stability of NHC ligands versus phosphines on a metal 19 1.6.6 Steric effect comparision between NHC and phosphine 20 1.6.7 Formation and stability of carbenes 21 1.6.8 Common NHC ligands and complexes in cross-coupling reactions 21 1.6.9 Synthesis of imidazolium salts 23 1.7 Previous success in alkyl-alkyl cross-coupling reactions 26 1.7.1 The Suzuki-Miyaura reaction 26 1.7.2 The Negishi reaction 28

vi 1.7.3 Kumada-Tamao-Corriu (KTC) cross-coupling reaction 31 1.8 Plan of study 33 1.8.1 Ligand design 33 1.8.2 Evaluation of NHC-Pd precatalyst 34 1.8.3 Application of Pd-PEPPSI catalysts in natural product synthesis 34 Chapter Two: N-Heterocyclic Carbene ligands: synthesis and application in 36 alkyl-alkyl Negishi cross-coupling reaction 2. Result and Discussion 37 2.1 Ligand precursor synthesis 37 2.1.1 Benzimidazolium salts 37 2.1.2 Benzimidazolium salts in Negishi and Suzuki coupling reaction 38 2.1.3 Synthesis of imidazolium ligands 41 2.2 Evaluation of NHC salts in alkyl-alkyl Negishi coupling reaction 44 2.2.1 Ligand screening 44 2.3 Substrate scope for the alkyl-alkyl Negishi cross-coupling reaction 50

Chapter Three: Development and application of Pd-PEPPSI complexes in 54 Negishi and Kumada-Tamao-Corriu cross-coupling reactions 3. Development of NHC-Pd precatalysts 55 3.1 Application of Pd-PEPPSI-complexes in Negishi reaction 5 7

3.1.1 Comparison between Pd2dba3/IPr HC1 and Pd-PEPPSI-IPr 5 8 3.1.2 Catalyst loading study 60 3.1.3 Evaluation of non-activated alkyl halides and pseudohalides 62 3.1.4 Substrate study 63 3.1.5 Use of additives 65 3.1.6 Alkyl-Aryl Negishi reaction 69 3.1.7 Optimization of aryl-aryl Negishi reaction 70 3.1.8 Substrate scope 71 3.2 The Kumada-Tamao-Corriu (KTC) reaction 74 3.2.1 Aryl-Aryl KTC reaction 74

vn 3.2.2 optimization of the Pd-PEPPSI catalyzed KTC reaction 75 3.2.3 Evaluation of different Pd-PEPPSI-complexes 76 3.2.4 Substrate scope for the KTC cross-coupling reaction 79 3.2.5 Comparison between Pd-PEPPSI-IPr and phosphine-based catalysts 83 Chapter Four: Evaluation of Pd-PEPPSI-IPr in natural product synthesis 87 4.1 Background 88 4.2 First retrosynthetic approach 90 4.2.1 Synthesis of fragment 147 91 4.3 Second retrosynthetic approach 93 4.3.1 Synthesis of fragment 151 97 4.3.2 Synthesis of 2,3-O-isopropylidene-D-glyceraldehyde nitrone 98 4.4 Third retrosynthetic approach 101 4.4.1 Synthetic route 102 4.5 Forth retrosynthetic approach 104 4.5.1 Synthesis of fragment 197 105 4.5.2 Synthesis of the fragment 188 108 4.5.3 Final cross-coupling reaction 109 Chapter Five: Experimental 111 5.1 General experimental for benzimidazolium ligand synthesis 112 5.2 General method for Suzuki reactions 117 5.2.1 General experimental for imidazolium type ligand synthesis 118 5.3 Negishi alkyl-alkyl cross-coupling reactions 129 5.4 Synthesis of the NHC-PdCl2-3-chloropyridine complexes 136 5.4.1 General procrdure for the alkyl-alkyl Negishi coupling 137 5.4.2 Cross-Coupling procedure and characterization for figure 24-26 140 5.5 Sp2-Sp2 Kumada cross-coupling reactions 151 5.5.1 Kumada-Tamao-Corriu (KTC) aryl-aryl cross-coupling procedures 152 5.6 Natural product synthesis 163 References 193

viii LIST OF FIGURES Page

Figure 1. General simplified mechanism for Pd-catalyzed alkyl-alkyl 5 cross-coupling Reactions

Figure 2. The reactivity of the organometallic reagents of common metals in 7 catalytic cycle

Figure J. The reactivity of different leaving group in cross-coupling reactions 8

Figure 4. Reactivity of the functional groups toward palladium 9

Figure 5. Cone angle of metal-trimethyl phosphine ligand 11

Figure 6. Mechanism of P-hydride elimination in alkyl-alkyl coupling reaction 13

Figure 7. Mono-phosphine palladium complexes effective in Suzuki coupling 14 reaction

Figure 8. Buchwald's ligands 15

Figure 9. Buchwald's mono-phosphine palladium complex 16

Figure 10. Stabilization of NHCs 17

Figure 11. Resonance structures of NHCs 18

Figure 12. Steric effects of NHC versus phosphine 21

Figure 13. Active NHC ligands and complexes for use in cross-coupling 23 reactions

Figure 14. Benzimidazolium carbenes 32

Figure 15. Imidazolylidine and imidazolinylidene type ligands 33

Figure 16. The structure of rizochalin 35

Figure 17. NHC ligands 46

Figure 18. Room-temperature Negishi cross-coupling reactions of unactivated 53 alkyl bromides with alkylzinc reagents

IX Figure 19. The structure of Pd-PEPPSI-complexes 57

Figure 20. Comparison between PEPPSI-protocol and in-situ protocol in the 60 Negishi cross-coupling reaction

Figure 21. Turn Over Number (TON) values for Pd-PEPPSI-IPr as a precatalyst 61 and in-situ protocol in alkyl-alkyl Negishi cross-coupling reaction

Figure 22. Pd-PEPPSI-IPr catalyzed room temperature Negishi cross-coupling 65 reaction

Figure 23. Variation of the percentage of DMI in THF in the Negishi reaction 69

Figure 24. Alkyl-alkyl Negishi cross-coupling reaction 73

Figure 25. Alkyl-Aryl Negishi cross-coupling reaction 74

Figure 26. Aryl-Aryl Negishi cross-coupling reaction 75

Figure 27. The effect of temperature on the reactivity of Pd-PEPPSI-IPr 79

Figure 28. Kinetic study of Pd-PEPPSI-IPr and SIPr in the KTC reaction 80

Figure 29. Substrate evaluation in aryl-aryl KTC reaction 81

Figure 30. Substrate evaluation in aryl-aryl KTC reaction 82

Figure 31. Substrate evaluation in aryl-aryl KTC reaction 83

Figure 32. Comparision between the reactivity of different catalysts in the KTC 84 reaction

Figure 33. Crude 'H-NMR spectra of the KTC reaction using different catalysts 86

Figure 34. Structure of rizochalin and naturally occurring aminoalcohol lipid 90

Figure 35. Structure of sphingosine and sphingolipid 91

Figure 36. First retrosynthetic approach 92

Figure 37. Second retrosynthetic plan 95

Figure 38. Third retrosynthetic approach 103 Figure 39. Stability of organozinc reagents in THF and DMF 105

Figure 40. Forth retrosynthetic approach 106 LIST OF TABLES Page

Table 1. Cone angle of common phosphine ligands 11

Table 2. Common phosphine ligands for cross-coupling reactions 12

Table J.Carbonyl stretching frequencies of LNi(CO)3 complexes 19

Table 4. Bond dissociation energy of different ligands to Ni 20

Table 5. Evaluation of benzimidazoliun ligands in Suzuki-Miyaura sp2-sp2 40 cross-coupling

Table 6. The activity of ligands 38-40 in Suzuki cross-coupling reaction 41

Table 7. Synthesis of unsymmetrical imidazolium salt 44

Table 8. Evaluation of different ligands in the Negishi cross-coupling reaction 45

Table 9. Optimization study in the alkyl-alkyl Negishi cross-coupling reaction 48

Table 10. Optimization of reaction conditions for the alkyl-alkyl Negishi cross- 50 coupling reaction

Table 11. Variation of palladium to ligand ratio in Negishi cross-coupling 51 reaction

Table 12. Synthesis of Pd-PEPPSI-complexes 57

Table 13. Evaluation of the Pd-PEPPSI-complexes in the alkyl-alky Negishi 58 cross-coupling reaction

Table 14 .Pd-PPEPSI-IPr loading study in Negishi coupling reaction 62

Table 15. Pd-PEPPSI-IEt kinetic study in the alkyl-alkyl Negishi cross- 63 coupling reaction

Table 16. Variations of the electrophiles in alkyl-alkyl Negishi cross-coupling 64 reaction

Table 17. Effect of additives and solvent polarity in Negishi coupling reaction 68 Table 18. Effect of solvent polarity on oxidative addition 69

Table 19. Alkyl-Aryl Negishi cross-coupling reaction 70

Table 20. Solvent study in aryl-aryl Negishi coupling reaction 71

Table 21. Aryl-Aryl Negishi cross-coupling reaction 72

Table 22. Optimization study for the aryl-aryl KTC reaction 77

Table 23. Catalyst screening in the aryl-aryl KTC reaction 78

Table 24. Epoxidation of compound 155 96

Table 25. Stereoselectivity of the Grignard addition to BIGN 163 99

Table 26. Diastereoselectivity ratio in compound 190 107

xiii LIST OF ABBREVIATIONS

AA aminohydroxylation

Ac acetyl acac acetylacetonate

ACN acetonitrile

Ad adamantyl

9-BBN-H 9-borabicy clo [3.3.1] nonane

BIGN 2,3-O-isopropylidene-D-glyceraldehydenitrone

BINAP 2,2'-bis (diphenylphosphino)-1,1 '-binaphthylbenzyl

Boc J-butyloxycarbonyl

°C degree Celsius

Cat. catalytic

Cbz benzyloxycarbonyl

Cy cyclohexyl

Cyp cyclopentyl dba dibenzylideneacetone

DEAD diethyl azodicarboxylate

(DHQD)2PHAL bis(dihydroquinidino)phthalazine

DIBAL-H diisobutylaluminium hydride

DMA dimethylacetamide

DMAP 4-dimethylaminopyridine

XIV DME dimethoxyethane

DMF dimethylformamide

DMI 1,3-dimethylimidazolidin-2-one

DMP Dess-Martin periodinane

DMP 2,2-dimethoxypropane

DMSO dimethyl sulfoxide dppb l,4-bis(diphenylphosphino)butane dppe 2-(diphenylphosphino)ethane dz'-ppp l,3-bis(diisopropylphosphino)propane equiv. equivalent

ESR electron spin resonance

GC/MS Gas Chromatography/Mass Spectrometry h. hour

HMDS 1,1,1,3,3,3-hexamethyldisilazane

HOMO highest occupied molecular orbital

HPvMS high-resolution mass-spectroscopy

IBX ort/zo-iodoxy benzoic acid

I/BuHCl 1,3-bis(2,6-di-z's0-butylphenyl)imidazolium chloride

IEtHCl 1,3-bis(2,6-diethylphenyl)imidazolium chloride

IMes-HCl 1,3-bis(2,6-trimethylphenyl)imidazolium chloride

I/PentHCl 1,3-bis(2,6-di-/s0-pentylphenyl)imidazolium chloride

IPrHCl 1,3-bis(2,6-di-z'so-propylphenyl)imidazolium chloride

xv IwPrHCl l,3-bis(2,6-n-propylphenyl)imidazol

KTC Kumada-Tamao-Corriu

LAH lithium aluminium hydride (LiAlFLt)

LUMO lowest unoccupied molecular orbital

Ms methanesulfonyl (mesyl) n normal

NHC N-heterocyclic carbene

NMI 7V-methylimidazole

NMP iV-methyl-2-pyrrolidone

NMR nuclear magnetic resonance

No-D NMR NMR without deuterated solvent

PDC pyridinium dichromate

PEPPSI™ pyridine-Enhanced Precatalyst Prepration, Stabilization, and Initiation ppm parts per million

PPTS pyridinium /?ara-toluenesulfonate

PTSA joara-toluenesulfonic acid it room temperature

SIPrHCl 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium chloride

SInPr HC1 1,3-bis(2,6-«-propylphenyl)-4,5-dihydroimidazolium chloride

SIMes.HCl 1,3-bis(2,6-trimethylphenyl)-4,5-dihydroimidazolium chloride

SN2 bimolecular nucleophilic substitution t tertiary

xvi TBAF tetra-n-butylammonium fluoride

TBDMS (TBS) ^-butyldimethylsilyl

TEA triethylamine

Tf trifluoromethanesulfonyl

THF tetrahydrofuran

TLC thin layer chromatography

TON turn over number

Ts /?ara-toluenesulfonyl (tosyl)

xvii Chapter One Introduction 1. Alkyl-Alkyl cross-coupling reactions

1.1 Background

Carbon-carbon bond formation is a fundamental operation in organic chemistry. This can be achieved by nucleophilic substitution whereby an electrophile reacts with an organometallic reagent. One of the oldest reported protocols to form a bond between two

5/?3-carbon centers in this way was developed by Wurtz in 1855.1 The so-called Wurtz coupling leads to cabon-carbon bond formation when R and R1 are different. (Scheme 1)

R, R1 = alkyl Product Homo-coupled Elimination X= halide Byproduct Byproduct

Scheme 1.

However, the formation of homo-coupled and elimination products are major drawbacks of this transformation. The synthesis of alkylated aromatic compounds, via the Wurtz-

Fittig reaction, does not suffer from byproduct formation as mentioned above. A variety of other organometallic reagents have been used in the coupling of alkyl halides, including organolithiums and organopotassiums.3 Difficulties in the preparation and handling of these reagents, in addition to low chemoselectivity and poor lifetime has made their use unattractive. The coupling of an organomagnesium compound with an alkyl halide, developed by Kharach in 1954, is recognized as one of the best routes for alkyl-alkyl couplings. However, this process suffers from limited synthetic utility because the Grignard coupling partner needs to be activated, such as an allylic or benzylic halide or an unhindered primary alkyl halide.5'6 A modified procedure by Kochi involving

2 the addition of Li2CuCl4 greatly improved this coupling protocol, although functional group compatibility was still a major concern.7 The discovery of the Corey-House reaction that involves the reaction of lithium dialkylcuprates and alkylhalides, opened a new window for the formation of unsymmetrical C-C bonds (Scheme 2).8

2RLi + Cul - R2CuLi + 2Lil

1 1 R2CuLi + R X R-R + RCu + LiX

Scheme 2.

The success of the Corey-House reaction requires the use of only primary alkyl halides and two equivalents of a nucleophile therefore it is not ideal when using precious synthons. The general mechanism of various reactions discussed above depends on the metal, the nature of the R group, and the catalyst. The major mechanistic pathways proposed for these reactions include; a nucleophilic substitution reaction (SN2), a free- radical mechanism or a combination of both. Evidence for a free radical mechanism in

Wurtz,9"11 Grignard, 12~14 and Corey-House reactions15'16 was obtained by the use of electron magnetic resonance spectroscopy (ESR), which is a technique for detecting chemical species that have one or more unpaired electrons. In the case when the most dominant product is the coupling product (RR1), and not homo-coupled byproducts (R'R1 or RR), it has been suggested that radicals involved in the process were in a solvent cage, and are not free in the solution. The reaction of an allylic or benzylic lithium reagent with a secondary halide is proposed to be an SN2-type reaction. In the case where aryl and vinyl halide react, the reaction must undergo metal halogen exchange first and this is followed by the substitution reaction.

3 The formation of C-C bonds employing organolithium or magnesium reagents is plagued by a number of limitations. First, the cross-coupling works only for unhindered alkyl halides and the protocol is not directly applicable to unsaturated alkyl halides. Even saturated alkyl halides suffer from side reactions such as non-selective metal-halogen exchange, P-hydride elimination, and disproportionation. Moreover, organolithium and organomagnesium compounds have a very low functional group tolerance. A more attractive combination could be the use of transition metals and less reactive organometallic reagents, such as organozincs. The discovery of Ni-catalyzed cross- coupling by Kumada and co-workers17 in 1972 revealed a more promising route to achieving alkyl-alkyl cross-coupling with better selectivity. Following these major discoveries, cross-coupling methodology has witnessed significant progress within the last 30 years as exemplified by its applications in natural product synthesis, drug discovery, and large-scale synthesis in industry.18

1.2 The mechanism of the cross-coupling reaction

Transition metal-catalyzed reactions between organometallic reagents and organic electrophiles to form C-C, C-N, C-0 and C-S bonds are important synthetic transformations in the preparation of organic building blocks.19'20 At the core of this versatile reaction is believed to be a general mechanism for all organometallic coupling partners (Figure 1). The first step is the oxidative addition of an organic halide (B) to a low-valent metal centre (A), producing organometallic C. This electrophilic intermediate then undergoes metal/metal exchange with the nucleophilic organometallic reagent D. In this step, an inorganic salt byproduct {E) is formed that has a very strong bond, thus

4 providing the enthalpy to push this process. The final process requires the cis placement of the organic ligands on Pd to facilitate the necessary alignment of orbitals for carbon- carbon bond formation (giving rise to G), while reducing the metal back to the zero oxidation state (A) in a process called reductive elimination. This process is amenable to a range of electrophiles including aryl, alkyl, alkynyl, alkenyl, allyl, and benzyl halides or pseudohalides and a variety of organometallic reagents such as boron (Suzuki-Miyaura coupling), magnesium (Kumada-Tamao-Corriu coupling), tin (Stille coupling), zinc, aluminium, zirconium (Negishi coupling), and silicon (Hiyama coupling).

Pd + nL catalyst precursor reductive I reductive elimination T elimination R'~\ Pd°L ^"~^ Hv n Pd"l_ active catalyst A y^ , n

• \ oxidative J addition /

Ri-^pa» N Pd"Ln H X

P-hydride elimination

Figure 1. General simplified mechanism for Pd-catalyzed alkyl-alkyl cross-coupling reactions.

This method has found broad application leading to the formation of sp2-sp2, sp2-sp and sp-sp bonds.19 However, while aryl and alkenyl halides have been used routinely in cross- coupling reactions, the use of unactivated alkyl electrophiles has been limited.

5 Two main problems have limited the successful application of sp3 centres in cross- coupling reactions. First, oxidative addition of unreactive alkyl halides to low-valent metals at the beginning of the catalytic cycle is sluggish. Second, once oxidative addition does occur, P-hydride elimination can occur, which is initiated by stabilizing agostic interactions between the electron-rich C-H bonds of the centre adjacent to the organometal bond and the electron-poor metal itself.22'23

In order to develop the optimal conditions for a specific cross-coupling reaction (e.g. alkyl-alkyl), several parameters can be changed, including the palladium source, the ligand, catalyst loading, the organometallic and electrophilic partners, additives that help to promote the reaction, solvent, temperature, concentration, and the order of the addition of the reagents. These variables will be discussed in the following sections and will focus on the use of Pd, which is the most widely used metal for these reactions.

1.3 Common metals used in cross-coupling reactions

The choice of the transmetalating reagent in cross-coupling applications is determined by the ease of preparing the reagent and its functional group tolerance. Organometallic reagents of highly electropositive metals, such as magnesium and lithium are highly nucleophilic and reactive in coupling reactions, although they both suffer from low chemoselectivity.24"29 Studies have shown that organolithium and organomagnesium reagents can diminish catalyst reactivity through poisoning and decomposition. ' ' '

The other members of group 1 and 2 also suffer the same difficulties. However, the high reactivity of these reagents could be modified by transmetalation to obtain the less reactive "second-generation" organometallic reagent, such as organozinc. Zn, B, Al and

6 Sn are used widely in coupling reactions. " Organometallic reagents of more electronegative metals, such as B and Si demonstrate lower reactivity toward the transmetalation step (Figure 2).

Li Mg Zn Sn Si B 0.9 1.2 1.6 1.8 1.8 2.C

• • Increasing reactivity, decreasing selectivity

Figure 2. The reactivity of common metals in catalytic cycle.

Bases have played important roles in the reaction of organoboranes. It has been suggested that coordinatively saturated organoboranes act as the reactive species in the transmetalation step.37" Organosilanes are one of the least reactive organometals in coupling reactions but can be activated by addition of fluoride sources.40'41 In summary, the most common nucleophiles that have been used in cross-coupling reactions are organozincs and organoboranes due to their ease of synthesis, their high reactivity, and functional group tolerance.

1.4 Leaving group effect

Another parameter that influences cross-coupling reactions is the nature of the leaving group. The leaving group is usually a halide (e.g. chloride, bromide, or iodide) or a pseudohalide (e.g. OTf, OTs, or OAc). The order of the reactivity of the leaving groups is listed in Figure 3. Although Cl-containing electrophiles are less reactive relative to I- and

Br- containing electrophiles, they are readily available, less expensive and more stable.19

7 I > OTf > Br > CI > OCOR > OR > OSiR3

Figure 3. The reactivity of different leaving groups in cross-coupling reactions.

In the 1970s, most cross-couplings employed organoiodides and organobromides; organochlorides were rarely used as the electrophile. However, major developments in catalyst design over the last decade have significantly affected the use of these less reactive electrophiles.42"44 The reactivity of R-X not only depends on the leaving group X, but also the organic group R. R-X bonds containing vinyl, allyl, and propargyl groups are more reactive than alkenyl and benzyl electrophiles. Alkyl groups are the least reactive and vinyl is the most reactive one. In 2003, Negishi and co-workers demonstrated the reactivity effect in the example below (Scheme 3). The vinylic iodide cross-coupled preferentially in the presence of the less reactive alkyl iodide.45

I Pd(dppf)CI2(2 mol%) Me3Sl Me3Si = v + \^A^^t 96% ., ^ZnBr 2

Scheme 3.

1.5 Palladium in cross-coupling reactions

Palladium, as a late transition metal, is one of the most versatile metals used in organic synthesis from the discovery lab scale to the industrial scale. The two major oxidation states of palladium are 0 and +2, which is optimal for use in redox catalytic reactions.

Unlike nickel, palladium does not undergo single-electron transfer and this assists in its high functional group tolerance. Low oxidation states of 0 and +2 lead to the formation of

8 d and d complexes that, in light of palladium's moderately large size, render it a soft transition metal. The ready formation of species containing 16 electrons or less opens one or more empty coordination sites. Consequently, palladium is a good candidate for concerted reactions for which electrophilic sites (LUMO) and nucleophilic sites (HOMO) are present simultaneously. As a result, palladium has a higher affinity for non-polar n- compounds such as alkenes and alkynes because of the ability to accommodate n electrons in its empty d orbitals. The C-Pd bond is relatively nonpolar (palladium's electronegativity is 2.2 and carbon is 2.5) thus it shows low reactivity with functional groups such as esters, ketones, and amides that otherwise demonstrate higher reactivity with organomagnesium and organolithium reagents. However, palladium is more reactive towards functional groups with proximal 71-electrons. Single-bonded polar electrophiles, such as alkyl halides, that lack n- or n-donor groups in the vicinity of the reactive site are relatively inert toward Pd(0) (Figure 4).30

^^X > Ar^X > RCOX > =_X > ArX » Alkyl-X

Figure 4. Reactivity of functional groups towards palladium.

Palladium facilitates three important C-C bond-forming reactions: 1) the reaction of 71- allyl cation with nucleophiles, 2) the cross-coupling of organohalides with organometallic reagents, and 3) the reaction of an organic halide with an olefin (Heck reaction). The catalytically active species in these reactions are Pd(0) or Pd(II).

9 1.6 The role of the ligand on the metal catalyst in the catalytic cycle

Research focusing on the development of new ligands to generate highly active catalysts has increased over the past few years.19 The ligand alters both the steric topography around the metal centre and the electronic property of the metal. Recent mechanistic studies suggest that palladium insertion into an alkyl-halide bond (oxidative addition) occurs via a bimolecular SN2-type reaction and is enhanced by an electron-rich palladium centre.46 Other studies have suggested that reductive elimination can be enhanced by adding large groups on the palladium centre to ensure rapid formation of the product.47

Therefore, a successful catalytic system must contain a balance between steric and electronic effects. Electron-rich ligands increase the nucleophilicity of the transition metal species, which aids in the oxidative addition step. Electron-withdrawing and sterically demanding ligands facilitate the reductive elimination step. To date, organophosphines and N-heterocyclic carbene-based catalysts have been the most intensively studied in cross-coupling chemistry.

1.6.1 Organophosphines

Organophosphines are one of the most common ligands in homogeneous catalysis.37 They are neutral two-electron donors (a-donation) and weak n acceptors. The reactivity of the metal center can be altered by changing the steric bulk of the organophosphine. One metric that has been developed to describe the steric bulk of a phosphine around a metal centre is the cone angle.

10 8 = 118°

Figure 5. Cone angle of metal- trimethyl phosphine ligand.

A cone angle is an angle formed with the metal at the vertex and the hydrogen atoms at the perimeters of the cone demonstrated in Figure 5 of trimethyl phosphines. As the cone angle increases, the steric influence of the ligand on and around the metal centre also increases. Tertiary phosphine ligands are commonly classified using this parameter, and some cone angles for common phosphine ligands are listed in Table 1.48

Phosphine Ligand Cone Angle

PMe3 118° PMe2Ph 122° PEt3 132° PPh3 145°

PCy3 170° P('-Bu)3 182° P(mesityl)3 212°

Table 1. Cone angle of common phosphine ligands.

Strongly basic trialkylphosphines can enhance the oxidative addition step and increasing the steric bulk of the phosphine ligands on the metal can enhance the reductive elimination. For example, PCy3 shows significant improvement over the commonly used

11 triphenyl phosphine in the Suzuki coupling of arylboronic acid and aryl chloride which is the result of altering the steric and electronic properties of the ligand.49 Significant improvements to catalyst stability have been achieved through the creation of bulky and electron-rich phosphine ligands to stabilize Pd(0) intermediates.50 A list of common phosphine ligands is provided in Table 2.

Monodentate Phosphines Bidentate Phosphines

PPh3 Ph2P(CH2)2PPh2 (dppe) PCf-Bu)3 Ph2P(CH2)4PPh2 (dppb) PCy3 /-Pr2P(CH2)3P/-Pr2 (d/'-ppp PTol3(TTP) P(2-Furyl)3(TFP)

Table 2. Common phosphine ligands for cross-coupling reactions.

1.6.2 Phosphines as ligands in cross-coupling reactions

A number of research groups have achieved high catalytic activity with the use of electron-rich bulky phosphines in the presence of a Pd(0) or Pd(II) source. In general,

Pd(0) complexes are nucleophilic and have basic properties.37 The nucleophilicity of

Pd(0) complexes can be increased by highly basic phosphines, which in turn aid the oxidative addition step. However, the electrophilicity of Pd(II) complexes is facilitated by less basic phosphines and aids the reductive elimination step. Since the catalytic cycle includes both Pd(0) and Pd(II) species, the benefit of using electron-rich phosphines depends on what Pd-species is present in the rate-determining step.37 For instance, when aryl chlorides are used in cross-coupling reactions, oxidative addition is believed to be the rate-determinating step; in this case, the use of a highly basic trialkylphosphine is more effective than a triarylphosphine.

12 While triphenylphosphine has been the first choice for a ligand, other ligands have been designed and synthesized to increase the efficiency of the catalytic cycle. For example, bisphosphines, such as dppp, dppb and dppf are good candidates for alkyl-alkyl cross- coupling reactions since they help suppress P-hydride elimination via a large cone angle and occupy two coordination sites on the metal.17'51'52 Major progress has been made in recent years to synthesize different phosphine ligands and evaluate them in a variety of cross-coupling reactions. For example, Littke and Fu have discovered that the mixture of

Pd2dba3 and P(Y-Bu)3 served as a highly active catalyst system in Suzuki-Miyaura coupling reactions for a broad range of aryl halides. They found that the optimal palladium/phosphine ratio was between 1 and 1.5, suggesting that a mono-ligated palladium was the catalytically active species in the coupling reactions. The same catalyst was also found to perform well in the Stille55'56 and Heck reactions.57 Furthermore,

Hartwig and co-workers found that this system was active in oc-arylation of ketones and malonates.58'59 They also investigated the formation of carbon-nitrogen bonds with palladium and bulky, electron-rich phosphines (e.g. P(/-Bu)3 and PCy3) finding an enhancement of the oxidative-addition step.60"62 It should be recognized that the balance of steric and electronic components of the ligand has to be properly tuned.47 For example, for the coupling of alkyl tosylates, PCy3 was less effective than P(z-Bu)2Me. When the donor ligand was too bulky, such as with P(7-Bu)3, the dialkyl-Pd11 precursor could coordinate only one phosphine ligand, and the coordinatively unsaturated Pd11 species underwent P-hydride elimination (Figure 6).63"66

13 f-Bu 0-R1 {-Bu, V f-Bu-P-Pd-^> • f-Bu-P-Pd +^r-R1

R = R-i = alkyl

Figure 6. Mechanism of P-hydride elimination in alkyl-alkyl coupling reaction.

Beller and coworkers reported their discovery of the catalytically active species derived

from Pd(OAc)2 and PAd2(n-Bu), a sterically demanding phosphine, for the amination of aryl chlorides, the Suzuki-Miyaura coupling of aryl halides, and the a-arylation of ketones.67'68 Later, they isolated mono phosphine-palladium(O) species 4 and 5 that were

successful in Suzuki-Miyaura coupling reactions (Figure 7).69 A

Cy3P-Pdx p

4// Figure 7. Mono-phosphine palladium complexes effective in Suzuki coupling reaction.

In the 1990's, Buchwald and co-workers discovered a group of highly active, bulky, and electron-rich phosphine ligands for use in palladium-catalyzed C-C , C-O, and C-N bond formations with a variety of aryl bromides and chlorides (Figure 8).49'70"72 This significant improvement was achieved by the appropriate choice of phosphine ligands in which the steric and electronic properties can favour both oxidative addition and reductive elimination in the catalytic cycle. They showed that the reactions not only depended on the palladium source but also the ratio of palladium to phosphine.

14 a:R = H a:R = H b: R = NMe2 P(t-Bu) b R = NMe2 c: R = /'-Pr 2 d: R = Et R /-Pr e: R = Me f: R = OMe

PCy2 MeO. OAc

Figure 8. Buchwald's ligands.

A second generation of Buchwald's ligands (Figure 8, compounds 8 and 10) possessed higher activity in many cross-coupling reactions.73'74 Palladacycle 11 is air- and moisture- stable and very active for aryl animations.75 Buchwald's group found that the phosphine/palladium ratio is one of the most important parameters in catalyst performance; mono-phosphine palladium is stabilized by a ^-interaction between the metal centre and the aromatic biaryl centre. Complex 12 has been isolated, which supports this proposed coordination about palladium (Figure 9).

15 Figure 9. Buchwald's mono-phosphine palladium complex.

Although phosphine ligands have been demonstrated to be good candidates in cross- coupling reactions, they suffer from some limitations including difficulty to separate steric and electronic aspect of their structure and their innate pyrophoric and air-sensitive properties. As a consequence, the use of excess organophosphine in coupling reactions is common to ensure that the metal remains homogeneous.76 The replacement of phosphine ligands with NHC ligands offers the potential to overcome these synthetic and handling problems associated with phosphines.

1.6.3 N-Heterocyclic Carbenes (NHCs)

Carbenes are divalent carbon species bearing six valence electrons; they have attracted little attention in synthetic chemistry in the past due to their low stability.77 Although the majority of non-stabilized carbenes are short-lived reactive intermediates, NHCs are stabilized entities.78 Stabilized singlet NHCs were first recognized by Wanzlick in the

1960s.79 The application of NHCs as ligands for transition metals was discovered independently by Wanzlick80 and Ofele81 in 1968. However, it was not until the first

16 stable, isolable NHC was prepared by Arduengo in 1991 that their application in catalysis took root (Scheme 4).

CI H 13 14

Scheme 4.

In spite of the fact that carbenes are electron-deficient, NHCs are electron-rich and nucleophilic. The singlet carbene centre is stabilized by a-electron-withdrawing, n- electron-donating nitrogens. The interaction of the empty p orbital on the carbene carbon with the lone pairs on nitrogens helps stabilize the singlet state. Normally, the nonbonding electrons of carbenes are in the P„ orbital of lowest energy. Electron- withdrawing groups increase the s character of the a orbitals by inductive effects. This causes an increase in the energy gap between o and Pn orbitals of the singlet state. In general the nitrogen adjacent to the carbenoic centre stabilizes singlet carbene by both inductive and mesomeric effects (Figure 10).83

Figure 10. Stabilization of NHCs.

The resonance structures for NHCs are illustrated in Figure 11. The N-C-N bond angle is smaller and the C-N bonds are longer in the free carbene, relative to the imidazolium

17 precursor 15 ( Scheme 7, comparable to 16a and 16b), which indicate increased cr-bond character in the carbene, therefore a large contribution of 16b relative to 16a and 16c.

R . R R N^L D.N^ N- 0<

R1 R R1 16a 16b 16c smaller N-C-N bond angle

R-N^ N-R1 Base t R-N<>N-R1 ©T / " X H longer N-C bond 15 16

Figure 11. Resonance structures of NHCs.

1.6.4 Electronic Features of NHCs versus phosphine ligands

Based on computational studies of complexes of nickel84 and ruthenium,85 NHCs were shown to be more electron-rich than the most basic trialkylphosphines. Also, the stretching frequency of carbonyl ligands of complexes LRh(CO)2Cl , LIr(CO)2Cl or

87 LNi(CO)3 when L is equal to NHC or PR.3; showed that NHCs are much stronger electron-donors than phosphines. The values of carbonyl stretching frequencies of

LNi(CO)3 are shown below (Table 3). The low stretching frequency of IMes means more electron density has been donated from the ligand to the n of the carbonyl groups which weakens the bond and decreases the frequency.

18 Ligand cm"1 IMes 2050.7 SIMes 2051.5 IPr 2051.5 SIPr 2052.2

PPh3 2068.9 PCy3 2056.4 f P Bu3 2056.1

Table 3. Carbonyl stretching frequencies in IR spectra of LNi(CO)3 complexes.

Remarkably, in the case of NHCs, the electron-donating ability remains almost constant when changing the substituents on nitrogen (Table 3). This is opposite for phosphorus, as substituents that are attached directly to phosphorus can greatly alter the electron density that is donated to the metal. One way to alter the electronic nature of the NHCs is to change the azole ring. Computational data show that the electron density on the metal increases in the order benzimidazole < imidazole < imidazoline. '

The higher electron-donating ability of the NHC ligands, relative to phosphine ligands, allows for the coupling of more challenging electrophiles, such as non-activated aryl- chlorides due to the enhancement of the oxidative addition step.42

1.6.5 Complex stability of NHC ligands versus phosphines on a metal

The bond dissociation energies of saturated and unsaturated NHCs to metal centres of comparable steric demand are similar whereas the value for phosphines are smaller, which indicates that phosphines have a weaker bond to the metal than do NHCs (Table

4).90

19 Ligand BDE [kcal/mol] for L in Ni(CO)3L IMes 41.1 SIMes 40.2 PPh3 26.7

Table 4. Bond dissociation energy of different ligands to Ni.

The higher dissociation energy of NHC ligands compared to phosphines disfavours dissociation from the metal; thus, the equilibrium lies strongly toward the formation of the metal/ligand complex (Scheme 5). This makes NHC complexes more robust to air, moisture and heat than the corresponding phosphine complexes.

R-Nysup ^ M + R„rQi~R M

3 T . M + PR3 M

Scheme 5.

1.6.6 Steric effect comparison between NHC and phosphine

While NHCs can be thought of as phosphine mimics, their coordination to metals is very different. The two substituents on the NHC nitrogen atoms point toward the metal centre

(pocket shape) whereas the three substituents on phosphine point away from the metal centre (cone shape) (Figure 12). This arrangement of the substituents on NHCs has a strong influence on the reactivity of the complex in the catalytic cycle.

20 Figure 12. Steric effects of NHC vs. phosphine.

1.6.7 Formation and stability of carbenes

Unlike phosphine, the formation of an NHC metal complex requires the deprotonation or activation of a carbene precursor. Formation of the free carbene can be achieved by the treatment of azolium salts with strong bases (for examples, NaH, f-BuOK, n-BuLi); once formed, the free carbene can then add to the metal centre. ' ' Free saturated NHCs can also be prepared by the reduction of cyclic thioureas93'94 and 1,1 elimination of alcohols.95"99 Free carbenes, even stabilized ones, are air-and moisture-sensitive and require handling under inert conditions. In order to avoid their isolation, the NHC salts can be combined with a base and a palladium source, such as Pd(OAc)2, Pd2(dba)3 or

PdCl2, to form the desired complex in situ.

1.6.8 Common NHC ligands and complexes in cross-coupling reactions

Nolan and co-workers have made major contributions to the field of NHC-Pd catalysis.

First, they examined the use of NHC salts 17 and 18 (Figure 13) to form the active catalyst in-situ in the presence of a palladium source.100 Later, they used the isolated complexes 22 to 26 in Suzuki-Miyaura cross-coupling reaction with a wide variety of aryl chlorides.101"104 Beller and co-workers synthesized a series of dimeric NHC-Pd naphthoquinone complexes (27 and 28) that were shown to be active complexes in various cross-coupling reactions.105

21 In 2002, Herrmann and co-workers reported a new bis-adamantyl NHC ligand (19). The palladium complex of 19 catalyzed the coupling of m- or/^-substituted aryl chlorides and an arylboronic acid at rt. However, it was not capable of coupling ortho-substituted biaryls.106 Later, the discovery of ligand 20 by Glorius and co-workers overcame this problem and the coupling of hindered ortho-substituted precursors became efficient. They believed that the "flexible steric bulk" of their penta-cyclic NHC ligands was the main

1 OT 1 OR reason for the higher activity than the adamantly-substituted NHC 19. '

22 Ad Ad N^N^ ^?y^ ^y^CIQ cW3 17 18 19 Ad Ad

Pd Pd AcO' 'OAc AcO' "OAc

20 21

Pd -, Pd ,, CI' VI cr >i

26 27 28

Figure 13. Active NHC ligands and complexes for use in cross-coupling reactions.

1.6.9 Synthesis of imidazolium salts

The synthesis of N,N'-diaryl or -dialkyl imidazolium salts and N,N'-dihydroimidazolium salts will be discussed in this section.

23 Synthesis of symmetrical imidazolium salt: trimethylsilyl-substituted imidazoles can be used as precursors (Scheme 6). Treatment of trimethylsilyl-substituted imidazole with two equivalents of a primary alkyl halide yields the desired imidazolium salt.109

f=\ 2R-CI ®f=\ R R Me3bi -N/ -TMSCI 0^ CI

Scheme 6.

Symmetrical imidazolium salts with N-alkyl or N-aryl substituents can also be prepared by reacting the corresponding amine with glyoxal to form a bisimine intermediate that further reacts with chloromethyl ethyl ether to provide the desired ligand (Scheme 7).110~

112

H H 2R-NH2. M , V-C ^^ RCVR O O R-N N-R K ^ K

Scheme 7.

Synthesis of unsymmetrical imidazolium salts: Potassium imidazolide reacts with primary halides, followed by the addition of another primary halide, to give the desired imidazolium salt (Scheme 8).113"115

©/=\ R-X f=\ R'-X ®[=\ N^N -KX R"N^N " R"N^f K® X0

Scheme 8.

24 It can also be prepared by alkylation of monosubstituted imidazoles (Scheme 9). The counteranion greatly affects the solubility of the imidazolium salt. The most common

116 125 counterions are CI", OTf and, BF4". "

H H o HX ^ / \ R2-X I + NH 1 N N 2 R -NH2 + y^t + x 3 •*• R ' ^/ ^R -H,0 O O H H X R1 = alkyl, aryl R2 = alkyl

base H^N^N + R1-X —j- R7= alkyl Scheme 9.

Synthesis of imidazolidinium salts: Unsymmetrical N,N'-diaryl or -alkyl-substituted 4,5- dihydroimidazolium salt can be prepared easily from chloroethyloxoacetate and an amine source (Scheme 10) 126-129

1)NaOH

Clx PEt NIFt THF Ar1HN OEt 2) f?^2 Ar1HN NHAr2 Ari-NH2 + y-i J^iyL. y^ -J^^ y^ 0 0 0 0 0 0

1)BH3.THF 2) CH(OEt)3 HCI

Ari-N^N-^Ar2 © X

Scheme 10.

25 1.7. Previous success in alkyl-alkyl cross-coupling reactions

1.7.1 The Suzuki-Miyaura reaction

The first alkyl-alkyl coupling of a primary alkyl iodide with an alkylborane was reported by Suzuki and co-workers in 1992.130 In the presence of Pd(PPli3)4 and a base, the coupling proceeds in moderate yields (<64%). However, the reaction is limited to primary alkyl iodides and alkyl-9-BBN derivatives; attempts to couple similar alkyl boranes,

Grignards, organozincs, -aluminiums, -tins, -zirconiums, or trialkylboranes all failed using this protocol. The major byproduct was p-hydride elimination (Scheme 11).

3% Pd(PPh3)4 I K PO R^^1 + alkyl-9-BBN 3-^ ^^-^ alkyl dioxane, 60°C, 24h R ^^

Scheme 11.

In 2001, Fu and co-workers reported the first Pd-catalyzed Suzuki-Miyaura reaction of unactivated alkyl bromides (Scheme 12).42*131 Among different ligands screened, PCy3 and P(/-Pr)3 were found to be optimal. Anhydrous bases tended to drastically slow the reaction rate. The presence of water is believed to enhance transmetalation by the formation of a hydroxyl-bound borate complex. This protocol tolerated a variety of functional groups in the precursors, such as amino, alkyne, ester, and cyano. However, these conditions were not amenable to alkyl chlorides.

4% Pd(OAc)2 1 R/\^Br + R -9-BBN 8% PCy3 R1 R 1.2K3P04H20 R1=alkyl,vinyl THF, rt

Scheme 12.

26 Later, the same group developed a new protocol for coupling alkyl chlorides, which are relatively difficult substrates to couple due to their lower reactivity toward oxidative addition (Scheme 13).132 As s result, higher temperatures were required to obtain adequate product yields.

5% Pd2(dba)3 1 R^\/CI + R -9-BBN 20% PCy3 R1

1.1 CsOH-H20 R^^^ R1= alkyl, vinyl dioxane, 90°C 65-83%

Scheme 13.

By modifying the reaction conditions, they developed a new protocol for the coupling of primary alkyl tosylates (Scheme 14).133 A variety of electron-rich, bulky phosphine ligands were screened, with di-tert-butylmethylphosphine proving optimal.

4% Pd(OAc)2 1 z^OTs + R -9-BBN 16% Me(f-Bu)2P t K dioxane, 50°C R^^"-" R1= alkyl.aryl 12Na0H 55-80%

Scheme 14.

While organo-9-BBN derivatives are easily prepared from the corresponding olefin, most are air-sensitive. On the other hand, boronic acids are stable and not air-sensitive, which would make the development of a general cross-coupling protocol employing them desirable. In 2002, Fu and co-workers reported that their catalyst could couple alkylboronic acids with primary alkyl bromide;134 a protic solvent and potassium tert- butoxide were necessary to achieve high yields (Scheme 15). Further investigation by Fu demonstrated that increasing the solvent polarity from aprotic solvent (i.e. THF) to protic solvent (i.e. tert-amyl alcohol) led to an increase in yield.46'135

27 5% Pd(OAc)2 1 R^Br + R1-B(0H)2 10%Me(f-Bu)2P> R^R f-amyl alcohol R^alkyl.aryl f.BuOK, rt 63.97%

Scheme 15.

In 2004, Caddick and Cloke achieved, for the first time, alkyl-alkyl Suzuki-Miyaura coupling using an in-situ-generated NHC-based palladium catalyst (Scheme 16). 136

4% Pd(dba)2 1 R^^Br + R -9-BBN 16%IPrHCI , R1 1.2 f-BuOK R^^^ 1 R = alkyl.vinyl 4%AgOTf 28-56% THF, 40°C

Scheme 16.

1.7.2 The Negishi reaction

Knochel and co-workers reported the first nickel-catalyzed alkyl-alkyl Negishi cross- coupling reaction in 1995 (Scheme 17).137 They reported that the presence of a double bond in the 4- or 5- position of the alkyl bromide was essential for catalytic activity; fully saturated alkyl bromides underwent metal-halogen exchange rather than cross coupling.

7.5% Ni(acac)2

Et2Zn ^^1 . B THF, -35°C, 4-18h R = Ph, 81% R = Bu, 82%

Scheme 17.

28 They postulated that the coordination of the transition metal to the double bond decreased the electron density around the metal centre and enhanced the reductive elimination step, which was believed to be rate-determining (Scheme 18).

1 R Ni°Ln> R 2Zn "Y "lx/Ni X ^Ni-R1

Scheme 18.

Later, they expanded the substrate scope of the reaction by the addition of electron-poor styrenes to serve as an external olefin for coordination to nickel (Scheme 19).138

However, the protocol was only successful with primary alkyl iodides.

/r,i ~, • v-, 10%Ni(acac)2 ^. ^. 1 R^^l + (R -CH2)2Zn i * -— R^^-^RI R THF/NMP(2:1) -78 to -35°C ^^s/ 59-81 %

Scheme 19.

Attention was then turned to the use of alkylzinc halides, which are less reactive than their dialkylzinc counterparts, as the transmetalating agent. The addition of tetrabutylammonium iodide was essential to these couplings, which presumably led to the formation of an "ate" complex to enhance transmetalation.

In 2003, Fu reported the first alkyl-alkyl Pd-catalyzed Negishi cross-coupling reaction of unactivated alkyl halides (Scheme 20). 137>138>140 The presence of N-methylimidazole

(NMI) in the reaction mixture was shown to be important, as the yield decreased by 29 approximately 15% in its absence. This protocol was compatible with a variety of alkyl electrophiles with different leaving groups including bromide, iodide, chloride and tosylate, and with alkyl, aryl and vinyl organozinc reagents. However, if the electrophile was branched in the a or p position, the efficiency of the reaction was reported to decrease.

2% Pd2(dba)3 8% PCyp3 -X + R1-ZnX 1.2 NMI R' R—* 1 NMP(21) X=Br, OTs.CI R = alkyl.aryl.vinyl ™0~ 52-90% oU O

Scheme 20.

In the same year, Fu and co-workers reported the first coupling of secondary alkyl bromides and iodides with alkylzinc halides (Scheme 21).43 Among the different types of ligands evaluated, Pybox (29) was found to be optimal. It has been suggested that the chelating nature of Pybox may suppress P-hydride elimination, which requires a vacant coordination site on the metal to occur.

4% Ni(cod)2 1 R^X + Ri-znX 8% s-Bu-Py-box _ R^R DMA, rt, 20h X= Br, I .. 62-88%

Y-N 29 N-V s-Bu s-Bu-Py-box s-Bu

Scheme 21.

30 1.7.3 Kumada-Tamao-Corriu (KTC) cross-coupling reaction

Given that Grignard reagents are readily accessible, the Kumada-Tamao-Corriu reaction is desirable and eliminates exchange to another metal (e.g. Zn or B), however it suffers from low functional group tolerance.141 Kambe and co-workers reported the Pd-catalyzed cross-coupling of alkyl Grignard reagents with alkyl bromides and tosylates in 2003

(Scheme 22).141 Even secondary alkyl Grignard reagents were coupled in good yield. This protocol could be extended to alkyl fluorides when a Ni or Cu catalyst was used. Addition of 1,3-butadiene was necessary for stabilization of the Ni catalyst and accelerated reductive elimination following the mechanism proposed in Scheme 22.138

1-3% NiCI2 1 10%1,3-butadiene .X R -MgX THF, rt X = Br, OTs, CI, F R1= alkyl.aryl

-,e ^^^ Ni(0) R^gX e MgX

R-R

Scheme 22.

31 1.8. Plan of study

1.8.1 Ligand design

In recent years, NHCs have emerged as alternatives to phosphines due to their high thermal stability, their strong coordination to the metal center (which reduces dissociation), and the possibility to tune the steric and electronic properties of the ligand independently.142 The goal of this project is to synthesize new and existing NHC ligands to probe their reactivity in alkyl-alkyl cross-coupling reactions. In order to achieve a highly active catalytic system, there needs to be an optimal balance between electronic and steric properties. Our NHC ligand design must ensure that we can tune the steric and electronic components of the ligand independently, while allowing great flexibility in their design and synthesis. Keeping these requirements in mind, we decided to synthesize NHC ligands of the benzimidazole type shown in Figure 14.

X = F, H, OMe Electronic effect to influence the rate X X of oxidative addition R =

30a 30b 30c R'N^% V. increasing steric bulkj 30 Bulky groups facilitate reductive elimination

Figure 14. Benzimidazolium carbenes.

Introducing electronically different substituents (i.e. MeO, F, and H) at positions 5 and

6 would remotely alter the electronic character of the palladium metal center. At the same time, attaching different substituents (30a, 30b or 30c) to the benzimidazole

32 nitrogen atoms would vary the steric topography around the metal centre while not greatly changing the electronics of the system. If the benzimidazolium ligands proved to be ineffective in cross-coupling applications, commercially available ligands would be employed (Figure 15). We were also interested in systematically varying the electronic and steric properties of unsymmetrical ligands (Figure 15, B and D) and studying the effects in cross-coupling reactions in comparison to the symmetrical ligands A and C.

/=\ f=\ r^ r^ N N N N N N Rf ^^Rl Rf x/ -R2 Rf ^Rl Rf ^ -R2 A B C D imidazolylidine imidazolinylidene

Figure 15. Imidazolylidine- and imidazolinylidene-type ligands.

We focused our initial studies on Negishi reactions for two reasons. Firstly, many organozinc reagents are commercially available or are easily prepared from their corresponding organic halides.143 Moreover, their functional group compatibility makes them attractive coupling partners. Secondly, to the best of our knowledge, Negishi alkyl-alkyl cross-coupling using NHC ligands has yet to be reported.

1.8.2. Evaluation of NHC-Pd precatalyst

Recently the group of Herrmann,144 Nolan,101'145'146 Beller,68 and Sigman147'148 have published an array of monoligated NHC-Pd complexes that show high reactivity in Pd- catalyzed reactions. Based on these observations, our research group has developed a new class of NHC-Pd complexes. They are comprised of stable Pd(II) species bearing a NHC

33 ligand, two anionic ligands (i.e. CI) and a throw-away ligand. Because these complexes are stabilized by pyridine as a ligand, we named them PEPPSI (Pyridine-Enhanced

Precatalyst Preparation, Stabilization, and Initiation) (Scheme 23). These complexes are easily prepared from the NHC salt and PdCk in air and were shown to be air- and moisture-stable. An evaluation of the reactivity of these catalysts in Negishi and Kumada cross-coupling reactions was explored.

N ^^N^NA^ PdCI2,K2C03 ^^V r^ <^=^R~ R ^_. © R~> ^ 80°C, 18h R I R ^^ CI ^N Cl-Pd-CI a„ a R = alkyl CI

Scheme 23.

1.8.3. Application of Pd-PEPPSI catalysts in natural product synthesis

The total synthesis of rhizochalin was undertaken to explore the application of Pd-PEPPSI mediated alkyl-alkyl cross-coupling in natural product synthesis (Figure 16). An antimicrobial galactopyranosyl pseudodimeric bipolar sphingolipid, rhizochalin was discovered in 1989 as the first member of this series. The 28-carbon chain contains four stereocenters, a ketone at CI 1, and a vicinal amino alcohol at both ends. On carbon 26, the alcohol functionality contains a galactopyranosyl moiety. A key step in the synthesis of rhizochalin could be an alkyl-alkyl Negishi cross coupling between carbon 18 and 19 that can be achieved by the use of the Pd-PEPPSI complex.

34 OH 0H

Grignard

Grignard Negishi

Figure 16. The structure of rizochalin.

35 Chapter Two N-Heterocyclic Carbene ligands: synthesis and application in alkyl-alkyl Negishi cross-coupling reaction

36 2. Results and Discussion:

2.1 Ligand precursor synthesis

2.1.1 Benzimidazolium salts

Benzimidazolidines provide an appropriate platform for tuning the electronic properties of the carbene.149'150 The addition of various substituted benzene rings on the backbone of the N-heterocyclic moiety might influence the electronic nature of the ligand without changing the steric environment around the palladium centre. We attempted to synthesize the benzimidazolium salts 38-40 using the protocol developed by Diver and co-workers

(Scheme 24).151"153 The Buchwald-Hartwig amination of 1,2-dibromoarenes 32-34 with excess 1-adamantylamine and sodium tert-butoxide furnished adducts 35-37 that were cyclized with ethyl orthoformate/HCl providing new benzimidazolium chlorides (38-40) in good overall yields.

X Br Pd2dba3> rac-BINAP X NHAd f-BuONa, AdNH2 5 equiv., Toluene, 135°C, 20h X Br X NHAd

32, X = OMe 35, X= OMe 47% 33, X = H 36, X = H 47% 34, X = F 37, X = F 70% Ad cone. HCI 0 38, X = OMe 67% 0/>CI 39, X = H 56% 40, X = F 57% (EtO)3CH N rt. to 80°C Ad

Scheme 24.

37 Attempts to prepare benzimidazolium salts from 2,4,6-trimethylphenylaniline (Figure

14, 30a) and 2,6-diisopropylphenylaniline (Figure 14, 30b) failed at the ring closure stage.

2.1.2 Benzimidazolium salts in Negishi and Suzuki coupling reaction

Initial studies were focused on the Negishi reaction for two reasons. Firstly, alkylzinc reagents are tolerant of a variety of functional groups and can be generated using very mild conditions.154"158 Secondly, to the best of our knowledge, Negishi cross-coupling using NHC ligands has not been reported previously. Bromo 3-phenylpropane 43 and n-butylzinc bromide 41 were selected as the coupling partners, as both, along with heptylbenzene 42, are commercially available, making it easy to produce a GC/MS calibration curve to monitor this transformation. Benzimidazolium salts 38-40 were reacted using conditions originally developed by Fu and co-workers.140 We assumed that the alkylzinc reagent would facilitate the formation of an active catalyst by deprotonating the benzimidazolium salt, so no external base was added. Unfortunately, under these conditions, the expected cross-coupling product 42 was not detected and the alkyl bromide 43 remained unaltered (Scheme 25). Whether this failure was due to a lack of NHC-Pd complex formation or catalyst deactivation at some stage in the catalytic cycle remains unclear at this point.

38 Br Pd2(dba)3 (2 mol %) 43 38-40 (8 mol %) NMI(1.2equiv.) | 5 THF-NMP(2:1) \^ 42 vZnBr 75°C, 18h (1.3equiv.) Q\

wer w-z© 38 39 40 Scheme 25.

Although ligands 38-40 were not active in the alkyl-alkyl Negishi cross-coupling reaction, their application in the Suzuki-Miyaura sp2-sp2 cross-coupling was successful

(Table 5).159 Initial trials involved the coupling of £>-chlorotoluene with electron-rich and electron-deficient boronic acids using conditions developed by Lebel.160 It is known that electron-deficient ligands accelerate the rate of reductive elimination.37

However, we found that the most electron-deficient ligand 40 gave lower yields than the electron-rich ligand 38. Consequently, even the most electron-poor boronic acids gave satisfactory results (Table 5, entry 6).

39 B(OH)2 Pd(OAc)2 (4 mol%) 38, 39 or 40 (8 mol%) rf~\ /=\ cs2co3 —'-Lrir dioxane, 80°C R 45, R = OMe 47, R = OMe 46, R = F 48, R = F

Entry Ligand R Yield (%)a

1 38 OMe 94 2 38 F 91 3 39 OMe 100 4 39 F 76 5 40 OMe 72 6 40 F 81 a GC/MS yields against a calibrated internal standard

Table 5. Evaluation of benzimidazoliun ligands in Suzuki-Miyaura

sp2-sp2 cross-coupling.

The electronic influence of the ligands on the oxidative addition step was investigated with electron-rich and electron-poor chloroarenes. The results indicated that the most electron-rich ligand 38 gave the highest yields (Table 6, entries 1 and 2), thus confirming that oxidative addition is enhanced by electron-rich metal centres.

40 CI B(OH)2 Pd(OAc);, (4 mol%) rS + (S 38, 39 or 40 (8 mol%) <^V/R=V- R Cs2C03 w\/ UT u dioxane, 80°C R 49, R = OMe 51 52, R = OMe 50, R = F 53, R = F Entry Ligand R Yield (%)a

1 38 OMe 83 2 38 F 100 3 39 OMe 72 4 39 F 100 5 40 OMe 53 6 40 F 89 a GC/MS yields against a calibrated internal standard

Table 6. The activity of ligands 38-40 in Suzuki cross-coupling reactions.

2.1.3 Synthesis of imidazolium ligands

Following the unsuccessful result of benzimidazolium ligands (38-40) in the Negishi alkyl-alkyl cross-coupling reaction, attention was switched to synthesizing symmetrical and unsymmetrical imidazolium ligands and evaluating their reactivity in the cross- coupling reaction (Figure 15). We decided to synthesize a library of ligands where the

N-aryl moiety was substituted at the 2,6 or 2,4,6 positions with different alkyl groups of various steric bulk and different electron-donating/withdrawing properties. Similar ligands have been prepared previously and have proven effective in Pd-catalyzed enolate arylation,161 Ru-catalyzed metathesis of olefins,162 asymmetric Cu-catalyzed allylic alkylation,162,163 and 1,4-addition to enones.164

41 The synthesis of NHC precursors 62-64 (Scheme 26) followed a protocol developed by

Grubbs et al.128 An oxanilic acid ester 55 was obtained from ethyl-2-chloro-2- oxoacetate and 2,6-diisopropylaniline in the presence of triethylamine. The synthesis of oxalamides 57-61 relied on the hydrolysis of the ester moiety on 56 followed by in-situ formation of the acyl chloride derivative.165 The unreacted oxalyl chloride was distilled, and the acid chloride was reacted with the subsequent aniline in the presence of triethylamine. Carbene precursors 62-64 were obtained by reduction of oxalanilides

57-61 with an excess of BH3-THF, followed by cyclization with triethylorthoformate/HCl (Scheme 26). While compounds 62-64 were successfully prepared, attempts to cyclize compound 57 were unsuccessful (Table 7, entry 1), presumably due to the decreased nucleophilicity of the amines possessing the electron- withdrawing pentafluorophenyl moiety. However, the ring closing of compound 59 to form compound 65 was successfully achieved, when ammonium hexafluorophosphate

142 (NH4PF6) was applied (Scheme 26).

42 NHAr CI O NHAr Ar-NH2 ^ W° 1)NaOH,THF "" \ ,0 1)(C0CI)?| 2 Ar NH O OEt NEt3 OE—t (fhH ) '" 2 54 THF, 0°C 55 56 NEt-,

Ar' ArN,,H. 1)BH -THF © 3 © N \ // THF.reflux -NrW HCfOEt), -IN ArH2N © 1 2 ©/) CI O^NHAr ) Conc.HCI 2CP 120°C C N HC(OEt)3 Ar 57-61 62-64 NH4PF6 37% THF,80°C 18h V< = Ar 'V-N^N'L^ Pif. JUV 65 °\

Scheme 26.

43 Ar' ArNH N

Entry Ar Ar' u: Yield(%)a Yield(%)o/.\'b O NHAr' Ar

tASW

57 54 NR

F^^^F

58 90 62 86

59 82 NR ON

60 72 63 30

61 71 64 78 <*>

a Isolated yields by column chromatography for compound 57-61 b Isolated yields by column chromatography for compound 62-64

Table 7. Synthesis of unsymmetrical imidazolium salts.

44 2.2 Evaluation of NHC salts in alkyl-alkyl Negishi coupling reaction 2.2.1 Ligands screening

A series of symmetrical and unsymmetrical imidazolium salts and 4,5- dihydroimidazolium salts were evaluated in the alkyl-alkyl Negishi reaction. The results revealed a very strong dependence on the steric bulk of the ligand (Figure 17).

Br Pd2(dba)3 (2 mol %) 43 Ligand (8 mol %) ^^^^H^ THF-NMP(2:1) * | T 5 rt, 24h \^ "ZnBr (1.3equiv.) 41 42

Entry Ligand Yield (%)a ~ IMesHCI(66) Z8 2 SIMesHCI(67) 1.2 3 IPrHCI(68) 76 4 SIPrHCI(69) 85 5 IEtHCI(70) 17 6 SIEtHCI(71) 11 7 SIPr-F3HCI(62) 1.6 8 SIPr-EtHCI(72) 47 9 SIPr-MesHCI(73) 23 10 lnPr-HCI(74) 15 11 SlnPrHCI(75) 12 12 l/BuHCI(76) 20 13 l/'PentHCI(77) 5 14 SIPr-(MeO),rHPFfi(65) 3.4 aGC/MS yields against a calibrated internal standard

Table 8. Evaluation of different ligands in the Negishi cross-coupling reaction.

45 66 67 68 IMesHCI SIMesHCI IPr-HCI

69 70 71 SIPrHCI lEt-HCI SIEtHCI OO*^ ) /fc*^ CI

62 72 73 SIPr-F3HCI SIPr-EtHCI SIPr-MesHCI

74 75 76 InPrHCI SlnPrHCI l/BuHCI

65 77 SIPr-(MeO)3HPF6 I/Pent-HCI

Figure 17. NHC ligands.

Results showed that sterically hindered ligands such as IPr-HCI and SIPrHCI performed best (Table 8, entries 3 and 4); decreasing the bulk, even slightly as in SIPr-Et-HCl 72, significantly affects the reaction.

46 The corresponding ethyl analogs 70 and 71, and n-propyl analogs 74 and 75 were even less effective (Table 8, entries 5-6 and 10-11). The mesityl-derived carbenes were ineffective as previously observed132140 (Table 8, entries 1 and 2). Screening of the unsymmetrical ligands showed that ligand 72 (Table 8, entry 8), which is the most sterically hindered arene in this class of ligands, yielded 47% of product compared to

11% for the symmetrical diethyl analog (Table 8, entry 6). An analogous yield increase was observed for the 2,6-diisopropylphenyl mesityl derivative 73 compared to the symmetrical mesityl NHC precursor 67 (Table 8, entries 2 and 9). In contrast, even though the o-methoxy groups in 65 are similar in size to the ethyl groups in 71, very little product was observed. Similarly, the 2,4,6-trifluoro analog 62 was ineffective (Table 8, entry 7). The failure with isopentyl analog 77 (Table 8, entry 13) is believed to be due to the lack of formation of active catalyst due to the increased steric bulk of the substituents.

2.2.2 Development of reaction conditions

Our initial study of benzimidazolium salts suggested that the steric bulk around the metal centre is one of the most important parameters in the catalytic cycle. As demonstrated earlier, even relatively electron-deficient fluoro ligands (i.e. 40) displayed acceptable levels of activity. Recent reports on the coupling of alkyl bromides in Sonogashira167 and Suzuki-Miyaura136 reactions and the results of our ligand study, encouraged us to submit the NHC precursor IPrHCl (68) to the alkyl- alkyl Negishi reaction.140

We were delighted to find that under the previously reported reaction conditions, the desired product was obtained in high yield (Table 9, entry l).140 Control reactions with no

47 added palladium source (Table 9, entry 3) or ligand (Table 9, entry 2) provided no cross- coupling product; these results indicate the necessity of both palladium and the N- heterocyclic carbene species to induce the desired product. Contrary to the observations by Fu and co-workers that N-methyl imidazolidinone (NMI) was necessary for the activation of organozinc reagents toward transmetalations,140 we found that NHC-Pd catalyst performed well in the absence of NMI (Table 9, entry 4). A temperature study revealed that the reaction proceeded with equal efficiency at either 55°C or rt (Table 9, entries 5 and 6). Byproducts of this reaction include alkylzinc chloride (present in the

Rieke zinc supplied from Aldrich), phenylpropane from reduction of 43, and P-hydride elimination.

~ Br Pd2(dba)3 (2 mol %) 43 IPrHCI(68)(8mol%) NMI(1.2equiv.) THF-NMP(2:1) ^ZnBr 75°C, 18h (1.3equiv.) 41 42

Entry Change in reaction condition Yield (%)a 1 none 75 2 no ligand 0.3

3 no Pd2(dba)3 0.0 4 no NMI 75 5 55°C 70 6 rt. , 24h 77 a GC/MS yields against a calibrated internal standard

Table 9. Optimization study in the alkyl alkyl Negishi cross-coupling reaction.

Following this initial success, we conducted a more detailed optimization of the reaction conditions. An evaluation of the palladium species demonstrated that

Pd2(dba)3, PdBr2, and Pd(OAc)2 had similar efficiencies at rt (Table 10, entries 1-3).

48 However, other palladium precursors were less effective (Table 10, entries 4-6).

Previous reports by Fu and co-workers showed that a mixture of THF and NMP was optimal for alkyl-alkyl cross-coupling reactions.138140168 A solvent study showed a strong dependence on the co-solvent used (Table 10, entries 11-12): ethereal solvents

(THF, DME) and non-polar solvents (CH2CI2, toluene) were ineffective for the coupling (Table 10, entries 7-10); polar solvents such as NMP, DMI or DMA were essential.140

Rr Pd2(dba)3 (2 mol %) 43 IPrHCI(68)(8mol%)

THF-NMP(2:1) rt, 24h 42 *ZnBr (1.3equiv.) 41

Entry Change in reaction condition Yield (%)a

1 Pd(OAc)2,75°C, 18 h 75 2 Pd(OAc)2 75

3 PdBr2 74 4 Pd(OCOCF3)2 40 5 PdCI2 19 6 [(-allyl)PdCI]2 6 7 substituted toluene for NMP 2

8 substituted CH2CI2 for NMP 2 9 substituted THF for NMP 0.4 10 substituted DME for NMP 0.4 11 substituted DMI for NMP 71 12 substituted DMA for NMP 76 a GC/MS yields against a calibrated internal standard

Table 10. Optimization of reaction conditions for the alkyl-alkyl Negishi cross-coupling reaction. Screening of the Pd:IPrHCl ratio confirmed that at least a 1:2 ratio was required for optimal conversions (Table 11, entry 3). However, only a slight erosion in yield was observed when the Pd:IPrHCl ratio was decreased, suggesting that a mono-ligated palladium species was serving as the active catalyst, in accordance with other recent studies.169'170 An excess of the ligand precursor is likely required as carbene formation or ligation to palladium is an inefficient process under these reaction conditions.

Br Pd2(dba)3 (2 mol %) 43 IPrHCI(68)(Xmol%) THF-NMP(2:1) rt, 24h ^ZnBr (1.3equiv.) 41 42

Entry Change in reaction condition Yield (%)a 1 Pd:IPr, 1:1 53 2 Pd:IPr, 1:1.5 63 3 Pd:IPr, 1:2 76 4 Pd:IPr, 1:2.5 77 5 Pd:IPr, 1:3 74 a GC/MS yields against a calibrated internal standard

Table 11. Variation of palladium to ligand ratio in Negishi

cross-coupling reaction.

2.3 Substrate scope for the Negishi alkyl-alkyl cross-coupling reaction

A variety of substrates was coupled in good to excellent yields at rt (Figure 18). These results illustrated that this newly developed protocol is mild and tolerant of a wide range of functional groups such as ester 78, cyano 79, amido 80, alkyne 85 and acetal

83. It is noteworthy that the yield at rt was generally higher when compared to reactions performed at 75°C (Figure 18, compound 78-81). The addition of a small

50 amount (12 mol %) of rc-butylzincbromid e to the precatalyst was necessary in order to achieve reproducible catalyst activation. Of particular interest was the coupling of P- substituted alkyl bromides and alkylzinc reagents (Figure 18, compound 88) which were found to be active substrates under these cross-coupling conditions. Moreover, we observed that alkyl chlorides were unreactive under these conditions as we were able to couple selectively an alkyl bromide in presence of an alkyl chloride (Figure 18, compound 87).

Pd2(dba)3 (2 mol %) IPt-HCI(68)(8mol%) 1 . R1-Br + R2ZnBr —- L R1-R IMinTHF "™F-NMP(2:1) 1.3 equiv. n' ^n

51 78, 92% (83%) 79, 92% (92%)

0 O 'N Xf O _) 80, 65% (65%) 78, 92% (75%)

O O

81, 62% (66%) 82, 76%

•v£> ^ 83, 66% 84, 70% X-O Si uo I CN 85,61% 86, 75%

CI CN CN 87,81% 88, 63%

88, 84%

Isolated yield by column chromatography (Isolated yield at 75°C in parentheses)

Figure 18. Room-temperature Negishi cross-coupling reactions of unactivated alkyl bromides with alkylzinc reagents. In summary, we have demonstrated the first high-yielding Negishi cross-coupling of unactivated alkyl bromides with alkylzinc reagents in the presence of a NHC-Pd catalyst at rt. Further investigation of various ligand precursors showed that IPr-HCl

(68) was optimal. The results obtained suggest an important role of the steric bulk around the metal centre. Under optimized conditions, a variety of functional groups was tolerated.

53 Chapter Three

Development and application of Pd-PEPPSI complexes in Negishi and Kumada-Tamao-Corriu cross-coupling reactions 3. Development of NHC-Pd precatalysts

Palladium-catalyzed protocols utilising imidazolium salts have been shown to offer significant advantages for a range of cross-coupling reactions. Isolated NHCs are moisture-sensitive, and necessitate handling under vigorously anhydrous conditions. The preparation of an active NHC-Pd precatalyst has been an excellent way to overcome this problem. Recently, we developed the first alkyl-alkyl Negishi cross-coupling protocol with an NHC salt (i.e. IPrHCl) and a palladium source (i.e. Pd2(dba)3) and proposed that an active catalyst was a mono-ligated NHC-Pd complex. However, the major drawback in this protocol includes the air-sensitivity of the NHC salt, use of the glove box and lack of reproducibility. Moreover, the unknown composition of the active species, which possibly led to a waste of palladium and ligand precursors, was another problem associated with our protocol.

These problems led to the design of a precatalyst that would be easy to prepare using routine bench chemistry. Since a mono-ligated NHC-Pd species is presumed to be the active species, three more coordination sites on the metal need to be filled by appropriate ligands. The nature of the ligands is crucial to the ease of the activation and the stability of the complex. Our research group decided to prepare a shelf-stable Pd(II) precatalyst that would generate the catalytically-active Pd(0) complex in situ. With the above factors in mind, Pd-PEPPSI-complexes were developed (Figure 19). Grubbs found that 3-Br pyridine was an effective ligand for his NHC-Ru catalyst, and it was found to be an excellent ligand for our NHC-Pd complexes as well.171

55 NHC ligand ensures ^catalyst performances P - Pyridine Cl-Pd-CI E- Enhanced ,N P - Precatalyst P - Preparation CI S - Stabilization Pd-PEPPSI-complexes / - Initiation Pyridine ligand aids in stability and monoligatedj J>d complex formation,

Figure 19. The structure of Pd-PEPPSI-complexes.

These complexes were easily prepared in excellent yield (91-98%) by heating a mixture of PdCk and 1.1 equivalent of the imidazolium salt with K2CO3 in 3-chloropyridine, without the need for anhydrous conditions. The excess 3-chloropyridine was removed via distillation and could be recycled. An array of these complexes was prepared in our lab

(Table 12) and they were evaluated in the Negishi reaction.172

,R1 f=\ Ri

PdCI2 K2C03 1 1> 80°C,'l8h -R T R ^-R2 R2 Cl-Pd-CI ,N i R1 = R2 = Me (66) 1 2 R = Et R = H (70) CI R1 = ,pr R2 = H (68) CI

R Precatalyst Yield(%)a Me Me Pd-PEPPSI-IMes 89 91 Et H Pd-PEPPSI-IEt 90 98 /Pr H Pd-PEPPSI-IPr 91 97 a Isolated yield by column chromatography Table 12. Synthesis of Pd-PEPPSI-complexes.

56 3.1 Application of Pd-PEPPSI-complexes in Negishi cross-coupling reactions

In order to investigate the reactivity of the Pd-PEPPSI-complexes, we submitted them to the alkyl-alkyl Negishi reaction of 41 and 43 using the conditions optimized for the in-situ protocol.

Br 43 catalyst (1 mol%) fT^T^^ THF-NMP(2:1) \^ ^ZnBr rt'24h 42 (1.3 equiv.) 41

CI PEPPSI Complex

Entry R1 R2 Precatalyst Complex Yield (%)a 1 /Pr H Pd-PEPPSI-IPr 91 100 2 Et H Pd-PEPPSI-IEt 90 34 3 Me Me Pd-PEPPSI-IMes 89 8.0 4 nPr H Pd-PEPPSI-lnPr 92 38 5 /Bu H Pd-PEPPSI-I/Bu 93 22 6 neoPent H Pd-PEPPSI-lneoPent 94 17 _7 /Pent H Pd-PEPPSI-I/Pent 95 70 aGC/MS yields against a calibrated internal standard

Table 13. Evaluation of the Pd-PEPPSI-complexes in the alkyl-alkyl Negishi coupling reaction.

57 This initial investigation showed that Pd-PEPPSI-IPr (91) provided the best yields (Table

13, entry 1). The corresponding ethyl 90, «-propyl 92, and iso-butyl 93 analogs were considerably less active; Pd-PEPPSI-IMes 89 was the least effective. Preliminary results suggested that complex 91 showed the highest reactivity in alkyl-alkyl Negishi cross- coupling reactions.

3.1.1 Comparison between Pdidba^IPrHCI and Pd-PEPPSI-IPr protocols

Following those successful results with highly reactive Pd-PEPPSI-IPr in alkyl-alkyl

Negishi cross-coupling reactions, more investigations were done to compare this protocol with our earlier in situ protocol (Pd2(dba)3/IPrHCl). When precatalyst 91 (4 mol% loading) was compared to Pd2(dba)3/IPrHCl 68 (4 mol% loading), a significant difference in rates was observed (Figure 20). It was not possible to accurately measure the reaction rate using 4 mol% of Pd-PEPPSI-IPr (91) so a loading of 0.1 mol% was therefore used.

Br 43 + Catalyst (X mol%) THF:NMP(2:1) ~ZnBr rt 42 (1.3 equiv.) 41

58 • 4 moi% PckPEPPSMPr91

A8mol%68ilPrHCI) 2 mol% (PdsSdba):,)

10 15 20 Time (h)

Figure 20. Comparison between PEPPSI-protocol and in-situ protocol in Negishi cross-coupling reaction.

Comparison of the two protocols at lh reaction time provided identical yields (30%), suggesting that the same amount of active catalyst is generated when employing either 4 mol% of Pd2(dba)3/IPrHCl (68) or 0.1 mol% of Pd-PEPPSI-IPr (91) (Figure 21).

Turnover numbers of 7.5 h"1 for the in-situ protocol and 300 h"1 for the Pd-PEPPSI-IPr protocol suggest that the in-situ protocol is very inefficient in forming active catalyst, thereby wasting precious Pd-metal and NHC salt precursor, a shortcoming that is avoided by using the preligated Pd-PEPPSI-IPr precatalyst.

59 350

Apparent TON tr 300 300 Yield %, 1h 250

200

150 ~

100

so - 30 7.5

a mol% 68 / 2 mol% [Pd;{c!ba}j) 0.1 mol%

Figure 21. Turn Over Number (TON) and 1-hour yields values for Pd-PEPPSI-IPr as a precatalyst and in-situ protocol in alkyl-alkyl cross-coupling Negishi reaction.

3.1.2 Catalyst loading study

In an effort to find out what the lowest precatalyst loading would be, we showed that a loading of Pd-PEPPSI-IPr as low as 0.5% resulted in a quantitative conversion of starting material to the desired product in just 30 minutes (Table 14, entry 8). Loading of 0.1% catalyst afforded 63% after 24 h of the cross-coupling product (Table 14, entry ll).173

60 Br 43 Pd-PEPPSI-IPr(91) (X mol%) THF:NMP(2:1), rt -ZnBr 42 (1.3 equiv.) 41

Entry Change in reaction condition Yield (%)'o/_\a 1 none quant. 2 30 min. 4 mol% quant. 3 30 min. 2 mol% quant. 4 5 min. 1 mol% 71 5 10 min. 1 mol% 82 6 15 min. 1 mol% 93 7 30 min. 1 mol% quant. 8 30 min. 0.5 mol% quant. 9 1h. 0.1 mol% 30 10 4h. 0.1 mol% 47 11 24h. 0.1 mol% 63 12 1h. 0.01 mol% SM 13 24h. 0.01 mol% 3 aGC/MS yields against a calibrated internal standard

Table 14. Pd-PPEPSI-IPr loading study in Negishi coupling reaction.

A time study using Pd-PEPPSI-IEt 90 showed that the reaction does not proceed to completion after 24 h, providing yields up to 34% (Table 15, entry 6). Unreacted starting material and l-chloro-3-phenylpropane were the other components of the reaction mixture. These results confirmed that decreasing the steric bulk from Pd-PEPPSI-IPr to

Pd-PEPPSI-IEt decreased the conversion of the starting material to the desired product, which agreed with our earlier findings that the steric bulk around the metal centre led to fast reductive elimination.

61 Br 43 Pd-PEPPSI-IEt (90) (1 mol%) THF:NMP(2:1) "ZnBr rt 42 (1.3 equiv.) 41

Entry Change in reaction condition Yield (%)a 1 15 min. 1 mol% 10 2 30 min. 1 mol% 19 3 1 h. 1 mol% 22 4 2 h. 1 mol% 25 5 4 h. 1 mol% 29 6 24h. 1 mol% 34 a GC/MS yields against a calibrated internal standard

Table 15. Pd-PEPPSI-IEt kinetic study in the alkyl-alkyl Negishi coupling reaction.

3.1.3 Evaluation of non-activated alkyl halides and pseudohalides

In order to expand the scope of our research beyond alkyl bromides, we evaluated alkyl chlorides, iodides, and tosylates. Unfortunately, all performed poorly under the optimal reaction conditions previously established for bromides (Table 16, entries 1-4). In the case of alkyl chlorides, this poor reactivity might be due to slow oxidative addition of the

C-Cl bond to Pd. When alkyl iodides or tosylates were used, transhalogenation to the corresponding alkyl chlorides occurred, leading to a failure of the cross-coupling reaction.

After some investigation, it was determined that the LiCl present in commercially available Rieke zinc was responsible for this Finkelstein-type reaction. Fu and co-workers observed a similar result in alkyl-alkyl cross-coupling reactions.1 °

62 X Pd-PEPPSI-IPr(91) 43 (2 mol%) ^ THF-NMP(2:1) *ZnBr rt, 24h 42 (1.3equiv.) 41

Entry X Yield (%)b 1 CI 6 2 Cla 9 3 OTs 24 4 I 17 a dba 2mol% at 75°C, b GC/MS yields against a calibrated internal standard

Table 16. Variations of the electrophiles in alkyl-alkyl Negishi cross-coupling reaction.

3.1.4 Substrate study-

In order to probe the generality of our optimized protocol, we decided to evaluate additional substrates and investigate functional groups and steric tolerance. As with the in-situ protocol, catalytic amounts of n-butylzinc bromide were added to the reaction mixture to activate the pre-catalyst. However, the results showed the addition of n- butylzinc bromide did not alter the yield (Figure 22, compound 87 and 88). A variety of substrates was coupled in good to excellent yields at room temperature without addition of H-butylzinc bromide.

63 Pd-PEPPSI-IPr(91) Ri-Br + R2ZnBr 0 ™°'%) R1-R2 IMinTHF THF-NMP(2:1) 1.3equiv. R • zn

CI <\ CN CN 87, 67% (61 %)' 88, 88% (87%);

N' ^ -o or O 96, 78% 97, 86% Isolated yield by column chromatograph a3mol% butylzinc bromide was added for the activation of the pre-catalyst

Figure 22. Pd-PEPPSI-IPr catalyzed room temperature Negishi cross-coupling reactions.

The above results led us to conclude that the activation of the Pd(II) complex could be achieved using any alkylzinc reagent. The proposed mechanism for activation of complex

91 by the organometallic reagent is illustrated in Scheme 27. Computational work has shown that the pyridine ligand has a lower binding energy to Pd(0) than to Pd(II).173 It is believed that reduction of the palladium(II) complex takes place by successive transmetalations of the organometallic followed by reductive elimination to give the catalytically-active Pd(0) species. In order to confirm this suggestion, Pd-PEPPSI-IPr was treated with excess n-heptylzinc bromide. The formation of n-tetradecane (R2-R2) and 3- chloropyridine (throw-away ligand) was observed by GC/MS.172

64 4>N N f=\ Cl-Pd-CI ,N 91 Pd°L CI

Scheme 27.

3.1.5 Use of additives

So far, all of our studies were performed using commercially-available zinc reagent produced under conditions developed by Rieke et al (Scheme 28). 57'17 However our attempt to make Rieke zinc reagents and applying it in our alkyl-alkyl Negishi protocol failed. It is common in the Rieke zinc preparation that LiX is taken out of the solution by washing and centrifuging several times with THF. When the organozinc reagent was prepared in-house, the Li-X salt was removed from the organozinc reagent, explaining the loss of activity in the Negishi coupling. However, addition of two equivalents of LiCl or

LiBr to the n-butylzinc bromide prepared via Rieke's protocol restored the high conversion (Table 17).

65 2

ZnX2 _ - Zn* + 2 LiX — - R-ZnBr + 2 LiX THF THF, rt to reflux

X= CI, Br or I

Scheme 28.

Further investigations revealed that LiCl (or LiBr) potentially activates the organozinc reagent toward transmetalation via formation of a higher-ordered zincate (Scheme

29)139,175

Scheme 29.

One of the most convenient routes to prepare an organozinc reagent, disclosed by Hou and co-workers, involves a direct insertion of zinc dust in an alkyl halide bond in a polar aprotic solvent in the presence of a catalytic amount of I2 at 70°C.155 This knowledge enabled us to couple alkyl bromides by adding two equivalents of LiBr to the reaction mixture when the organozinc was prepared using Hou's method.

We revisited the coupling of unactivated alkyl chlorides, iodides, and pseudohalides with the organozinc reagent prepared via Hou's protocol. Unfortunately, the reaction condition applied to alkyl bromides was not the optimal one for alkyl chlorides, iodides, and pseudohalides. Later, we found that changing the polarity of the media now led to an excellent conversion (Table 17).176 With the success recorded in coupling chlorides and pseudohalides, we decided to conduct a detailed investigation of the effects of solvent polarity on the alkyl-alkyl Negishi cross-coupling reaction. 66 X Pd-PEPPSI-IPr(91) (4 mol%) ^- 3.2 equiv. LiCI or LiBr \^ 42 "ZnBr THF/DMI, rt, 24h (1.6 equiv.) 41 IMinDMIorTHF Entry X THF:DMI Yield (%)a 1 Br 2:1 100 2 CI 1:3 88 3 I 1:3 68 4 OTs 1:3 100 5 OMs 1:3 100 a GC/MS yields against a calibrated internal standard

Table 17. Effect of additives and solvent polarity in Negishi coupling reaction.

Selective activation of one carbon-halide bond in the presence of other carbon-halides is synthetically attractive. Altering the solvent polarity, as previously discussed, could potentially provide the desired selectivity. This would allow for selective and sequential cross-couplings to be performed, providing rapid access to diverse products where the dihaloalkane acts as a lynch-pin. This study showed that an alkyl bromide could indeed be activated selectively in the presence of an alkyl chloride when employing a THF/DMI ratio of 2:1 or greater. It was not possible to selectively couple an alkyl iodide in the presence of an alkyl bromide (Table 18). The results clearly show that a solvent window exists for selectively coupling an alkyl bromide in the presence of an alkyl chloride

(Figure 23), providing a means for selective, sequential cross-couplings.

67 X Pd-PEPPSI-IPr(91) (4 mol%) LiBr 3.2 equiv. solvent, rt, 2h ^ZnBr 42 (1.6equiv.) 41 1 MinDMIorTHF X = Br, CI, I

THF:DMI X Yield (%)a'b X Yield (%)a X Yield (%)a 26.4 Br 1.1 CI 0 40.6 Br 28.8 CI 0 42.6 Br 64.5 CI 0 64.8 Br 99.9 CI 28.3 62.2 Br 99.1 CI 76.3 29.3 Br 95.3 CI 69.3 * GC/MS yields against a calibrated internal standard, b 4.8 equiv. of LiBr was used.

Table 18. Effect of solvent polarity on oxidative addition.

* Alky! Chloride o Alkyl Bromide •» Alkyl Iodide

20 40 60 80 100 DMI {%) in THF

Figure 23. Variation of the percentage of DMI in THF in the Negishi reaction.

68 3.1.6 Alkyl-Aryl Negishi reaction

In order to investigate the generality of our Negishi protocol, we expanded the scope of our study to the aryl-alkyl Negishi cross-coupling reaction. The alkyl-alkyl Negishi reaction conditions were applied to the sp2-sp3 cross-coupling reaction. We were delighted that without any further modification of our alkyl-alkyl Negishi protocol, complete conversion of the starting material to desired product was achieved with an aryl bromide, aryl chloride or aryl triflate as an electrophile (Table 19, entries 1, 2, and 4).

Pd-PEPPSI-IPr(91) i 0 mol%) „ , „, Ar1-X + R2-ZnBr — Ar1-R2 M «**&•> LiB™2 ;quiv..rt,24h

Entry Ar1 X R2 Yield (%)a 1 Ph Br n-heptylb 100 2 Ph CI n-heptylc 100 3 Ph I n-heptylc 95 4 Ph OTf n-heptylc 100 5 Ph OMs n-heptylc 0 6 Ph OTs n-heptylc 0 a GC yield against calibrated internal standard (undecane) performed indulicatebTHF:DMI,2:l CTHF:DMI, 1:3

Table 19. Alkyl-aryl Negishi cross-coupling reaction

In spite of the successful coupling of alkyl tosylates and mesylates in high yields (Table

17, entries 4 and 5), other aryl analogs were unreactive (Table 19, entries 5 and 6). The conversion of alkyl sulfonates into alkyl bromides in the presence of LiBr via an SN2 mechanism is a likely explanation for the successful coupling of alkyl sulfonate.4 177

Formation of l-bromo-3-phenylpropane was observed by GC/MS by addition of LiBr to

3-phenylpropyl tosylate. A similar exchange reaction is not possible with aryl sulfonates

(Table 19, entries 5 and 6).

69 3.1.7 Optimization of aryl-aryl Negishi reaction

More than 80% of all current pharmaceuticals contain aromatic or heteroaromatic units as building blocks.178 Therefore, the synthesis of heterocycles is of major importance for the synthesis of organic building blocks. For further evaluation of Pd-PEPPSI-complexes, we applied them to the aryl-aryl Negishi cross-coupling reactions.

Ov n Pd-PEPPSI-IPr(91) ^^^ (1 mol%)

+ BHVkf^ Bf^^ ZnCI2,1.6equiv. a solvent, rt, 24h 98 99 100

Entry Change in reaction condition Yield (%)a 1 THF 22 2 THF:NMP(2:1) 77 3 THF:DMI (2:1) 72 4 THF:DMA(2:1) 71 a GC/MS yields against a calibrated internal standard

Table 20. Solvent study in aryl-aryl Negishi coupling reaction.

Arylzinc reagents were prepared by transmetalation of the corresponding Grignard reagent with ZnEfo or ZnCb. Optimal yields of cross-coupled product were obtained when 1.6 equivalents of the organozinc was used. Similar to the previous conditions

(alkyl-alkyl Negishi cross-coupling reaction), the reaction required a polar amide co- solvent to be efficient. However, unlike the alkyl-alkyl coupling case, the reaction proceeded in the absence of any halide additive, suggesting that transmetalation of arylzinc reagents is more facile than the corresponding alkylzinc reagent. Attempts to couple aryl tosylates and mesylates with arylzinc reagents failed (Table 21, entries 5 and

6) for the same reason as in aryl-alkyl Negishi cross-coupling reaction.

70 .0. CX Pd-PEPPSI-IPr(91) (4 mol%) ZnCI ,1.6 equiv. BrMg X 2 THF:NMP(2:1), rt, 24h 98 100

Entry X Yield(%)a 1 Br 77 2 CI 75 3 I 73 4 OTf 71 5 OTs 0 6 OMs 0 aGC/MS yields against a calibrated internal standard

Table 21. Aryl-aryl Negishi cross-coupling reaction.

3.1.8 Substrate scope

In order to evaluate our optimized Negishi protocol, we used the optimal conditions to synthesize substrates that are more challenging. The protocol was sufficiently gentle to tolerate sensitive functional groups including ester 102, cyano 87, amido 96 and acetal 97

(Figure 24). The stability of the TMS group 103 and the coupling of (S)-citronellyl bromide 102 in high yield was notable (Figure 24). Controlling solvent polarity enabled us to couple an alkyl bromide in the presence of a chloride (Figure 24, compound 87).

The coupling of alkylzinc reagents with aryl halides occurred in high yield with no disproportionation (Figure 25). An N-Boc-protected indole 106 and a nitrile group 104 were also tolerated (Figure 25).

71 Pd-PEPPSI-IPr(91) (1 mol%) 1 2 R1-X + R2ZnBr R -R 16equiv THF-DMI(2:1) IMinDMI LiBr, 3.2 equiv. rt, 2n

sp3-sp3

88, X = Br, 85% 101,X = OTs,70% Q Or -N .--V^O^CM O 96, X = Br, 63.5% 87, X = Br, 81% C^- OEt 97, X = Br, 86% 102, X = Br, 87%

TMS- ^O ^ ^ CN 42, X = Br, 100% ( by GC/MS) 103, X = CI, 74%

Isolated yields after column chromatography

Figure 24. Alkyl-Alkyl Negishi cross-coupling reaction.

72 Pd-PEPPSI-IPr(91) 2 1 2 Ari_x + R ZnBr -^^ *r -R «,• nin THF-DMI(2:1) MinDMI LiBr>3.2equiv. 1.6equiv. n 2h

sp2-sp3

EtO, NC >o^^ 0. > 0

104, X = OTf, 81% 106, X = Br, 83% I Q^Q

N ^ ^^ "OEt O 105, X = CI, 98% 107, X = CI, 87%

Isolated yields after column chromatography

Figure 25. Alkyl-Aryl Negishi cross-coupling reactions.

Heteroaromatics and sterically congested biaryls were also synthesized in high yields

(Figure 26, compound 108-113). Noteworthy is the high-yielding coupling of o- chlorotoluene with 2,4,6-tripropylphenylzinc chloride at 60°C to give 112, which is by far the lowest temperature used to couple this substrate pair so far reported in the literature and speaks to the high activity of Pd-PEPPSI-IPr.179"181 An array of multiple heteroatom- containing heterocycles was coupled in excellent yields (Figure 26, compound 109-111 and 113). In summary, these results demonstrated the effectiveness and stability of the catalyst and high functional group tolerance of this mild protocol.

73 Pd-PEPPSI-IPr(91) 1 Ar -X + A^MgRr (1 mol%) Ari.Ar2 IMinTHF THF-NMP(2:1) ZnCI2, 1.6 equiv. rt,2h

Isolated yields after column chromatography

Figure 26. Aryl-Aryl Negishi cross-coupling reaction.

3.2 The Kumada-Tamao-Corriu (KTC) reaction

3.2.1 Aryl-Aryl KTC reaction

In recent years, several advances have been achieved in the Suzuki-Miyaura and Negishi cross-couplings.19,37 However, less attention has been given to the development of the

Kumada-Tamao-Corriu (KTC) coupling reaction. Since arylzinc halides and boronic acid derivatives are often prepared from the corresponding Grignard reagents by a transmetalation, the KTC reaction would allow for a more direct and efficient cross- coupling protocol. In addition, the ease of synthesis of Grignard reagents, their low

74 cost, high reactivity and stability are attractive features of the KTC reaction. Drawbacks include a relatively low tolerance toward various functional groups. Despite this, the KTC is still a common and effective means for forming a variety of biaryl species.183"185

In 1999, Huang and Nolan186 reported the first aryl-aryl KTC reaction using an NHC- based catalyst formed in situ from IPrHCl and Pd2(dba)3 at 80°C in THF/dioxane. Aryl bromides, chlorides, and iodides were all permissible substrates. However, the coupling of di-ortho-substituted aryl halides with ortho-substituted aryl Grignard reagents did not proceed. Later, Beller and co-workers extended this methodology to aryl and alkyl halides using monoligated naphthoquinone complexes.105 In this section, an optimized protocol with Pd-PEPPSI-complexes is developed.

3.2.2 Optimization of the Pd-PEPPSI catalyzed KTC reaction

In our initial studies, we applied Pd-PEPPSI-IPr 91, the most reactive complex in the

Negishi reaction, using modified conditions developed by Beller in 2003.187 A THF/DMI solvent mixture led to the desired product in acceptable yield at rt after 24h in the presence of 2 mol% 91 (Table 22, entries 4 and 5). Providing the temperature was elevated to 50°C, THF (Table 22, entry 6) THF/DME (Table 24, entry 7-8) or THF/DMI

(Table 22, entries 9-10) could also be used. The addition of LiCl to the reaction improved overall yields (Table 22, entries 11-13), presumably increasing the dielectric constant of the reaction favoured one or multiple steps of the catalytic cycle.188

75 Pd-PEPPSI-IPr(91) (2 mol%) ^ Solvent, 24 h MeO 100

Entry Additive Solvant T[°C] YieldC^oy,a, b 1 THF rt 7 2 THF/DME1:1 rt 5 3 THF/DME 2:1 rt 10 4 THF/DMI1:1 rt 68 5 THF/DMI 2:1 rt 74 6 THF 50 66(60) 7 THF/DME 1:1 50 75 8 THF/DME 2:1 50 80 9 THF/DMI 1:1 50 77(74) 10 THF/DMI 2:1 50 67 11 2 equiv. LiCI THF rt 61(60) 12 2 equiv. LiCI THF/DME 1:1 rt 69 13 2 equiv. LiCI THF/DME 2:1 rt 73 14 2 equiv. LiCI THF/DMI 1:1 rt 71 15 2 equiv. LiCI THF/DMI 2:1 rt 56 16 2 equiv. LiCI THF 50 74(77) 17 2 equiv. LiCI THF/DME 1:1 50 67 18 2 equiv. LiCI THF/DME 2:1 50 73 19 2 equiv. LiCI THF/DMI 1:1 50 46 20 2 equiv. LiCI THF/DMI 2:1 50 51 a GC/MS yields against a calibrated internal standard b Yield in parentheses are isolated yields after column chromatography

Table 22. Optimization study for the aryl-aryl KTC coupling.

3.2.3 Evaluation of different Pd-PEPPSI-complexes

The impact of the ligand structure on the KTC reaction was investigated next. In order to do this, we subjected Pd-PEPPSI-IPr 91, -IEt 90, and -IMes 89 to the test reaction (Table

23). The results showed that the greater the steric crowding around the metal centre, the greater the reactivity. Pd-PEPPSI-IPr 91 was the most reactive and Pd-PEPPSI-IMes 89 was the least reactive catalyst in this sp2-sp2 Kumada cross-coupling reaction. It is possible that in the case of Pd-PEPPSI-IEt and -IMes, complex degradation due to slow

76 reductive elimination is responsible for the lower yields. These results are parallel to those observed in the Negishi reaction and further support the importance of sterics on reductive elimination.

Pd-PEPPSI-complexes (2 mol%) THF, 50°C, 24h MgBr MeO 114 100

Entry Catalyst Yield (%)a 1 Pd-PEPPSI-IPr 91 85 2 Pd-PEPPSI-IEt 90 15 3 Pd-PEPPSI-IMes 89 4 a GC/MS yields against a calibrated internal standard

Table 23. Catalyst screening in the aryl-aryl KTC reaction.

A temperature study on the reactivity of Pd-PEPPSI-IPr 91 and Pd-PEPPSI-SIPr 115 was carried out (Figure 27). The yield of the reaction increased drastically between 25°C and

40°C for Pd-PEPPSI-SIPr, whereas the same increase occurred between 40°C and 60°C for Pd-PEPPSI-IPr. The exact reason for this effect is not clear. However, it is possible that Pd-PEPPSI-SIPr is more active due to its increased flexibility or that the activation of this complex is more facile.

77 Pd-PEPPSI-IPror-SIPr (2 mol%)

THF, 24h MeO

100

• Pd-PEPPSI-IPr 91 TPd-PEPPSI-SIPrll5

Figure 27. The effect of temperature in the reactivity of Pd-PEPPSI-IPr and SIPr on the aryl-aryl KTC reaction.

In order to investigate further differences between these two complexes, the reaction was monitored over a 24h period (Figure 28). As before, the rate of reaction was higher for the saturated derivative. We assume that during the catalytic cycle, the N-aryl moiety rotates back and forth to accept the incoming reaction partner during oxidative addition and expels the coupling partners in reductive elimination. This "flexible steric bulk" partner enhances the catalytic activity of the saturated complex over the unsaturated one; a similar case of "flexible steric bulk" being beneficial was reported by Glorius and co workers.189

78 Pd-PEPPSI-IPr or -SIPr (2 mol%) m THF, 50°C, 24h MeO 100

• Pd-PEPPSI-IPr TPd-PEPPSI-SIPr

0 5 10 15 ?[h] m

Figure 28. Kinetic study of Pd-PEPPSI-IPr and SIPr in the KTC reaction.

3.2.4 Substrate scope for the KTC alkyl-alkyl cross-coupling reaction

Pd-PEPPSI-IPr was further evaluated over a range of more challenging coupling partners.190 Several optimal protocols were used, based on steric hindrance of the substrates as well as solubility of the various Grignard reagents. The use of a THF:DMI mixture allowed for the synthesis of hindered biaryl 115 (Figure 29), whereas heterocycles 119-122 (Figure 30), were effectively produced utilizing a THF:DME combination. Nevertheless, the use of a single solvent greatly simplified the protocol and it was found that THF was a very effective solvent for both hindered biaryls (Figure 31,

115 and 125) and heterocyclic compounds (Figure 31, 124-129). The formation of tetra- ort/?0-substituted heterocyclic biaryl 125 at rt is notable. The coupling of biaryl Grignard

79 reagents to indole-, benzothiophene-, and quinoline-derived halides to form 128,127, and

126 proceeded very smoothly.

Pd-PEPPSI-IPr(91) 1 2 (2 mol%) 1 2 Ar -X + Ar MgBr Ar -Ar THF-DMI(2:1) rt, 24h

THF:DMI, 2:1

115a,X = Br, 62%, 50°C 116, X = Br, 64 %, rt 117, X = Br, 83 %, rt

MeO,

N TO S. N

118, X = Br, 60%, rt

Isolated yields after column chromatography a Reaction at 50°C

Figure 29. Substrate evaluation in aryl-aryl KTC reaction.

80 Pd-PEPPSI-IPr(91) 1 (2 mol%) 2 Ar -X + Ar^MgBr A^-Ar THF-DME (2:1) rt, 24h

THF:DME, 1:1 MeCv^s. y MeO D -CO 119a, X = CI, 90 %, 50°C, 2.6 LiCI 120, X == Br, 91% 118, X= Br, 74%

MeO

121, X = CI, 87% 122, X = CI, 97%

Isolated yields after column chromatography "Reaction at 50°C

Figure 30. Substrate evaluation in aryl-aryl KTC reaction. Pd-PEPPSI-IPr(91) (2 mol%) Ar1-X + Ar2MgBr Ar1-Ar2 ^ rt or 50°C, 24h THF

THF

N /= XX y OMe F-,C s A' 123, X = CI, 99 %, 50°C 115,X = Br, 86%,50°C 119,X = CI, 90%, rt X = CI, 90 %, rt [ A'•Q aXX A 122, X = CI, 86%, rt 124, X = Br, 80 %, 50°C & rt 116' J " ?' ^ ?' 5°°C X = Br, 93%, rt

V, N-

125, X = Br, 70 %, 50°C 126, X = CI, 90 %, 50°C & rt 127, X = Br, 91 %, 50°C X = Br, 85 %, 3.2 LiCI, rt X = Br, 99 %, rt

OH Ph

S02Ph

128, X = Br, 67 %, 50°C 129, X = CI, 65 %, 70 °C 130, X = CI, 79%, rt X = Br, 78 %, rt Isolated yield after column chromatography

Figure 31. Substrate evaluation in aryl-aryl KTC reaction.

82 3.2.5 Comparison between Pd-PEPPSI-IPr and phosphine-based catalysts

In order to evaluate Pd-PEPPSI-IPr 91 against other known, highly active phosphine- based catalysts, a direct comparison was carried out using highly active phosphines 133,

8,74181 and 9180 (Figure 32). They represented the best current commercially available ligands for cross-coupling procedures when used in conjunction with suitable palladium sources. We also evaluated Pd(PPh3)4 132, which is one of the most widely employed palladium catalysts.

MgBr Ph

|| ~| catalyst (2 mol%) N THF, rt, 24h <-A 1.6 equiv 130

Pd(PPh3)4 P(Cyp)3 132 133a

/-Pr- MeO

/-Pr

8a 9a

"With these ligands, 1 mol% Pd2dba3 was used as palladium source.

Figure 32. Comparison between the reactivity of different catalysts in the KTC reaction.

83 The coupling of 3-chloro-6-phenylpyridazine 131 with mesitylmagnesium bromide was carried out at rt under identical reaction conditions for each catalyst system. Figure 33 represents the crude :H NMR spectra of the reaction mixture after aqueous work-up.

Comparing the spectra of starting chloride 131 (spectrum A), product 130 (spectrum H), and Pd-PEPPSI-IPr 91 as a catalyst (spectrum G) showed that with catalyst 91, complete conversion of the starting material to the product is achieved. Comparing the spectra C,

D, E, F of the catalysts 8, 9, 132, and 133 to the spectra A (starting material 131) and H

(product, 130) represented almost complete recovery of the starting material 131. These results show that Pd-PEPPSI-IPr 91 performed best and the product was synthesized cleanly with high yield. All other catalysts performed with minimal conversion in this cross-coupling reaction.

84 Starting A chloride JI 131(A)

m Control (B) ...A M jtf it

132

A (C) ,._^A_ s V..™L.^..^Jv. L jUl /

133 (D) W !! ,A_M „M JVU. ^1 r^,.,.*Jlv * 1_ .."..*, ,^/^

8 l! ii (E) u...,. A A ,. J

9 i ;y \ (F)

ii Pd-PEPPSMpr , > 91(0) All .j{ ,._/H.. ,

Product IJ 130(H) A 1 , , v vt-r r g ^yy t 'J'T'V v v w? ^-s ^v v 'j v 'TT t-yvj •j'rvvy vv; ; vy v vv ^'rr ^ v^v ve-y w 'JV v v v a vr w; • v WJ va „.,,i,!,r;Mr;.)...,.).^?lj..;...;.yijV.iM.,.;.,.ij?.t.iTyV..j.,r!?¥V.rJ.n.,.VH.m.f...yyV.i r>w-mmrrn";\Trr??mr\ 8.1 8.3 8.2 .2 7.1 7.0 6S 6 ft ft

Figure 33. Crude H-NMR spectra in CDCI3 of the KTC reaction using different catalysts.

85 In conclusion, Pd-PEPPSI-IPr 91 complex effectively catalyzes the cross-coupling of alkyl bromides, chlorides and iodides, aryl triflates and alkyl tosylate and mesylates in alkyl-alkyl cross-coupling reactions and aryl halides with arylzinc halides in aryl-aryl couplings. Pd-PEPPSI-IPr 91 is capable of coupling sp3and sp2 carbon centres. To the best of our knowledge, this protocol and complex were the first ones that could cover such a wide range of different substrates in cross-coupling reactions.172 We have also developed an easily employed, highly versatile Kumada-Tamao-Corriu (KTC) protocol utilizing Pd-PEPPSI-IPr. The ease of use and synthesis of a wide range of hindered biaryl and drug-like heterocycles made this protocol highly attractive.

86 Chapter Four

Evaluation of Pd-PEPPSI-IPr in natural product synthesis

87 4.1 Background

Carbon-carbon bond formation is arguably the most important transformation in organic synthesis. Although Stille and Suzuki-Miyaura reactions are used widely in total synthesis, Negishi reactions are less so. The major drawback of the Negishi coupling is the incompatibility of organozinc reagents with some common functional groups, together with their sensitivity towards oxygen and water.191

Rhizochalin 31, a long-chain sphingolipid from a marine sponge, was chosen as an ideal candidate for Pd-PEPPSI-IPr-catalyzed alkyl-alkyl Negishi cross-coupling reaction

(Figure 34). Rhizochalin was isolated in 1989 from the sponge, rhizochalina incrustata, near the north-west shore of Madagascar. Rhizochalin is an essential component of eukaryotic cell membranes and plays an important role in cellular regulation. The absolute configuration of this compound has been established by circular dichroism.195 Rhizochalin was the first representative of the new so-called "two- headed" bipolar sphingolipids. To date, there are a number of such compounds that have been discovered, including glycosylated and non-glycosylated derivatives with serine- or alanine-based ends, such as calycoside (Figure 34, 134) from Calyx sp.196 and leucettomols (Figure 34,135 and 136) from Leucetta microraphis.' 7

88 Figure 34. Structure of rhizochalin and naturally occurring aminoalcohol lipids.

Sphingolipids (138, Figure 35) are a class of lipids derived from the aliphatic amino alcohol sphingosine (137). Sphingolipids are ubiquitous, playing important roles in signal transmission and cell recognition. Sphingosine (2-amino-4-octadecene-l,3-diol) creates a primary part of sphingolipids and includes an olefin moiety and an 18-carbon amino alcohol.

89 OH

138

Figure 35. Structure of sphingosine and sphingolipid

4.2 First retrosynthetic approach

The synthesis of rhizochalin was started from three seemingly easy-to-prepare fragments

142,143, and 144 via sequential Negishi cross-couplings (Figure 36). Fragments 142 and

144 are identical except for their ether functionality, and thus can be prepared in a similar fashion. Enantioselective amino-hydroxylation of tert-bu\y\ crotonate (139) will set the necessary stereochemistry for the two chiral centre-containing terminal ends of the target.

This synthetic plan is highly convergent, making for an extremely efficient synthesis of rhizochalin.

90 Negishi reaction

142 143 144

V Cbz. NH O | O i Cbz- N f ^ZnBr 0 OH 141 140 139

Figure 36. First retrosynthetic approach.

4.2.1 Synthesis of fragment 147

The asymmetric aminohydroxylation (AA), discovered in 1996198 by Sharpless et al., allows for the enantioselective synthesis of N-protected vicinal amino alcohols, which is a common motif in a number of biologically-active compounds.199 With appropriate ligand choice, regioselectivity of the reaction can be controlled efficiently.200 Synthesis of 140 followed a protocol developed by Janda and co-workers201 and the desired product was

91 obtained in acceptable yield (Scheme 30). Conversion of the amino alcohol 140 to the N- protected oxazolidine 145, " using 2,2-dimethoxypropane (DMP) in the presence of a catalytic amount of /?-toluenesulfonic acid (PTSA) at rt in benzene afforded 145 in 65% yield, the mass balance being unreacted starting material. Reduction of 145 with UBH4 to the corresponding alcohol, following a protocol by Han and co-workers in 2003,205 afforded 146 in excellent yield. Attempts to convert alcohol 146 to the corresponding bromide 147 proceeded in very low yield; access to the corresponding organozinc was therefore hindered.

K20s04.2H20 (4 mol%) (DHQD)2PHAL (5 mol%) 2,2 DMP Benzyl carbamate ~ PTSA '-, o i U O , f-BuOCI %H 0 C6H6 ^^K J<

0H 145 139 A.n 1JS 140

CBrCI2CBrCI2 PPh3 LiBH4 ou /\^ CH2CI2 Ether Cbz^N r\)H -78°C Cbz-N Y ^Br 86% "7 ° 26% -7° 147 ' 146 '

Scheme 30.

Consequently, we decided to oxidize alcohol 146 to the corresponding aldehyde 148, which would be followed by a Wittig reaction in order to extend the chain as required

(Scheme 31). Unfortunately oxidation of the alcohol 146 by PDC, IBX206 and Dess

Martin periodinane ' provided either a complex mixture or unreacted starting

92 material. Ultimately, we abandoned this route because the syntheses of both 148 and 149 were problematic.

O Cbz-N^y-X oxidation Cbz^N^Tu 4 o 0H *• ^V-o H 146

Scheme 31.

4.3 Second retrosynthetic approach

In this approach, we began with the aminohydroxylation of 139. Reduction of the ester

140 to the alcohol 151, mesylation of the primary alcohol and an intermolecular SN2 reaction provided epoxide 152. An organocuprate addition to the epoxide provided intermediate 153, which could be converted easily to the organozinc 154 for use in the

Negishi coupling key step (Figure 37). To test the route, we opted to use racemic commercially available aminodiol 155.

93 OH 0H

OH ZnBr

143 144

V Cbz

OTBS

153

Cbz Cbz^ Cbzv VNH NH OH NH O i o i O OH OH 152 151 140 139

Figure 37. Second retrosynthetic plan.

Formation of epoxide 156 was attempted using three different protocols (Table 24).

Although the crude 'H-NMR spectrum for the first attempted reaction appeared to be promising, the desired product eluted with reduced DEAD, which is a byproduct of the reaction209-210 (Table 24, entry 1); for this reason, the route was discarded. In our second attempt, tosylation of the primary alcohol followed by epoxide formation, the desired product was achieved in poor yield (Table 24, entry 2). The third reaction tried,211

94 following a protocol by Martin and co-workers,212"214 provided the desired product in good yield (Table 24, entry 3).

CbZ^NH T X)H H X0 OH 155 156

Entry Condition Result

1 PPh3, DEAD purification problem 2 TsCl, TEA K2C03, MeOH, CH2C12 25%

3 MsCl, pyridine NaOH, DMSO 80%

Table 24. Epoxidation of compound 155.

The epoxide was efficiently opened and the corresponding 158 was obtained (Scheme 32) by using a modified procedure reported by Nicolaou in 1995 en route to rapamycin.215

The alcohol and carbamate in 158 were protected concurrently by N-protected oxazolidine formation, ' leading to 159 and desilylated compound 160, which is likely a result of acid hydrolysis. The desilylation was of no consequence as removal of the TBS group was the next synthetic transformation, so treatment of a mixture of 159 and 160 with TBAF provided pure 160. Subsequent conversion to the bromide provided

161.216

95 1)f-BuLi, -78°C ^-S Li

^ CN Cbz. OTBS OTBS 157 2)Cbz. OH 158 H 156 O 83%

Cbz DMP, PTSA quantitative Benzene 159 50%

Br2, imidazole Cbz PPh3,ACN quantitative \6 160 33% Cbz

Scheme 32.

After bromide formation, 161 was converted to the corresponding organozinc reagent as confirmed by no D-NMR spectroscopy.217 Subsequent Negishi cross-coupling with acid- chloride 143 provided 162 in moderate yield (Scheme 33). With the model-study complete, attention was turned to the preparation of fragment 151.

1)Zndust, l2 DMI 2) Pd-PEPPSI-IPr LiBr Cbz. Cbz„

48%

Scheme 33.

96 4.3.1. Synthesis of fragment 151

Following the initial success in preparing compound 162, the next goal was to apply these conditions to prepare compound 151 beginning with the aminohydroxylation product 140.

Reduction of the ester in 140 to the corresponding alcohol 151 was attempted using various reducing agents such as DIBAL-H, NaBH4, LAH, and LiBFLj (Scheme 34). The best yield was attained using LiBtLj; however, it only proceeded in 30% yield. An alternate route was therefore explored for the preparation of 151.

Cbzs Cbz, NH O I LiBH4 NH OH

OH OH 140 151

Scheme 34.

In 1998, Merino et al. reported the synthesis of diastereomers 164 and 165 by Grignard addition to 2,3-O-isopropylidene-D-glyceraldehyde nitrone (BIGN) (Table 25).218,219

Stereocontrol depended on using different Lewis acid. A higher syn-selectivity was obtained when ZnBr2 was complexed to 163 prior to addition of the Grignard reagent.

Anti-selectivity could be achieved by using Et2AlCl as the pre-complexing reagent.

97 BrKeJ Bn.N.OH Bn.^OH

II CH3MgBr X^ A /\

O—/ see table below ~~f\ T^ BIGN I 163 164 165

Entry Solvent Lewis acid Syn:Antia 1 THF None 76:24 2 Et20 ZnBr2 91:9 _3 EtgO Et2AICI 18:82 a Measured from the intensities of *H NMR signals

Table 25. Stereoselectivity of the Grignard addition to BIGN 163.

Following this protocol, compound 151 could be achieved by synthesis of compound 163 as an intermediate, followed by hydrogenation and amine protection by di-tert-butyl dicarbonate.

4.3.2. Synthesis of 2,3-O-isopropylidene-D-glyceraldehyde nitrone (163)

Since BIGN (163) is not commercially available, synthesis was started with D-mannitol, a sugar alcohol derived from mannos by reduction. Treatment of D-mannitol (166) with

2,2-dimethoxypropane and SnCk yielded 1,2,5,6-diisopropylidene-D-mannitol (167,

Scheme 35).

MeO QMe nH nV Y/ X QH ? O Nal°4 CTV '\ O^' J ^ T J—/ r.H.r.^~+u H 1 P SnCI 2 -O OH 75% 60% O 167 168

Scheme 35.

98 Oxidative cleavage of 167 with sodium metaperiodate afforded 2,3-O-isopropylidene-D-

910 990 glyceraldehyde (168) in excellent yield. ' Benzaldehyde was reductively aminated to the corresponding secondary amine 170 (Scheme 36).

.Bn H202 e,Bn 1.BnNH2 Na2W04 (cat.) I

2. NaBH4 MeOH, rt. o MeOH, rt 94% © 171 169 quantitative 170 NH2OH.HCI ether 80%

H -HCI

172

Scheme 36.

Benzyl amine 170 was oxidized to afford nitrone 171 which was then treated with hydroxylamine hydrochloride to give hydroxylamine 172.221 Finally, treatment of 168 with 172 in the presence of sodium sulphate yielded the desired nitrone (compound 163,

999 991

Scheme 37). ' Addition of methylmagnesium bromide to 163, yielded the desired product 164 and undesired diastereomer 165 with the ratio of 82:18 syn:anti (measured from the intensities of *H NMR signals) which were separated via flash chromatography. 218

99 ~ Q Bru©,0 ,0H N Na2S04 I ?K *- H H TEA O quantitative 168 172 163 '

Bru.^OH Bn. .OH N K1N CH3MgBr v + THF H3C >f O H3C^^O 60% 164 165

Scheme 37.

Catalytic hydrogenation and subsequent conversion of the N-protecting group from benzyl to f-Boc proceeded in good yield to give 173 (Scheme 38).218 Deprotection of the acetonide followed by an intramolecular Mitsunobu reaction provided the desired epoxide

175.22 4

1)Pd(OH) /C BruK1.OH 2 l-L ,.Boc N N hkK1.Boc H2 TSA N 1 MeOH 2) B0C2O *- OH Dioxane reflux OH 65% 164 173 55% 174

MsCI, pyridine; NaOH ,DMSO: t l-L ,.Boc N ^1 175

Scheme 38.

100 At this point, this route was abandoned due to a large step-count to obtain 175. Among other purification difficulties encountered, for example, the separation of diastereomers

164 and 165, and the instability of the compound 168 due to the easy polymerization during distillation.225

4.4 Third retrosynthetic approach

The synthesis of the fragment 140 begins with asymmetric amino-hydroxylation of trans- terf-butylcrotonate 139, followed by protecting resulting alcohol with TBS. Reduction of the corresponding tert-butyl ester to give aldehyde 176 followed by a Wittig reaction affords the desired compound 177 (Figure 38). Reduction of the olefin and conversion of the alcohol to the corresponding bromide would provide intermediate 142.

101 OH 0H H0^o Cl OH ZnBr Br Br

143 144

V Cbz

0 I OTBS 142 139

Cbz. Cbz. NH O INI-NHI Ou |

OTBS OH 177 176 140

Figure 38. Third retrosynthetic approach.

4.4.1 Synthetic route

Aminoalcohol 140 was silylated, providing 178 that was reduced to the aldehyde using

DIBAL-H (Scheme 39).226 With 176 in hand, the Wittig reagent was prepared next. The phosphonium salt 180 was prepared by treating 179 with PPI13 in refluxing ethanol.227

Phosphinium salt 180 and aldehyde 176 were subjected to Wittig reaction in the presence

102 of f-BuOK in benzene. Unfortunately, the reaction proceeded in poor yield. Attempts to optimize further the reaction conditions were not successful. Conversion of alcohol 177 to the corresponding bromide 181 followed. The best results were achieved with carbon tetrabromide and triphenylphosphine in dichloromethane. 2,6-Lutidine was used to neutralize the reaction media, otherwise deprotection of the protected alcohol was problematic.228

TBDMSCI Cbzv imidazole Cbz. DIBAL-H Cbzx NH O E" tf I ^ DMAP (cat.) NH O i CH2CI2 ^H O CH2C -78°C -A^ AH 90% i 65% H OTBS OTBS OH 140 OTRR 178 176 PPh3 Ethanol reflux

180

C CB,4 ""NH

PPh3 2,6-lutidine Cbz 85% NH O 50-55% 2) 177 181 A^H 176 OTBS

Scheme 39.

Unfortunately, all attempts to prepare the organozinc of 181 failed; a complex mixture was obtained each time. Although the failure may be due to the presence of an acidic proton in 181, other similar compounds (i.e. 182) have been reported in the literature.229"

231

MeOOC Znl 182 NHBoc

103 Jackson and co-workers found that the stability of the organozinc reagent is improved by using a solvent that is more polar than THF (Figure 39). This is due to the inhibition of intramolecular coordination of the urethane carbonyl to zinc, which in turn can lead to |3- elimination.231 Attempts to synthesize the organozinc reagent of 181 in DMF failed.

R1 R1 IZn IZn T T OR NMe2 O THF, intramolecular coordination DMF, no intramolecular coordination

Figure 39. Stability of organozinc reagents in THF and DMF.

4.5 Fourth retrosynthetic approach

Given that the first key cross-coupling was not possible due to the instability of the organozinc, we altered the synthetic plan. In this route, the cross-coupling between 187 and 188 is the key step (Figure 40). Formation of the key intermediate 186 begins with the inexpensive amino acid D-alanine (183). Asymmetric Grignard addition to the corresponding aldehyde would provide 184. A series of chain elongations via the Wittig reaction would provide the alkyl organozinc bromide precursor 187 (Figure 40).

104 V BocN OTBS

NHBoc 188

BocN BocN c=>

186 185

NH2 /-Q .OH • N BocN- ^> O 183 184

Figure 40. Forth retrosynthetic approach.

4.5.1 Synthesis of fragment 197

Following a protocol by Kumar and co-workers/23^2 D-Boc-alaninol (189) was synthesized from D-alanine (183) in good overall yield by sequential reduction of the carboxylic acid and Boc protection of the amine.232 Swern oxidation of aminoalcohol 189 followed by

Grignard addition without work-up afforded terminal olefin 190 in poor yield but good

105 diastereoselectivity (syn:anti 82:12), which is in agreement with the reported values

(Table 26, entry 1). " Optimization of the reaction protocol ultimately provided 190 in

90% yield and excellent diastereoselectivity (symanti 91:9). The assigned stereochemistry was further confirmed from the subsequent TV-protected oxazolidine derivatives 184, where the observed coupling constant between the two ring protons (J4j = 6.0 Hz) is indicative of their trans-relationship.

i)LiAIH4 i)(COCI)2 NH2 THF NHBoc DMSO,CH2CI2 NHBoc OH Reflux ^ ^X^OH -78°C ii) Boc 0 0 2 vMgBr 183 82% 189

Entry Condition Yield(%)a Syn:Antib

1 Grignard in Et20 35 82:12 2 f-BuLi / CuBr.SMe2 46 87:13 3 Grignard in THF (rt) 65 85:15 4 Grignard in THF (reflux) 90 91:9 a Isolated yields by column chromatography b Measured from the intensities of 1H-NMR spectra of methyl protons at C11 Table 26. Diastereoselectivity ratio in compound 190.

N-protected oxazolidine 184 was obtained by treatment of 190 with 2,2-dimethoxy propane (DMP) (Scheme 40). Hydroboration of the terminal olefin in 184 using 9-BBN followed by oxidation yielded the corresponding alcohol 185 in excellent yield. Oxidation of 185 with IBX yielded the corresponding aldehyde 192 in excellent yield. IBX is a mild oxidizing reagent that can be synthesized from inexpensive starting materials.

106 DMP PPTS NHBoc Toluene ^ i) 9-BBN dimer ^9 80°C _ BocN. THF (reflux^ BocN,

83% ii) NaOH,H202 95% 190 184 185

IBX, DMSO rt, 2 hours BocN 82% 192

Scheme 40.

Addition of aldehyde 192 to 1-heptenylmagnesium bromide solution 193 afforded alcohol

186; oxidation with IBX yielded the corresponding ketone 194 (Scheme 41). The hydroboration/oxidation sequence was carried out again to provide alcohol 195, which was then converted to the primary bromide 196 in excellent overall yield. Unfortunately, formation of organozinc reagent from 196 was unsuccessful. Protection of the ketone in

196 as a terminal olefin by a Wittig reaction afforded 197.236

107 -MgBr S~Q OH BocN BocN THF 193

186

BocN o i) 9-BBN dimer IBX, DMSO THF (reflux) quantitative ii) NaOH,H202 194 80%

CBr4 O PPh3 O BocN CH2CI2 BocN 2hours, rt r i_tr\ s^y 92% Br- 195 196

CH3PPh3Br ^5 NaHMDS BocN^l^^^^^ -78°C 60% 197

Scheme 41.

4.5.2 Synthesis of the fragment 188

Again, a one-pot Swern oxidation of 189 followed by addition of 1-heptenylmagnesium bromide provided alcohol 198 (Scheme 42) with similar distereoselectivity as for 190.

Silylation of 198 provided silyl ether 199 as expected. Consequently, 188 was prepared from 200, which serves as the electrophile in the alkyl-alkyl Negishi reaction that follows.

108 i) (COCI)2 DMSO NHBoc TBSCI NHBoc -78°C Imidazole DMAP v 189 MgBr OH 198 83% 75% THF 193

CBr4 NHBoc NHBoc i) 9-BBN dimer PPh3 THF (reflux) CH2CI2 ii) NaOH,H 0 78% OTBS 2 2 OTBS 199 95% 200

NHBoc

OTBS 188 Scheme 42.

4.5.3 Final cross-coupling reaction

With fragments 188 and 197 in hand, we decided to perform the alkyl-alkyl Negishi cross-coupling reaction. The coupling proceeded as expected to provide the carbon- skeleton of rhizochalin 201 in good yield (Scheme 43).

1)Zndust, l2 DMI -^ BocN 2) Pd-PEPPSI-IPr BocN NHBoc LiBr

OTBS 201

OTBS 188 45%

Scheme 43.

109 Due to time constraints, the total synthesis of rhizochalin was not accomplished.

However, future work to achieve the complete synthesis of the target natural product would require three more steps. These include oxidation of the olefin at carbon 11, deprotection and glycosylation at carbon 26, and deprotections at carbons 2, 3 and 27.

The above synthesis demonstrates that the Pd-PEPPSI catalyst system is suitable for the synthesis of long carbon chains such as that seen in the structure of rhizochalin.

110 Chapter Five

Experimental 5.1 General experimental for benzimidazolium ligand synthesis

All reactions were carried out under an atmosphere of dry argon. Glovebox manipulations were performed in an MBraun Unilab glovebox under an atmosphere of dry argon. All solvents and reaction vials (screw-cap threaded, caps attached, 17 x 60 mm) were purchased from Fischer Scientific. CDCI3 was purchased from Cambridge Isotopes. Dry

NMP and DME (stored over 4A molecular sieves) were purchased from Fluka and handled under argon. THF was dried under argon over sodium-benzophenone whereas toluene and dichloromethane were dried under argon over CaF^. Dry DMA was purchased from Aldrich and handled under argon. DMF was vacuum distilled over anhydrous MgS04, stored over 4A molecular sieves, and handled under argon. All reagents were purchased from commercial sources and were used without further purification, unless indicated otherwise. Thin layer chromatography (TLC) was performed on Whatman 60 F254 glass plates and were visualized using UV light (254 nm), potassium permanganate or phosphomolybdic acid stains. Column chromatography purifications were carried out using the flash technique on Silicycle silica gel 60 (230-400 mesh). NMR spectra were recorded on a Bruker 300 or 400 AV spectrometer. The chemical shifts (5) for 'H are given in ppm referenced to the residual proton signal of the

1 ^ deuterated solvent. The chemical shifts (8) for C are referenced relative to the signal from the carbon of the deuterated solvent. Gas chromatography was performed on Varian

Series GC/MS/MS 4000 System.

112 ^0^ANHAd 35 l,2-di-(l-adamantylamino)-3,4-dimethoxybenzene35

In a pressure vessel, were added 0.55 g of Pd2(dba)3, (0.60 mmol, 4 mol %), 0.75 g of rac-BINAP (1.20 mmol, 8 mol %) and 70 mL anhydrous toluene. The solution was heated to 135 °C for 15 min. After cooling to it, 5.84 g of sodium terf-butoxide (60.75 mmol, 4.05 equiv.), 11.35 g 1-adamantylamine (75.0 mmol, 5.0 equiv.) and 4.44 g of 1,2- dibromo-3,4-dimethoxybenzene (15.0 mmol, 1.0 equiv.) were added in succession, followed by additional 35 mL anhydrous toluene. The mixture was degassed for 10 min with Ar and then heated at 135 °C for 20 h. After cooling, the resulting slurry was filtered through a pad of Celite followed by rinsing with dichloromethane. The solvents were removed on a rotary evaporator and the crude reaction mixture was purified by flash chromatography on silica gel (dichloromethane Rf = 0.80). 5.08 g of 35 (47 %) were obtained as an off-white solid. Mp 192-193 °C. 'H NMR (300 MHz, CDC13): 5 6.60 (s,

2H), 3.82 (s, 6H), 3.45 (br s, 2H), 2.07 (br s, 6H), 1.77 (br m, 12H), 1.62 (br m, 12H). 13C

NMR (75 MHz, CDC13): 5 143.9, 132.3, 109.7, 56.6, 53.5, 44.2, 36.8, 30.0. Anal. Calcd. for C28H40N2O2: C, 77.02; H, 9.23; N, 6.42. Found: C, 77.35; H, 9.41; N, 6.40.

113 ,NHAd

'NHAd 36 l,2-di-(l-adamantylamino)benzene 36

1,2-dibromobenzene (15.0 mmol, 1.0 equiv.) were added in succession, followed by additional 35 mL anhydrous toluene. The mixture was degassed for 10 min with Ar and then heated at 135 °C for 20 h. After cooling, the resulting slurry was filtered through a pad of Celite followed by rinsing with dichloromethane. The solvents were removed on a rotary evaporator and the final product was purified by flash chromatography on silicagel

(dichloromethane Rf= 0.21). 2.66 g of 36 (47 %) were obtained as an off-white solid. Mp

168-170°C. 'H NMR (300 MHz, CDC13): 5 6.92 (m, 2H), 6.75, (m, 2H), 3.67 (br s, 2H),

13 2.09 (br s, 6H), 1.86 (br m, 12 H), 1.63 (br m, 12 H). C NMR (75 MHz, CDC13): 5

138.4, 122.1, 120.5, 52.8, 43.7, 36.8, 30.0. Anal. Calcd. for C26H36N2: C, 82.93; H, 9.64;

N, 7.44. Found: C, 82.62; H, 10.04; N, 7.24.

R ^ ^NHAd

F ^ NHAd 37 l,2-di-(l-adamantylamino)-3,4-difluorobenzene37

114 In a pressure vessel, were added 0.55 g of Pd2(dba)3, (0.60 mmol, 4 mol %), 0.75 g of rac-BINAP (1.20 mmol, 8 mol %) and 70 mL anhydrous toluene. The solution was heated to 135 °C for 15 min. After cooling to rt, 5.84 g of sodium tert-butoxide (60.75 mmol, 4.05 equiv.), 11.35 g 1-adamantylamine (75.0 mmol, 5.0 equiv.) and 4.08 g of 1,2- dibromo-3,4-difluorobenzene (15.0 mmol, 1.0 equiv.) were added in succession, followed by additional 35 mL anhydrous toluene. The mixture was degassed for 10 min with Al and then heated at 135 °C for 20 h. After cooling, the resulting slurry was filtered through a pad of Celite followed by rinsing with dichloromethane. The solvents were removed on a rotary evaporator and the final product was purified by flash chromatography on silicagel (hexane-ethyl acetate = 20:1, R/= 0.27). 4.27 g of 37 (70%) was obtained as an off-white solid. Mp 159-161°C. 'H NMR (300 MHz, CDC13): 8 6.73, (t, J = 10.5 Hz,

2H), 3.57 (broad s, 2H), 2.11 (broad s, 6H), 1.81 (broad m, 12H), 1.67 (broad m, 12H).

13 C NMR (75 MHz, CDC13) 8 144.1 (dd, 'JC-F = 241 Hz; VC.F = 14.9 Hz), 134.1 (app. t,

2 JC-F = 7.0 Hz), 110.0 (dd, JC.F = 14.9 Hz; VC-F = 7.7 Hz), 52.7, 43.2, 36.4, 29.8. Anal.

Calcd. for C26H34F2N2: C, 75.44; H, 8.62; N, 6.63. Found: C, 75.69; H, 8.31; N, 6.79.

38 Ad l,3-di-(l-adamantyI)-5,6-dimethoxybenzimidazolium chloride 38

115 1.84 g of 35 (6.35 mmol, 1.0 equiv.) was dissolved with stirring in 74 mL of triethyl orthoformate and 0.42 mL of cone. HC1 (5.05 mmol, 1.20 equiv.). The mixture was stirred at rt for 30 min. and the heated at 80°C for 4h. Hot toluene (equal volume to the triethyl orthoformate) was added and after cooling, the precipitated salt was vaccum filtered, rinsed successively with toluene and hexane, and then dried under high vaccum.

3.41 g of 38 (67%) were obtained as a white solid, mp. 271-272°C. 'H NMR (300 MHz,

CD2C12): 5 9.14 (s, 1H), 7.36 (s, 2H), 4.00 (s, 6H), 2.58 (br m, 12H), 2.38 (br s, 6H), 1.90

13 (br m, 12H). C NMR (CDC13, 75 MHz): 8 148.8, 135.0, 125.3, 98.9, 62.4, 56.5, 41.1,

35.6, 29.7.

39 Ad l,3-di-(l-adamantyl)-benzimidazolium chloride 39

4.53 g of 36 (12.0 mmol, 1.0 equiv.) was dissolved with stirring in 200 mL of triethyl orthoformate and 1.20 mL of con. HC1 (14.4 mmol, 1.20 equiv.). The mixture was stirred at rt for 30 min. and heated at 80°C for 2h. Hot toluene (equal volume to the triethyl orthoformate) was added and after cooling, the precipitated salt was vaccum filtered, rinsed successively with toluene and hexane, and then dried under high vaccum. 2.85 g of

! 39 (56%) were obtained as a white solid. Mp 322°C. H NMR (300 MHz, CD2C12): 5 9.31

(s, 1H), 8.07 (m, 2H), 7.56 (m, 2H); 2.59 (br m, 12H), 2.36 (br s, 6H), 1.63 (brm, 12H). l3 CNMR(75MHz,CD2Cl2):5 138.8, 131.8, 126.0, 117.4, 63.4,41.6,36.1,30.3.

116 Ad

40 Ad

l,3-di-(l-adamantyl)-5,6-difluorobenzimidazolium chloride 40

2.62 g of 37 (6.35 mmol, 1.0 equiv.) was dissolved with stirring in 106 mL of triethyl orthoformate and 0.64 mL of con. HC1 (7.62 mmol, 1.20 equiv.). The mixture was stirred at rt for 30 min. and the heated at 80°C for 2h. Hot toluene (equal volume to the triethyl orthoformate) was added and after cooling, the precipitated salt was vaccum filtered, rinsed successively with toluene and hexane, and then dried under high vaccum. 1.65 g of

40 (57%) were obtained as a white solid. Mp 319 °C 'H NMR (300 MHz, CD2C12): 5 9.55

(s, 1H), 7.95 (t, J= 8.5 Hz, 2H), 2.60 (br s, 6H), 1.84 (br m, 12H), 1.67 (br m, 12H). 13C

l NMR (75 MHz, CDC13): 5 148.6 (dd, Jc.F = 252 Hz; VC-F = 16.7 Hz), 140.5, 126.7 (t, Jc.

F = 6.0 Hz), 105.2 (dd, VC-F = 16.7 Hz; VC.F = 5.4 Hz), 63.6, 40.8, 35.4, 29.7. Anal.

Calcd. for C27H33C1F2N2: C, 70.65; H, 7.25; N, 6.10. Found: C, 70.36; H, 7.63; N, 5.96

5.2 General method for Suzuki reactions

In a glovebox, a vial was charged with Pd(OAc)2 (4.5 mg, 0.02 mmol), ligand 41, 42 or

43 (0.04 mmol) and CS2CO3 (312 mg, 1.00 mmol) after which it was removed from the glovebox and dioxane (1 mL) was added via syringe. The suspension was stirred vigorously at 80 °C for 30 min, and then cooled to rt where upon the aryl choride (0.5 mmol) was added followed by a solution of boronic acid (0.75 mmol) in dioxane (0.5 mL). Undecane (50 uL) was added via syringe, the argon inlet was removed, and the reaction vessel was placed in an oil bath at 80 °C. Stirring was continued for 24h after

117 which the reaction mixture was cooled to rt. GC/MS analysis was conducted by removing an aliquot (2 uL) of the reaction mixture and diluting with distilled hexane (1 mL).The solution was then filtered though a plug of celite and analyzed. Isolation of product was achieved by filtering the reaction mixture through a plug of celite using dichloromethane

(20 mL) to rinse, dry-loaded and purified by column chromatography (Hexane/EtOAc).

4-Methyl-4'-methoxybiphenyl 47 (Table 4, Entry 3)

The procedure afforded 98 mg (98 %) of the title compound. The reported yield is the average of two runs. NMR spectrum was identical to those previous reported.237

4-Fluoro-4*-methylbiphenyI 48(Table 5, Entry 2)

The procedure afforded 90 mg (97 %) of the title compound. The reported yield is the average of two runs. NMR spectrum obtained were identical to those previous reported.238

5.2.1 General experimental for imidazolium type ligand synthesis

All reactions were carried out under an atmosphere of dry argon in screw-cap threaded vials (caps attached, 17 x 60 mm). All reagents and solvents were purchased from commercial sources and were used without further purification, unless indicated otherwise. Dry NMP, DMI and, DME (stored over 4A molecular sieves) were purchased from Fluka and handled under argon. THF was dried under argon over sodium- benzophenone and CH2CI2 was dried under argon over CaH2. Dry DMA was handled

118 under argon. DMF was vacuum distilled over anhydrous MgS04 and stored over 4A molecular sieves and handled under argon. l,3-bis(2,6-diisopropylphenyl)imidazolium chloride (IPr-HCl, 68),m l,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium chloride (SIPrHCl, 69),112 l,3-bis(2,6-diethylphenyl)imidazolium chloride (IEtHCl,

70),112 l,3-bis(2,4,6-trimethylphenyl) imidazolium chloride (IMes-HCl, 66),112 1,3- bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazolium chloride (SIMes-HCl, 67),112 and 1,3- bis(l-adamantyl)benzimidazolium chloride (42)127 were prepared according to published procedures. Thin layer chromatography (TLC) was performed on Whatman 60 F254 glass plates and were visualized using UV light (254 nm), potassium permanganate or phosphomolybdic acid stains. Column chromatography purifications were carried out using the flash technique on Silicycle silica gel 60 (230-400 mesh). The NMR chemical shifts (5) for 'H are given in ppm referenced to the residual proton signal of the deuterated solvent (commercial CDCI3, CD2CI2 or CD3OD). The chemical shifts (5) for

13C are referenced relative to the signal from the carbon of the deuterated solvent.

Imidazolium salts and Pd precursors for catalyst preparation were weighed in a glovebox under an atmosphere of dry Ar.

N-(2,6-Diisopropylphenyl)-oxanilic acid ethyl ester 55

119 15 mL of 2, 6-diisopropyl aniline ( 72 mmol, 1.1 equiv.) and 10.95 mL of triethylamine (

72 mmol, 1.0 equiv.) were dissolved in 225 mL dry THF. This solution was cooled to

0°C, and 7.70 mL of ethylchlorooxoacetate (72 mmol, 1.0 equiv.) was added slowly via syringe. A white precipitate appeared immediately. The mixture was warmed to rt and stirred overnight. At that point, the white solid was filtered off, and the organic layer was washed with 2 M HC1 solution. The aqueous layer was washed with ethyl acetate, and the combined organic layers were washed with brine, and dried over MgSCV The solvent was removed and the yellow solid was recrystallized from hexane/ethylacetate (9:1). The white crystals obtained (85%) *H NMR (300 MHz, CDC13): 8 8.5 (s, 1H), 7.3 (m, 3H),

13 4.45 (m, 2H), 3.03 (m, 2H), 1.48(m, 3H), 1.23(m, 12H). C NMR (75 MHz, CD2C12): 8

160.8, 155.7, 145.6, 129.2, 128.7, 123.5, 63.4, 28.6, 23.4, 13.7. Spectra were identical to values reported in the literature.239

N-(2,6-DiisopropylphenyI)-oxanilic acid 56

1.18 g of N-(2,6-diisopropylphenyl)-oxanilic acid ethyl ester (4.25 mmol, 1.0 equiv) was dissolved in 25 mL of THF followed by 20 mL of 1M NaOH and stirred for 2 h at rt.The solution was then acidified with 2 M HC1. The reaction mixture was transferred to a separatory funnel and washed with ethyl acetate and brine, and dried over MgSCV The

120 solvent removed and the product obtained as a white solid (99%) and subjected to the next step without further purification.128

General procedure for synthesis of 57-61:

In a flame dried flask was added 0.37 g of N-(2,6-Diisopropylphenyl)-oxanilic acid (56)

(1.5 mmol, 1.0 equiv), followed by 4 mL of dry THF. 0.14 mL of oxalyl chloride (1.57 mmol, 1.04 equiv) was added to the mixture followed by 10 uL of DMF. The mixture was stirred for 4 h at rt. At that time, the solution was transferred by cannula to a flask that was charged with the corresponding aryl amine (1.5 mmol) and triethylamine (1.5 mmol) at 0°C, dropwise with vigorous stirring. The reaction mixture was warmed to rt and stirred for a further 24 h. At that time water was added to the reaction mixture and the crystals were filtered, then partitioned between water and ethylacetate (1:1). The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated NaHC03 solution and brine. The crude product was dried over MgS04.

i° F HN /

l-(2, 6-DiisopropylphenyI)-2-(perfluorophenyl) ethane-l,2-dione 57

0.37 g of 1,2,3,4,5,6- pentafluoro aniline (1.5 mmol) was used. 0.33 g of 57 (54%) were obtained as a white crystals. Mp = 230-232 °C. *H NMR (300 MHz, CDC13): 5 9.07 (br s,

121 1H), 8.77 (br s, 1H), 7.37 (m, 3H), 3.02 (m, 2H), 1.22 (d,J= 6.8 Hz, 12H). 13C NMR (75

MHz, CDC13): 5 158.3, 157.8, 145.8, 143.6, 141.9, 139.8, 138.8, 137.1, 129.2, 129.0,

123.6, 110.5, 29.2, 23.6. HRMS (EI) m/z calcd for C21H22F5N2O2: 414.1362, Found:

414.1367. Anal. Calcd. for CzifeF^Ch: C, 58.74; H, 5.16; N, 6.52. Found: C, 58.95; H,

4.95; N, 6.63.

/- O HN /

N-(2, 6-DiisopropyIphenyl)-N'-(2,4,6-trifluorophenyl)oxalamide58

0.22 g of 2,4,6- trifluoro aniline (1.5mmol) was used. 5.14 g of 58 (90%) were obtained as a white crystals. Mp = 229-230 °C. 'H NMR (300 MHz, CDCI3): 8 8.98 (br s, 1H),

8.83 (br s, 1H), 7.37 (t, J= 7.6 Hz, 1H), 7.23 (d, J= 7.6 Hz, 2H), 6.82 (t, VC-F = 7.9 Hz,

13 2H), 3.05 (m, 2H), 1.22 (d, J= 6.8 Hz, 12H). C NMR (75 MHz, CDC13): 5 161.3 (dt,

'JC-F = 250.5, VC-F = 14.5 Hz), 158.5, 158.2, 157.8 (ddd, VC-F = 25.9, VC-F = 14.8 Hz, Vc.

F = 6.8 Hz), 145.8, 129.2, 129.0, 124.0, 109.1 (td, VC.F = 25.6, VC-F = 3.2 Hz), 100.9(dt,

VC-F = 16.6, VC-F = 5.1 Hz), 28.9, 23.8. Anal. Calcd. for C20H21F3N2O2: C, 63.48; H,

5.59; N, 7.40. Found: C, 63.72; H, 5.93; N, 7.38.

122 N-(2, 6-Diisopropylphenyl)-N'-(2, 4,6-trimethoxyphenyl) oxalamide 59

0.37 g 2,4,6- trimethoxy aniline (1.5 mmol) was used. 0.87 g of 59 (84%) were obtained as a beige crystals. Mp = 172-173 °C. 'H NMR (300 MHz, CDC13): 5 8.88 (br s, 1H),

8.61 (brs, 1H), 7.35 (t, J= 7.3 Hz, 1H), 7.23 (d, J= 7.3 Hz, 2H), 6.21 (s, 2H), 3.86 (s,

3H), 3.85 (s, 6H), 3.11 (m, 2H), 1.24 (d, J= 6.9 Hz, 12H). 13H NMR (75 MHz, CDCI3):

8 159.4, 158.4, 155.9, 145.8, 129.9, 128.6, 123.6, 125.0, 91.0, 91.0, 56.4, 55.5, 28.8, 23.6.

Anal. Calcd. for C23H30N2O5: C, 66.65; H, 7.30; N, 6.76. Found: C, 66.80; H, 7.67; N,

6.59.

N-(2, 6-Diisopropylphenyl)-N'-(2,4,6-trimethylphenyl)oxalamide 60

123 0.21 ml of 2,4,6- trimethyl aniline (1.5 mmol) was used. 2.64 g of 60 were obtained as a

J Pale pink crystals (72%). Mp = 214-216 °C. H NMR (300 MHz, CDC13): 5 8.87 (br s,

1H), 8.82 (br s, 1H), 7.37 (t, J= 7.5 Hz, 1H), 7.25 (d, J= 7.5 Hz, 2H), 6.98 (s, 2H), 3.08

(m, 2H), 2.32 (s, 3H), 2.27 (s, 6H), 1.25 (d, J = 6.9 Hz, 12H). 13H NMR (75 MHz,

CDCI3): 8 159.4, 158.3, 145.8, 137.6, 134.6, 129.7, 129.1, 128.7, 123.7, 123.7, 29.0, 23.6,

20.9, 18.3. Anal. Calcd. For C23H30N2O2: C, 75.37; H, 8.25; N, 7.64. Found C, 75.72; H,

8.50; N, 7.66.

y- ^ > / O HN /

7V-(2,6-diisopropylphenyl)-A^-(2,6-diethylphenyl)oxalamide 61

0.25 mL of 2,6-diethylaniline (1.5 mmol) was used. 0.34 g of 61 (71 %) were obtained as a white solid. Mp = 261-263 °C. *H NMR (400 MHz, CDC13): 8 8.87 (br s, 1H), 8.97 (br s, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.31 (t, J= 7.6 Hz, 1H), 7.25 (d,J= 7.6 Hz, 2H), 7.19 (d,

J= 7.7 Hz, 2H), 3.09 (m, 2H), 2.63 (q,J= 7.6 Hz, 4H), 1.24 (d, J= 6.7 Hz, 12H), 1.23 (t,

J=7.6Hz,6H). ,3C NMR (100 MHz, CDCI3): 8 159.4, 159.0, 145.8, 141.0, 131.2, 129.7,

128.9, 128.5, 126.6, 123.7, 29.0, 25.0, 23.6, 14.4. Anal. Calcd. for Ci^N^: C, 75.75;

H, 8,48; N, 7.36. Found: C, 76.10; H, 8.32; N, 7.75.

124 62 r l-(2,6-Diisopropylphenyl)-3-(2,4,6-trifluorophenyl)-4,5-dihydro-imidazolium chloride 62

3.02 g of N-(2,6-Diisopropylphenyl)-N'-(2,4,6-trifluorophenyl)oxalamide 58 (8 mmol, 1 equiv.) was added to a flame dried round-bottom flask followed by 64 mL of BH3-THF

(1M in THF, 64 mmol, 8 equiv.) and was heated to reflux overnight. After cooling to rt, methanol was added very slowly, followed by 2.45 mL of cone. HC1 solution, and then the solvent removed. Methanol was added two more times and solvent removed again.

The solid crystals which was the dihydrochloride salt of the diimine was not isolated. 25 mL of triethylorthoformate was added to the solid and heated to 120°C for 1.5 h. After cooling to rt, the mixture was diluted with 25 mL of diethyl ether and filtered, washed with small portion of diethyl ether and dried in vaccum. 2.60g of the imidazolium salt 62

(84%) was obtained as a white crystals. Mp = 318-319 °C. *H NMR (300 MHz, CD3OD):

8 9.50 (s, 1H), 7.57 (t, J= 7.8 Hz, 1H), 7.42 (d, J= 7.8 Hz, 2H), 7.28 (t, VC-F = 8.4 Hz,

2H), 4.75 (m, 2H), 4.53 (m, 2H), 3.09 (m, 2H) 1.38 (d, J= 6.9 Hz, 6H), 1.30 (d, J= 6.6

13 Hz, 6H). C NMR (75 MHz, CD3OD): 8 164.3 (dd, 'JC-F = 253.0 Hz, %.F = 15.4 Hz),

159.3(ddd, 'JC-F = 253.0 Hz, %.F = 15.4 Hz, VC.F = 5.7 Hz), 147.8, 133.0, 131.0, 126.4,

2 2 112.0 (m, JC-F = 15.7 Hz, VC.F = 5.7 Hz), 103.2 (m, JC.F =15.1 Hz, VC-F = 3.6 Hz), 55.7,

125 53.1, 30.1, 25.2, 24.3.Anal. Calcd. For C21H24CIF3N2: C, 63.55; H, 6.10; N, 7.06. Found

C, 63.41; H, 6.30; N, 7.00.

l-(2,6-Diisopropylphenyl)-3-(2,4,6-trimethylphenyl)-4,5-dihydro-imidazolium chloride 63

3.07 g of N-(2,6-Diisopropylphenyl)-N'-(2,4,6-trimethylphenyl)oxalamide 58 (8.4 mmol,

1 equiv.) was added to a flame dried round-bottom flask followed by 67.2 mL of BH3-

THF (1M in THF, 67.2 mmol) and was heated to reflux overnight. After cooling to rt, methanol was added very slowly, followed by 2.56 mL of cone. HC1 solution then the solvent removed. Methanol was added two more times and solvent removed again. The solid crystals which was the dihydrochloride salt of the diimine was not isolated . 25.6 mL of triethylorthoformate was added to that solid and heated to 120°C for 1.5. 0.95g of

63 (30%).were obtained as a pale pink crystals obtained 'H NMR (300 MHz, CDC13): 5

8.98 (s, 1H), 7.42 (t, J= 7.8 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 6.94 (s, 2H), 4.67 (broad s,

4H), 2.99 (m, 2H) 2.34 (s, 6H), 2.28 (s, 3H), 1.33 (d, J= 6.9 Hz, 6H), 1.23 (d, J= 6.6 Hz,

13 6H). H NMR (75 MHz, CDC13): 5 159.0, 146.1, 140.6, 134.8, 131.3, 130.0, 129.6,

129.6, 124.8, 54.7, 52.5, 29.0, 25.2, 28.8, 23.7, 21.0, 17.7. Anal. Calcd. For C24H33CIN2:

C, 74.87; H, 8.64; N, 7.28. Found C, 74.60; H, 8.72; N, 7.23.

126 l-(2,6-diisopropylphenyl)-3-(2,6-diethylphenyl)-4,5-dihydroimidazolium chloride

SIPr-EtHCl, 64

4.20 g of N-(2,6-Diisopropylphenyl)-N-(2,4,6-trimethylphenyl)oxalamide 58 (11.0 mmol, 1.0 equiv.) was added to a flame dried round-bottom flask followed by 88 mL of

BH3-THF (1M in THF, 88 mmol) and was heated to reflux overnight. After cooling to rt, methanol was added very slowly, followed by 3.35 mL of cone. HC1 solution then the solvent removed. Methanol was added two more times and solvent removed again. The solid crystals which was the dihydrochloride salt of the diimine was not isolated. 33.5 mL of triethylorthoformate was added to that solid and heated to 120°C for 1.5. 3.4lg of 64

(78%) were obtained as off-white solid. Mp = 274-275°C. 'H NMR (300 MHz, CDC13): 8

8.61 (s, 1H), 7.47 (t, J= 7.8 Hz, 1H), 7.42 (t, J= 7.3 Hz, 1H), 7.29 (d, J= 7.3 Hz, 2H),

7.24 '(d,J= 7.8 Hz, 2H), 4.85-4.78 (m, 4H), 3.04 (m, 2H), 2.75 (q, J= 7.6 Hz, 4H), 1.39

(d, J= 6.8 Hz, 6H), 1.33 (t, J= 7.6 Hz, 6H), 1.28 (d, J= 6.9 Hz, 6H). 13C NMR (75 MHz,

CDCI3): 6 158.5, 146.1, 141.1, 131.5, 131.1, 131.1, 129.3, 127.5, 124.9, 55.0, 54.0, 29.0,

25.2, 24.3, 23.8, 15.3. Anal. Calcd. for C25H35CIN2: C, 75.25; H, 8.84; N, 7.02. Found: C,

74.79; H, 8.55; N, 6.79.

127 l-(2,6-diisopropylphenyl)-3-(2,4,6-trimethoxyphenyl)-4,5-dihydroimidazolium hexafluoro-phosphate(SIPr-(MeO)3HPF6, 65

2.26 g of 58 (5.45 mmol, 1.0 equiv), were placed in a vacuum-dried round-bottomed flask equipped with a reflux condenser, 44 mL of BH3THF solution (1M in THF, 44.0 mmol,

8.0 equiv) was added via cannula under Ar. The resultant solution was refluxed with stirring over 24 h, then a second portion of 1M BH3THF solution (22 mL, 22.0 mmol, 4 equiv.) was added. After refluxing for an additional 24 h, the solution was cooled to rt and the excess borane was destroyed with methanol. 2 mL of cone. HC1 were added and most of the organic solvents were removed on a rotary evaporator. The crude product was partitioned between 100 mL of 1M NaOH and 50 mL of diethyl ether and the organic layer was separated. The aqueous layer was extracted with diethyl ether (2 x 25 mL), the organic layers were combined, washed with water (2 x 100 mL), brine (30 mL), dried

(Na2SC>4) and evaporated. The diamine intermediate was dissolved under Ar in 13.5 mL of dry THF. 1.81 mL of triethylorthoformate (10.9 mmol, 2.0 equiv) and 0.89 g of solid

NH4PF6 (5.45 mmol, 1.0 equiv) were added and the mixture was heated at 80 °C over 18h with vigorous stirring. After cooling to rt, the organic solvents were removed on a rotary evaporator, the crude product was redissolved in a small volume of CH2C12 and passed through a short pad of Celite with CH2CI2. 1.10 g of 65 (37 %) was obtained as off-white solid after column chromatography on silicagel (CH2Cl2:ethyl acetate = 100:1; Rf= 0.22).

128 Mp = 268-269 °C. 'H NMR (300 MHz, CD2C12): 5 7.81 (s, 1H), 7.56 (t, J= 7.9 Hz, 1H),

7.37 (d, J= 7.9 Hz, 2H), 6.28 (s, 2H), 4.59 (m, 2H), 4.38 (m, 2H), 3.94, (s, 6H), 3.01 (m,

2H) 3.04 (s, 3H), 1.39 (d, J= 6.8 Hz, 6H), 1.31 (d, J = 6.8 Hz, 6H). 13C NMR (75 MHz,

CD2C12): 5 162.5, 159.1, 155.9, 146.4, 131.5, 129.4, 125.0, 90.9, 90.9, 56.4, 55.8, 53.7,

51.4, 28.8, 24.6, 23.8. Anal. Calcd. for C24H33F6N203P: C, 53.14; H, 6.13; N, 5.16.

Found: C, 53.56; H, 6.45; N, 5.25.

5.3 Negishi alkyl-alkyl cross-coupling reactions

Representative procedure for Table 10 (Entry 2).

A vial in the glove box, was charged with 4.4 mg of Pd (OAc)2 (0.02 mmol, 2 mol %), 17 mg of IPr-HCl 68 (0.04 mmol, 8 mol %), and a stirbar. The vial was sealed with a septum and removed from the glove box and 0.3 mL of dry THF and 0.8 mL of dry NMP added via syringe. After stirring for 5-10 min at rt, 1.30 mL n-butylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) was added and the reaction mixture was stirred at rt for an additional 15 min. 76 uL of 3-Bromopropylbenzene (0.5 mmol, 1.0 equiv.) and 50 uL of «-undecane (GC internal standard) were added. The septum was replaced with a

Teflon-line screw cap under an inert atmosphere and the vial was heated with stirring for

18 h at 75 °C. After cooling to rt, the reaction mixture was diluted with hexane and passed through a short pad of silica gel and analyzed by GC-MS. The GC retention time and EI fragmentation pattern were identical to the commercially available product from Aldrich.

129 General Procedure for Figure 18

A vial equipped with a stirbar was charged with 9.2 mg of Pd2dba3 (0.010 mmol, 2 mol

%) and 17 mg of IPr-HCl 68 (0.040 mmol, 8 mol %) in a glove box and the vial was capped with a septum. The vial was removed from the glove box and 0.3 mL of dry THF and 0.8 mL of dry NMP were added via syringe. After stirring for 5-10 min at rt, 0.12 mL rc-butylzinc bromide (0.5 M THF solution, 0.06 mmol, 12 mol %) was added and the reaction mixture was stirred for 1 h at rt, after which 1.3 mL alkylzinc reagent (0.65 mmol, 1.3 equiv.) and alkyl bromide (0.50 mmol, 1.0 equiv.) were added. The septum was replaced with a Teflon-lined screw cap under an inert atmosphere and the solution stirred at rt for 24 h. The reaction mixture was then transferred to a separatory funnel with diethyl ether (10 mL) and the organic layer successively washed with 1 M NasEDTA solution (prepared from EDTA and 3 eq. NaOH), water, and brine. After drying over anhydrous MgS04, the solution was filtered and concentrated and the residue purified by flash chromatography.

Ethyl octanoate 78 CAS # [106-32-1]

(Figure 18) Following the general procedure, 1.3 mL of «-butylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) and 71 uL of ethyl 4-bromobutyrate (0.5 mmol, 1.0 equiv.) provided 79 mg of 78 (92 %) as a colorless oil. The spectroscopic data were identical to the spectrum included in the Aldrich database.

130 (Figure 18) Following the general procedure, 1.3 mL of 4-ethoxy-4-oxobutylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) and 53 uL of 1-bromobutane (0.5 mmol, 1.0 equiv.) provided 79 mg of 78 (92 %)as a colorless oil.

79 n-Decanenitrile 79 CAS # [1975-78-6]

(Figure 18) Following the general procedure, 1.3 mL of n-butylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) and 66 uL of 6-bromohexanonitrile (0.5 mmol, 1.0 equiv.) provided 70 mg of 79 (92 %) as a colorless oil. The *H NMR spectrum was identical to the spectrum included in the Aldrich database. f

80 o

W-ocrylphthalimide 80 CAS # [59333-62-9]

(Figure 18) Following the general procedure, 1.3 mL of «-butylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) and 141.0 mg of JV-(4-bromobutyl)phthalimide (0.5 mmol, 1.0 equiv.) provided 84 mg of 80 (65%) yield after column chromatography

(hexane:ethyl acetate = 8:1; Rf= 0.22). The *H and 13C NMR spectra were identical to the spectra previously reported.240

81 O

131 Ethyl 9-cyanononanoate 81 CAS # [133309-93-0]

(Figure 18) Following the general procedure, 1.3 mL of 4-ethoxy-4-oxobutylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) and 66 uL of 6-bromohexanonitrile

(0.5 mmol, 1.0 equiv.) provided 66 mg of 81 (62%) as a colorless oil, after column chromatography (pentane:ethyl acetate = 20:1; Rf= 0.1). 'H NMR (400 MHz, CDC13): 5

4.12 (q, / = 7.2 Hz, 2H), 2.34 (t, J= 7.1 Hz, 2H), 2.29 (t, J= 7.5 Hz, 2H), 1.65 (m, 4H),

1.44 (t, J= 6.1 Hz, 2H), 1.33 (m, 6H), 1.25 (t, J= 7.2 Hz, 3H). ,3C NMR (100 MHz,

CDCI3): 5 177.8, 119.8, 60.2, 34.2, 28.9 (2C), 28.6 (2C), 25.3, 24.9, 17.1, 14.3. Anal.

Calcd. for C12H2iN02: C, 68.21; H, 10.02; N, 6.63. Found: C, 68.41; H, 9.75; N, 6.47.

The 'H and 13C NMR spectra were identical to the spectra previously reported.

O^ 82

Ethyl 7-phenylheptanoate 82 CAS # [134511-26-5]

(Figure 18) Following the general procedure, 1.3 mL of 4-ethoxy-4-oxobutylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) and 76 uL of 3- bromopropylbenzene (0.5 mmol, 1.0 equiv.) provided 89 mg of 82 (76%) as a coloeless oil after column chromatography (pentane:ethyl acetate = 20:1; Rf= 0.25). The *H and

C NMR spectra were identical to the spectra previously reported.

132 83

2-Undecanyl-l, 3-dioxoIane 83 CAS # [5735-88-6]

(Figure 18) Following the general procedure, 1.3 mL of [2-(l,3-dioxolan-2-yl)]-ethylzinc bromide (0.5 M in THF solution; 0.65 mmol, 1.3 equiv.) and 95 uL of rc-nonylbromide

(0.5 mmol, 1.0 equiv.) provided 75 mg of 83 (66%) as an oil after column chromatography (pentane:diethyl ether = 95:5; Rf= 0.25). The *H and 13C NMR spectra were identical to the spectra previously reported.243

2-(5-phenylpentyl)-l, 3-dioxolane 84

(Figure 18) Following the general procedure, 1.3 mL of [2-(l,3-dioxolan-2-yl)]-ethylzinc bromide (0.5 M THF solution; 0.65 mmol, 1.3 equiv.) and 76 uL of 3- bromopropylbenzene (0.5 mmol, 1.0 equiv.) provided 77 mg of 86 (70%) yield as a colorless oil after column chromatography (pentane:diethyl ether = 9:1; Rf= 0.32). 'H

NMR (400 MHz, CDC13): 5 7.32-7.19 (m, 5H), 4.87 (t, J= 3.6 Hz, 1H), 4.01-3.98 (m,

2H), 3.88-3.85 (m, 2H), 2.64 (t, J = 7.5 Hz, 2H), 1.68-1.63 (m, 4H), 1.50-1.41 (m, 4H).

13 C NMR (100 MHz, CDC13): 5 142.7, 128.4, 128.2, 125.6, 104.6, 64.8, 35.8, 33.8, 31.4,

29.2, 23.9. Anal. Calcd. For C14H20O2: C, 76.33; H, 9.15. Found C, 76.46; H, 9.47.

133 r^ TMS^=—' 85

(6-(l, 3-dioxolan-2-yl) hex-1-ynyl) trimethylsilane) 85

(Figure 18) Following the general procedure, 1.3 mL of [2-(l,3-dioxolan-2-yl)]-ethylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) and 105 mg of 4-trimethylsilyl-l- bromobut-3-yne (0.5 mmol, 1.0 equiv.) provided 69 mg of 85 (61%) as a colorless oil after column chromatography (pentane:diethyl ether = 19:1; Rf= 0.1). *H NMR (400

MHz, CDC13): 6 4.87 (t, J= 4.6 Hz, 1H), 4.00-3.97 (m, 2H), 3.88-3.85 (m, 2H), 2.25 (t, J

= 6.7 Hz, 2H), 1.71-1.67 (m, 2H), 1.61-1.51 (m,4H) 0.16 (s, 9H). 13C NMR (100 MHz,

CDCI3): 5 107.3, 104.5, 84.5, 64.9, 33.3, 28.5, 23.3, 19.8, 0.17. Anal. Calcd. For

Ci2H2202Si: C, 63.66; H, 9.80. Found C, 63.51; H, 10.18.

8-(l, 3-dioxolan-2-yl)-2,2-dimethyl octanenitrile 86

(Figure 18) Following the general procedure, 1.3 mL of [2-(l,3-dioxolan-2-yl)]-ethylzinc bromide (0.5 M THF solution; 0.65 mmol, 1.3 equiv.) and 85 uL of 6-bromo-2,2- dimethylhexanenitrile (0.5 mmol, 1.0 equiv.) provided 84.6 mg of 86 (75%) as a colorless oil after column chromatography (pentane-diethyl ether = 4:1; Rf= 0.18). *H NMR (400

MHz, CDCI3): 5 4.86 (t,J= 4.8 Hz, 1H), 4.00-3.97 (m, 2H), 3.91-3.85 (m, 2H),1.70-1.65

I3 (m, 2H), 1.45-1.29 (m, 10H), 1.27 (s, 6H). C NMR (100 MHz, CDC13): 5 125.3, 104.6,

134 64.9, 41.0, 33.8, 32.4, 29.5, 29.3, 26.7, 25.2, 24.0. Anal. Calcd. For C13H23NO2: C, 69.29;

H, 10.29; N, 6.22. Found C, 69.67; H, 10.40; N, 5.91.

87 7^

12-chloro-2,2-dimethyldodecanitrile87

(Figure 18) Following the general procedure, 1.3 mL of 5-cyano-5-methylhexylzinc bromide (0.5 M THF solution; 0.65 mmol, 1.3 equiv.) and 75 uL of l-bromo-6- chlorohexane (0.5 mmol, 1.0 equiv.) provided 98.5 mg of 87 (81%) as a colorless oil after column chromatography (3 vol. % diethyl ether in pentane; Rf= 0.18). *H NMR (300

MHz, CDCI3): 5 3.55 (t, J = 6.8 Hz, 2H), 1.77 (m, 2H), 1.55-1.39 (m, 4H), 1.35 (s, 6H),

13 1.34-1.27 (m, 12H). C NMR (75 MHz, CDC13): 5 125.3, 53.5, 45.2, 41.1, 32.6, 32.4,

29.6, 29.4, 29.4, 28.8, 26.9, 26.7, 25.3. Anal. Calcd. For C,4H26C1N: C, 68.97; H, 10.75;

N, 5.74. Found C, 69.34; H, 11.01; N, 5.40.

7-cyclohexyl-2,2-dimethylheptanitrile88

(Figure 18) Following the general procedure, 1.3 mL of 5-cyano-5-methylhexylzinc bromide (0.5 M THF solution; 0.65 mmol, 1.3 equiv.) and 69 uL of bromomethylcyclohexane (0.5 mmol, 1.0 equiv.) provided 69.5 mg of 88 (63%) as a colorless oil after column chromatography (3 vol. % diethyl ether in pentane; Rf= 0.15).

135 'H NMR (400 MHz, CDCI3): 5 1.72-1.67 (m, 5H), 1.53-1.45 (m, 4H), 1.34 (s, 6H), 1.32-

13 1.29 (m, 6H), 1.27-1.16 (m, 6H), 0.98-0.80 (m, 2H). C NMR (100 MHz, CDC13): 8

125.2, 41.1, 37.6, 37.3, 33.4, 29.9, 26.7, 26.6, 26.5, 26.4, 25.2. Anal. Calcd. for Ci5H27N:

C, 81.38; H, 12.29; N, 6.33. Found C, 81.77; H, 12.01; N, 5.96.

7-cyclohexyl-2,2-dimethylheptanitrile88

(Figure 18) Following the general procedure, 1.3 mL of cyclohexylmethylzinc bromide

(0.5 M THF solution; 0.65 mmol, 1.3 equiv.) and 85 uL of 5-cyano-5-methyl-l- bromohexane (0.5 mmol, 1.0 equiv.) provided 94 mg of 88 (84%) after column chromatography (Analytical data as above).

5.4 Synthesis of the NHC-PdCl2-3-chloropyridine complexes

In air a vial was charged with 177 mg of PdCk (1.0 mmol, 1.0 equiv.), NHC.HC1 salt (1.1 mmol, 1.1 equiv.), 691 mg of K2CO3 (5.0 mmol, 1.0 equiv.), and a stir bar. 4.0 mL of 3- chloropyridine was added; the vial was capped with a Teflon-lined screw cap and heated with vigorous stirring for 16 h at 80°C. After cooling to rt, the reaction mixture was diluted with CH2CI2 and passed through a short pad of silica gel covered with a pad of

Celite eluting with CH2CI2 until the product was completely recovered. The CH2CI2 was removed by rotary evaporator at rt, and 3-chloropyridine was vaccum-distilled (water

136 aspirator) and saved for reuse. The pure complexes were isolated after triturating with pentane, decanting the supernatant, and drying under high vaccum. trans-dichloro(l,3-bis-(2,6-diisopropylphenyl)imidazolylidinium)(3-chloropyridine)palladium (II) 91

From 468 mg of IPr.HCl 68 (1.1 mmol, 1.1 equiv.), 677 mg of the complex 91 (97%) was obtained as a yellow solid. Mp = 240°C (with decomposition).188 *H NMR (400 MHz,

CDC13) 6: 8.62 (d, J= 1.6 Hz, 1H), 8.54 (d, J= 5.6 Hz, 1H), 7.57 (d, J= 8.2 Hz, 1H),

7.52 (t, J= 7.7 Hz, 2H), 7.38 (d, J= 7.6 Hz, 4H), 7.16 (s, 2H), 7.08 (dd, J= 8.0 Hz, J =

5.7 Hz, 1H), 3.19 (qn, J= 6.7 Hz, 4H), 1.52 (d, J= 6.8 Hz, 12H), 1.47 (d, J= 6.7 Hz,

13 12H); C NMR (100 MHz, CDC13) 5: 153.5, 150.5, 149.4, 146.7, 137.4, 135.0, 132.0,

130.3, 125.1, 124.3, 124.1, 28.7, 26.3, 23.2; Anal. Calcd. For CsaH^ClsNsPd: C, 56.48;

H, 6.07; N, 6.18. Found: C, 56.90; H, 5.99; N, 6.52.

5.4.1 General procrdure for the alkyl-alkyl Negishi coupling reaction using PEPPSI complexes

All reagents were purchased from commercial sources and were used without further purification, unless indicated otherwise. Dry NMP and DMI (stored over 4A molecular sieves) were purchased from Fluka and handled under Argon. THF was distilled from sodium/benzophenone prior to use. All reaction vials (screw-cap threaded, caps attached,

17 x 60 mm) were purchased from Fischer Scientific. CDCI3 was purchased from

Cambridge Isotopes. Thin layer chromatography (TLC) was performed on Whattman 60

137 F254 glass plates and chromatograms visualized using UV light (254 nm), potassium permanganate or phosphomolybdic acid stains. Column chromatography purifications were carried out using the flash technique on Silicycle silica gel 60 (230-400 mesh).

NMR spectra were recorded on a Bruker 400 AV spectrometer or a Bruker 300 AV spectrometer, as indicated. The chemical shifts (8) for *H are given in ppm referenced to the residual proton signal of the deuterated solvent. The chemical shifts (8) for 13C are referenced relative to the signal from the carbon of the deuterated solvent. The following abbreviations are used: s = singlet, d = doublet, t = triplet, m = mulitplet, dd = doublet of doublets, q = quartet, and qn = quintet. Gas chromatography was performed on Varian

Series GC/MS/MS 4000 System. Optical rotations were measured on a Perkin Elmer

Model 241 polarimeter using 10 cm cells and the sodium D line at ambient temperature in the solvent specified (concentration c is given as g/lOOmL). Melting points were determined using a Fisher-Johns melting point apparatus.

(Table 13, Entry 1)

A vial equipped with a stirbar was charged with 3.4 mg of Pd-PEPPSI-IPr 91 (1 mol %) then sealed with a septum and purged with argon, after which 0.3 mL of THF and 0.8 mL of dry NMP were added via syringe. After stirring for 5-10 minutes at rt, 1.3 mL of n- butylzinc bromide (0.5 M THF solution, 0.65 mmol, 1.3 equiv.) was added followed by

76 uL of 3-bromopropylbenzene (0.5 mmol, 1.0 equiv.) and 50 uL of n-undecane

(GC/MS internal standard), the septum was replaced with a Teflon-lined screw cap under an inert atmosphere and the reaction stirred for 15 minutes before analysis by GC/MS.

138 (Table 17, Entry 1)

In air, a vial was charged with 3.4 mg of Pd-PEPPSI-IPr 91 (1 mol%) and under an inert atmosphere with 139.0 mg of LiBr (1.6 mmol, 3.2 equiv.). The vial was then sealed with a septum and purged with argon. 1.6 mL of THF was added via syringe. After stirring for

5-10 minutes at rt, 0.8 mL of the organozinc (1 M in DMI, 0.8 mmol, 1.6 equiv.) was added followed by the organohalide (0.5 mmol, 1.0 equiv.) and 50 uL of n-undecane

(GC/MS internal standard). The septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction stirred for 24 h before analysis by GC/MS.

(Table 17, Entries 2-5)

In air, a vial was charged with 3.4 mg of Pd-PEPPSI-IPr 91 (1 mol%) and under an inert atmosphere with 139.0 mg of LiBr or LiCl (1.6 mmol, 3.2 equiv.). The vial was then sealed with a septum and purged with argon. 0.6 mL of THF and 1.0 mL of DMI were then added via syringe and after stirring for 5-10 minutes at rt, 0.8 mL of the organozinc

(1 M in DMI, 0.8 mmol, 1.6 equiv.) was added followed by the organohalide (0.5 mmol,

1.0 equiv.) and 50 uL of n-undecane (GC/MS internal standard). The septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction stirred for 24 h before GC/MS analysis.

(Table 21, Entries 1-6)

In air, a vial was charged with 3.4 mg of Pd-PEPPSI-IPr 91 (1 mol %) and under an inert atmosphere with 108 mg of ZnCL; (0.8 mmol, 1.6 equiv.). The vial was then sealed with a septum and purged with argon. 1.6 mL of 4-methoxyphenylmagnesium bromide (0.5 M in THF, 0.8 mmol, 3.2 equiv.) was added and stirring continued for 15 minutes at which

139 time a white precipitate formed. 0.8 mL of NMP was added, followed by the organohalide or pseudo halide (0.5 mmol, 1.0 equiv.) and 50 uL of n-undecane (GC/MS internal standard) after which the septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction stirred for 24h before analysis GC/MS.

5.4.2 Cross-Coupling procedures and characterization data for figure 24-26

All cross-coupling reactions were run to a final solvent volume of 2.4 mL. The specific solvent ratio for each reaction is listed within the experimental results for each compound following the general procedures.

General Procedure A (sp3-sp3)

In air, a vial was charged with 3.4 mg of Pd-PEPPSI-IPr 91 (1 mol%) and under an inert atmosphere 139.0 mg of LiBr (1.6 mmol, 3.2 equiv.) and a stirbar were added. The vial was then sealed with a septum and purged with argon after which 1.6 mL of THF was added and the suspension was stirred until the solids dissolved. After this time, 0.8 mL of the organozinc (1.0 M in DMI, 0.8 mmol, 1.6 equiv.) and the organohalide or pseudo halide (0.5 mmol, 1.0 equiv.) were added. The septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction stirred for 2h. After this time, the reaction mixture was diluted with 15 mL of ether and washed successively with 1 M

Na3EDTA solution (prepared from EDTA and 3 equiv of NaOH), water and brine. After drying (anhydrous MgS04) the solution was filtered, the solvent removed in vacuo, and the residue purified by flash chromatography.

General Procedure B (sp2-sp3)

140 In air, a vial was charged with 3.4 mg of Pd-PEPPSI-IPr 91 (1 mol%) and under an inert atmosphere with 139.0 mg of LiBr (1.6 mmol, 3.2 equiv.).The vial was then sealed with a septum and purged with argon. 1.6 mL of THF was then added and suspension stirred until the solids had dissolved. After this time, 0.8 mL of the organozinc (1.0 M in DMI,

0.8 mmol, 1.6 equiv.) and the organohalide or pusedo halide (0.5 mmol, 1.0 equiv.) were added. The septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction stirred for 2h. After this time, the mixture was diluted with

15 mL of ether and washed successively with 1 M Na3EDTA solution (prepared from

EDTA and 3 equiv of NaOH), water, and brine. After drying (anhydrous MgS04), the solution was filtered, the solvent removed in vacuo and the residue purified by flash chromatography.

General Procedure C (sp2-sp2)

In air, a vial was charged with 3.4 mg of Pd-PEPPSI-IPr 91 (1 mol%) and under an inert atmosphere with 108 mg of ZnCk (0.8 mmol, 1.6 equiv.). The vial was sealed with a septum and purged with argon. 0.8 mL of THF was then added followed by the requisite

0.8 mL of the Grignard reagent (1.0 M in THF, 0.8 mmol, 1.6 equiv.) and stirring continued for 15 minutes, at which time a white precipitate formed. 0.8 mL NMP was then added followed by the organohalide or pusedo halide (0.5 mmol, 1.0 equiv.) and the septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction stirred for 2h. After this time, the reaction mixture was diluted with 15 mL of ether and washed successively with 1 M NasEDTA solution (prepared from EDTA and 3

141 equiv. of NaOH), water, and brine. After drying (anhydrous MgS04) the solution was filtered, the solvent removed in vacuo, and the residue purified by flash chromatography.

(Figure 24, 87) Following general procedure A (THF:DMI, 2:1), 104 mg of 13-chloro-

2,2-dimethyltridecane nitrile 87 (81%) was isolated (3 vol. % diethyl ether in pentane Rf

= 0.18) as a clear oil. The 'H and 13C NMR spectra were identical to those previously described.244

(Figure 24, 96) Following general procedure A (THF:DMI, 2:1), 115 mg of 2-(5- cyclohexylpentyl)isoindole-l,3-dione 96 (80%) was isolated ( 20 vol. % diethyl ether in pentane Rf= 0.40) as a white solid (Mp: 74-75°C). "H NMR (300 MHz, CDC13): 5 7.86-

7.80 (m, 2H), 7.75-7.67 (m, 2H), 3.68 (t, J= 7.2 Hz, 2H), 1.80-1.65 (m, 7H), 1.36-1.27

I3 (m, 4H), 1.25-1.10 (m, 6H), 0.97-0.85 (m, 2H). C NMR (75 MHz, CDC13): 5 168.4,

133.8, 132.2, 123.1, 38.0, 37.5, 37.3, 33.3, 28.6, 27.1, 26.7, 26.4. Anal. Calcd. for

C19H25NO2: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.49; H, 8.42; N, 5.08.

142 (Figure 24, 97) Following general procedure A (THF:NMP, 2:1), 107 mg of 2-(5- phenylpentyl)-[l,3]dioxane 97 (86%) was isolated (5 vol. % diethyl ether in pentane, Rf=

0.20) as a clear oil. 'H NMR (300 MHz, CDC13): 5 7.29 (t, J= 7.2 Hz, 2H), 7.19 (d, J =

7.3 Hz, 3H), 4.52 (t, J= 4.8 Hz, 1H), 4.12 (dd, J= 11.7, 4.8 Hz, 2H), 3.76 (dt, J= 12.6,

2.4 Hz, 2H), 2.63 (t, J= 7.5 Hz, 2H), 2.17-2.00 (m, 1H), 1.74-1.55 (m, 4H), 1.50-1.28 (m,

13 5H). C NMR (75 MHz, CDC13): 5 142.7, 128.4, 128.2, 125.5, 102.3, 66.9, 35.8, 35.1,

31.3, 29.1, 25.8, 23.8. Anal. Calcd. for Ci5H2202: C, 76.88; H, 9.46. Found: C, 76.57; H,

9.85.

101

(Figure 24, 101) Following general procedure A (THF:NMP, 1:2), 85 mg of 2,2- dimethyl-9-phenylnonanenitrile 101 (70%) was isolated (5 vol. % diethyl ether in pentane, Rf = 0.50) as a clear oil after removing volatile impurities under reduced pressure for 12h. 'H NMR (400 MHz, CDC13): 5 7.29 (t, J= 6.8 Hz, 2H), 7.21 (d, J= 6.4

Hz, 3H), 2.64 (t, J= 7.6 Hz, 2H), 1.70-1.60 (m, 2H), 1.58-1.45 (m, 4H), 1.40-1.30 (m,

13 12H). C NMR (100 MHz, CDC13) 5: 142.8, 128.4, 128.3, 125.6, 125.3, 41.1, 35.9, 32.4,

31.5, 29.5, 29.3, 29.2, 26.7, 25.3. HRMS (EI) m/z calcd for C17H25N: 243.1983, Found

243.1987. Anal. Calcd. for C17H25N: C, 83.89; H, 10.35, N, 5.75, Found C, 83.70; H,

9.98, N, 6.09.

143 (Figure 24, 102) Following general procedure A (THF:DMI, 2:1), 123 mg of (9S,13)- dimethyltetradec-12-enoic acid ethyl ester 102 (87%) was isolated (5 vol. % diethyl ether

23 ! in pentane, Rf= 0.60) as a clear viscous oil. [a]D = +0.84 (c = 2.5, CH2C12). H NMR

(300 MHz, CDC13): 5 5.11 (t, J= 6.0 Hz, 1H), 4.13 (q, J= 7.1 Hz, 2H), 2.30 (t, J= 7.4

Hz, 2H), 2.05-1.90 (m, 2H), 1.75-1.58 (m, 8H), 1.45-1.20 (m, 14H), 1.20-1.05 (m, 2H),

13 0.86 (d, J= 6.3 Hz, 3H). C NMR (75 MHz, CDC13): 5 173.9, 130.9, 125.0, 60.1, 37.1,

36.9, 34.4, 32.4, 29.8, 29.3, 29.1, 26.9, 25.7, 25.5, 25.0, 19.5, 17.6, 14.2. Anal. Calcd. for

C18H34O2: C, 76.54; H, 12.13. Found: C, 76.08; H, 12.48.

103 (Figure 24,103) Following general procedure B (THF: NMP, 1:2), 115 mg of trimethyl-

[5-(2,4,6-trimethylphenyl)pent-l-ynyl]silane 103 (89%) was isolated (pentane, Rf= 0.80) as a clear oil. *H NMR (300 MHz, CDC13): 8 6.88 (s, 2H), 2.80-2.72 (m, 2H), 2.39 (t, J =

6.8 Hz, 2H), 2.30 (s, 6H), 2.26 (s, 3H), 1.75-1.66 (m, 2H), 0.22 (s, 9H). 13C NMR (75

MHz, CDCI3): 5 136.1, 135.6, 135.1, 128.9, 107.3, 85.0, 28.5, 28.1, 20.8, 20.3, 19.7, 0.2.

Anal. Calcd. for Ci7H26Si: C, 79.00; H, 10.14. Found: C, 78.69; H, 10.42.

144 104 ^V

(Figure 25, 104) Following general procedure B (THF: DMI, 2:1), 99 mg of 6- benzo[l,3]dioxol-5-yl-2,2-dimethylhexanenitrile 104 (81%) was isolated (25 vol. % diethyl ether in pentane, Rf= 0.25) as a clear oil. 'H NMR (300 MHz, CDC13): 8 6.74 (d,

J= 8.0 Hz, 1H), 6.69 (s, 1H), 6.63 (d, J= 8.0 Hz, 1H), 5.94 (s, 2H), 2.58 (t, J = 7.6 Hz,

2H), 1.67-1.59 (m, 2H), 1.57-1.50 (m, 4H), 1.35 (s, 6H). 13C NMR (75 MHz, CDCI3):

5 147.5, 145.6, 136.0, 125.2, 121.0, 108.7, 108.1, 100.7, 40.9, 35.4, 32.4, 31.7, 26.7, 24.8.

105

(Figure 25,105) Following general procedure B (THF: DMI, 2:1), 108 mg of 6-pyridine-

2-yl-hexanoic acid ethyl ester 105 (98%) was isolated (30 vol. % diethyl ether in pentane,

Rf= 0.10) as a clear oil. 'H NMR (300 MHz, CDC13): 8 8.50 (dd, J= 4.2Hz, 1H), 7.56

(dt, J= 7.2 Hz, 1H), 7.14-7.03 (m, 2H), 4.10 (q, J = 7.2 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H),

2.28 (t, J= 7.5 Hz, 2H), 1.82-1.60 (m, 4H), 1.48-1.30 (m, 2H), 1.21 (t, J= 7.1 Hz, 3H).

13 C NMR (75 MHz, CDC13): 8 173.7, 162.1, 149.2, 136.2, 122.7, 120.9, 60.1, 38.2, 34.2,

29.5, 28.8, 24.8, 14.2. Anal. Calcd. for C13H19NO2: C, 70.56; H, 8.65. Found: C, 70.67;

H, 8.95.

145 (Figure 25,106) Following general procedure B (THF: DMI, 2:1), 149 mg of 6-(N-Boc- indol-5-yl) hexanoic acid ethyl ester 106 (83%) was isolated (3 vol. % diethyl ether in

! pentane, Rf= 0.15) as a clear viscous oil. H NMR (400 MHz, CDC13): 8 8.04 (d, J= 8.1

Hz, 1H), 7.60 (d, J= 3.4 Hz, 1H), 7.38 (s, 1H), 7.16 (d, J= 8.5 Hz, 1H), 6.54 (d, J= 3.4

Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 2.73 (t, J= 7.5 Hz, 2H), 2.32 (t, J= 7.5 Hz, 2H), 1.75-

13 1.65 (m, 13H), 1.44-1.35 (m, 2H), 1.28 (t, J= 7.1 Hz, 3H). C NMR (100 MHz, CDC13):

8 173.8, 149.8, 136.9, 133.6, 130.8, 125.9, 125.0, 120.3, 114.9, 107.2, 83.4, 60.2, 35.6,

34.3, 31.6, 28.7, 28.2, 24.9, 14.3. Anal. Calcd. for C21H29NO4: C, 70.17; H, 8.13. Found:

C, 70.49; H, 8.39.

yX^ 107 O

(Figure 25, 107) Following general procedure B (THF:DMI, 2:1), 114 mg of l-(4- fluorophenyl)-4S,8-dimethylnon-7-en-l-one 107 (87%) was isolated (3 vol. % diethyl

23 l ether in pentane, Rf= 0.40) as a clear viscous oil. [a]D = +1.07 (c = 1.68, CH2C12). H

NMR (300 MHz, CDC13): 8 8.01 (m, 2H), 7.14 (t, J= 8.6 Hz, 2H), 5.11 (t, J= 5.9 Hz,

1H), 3.00-2.87 (m, 2H), 2.07-1.95 (m, 2H), 1.90-1.65 (m, 4H), 1.60-1.48 (m, 5H), 1.47-

I3 1.30 (m, 1H), 1.25-1.13 (m, 1H), 0.95 (d, J= 6.3 Hz, 3H). C NMR (75 MHz, CDC13):

146 3 2 5 199.1, 167.2 (VCF= 337 Hz), 133.4, 131.3, 130.7 ( JCF= 12.2 Hz), 124.6, 115.5 ( JCF =

27.8 Hz), 36.8, 36.2, 32.2, 31.3, 25.7, 25.5, 19.4, 17.6. Anal. Calcd. for Ci7H23FO: C,

77.82; H, 8.84. Found: C, 78.07; H, 9.05.

(Figure 26, 108) Following general procedure C (THF:NMP, 1:1), 118 mg of 1- mesitylnaphthalene 108 (96%) was isolated (pentane, Rf= 0.65) as a colourless, viscous oil. The *H and 13C NMR spectra were identical to those previously described.245 vUJ

(Figure 26, 109) Following general procedure C (THF:NMP, 2:1), 114 mg of 5-(2,4,6- trimethylphenyl)benzo[l,2,5]thiadiazole 109 (90%) was isolated (2 vol. % diethyl ether in

! pentane, Rf= 0.26) as yellow crystals. M.p = 54-55°C). H NMR (300 MHz, CDC13): 5

8.07 (d, J= 9.0 Hz, 1H), 7.81 (s, 1H), 7.42 (dd, J= 4.5, 1.5 Hz, 1H), 7.02 (s, 2H), 2.39 (s,

3H), 2.08 (s, 6H). 13C NMR (75 MHz, CDCI3): 5 155.3, 154.0, 142.8, 137.5, 137.3, 135.7,

132.4, 128.4, 121.2, 21.1, 20.8. Anal. Calcd. for C15H14N2S: C, 70.83; H, 5.55; N, 11.01.

Found: C, 70.61; H, 5.92; N, 11.06.

147 b. 110 \^^0

(Figure 26, 110) Following general procedure C (THF: NMP, 2:1), 106 mg of 5-(4- fluorophenyl) benzo [1, 3] dioxole 110 (98%) was isolated (5 vol. % diethyl ether in pentane, Rf= 0.60) as a white solid. Mp = 42-43°C. *H NMR (400 MHz, CDC13): 5 7.52-

7.48 (m, 2H), 7.13 (t, J = 9.2 Hz 2H), 7.01 (d, J= 9.2 Hz, 2H), 6.90 (d, J= 8.0 Hz, 1H),

13 6.03 (s, 2H). C NMR (100 MHz, CDC13): 5 162.2 (%? = 245 Hz), 148.2, 147.1, 137.1,

2 134.6, 128.4, 120.5, 115.6 ( JCF = 21 Hz), 108.6, 107.6, 101.2.

N CN 6 111 (Figure 26, 111) Following general procedure C (THF: NMP, 1:2), 95 mg of 2-cyano-6-

(2-methoxyphenyl) pyridine 111 (90%) was isolated (50 vol. % diethyl ether in pentane,

Rf= 0.30) as white crystals. Mp = 109-110°C. The melting point, *H and 13C NMR spectra were identical to those previously described.246

148 (Figure 26, 112) This reaction was carried out at 60°C. Following general procedure C

(THF: NMP, 1:1), 133 mg of 2,4,6-triisopropyl-2'-methylbiphenyl 112 (90%) was isolated (hexane, Rf= 0.30) as a white solid. Mp = 94-95°C. The melting point, lH and

13C NMR spectra were identical to those previously described.247

(Figure 26,113) Following general procedure C (THF:NMP, 1:1), 114 mg of 3-phenyl-6- thiophen-2-yl pyridazine 113 (96%) was isolated (33 vol. % ethyl acetate in hexane, Rf=

! 0.48) as pale yellow crystals. Mp = 161-162°C. H NMR (300 MHz, CDC13): 5 8.16 (dd, J

= 3.9, 1.5 Hz, 2H), 7.87 (q, J= 4.8 Hz, 2H), 7.76-7.70 (m, 1H), 7.58-7.47 (m, 4H), 7.24-

13 7.15 (m, 1H). C NMR (75 MHz, CDC13): 5 157.4, 153.5, 140.7, 136.0, 130.0, 129.2,

129.0, 128.1, 126.7, 126.1, 124.0, 122.6. Spectral data are provided as these are more detailed relative to literature values.

149 5.5 Sp2-Sp2 Kumada cross-coupling reactions

Synthetic Procedures:

Synthesis of o-methoxyphenylmagnesium bromide (1M solution in THF) A 100 mL round-bottom flask equipped with a stir-bar, reflux condenser, and a rubber septum was flame-dried in vacuo until no visible moisture was detected on the glass. The apparatus was then purged with argon and allowed to cool to rt; this process was repeated twice more to ensure complete dryness. A second 100 mL round-bottom flask with stir-bar was also flame-dried using the same procedure. While cooling under argon, 2.50 g of magnesium metal turnings (60 mmol, 1.2 equiv.) was weighed out in a vial and was transferred to the first flask under a cone of argon, which was then re-sealed and purged with argon. 2 mL of THF was added to the first flask. To the second round-bottomed flask was added 6.2 mL of o-bromoanisole (50 mmol, 1.0 equiv.) along with the remaining THF (41.8 mL). The reaction was then initiated by warming with a heat gun and the remaining halide was cannulated dropwise to the first flask maintaining a steady exotherm. A 10 uL sample was withdrawn and quenched with 100 uL water and extracted with 2 mL of hexane. The organic layer was passed through a plug of silica gel and analyzed by GC-MS. One single peak corresponding to anisole was observed, ensuring Grignard formation.

Synthesis of p-tolylmagnesium bromide (1M solution in THF) The procedure for o- methoxyphenylmagnesium bromide was used with the following exceptions: 3.14 mL of

/7-bromotoluene (25 mmol, 1.0 equiv.), 720 mg of Mg turnings (30 mmol, 1.2 equiv.) and

150 21.86 mL of THF were used to generate the Grignard. The freshly-prepared reagent was allowed to cool to rt, and was ready for use after approximately 3h.

Synthesis of mesitylmagnesium bromide (1M solution in THF) Following the procedure for o-methoxyphenylmagnesium bromide, 2-bromomesitylene (3.86 mL, 25 mmol) was diluted with THF (21.14 mL) and added dropwise to the Mg-containing flask, while maintaining a steady exotherm. Following cannulation, the reagent was allowed to stir under argon at rt. prior to use.

Cross-Coupling procedures

Some cross-coupling reactions were run with a final solvent volume of 1.6 to 2.1 mL (0.5 mmol), while others include a final solvent volume of 0.4 mL (0.25 mmol), and 0.8 mL

(0.5 mmol). A specific solvent ratio for each reaction is listed within the experimental results for each isolated compound following the general procedures.

5.5.1 Kumada-Tamao-Corriu (KTC) aryl-aryl cross-coupling procedures

Procedure A (THF.DMI)

In air, a vial equipped with a stir-bar was charged with 6.8 mg of Pd-PEPPSI-IPr 91 (2 mol %), sealed with a septum, and purged with argon. Distilled THF (0.26 to 0.7 mL) and dry DMI (0.53 to 0.7 mL) were added by syringe and stirred for 1-2 minutes, after which the aryl halide (0.5 mmol, 1.0 equiv.), and 50 \iL of n-undecane (GC/MS internal 151 standard) were injected via syringe. Alternatively, if the aryl halide was solid at rt, it was weighed out and added to the vial in air following Pd-PEPPSI-IPr 91 addition. After 1-2 minutes of stirring, the Grignard reagent (0.65 to 0.8 mmol, 1.3 to 1.6 equiv.) was added in one rapid shot by syringe. The septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction mixture was allowed to stir for approximately

24 hs at rt or 50°C prior to GC/MS and/or TLC analysis. Once product was identified, the general work-up procedure for compound isolation was followed.

Procedure B (THF.DME)

In air, a vial equipped with a stir-bar was charged with 6.8 mg of Pd-PEPPSI-IPr 91 or

Pd-PEPPSI-SIPr 89 (2 mol %), sealed with a septum, and purged with argon. Dry THF

(0.35 mL) and dry DME (0.8 to 1.0 mL) was added by syringe and stirred for 1-2 minutes, after which the aryl halide (0.5 mmol), and 50 uL of «-undecane (only for

GC/MS analysis, internal standard) were injected via syringe. Alternatively, if the aryl halide was solid at rt, it was weighed out and added to the vial in air following complex

91 additions. After 1-2 minutes of stirring, the Grignard reagent (1.3 to 1.6 equiv.) was added in one rapid shot by syringe. The septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction mixture was allowed to stir for approximately 24 h at rt or 50°C prior to GC/MS and/or TLC analysis. Once product was identified, the general work-up procedure for compound isolation was followed.

152 Procedure C (THF)

In air, a vial equipped with a stir-bar was charged with complex 6.8 mg of Pd-PEPPSI-IPr

91 or Pd-PEPPSI-SIPr 89 (2 mol %), sealed with a septum, and purged with argon. The aryl halide (0.5 mmol), and 50 uL of n-undecane (only for GC/MS analysis, internal standard) were injected via syringe. Alternatively, if the aryl halide was solid at rt, it was weighed out and added to the vial in air following complex 91 (or 89) addition. The

Grignard reagent (0.8 mmol, 1.6 equiv.) was added in one rapid shot by syringe, followed by septum replacement for a Teflon®-lined screw cap under an inert atmosphere. The reaction mixture was allowed to stir for approximately 24 h at rt/60°C prior to GC/MS and/or TLC analysis. Once product was identified, the general work-up procedure for compound isolation was followed.

Experimental Work-Up for Product Isolation

When couplings were judged complete, a 1M Na3EDTA solution (prepared from EDTA and 3 equiv. NaOH) was added, the solution stirred for a minute and then transferred to a separatory funnel. The layers were separated and the aqueous layer extracted with diethyl ether (20 mL). The combined organic layers were then sequentially washed with distilled water and brine. After drying over anhydrous MgS04, the solution was filtered, concentrated, and the residue was purified by flash chromatography on silica gel.

153 (Figure 29,115) Following general procedure A (THF:DMI, 2:1), 70 mg of l-mesityl-2- methoxybenzene 115 (62%)was isolated (2 vol. % diethyl ether in pentane, Rf= 0.35) as a crystalline, colorless solid. Mp = 54-56°C. Spectral data were in agreement with literature.249

(Figure 29, 116) Following general procedure C (THF) at 50°C using complex Pd-

PEPPSI-IPr 91, 113 mg of 2-mesitylnaphthalene 116 (92%) was isolated (pentane, Rf=

0.35) as a viscous oil. Spectral data were in agreement with literature.25 „-MeO«, N'

oAQ 117

(Figure 29,117) Following general procedure A (THF:DMI, 2:1), using complex 91 at rt,

537 mg of tert-buty\ 5-(2-methoxyphenyl)-l//-indole-l-carboxylate 117 (83%) was prepared from 2.6 mmol of Grignard reagent and 2 mmol of aryl bromide, and isolated (3 vol. % diethyl ether in pentane, Rf= 0.3) as a clear oil. Spectral data were in agreement with literature.251

MeO N TD SV^^ 118

154 (Figure 29, 118) Following general procedure B (THF:DME, 1:1), using complex 91 at rt, 89 mg of 5-(2-methoxyphenyl)benzo[c][l,2,5]thiadiazole 118 (74%) was prepared and isolated (5 vol. % diethyl ether in pentane, Rf= 0.26) as a yellow, crystalline solid. M.p. =

82-85°C. 'H NMR (400 MHz, CDC13) 5: 8.12 (s, 1H), 8.03 (d, J= 9.1 Hz, 1H), 7.85 (d, J

= 9.1 Hz, 1H), 7.44 (t, J= 7.6, 2H), 7.05 (m, J= 8.1 Hz, 2H), 3.88 (s, 3H); 13C NMR (100

MHz, CDCI3) 5: 156.6, 155.2, 154.1, 140.4, 132.6, 130.8, 129.8, 129.1, 121.1, 120.1,

111.5, 55.6; Anal. Calcd. for Ci3Hi0N2OS: C, 64.44; H, 4.16; N, 11.56. Found: C, 64.77;

H, 4.59; N, 11.29.

119

(Figure 30,119) Following general procedure C (THF) using complex 91 at rt, 115 mg 2- mesitylbenzothiazole 119 (90%) from 0.5 mmol of aryl chloride was prepared and isolated(5 vol. % diethyl ether in pentane, Rf= 0.3) as a clear, yellow oil; *H NMR (300

MHz, CDCI3) 5: 8.15 (d, J= 8.3 Hz, 1H), 7.97 (d, J= 7.9, 1H), 7.55 (t, J= 7.6 Hz, 1H),

7.45 (t, J = 7.6 Hz, 1H) 6.99 (s, 2H), 2.37 (s, 3H), 2.22 (s, 6H); 13C NMR (75 MHz,

CDCI3) 5: 167.7, 153.5, 139.4, 137.1, 129.0, 128.3, 125.9, 125.0, 123.4, 121.5, 21.2, 20.2,

15.8; Anal. Calcd. for d6Hi5NS: C, 75.85; H, 5.97; N, 5.53 Found: C, 75.41; H, 6.25; N,

5.78.

MeO

120

155 (Figure 30, 120) Following general procedure B (THF:DME, 1:1), using complex 91,

82.3 mg of 2-(2-methoxyphenyl)thiophene 120 (91%) was prepared and isolated (5 vol.

% diethyl ether in pentane, Rf = 0.4) as a viscous, yellow oil. Spectral data were in agreement with the literature.252

MeO

121

(Figure 30, 121) Following general procedure B (THF:DME, 1:1), using complex 91,

105 mg of 2-(2-methoxyphenyl)benzothiazole 121 (87%) was isolated (3 vol. % ethylacetate in hexane Rf= 0.2)as a yellow, crystalline solid. Mp = 95-98°C. 'H NMR

(300 MHz, CDC13) 5: 8.56 (d, J= 7.6 Hz, 1H), 8.12 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.6

13 Hz, 1H), 7.54-7.37 (m, 3H), 7.19-7.08 (m, 2H), 4.08 (s, 3H); C-NMR (75 MHz, CDC13)

5: 191.9, 163.1, 157.2, 152.2, 136.1, 131.7, 129.5, 125.8, 124.6, 122.8, 121.2, 111.7, 55.6;

Anal. Calcd. for Ci4H,iNOS: C, 69.68; H, 4.59; N, 5.80; O, 6.63. Found: C, 69.55; H,

4.54; N, 5.78. 1 X")N A 122 (Figure 30,122) Following general procedure C (THF) using complex 91, 85.3 mg of 2- mesitylpyrazine 122 (86%) was isolated (20 vol. % diethyl ether in pentane Rf= 0.2) as a

[ clear, yellow oil H NMR (300 MHz, CDC13) 8: 8.71 (s, 1H), 8.54 (s, 2H), 6.98 (s, 2H),

13 2.34 (s, 3H), 2.04 (s, 6H); C NMR (75 MHz, CDC13) 5: 155.9, 146.0, 144.4, 142.5,

156 138.4, 136.1, 134.0, 128.6, 21.1, 20.1; Anal. Calcd. for C13H14N2: C, 78.75; H, 7.12; N,

14.13. Found: C, 78.33; H, 7.43; N, 14.68. Tf

F3cr ^ 123

(Figure 31, 123) Following general Procedure C (THF) using complex 91 at it, 105 mg of l-mesityl-4-(trifluoromethyl)benzene 123 (80%) was isolated (pentane Rf= 0.65) as a

! clear, crystalline solid. Mp = 59-60°C; H NMR (300 MHz, CDC13) 5: 7.72 (d, J= 8.1 Hz,

2H), 7.31 (d, J= 8.2 Hz, 2H), 7.01 (s, 2H), 2.34 (s, 3H), 2.03 (s, 6H). Spectral data were in agreement with literature.

(Figure 31, 124) Following general procedure C (THF) using complex 91, 80 mg of 3- mesitylthiophene 124 (76%) was isolated (pentane Rf= 0.70) as a viscous, clear oil; !H

NMR (400 MHz, CDC13) 5: 7.41 (d, J= 7.3 Hz, 2H), 7.05 (s, 1H), 6.96 (s, 2H), 2.36 (s,

3H), 2.09 (s, 6H); 13C NMR (100 MHz, CDCI3) 5: 140.7, 136.9, 136.8, 133.9, 129.0,

128.0, 125.0, 122.2, 21.0, 20.6; Anal. Calcd. for C13Hi4S: C, 77.18; H, 6.97.

N" V, N 125

157 (Figure 31,125) Following general procedure C (THF), using complex 89 at rt, 98 mg of

4-mesityl-l,3,5-trimethyl-l//-pyrazole 125 (85%) was prepared from 0.8 mmol of

Grignard reagent with 1.6 mmol of LiCl additive, 0.5 mmol of aryl bromide, and was isolated (50 vol. % diethyl ether in pentane Rf= 0.2) as a yellow oil; 50:50); !H NMR

13 (300 MHz, CDC13) 5: 6.94 (s, 2H), 3.80 (s, 3H), 2.33 (s, 3H), 2.03 (s, 12H); C NMR (75

MHz, CDCI3) 5: 145.3, 138.1, 136.6, 136.1, 129.7, 127.9, 117.0, 36.0, 21.1, 20.4, 12.1,

9.81; Anal. Calcd. for C15H20N2: C, 78.90; H, 8.83; N, 12.27. Found: C, 79.02; H, 8.81;

N, 12.57.

(Figure 31,126) Following general procedure C (THF) using complex 91 at rt, 69 mg of

2-phenyl-(2'-phenyl)-4-methylquinoline 126 (93%) was isolated (10 vol. % diethyl ether in pentane Rf= 0.2) as a white solid. M.p. = 116-119°C. *H NMR (300 MHz, CDC13) 5:

8.18 (d, J= 8.5 Hz, 2H), 7.93(d, J= 8.3 Hz, 1H), 7.86 (m, 1H), 7.73 (t, J= 6.9 Hz, 1H),

13 7.58-7.51 (m, 4H), 7.23 (s, 4H), 6.82 (s, 1H), 2.44 (s, 3H); C NMR (75 MHz, CDC13) 5:

159.5, 148.0, 142.8, 141.2, 140.8, 139.8, 130.7, 130.4, 130.1, 129.7, 128.9, 128.7, 128.0,

127.8, 126.7, 126.6, 126.0, 124.2, 123.6, 18.4; Anal. Calcd. for C22H17N: C, 89.46; H,

5.80; N, 4.74. Found: C, 90.01; H, 5.96; N, 4.81.

158 (Figure 31,127) Following general procedure C (THF), using complex 89 at rt, 70 mg of

3-biphenylylbenzothiazole 127 (98%) was prepared from 0.4 mmol of Grignard reagent and 0.25 mmol of aryl bromide, and was isolated (pentane Rf= 0.2) as a white solid. Mp

= 103-105°C. *H NMR (300 MHz, CDC13) 5: 7.84 (d, J= 6.9 Hz, 1H), 7.57-7.47 (m, 5H),

7.29 (q, J= 7.2 Hz, 2H), 7.18-7.13 (m, 5H), 7.01 (s, 1H); 13C NMR (75 MHz, CDCI3) 5:

141.9, 141.3, 139.8, 138.7, 136.9, 134.1, 131.0, 130.5, 129.2, 129.1, 128.0, 127.8, 127.3,

126.6, 125.0, 124.0, 123.0, 122.5; Anal. Calcd. for C2oH,4S: C, 83.88; H, 4.93. Found: C,

83.34; H, 4.75.

(Figure 31, 128) Following Procedure C (THF), using complex 91 at rt, 79 mg of 3- biphenylyl-l-phenylsulfonyl-li/-indole 128 (77%) was prepared from 0.4 mmol of

Grignard reagent and 0.25 mmol of aryl bromide, and isolated (7 vol. % diethyl ether in pentane Rf= 0.3) as a colorless, crystalline solid. Mp = 141-144°C. 'H NMR (300 MHz,

CDCI3) 5: 7.98 (d,J= 8.4 Hz, 1H), 7.7l(d, J= 7.8 Hz, 2H), 7.60-7.52 (m, 2H), 7.48-7.42

(m, 5H), 7.36 (d, J= 7.8 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.18-7.07 (m, 7H); 13C NMR

(75 MHz, CDCI3) 5: 141.6, 141.3, 138.2, 134.8, 133.6, 130.8, 130.6, 130.3, 130.2, 129.2,

159 127.9, 127.4, 126.8, 126.6, 124.9, 124.6, 123.3, 123.2, 120.5, 113.5; Anal. Calcd. for

C26H19NO2S: C, 76.26; H, 4.68; N, 3.42. Found: C, 76.43; H, 4.61; N, 3.51.

(Figure 31, 129) Following Procedure C (THF), using complex 91 at rt, 171 mg of 5- mesitylquinolin-8-ol 129 (65%) was prepared from 0.62 mmol of Grignard reagent and

0.25 mmol of aryl bromide and isolated ( dichloromethane, Rf = 0.2) as a yellow,

J crystalline solid. Mp = 128-132°C. H NMR (300 MHz, CDC13) 5: 8.80 (s, 1H), 7.68 (d, J

= 8.5 Hz, 1H), 7.34 (q, J= 4.3 Hz, 1H), 7.27 (s, 2H), 7.02 (s, 2H), 2.40 (s, 3H), 1.86 (s,

13 6H); C NMR (75 MHz, CDC13) 8: 151.1, 147.6, 138.4, 137.4, 137.1, 135.1, 134.2,

129.1, 128.2, 128.1, 127.1, 121.8, 109.7, 21.1, 20.3; Anal. Calcd. for Ci8H,7NO: C, 82.10;

H, 6.51; N, 5.32. Found: C, 82.02; H, 6.76; N, 4.99.

(Figure 31, 130) Following general Procedure C (THF), using complex 91 at rt, 110 mg of 3-mesityl-6-phenylpyridazine 130 (80%) was prepared from 0.8 mmol of Grignard

160 reagent and 0.5 mmol of aryl chloride, and isolated (25 vol. % diethyl ether in pentane Rf

= 0.3) as white solid. Mp = 96-99°C. *H NMR (300 MHz, CDC13) 5: 8.21 (d, J= 7.3 Hz,

2H), 7.96 (d, J= 8.7 Hz, 1H), 7.61-7.46 (m, 4H), 7.01 (s, 2H), 2.38 (s, 3H), 2.11 (s, 6H);

13 C NMR (75 MHz, CDC13) 6: 160.6, 157.3, 138.4, 136.2, 136.3, 136.1, 134.4, 130.0,

129.0, 128.6, 127.1, 123.6, 21.1, 20.3; Anal. Calcd. for Ci9H18N2: C, 83.18; H, 6.61; N,

10.21. Found: C, 82.91; H, 6.85; N, 10.14.

161 5.6 Natural product synthesis

Cbzv NH O I

OH 140

(2S, 3R)-tert-butyl 2-Hydroxy-3-(N-benzyloxycarbonyl)-aminobutanoate 140

2.44 g of sodium hydroxide (61 mmol, 3.05 equiv.) in 150 mL of water was prepared in a single-necked round-bottom flask equipped with a magnetic stir bar. Approximately 10 mL of this solution was transferred into a 25 mL flask with a Pasteur pipet and 294 mg of potassium osmate dihydrate (0.8 mmol, 4 mol%) was solubilized by swirling. 9.38 g of benzyl carbamate (62 mmol, 3.1 equiv.) was added in 80 mL of acetonitrile and was stirred for 10 minutes. At this time, the rest of sodium hydroxide solution was added to this flask. Then the flask was immersed in a rt water bath and 6.92 mL of freshly prepared tert-butyl hypochlorite (61 mmol, 3.1 equiv.) was added dropwise with stirring over a period of 10 min .In another flask, 780 mg of hydroquinidine 1,4-phthalazinedyl diether

(DHQD)2PHAL (1 mmol, 5 mol%) and 3.20 mL of tert-butyl crotonate 139 (20 mmol,

1.0 equiv.) was added to 70 mL of acetonitril. This solution was transferred to the reaction mixture followed by the pink K2[Os02(OH)4] solution. After 1 h, 20 g of sodium sulfite (160 mmol) was added and stirred for 1 more h. The two phases were separated, and the aqueous phase was extracted with ethyl acetate (4 x 100 mL). The combined organic layer was washed with water and brine, dried over MgS04, and concentrated.

Purification by flash chromatography (30 vol. % hexane in ethyl acetate Rf = 0.25)

162 23 provided 3g.(58%) of desired product as a white crystals. Mp = 82-85°C. [a]D = -9.7 (c

= 0.34, CHCI3). *H NMR (300 MHz, CDC13): 5 7.33 (m, 5H), 5.03(m, 3H), 4.28 (m, 1H),

4.01 (m, 1H), 3.09 (d, J = 3.6 Hz, 1H) 1.46 (s, 9H) 1.27 (d, J= 6.9 Hz, 3H). 13C NMR (75

MHz, CDCI3): 8 172.4, 155.5, 136.5, 128.4, 127.9, 83.5, 73.3, 66.6, 48.9, 28.3, 27.7,

18.3.254

' 145

(4R, 5S)-3-benzyl 5-tert-butyl 2,2, 4-trimethyloxazolidine-3, 5-dicarboxylate 145

A solution 0.248 g of 140 (0.81 mmol, 1.0 equiv.), 1 mL of DMP (8.1 mmol, 10 equiv.), and 0.016 g of TSOH.H2O (0.081 mmol, 10 mol%) in 4 mL of benzene was heated in the oil bath at 50°C for 4 h. The solution was partitioned between saturated NaHCC>3 solution and ether. The organic layer was washed with saturated NaHC03 solution followed by brine, then dried with MgSC>4; filtered and concentrated. The crude product was purified by column chromatography (30 vol. % ethyl acetate in hexane Rf= 0.6) afforded, 185 mg

23 of the desired product as a colorless oil (65%). [a]D = + 8.1 (c = 4.3, CHC13). *H NMR

(300 MHz, CD3OD): 8 7.33 (m, 5H), 5.18 (m, 2H), 4.25 (m, 2H), 1.59 (br m, 6H), 1.49

(s, 9H), 1.39 (br d, 3H). 13C NMR (75 MHz, CD3OD):

8 19.5, 25.3, 27.1, 55.6, 66.6, 80.3, 82.0, 95.9, 127.7, 127.9, 128.2, 136.5, 152.2, 170.1. A nal. Calcd. for C19H27NO5: C, 65.31; H, 7.79; N, 4.15. Found: C, 65.64; H, 7.92; N, 4.15.

163 Cbz-N ]— -QH

146

(4R, 5S)-Benzyl 5-(hydroxymethyI)-2,2, 4,-trimethyloxazolidine-3-carboxylate 146

To a solution of 0.216 g of compound 145 (0.62 mmol, 1.0 equiv.) in 7 mL of ether, under argon, was added 0.38 mL of LiBH4 (0.74 mmol, 1.20 equiv.). The mixture stirred for 3 h. At that time, the reaction mixture was extracted from the organic layer, washed with brine, and dried over MgS04. Purification by column chromatography (50 vol. % hexane in ethyl acetate Rf = 0.20) afforded 150 mg (87%) of the desired product as a

23 [ colorless oil. [a]D = -7.9 (c = 4.3, CHC13). H NMR (300 MHz, CDC13): 5 7.32 (s, 5H),

5.15 (m, 2H), 3.89-3.73 (m, 3H), 3.64 (m, 1H), 2.38 (br s, 1H) 1.65 (s, 3H), 1.54 (s, 3H),

+ 1.11 (br d, J = 6.3 Hz, 3H). HRMS (EI) m/z calcd for Ci5H2iN04: M-CH3 264.1234,

Found: 264.1236. Spectral data were in agreement with the literature.255

Cbz^N y- -Br O 147

(4R, 5S)-Benzyl 5-(bromo methyl)-2, 2, 4,-trimethyloxazolidine-3-carboxyIate 147

To the solution of 0.16 g of dibromotetrachloroethane (0.47 mmol, 1.04 eqiuv. ) in 2 mL of dichloromethane was added a solution of 0.12g of triphenyl phosphine (0.45 mmol, 1.0 equiv.) in 1 mL of dichloro methane at -78°C. After stirring for 1 h, a solution of 0.12 g of

146 (0.45 mmol, 1.0 equiv.) in 1.5 mL of dichloromethane was added to the reaction

164 mixture. The reaction was warmed to the it slowly. After 30 min., TLC showed the

completion of the reaction. Purification by column chromatography (20 vol. % ethyl

acetate in hexane Rf= 0.4) afforded 44 mg (26%) of the desired product as a colorless oil.

23 ! [a]D = -10.3 (c = 0.14, CHC13). H NMR (300 MHz, CD3OD): 5 7.36 (m, 5H), 5.15 (m,

2H), 3.95-4.04 (m, 2H), 3.51-3.57 (m, 2H), 1.53 (s, 3H), 1.30 (s, 3H), 1.11 (br d, 3H). 13C

NMR(75MHz,CD3OD):5 151.5, 137.2, 128.1, 127.8 (2C), 95.1, 81.3, 66.1, 57.2, 33.3, 25.

3, 18.2. HRMS (CI) m/z calcd for Ci5H2oBrN03: 342.0705, Found: 342.071.

Cbz. H N0 156

Benzyl oxiran-2-2ylmethylcarbamate 156

0.092 mL of methylsulfonyl chloride (1.14 mmol, 1.1 equiv.) was added to a stirred

solution of 0.24 g of 155 (1.05 mmol, 1.0 equiv.) in 1.30 mL of pyridine at 0°C. After 10 min, the resulting solution was added over 10 min to a stirred solution of 0.13 g of sodium hydroxide (3.04 mmol, 2.6 equiv.) in 1.30 mL of water and 0.86 mL of dimethyl sulfoxide at 0°C. After 10 min stirring, the solution was poured in an ice-water mixture and then extracted with ether. The organic layer was washed with water and brine and dried over sodium sulphate and concentrated. Purification by column chromatography (40 vol. % ethyl acetate in hexane Rf= 0.1) afforded 166 mg (80%) of the desired product as a colorless oil yield. Spectral data were in agreement with the literature.256

165 Benzyl 9-(fe/,f-butyldimethylsilyloxy)-2-hydrononyIcarbamate 158

To the solution of 0.19 mL of 6-bromohexyloxy-tert-butyl-dimethylsilane (0.68 mmol,

3.4 equiv.) in 1 mL of dry ether at -78°C was added t-BuLi (1.6 mmol, 1.7 M in pentane,

6.7 equiv.) dropwise over 15 min. After stirring for 1 h, 2.72 mL of lithium 2- thienylcyanocuprate (0.68 mmol, 0.25 M in THF, 3.4 equiv.) was added dropwise. The reaction temperature was allowed to increase to -30°C. At that point, a solution of 41 mg of 156 (0.2 mmol, 1.0 equiv.) in 0.5 mL of dry ether was added dropwise. The reaction mixture was stirred for an additional 2 h at 0°C. A solution of ammonium hydroxide and ammonium chloride (1:9) was added to the solution and extracted with ether (3x10 mL).

The organic layer was washed with water and brine and dried over sodium sulphate and concentrated. Purification by column chromatography (40 vol. % ethyl acetate in hexane

Rf= 0.1) afforded 70 mg (83%) of the desired product as a colorless oil. 'H NMR (300

MHz, C6D6): 5 7.22 (m, 5H), 5.19 (s, 2H), 4.71 (br m, 1H), 3.68 (t, J= 6.3 Hz, 2H), 3.51

(br s, 1H), 3.25 (br s, 1H), 2.95 (br s, 1H), 2.01 (br s, 1H) 1.62 (qn., J= 6.6 Hz, 2 H) 1.22-

13 1.32 (m, 10 H), 1.12 (s, 9 H), 0.20 (s, 6H). C NMR (75 MHz, C6D6):

5 156.9, 137.1, 129.0, 128.5, 128.4, 71.0, 66.6, 63.1, 47.2, 34.7, 33.0, 29.9, 29.8, 26.0, 25.

9, 25.5, 18.3, -5.25. HRMS (CI) m/z calcd for C23H4iN04Si: 424.2883, Found: 424.2873.

166 Benzyl 5-(7- fert-butyldimethylsilyloxy) heptyl-2,2-dimethyloxazolidine-3-

carboxylate 159

A solution of 0.60 g of 158 (1.4 mmol, 1.0 equiv.), 1.72 inL of DMP (14 mmol, 10 equiv.), and 0.026 g of TsOH.H20 (0.14 mmol, 10 mol %) in 14 mL benzene was stirred at rt for 2 h. The solution was partitioned between saturated NaHCC>3 solution and ether.

The organic layer was washed with saturated NaHCCh solution followed by brine, then dried with MgSC>4; filtered and concentrated as the crude product. Purification by column chromatography (10 vol. % ether in pentane Rf= 0.2) afforded 330 mg (50%) of the desired product as a colorless oil. 'H NMR (300 MHz, C6D6): 5 7.22 (m, 5H), 5.25 (m,

2H), 3.85 (m, 1H), 3.66 (t, J= 6.3 Hz, 2H), 3.51 (b s, 1H), 2.99 (bs, 1H), 1.89 (s, 3H),

13 1.27-1.73 (m, 15H), 1.09 (m, 9H), 0.09 (s, 6H), C NMR (75 MHz, C6D6):

8 152.0, 137.4, 129.0, 128.6, 128.4, 93.6, 73.9, 66.3, 62.9, 50.76, 33.1, 33.2, 29.7, 29.9, 2

6.8,26.0,25.9,23.9,18.2,-5.25. HRMS (CI) m/z calcd for C26H45N04Si; 464.3195,

Found: 464.3196.

Benzyl 5-(7-hydroxyheptyl)-2,2-dimethyIoxazolidine-3-carboxylate 160

167 To the solution of 0.20g of 159 (0.44 mmol, 1.0 equiv.) in 2 mL dry THF was added

TBAF 3 mL (3 mmol, 1M in THF, 6.8 equiv.). The solution stirred at rt for 1 h.

Purification by column chromatography (50 vol. % ether in pentane Rf= 0.2) afforded,

152 mg (99%) of the desired product as a colorless oil. 'H NMR (300 MHz, C6D6): 8 7.19

(m, 5H), 5.21-5.30 (m, 2H), 3.81-3.86 (m, 1H), 3.55-3.60 (m, 1H), 3.44 (t, J= 6.3 Hz,

I3 2H), 3.00 (t, J = 9.3 Hz, 1H), 1.45-1.91, (m, 18H). C NMR (75 MHz, C6D6):

5 153.0,137.3, 129.0, 128.6, 128.4, 93.7, 73.8, 66.3, 62.3, 51.8, 33.2, 32.8, 29.6,29.3, 25.

7, 25.5. HRMS (CI) m/z calcd for C20H31NO4: 350.2338, Found: 350. 2331.

Bezyl 5-(7-bromoheptyl)-2,2-dimethyIoxazolidine-3-carboxylate 161

To the solution of 0.38 g of triphenyl phosphine (1.44 mmol, 1.5 equiv.) in 4 mL of acetonitrile in an icebath was added dropwise a solution of 0.073 mL of bromine (1.44 mmol, 1.5 equiv.) in 1 mL of acetonitrile. After stirring for 30 min., a solution of 0.13 g of imidazole (1.92 mmol, 2.0 equiv.) and 0.32 g of 160 (0.96 mmol, 1.0 equiv.) in 2 mL of acetonitrile was added. The solution was stirred at rt overnight. After that, the solution was partitioned between saturated NaHCCh solution and ether. The organic layer was washed with saturated NaHCC>3 solution followed by brine, then dried with MgS04; filtered and concentrated. The crude product was used without furthure purification.

168 o Cbz ^^y^^^^^K^^^-^/ Br \-0 162

Benzyl 5-(l 4-bromo-7-oxotetradecyl)-2,2-dimethoxy oxazolidine-3-carboxyIate 162

In air, a vial was charged with 15 mg of PEPPSI-IPr 91 (0.02 mmol, 4 mol %) under an inert atmosphere. 86.8 mg of LiBr (1.0 mmol, 2.0 equiv.) and a stirbar were added. The vial was then sealed with a septum and purged with argon after which 1 mL of THF was added and the suspension was stirred until the solids dissolved. After this time, 0.5 mL of the organozinc reagent of 161 (prepared from zinc dust and iodine in DMI) (0.5 mmol,

1.0 M in DMI, 1.0 equiv.) and 0.13 g of 8-bromo octanoyl chloride 143 (0.52 mmol, 1.04 equiv.) were added. The septum was replaced with a Teflon®-Hned screw cap under an inert atmosphere and the reaction stirred for 24h. After this time the reaction mixture was diluted with 15 mL of ether and washed successively with 1 M NasEDTA solution

(prepared from EDTA and 3 equiv of NaOH), water and brine. After drying (anhydrous

MgS04) the solution was filtered, the solvent removed in vacuo. Purification by column chromatography (20 vol. % ether in pentane Rf= 0.3) afforded 125 mg (48%) of the desired product as a pale yellow oil. 'H NMR (300 MHz, C6D6): 5 7.22 (m, 5H), 5.20-

5.30 (m, 2H), 3.87 (br m, 1H), 3.56-3.58 (m, 1H), 3.23 (m, 1H), 3.09 (m, 2H), 2.11-2.14

13 (m, 4H), 1.41-1.89, m, 32H). C NMR (75 MHz, C6D6):

5 208.5, 152.1, 137.3, 128.6, 128.4, 127.9, 93.7, 73.8, 66.8, 50.7, 42.3, 33.8, 33.4, 33.1, 3

2.5, 29.5, 29.4, 29.2, 28.5, 27.9, 25.6, 24.0, 23.8, 23.6. HRMS (CI) m/z calcd for

C28H44BrN04: 538.2532, Found: 538.2511.

169 1,2,5,6-DiisopropyIidene-D-mannitol 167

A 100 mL round-bottom flask was charged with 20 g of D-mannitol 166 (110 mmol, 1.0 equiv.), 48 mL of anhydrous DME, 32 mL of DMP (260 mmol, 2.35 equiv.), and 0.02 g of stannous chloride. The mixture was heated to reflux and stirring until a clear solution obtained. After 30 min stirring, the solution was cooled below reflux. At that point, 0.040 mL of pyridine was added. The solution.was concentrated on a rotary evaporature by increasing the temperature to 100°C. The solid product was cooled to it and dried under vaccum overnight and used in the next step without any further purification.257

r o

O 168

2,3-O-Isopropylidine-D-glyceraIdehyde 168

A 200 mL flask was charged with 14.6 g of 167 and 70 mL of DCM. The mixture was heated until refluxing for 1 h. After that, the slurry was cooled to rt, and 1 g of celite was added while stirring.The mixture was vaccum filtered through a pad of celite and rinsed with 10 more mL of dichloromethane. A solution of 3.5 mL saturated sodium bicarbonate was added followed by 13.5 g of sodium metaperiodate portionwise. After 3 h stirring, 4 g of magnesium sulphate was added. After 30 min. stirring, the slurry was suction filtered and the filterate was purified by distillation at 75°C. Collecting the fraction at 50°C in the 170 23 l receiver, afforded 5 g (75%) of the desired product. [a] D+70-80° (c 1.0-1.5, benzene) H

NMR (300 MHz, CDC13): 5 9.70 (d, /= 1.9 Hz, 1H), 4.36 (m, 1H), 4.12 (m, 2H), 1.47 (s,

3H), 1.40 (s, 3H). 13C NMR (75 MHz, CDCI3): 5 201.3, 110.8, 79.5, 65.1, 25.8, 24,7. The

*H and 13C NMR spectra were identical to those previously described257

6 171 0

C-Phenyl-N-benzyl-nitrone 171

To a solution of 0.3 mL of benzaldehyde 169 (3 mmol, 1.0 equiv.) and 4.5 mL of methanol, was added a solution of 0.33 mL of benzylamine 170 (3 mmol, 1.0 equiv.) in

0.6 mL of methanol dropwise. The mixture was stirred at rt overnight. At that point 0.12 g of sodium borohydride (3 mmol, 1.0 equiv.) was added dropwise and stirred for 1 more h.

The solvent was evaporated and 1 M hydrochloric acid was added very slowly to the solution very slowly and extracted by ether (3x5 mL). The aqueous layer was basified with ammonia and extracted with ether. The combined organic layers were dried over sodium sulphate and concentrated. The residue was dissolved in 5 mL of methanol, 1.22 mL of H202, 30% (12 mmol, 4 equiv.) and 0.05 g of Na2W04 (0.15 mmol, 5 mol%). The mixture was stirred at rt for lh and 10 mL of water was added. The solution was extracted with dichloromethane (4x5 mL) and dried over sodium hydroxide. The crystals were recrystallized in diisopropyl ether and 0.63 g (65%) of the pure product obtained. !H

13 NMR (300 MHz, CDC13): 8 8.12 (m, 2H), 7.35 (m, 2H), 7.30 (m, 7H), 4.95 (s, 2H). C

NMR (75 MHz, CDC13): 5 134.62, 133.71, 130.88, 130.84, 130.01, 129.62, 129.37,

171 129.01, 128.86, 71.67. The 'H and 13C NMR spectra were identical to those previously

991 described.

,X>H .HCI N H 172 N-Benzylhydroxylamine 172

To a solution of 0.18 g of nitrone 171 (0.85 mmol, 1.0 equiv.) in 10 mL of ether, was added a solution of 0.06 g of hydroxylaminehydrochloride (0.85 mmol, 1.0 equiv.) in 2 mL of methanol. After 4 h stirring, the solvent was evaporated and the desired product solidified after addition of ether. 0.13g (97%) of the product was filtered and dried under vaccum. The product was used for the next step without further purification.

N-Benzyl-2,3-0-isopropyIidene-D-glyceraIdehyde nitrone (BIGN) 163

To the solution of 2.10 g of D-glyceraldehyde 168 (16.2 mmol, 1.0 equiv.) in 150 mL of dichloromethane was added 2.53 g of anhydrous sodium sulphate (17.8 mmol, 1.1 equiv.), 2.84 g of N-benzylhydroxyl amine 172 (17.8 mmol, 1.1 equiv.) and 2.48 mL of triethyl amine (17.8 mmol, 1.1 equiv.). After stirring for 3 h at rt, it was filtered through celite and concentrated. Purification by flash chromatoghraphy (ethyl acetate Rf= 0.5)

23 afforded 3.8 g (100%) of the desired product as a white crystals. [a] D+96.8° (c 0.05,

CHC13) 'H NMR (300 MHz, CDCI3): 8 7.37 (m, 5H), 6.78 (d, J= 4.6 Hz, 1H), 5.08 (

172 ddd, J= 7.1, 5.9, 4.6 Hz, 1H), 4.80 (br s, 2H) 4.35 (dd, 1H, J= 7.1, 8.7 Hz), 3.82 (dd, J =

13 8.7, 5.9 Hz, 1H), 1.37 (s, 3H), 1.34 (s, 3H)., C NMR (75 MHz, CDC13): 8 139.1, 132.1,

129.4, 129.2, 129.1, 109.8, 72.0, 67.0, 67.8, 26.2, 24.9. The 'H and I3C NMR spectra were identical to those previously described.223

Bru .OH K1N

164 °-f

(2S, 3R)-N-Benzyl-3-(hydroxyamino)-l,2-0-isopropylidene-l,2 butanediol 164

To a solution of 0.23 g of nitrone, 163 (1.0 mmol, 1.0 equiv.) in 20 mL of diethyl ether was added 0.22 g of zinc bromide (1.0 mmol, 1.0 equiv.) and stirred at rt for 15 min. The mixture was cooled to -60°C and 1.0 mL of methylmagnesium bromide (3 mmol, 3M in ether, 3.0 equiv.) was added dropwise. The reaction was stirred for 6 h at -60°C. After this time, the reaction mixture was warmed up to rt and diluted with 15 mL of ether and washed successively with 1 M Na3EDTA solution (prepared from EDTA and 3 equiv of

NaOH), water and brine. After drying with anhydrous MgSC>4, the solution was filtered, the solvent removed in vacuo. Purification by column chromatography (20 vol. % ethylacetate in hexane Rf = 0.3) afforded 150 mg (60%) of the desired product as a

23 ! colorless oil. [a] D -19.8° (c 1.0, CHC13). H NMR (300 MHz, CDC13): 6 7.28-7.40 ( m,

5H),6.40 (br s, 1H), 4.23 (m, 1H), 3.92 ( d, 1H, J= 13.2 Hz) 3.88 ( dd, 1H, J= 8.8, 5.8

Hz), 3.80 ( d, 1H, J= 13.2 Hz), 3.72 (dd, J= 8.8, 5.8 Hz, 1H), 2.91 (quin, J= 6.6 Hz,

1H),1.34 (s, 3H), 1.33 (s, 3H), 1.02 (d, J = 6.6 Hz, 3H) 13C NMR (75 MHz, CDCI3):

173 5 137.7, 129.2, 128.3, 127.3, 108.8, 76.7, 66.7, 63.7, 60.9, 26.5, 25.6, 9.1. Spectral data were in agreement with the literature.218

H. ,Boc klN

173

(2S, 3R)-3-(tert-butoxycarbonylamino)l,2-0-isopropylidene-l,2 butanediol 173

A solution of 0.24 g of 164 (1 mmol, 1.0 equiv.) in 15 mL of methanol was treated with

Pd (OH) 2-C (13 mg, 10 mol%) and the resulting suspension was stirred under hydrogen at 40 psi for 2 days. The mixture was filtered through celite and concentrated. The residue was dissolved in 10 mL of dioxane and 0.28 g of ditert-butyl dicarbonate (1.3 mmol, 1.3 equiv.) was added to the mixture and stirred at rt for 20 h. At that point, the solution was partitioned between saturated NaHC03 solution (15 mL) and dichloromethane (15 mL).

The organic layer was washed with saturated NaHCC>3 solution followed by brine, then dried with MgS04, filtered and concentrated to the crude product. Purification by column chromatography (10 vol. % ethylacetate in hexane Rf= 0.1) afforded 155 mg (65%) of

23 the desired product as a white solid. [a] D -28.7° (c 0.25, CHC13). *H NMR (300 MHz,

CDCI3): 4.47 (br s, 1H), 3.96-4.04 (m, 2H), 3.71-3.77 (m, 2H), 1.42 (s, 9H), 1.40 (s, 3H),

1.32 (s, 3H), 1.11 (d, J= 7.0 Hz, 3H) 13C NMR (75 MHz, CDCI3): 8 155.2, 109.4, 79.3,

78.8, 66.6, 48.5, 28.3, 26.2, 20.0, 16.1. Spectral data were in agreement with the literature.218

174 HU^Boc N

174 OH

(2S, 3R)-3-(tert-butoxycarbonylamino) 1, 2-butanediol 174

A solution of 100 mg of 173 (0.4 mmol, 1.0 equiv.) in 10 mL of methanol was treated with 15 mg of p-toluensulfonic acid (0.08 mmol, 0.2 equiv.). The resulting mixture was refluxed for 4h. At that point 10 mL of saturated aqueous sodium bicarbonate was added.

The mixture was extracted with ethyl acetate (3x5 mL). The combined organic layers were dried over magnesium sulphate and concentrated. Purification by column chromatography (10 vol. % ethylacetate in hexane Rf= 0.1) afforded 45 mg (55%) of the

! desired product as a white solid. H NMR (300 MHz, CDC13): 4.58 (br s, 1H), 3.57-3.70

(m, 3H), 3.32-3.38 (m, 1H), 2.80 (br s, 2H), 1.45 (s, 9H), 1.23 (d, J = 6.7 Hz, 3H) 13C

NMR (75 MHz, CDC13): 5 156.5, 80.2, 75.5, 63.0, 47.8, 28.2, 17.01. Spectral data were in agreement with the literature.218

Cbzs NH O 1

OTBS 178

(2S, 3R)-tert-butyl-2-(tert-butyldimethylsilanyloxy)-3-(N-benzyloxycarbonyl)-

aminobutanoate 178

To a stirred solution of 0.48 g of alcohol 140 (1.55 mmol, 1.0 equiv.) in 7 mL of dry dichloromethane, 0.21 g of imidazole (3.1 mmol, 2.0 equiv.), 0.35 g of TBSC1 (2.32 mmol, 1.3 equiv.), and 0.019 g DMAP (0.15 mmol, 10 mol %) were added sequentially.

175 The reaction mixture was stirred at rt for 24 h. At that point, water was added to the reaction mixture and the reaction mixture was extracted with dichloromethane (3x10 mL). The combined organic layer was washed with brine and dried over sodium sulphate.

Purification by column chromatography (10 vol. % ether in pentane Rf= 0.2) afforded

25 613 mg (90%) of the desired product 178 as a colorless liquid. [a] D -14.6° (c 0.56,

CHC13). 'H NMR (300 MHz, CDCI3): 5 7.33-7.38 (m, 5H), 5.17 (s, 1H), 4.83-4.89 (m,

1H), 4.76 (s, 2H), 4.13 (t, J= 6.6 Hz, 1H), 1.46 (s, 9H), 0.96 (s, 9H) 0.89 (d, J= 5.4 Hz,

13 3H), 0.13 (s, 3H ), 0.12 (s, 3H) C NMR (75 MHz, CDC13): 5 170.2, 158.0, 128.5, 128.3,

128.2, 128.1, 127.5, 126.8, 125.9, 69.6, 69.3, 64.9, 25.9, 25,7, 25.5, 25.3, 10.1, -5.3, -5.4.

Spectral data were in agreement with the literature.226

Cbzv NH O

OTBS 176

Benzyl (2R, 3S)-3-(tert-butyldimethylsilyIoxy)-4-oxobutan-2-yIcarbamate 176

To the stirred solution of 0.5 g of 178 (1.2 mmol, 1.0 equiv.) in 5 mL of dry DCM was added 2.2 mL of DIBAL-H (2.2 mmol, 1 M solution in toluene, 1 equiv.) at -78°C. The reaction was stirred for 6 h, and then quenched with 5 mL of saturated sodium potassium tartrate and filtered through a celite pad, dried over sodium sulphate, and concentrated to near dryness. The crude product was used as such for the next reaction. e Ph Br

Ph 180

176 6-HydroxyhexyltriphenyIphosphonium bromide 180

A solution of 35g of 6-Bromo-l-hexanol 179 (7.5 mmol, 1.0 equiv.) in 18 mL of absolute ethanol was added to 1.96 g of triphenyl phosphine (7.5 mmol, 1.0 equiv.) and heated under reflux overnight. The solvent was removed and the crude was stirred at 100°C in 5 mL of toluene for 30 min. The phosphonium salt was solidified, while the solution was cooling to rt. The toluene was decanted and 3.3 g (100%) of the product was obtained as a white solid. Mp = 148-149°C 'H NMR (300 MHz, CDC13): 6 7.90-7.69 (m, 15H), 3.59-

3.43 (m, 4H), 2.58 (s, 1H), 1.86-1.23 (m, 8H) 13C NMR (75 MHz, CDC13): 8 135.35,

134.17, 134.04, 130.96, 130.80, 119.42, 61.94, 32.31, 30.65, 29.92, 25.16, 23.74. Spectral data were in agreement with the literature 227

Benzyl (2R, 3R, E)-3-(tert-butyl dimethylsilyloxy)-10-hydroxydec-4-en-2-yl carbamate 177

To the solution of 1.98 g of 179 (4.5 mmol, 1.0 equiv.) in 25 mL of dry benzene was added 0.53 g of potassium tert-butoxide (4.5 mmol, 1.0 equiv.) at rt. The mixture was stirred at 80°C for 1 h and then cooled to 40°C. At that point, 1.05 g of compound 176 (3 mmol, 0.6 equiv.) in 10 mL of benzene was added to the reaction mixture and stirred for 2 more h at rt. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was washed with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine and dried over sodium sulphate. Purification by column

177 chromatography (20 vol. % ethylacetate in hexane Rf= 0.2) afforded 605 mg (55%) of

23 ] the desired product as a colorless liquid. [

400 MHz): 8 7.33-7.38 (m, 5H), 5.38-5.45 (m, J= 8.2 Hz, 2H), 5.11 (d, J= 10.6 Hz, 2H),

4.89 (m, 1H), 4.40-4.42 (m, 2H), 3.65 (t, J= 6.12 Hz, 2H), 2.04-2.06 (m, 2H), 1.78 (br s,

1H), 1.54-1.57 (m, 2H), 1.39 (br m, 4H), 1.16 (d, J= 6.5 Hz, 3H), 0.89 (s, 9H), 0.09 (s,

3H ), 0.07 (s, 3H). 13C NMR (CDC13, 100 MHz): 5 155.9, 136.5, 131.5, 130.4, 128.5,

128.15, 128.1, 70.4, 66.6, 62.9, 52.2, 32.6, 29.2, 27.5, 25.5, 25.8, 17.4, 14.2, -4.3, -4.9.

Anal. Calcd. For C24H4iON04Si: C, 66.16; H, 9.49, N, 3.21. Found C, 66.09; H, 9.82, N,

3.36.

Benzyl (2R, 3R, E)-10-bromo-3-(tert-butyldimethylsilyloxy) dec-4-en-2-ylcarbamate 181

To the solution of 1.0 g of 177 (2.5 mmol, 1.0 equiv.) in 30 mL of dichloromethane was added 0.58 mL of lutidine (5.0 mmol, 2.0 equiv.), 1.24 g of carbon tetrabromide (3.75 mmol, 1.5 equiv.) and 1.11 g of triphenyl phosphine (4.25 mmol, 1.7 equiv.).The reaction mixture was stirred for lh. Purification by column chromatography (5 vol. % ethylacetate in hexane Rf= 0.4) afforded 1.1 g (85%) of the desired product as a colorless liquid.

23 [a] D -6.1 (c 0.36, CHCI3). 'H NMR (300 MHz, CDCI3): 5 7.33-7.38 (m, 5H), 5.39-5.45

(m, 2H), 5.12 (d, J= 3.3 Hz, 2H), 4.87-4.89 (m, 1H), 4.40-4.42 (m, 1H), 3.74 (m, 1H),

3.40 (t, J = 6.0 H, 2H), 2.02-2.06 (m, 2H), 1.85 (quin, J = 7.2 Hz, 2H), 1.41 (br m, 4H),

178 1.16 (d, /= 6.9 Hz, 3H),.0.96 (s, 9H), 0.09 (s, 3H ), 0.07 (s, 3H) 13C NMR (75 MHz,

CDC13): 5 156.0, 136.5, 131.2, 130.4, 128.4, 128.0, 128.1, 70.3, 66.5, 52.0, 33.7, 32.6,

28.6, 27.9, 27.7, 25.7, 18.0, 17.2, -4.3, -4.9. Anal. Calcd. For C24H4oBrN03Si: C, 57.82;

H, 8.09, N, 2.81. Found C, 57.84; H, 8.28, N, 3.04.

NHBoc

189

(R)-2-[(tert-ButoxycarbonyI) amino]-l-propanol 189

4.45g of D-alanine 183 (50 mmol, 1.0 equiv.) was added in small portions to a suspension of 3.8g of lithium aluminum hydride (100 mmol, 2.0 equiv.) in 130 mL of refluxing THF and refluxing continued for another 7h. The reaction mixture was then cooled to 0°C in an ice-bath and excess reagent quenched by careful addition of 4 mL of an aqueous 15%

NaOH solution and 12 mL of water. After stirring at rt for 10 min, a solution of 1 lg of di- tert-butyl dicarbonate (48.4 mmol, 0.96 equiv.) in 50 mL of dichloromethane was added to the mixture and stirred at 60°C overnight. The reaction mixture cooled to rt, filtered throuth a pad of anhydrous Na2SC>4 and the filterate concentrated under vaccum.

Purification by column chromatography (30 vol. % ethylacetate in hexane Rf = 0.2)

26 afforded 6.5 g (82%) of the pure N-BOC amino alcohol as a white solid. [a] D= +10.0 (c

1.0, MeOH) 'H NMR (300 MHz, CDC13): 5 4.71 (br s, 1H), 3.75 (br m, 1H), 3.63 (m,

1H), 3.51 (m, 1H), 2.63 (br s, 1H), 1.47 (s, 9H), 1.15 (d, J= 6.0 Hz, 3H). Spectral data were in agreement with the literature.258

179 NHBoc

OH 190

(9R, 10R)-10-[(ter/-butoxycarbonyI) amino]-9-hydroxy-l-undecane 190

To a stirred solution of 3.2 mL of oxalyl chloride (36.86 mmol, 1.5 equiv.) in 50 mL of

CH2C12 at -78°C under argon 3.5 mL of DMSO (49.14 mmol, 2.0 equiv.) was added dropwise. After stirring for 30 min, a solution of 4.3 g of amino alcohol 189 (24.57 mmol,

1.0 equiv.) in 100 mL of CH2CI2 was added to the reaction mixture over 30 min. The mixture was warmed to -35°C and stirred for 30 min at this temperature, followed by dropwise addition of 24.3 mL of diisopropylethyl amine (142.52 mmol, 5.8 equiv.) over 5 min. The reaction mixture was warmed to 0°C. Then 100 mL of saturated NH4CI and 100 mL of H2O was added to the reaction flask. The organic layer was washed with 100 mL of

5% citric acid, water and brine, and dried over Na2SC>4. The resulted yellow solid was applied directly to the next step. To a solution of the aldehyde in 33 mL of THF, 26.9 mL of 7-octenyl magnesium bromide ((prepared from Mg, 2.34g, 97.8 mmol, 2.0 equiv, and

8-bromooctene ,8.15 mL, 48.9 mmol, 1.0 equiv. in THF) was added dropwise. After stirring for 2 h at rt the reaction mixture was poured into aqeous saturated NH4CI solution and acidified to pH 4 by adding 10% aqueous HC1 solution. The organic layer was separated, aqeous layer extracted with ether and the combined organic layers were washed with water and brine. After drying over Na2SC>4, solvent was removed and the residue was column chromatographed (20 vol. % ether in pentane Rf= 0.1) to yield 6.3g

(90%) of the desired amino alcohol 190 as a colorless oil. 'H NMR (300 MHz, CDC13):

8 5.75-5.84 (m, 1H), 4.90-5.01 (m, 2H), 5.12 (s, 1H), 4.77 (d, J = 8.6 Hz, 1H), 3.63 (br m,

180 lH),3.47(brm, 1H), 2.35 (br s, 1H), 2.02 (m, 2H), 1.44 (s,9H), 1.32-1.40 (m, 19H),.1.16

13 (d, J= 6.8 Hz, 3H), 1.06 (d, J= 6.8 Hz, 3H), C NMR (75 MHz, CDC13): 5 156.1, 139.0,

114.1, 77.4, 74.8, 50.2, 34.1, 33.6, 29.4, 28.9, 28.8, 28.3, 25.5, 18.3. Anal. Calcd. For

Ci6H3iN03:C, 67.33; H, 10.95, N, 4.91. Found C, 67.61; H, 11.22, N, 4.96.

Boclsfl ^^^ ^.^ /

184

(4R, 5R)-ferf-butyl 2,2,4-trimethyl-5-(oct-7-enyl)oxazolidine-carboxylate 184

A solution of 5.0 g of 189 (17.6 mmol, 1.0 equiv.), 26 mL of 2, 2-dimethoxypropane

(211.6 mmol, 12.0 equiv.) and 88 mg of pyridinium p-toluenesulfonate (0.35 mmol, 2 mol%) in 110 mL of toluene was stirred at 80°C for 4 h. Removal of solvent under vaccum and purification of the residue by column chromatography (10 vol. % ethylacetate in hexane Rf= 0.1) afforded 4.7 g (83%) of the pure oxazolidine 184 as a colorless oil. 'H NMR (300 MHz, CDC13): 5 5.78-5.88 (m, 1H), 4.94-5.03 (m, 2H), 3.65-

3.69 (q , J= 4.5 Hz, 1H), 3.51 (m, 1H), 2.04-2.09 (q , J = 4.5 Hz, 2H), 1.21-1.59 (m,

13 28H), C NMR (75 MHz, CDC13): 5 156.0, 139.0, 115.1, 94.4, 81.4, 79.8, 57.9, 33.7,

33.4, 29.4, 28.9, 28.7, 28.4, 26.8, 25.8. Anal. Calcd. For C19H35NO3: C, 70.11; H, 10.84,

N, 4.30. Found C, 70.15; H, 10.97, N, 4.18.

181 4-, BocN 1^ ' 185

(4R, 5R)-tert-butyl 5-(7-hydroxyheptyl)-2,2,4-trimethyloxazolidine-3-carboxylate 185

A solution of 1.5g of 183 (4.8 mmol, 1.0 equiv.) and 0.64g of 9-BBN (2.64 mmol, 0.5 equiv.) was refluxed in 45 mL of THF for 4h. While the flask was in the ice bath, a solution of 4.2 mL of 2M NaOH and 3.6 mL of 35% H202 was added dropwise. After 1 h, the organic layer was separated and the aqueous layer extracted with ethyl acetate.

Combined extracts were washed with brine, dried over Na2S04, and concentrated.

Purification of the residue by column chromatography (30 vol. % ethylacetate in hexane

Rf= 0.1) afforded 1.4 g (83%) of 185 as a colorless oil. ]H NMR (300 MHz, CDC13):

5 3.64 (t, J= 6.6 Hz, 2H), 3.42-3.71 (m, 2H), 1.33-1.57 (m, 32H) 13C NMR (75 MHz,

CDC13): 5 152.1, 92.4, 81.4, 79.8, 62.7, 57.8, 33.6, 32.7, 29.5, 29.4, 29.2, 28.4, 26.0, 25.8,

25.7, 25.6. Anal. Calcd. For C19H37NO4: C, 66.43; H, 10.86, N, 4.08. Found C, 66.22; H,

11.06, N, 4.10.

' 192

(4R, 5R)-fert-butyl 2,2,4-trimethyl-5-(7-oxoheptyl)oxazoIidine-3-carboxylate 192

To a rt solution of 1.47g of 185 (4.3 mmol, 1.0 equiv.) in 60 mL of DMSO was added 4.8 g of IBX (17.2 mmol, 4 equiv.). The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water and the solid precipitate was filtered. The

182 filtrate was extracted with ether and dried over Na2SC>4. Evaporation of solvent and purification of the crude product by column chromatography (2 vol. % ether in pentane Rf

= 0.3) afforded the pure aldehyde 1.35 g (92%) of 192 as a colorless oil. *H NMR (300

MHz, CDC13): 5 9.81 (s, 1H), 3.65 (q, J= 6.2 Hz, 1H), 3.50 (br m, 1H), 2.42 (td, J= 1.8

Hz, 2H), 1.53-1.66 (m, 10 H), 1.48 (s, 9H), 1.08-1.33 (m, 11H).13C NMR (75 MHz,

CDC13): 5 202.7, 154.0, 93.0, 81.3, 80.3, ,57.8, 43.8, 33.6, 29.3, 29.1, 29.0, 28.4, 25.6,

21.9. Anal. Calcd. For Q9H35NO4: C, 66.83; H, 10.33, N, 4.10. Found C, 66.57; H, 10.57,

N,4.18.

186

(4R, 5R)-tert-butyl 5-(8-hydroxypentadec-14-enyl)-2,2,4-trimethyloxazolidine-3- carboxylate 186

Heptenylmagnesium bromide 193 [prepared from Mg (0.86g, 36 mmol, 2.4 equiv.) and 7- bromoheptene (2.8 mL, 18 mmol, 1.2 equiv.) in THF (15 mL)] was added dropwise to the solution of 5.0 g of 192 (14.8 mmol. 1.0 equiv.) in 13 mL of THF. The reaction was quenched with 80 mL of ammonium chloride, extracted in ether and dried over Na2SC>4.

Column chromatography of the crude product (5 vol. % ether in pentane Rf = 0.1) afforded 4.42 g (68%) of 186 as a colorless oil. *H NMR (300 MHz, CDC13): 5.82 (m,

1H), 4.94-5.04 (m, 2H), 3.67 (m, 3H), 2.07 (m, 2H), 1.30-1.58 (m, 40H). 13C NMR (75

MHz, CDC13): 5 152.1, 139.0, 114.2, 94.1, 81.4, 79.2, 71.9, 57.8, 37.5, 37.4, 33.7, 29.6,

183 29.6, 29.5, 29.1, 28.3, 28.4, 28.8, 28.7, 25.9, 25.7, 25.6, 25.5. Anal. Calcd. For

C26H49NO4: C, 71.03; H, 11.23.N, 3.19. Found C, 71.30; H, 11.18,N, 3.25.

BocN

194

(4R, 5R)-fer/-butyl-2,2,4-trimethyl-5-(8-oxopentadec-14-enyl)oxazolidine-3- carboxylate 194

To a rt solution of 4.0 g of 186 (9 mmol, 1.0 equiv.) in 60 mL of DMSO was added 9.0 g of IBX (32 mmol, 3.5 equiv.). The reaction mixture was stirred at rt for 2 h. Then it was quenched with water and the solid precipitate was filtered. The filtrate was extracted with ether and dried over Na2SC>4. Evaporation of solvent and purification of the crude product by column chromatography (10 vol. % ether in pentane Rf= 0.2) afforded 1.35 g (90%) of 194 as a colorless oil. *H NMR (300 MHz, CDC13): 5 5.74-5.83 (m, 1H), 4.91-5.02 (m,

2H), 3.61-3.65 (m, 2H), 2.35-2.41 (m, 4H), 2.03 (m, 2H), 1.26-1.59 (m, 36H). 13C NMR

(75MHz,CDCl3):5 211.4, 152.1, 138.8, 114.3, 94.2, 81.3, 79.7, 57.8, 42.8, 42.7, 33.5, 29.

4, 29.3, 29.2, 28.7, 28.6, 28.5, 25.7, 23.8, 23.6 Anal. Calcd. For C26H49NO4: C, 71.35; H,

10.82, N, 3.20. Found C, 71.36; H, 10.60, N, 3.20.

195

184 (4R, 5R)-tert-butyl 5-(15-hydroxy-8-oxopentadecyl) 2,2,4-trimethyl-oxazolidine-3- carboxylate 195

A solution 2.45 g of 194 (5.6 mmol, 1.0 equiv.) and 0.75g of 9-BBN (3.08mmol, 0.5 equiv.) was refluxed in 35 mL of THF for 4h. While the flask was in the ice bath, a solution of 5.4 mL of 2M NaOH and 4.5 mL of 35% H2O2 was added dropwise. After 1 h, the organic layer was separated and the aqueous layer extracted with ethylacetate. The combined extracts were washed with brine, dried over Na2SC>4, and concentrated. The residue was column chromatographed (50 vol. % ether in pentane Rf= 0.2) and afforded

2.05 g (82%) of 195 as a colorless oil. 'H NMR (300 MHz, CDC13): 8 3.47-3.61 (m, 4H),

2.40 (t, J = 7.2 Hz, 4H), 1.30-1.69 (m, 40H). 13C NMR (75 MHz, CDC13):

8 211.6, 152.1, 93.9, 81.4, 77.4, 62.9, 57.8, 42.7, 42.6, 33.7, 33.6, 32.6, 29.4, 29.3, 29.2, 2

9.1, 28.4, 28.3, 25.7, 25.5, 23.8, 23.7. Anal. Calcd. For C26H49NO5: C, 68.53; H, 10.84, N,

3.07. Found C, 68.67; H, 10.94, N, 3.14.

(4R, 5R)-tert-butyl 5-(15-bromo-8-oxopentadecyl) 2,2,4-trimethyl-oxazolidine-3-

Carboxylate 196

To a solution of 1.81 g of 195 (4.0 mmol, 1.0 equiv.) in 50 mL of dichloromethane was added 0.92 mL of lutidine (8.0 mmol, 2.0 equiv.), 1.97 g of carbon tetrabromide (6.0 mmol, 1.5 equiv.), and 1.78 g of triphenylphosphine (6.8 mmol, 1.7 equiv.). After lh, 185 TLC analysis confirmed the consumption of the starting material. At this time, evaporation of the solvent and purification by column chromatography (4 vol. % ether in pentane Rf= 0.2) yielded 1.9g (92%) of the desired product as a colorless oil. *H NMR

(300 MHz, CDC13): 5 3.63-3.94 (m, 2H), 3.42 (t, J= 6.9 Hz, 2H), 2.04 (t, J= 7.2 Hz, 4H),

13 1.87 (m, 2H), 1.28-1.58 (m, 38H). C NMR.(75 MHz, CDC13): 5 211.2, 152.1, 94.0,

81.3, 79.7, 57.8, 42.8, 42.6, 33.8, 32.6, 29.5, 29.4, 29.2, 29.1, 29.0, 28.9, 28.5, 28.2, 27.9,

26.8, 25.9, 23.8, 23.6 . Anal. Calcd. For Cie^BrNC^: C, 60.22; H, 9.33, N, 2.70. Found

C, 60.44; H, 9.60, N, 2.82.

(4R, 5R)-tert-butyl 5-(15-bromo-8-methylenepentadecyl) 2,2,4-trimethyloxazolidine-

3-carboxyIate 197

To the solution of 3.57g of methyltriphenylphosphine (3 mmol, 1.5 equiv.) in 10 mL of toluene at -78°C, was added 10 mL of NaHMDS (10 mmol, 1M solution in THF, 5.0 equiv.) dropwise. The reaction mixture was warmed to 0°C and stirred for 30 min at this temperature. The temperature was returned to -78°C and a solution of l.Og of 196 (2 mmol, 1.0 equiv.) in 10 mL toluene was added dropwise. The temperature was increased slowly to rt. The reaction mixture was quenched with water. The organic layer was extracted by ethylacetate and dried over Na2SC>4. Purification by column chromatography

(2 vol. % ethylacetate in hexane Rf= 0.2) afforded 0.6 g (60%) of the desired product as a

186 colorless oil. lU NMR (300 MHz, CDC13): 5 4.70 (s, 2H), 3.65-3.67 (m, 2H), 3.42 (t, J =

6.8 Hz, 2H), 2.00 (m, 4H), 1.87 (m, 2H), 1.29-1.58 (m, 38H). I3C NMR (75 MHz,

CDC13):8 152.1, 150.0,108.4, 92.4, 81.4, 79.7, 57.8, 36.0, 35.9, 34.00, 32.7, 29.6, 29.4, 2

9.3, 29.1,28.6, 28.4, 28.1, 27.7, 27.6,25.7. Anal. Calcd. For C27H5oBrN03: C, 62.77; H,

9.76, N, 2.71. Found C, 62.92; H, 10.06, N, 2.86.

NHBoc

OH 198

(8R, 9R)-9-[(ferf-butoxycarbonyl) amino]-10-hydroxy-l-decane 198

To a stirred solution of 3.2 mL of oxalyl chloride (36.86 mmol, 1.5 equiv.) in 50 mL of dichloromethane at -78°C under argon was added 3.5 mL of anhydrous DMSO (49.14 mmol, 2.0 equiv.) dropwise. After stirring for 30 min, a solution of 4.3 g of amino alcohol

189 (24.57 mmol, 1.0 equiv.) in 100 mL of CH2CI2 was added to the reaction mixture over 30 min. The mixture was warmed to -35°C and stirred for 30 min at this temperature, followed by dropwise addition of diisopropylethyl amine (24.3 mL, 142.52 mmol) over 5 min. The reaction mixture was warmed to 0°C. Then 100 mL of saturated NH4C1 and 100 mL of H20 was added to the reaction flask. The organic layer was washed with 100 mL of 5% citric acid, water and brine, dried over Na2S04. The yellow solid was applied directly to the next step. To the solution of aldehyde in 33 mL of THF was added, 7- heptenylmagnesium bromide [prepared from 2.34g of Mg (97.8 mmol, 4.0 equiv.) and

7.45 mL of 7-bromoheptene (48.9 mmol, 2.0 equiv.) in 27.6 mL of THF] dropwise. After stirring at rt for 2 h, the reaction mixture was poured into aqeous saturated NH4CI solution and acidified to pH 4 by adding 10% aqueous HC1 solution. The organic layer

187 was separated, the aqueous layer extracted with ether and combined organic layers were washed with water and brine. After drying over Na2SC>4, solvent was removed and the residue was column chromatographed (30 vol. % ether in pentane Rf= 0.1) to yield 5.0 g

(75%) of the amino alcohol 198 as a colorless oil. *H NMR (300 MHz, CDC13): 8 5.76-

5.85 (m, 1H), 4.91-5.03 (m, 2H), 4.85 (br s, 1H), 3.65 (br m, 1H), 3.48 (m, 1H), 2.12 (br s, 1H), 2.02-2.08 (m, 2H), 1.45 (s, 9H), 1.35-1.43 (m, 8H), 1.17 (d, J = 6.8 Hz, 3H). 13C

NMR (75 MHz, CDC13): 5 156.1, 139.0, 114.2, 79.3, 74.9, 53.3, 34.1, 33.6, 29.0, 28.7,

28.3, 25.3, 18.3. Anal. Calcd. For Ci6H3iN03: C, 67.33; H, 10.95, N, 4.91. Found C,

67.61; H, 11.22, N, 4.96.

NHBoc

OTBS 199

Tert-butyl (2R, 3R)-3-(fe/*f-butyldimethylsilyIoxy) dec-9-en-2-ykarbamate 199

To the solution 3.2 g of 198 (11.5 mmol, 1.0 equiv.) in 60 mL of dichloromethane was added 2.3 g of imidazole (34.5 mmol, 3.0 equiv.), 3.5 g of TBSC1 (23 mmol, 2.0 equiv.) and 0.15 g of DMAP (1.15 mmol, 10 mol%). The reaction mixture stirred at room temperature overnight. When the reaction was juged complete by TLC analysis, water was added. The aqueous layer was extracted with dichloromethane, washed with brine and dried over Na2S04. Column chromatography of the crude (2 vol. % ether in pentane

Rf= 0.4) afforded 3.5 g (77%) of the desired product as a colorless oil. NMR (300 MHz,

CDCI3): 5 5.77-5.86 (m, 2H), 5.77-5.86 (m, 1H), 4.65 (br m, 1H), 3.73 (br m, 1H), 3.54

(br m, 1H), 2.02-2.08 (m, 2H), 1.46 (s, 9H), 1.30-1.39 (m, 8H), 1.11 (d, J = 6.7 Hz, 3H),

13 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). C NMR (75 MHz, CDC13): 8 155.5, 139.0, 188 114.2, 78.8, 75.0, 48.8, 33.6, 29.2, 28.7, 28.4, 25.9, 25.2, 18.7, 18.0, -4.2, -4.6. Anal.

Calcd. For C2iH43N03Si: C, 65.40; H, 11.24, N, 3.36. Found C, 65.73; H, 11.50, N, 3.63.

NHBoc

OTBS 200

Tert-butyl (2R, 3R)-3-(fe/"f-butyldimethylsilyloxy) -10-hydroxydecan-2-ylcarbamate

200

A solution of 2.0 g of 199 (5 mmol, 1.0 equiv.) and 0.67 g of 9-BBN (2.75mmol, 0.5 equiv.) was refluxed in 30 mL of THF for 4h. While the flask was in the ice bath, a solution of 4.8 mL of 2M NaOH and 3.0 mL of 35% H2O2 was added dropwise. After 1 h, the organic layer was separated and the aqueous layer extracted with ethyl acetate. The combined extracts were washed with brine and dried (Na2SC>4), and concentrated. The residue from the column chromatography (10 vol. % ethylacetate in hexane Rf= 0.4) afforded 1.7 g (85%) of 200 as a colorless oil. NMR (300 MHz, CDC13): 5 4.65 (br m,

1H), 3.73 (br m, 1H), 3.64 (t,J= 6.5 Hz, 2H), 3.53 (m, 1H), 1.24-1.66 (m, 21H), 1.11 (d,

13 J= 6.7 Hz, 3H), 0.91 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H). C NMR (75 MHz, CDC13): 8

155.6, 79.0, 75.0, 62.9, 48.3, 34.2, 32.6, 29.0, 28.4, 25.8, 25.4, 25.2, 18.8, 18.0, -4.2, -4.6.

Anal. Calcd. For C21H45NO4S1: C, 63.57; H, 10.91, N, 3.37. Found C, 63.81; H, 11.20, N,

3.52.

189 NHBoc

OTBS 188

Tert-butyl (2R, 3R)-10-bromo-3-(tert-butyldimethylsilyloxy)decan-2-yl carbamate

188

To the solution of 1.81 g of 200 (5.5 mmol, 1.0 equiv.) in 60 mL of dichloromethane was added 1.28 mL of lutidine (11 mmol, 2.0 equiv.), 2.73 g of carbon tetrabromide (8.25 mmol, 1.5 equiv.), and 2.44g of triphenylphosphine (9.35 mmol, 1.7 equiv.). After lh,

TLC analysis confirmed the consumption of the starting material. At this time, evaporation of the solvent and purification by column chromatography (5 vol. % ether in pentane Rf= 0.4) yielded 1.67 g (78%) of the desired product as a colorless oil. NMR

(300 MHz, CDC13): 5 4.67 (d, J= 4.3 Hz, 1H), 3.73 (br m, 1H), 3.54 (m, 1H), 3.42 (t, J =

6.8 Hz, 2H), 1.86 (quin, J= 7.0 Hz, 2H), 1.46 (s, 9H), 1.41-1.30 (m, 10 H), 1.12 (d, J =

6.7 Hz, 3H), 0.91 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). 13C NMR (75 MHz, CDCI3): 5 155.6,

78.8, 75.6, 48.3, 34.2, 33.9, 32.7, 29.5, 28.6, 28.5, 28.4, 28.0, 25.9, 18.8, 18.0, -4.2, -4.6.

Anal. Calcd. For C2iH44BrN03Si: C, 52.21; H, 9.27, N, 2.93. Found C, 52.47; H, 9.41, N,

3.11.

190 (4R, 5R)-tert-butyl 5-((23R, 24R)-24-(fert-butoxycarbonyl)-23(te/tf- butyldimethyIsilyoxy)-8-methylenepentacosyl)-2,2,4-trimethyloxazolidine-3- carboxylate 201

A vial was charged with 10 mg of PEPPSI-IPr 91 (0.015 mmol, 4 mol %) and under an inert atmosphere 104 mg of LiBr (3.2 mmol, 3.2 equiv.) and a stirbar were added. The vial was then sealed with a septum and purged with argon after which 1.2 mL of dry THF was added and the suspension was stirred until the solids dissolved. At this time, 0.6 mL of the organozinc reagent 188 (0.6 mmol, 1M in DMI, 1.6 equiv.) [prepared from zinc dust and iodine in DMI] and 0.18 g of compound 197 (0.37 mmol, 1.0 equiv.) were added. The septum was replaced with a Teflon®-lined screw cap under an inert atmosphere and the reaction stirred for 1.5 h. At this time the reaction mixture was diluted with 15 mL of ether and washed successively with 1 M NasEDTA solution (prepared from EDTA and 3 equiv. of NaOH), water, and brine. After drying (anhydrous MgS04), the solution was filtered, the solvent removed in vacuo. Purification by column chromatography (1 vol. % ethylacetate in hexane Rf= 0.2) afforded 100 mg (45%) of the desired product as a colorless oil. 'H NMR (300 MHz, C6D6): 8 4.70 (s, 2H), 3.67 (m,

2H), 3.54 (b m, 1H), 3.41 (b m, 1H), 2.00 (m, 4H), 1.49 (m, 65 H), 1.11 (br d, 3H), 1.03

13 (b d, 3H), 0.91 (s, 9H), 0.07 (s, 6H). C NMR (75 MHz, C6D6):

5 155.6, 152.5, 150.3, 106.3, 92.4, 81.4, 79.8, 79.6, 57.9, 48.4, 36.0, 35.9, 34.1, 29.7, 29.

6, 29.5, 29.4, 29.3, 29.2, 28.4, 28.3, 27.8, 27.7, 25.8, 25.7, 25.4, 18.7, 18.03, -4.2, -4.7.

Anal. Calcd. for Csg^NzOsSi; C, 70.02; H, 11.51, N, 3.40. Found C, 70.11; H, 11.78, N,

3.63.

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