ABSTRACT

REDUCTION OF KETONES TO ALCOHOLS AND TERTIARY AMINES USING 1-HYDROSILATRANE

Sami E. Varjosaari, Ph.D. Department of and Biochemistry Northern Illinois University, 2018 Marc J. Adler, Co-Director Thomas M. Gilbert, Co-Director

1-Hydrosilatrane is an easily synthesized, stable, solid which can be made into an efficient reducing agent in the presence of a Lewis base, by taking advantage of the properties of hypervalent . Due to the simplicity of use and handling, 1-hydrosilatrane has the potential to be an appealing alternative to other more widely used reducing agents. Aromatic and aliphatic ketones were readily reduced with 1-hydrosilatrane in the presence of potassium tert-butoxide. The discovery of diastereoselectivity in the reduction of menthone, a chiral ketone, led to enantioselective reductions of prochiral ketones using chiral Lewis base activators. Enantiomeric excesses of up to 86% were observed. It was also shown that 1-hydrosilatrane could act as a chemoselective reducing agent in the formation of tertiary amines via direct reductive aminations, in the absence of activator or solvent.

Attempts were also made to take advantage of the steric properties of silicon protecting groups in meta-directing electrophilic aromatic substitution of phenols, leading to a one-pot synthesis of O-aryl carbamates. i

NORTHERN ILLINOIS UNIVERSITY

DEKALB, ILLINOIS

MAY 2018

REDUCTION OF KETONES TO ALCOHOLS AND

TERTIARY AMINES USING 1-HYDROSILATRANE

BY

SAMI ENSIO VARJOSAARI ©2018 SAMI ENSIO VARJOSAARI

A DISSERTATION SUBMITTED TO THE GRADUATE SCHOOL

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

FOR THE DEGREE

DOCTOR OF PHILOSOPHY

DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY

Doctoral Co-Directors:

Marc J. Adler and Thomas M. Gilbert DEDICATION

Varjosaarille ja Rautosille,

mahtavuus on sukuvika. TABLE OF CONTENTS

Page

LIST OF TABLES ...... viii

LIST OF FIGURES ...... x

LIST OF APPENDICES ...... xviii

Chapter

1. INTRODUCTION ...... 1

1.1. Overview ...... 1

1.2. History of Silicon ...... 1

1.2.1. Elemental Silicon ...... 1

1.2.2. Compounds ...... 2

1.3. Properties of Silicon ...... 3

1.3.1. Silicon vs Carbon ...... 3

1.3.2. Hypervalency...... 6

1.3.3. Applications of Hypervalent Silicon ...... 9

1.3.3.1. Lewis Acid ...... 10

1.3.3.2. Hydride Transfer Agent ...... 12

1.3.3.3. Carbanion Transfer Agent ...... 14

1.3.4. Stereoelectronic effects ...... 14

1.3.4.1. β-Silicon effect ...... 15

1.3.4.2. -Silicon effect ...... 18

1.4. Silatranes ...... 20

1.4.1. Atranes ...... 20

1.4.2. Silatranes ...... 21

1.4.2.1. 1-Hydrosilatrane ...... 24 iv 1.4.2.2. Toxicity of 1-Hydrosilatrane ...... 28

1.4.2.3. Safety of 1-hydrosilatrane ...... 31

1.5. Reduction of Ketones to Alcohols ...... 32

1.5.1. Common Reagents for the Reduction of Ketones ...... 32

1.5.1.1. Lithium Aluminium Hydride ...... 32

1.5.1.2. Sodium borohydride and boranes ...... 34

1.5.1.3. Hydrogen ...... 36

1.5.2. Organosilicon Hydrides ...... 37

1.5.2.1. Transition metal calatyzed hydrosilylation ...... 37

1.5.2.1.1. Metal hydride formation ...... 37

1.5.2.1.2. Oxidative addition ...... 38

1.5.2.1.3. Oxo complexes ...... 39

1.5.2.2. Lewis acid activation ...... 40

1.5.2.2.1. Ketone activation ...... 40

1.5.2.2.2. Silane activation ...... 41

1.5.2.3. Lewis base activation ...... 42

1.6. Asymmetric Reduction of Ketones to Alcohols ...... 44

1.6.1. Common asymmetric reduction methods ...... 46

1.6.1.1. Transition metal catalysed hydrogenation ...... 46

1.6.1.2. Chiral Boranes ...... 48

1.6.2. Asymmetric reduction of ketones using organosilicon hydrides ...... 55

1.6.2.1. Transition metal catalysed hydrosilylation ...... 56

1.6.2.1.1. Metal Hydride formation ...... 56

1.6.2.1.2. Oxidative addition ...... 59

1.6.2.2. Lewis base catalysed asymmetric hydrosilylation ...... 60

1.6.2.2.1. Chiral Silane ...... 61

1.6.2.2.2. Chiral Lewis Base ...... 62 v 1.6.2.3. Lewis acid activated asymmetric hydrosilylations...... 67

1.7. Direct Reductive Aminations Using Organosilicon Compounds ...... 70

1.7.1. Common Reagents for Direct Reductive Amination ...... 71

1.7.1.1. Sodium Borohydride derivatives ...... 71

1.7.1.1.1. Sodium Cyanoborohydride ...... 72

1.7.1.1.2. Sodium Triacetoxyborohydride ...... 74

1.7.1.2. Hantzsch Esters ...... 76

1.7.2. Organosilicon hydrides ...... 80

1.8. meta-Directed Electrophilic Aromatic Substitution ...... 87

1.8.1 Electrophilic Aromatic Substitution ...... 87

1.8.1.1. Mechanism of electrophilic aromatic substitution ...... 88

1.8.1.2. Substituent effects on electrophilic aromatic

substitution ...... 89

1.8.2. meta- substitution ...... 93

1.8.2.1 Half-sandwich compounds ...... 93

1.8.2.2 “Traceless” directing groups ...... 96

1.8.2.3 Directing scaffolds ...... 98

1.8.2.4 The Gaunt anomaly ...... 102

1.8.3. O-Aryl Carbamates ...... 103

1.8.4. Stereoelectronic Chameleon ...... 108

2. 1-HYDROSILATRANE TO REDUCE KETONES ...... 112

2.1. Overview ...... 112

2.2. Introduction ...... 112

2.3. Development of Methodology ...... 114

2.3.1. Optimization ...... 114

2.3.2. Scope of reaction ...... 115 vi 2.3.3. Diastereoselectivity ...... 118

2.3.4. Mechanistic Considerations ...... 119

2.4. Conclusions...... 120

2.5. Experimental and Supplemental Information ...... 121

3. ASYMMETRIC REDUCTION OF KETONES WITH 1-HYDROSILATRANE ...... 143

3.1. Overview ...... 143

3.2. Introduction ...... 143

3.2.1. Asymmetric reductions of ketones with organosilicon compounds ...... 144

3.3. Asymmetric reduction of ketones with 1-Hydrosilatrane ...... 144

3.3.1. Proof of Concept ...... 144

3.4. Optimization of Conditions ...... 145

3.4.1. Optimization of activator ...... 146

3.4.2. Optimization of Solvent ...... 147

3.4.3. Optimization of Temperature ...... 148

3.4.4. Optimization of Activator Loading ...... 149

3.5. Effect of Activator Stereochemistry ...... 151

3.6. Scope of reaction ...... 152

3.7. Conclusions...... 153

3.8. Experimental and Supplemental information ...... 154

4. 1-HYDROSILATRANE FOR DIRECT REDUCTIVE AMINATIONS ...... 166

4.1. Overview ...... 166

4.2. Introduction ...... 166

4.2.1. Direct Reductive Amination using Organosilanes ...... 167

4.2.2. Direct Reductive Amination Using 1-Hydrosilatrane ...... 167

4.3. Optimization ...... 168 vii 4.4. Aldehydes with secondary amines ...... 169

4.5. Aldehydes with primary amines ...... 172

4.6. Ketones with secondary amines ...... 172

4.7. DRA with Ammonium Salts ...... 173

4.8. Chemoselectivity ...... 174

4.9. Insight into DRA Mechanism ...... 176

4.10. Conclusions ...... 176

4.11. Experimental and Supplemental Information ...... 176

5. SILICON PROTECTING GROUPS AS META-DIRECTING SUBSTITUENTS IN EAS ...... 219

5.1. Overview ...... 219

5.2. Introduction ...... 219

5.3. m-Directing Electrophilic Aromatic Substitution ...... 222

5.3.1. Substrate synthesis ...... 222

5.3.2. Initial Studies ...... 224

5.4. O-Aryl Carbamates ...... 228

5.4.1. Methodology development ...... 230

5.4.2. Substrate Scope ...... 231

5.5. Conclusion ...... 234

5.6. Experimental and Supplemental information ...... 234

6. CONCLUSION ...... 271

REFERENCES...... 272

APPENDICES ...... 296

LIST OF TABLES

Table Page

Table 1.1. Bond Lengths (A)...... 4

Table 1.2. Bond Energies (kJ/mol)...... 4

Table 1.3. of select elements...... 5

Table 1.4. IR stretches of different ...... 22

Table 1.5. Toxicity (LD50) of various silatranes and common reducing agents ...... 30

Table 2.1. Optimization of reaction...... 115

Table 2.2. Stereoselectivity in the reduction of (-)-menthone...... 118

Table 3.1. Screening of Activators...... 146

Table 3.2. Solvent optimization...... 148

Table 3.3. Effect of temperature on enantioselectivity...... 149

Table 3.4. Activator loading-to-enantioselectivity relationship...... 150

Table 3.5. Recyclability of activator...... 150

Table 3.6. Enantiomer and epimer effect on enantioselectivity...... 152

Table 4.1. Optimization of reaction conditions...... 169

Table 5.1. Effect of silicon bulk on catalytic ability...... 221

Table 5.2. Effect of silicon bulk on carbonyl stretch...... 221

Table 5.3. Silylation of various phenol derivatives...... 223

Table 5.4. Silylation of resorcinol...... 223 ix Table 5.5. Friedel-Craft acylation on various silylated phenols...... 225

Table 5.6. meta-Acetoxylation reactions...... 227

Table 5.7. Arylation of O-aryl carbamates ...... 227

Table 6.1. Catalytic Experiments...... 319

Table 6.2. Chiral GC/MS data...... 320 LIST OF FIGURES

Figure Page

Figure 1.1. Carbon coordination vs silicon coordination ...... 6

Figure 1.2. First examples of hypervalent silanes...... 6

Figure 1.3. Changes in Properties of Silicon Species with respect to Coordination...... 8

Figure 1.4. 3c-4e most likely form of coordination...... 9

Figure 1.5. Lewis acid catalyzed Diels-Alder reactions...... 10

Figure 1.6. Achiral silicon activated with chiral amine...... 11

Figure 1.7. Asymmetric C-C bond formation using silicon-phosphoamide catalysts...... 12

Figure 1.8. Fluoride catalyzed hydrosilylation...... 13

Figure 1.9. Alkoxide catalyzed hydrosilylation...... 13

Figure 1.10. Neutral Lewis base catalyzed hydrosilylation...... 13

Figure 1.11. Allylation of aldehydes via hypervalent siloxane ...... 14

Figure 1.12. Allyl transfer with different activators...... 14

Figure 1.13. β-silicon effect...... 15

Figure 1.14. Reaction suggesting β-silicon effect...... 16

Figure 1.15. Further reactions suggesting  and β-silicon effect...... 16

Figure 1.16. Regiochemical control perpetrated by β-silicon effect...... 17

Figure 1.17. Stereospecific substitution of silicon...... 17

Figure 1.18. Effect on pkas of β-silicon effect...... 18

Figure 1.19. The -silicon effect...... 18 xi Figure 1.20. Nucleophilic attack on β-position leads to stabilized  species...... 19

Figure 1.21. Examples of regioselectivity arising from -silicon effect...... 20

Figure 1.22. Atrane and X- trioxoatrane...... 20

Figure 1.23. Three possible structural conformers...... 21

Figure 1.24. Basic atrane structure with arrow showing coordination...... 21

Figure 1.25. General structure of silatrane...... 22

Figure 1.26. Various biologically active silatranes...... 24

Figure 1.27. 1-Hydrosilatrane...... 24

Figure 1.28. Synthesis of 1-hydrosilatrane via boratrane...... 25

Figure 1.29. Reactions of 1-hydrosilatrane to 1-halosilatrane...... 26

Figure 1.30. Reactions of 1-hydrosilatrane...... 27

Figure 1.31. Reactions with 1-hydrosilatrane reported by Eaborn...... 27

Figure 1.32. 1-Hydrosilatrane reactions with metal salts...... 28

Figure 1.34. Reduction of a ketone with a hydride source ...... 32

Figure 1.35. Reduction of a ketone with aluminium hydride...... 33

Figure 1.36. Overreduction using chloroalanes formed in situ...... 33

Figure 1.37. Diastereoselective reduction of chiral cyclic ketone...... 34

Figure 1.38. Reduction of carbon dioxide using sodium borohydride...... 35

Figure 1.39. Chemoselectivity of sodium borohydride...... 35

Figure 1.40. Varying reactivity of sodium borohydride with different additives...... 36 xii Figure 1.41. Reduction of ketone using hydrogen gas requires a catalyst...... 36

Figure 1.42. Nickel as the catalayst for hydrogenation of acetone...... 37

Figure 1.43. Hydrosilylation via metal hydride formation...... 38

Figure 1.44. Mechanism of hydrosilylation via oxidative addition...... 39

Figure 1.45. Mechanism via [2+2] addition...... 39

Figure 1.46. Mechanism of hydrosilylation via cationic oxo species...... 40

Figure 1.47. Transfer of hydride to activated carbonyl...... 41

Figure 1.48. Piers hydrosilylation...... 41

Figure 1.49. Lewis base activated hydrosilylation via hypervalent silicon...... 42

Figure 1.50. Amide activated hydrosilylation via hypervalent silicon...... 43

Figure 1.51. Polymer mounted N-heterocylic carbene activating silane...... 44

Figure 1.52. Asymmetric reduction using chiral reducing agent...... 44

Figure 1.53. Asymmetric reduction using chiral activator...... 45

Figure 1.54. Asymmetric reduction using chiral catalyst...... 45

Figure 1.55. Transition metal catalyzed asymmetric hydrogenation...... 46

Figure 1.56. Nobel prize winning asymmetric hydrogenation...... 47

Figure 1.57. Cheaper metal alternatives to ruthenium...... 48

Figure 1.58. Asymmetric reduction via chiral boranes...... 49

Figure 1.59. Evolution of aminoborane reductions...... 50

Figure 1.60. Amount of hydrogen formed depends on temperature...... 51 xiii Figure 1.61. Air-stable -methylated oxazaborolidine...... 52

Figure 1.62. Mechanism of reduction via CBS method...... 53

Figure 1.63. Other chiral additives for sodium borohydride...... 54

Figure 1.64. Asymmetric reduction via organocatalyzed hydroboration...... 55

Figure 1.65. Chiral titanocene derivative catalyzed hydrosilylation...... 57

Figure 1.66. Chiral BINAP auxiliary in copper catalyzed hydrosilylation...... 58

Figure 1.67. Asymmetric hydrosilylation catalyzed by chiral zinc salt...... 59

Figure 1.68. Examples of asymmetric hydrosilylations via Oxidative addition...... 60

Figure 1.69. Asymmetric reduction with chiral silane...... 61

Figure 1.70. Chiral silane formed in situ for asymmetric hydrosilylation...... 61

Figure 1.71. Chiral Lewis base activated symmetric hydrosilylation of ketones...... 63

Figure 1.72. Competing reaction lowers overall ee...... 63

Figure 1.73. Various amino acid derivatives for asymmetric hydrosilylations...... 64

Figure 1.74. Phase transfer catalyst for asymmetric hydrosilylation...... 65

Figure 1.75. Hydrosilylation using trichlorosilane and a proline derived catalysts...... 66

Figure 1.76. Hydrosilylation using trichlorosilane and picolinic acid derived catalysts...... 66

Figure 1.77. Hydrosilylation using trichlorosilane and Pyridyloxazoline derived catalysts...... 67

Figure 1.78. Chiral silanes in Piers hydrosilylation...... 68

Figure 1.79. Axially chiral boranes for asymmetric Piers hydrosilylation...... 68

Figure 1.80. Chiral for asymmetric hydrosilylation via FLPs...... 69 xiv Figure 1.81. Overview of direct reductive amination and importance of chemoselectivity...... 71

Figure 1.82. Direct reductive aminations with sodium borohydride...... 72

Figure 1.83. Direct reductive aminations with sodium cyanoborohydride...... 73

Figure 1.84. Modifying conditions of sodium cyanoborohydride...... 74

Figure 1.85. Chemoselectivity of sodium triacetoxyborohydride...... 75

Figure 1.86. Reduction noted by Gribble et al...... 75

Figure 1.87. Direct reductive aminations using sodium triacetoxyborohydride...... 76

Figure 1.88. Hantzsch esters are biomimetics of NADH...... 77

Figure 1.89. Hantzch esters as reducing agents...... 78

Figure 1.90. Asymmetric direct reductive amination using hanztch ester and chiral phosphoric acid derivative...... 79

Figure 1.91. Direct reductive amination with ammonium salts and hanztch ester...... 79

Figure 1.92. Lewis acid activation of carbonyl and ...... 80

Figure 1.93. First practical use of lewis acid catalysed reductive amination with silane...... 81

Figure 1.94. Further application of silane/TFA system...... 82

Figure 1.95. Various silanes for direct reductive aminations...... 83

Figure 1.96. Various metal lewis acid catalysed direct reductive aminations using silanes...... 84

Figure 1.97. Transition metal catalysed direct reductive aminations using silanes...... 85

Figure 1.98. Direct reductive amination with silane catalysed by P-N bidentate iron complex. ...86

Figure 1.99. Direct reductive amination using aminohydrodimethylsilane...... 86 xv Figure 1.100. Electrophilic aromatic substitution...... 87

Figure 1.101. Relationship between an ouroboros and ...... 88

Figure 1.102. Mechanism for electrophilic aromatic substitution...... 89

Figure 1.103. Relative positions on an monosubstituted aromatic ring...... 90

Figure 1.104. Resonance of donation...... 90

Figure 1.105. Stabilization of the carbocation...... 91

Figure 1.106. Resonance of electron withdrawal...... 91

Figure 1.107. Destabilization of the carbocation...... 92

Figure 1.108. Inductively electron withdrawing...... 92

Figure 1.109. Deprotonation of half-sandwich compound...... 93

Figure 1.110. meta-Substitution on aniline derivatives...... 95

Figure 1.111. meta-Substitution on silylated phenol derivatives...... 95

Figure 1.112. Overall mechanism for meta-substitution via traceless directing group...... 96

Figure 1.113. meta-Substitution via traceless directing groups...... 97

Figure 1.114. Carbon dioxide as a traceless directing group on phenols...... 98

Figure 1.115. meta-Substitution via directing scaffold...... 98

Figure 1.116. C-C bond formation at meta-position via “end-on” directing...... 99

Figure 1.117. Various meta-directied reactions via elaborate scaffolds...... 101

Figure 1.118. meta-Arylations on electron rich aromatic rings...... 102

Figure 1.119. Proposed mechanism for Gaunts meta-arylation...... 103 xvi Figure 1.120. General structure of O-aryl carbamate...... 104

Figure 1.122. O-Aryl carbamates with medicinal properties...... 105

Figure 1.123. Substitution pattern determines biological activity...... 105

Figure 1.124. O-Aryl carbamates as potential chemical warfare agents...... 106

Figure 1.125. O-Aryl carbamate synthesis via chloroformamide or isocyanate...... 107

Figure 1.126. O-Aryl carbamate synthesis via chloroformate...... 107

Figure 1.127. Electron donation by methoxy group...... 109

Figure 1.128. Electronwithdrawing effect caused by σ* interaction...... 109

Figure 1.129. Differences in stabilization of benzylic cation and anion...... 110

Figure 1.130. Regioselectivity of enediyne cyclization...... 110

Figure 1.131. Relationship between relative energy and torsion angle...... 111

Figure 1.132. Alignment of p-orbitals through complete rotation...... 111

Figure 2.1. Scope of the reaction...... 117

Figure 2.2. Steric hindrance on (-)-menthone...... 119

Figure 2.3. Proposed mechanism...... 120

Figure 3.1. Enantioselectivity...... 145

Figure 3.2. Scope of asymmetric reduction of select acetophenone derivatives...... 153

Figure 4.1. Scope of aldehydes and secondary amines to form tertiary amines...... 170

Figure 4.2. Aldehydes with primary amines...... 172

Figure 4.3. Scope of ketones and secondary amines to form tertiary amines...... 173 xvii Figure 4.4. DRA with ammonium salt...... 174

Figure 4.5. Chemoselectivity of DRA with 1-hydrosilatrane...... 175

Figure 4.6. Gram scale reaction using 1-hydrosilatrane under solvent free conditions...... 175

Figure 5.1. Difference in alignment of lone pair in methoxy- and silyloxy benzoic acids. .220

Figure 5.2. Friedel-Craft acylation of TIPS-protected resorcinol...... 225

Figure 5.3. O-aryl carbamate-containing active agents...... 229

Figure 5.4. Reaction route...... 230

Figure 5.5. Formation of aryl chloroformate followed by addition of an amine is unsuccessful at forming desired O-aryl carbamates...... 231

Figure 5.6. Scope of O-aryl carbamate synthesis...... 233 LIST OF APPENDICES

Appendix Page

A. 1H AND 13C NMR SPECTRA OF ALCOHOLS FROM KETONE REDUCTIONS ...... 297

B. GCMS, 1H AND 13C NMR SPECTRA OF ASYMMETRIC ALCOHOLS ...... 319

C. 1H AND 13C NMR SPECTRA OF SYNTHESIZED TERTIARY AMINES ...... 340

D. 1H AND 13C NMR SPECTRA OF MATERIALS IN META-SUBSTITUTION PROJECT ...... 382

E. 1H AND 13C NMR SPECTRA OF SYNTHESIZED O-ARYL CARBAMATES ...... 404 1

CHAPTER 1

1. INTRODUCTION

1.1. Overview

Due to the interesting properties of silicon containing organic , they can be exploited in the development of novel synthetic methodologies in organic chemistry. These new “tools” for organic chemists can often be an improvement over previous methodology due to the low cost, abundance, and low toxicity of organosilicon species.

1.2. History

1.2.1. Silicon

Silicon is the 14th element on the periodic table, found directly below carbon in group 4. It is the second most abundant element in the earth’s crust, after oxygen. Despite its abundance, it was only the 47th element to be discovered. Although the discovery of silicon is accredited to Jöns Jacob

Berzelius in 1823,1 when he successfully isolated elemental silicon, it was only the final formality in a long and arduous journey. In 1771 Carl Wilhelm Scheele reported the formation of an unknown volatile compound, now known to be silicon tetrafluoride, upon reacting silica with hydrofluoric acid (eq 1).2

This led Antoine Lavoisier to predict that silica was an oxide of a yet unknown in

1787.3 Furthermore, Berzelius seemed to follow a method already reported by Joseph Louis Gay-Lussac and Louis Jacques Thénard in 1811,4-5 where silicon tetrafluoride was heated with potassium metal, to give amorphous silicon (eq. 2).

SiO2 + 4HF  SiF4 + 2 H2O (eq. 1)

4 K + SiF4  Si + 4 KF (eq. 2) 2 However, Gay-Lussac and Thenard failed to identify the new element, whilst Berzelius purified and characterized the resulting brown solid. Sir Humphry Davy had coined the term silicium as the name of the unknown element in 1808,6 combining the words silex (latin: flint) and -ium, suspecting the element was a metal. The term silicon was coined by Thomas Thomson in 1817,7 claiming there was no evidence for the element’s metallic nature, and that it appeared to have more resemblance to nonmetals carbon and .

Silicon has become an extremely important element to modern society. The information age is often dubbed the “silicon age” due to the importance of elemental silicon in the production of semiconductors universally used in electronics.8 As of 2011, 7 million tonnes of silicon was being produced annually by heating sand with coke (eq. 2).9 To make ultrapure silicon for the semiconductor industry, impure silicon is reacted with chlorine gas to form tetrachlorosilane, which is volatile (eq. 3).

Tetrachlorosilane can be purified by fractional distillations, and reduced to form ultrapure silicon.9

SiO2 + 2 C  Si + CO (eq. 2)

Si + 2 Cl2  SiCl4 (eq. 3)

1.2.2. Organosilicon compounds

The first organosilicon compound was synthesized in 1863 by Charles Friedel and James Crafts by treating diethylzinc with tetrachlorosilane to form tetraethylsilane (eq. 4).10

2 Zn(C2H5)2 + SiCl4  Si(C2H5)4 + 2 ZnCl2 (eq. 4)

Tetramethylsilane was synthesized in an analogous method in 1865.11 Tetrachloro- and tetraethoxysilanes were subsequently reacted with organometallic reagents,12-13 including Grignard reagents (eq. 5),14-15 to give a large series of organosilicon compounds with varying substituents.

Si(OEt)4 + 2 EtMgBr  (EtO)2SiEt2 + 2 MgBrOEt (eq. 5) 3 In 1871, Albert Landenburg reported the first silicon polymer (silicone), albeit without knowing it. An oil that only decomposed at very high temperatures was formed when diethoxydiethylsilane was mixed with a slightly acidic solution (eq. 6).16

+ n (EtO)2SiEt2 + n H3O  HO-[Et2SiO]n-OH + 2n EtOH (eq. 6)

Due to the inactivity of tetrasubstituted organosilanes, the reactions were seen as mere laboratory curiosities, and in 1937 Kipping declared the class of compounds practically useless, with little chance of useful applications developed in the future.17 However, Kipping jumped the gun, as these organosilanes had already been shown to form silicones, which in turn were discovered to be extremely practical as heat insulating materials.18 With the development of methylchlorosilane synthesis in 1941-1942 via the metal catalyzed reaction of silicon and chloromethane (eq. 7),19-20 industrial scale synthesis of silicones was established (eq. 8).

x Si + y CH3Cl + Cu (cat.)  Me2SiCl2 (eq. 7)

Me2SiCl2 + H2O  Me2Si(OH)2  HO-[Me2SiO]n-OH + H2O (eq. 8)

Hydrosilylation of C-C multiple bonds was discovered in 1947,21-22 and the subsequent discovery that the hydrosilylation could be controlled with a metal catalyst in 1957,23 lead to the easy access of a large number of new silicon compounds (eq. 9).

MeHSiCl2 + H2C=CH2 + M (cat.)  MeEtSiCl2 (eq. 9)

1.3. Properties of Silicon

1.3.1. Silicon vs Carbon

Although silicon is directly below carbon in the periodic table, it has several different physical characteristics. Due to silicon being in the second period, it must use its p orbitals for bonding, which are larger than the p orbitals available for carbon. This leads to longer bond lengths than the carbon equivalent (Table 1.1). 4

Table 1.1. Bond Lengths (Å).24

C Si H O F

C 1.54 1.85 1.09 1.43 1.35

Si 1.85 2.33 1.48 1.66 1.60

For example, the average C-C bond length is 1.54 Å, whilst that of C-Si is 1.85 Å, and the C-O bond is 1.43 Å compared to 1.66 Å for the Si-O bond. A similar trend can be seen with bond strengths

(Table 1.2).

Table 1.2. Bond Energies (kJ/mol).24-25

C Si H O F

C 356 290 416 336 485

Si 290 230 323 466 582

A C-C bond (356 kJ/mol) is stronger than that of the C-Si bond (290 kJ/mol), which in turn is stronger than the Si-Si bond (230 kJ/mol). This is due to increasingly poor orbital overlap. However, silicon does form stronger bonds than carbon with highly electronegative elements such as oxygen and fluorine. This is due to the difference in between silicon and carbon (Table 1.3).

5 Table 1.3. Electronegativities of select elements.24

Element Relative Electronegativity

F 4.0

O 3.5

C 2.5

H 2.1

B 2

Si 1.8

In a nutshell, electronegativity is an atoms ability to attract electron density to itself.

Therefore, larger the difference in electronegativities, the more polarized the bond is towards the more electronegative element, and stronger the bond. As silicon (1.8) is much less electronegative than carbon (2.5), it forms stronger bonds with more electronegative elements. In fact, the strength of

Si-F and Si-O bonds tends to be the driving force for most organosilicon reactions.

Silicon has different bonding characteristics when compared to carbon. Although both elements prefer existing as 4-coordinate complexes, that is where their similarity ends (Figure 1.1.). Carbon can exist as a 3-coordinate carbocation, as well as 4-coordinate complexes, in the form of sp3, sp2 and sp carbon centers, but it is unable to coordinate further to become hypervalent. Silicon on the other hand, can readily forms 5- and 6-coordinate complexes, which have very distinct reaction profiles as they become more hypervalent.

6

Figure 1.1. Carbon coordination vs silicon coordination

This tends to be explained as the silicon being larger than carbon, making it more accessible, as well as the availability of vacant valent outer shell 3d orbitals, which are not available for carbon.

Although the size is definitely a factor, the invocation of available d orbitals is an oversimplified notion that the following section should disprove.

1.3.2. Hypervalency

Hypervalent silicon compounds have been known since the early 1800s, predating the official discovery of elemental silicon, when in 1809 Guy-Lussac reported a salt containing one equivalent of

2- silicon to six equivalents of fluoride, now known to be the [SiF6] anion, and in 1812 Davy reported the formation of a salt when mixing SiF4 with ammonia, consistent with a molecular formula of

2- 26-27 [SiF4(NH2)2] (Figure 1.2).

Figure 1.2. First examples of hypervalent silanes. 7 The differences in properties of hypervalent organosilicon compounds have been exploited extensively in organic synthesis. The Lewis acidity of several 5-coordinate organosilicon compounds has been used in Lewis acid-catalyzed systems,28 whilst 5- and 6-coordinate organosilicon compounds are used as carbanion or hydride donors.29-30 How does this variety in reactivity arise?

Consider a 4-coordinate oraganosilicon compound, with three silaphilic Lewis base ligands (e.g. fluoride, chloride, alkoxide or aryloxide) and one H or C based ligand (sp, sp2 or sp3) (Figure 1.3.). As every atom attached to the silicon is more electronegative, the silicon center has a partial positive charge and is Lewis acidic in nature, making it electrophilic. The extent of this Lewis acidity of the silicon is proportional to the electronegativity of all the surrounding ligands. If another silaphilic Lewis base ligand is introduced, it can coordinate to the electrophilic silicon center making the silicon 5- coordinate. Counterintuitively, the electron density at the silicon center decreases, making it even more electropositive, and hence more Lewis acidic in nature. The electron density on all the surrounding ligands increases, making the non-silaphilic H or C based ligand more electron rich and so more nucleophilic. If another silaphilic Lewis base ligand is present, it can further coordinate to the silicon center to form a 6-coordinate complex. The electron density of the silicon center is further decreased, whilst increased on the surrounding ligands. The increase in electron density on the H or C based ligand further increases its nucleophilicity. Although the electrophilic nature of the silicon center is enhanced, it cannot further coordinate bases easily due to steric encumbrance. However, although no 7-coordinate silicon compounds are known, their existence as intermediates or transitions state in nucleophilic attacks on 6-coordinate silicon centers cannot be ruled out.31-33 Several compounds have been synthesized which, when studied by NMR and X-ray , imply 7- coordination (Figure 1.3).29,34-35 8

Figure 1.3. Changes in Properties of Silicon Species with respect to Coordination.

How is silicon able to become hypervalent? This has been a relatively controversial topic in the field. The original explanation, which is often still quoted, dictated that the silicon is able to access its vacant d-orbitals. Using the Valence Shell Electron Pair Repulsion Theory (VSEPR), one can easily account for the geometries of the ligands around the silicon center.36 4-coordinate silicon is tetrahedral, 5-coordinate silicon is trigonal bipyramidal, and 6-coordinate silicon is octahedral. Valence

Bond Theory can be used to predict the hybrid orbitals that match the geometries. Tetrahedral coordination can be described as sp3 rehybridized, trigonal bipyramidal coordination can be described as sp3d rehybridized, and octahedral coordination can be described as sp3d2 rehybridized (Figure 1.4).

However, for rehybridization to occur, the orbital energies of the s, p, and d-orbitals must be close enough in energy for a favorable interaction. Using 5-coordinate silicon as an example, calculations have shown that 3sp2dp hybridization is extremely energetically unfavorable, at a cost of more than

200Kcal/mol, making it very unlikely to occur.37 However, the same computational calculations do imply a small role of the d-orbitals in polarizing the p-orbitals. Either way, a more realistic alternative for the 5-coordinate silicon is an sp2p hybridization model, with three sp2 hybridized orbitals and a 3 center 4 electron (3c-4e) bond with a p orbital.37-39

9

Figure 1.4. 3c-4e most likely form of coordination

The MO model also explains a lot of the unique characteristics observed in hypervalent silicon.

The non-bonding orbital is filled, locating all the electron density on the ligand atoms. Consequently, any electronegative ligands or atoms that are able to stabilize the increased electron density promotes

3c-4e bonding. This in turn explains why practically all hypervalent silicon compounds are bonded to highly electronegative fluoride, chloride, or oxygen ligands. Furthermore, Bent’s rule states that

“Atomic s character concentrates in orbitals directed toward electropositive substituents”,40 or inversely, p character concentrates in orbitals directed towards electronegative substituents. This results in the central atom, in this case silicon, having a larger partial positive charge, and the most electronegative ligands preferring the axial position. Calculation of the charge distribution of several hypervalent silicon species clearly indicate the increased electron density on the ligands, and decreased electron density on the central silicon.41 Bent’s rule also seems to be followed as the axial ligands of the 5-coordinate bipyramidal species are found to have more electron density than the equatorial ligands, which is consistent with 3c-4e bonding.

1.3.3. Applications of Hypervalent silicon

Due to the enhancement in Lewis acidity of the silicon in hypervalent species, as well as the increased nucleophilicity of the adjacent ligands, hypervalent silicon compounds have been used for a range of different applications within organic synthesis.42 This unique reactivity has been coined as

“Lewis base activation of Lewis acids”, as a Lewis base is used to make a better Lewis acid.43 10 1.3.3.1. Lewis Acid

Tetravalent silicon compounds such as tetrachlorosilane are common Lewis acids to which

Lewis basic moieties can coordinate to, forming more reactive intermediates.28 Although not exciting in itself, altering the system to generate asymmetric Lewis acids greatly enhances the usefulness of this strategy. Two different approaches can be made: (I) making asymmetric silicon compounds with chiral backbones or (II) activating achiral silicon compounds with chiral ligands in situ. The former compound types have been used in several instances, most notably as Lewis acids for asymmetric Diels Alder reactions, with resulting high yields and moderate enantioselection (Figure 1.5.).44-45

Figure 1.5. Lewis acid catalyzed Diels-Alder reactions

The second approach was first achieved in a desymmetrizing enolation reaction, where an achiral silicon was activated with stoichiometric amounts of a chiral amine (Figure 1.6.).46 11

Figure 1.6. Achiral silicon activated with chiral amine.

In the above-mentioned case, the chiral amine is consumed in the reaction. However, due to the reversibility of the interaction of a chiral Lewis base and an achiral silicon compound to form the chiral Lewis acid, one could envision the system being catalytic as long as the chiral ligand acts solely as an activator. This approach was successfully exploited by Scott Denmark in several enantioselective

C-C bond forming reactions, most notably allylation of aldehydes,47 and aldol reactions with silylketeneacetals, silylenolethers,48-52 and even isocyanides (Figure 1.7).53 Stoichiometric amounts of tetrachlorosilane were activated by catalytic amounts of chiral bidentate phosphoamide.

These reactions take advantage of the Lewis acidity of the silicon species activating an electrophile, lowering the energy of the LUMO, in the presence of a nucleophile. However, the system can be enhanced further by combining the Lewis acidity with the increased nucleophilicity of H or C based ligand on the hypervalent species. In other words, the silicon species could be both the Lewis acid and the source of the nucleophile in a single transformation.

12

Figure 1.7. Asymmetric C-C bond formation using silicon-phosphoamide Lewis acid as a catalysts.

1.3.3.2. Hydride transfer agent.

Hypervalent silicon as a hydride transfer agent was first observed and reported by Corriu in

1981, when triethoxysilane was activated using fluoride to reduce ketones and aldehydes (Figure

1.8).54-55

Usually alkoxysilanes do not react with carbonyl compounds, but the extra electronegative fluoride ligand formed a much stronger hypervalent reducing agent in situ. This system was exploited throughout the eighties,56-58 climaxing when Hosomi showed that alkoxides could also be used to activate the reduction of carbonyls with trialkoxysilanes (Figure 1.9).59 This opened up the possibility for asymmetric reduction of ketones using chiral alkoxides.

13

Figure 1.8. Fluoride catalyzed hydrosilylation.

Figure 1.9. Alkoxide catalyzed hydrosilylation.

More recently, trichlorosilane has been used as a reducing agent in the presence of neutral

Lewis bases to give high yields in the reduction of carbonyls and (Figure 1.10.).60-61

Figure 1.10. Neutral Lewis base catalyzed hydrosilylation.

14 1.3.3.3. Carbon transfer agent

Not long after the discovery of the hydride transfer, it was observed that an excess of Lewis bases such as fluoride and alkoxide could promote allylation of aldehydes via an activated hypervalent allylic siloxane species (Figure 1.11.).62-68

Figure 1.11. Allylation of aldehydes via hypervalent siloxane.

This method was further improved when it was realized that neutral Lewis bases such as formamides,69 phophoramides,43 phopshineoxides,34 and sulfoxides70 – referred to collectively as neutral coordinate organocatalysts – could activate allyltrichlorosilane (Figure 1.12).71

Figure 1.12. Allyl transfer with different activators.

1.3.4. Stereoelectronic effects

By far the most common use for organosilicon compounds in organic chemistry is as protecting groups.72-74 Silyl ethers and silyl enol ethers are readily synthesized combining trialkylchlorosilanes with the alcohols or ketones in the presence of mild base, and easily cleaved to reform the starting material in the presence of aqueous fluoride.74 However, the differences between trialkylsilanes and their 15 carbon analogs are often overlooked. For example, the trimethylsilyl group, analogous to tert-butyl, is actually less sterically demanding due to the increased Si-O bond length, even when the trimethylsilyl group has a larger cone angle resulting from a more obtuse Me-Si-Me bond angle.75-76

The electronegativity of silicon must also be taken into account, as substituents attached to silicon have considerably more negative charge compared to those found in carbon analogues.76 In fact, this low electronegativity of silicon directly leads to two electronic effects associated with said atom: the β-silicon effect and the α-silicon effect.

1.3.4.1. β-silicon effect

Silicon stabilizes a positive charge on the β-carbon.77-78 The Si-C σ bond, which has higher electron density towards the carbon (due to electronegativity), shares with the empty p- orbital of the carbocation (hyperconjugation) (Figure 1.13).79 For maximum stabilization, the Si-C bond must be coplanar with the p-orbital.80 Although this effect is usually discussed with carbosilanes, it is equally present in other silicon species.

Figure 1.13. β-silicon effect.

This effect was first discovered in 1946.81-82 Mono-chloroethyltrichlorosilane derivatives reacted with sodium hydroxide, leading to an interesting observation: in the -chlorinated compound, all the

Si-Cl bonds hydrolyzed to Si-OH, but the C-Cl remained (see 1.3.4.2.). The β-chlorinated compound underwent elimination to form tetrahydroxysilane and ethylene gas (Figure 1.14).

16

Figure 1.14. Reaction suggesting β-silicon effect.

Subsequent reactions with monochloro-n-propyltrichlorosilanes with sodium hydroxide showed that both the - and - C-Cl were resistant to substitution, whilst the B-Cl was readily converted to an alcohol (Figure 1.15.).83

Figure 1.15. Further reactions suggesting  and β-silicon effect.

The β-silicon effect justifies the regioselectivity of electrophilic attacks on allylsilanes.

Electrophilic addition always occurs at the position, as this forms the carbocation on the β-position with respect to silicon.84 This gives good regiochemical control in several reactions that would be difficult to achieve otherwise (Figure 1.16).85-87

17

Figure 1.16. Regiochemical control perpetrated by β-silicon effect.

Another example of regioselectivity is observed with electrophilic substitution on vinylsilanes.88

The silane is replaced by the electrophile with retention of the stereochemistry. Electrophilic attack occurs on the position, to form a carbocation β to the silicon. To increase the stability of the carbocation, rotation around the C-C bond occurs to put the Si-C bond coplanar with the empty p- orbital. This also favors elimination of the silicon substituent (Figure 1.17).84

Figure 1.17. Stereospecific substitution of silicon.

18 Other chemical properties can also be affected by the β-silicon effect.79

Trimethylsilylmethylamine is more basic than 2,2-dimethylpropylamine due to the silicon stabilizing the positive charge on the in the conjugate acid. In contrast, trimethylsilylacetic acid is a weaker acid than tbutylacetic acid due to the destabilizing effect of the β-silicon on anionic conjugate base (Figure 1.18).89

Figure 1.18. Effect on pKas of β-silicon effect.

1.3.4.2. α-Silicon effect

The -silicon effect can be thought off in two ways: as a destabilizing effect for positive charge, or a stabilizing effect for negative charge, on the position with respect to silicon.78 The partial positive charge located on the silicon (in the σ* orbital of the Si-C bond), destabilizes any positive charge adjacent to it, whilst stabilizing any negative charge (Figure 1.19.).

Figure 1.19. The -silicon effect. 19

This effect was discovered during the same studies as the -silicon effect.81-82 The C-Cl bond  to the silicon did not hydrolyze under basic conditions, implying decrease in the electrophilicity of that carbon (Figure 1.14 and 1.15).90-91

The stabilizing effect on negative charge is evident when observing the regioselectivity of nucleophilic attacks on vinylsilanes (Figure 1.20.). Much like a Michael addition, where the negative charge is stabilized by a , nucleophilic attack β- to the silicon leads to a negative charge on the position which can subsequently be stabilized by the silicon.92

Figure 1.20. Nucleophilic attack on β-position leads to stabilized species.

This regioselectivity gives access to the formation of -metallated silanes which are useful organometallic reagents (Figure 1.21).93

20

Figure 1.21. Examples of regioselectivity arising from -silicon effect.

1.4. Silatranes

1.4.1. Atranes

The suffix atrane is now used to encompass a wide range of molecular structures consisting of a cage based on a 1.5-heterosubstituted bicyclo [3.3.3] undecane template (Figure 1.22., a),94 although a more traditional view specifies position 1 to be occupied by a (such as silicon, boron, or aluminium), positon 5 to be occupied by a nitrogen atom, and positions 2,8,9 to be occupied by oxygen atoms (Figure 1.22., b).95

Figure 1.22. Atrane and X- trioxoatrane.

Three conformations can exist: exo-exo (biconvex, out-out) where the atoms at positions 1 and

5 point away from the center of the cage, endo-exo (concave-convex, in out) where one atom points at the cage and the other away, and endo-endo (biconcave, in-in) where both point at the center (Figure

1.23).96-98 When the 1 or 5 position is occupied by an atom that can invert, such as nitrogen or 21 phosphorous,99 the structure can undergo conformational changes between exo and endo, giving atranes interesting properties. On the other hand, if the 1 or 5 position is occupied by a moiety that cannot invert, such as Si-X, C-X, or Ge-X, the atom in the moiety remains in the exo conformation.

Figure 1.23. Three possible structural conformers.

A feature mostly associated with atranes, albeit via the more traditional definition of atranes, is a transannular interaction between the atoms in the 1 and 5 positions due to the presence of a lone pair on one atom (nitrogen) and the electron accepting nature of the other (metalloid).95,100 This is usually depicted with an arrow, indicating a dative covalent bond (Figure 1.24).94

Figure 1.24. Basic atrane structure with arrow showing coordination.

1.4.2. Silatranes

Although a plethora of different atranes exist, the most well-known are silatranes, consisting of a substituted silicon at the 1 position, a nitrogen at the 5 position, and three at the 2, 8, and 9 positions (Figure 1.25.). 22

Figure 1.25. General structure of silatrane.

The first silatranes (originally named triptych-siloxazolidines) were synthesized in 1961 by Frye et al., condensing trialkoxysilanes and trialkanolamines to give crystalline monomeric products.101 A strong case was presented for the existence of a transannular dative bond that made the silicon pentacoordinate. Analogous to the previously synthesized boratranes,102 the compounds only reacted slowly with acids, indicating the nitrogen lone pair was unavailable for protonation. Futhermore, previous studies had shown that the Si-H stretching frequency would decrease when the electron density on the silicon was increased,103 which matched well with the observed decrease in energy of the Si-H stretching frequency in 1-hydrosilatrane compared to that of other alkoxysilanes (Table 1.4.).

Table 1.4. IR stretches of different silanes.101

Silane Si-H stretch (cm-1)

Trimethoxysilane 2203

Triethoxysilane 2196

Triisopropyloxysilane 2191

1-Hydrosilatrane 2117

Triphenylsilane 2126

Triethylsilane 2097

23 The nature of the interaction between silicon and nitrogen in silatranes, or even the existence of it, has been a controversial matter. However, the common consensus is that the interaction can be described as 3 center 4 electron bonding, like in other axially bonded pentacoordinate silanes.104 This is consistent with the physically observed relationship between the bond lengths of the silicon and its substituent, and the distance between silicon and the nitrogen. As the bond length of the silicon and its substituent decreases (stronger interaction), the distance between silicon and nitrogen increases

(weaker interaction).100,105 X-ray diffraction studies have shown that the Si-N distance in silatranes ranges from 1.97-2.89 Å,106 which is longer than that of a typical Si-N bond (1.75 Å), but much shorter than the combined van der Waals radii of silicon and nitrogen (3.5 Å). Furthermore, the Si-N distance increases when analyzed in the gaseous phase, indicating a weak interaction.107 Analysis of photoelectron spectra and calculations have strongly indicated that the interaction is not covalent, nor is there significant intramolecular charge transfer between silicon and nitrogen; the interaction is apparently electrostatic.108

A common feature of silatranes, compared to their noncyclic trialkoxysilane, is their decreased reactivity towards nucleophilic substitution at the silicon.106 Furthermore, most likely due to their caged structure, they are relatively stable to atmospheric moisture and undergo hydrolysis much slower than their analogous trialkoxysilanes.98 These features make silatranes much more stable and hence easier to handle.

Although most of the attention silatranes receive is in the form of structural and theoretical studies, they have been observed to have a wide range of biological effects,109 ranging from high toxicities to the point they are used as zooicides,95,110-112 to positive effects like hair growth stimulation,113 wound healing, crop yield enhancement,114 and antitumor behavior (Figure 1.26).115

24

Figure 1.26. Various biologically active silatranes.

1.4.2.1. 1-Hydrosilatrane

1-Hydrosilatrane is the simplest silatrane, where the substituent on the silicon is hydrogen

(Figure 1.27). It was amongst one of the first silatranes to be synthesized by Frye in 1961.101

Figure 1.27. 1-Hydrosilatrane.

1-Hydrosilatrane is an air stable white crystalline solid that requires no specific precautions when handled. Although it can be directly made via condensation of triethanolamine and trialkoxysilane,101 the yields are low. A higher- yield approach was developed by Voronkov, where triethanolamine is reacted first with boric acid to form boratrane, which is subsequently reacted with trialkoxysilane in the presence of an aluminium catalyst to give 1-hydrosilatrane (Figure 1.28).116 The second step is performed under aprotic conditions, excluding any side processes that could destroy the

Si-H bond.117

25

Figure 1.28. Synthesis of 1-hydrosilatrane via boratrane.

1-Hydrosilatrane has very interesting reactivity. For example, the corresponding 1- halosilatranes (excluding Iodide) are formed when 1-Hydrosilatrane is treated directly with the

118 dihalogen (X2), HX, or the N-halosuccinamide in chloroform (Figure 1.29.). Tetracoordinate silanes such as triethylsilane do not react in this manner, highlighting the increased hydridic character of the

Si-H bond in 1-hydrosilatrane.118 1-Halosilatranes can also be formed from 1-hydrosilatranes via the reduction of polyhalomethanes in the presence of organic peroxides, most likely via a radical mechanism.119 1-Iodosilatrane cannot be synthesized in the same manner as the other 1-halosilatranes, but it can still be made by reacting 1-hydrosilatrane and perfluoroalkyl iodides in the presence of UV irradiation.120 An alternative method to the synthesis of 1-fluorosilatrane is direct reaction of trifluorophenylsilane with 1-hydrosilatrane.121

26

Figure 1.29. Reactions of 1-hydrosilatrane to 1-halosilatrane.

1-Hydrosilatrane also readily reacts with phenols and alcohols, in the presence of an alkoxide or phenoxide base, when refluxed in xylenes (Figure 1.30).122 There is an inverse relationship in the acidity of the phenol and the rate of the reaction. The opposite trend is observed with alkoxide ions, indicating a strong steric effect in the reaction rate. Alkanediols react with two equivalents of 1- hydrosilatrane quantitatively to give bis(silatranoyl)alkanes.123 Hydroxyethylamines and even oximes react in the same fashion as alcohols.124-125 Carboxylic acids react with 1-hydrosilatrane in the presence of Zinc chloride to give 1-Acyloxysilatranes.98 Organolithium and Grignard reagents cleave the Si-O bonds of 1-hydrosilatrane, forming tri-and tetra-alkylsilanes.126

27

Figure 1.30. Reactions of 1-hydrosilatrane.

The hydridic character of 1-hydrosilatrane is most obvious in its ability to reduce benzyl bromide, benzoyl chloride and ,β-unsaturated carbonyls in the absence of an activator, albeit at high temperatures and long reaction times (figure 1.31.).127 However, although the reduction of 4- hydroxybenzaldehyde and acetone were also reported, recent attempts in our group to reproduce the results have been unsuccessful.128 This goes a long way in explaining why 1-hydrosilatrane has been touted as a good reducing agent since the 1970s, yet no one had utilized it since then.

Figure 1.31. Reactions with 1-hydrosilatrane reported by Eaborn.

28 Finally, 1-hydrosilatrane has also been shown to act as a reducing agent in redox reactions with metal salts (Figure 1.32). For example, it can reduce metal nitrate salts to metal, forming 1-

129-130 nitrosilatrane and hydrogen as byproducts. 1-Hydrosilatrane can also reduce CuCl2 to CuCl, forming 1-chlorosilatrane and hydrogen gas as side product.129 Most recently, it has also been shown to reduce mercury salts, HgX2, (X = -OCOR, NCS, Br) to X-silatrane, hydrogen gas, and elemental mercury.131

Figure 1.32. 1-Hydrosilatrane reactions with Metal salts.

1.4.2.2. Toxicity of 1-Hydrosilatranes

A stigma associated with silatranes is their assumed toxicity, and not without due cause. As mentioned previously, silatranes are biologically active moieties,109 that have even been used as zooicides.95 1-Arylsilatranes stimulate the central nervous system of warm blooded animals,132 causing convulsions and rapid death from organ failure, but has no effect of cold-blooded animals or other

133 organisms. This, along with their extremely high toxicity (LD50 0.1-0.5 mg/kg), have made them ideal for killing rodents.95,110-112,134 Furthermore, arylsilatranes rapidly decompose in the dead rodents, making the carcasses safe to be eaten by scavengers, making arylsilatranes environmentally safe zooicides.109 Due to their low volatility, lack of smell and taste, and rapid decay making them extremely hard to detect, 1-arylsilatranes have gained a certain notoriety that has made it into pop 29 culture. “Silatrane” was referred to as “ideal poison” in an early episode of the German crime drama

Derrick.135 “Silatrane” was also highlighted on an episode of 60 minutes as a chemical agent in the

South African apartheid-era chemical and biological warfare program codenamed Project Coast - involving ominous characters such as Dr Death - and having been designed to be used in a conspiracy to kill members of Nelson Mandela’s African National Congress officials with altered umbrellas as delivery systems.136 Apart from being highly memorable, these stories also failed to specify the “silatrane” as 1- arylsilatranes, causing an unjustified prejudice to other silatrane derivatives. In reality, the toxicity of silatrane derivatives depends on what is attached to silicon (Table 1.5).113

With rare exceptions, an aryl ring is required for high toxicity (LD50 <1.0 mg/kg). If the aryl ring is replaced with an O-alkoxide, or an sp2 carbon derivative, the toxicity drops dramatically. 1-

Hydrosilatrane (LD50 100 mg/kg: intraperitoneal – rat) is 2 orders of magnitude less toxic than arylsilatranes, and is much more readily hydrolyzed than other silatrane derivatives. Comparing it with

137 other reducing agents such as NaBH4 (LD50 18 mg/kg intraperitoneal -rat & mouse), and LiAlH4 (LD50 7 mg/kg intraperitoneal - mouse),138 it comes across as a safer alternative.

30 Table 1.5. Toxicity (LD50) of various silatranes and common reducing agents

Silatrane - X LD50 mg/kg

CH3 >3000

CH2=CH >3000

CH3CH2O >3000

(CH3CH2O)2P(O)CH2 3000

ClCH2 2800

C6H5CH2O 2250

CH3O 2100

C6H5CH2 1115

BrCH2 916

(CH3)3CO 230

C6H5O 200

H 100

C7H11 80

NaBH4 18

4-CH3OC6H4 17

LiAlH4 7

BrCH2CH2CH2 5

4-ClC6H4 1.7

C6H5 0.3

4-CH3C6H4 0.1

31 1.4.2.3. Safety of 1-Hydrosilatrane

As mentioned earlier (see 1.4.2.1), 1-hydrosilatrane is an easily handled crystalline solid which requires no special precautions when used. Although it does undergo hydrolysis in the presence of water,139 the process is extremely slow with small quantities such as atmospheric moisture. This is partially verified by the fact that no steps were taken to keep our synthesized 1-hydrosilatrane out of atmospheric conditions, yet the reactivity was unhindered up to 7 months later. This gives a clear advantage in handling compared to the relatively rapid rate of hydrolysis of sodium borohydride and lithium aluminium hydride under atmospheric conditions.140-141 The stability of 1-hydrosilatrane is emphasized when compared to its precursor, triethoxysilane, which readily undergoes rapid hydrolysis with atmospheric moisture.142 Furthermore, broadly used chlorosilanes such as trichlorosilane readily hydrolyze in the presence of atmospheric moisture releasing corrosive gaseous hydrochloric acid, which, combined with their inherent flammability and extreme volatility, make them extremely hazardous.143

The fact that 1-hydrosilatrane is a non-volatile solid adds to its safety compared to triethoxysilane. The volatile nature of Triethoxysilane has led to incidents of temporary blindness caused by the fumes reacting rapidly with the eye, coating the cornea with a layer of silica.144

Currently, the safest organosilicon hydride used as a reducing agent is PMHS, polymethylhydrosiloxane. It is an easily handled viscous oil, with low toxicity, relatively high stability, and low cost.145 However, mechanistic studies have shown that PMHS may generate methylsilane, a highly reactive and volatile , in situ as the active reducing species.146 Triethoxysilane has been shown to follow a similar disproportionation to form tetrahydrosilane, a highly pyrophoric species.147

Although these reactions can be relatively safe on a small scale, on a larger scale they could be catastrophic. Studying the observed products of ketone reduction using Lewis base activated 1- hydrosilatrane shows that no apparent disproportionation occurs, as the silatrane cage is intact in the silylether products.148 This makes 1-Hydrosilatrane a safe alternative, even in large scale reactions.

32 1.5. Reduction of Ketones to Alcohols

The reduction of a carbonyl functionality is one of the most used functional group transformations in organic chemistry, providing access to numerous commodity chemicals from simple building blocks.149-152 The reduction of ketones produces secondary alcohols, which is important in itself, but also raises the possibility of creating chiral centers (more about this in the next chapter).

The reaction can quite simply be summarized as a transfer of a hydride (from any hydride source) onto the carbon of the ketone carbonyl followed by a protonation of the corresponding alkoxide to give the product alcohol (Figure 1.34.).

Figure 1.34. Reduction of a ketone with a hydride source.

Many methods exist to reduce ketones, but this chapter will only discuss the most common reducing agents, before going into detail about organosilicon hydrides as reducing agents.

1.5.1. Common reagents for the reduction of ketones

1.5.1.1. Lithium aluminium hydride and derivatives

Aluminium has a low electronegativity. Hydrogen has a higher electronegativity, so an Al-H bond is polar with negative charge located on the hydrogen, which in turn makes the hydrogen hydridic and so, nucleophilic. This hydride reacts with electrophilic carbonyls, such as that of ketones, to give alcohol as the reduced product (Figure 1.35.).

33

Figure 1.35. Reduction of a ketone with aluminium hydride.

153 Lithium Aluminium Hydride, LiAlH4, (LAH) was first prepared in 1947, and its usefulness as a reducing agent was immediately employed as a reducing agent in organic chemistry.154 Since then It has been extensively studied.155 Although excellent at reducing ketones, it has very low chemoselectivity, reducing most other functional groups except carbon double and triple bonds.156-158 This limits LAH use to reducing molecules with low functionality. It is also relatively unstable under atmospheric conditions, hydrolyzing readily in the presence of any moisture. Furthermore, it reacts violently with liquid water, releasing hydrogen gas which subsequently ignites spontaneously due to the high energy

0 159 of hydrolysis (ΔH 298 = -714 kJ/mol). This makes LAH difficult and dangerous to handle outside of an inert atmosphere. LAH is insoluble in hydrocarbon solvents, limiting most reaction solvents to polar aprotic ones such as ethers. The solubility of LAH can be increased in the presence of certain ethers,160 and tertiary amines,161 which can form stable complexes that are soluble in hydrocarbons such as toluene. The reactivity of LAH can be modified with the addition of various additives. For example, addition of AlCl3 forms alanes (AlH3) and chloroalanes in situ (AlClH2), which are milder reducing agents.156 However, this is not ideal as chloroalanes tend to favour hydrogenolysis, and reduce a ketone directly to the hydrocarbon (Figure 1.36.).159

Figure 1.36. Overreduction using chloroalanes formed in situ. 34 Alkoxy alanes can also be made in situ by adding alcohols to LAH. These are more selective reducing agents that can, as an example, reduce ketones in the presence of esters.159 Alkoxyalanes such as tri-tert-butoxy aluminium hydride have the added benefit of being very bulky, which can be exploited in diastereoselective reductions of cyclic ketones (Figure 1.37.).162

Figure 1.37. Diastereoselective reduction of chiral cyclic ketone.

1.5.1.2. Sodium borohydride and boranes

Just like with aluminium, hydrogen is more electronegative than boron, making the H-B bond polarized, and the hydrogen hydridic. Although this chemical property has been exploited by chemists for over 70 years, use of borohydride reducing agents came about somewhat serendipitously during the

1940s. Metal Borohydrides were first discovered in 1901,163 and the increased volatility of metal borohydrides compared to other metal salts was observed in 1939.164 During the second world war

(1939-1945), a push was made to develop more volatile uranium salts that could help in the purification and isolation of 239U.165 Although the efforts with regards to uranium borohydride were unsuccessful, a litany of new reactions were observed, yet could not be further developed at the time.165 Regardless,

Sodium borohydride, NaBH4, was singled out as the most useful metal borohydride due to the much lower cost, and ease of synthesis.166 It was first applied as a reducing in inorganic chemistry,167-169 most notably to reduce carbon dioxide to formate (Figure 1.38.).167 In 1949, the reducing properties of

NaBH4 was first applied to organic chemistry, when it was shown to reduce aldehydes, ketones and acid 35 chlorides.170 Its relative low-cost and stability compared to LAH made it an instant hit amongst organic chemists. NaBH4 is now one of the most produced hydride reducing agent in the world.159

Figure 1.38. Reduction of carbon dioxide using sodium borohydride.

Unlike LAH, NaBH4 can be used in the presence of polar protic solvents such as methanol or even water due to its lower reactivity. Under normal conditions it is much more chemoselective, as it can reduce aldehydes, ketones, and acid chlorides, without reducing other carbonyls present such as esters, carboxylic acids, acid anhydrides, or amides (Figure 1.39.).171

Figure 1.39. Chemoselectivity of sodium borohydride.

The reactivity of NaBH4 can be altered adding metal salts or chelating agents, or using

172-173 different solvents (Figure 1.40.). For example, TiCl4 can be added to make sodium borohydride reduce carboxylic acids and nitro groups to alcohols and amines respectively, whilst addition of CoCl2 allows it to hydrogenate . In these cases, the active reducing agent is most likely a transition 36 metal hydride. In the presence of acetic acid, sodium borohydride forms triacetoxyborohydride, a

174 much weaker reducing agent which can reduce aldehydes but not ketones. BF3 can be added to sodium borohydride to form a more reactive reducing agent in situ.175 The reducing agent is most likely

176 diborane (B2H6 or BH3), which is known to reduce ketones and aldehydes to alcohols. Boranes tend to

177 be less selective towards other functionalities compared to NaBH4. However, an advantage of

178-180 diboranes over NaBH4 is that they show interesting diastereoselectivity in cyclic ketones.

Figure 1.40. Varying reactivity of sodium borohydride with different additives.

1.5.1.3. Hydrogen gas

Hydrogen gas is not itself reactive towards carbonyls, but readily reduces ketones to alcohols in the presence of an appropriate catalyst (Figure 1.41.).

Figure 1.41. Reduction of ketone using hydrogen gas requires a catalyst.

37 In 1903, acetone was successfully reduced to 2-propanol in the presence of hydrogen and reduced nickel (Figure 1.42.).181-182 Multiple transition metal hydrogenation reduction catalysts have been developed since the 1960s,183-185 with more recent advances involving earth abundant metals such as Fe to bring down cost and toxicity of the catalysts.186-187 The focus has been on asymmetric reductions, as the transition metal ligand complexes allow for numerous possibilities to develop chiral environments.188

Figure 1.42. Nickel as the catalayst for hydrogenation of acetone.

Hydrogenation of ketones is not limited to transition metal catalysts, as Frustrated Lewis Pairs have been shown to activate hydrogen gas to reduce aromatic and aliphatic ketones in high yields.189-190

1.5.2. Organosilicon hydrides for the reduction of ketones

Ketones can be reduced using organosilicon hydrides. However, organosilicon hydrides are relatively stable and only mildly hydridic, requiring a catalyst or an activator to be present to activate either the silane species or the electrophilic carbon center of the carbonyl for reduction to occur.191

This has practical applications in that organosilicon hydrides are easy to handle and do not tend to require special precautions. There are several different approaches that can be used, which have drastically different mechanisms.

1.5.2.1. Transition metal catalyzed hydrosilylation

1.5.2.1.1. Metal hydride formation. Early (group 4, Ti)192 and late (group 11-12, Cu, Zn)193-195 transition metals extract the hydride from the organosilicon hydride, via a σ-bond metathesis, to give a metal 38 hydride (Figure 1.43.). This metal hydride reduces the ketone to the corresponding alkoxide independently of the silane. A catalytic cycle is formed when the metal alkoxide is then exchanged for another hydride, regenerating the metal hydride and a silylether. The silylether product is then hydrolyzed to give the corresponding alcohol product.

Figure 1.43. Hydrosilylation via metal hydride formation.

1.5.2.1.2. Oxidative addition. Si-H can oxidatively add to low valent transition metals (group 8-10),196 such as rhodium,197 platinum,198 iridium,199 and iron.200-201 Coordination of the carbonyl to the transition metal leads to migratory insertion followed by reductive elimination, resulting in the formal addition of the hydride and the organosilicon moiety across the carbonyl to give a silylether which can be hydrolyzed to the corresponding alcohol (Figure 1.44.). In this reaction, the silane acts analogously to hydrogen in hydrogenation

39

Figure 1.44. Mechanism of hydrosilylation via oxidative addition.

1.5.2.1.3. oxo complexes. High valent oxo complexes of rhenium (and molybdenum) have also been shown to activate hydrosilylation of ketones.202-206 Two plausible mechanisms have been proposed. The first involves a [2+2] addition of the hydrosilane across a TM=O bond, followed by coordination of a ketone carbonyl, subsequent reduction of the ketone, and a retro [2+2] addition to give the silylether

(Figure 1.45.).202

Figure 1.45. Mechanism of hydrosilylation via [2+2] addition. 40 An alternative mechanism involves η2-coordination between Si-H and a cationic oxorhenium species (Figure 1.46.), increasing the electrophilicity of the silicon. This leads to coordination of the carbonyl oxygen to the silicon, and an immediate reduction and expulsion of the silylether in one step.

Essentially, the cationic oxorhenium species acts as a strong Lewis acid.

Figure 1.46. Mechanism of hydrosilylation via cationic oxo species.

1.5.2.2. Lewis Acid Activation

207-208 1.5.2.2.1. Ketone activation. In the presence of a Lewis acid (eg BF3, AlCl3), or a Brønsted acid (eg

209-210 H2SO4, CF3COOH), the carbonyl oxygen of a ketone can form a complex with the acid atom, greatly increasing the electrophilicity of the carbon of the carbonyl.207-215 This in turn allows for hydrosilanes to transfer the hydride to the carbon (Figure 1.47.). Whether this transfer is concerted, or if a trivalent sillylium cation intermediate is formed, is still a debated topic.216-219

41

Figure 1.47. Transfer of hydride to activated carbonyl

1.5.2.2.2. Silane activation. Lewis acids can also activate the silicon hydrogen bond, making the hydride more nucleophilic. In 1996, tris(pentafluorophenyl)borane B(C6F5)3, a strong Lewis acid, was shown to catalyze the hydrosilane based reduction of ketones to alcohols by activating the silane instead of the ketone (Figure 1.48.).220 This was the first case of Frustrated Lewis Pair chemistry, which has become a topic of much interest.221 Further mechanistic studies revealed that there was most likely some activation of the carbonyl by a silylium intermediate.222

Figure 1.48. Piers hydrosilylation.

42 1.5.2.3. Lewis Base Activation

Lewis bases can also be used to activate organosilicon hydrides in a relatively unique manner.

The Lewis base coordinates with the silicon center, making it hypervalent, which in turn increases the

Lewis acidity of the silicon as well as the nucleophilicity of the adjacent hydride (see 1.3.3). The carbonyl of the ketone coordinates with the more Lewis acidic silicon, at which point the hydride transfers to the carbon of the carbonyl, completing the reduction (Figure 1.49.).

Figure 1.49. Lewis base activated hydrosilylation via hypervalent silicon.

This type of “Lewis base activation of Lewis acids” was first pioneered by Corriu et al. in the late 1970s, when he discovered that ,β-unsaturated ketones could be reduced with diphenyl- and naphtylsilane in the presence of siliphilic oxide or fluoride salts.1 The system was further expanded and improved to unsaturated and aromatic ketones in the early 1980s, when trialkoxysilanes were activated by fluoride salts (see fig.1.9 Corriu).54-55 The hypervalent silicon species is favoured in this system due to the electronegative nature of the alkoxide substituents (see 1.3.2). Exchanging the alkali metal fluoride salts for more soluble TBAF, and other modified fluoride salts, gave way to high yields and good diastereoselectivities.56-57,224-226 Soon after it was realized that alkoxide activators were also very effective at activating trialkoxysilanes to reduce ketones,58-59,227-228 opening the possibility of inducing asymmetric reductions with chiral alkoxides (see 1.6.3).

Neutral Lewis bases also act as activators, albeit with more reactive silicon species such as trichlorosilane. Just like other organosilicon hydride species, trichlorosilane does not react with 43 aldehydes or ketones without an activator. However in 1996, Kobayashi et al. observed that ketones were reduced by trichlorosilane in excess DMF.229 The amide apparently coordinated with the trichlorosilane to give a hypervalent silane species, which was not suprising as allylic trichlorosilane had been used as an allyl transfer agent in the presence of amides (Figure 1.50.).69 This mechanism was exploited by Matsumura et al. in 1999, by using N-formyl pyrrolidine as a neutral Lewis base activator in the reduction of aromatic ketones.60 Due to the ubiquity of asymmetric secondary amines, this approach has become a powerful and highly exploited approach to asymmetric reduction of ketones

(see 1.6.3)

Figure 1.50. Amide activated hydrosilylation via hypervalent silicon.

Finally, it is worth mentioning that a new type of Lewis base activator has garnered attention as an organosilicon hydride activator – N-heterocylic carbenes. The first example was discovered in

2008, where a polymer-mounted N-heterocyclic carbene was used to reduce ketones in high yields

(Figure 1.51).230 44

Figure 1.51. Polymer mounted N-heterocylic carbene activating silane.

1.6. Asymmetric Reduction of Ketones

Chiral alcohols are extremely important in agrochemical, flavor, and pharmaceutical industries, and the most efficient way to obtain them is through the asymmetric reduction of prochiral ketones.149,152,150,231 Obviously, the tricky part in this transformation is the induction of asymmetry from a chiral source. Numerous methods have been developed that are highly efficient and enantioselective, yet the asymmetry can only be induced in three different ways. The first approach is with a chiral reducing agent (Figure 1.52.). Although effective, this requires stoichiometric amounts of the reducing agent, and the reducing agent itself must be obtained beforehand.

Figure 1.52. Asymmetric reduction using chiral reducing agent.

The second approach is to add a chiral activator into the reaction (Figure 1.53.). This activator creates a chiral environment as it coordinates with the reducing agent, but is either consumed during 45 the reaction, or is not necessary for the reaction to proceed. This also leads to the necessity of stoichiometric amounts of activator for high enantioselectivity.

Figure 1.53. Asymmetric reduction using chiral activator.

The third approach is to have a chiral catalyst (Figure 1.54.). This catalyst is the driving force of the reaction, and hence reductions only occur in its presence.

Figure 1.54. Asymmetric reduction using chiral catalyst.

A huge variety of methods have been developed using both transition metal catalysts and organocatalysts.232-233 Transition metal catalysts are extremely efficient in asymmetric hydrogenation and hydride transfers, but they can be relatively expensive, difficult to handle due to instability in ambient conditions, or they can contaminate the asymmetric product via metal-leaking.234-237 A safer 46 alternative has emerged in the form of organocatalysts, which perform the same feats as transition metal catalysts, but without the drawbacks.237-238 The most effective organocatalyst systems include chiral boranes, chiral Lewis acids with Hantzsch esters, and chiral Lewis base catalyzed hydrosilylations.

1.6.1. Common reaction systems for the asymmetric reduction of prochiral ketones

1.6.1.1. Transition metal catalysed hydrogenation

Enantioselective transition metal catalyzed hydrogenation of prochiral ketones is widely regarded as the most efficient way of producing chiral alcohols (Figure 1.55.). The reaction is practically 100% atom efficient, making it very environmentally friendly and cost effective.239 The H-H bond adds to a metal via oxidative addition, which then coordinates with the corresponding ketone.

The ketone inserts into the H-H bond and reductive elimination results in formal addition of the two hydrogen atoms across the carbonyl to give an alcohol. Asymmetry is successfully induced when the environment around the metal is chiral.

Figure 1.55. Transition metal catalyzed asymmetric hydrogenation.

47 The earliest example of asymmetric hydrogenation of ketones was reported in the 1960s, using

Raney nickel modified with optically active compounds such as tartaric acid and various amino acids.240

The enantioselectivity was rate dependent, varying with both the time of reaction and the amount of catalyst.241 Further developments were made in the 1970s, when rhodium complexes with chiral tertiary phosphines were shown to hydrogenate ketones in up to 50% ee.242-245 Iridium complexes were far less effective.243 Finally, the breakthrough in asymmetric hydrogenation of ketones came in 1987, when Noyori et al. used ruthenium BINAP complex to reduce β-keto esters to the corresponding β- hydroxyesters in 99% ee.184,244 This method was further improved in 1995 when ruthenium BINAP diamine complexes were shown to act as a catalyst in reducing non-chelatable and unfunctionalized ketones at the same level of enantioselectivity (Figure 1.56.).245 These developments caused such a paradigm shift in organometallic chemistry that Noyori won the Nobel prize in 2001.244

Figure 1.56. Nobel prize winning asymmetric hydrogenation.

48 Although ruthenium has been the dominant element in asymmetric hydrogenations,188,246-256 osmium,257-260 iridium,261-264 and palladium,265-268 have all been successfully utilized. More recently, the trend has been to replace precious metals with more economical, less toxic options (Figure 1.57.) such as cobalt,269 nickel,270-271 copper,272-278 and iron.279-282

Figure 1.57. Cheaper metal alternatives to ruthenium.

A challenge with asymmetric hydrogenation of ketones is the lack of a single catalyst for any substrate, requiring trial and error to find out which side functional groups are tolerated on the ketone, and to sift through the relatively large scope of ligands available.239 This has been attacked using robotic screening technology.283

1.6.1.2. Chiral Boranes

Unlike sodium borohydride (see 1.5.1.2), boranes are charge neutral B-H containing species

(BH3, B2H6, etc.) that are Lewis acidic in nature and hence, like silanes, do not readily transfer a 49 hydrogen as a hydride unless activated by a Lewis base. Due to this need of an activator, a chiral environment can be easily created for asymmetric reductions with a chiral activator. Chiral boranes are probably the most common way of introducing chirality in carbonyl reductions (Figure 1.58.). The concept is simple: introduce a chiral organoboron compound with a Lewis base moiety that can reversibly complex with a B-H containing reducing agent. This chiral complex becomes a more reactive hydride source than the original reducing agent, becoming the exclusive reducing agent in the mixture.

Consequently, the ketone is reduced enantioselectively to give a chiral alkoxyborane product. Under the correct conditions, the original chiral borane cleave and complex with another B-H containing reducing agent to complete a catalytic cycle.

Figure 1.58. Asymmetric reduction via chiral boranes.

The use of boranes can be traced back to 1960, with the discovery of amine-boranes as reducing agents for the reduction of aldehydes and ketones.284-286 These molecules gained a lot of attention due to their thermal and hydrolytic stability, as well as its high solubility in both protic and aprotic solvents.287-288 (In fact, it was this innate stability that led to amine-boranes not becoming as

289 widespread a reducing agent as NaBH4. ) As the amine could have practically any substituents, their 50 potential for asymmetric reduction of ketones in case of a chiral amine did not go unnoticed for long.

Around 1970, the first reported asymmetric ketone reductions with ephedrine and -phenylethylamine borane complexes gave very low enantioselectivity (<5% ee).290-291 In 1976, amino acid esters complexed to BH3 gave enantioselectivity of up to 20% ee in the reduction of acetophenone to phenylethanol.292 Replacing the ester group with an alcohol increased selectivity drastically, as reported by Itsuno et al. in 1981.293 Aminoalcohol-borane complexes in stoichiometric amounts gave enantioselective reduction of ketones with up to 60% ee. By 1983, after further optimization of the method, and using a much bulkier aminoalcohol derivative, the enantioselectivity was increased to 99% ee with aromatic ketones (Figure 1.59).294

Figure 1.59. Evolution of aminoborane reductions

51 The procedure was relatively simple. Two to three equivalents of borane reacted with one equivalent of chiral aminoalchohol in THF at low temperatures (-70 oC – 0oC), releasing one equivalent of hydrogen gas to form an alkoxyborane, with the amine further coordinating with the boron center to give a relatively rigid, cyclic structure (alkoxyamine-borane complex) (Figure 1.60). One equivalent of ketone was then added to the reaction mixture and complete reduction occurred within a couple of hours. Itsuno also reported that increasing the temperature of the alkoxyamine-borane complex formation to 30 oC, two equivalents of hydrogen gas would be released to instead form chiral oxazoborolidine.295

Figure 1.60. Amount of hydrogen formed depends on temperature.

The great leap forward in chiral borane catalyzed asymmetric reductions of ketones came in

1987, when Corey et al. reported the reduction of ketones using catalytic amounts of chiral oxazaborolidine.296 After performing kinetic studies on the asymmetric reductions reported by Istuno et al., Corey et al. realized that only substoichiometric amounts of the chiral oxazaborolidine (5 mol %) were necessary for complete reduction of ketones to occur at room temperature, in high yields and with up to 97% ee. Although the catalyst was extremely efficient and easily isolated, it suffered the drawback of being highly air and moisture sensitive. This, however, rapidly became a non-issue as a follow up paper introduced the chiral -methylated oxazaborolidine, which performed just as well but was much more stable, and could be handled in the presence of air (Figure 1.61).297

52

Figure 1.61. Air-stable -methylated oxazaborolidine.

The mechanism has been extensively studied, and is extremely elegant (Figure 1.62).298 The cycle is initiated by the rapid coordination of borane with the nitrogen on the oxazaborolidine. This has the dual effect of making the BH3 more hydridic, and the boron on the oxazaborolidine more Lewis acidic. The carbonyl oxygen of the ketone coordinates with the Lewis acidic boron in a manner that minimizes negative steric interactions with the oxazaborolidine structure. The activated BH3 then reduces the ketone via face selective hydride transfer in a six memebered cyclic transition state to give an oxazaborolidine-alkoxide complex. This decomposes in the presence of excess BH3 to reform the catalyst.

Since the introduction of the “CBS” (Corey-Bakshi-Shibata) method, different oxazaborolidine catalyst derivatives have been developed to improve different aspects of the method.231,299-302 For example, dimethylsufloxide can be used to convert sodium borohydride into borane in situ, without affecting the overall yield or enantioselectivity.303-304

.

53

Figure 1.62. Mechanism of reduction via CBS method.

Asymmetric reductions of ketones are also possible with sodium borohydride when mediated by other chiral catalysts (Figure 1.63). Chiral metal catalysts such as β-ketoiminato Co(II) or Fe(II) complexes,305-306 as well as chlorovinylketoiminato Co(III) complexes,307 have been shown to mediate sodium borohydride in the asymmetric reduction of ketones extremely efficiently. Several notable

308-310 examples of organocatalysts include TARB-NO2, developed by Singaram et al., chiral aza- crowns,311 and more recently chiral ionic liquids,312-313 all of which give enantioselectivity of up to 99%.

54

Figure 1.63. Other chiral additives for sodium borohydride.

Several other organocatalytic methods are worth mentioning here (Figure 1.64.). Falck et al. have developed a highly enantioselective reduction of aromatic ketones using catecholborane and chiral thiourea-amine complexes as catalyst.314 The method of is very similar to that of CBS, where the borane is activated by an amine, whilst the ketone is coordinate by a Lewis acid, in this case by the thiourea moiety. Antilla et al. also used catecholborane as the hydride source, but used chiral 55 phosphoric acids as the catalyst instead.315 Spectral studies indicated a phosphorylcatecholboronate active species, which also activates the borane and acts as a Lewis acid towards the ketone.

Figure 1.64. Asymmetric reduction via organocatalyzed hydroboration

1.6.2. Asymmetric reduction of ketones using organosilicon hydrides

As was discussed in section 1.5.2, organosilicon hydrides are mild reducing agents that require activators or catalysts to be present before any reduction can occur. This makes the method attractive 56 for the asymmetric reduction of ketones as, upon introduction of a chiral activator or catalyst, the reaction should only proceed in a chiral environment. Multiple methods have been developed for the asymmetric reduction of ketones using organosilicon hydrides,191,213,316-318 including transition metal catalyzed hydrosilylations (1.6.2.1), Lewis base catalyzed asymmetric hydrosilylations (1.6.2.2), and

Lewis acid catalyzed asymmetric hydrosilylations (1.6.2.3)

1.6.2.1. Transition metal catalyzed asymmetric hydrosilylation

Asymmetric hydrosilylation of ketones using transition metal complexes as catalysts can be categorized into two different mechanisms that they go through to achieve hydrosilylation.

1.6.2.1.1. Metal hydride formation. Ti, Cu and Zn complexes can extract a hydride from organosilicon hydrides via σ-metathesis to form a highly hydridic metal-hydride intermediate species (see 1.5.2.1.1).

By the use of chiral ligands, the metal centre is found in a highly asymmetric environment, which can easily induce chirality and high enantioselection.

The first asymmetric protocols for the reduction of prochiral ketones using titanium based catalysts were developed in the early 1990s with the use of chiral titanocene complexes in the reduction of aromatic and ,β-unsaturated ketones giving moderate to high enantioselectivity.319-321

Chiral titanocene dihalides reacted with various phenylsilane derivatives, triethoxysilane, and PMHS to give the active titanocene hydride species in situ. This species rapidly reduced the prochiral ketone to its corresponding alcohol, which then underwent σ-metathesis by exchanging its alkoxide for a hydride in a silane to reform the metal hydride species and an alkoxysilane product. When using PMHS, it was noted that the reaction proceeded more rapidly and with higher enantioselectivity in the presence of methanol.321 This was originally postulated to be due to an alkoxide exchange between the reduced alcohol and the methanol decreasing the steric hindrance and increasing the rate of σ-metathesis of the silane, but recent studies have suggested that the reaction rate increase could also be due to an increase in the Lewis acidity of the titanocene complex in the presence of the alcohol.322 Although enantioselectivity was very high in aromatic and ,β-unsaturated ketones (up to 99% ee), the method did not fare well with aliphatic ketones yielding enantioselectivies only up to 70% ee (Figure 1.65.).323 57 As a side note, both Halterman and Buchwald came to use C2-symmetric systems of bistetrahydroindenyl sandwich complexes, which were tethered by a bridge. Halterman group used chiral bridges such as binaphthyl,319 whilst Buchwald used a simple ethylene bridge.320 More asymmetry and complexity did not improve enantioselectivity, as Buchwald complex gave much higher enantiomeric ratios of product alcohol. Various other asymmetric backbones have also been developed, but none have been as selective.319, 324-326

Figure 1.65. Chiral titanocene derivative catalyzed hydrosilylation.

The first asymmetric hydrosilylation of prochiral ketones using a copper catalyst was reported in 1984.327 Brunner et al. reported that Cu(I) alkoxides, in tandem with chiral bidentate phosphine ligands and diphenylsilane, would reduce acetophenone with up to 40% ee. Surprisingly, this method remained undeveloped until the early 2000s when Lipshutz et al. reported a highly enantioselective hydrosilylation of ketones using a copper salt, alkoxide base, axially chiral diphosphine ligands, and

PMHS as the stoichiometric hydride source.328 This method was shown to be very versatile, reducing substituted aromatic and heteroaromatic ketones with high enantioselectivity.328-350 Most notably, the substrate-to-ligand ratio can be as low as 100000:1, with no reduction of enantioselectivity.330

Furthermore, as the Cu-H species is inherently unstable unless complexed with the diphosphine species, the ligand-to-metal ratio can be less than one. Although limited to axial chirality, the diphosphine ligand can vary between biphenyl,328-334 bipyridyl,335-338 and binaphthyl backbones.339-344 In 58 the case of using chiral BINAP as the ligand,334-337 the choice of silane seems to affect the enantioselectivity, as an improvement is seen when using phenymethylsilane over PMHS (Figure

1.66.).341 The system is not limited to phosphine ligands; N-heterocylcic carbenes have also shown great potential and high enantioselectivity.345-350

Figure 1.66. Chiral BINAP auxiliary in copper catalyzed hydrosilylation.

Chiral zinc complexes have also been developed to do asymmetric hydrosilylation of ketones.

Dialkyl- or diacetyl- zinc salts are mixed with a chiral diamine to give chiral complexes, which undergo similar reactions as the previously mentioned copper hydride complexes.195,351 The first example was shown by Mimoun in 1999, when zinc salts in the presence of chiral amines and PMHS reduced aromatic ketones in relatively high enantioselectivity of up to 81% ee (Figure 1.67.).352-353 Since then, several methods have been developed using diethylzinc and zinc diacetate, which give enantioselectivities up to 99% ee.354-361 The ligands are not limited to diamines, as Schiff bases,355 as well as N-S chelating ligands,360-361 have been shown to give high enantioselectivity. The actual mechanism is still debatable, as the catalytic reducing species is unlikely to be Zn-H, with suggestions that the zinc complex actually acts as a Lewis acid activating the carbonyl of the ketone.362

59

Figure 1.67. Asymmetric hydrosilylation catalyzed by chiral zinc salt.

1.6.2.1.2. Oxidative addition. Just like with Hydrogen gas (see 1.6.1.1), chiral transition metal complexes can oxidatively add to a silane and reduce ketones asymmetrically. As long as the environment around the metal is chiral, the ketone coordinates with the metal via the oxygen on the carbonyl in the least sterically hindered approach, at which point silylmetallation followed by reductive elimination gives the non-racemic hydrosilylation product. This proposed asymmetric reduction method was first shown in 1976 using a rhodium catalyst.363 Although non-asymmetric variants have been developed with other transition metals (see 1.5.2.1.2), only rhodium complexes have been used for the asymmetric hydrosilylation of ketones via an oxidative addition mechanism

(Figure 1.68). A plethora of different chiral ligands can be used, ranging from trans-chelating bidentate,364-365 tridentate,366-368 and tetradentate phosphine ligands,369 N,N-ligands,370-371 P,N- ligands,372-374 P,O-ligands,375-382 P,S- ligands,383 and even N-heterocyclic carbene ligands.384-385 The enantioselectivity of this reaction is highly dependent on the substituents around the silane source,

374 with highest enantioselectivity of 98% ee observed using the sterically bulky MesPhSiH2. The substituent effect is such that using a bulky chiral silane with achiral Wilkinsons catalyst yields up to

26% ee in the reduction of octanone.386 60

Figure 1.68. Examples of asymmetric hydrosilylations via Oxidative addition.

1.6.2.2. Lewis base activated asymmetric hydrosilylations.

Lewis bases coordinate with the silicon center in silanes, forming a hypervalent species that is more Lewis acidic in nature at the silicon center, and a much better hydride donor (see 1.3.2). This approach has been used in asymmetric hydrosilylation via two general methods: using a chiral silane that transfers chirality to a carbon centre, and using chiral activators that induce asymmetry to the system. 61 1.6.2.2.1. Chiral Silane. The first Lewis base activated asymmetric hydrosilylation of a ketone was reported by Frye et al. in 1984.387 A chiral silane was activated with a fluoride anion to create a chiral hypervalent silane, which reduced ketones with low enantioselectivity (high of 12.7% ee) (Figure 1.69).

The low selectivity was most likely due to racemization of the chiral silane in the presence of the fluoride. More recently, N-heterocyclic olefins were used to couple diphenylsilane with chiral menthol to form a chiral silane in situ, which was subsequently used in an NHO catalyzed hydrosilylation of acetophenone to give high yields and good enantioselectivity of up to 63% ee (Figure 1.70).230,388

Figure 1.69. Asymmetric reduction with chiral silane.

Figure 1.70. Chiral silane formed in situ for asymmetric hydrosilylation. 62 1.6.2.2.2. Chiral Lewis base. In 1988, after alkoxides had been shown to act as activators for hydrosilylation, Hosomi et al. developed a method for asymmetric hydrosilylation using lithium salts of various chiral diols and aminoalcohols with trimethoxysilane.389 The method was extremely successful with aromatic ketones, giving excellent yields and enantioselectivity of up to 84%. Remarkably, even catalyst loading of 0.4 mol% gave similar yields and only small a small decrease in ee. The reactivity of the system was highly dependent on the silane, as triethoxysilane and dimethoxymethylsilane gave significantly lower yields. Since then, several attempts have been made to improve the method by using bulkier diols and aminoalcohols, but with minimal success.390-393 Pini et al. noted a direct correlation with low yields and low ee, implying that a weak interaction between the carbonyl and the hypervalent silane is responsible for low asymmetric induction.390 Brook et al. reported relatively low enantioselectivities with diarylprolinols, with the highest enantioselectivy occurring at room temperature and a decrease in selectivity at both higher and lower temperatures. This gave an insight into the mechanism, implying non-classical kinetic control.391 Attempts to use more affordable LiOH instead of t-BuLi to deprotonate the diols were unsuccessful due to the presence of excess hydroxide ions.392 Kagan et al. investigated different conditions and expanded on the selection of diols, reaching the highest reported enantioselectivity of 93% ee (Figure 1.71).393 They also pointed out the crux of the method; if the product does not remain with the silicon, it acts as a competing alkoxide activator with less enantioselectivity, lowering the overall ee of the product (Figure 1.72). 63

Figure 1.71. Chiral Lewis base activated symmetric hydrosilylation of ketones

Figure 1.72. Competing reaction lowers overall ee. 64 In 1999, Brook & LaRonde developed a method using amino acid derived lithium salts that gave good yields and good enantioselectivity, up to 70% ee (Figure 1.73). They observed that more electron dense aromatic ketones also gave better conversion and ee. Bidentate diimidazole ligands were also tested, but these gave lower enantioselectivities than the amino acids.394 The group went further to derive a biproline ligand, which was able to reduce acetophenone with 64% ee, albeit in only 35% yield.395

Figure 1.73. Various amino acid derivatives for asymmetric hydrosilylations

An interesting variation to the Lewis base activated hydrosilylation was reported by Lawrence et al.396 Instead of using a chiral anion as the activator, they used a chiral cation as the counterion.

Ammonium fluoride salts derived from cinchona alkaloids gave up to 78% ee, when combined with a bulky silane (Figure 1.74.). PMHS gave low ees of >36%. The presence of the aryl group next to the 65 ketone, and a sterically bulky alkyl substituent, are crucial for good enantioselectivity, implying the ketone and the chiral counterion coordinate through the aryl group.396

Figure 1.74. Phase transfer catalyst for asymmetric hydrosilylation.

A more recent approach in Lewis base-activated asymmetric hydrosilylation is to use neutral chiral amide activators, albeit with the more reactive trichlorosilane as the hydride source. The first example was reported by Matsumura et al. in 1999, using N-formyl cyclic amine derivatives as the catalyst. Yields were high and ees were up to 51%, which was impressive considering the low catalyst loading of 10mol% with respect to ketone. However, the system seemed to only work well with arylketones, as the ee dropped to 8% with an alkylketone.60 Improved proline-derived catalysts increased the ee up to 99.7% (using cis-5) in arylketones (Figure 1.75).397

66

Figure 1.75. Hydrosilylation using trichlorosilane and proline derived catalysts

In 2007, Sun et al. reported pipecolinic acid-derived formamides catalyzing the hydrosilylation of ketones in consistently high yields, with up to 93% ee with arylketones, and up to 88% ee with alkylketones (Figure 1.76.). They emphasized the importance of the methoxy group at the C2-position, as changing its steric bulk or electron wealth of the oxygen led to a drastic loss in reactivity and enantioselectivity.398

Figure 1.76. Hydrosilylation using trichlorosilane and picolinic acid derived catalysts

67 Pyridyloxazoline catalysts were also shown to be effective in 2006 by Malkov et al., with fair to excellent yields and up to 94% ee (Figure 1.77.). However, the enantioselectivity only seemed to apply to arylketones. This catalyst was also shown to asymmetrically reduce ketimines, making it the first catalyst to be effective in the asymmetric hydrosilylation of both ketones and ketimines. Observations led to a plausible mechanism in which the trichlorosilane chelates with the catalyst, whilst another trichlorosilane molecule activates the ketone. The steric hindrance of the catalyst dictates the facial selectivity, which is further enhanced by arene-arene pi stacking.399-400

Figure 1.77. Hydrosilylation using trichlorosilane and Pyridyloxazoline derived catalysts

1.6.2.3. Lewis acid activated asymmetric hydrosilylations

Non-metal Lewis acid activated asymmetric hydrosilylations have only been shown to occur a handful of times. In 2008 Oestreich et al. reported a mechanistical study on the borane-catalyzed hydrosilylation of ketones (Piers hydrosilylation). Using a cyclic Si-chiral silane, the reaction proceeded enantioselectively with up to 38% ee (Figure 1.78.). This, along with mechanistic data, led to the observation that higher enantioselectivity would depend on the asymmetric induction from a chiral borane.401 68

Figure 1.78. Chiral silanes in Piers hydrosilylation.

In 2016, using phenylsilane and an axially chiral binaphthyl-based cyclic borane as the catalyst, enantioselective reduction of arylketones was achieved in good yields and up to 99% ee (Figure 1.79).

No extra Lewis base was needed for the reaction to proceed, so the reaction does not proceed via a

FLP.402

Figure 1.79. Axially chiral boranes for asymmetric Piers hydrosilylation. 69 Around the same time, Du et al. reported a highly enantioselective hydrosilylation of 1,2- dicarbonyl compounds that did proceed via a frustrated Lewis pair catalyst.403 Axially chiral diyines reacted with boranes to make chiral alkenylborane derivatives in situ, which were then paired with tricyclohexylphosphine to form the FLP (Figure 1.80.). Hydrosilylation proceeded in good to excellent yields (52-98%) and high enantioselectivity (86-99% ee) to give a broad range of -hydroxy ketones and esters.403 This method is complimentary to Oestereichs method, which was unable to reduce 1,2- dicarbonyl compounds enantioselectively (if at all).402

Figure 1.80. Chiral alkynes for asymmetric hydrosilylation via FLPs.

A very recent addition to chiral Lewis acid catalsysts for hydrosilylation are chiral oxazaborolidinium ions (COBI).404 These catalysts act very much like the CBS catalyst (see 1.6.1.2). Aryl 70 alkyl ketones are reduced in high yields and enantioselectivity of up to 99% ee. Although the reaction might proceed via a Piers hydrosilylation, a more classical transition state has been proposed, involving pi-pi stacking between the substrate and the phenyldimethylsilane, and steric hindrance.

All three of these methods are limited to arylsilanes and do not proceed in the presence of alkoxysilanes. This rules out their adaptation as activators for 1-hydrosilatrane.

1.7. Direct Reductive Aminations

Amines are ubiquitous to all walks of chemistry, whether it is in nature or in industry.

Therefore, the formation of C-N bonds has wide applicability and development of new synthetic methods to achieve it are of great importance.405-406

Direct reductive amination, or reductive alkylation, is one of the most powerful tools available for chemists to form amines. The premise is simple: an aldehyde or a ketone is condensed with an amine to form an imine or iminium ion in situ, which in the presence of a reducing agent is reduced to give the substituted amine product.407 Direct reductive aminations is a much more attractive synthetic procedure than reductive aminations of imines or iminium ions as it does not require the isolation of said unstable imines or iminium ions. Theoretically, the concept is only limited by the availability of the aldehyde/ketone or amine required, and their subsequent ability to form an imine or iminium ion in situ, making direct reductive amination the most practical, and hence most used, method for amine synthesis.408-409 The choice of reducing agent is central to the method. It must be chemoselective and not reduce the aldehyde or ketone prior to imine/ iminium formation, as this would form alcohols instead (Figure 1.81).410 To avoid limited scopes, it should also not reduce other reducible functionalities that might be present in the system.

71

Figure 1.81. Overview of direct reductive amination and importance of chemoselectivity.

Although the literature is full of examples of direct reductive amination to form secondary amines,408-409 methods for the formation of tertiary amines are much more scarce due to steric hindrance in the formation of enamines/iminium ions.411 Futhermore, the synthesis of aromatic tertiary amines via reductive aminations with arylamines is considered a challenging reaction,412 with only several procedures known.411,413

Alternative methods for C-N bond formation include direct alkylation of amines via substitution reactions, transition metal catalyzed coupling reactions,415-416 and the reduction of nitrogen containing functional groups such as imine, amide, enamide, nitro, and nitrile groups with strong reducing agents and transition metal catalysed hydrogenation/hydride transfer.417-419 Although effective in their way, these methods will not be discussed further in this section.

1.7.1. Common reducing agents for direct reductive amination

1.7.1.1. Sodium Borohydride derivatives

Sodium borohydride is a very effective reducing agent (see 1.5.1.2) which can reduce imines and iminium ions effectively. However, due to sodium borohydrides ability to also reduce aldehydes and ketones, the imine or iminium ion must be pre-formed before the reducing agent can be added.

This would therefore not be called a direct reductive amination, but is a relatively effective method to 72 form amines.408 The sodium borohydride moiety can be modified to make much more chemoselective reducing agents. Derivatives such as Sodium cyanoborohydride and sodium triacetoxyborohydride are the most commonly used reducing agents for direct reductive aminations because of their wide availability, ease of use, and mildness of reaction conditions. Other modifications include the addition of Brønsted or Lewis acids,420-422 using an exchange resin,423 a combination of Zinc and acetic acid,424 magnesium perchlorate,425 zinc chloride,426 or even silica gel (Figure 1.82).427 Although effective in propagating direct reductive aminations, these methods also lead to more complicated work-ups and additional purification steps.

Figure 1.82. Direct reductive aminations with sodium borohydride

1.7.1.1.1. Sodium Cyanoborohydride. Sodium cyanoborohydride is a mild reducing agent. The electron- withdrawing properties of the cyano group decrease the hydridic nature of the borohydride, making it much more chemoselective than sodium borohydride. 73 The cyanoborohydride moiety was first discovered by Wittig in 1951.428 Not long after, it was reported as a poor reducing agent towards carbonyl compounds, only being able to reduce aldehydes.429 However, this low reactivity, and an observed stability in acidic conditions of around pH

3,430 made it an ideal candidate for Borch et al. in their quest to reduce imines in acidic conditions.431

In 1971, Borch et al. introduced sodium cyanoborohydride as a reducing agent for direct reductive aminations.407 A wide range of aromatic and aliphatic ketones and aldehydes were readily reduced with primary and secondary amines, as well as ammonia (Figure 1.83.). The reaction was observed to be pH dependent, with the pH range of 5-7 deemed optimal for direct reductive aminations. Due to the limited solubility of sodium cyanoborohydride, polar solvents like alcohols are required. The sodium counterion can be exchanged for tetrabutylammonium ions, increasing the cyanoborohydride solvent scope to include nonpolar solvents such dichloromethane and benzene.432-433

Figure 1.83. Direct reductive aminations with sodium cyanoborohydride

Due to the sluggishness of direct reductive aminations with sodium cyanoborohydride, several approaches can be taken to facilitate the reaction. Excess amine tends to be used to push the imine/iminium ion equilibrium forward. The presence of a Lewis acids such as TiCl4, Ti(OiPr)4, and 74 ZnCl2 have also been shown to increase the rate of imine formation by coordinating with the oxygen on the carbonyl to make the carbon more electrophilic (Figure 1.84).434-436 The Lewis acid most likely also coordinates with the imine to increase its electrophilicity, and hence reactivity with sodium cyanoborohydride. Molecular sieves,407, 437-438 or other dehydrating agents such as sodium and magnesium sulphate,439-441 increase the rate of iminium ion formation, and hence can increase the rate of reaction.

Figure 1.84. Modifying conditions of sodium cyanoborohydride.

The big downside of using sodium cyanoborohydride is its toxicity.442 The compound itself is toxic, and releases hydrogen cyanide when hydrolysed, making any reaction work up relatively hazardous.

1.7.1.1.2. Sodium Triacetoxyborohydride. Sodium triacetoxyborohydride can be considered a safer alternative to sodium cyanoborohydride.442 Compared to sodium borohydride, the hydridic nature of the triacetoxyborohydride ion is greatly reduced, due to steric bulk and electronic effects caused by the acetoxy groups. Sodium triacetoxyborohydride is an even milder hydride source than sodium cyanoborohydride, unable to reduce ketones (Figure 1.85).443

75

Figure 1.85. Chemoselectivity of sodium triacetoxyborohydride.

The use of sodium triacetoxyborohydride was first eluded to as a reducing agent for direct reductive aminations in 1974, when Gribble et al. noted that sodium borohydride in glacial acetic acid reacted with indole to give N-ethylindoline (Figure 1.86).444 Although the mechanism was unclear at the time, the reactive species for the reductive amination is now known to be triacetoxyborohydride formed in situ. Further development showed that the reaction was not limited to acetic acid, as solid carboxylic acids could be reacted with sodium borohydride in non polar solvents,445-447 and bulky carboxylic acids could provide stereocontrol in diastereoselective reductive aminations.448

Figure 1.86. Reduction noted by Gribble et al.

Due to the low cost of its synthesis, sodium triacetoxyborohydride became commercially available and it was shown to be an outstanding reducing agent for direct reductive aminations of aldehydes and ketones with amines.442,449-450 Aliphatic and aromatic aldehydes, as well as aliphatic ketones, readily undergo reductive aminations with a wide range of amines (even weakly basic arylamines and sulfonamides) (Figure 1.87.).442 Aprotic solvents such as dichloromethane or THF are required, as the presence of methanol creates a more reactive species that reduces carbonyls. 76

Figure 1.87. Direct reductive aminations using sodium triacetoxyborohydride.

Sodium triacetoxyborohydride has some limitations. It readily decomposes in the presence of water, so excess amounts of the reducing agent are needed if substrates in aqueous solutions are used.442 Furthermore, ,β-unsaturated ketones, arylketones such as acetophenone and secondary arylamines undergo direct reductive amination extremely slowly, or not at all.406,451

1.7.1.2. Hantzsch esters

Most reductions in nature occur through enzyme process and hydride reduction cofactors such as NADH and NADPH.452 Hantzsch esters (HEH), also known as 1,4-dihydropyridines, are nicotinamide analogues which, for all intents and purposes, can be considered NADH mimetics (Figure 1.88).453

Hantzsch esters are good hydride donors because of their energetically unfavourable structure. Upon deprotonation and hydride donation, a much more stable aromatic pyridine is formed. 77

Figure 1.88. Hantzsch esters are biomimetics of NADH.

The reduction potential of Hantzsh esters was first shown in 1936, in the reduction of methylene blue.454 Since then they have been widely used as a reducing agent for C=C, C=N, and C=O double bonds.453,455-456 Hantzsch esters offer very mild reaction conditions and are ideally suited for direct reductive aminations as they do not reduce carbonyls without an activator. Although Hantzsch esters were shown to reduce imines in the presence of a Lewis acid in the early 1980s,457 the first direct reductive amination was only reported by Itoh et al. in 2002 (Figure 1.89).458 Catalytic amounts of scandium triflate catalyzed the direct reductive amination of aldehydes and ketones by Hantzsch esters. A follow up study showed that the reaction would exclusively undergo direct reductive

459 amination on aldehydes in the presence of ketones! Other Lewis acids such as ZrCl4, Au(I) complexes, and TMSCl have also been shown to catalyze direct reductive aminations with hantzsch esters.460-462 78

Figure 1.89. Hantzch esters as reducing agents

The first organocatalyst to be used in a direct reductive amination was introduced in 2005.463

List et al. reported a Brønsted acid catalyzed asymmetric direct reductive amination between acetophenone and p-methoxyaniline in high yield (92%) and 88% ee (Figure 1.90). In 2006, MacMillan et al. reported a slightly wider scope, but the reductive aminations were limited to methylketones.464

Around the same time, Menche et al. developed non-enantioselective methods using thiourea as the catalyst.465 All these methods follow a similar pattern of imine activation by hydrogen bond donors, which are subsequently reduced by hydride transfer from the Hantzsch ester. These methods have been further developed to include a wide scope or aliphatic and aromatic ketones, as well as a wide variety of primary and secondary amines.466-473

79

Figure 1.90. Asymmetric direct reductive amination using hanztch ester and chiral phosphoric

acid derivative

More recently, Hantzsch ester direct reductive aminations have been developed which require no catalysts.474-475 Aromatic aldehydes in the presence of ammonium formate and HEH, formed secondary amines under relatively mild conditions (Figure 1.91.).474 A large combination of aromatic and aliphatic ketones and aldehydes were also reacted with aromatic and aliphatic primary and secondary amines were condensed and reduced with HEH in the absence of solvent or catalyst, in exceptionally high yields (lowest yield of 75%).475

Figure 1.91. Direct reductive amination with ammonium salts and hanztch ester.

80 1.7.2. Organosilicon Hydrides

As has already been mentioned previously, organosilicon hydrides are relatively stable and hence poor reducing agents in the absence of an activator (see 1.5.2). This makes organosilicon hydride reactivity tuneable, and hence an ideal reducing agent for direct reductive aminations. By choosing a

“weak” activator, the organosilane only reacts with the highly reactive iminium ion, whilst leaving other reactive functional groups such as aldehydes untouched. Furthermore, by using a Brønsted or

Lewis acid catalyst to activate the organosilane, one gains the advantage of also accelerating the formation of the imine or iminium ion. The acid can coordinate with the oxygen of the carbonyl, increasing the electrophilicity of the carbonyl carbon, making it more susceptible to nucleophilic attack by the amine. In the case of imine formation with primary amines, the acid can also coordinate with the imine to form more reactive quasi-iminium ions which are then more readily reduced (Figure

1.92).

Figure 1.92. Lewis acid activation of carbonyl and imine.

Although organosilicon hydrides are widely used in reduction chemistry, their use in direct reductive aminations has been less explored.417,476 Practically all known methods have a Brønsted or

Lewis acid as an activator/catalyst. The most commonly used organosilanes are triethylsilane,413,477-487 and PMHS,145,411,488-495 although phenylsilane,451,496-500 TMDS (tetramethydisiloxane),501 and trichlorosilane,229,238,502-503 have also been shown to be effective. 81 The first example of direct reductive amination with an organosilicon hydride was achieved in

1975, when amides were methylated by using formaldehyde. The reagents were condensed together to form methylol intermediates, which were then reduced with triethylsilane in excess trifluoroacetic acid.477 The usefulness of this method was exploited in 1994 by scientists at Genentech, using triethylsilane as the hydride source and 20mol% trifluoroacetic acid as catalyst (Figure 1.93).478

Figure 1.93. First practical use of lewis acid catalysed reductive amination with silane.

This method arose from necessity, as no other reducing agent would give the correct product.

The reactivity of TESH/TFA was further developed in subsequent years as an efficient system with aldehydes with primary/secondary amines, and amides, which in turn gave an efficient synthesis of primary amines in the form of alkylation of Boc- protected amines followed by removal of Boc- group

(Figure 1.94).479-480 More recently, it was shown the TESH could be replaced with PMHS in the presence of excess amounts of TFA.488 Although the system is not ideal due to the requirement of excess TFA, the system is overall still beneficial compared to using TESH, as PMHS has a much lower cost and is easier to handle due to its stability and non-toxicity.145 A significant drawback of using this system is the high acidity of TFA, making it incompatible with acid labile functional groups.479 82

Figure 1.94. Further application of silane/TFA system

Apart from TFA, there are only a few other known systems for direct reductive amination in the absence of a metal activator/catalyst (Figure 1.95). Iodine has been shown to activate TESH in reductive amination of acetals (masked aldehydes and ketones per se).487 A wider applicability might be limited as the mechanism most likely proceeds via the formation of HI, putting acid labile functional groups at risk. Another system includes the use of trichlorosilane with an amide activator. The first example of this was developed in 1996, when Cl3SiH was discovered to be an extremely versatile reducing agent in DMF, including in direct reductive amination.229 In the presence of chiral amides, this method has been extensively developed in the asymmetric reduction of chiral imines to their corresponding amines,238,502-503 but it’s use in direct reductive aminations has barely been exploited.502 83

Figure 1.95. Various silanes for direct reductive aminations.

490 451,496-499 412 411 491 Metal Lewis acid activators such as Ti(iOPr)4, Bu2SnCl2, Sn(OTf), SnCl2, AlCl3,

481 413,482 476 Ga(OTf)3, InCl3, and BiCl3, have all shown to effectively activate direct reductive aminations in the presence of organosilanes (Figure 1.96). However, all these systems have drawbacks: Ti(IV),

Ga(III) and Al(III) activators do not tolerate the presence of water;490 Sn and Bi activators are highly toxic;411,476, 482,499 In(III) is toxic, expensive, and have been shown to be teratogenic.504 84

Figure 1.96. Various metal lewis acid catalysed direct reductive aminations using silanes.

Transition metal catalysts have also been used for direct reductive amination (Figure 1.97).417

In 2005, iridium compound [IrCl(cod)2] was shown to effectively catalyse the reductive aminations of

483 aldehydes with secondary amines to form tertiary amines in the presence of TESH. IrCl3 was shown to be just as effective when combined with PMHS.492 A setback to the system was the intolerance of other reducible functional groups. Mechanistic studies showed that the catalytically active species was [Ir-H], implying a metal hydride mechanism (see 1.5.2.1.1). More functional group tolerant systems have been

484 500 developed using Pd/C with TESH, and MoO2Cl2 in combination with PhSiH3. Oxo-rhenium(VII) 85 catalyst, ReO7, has also been shown to catalyse the reductive amination of aldehydes and aliphatic

485-486 ketones with electron deficient amines. For ketones, the system required NaPF6, potentially suggesting a cationic oxo-rhenium active species, although the presence of anionic fluorides could also be involved in activating the triethylsilane via a hypervalent silicon species.

Figure 1.97. Transition metal catalysed direct reductive aminations using silanes.

More environmentally friendly and economical transition metal catalysts have also been

493 494 developed. As Lewis acids, Zn(OTf)2, and FeCl3, have been combined with PMHS to form primary and secondary amines in high yields and with great chemoselectivity. P-N bidentate iron complexes,495

501 and Ni(OAc)2, have also been applied successfully with organosilicon hydrides in direct reductive amination of aldehydes and ketones (Figure 1.98).

86

Figure 1.98. Direct reductive amination with silane catalysed by P-N bidentate iron complex.

Finally, a system worth mentioning is that with aminohydrodimethylsilane (Figure 1.99.).505

This method is unique as the amine is combined with the organosilane. In the presence of TiCl4 (Lewis acid), the system undergoes direct reductive amination of aldehydes in high yields. Although very atom economical, the silane reagent is relatively unstable and tedious to synthesize, and hence the method is currently just a chemical curiosity.

Figure 1.99. Direct reductive amination using aminohydrodimethylsilane.

Although organosilicon hydrides are effective reducing agents in direct reductive aminations, a system that does not require further additives would be extremely beneficial.

87 1.8. Meta-directed electrophilic substitution

1.8.1. Electrophilic Aromatic Substitution

Aromatic rings are ubiquitous in all aspects of organic chemistry.506 The complexity of molecules can be readily enhanced by adding substituents to an aromatic ring, which can be achieved with electrophilic aromatic substitution (EAS).

Electrophilic aromatic substitution is pretty much summarized by its name. An aromatic ring replaces a substituent on one of the carbons in the ring (usually a H) with an electrophile, to yield a modified product (Figure 1.100). But what makes the aromatic ring susceptible to substitution reactions, as opposed to, say, addition reactions? In fact, what is an aromatic ring?

Figure 1.100. Electrophilic aromatic substitution.

The term “aromatic” originates from 1855, when August Wilhelm Hofmann classified several phenyl containing compounds by their aroma, by the amateur chemists’ favorite chemical characterization methods: olifactoscopy (smelling it, in layman terms).507 The descriptor stuck, and was later used to describe the class of molecules for their electronic properties.

In 1865, after having a revelation whilst daydreaming about an ouroboros, Friedrich August

Kekule first proposed the structure of cyclohexatriene, also known as benzene, suggesting that it existed as two isomers of three C=C double bonds connected by three single C-C bonds (Figure

1.101).508 The structure was widely accepted as it explained the observed isomeric relationships in reactions with aromatic compounds. However, the puzzling stability of benzene towards addition 88 reactions compared to other non-aromatic unsaturated compounds was not explained fully until 1890, when Henry Edward Armstrong suggested that the ring had a stabilizing inner cycle of “affinity” which was disrupted on addition reactions.509 What is remarkable here is that Armstrong was suggesting conjugation between the double bonds was creating stabilization a decade before J. J. Thompson had even discovered the electron!510 Due to Armstrongs terminology of “affinity” instead of electrons, he has been usurped by Sir Robert Robinson as the discoverer of electron delocalization and the exceptional stability of benzene rings.511 Quantum mechanical explanations for the stability were introduced in 1931 by Erich Hückel, who also separated the bonding into σ and pi orbitals, which is used to justify and reactivity to this day.512

Figure 1.101. Relationship between an ouroboros and benzene.

1.8.1.1. Mechanism of electrophilic aromatic substitution

The benzene ring is very stable due to the delocalization of its electrons throughout the ring by conjugation, or resonance. These electrons can be depicted as being located in the pi-orbitals, in an electron cloud above the plane of the planar cycle. This relatively high electron density allows for the benzene to act as a nucleophile towards electrophiles (Figure 1.102). However, by acting as a nucleophile and donating electrons, the stabilizing effect of the aromaticity is lost, as the electrons are not fully conjugated in the cycle. So unlike with a regular addition reaction across a double bond, where a nucleophile reacts with the formed carbocation, it is more energetically favored for the 89 benzene ring to deprotonate, reforming a double bond and regaining aromaticity. Therefore, the overall electrophilic aromatic substitution can be seen as combination of addition and elimination reactions.

Figure 1.102. Mechanism for electrophilic aromatic substitution.

1.8.1.2. Substituent effects on electrophilic aromatic substitution

Due to the symmetry of benzene, all the carbons are the same, and hence a substitution on any of the carbons give the same product. However, on addition of a substituent to the ring, things become a bit more complex. Obviously, the positions around the substituted benzene ring are not equal any more, and can now be assigned as positions with respect to the substituent: the position of the substituent is referred to as the ipso- position, 1 carbon away is referred to as ortho-, 2 carbons away as meta- and 3 carbons away as para- (Figure 1.103). The substituent can also have different effects on the reactivity of the ring. Substituent effects on electrophilic aromatic substitution has been widely studied since the ground-breaking work by Friedel and Crafts in the 1870s.513 The substituents can be classified into two types: electron donating groups and electron withdrawing groups.

90

Figure 1.103. Relative positions on an monosubstituted aromatic ring.

As the name goes, electron donating groups are substituents that can donate electrons to the aromatic ring. This can either be via an available lone pair of electrons or hyperconjugation. This donation of electrons increase the electron density of the aromatic ring, making the system more nucleophilic. This in turn leads to an increase in the rate of electrophilic aromatic substitution compared to unsubstituted benzene. Electron donating groups are also ortho- or para- directing, meaning that electrophilic substitution is favored on the ortho and the para position. This is consistent with the observation that resonated negative charges reside on the ortho- and para- positions, and hence increase the negative charge relatively more on those positions (Figure 1.104). Alternatively, one can think of these electron-donating groups as stabilizing towards the carbocation formed on the ipso- or meta- positions (Figrue 1.105).

Figure 1.104. Resonance of electron donation.

91

Figure 1.105. Stabilization of the carbocation.

Electron withdrawing groups decrease electron density from the aromatic ring. Therefore, these substituents make the aromatic ring much less nucleophilic, and hence the rate of electrophilic substitution is lower than on an unsubstituted benzene ring. These substituents tend to be meta- directing, but this is because they disfavor substitution on the ortho- and para- positions by decreasing the electron density at those positions. Alternatively, they destabilize a positive charge on the ipso- or meta- position (Figrue 1.106). Technically, the meta position is not favored for substitution, it is just less disfavored (Figure 1.107).

Figure 1.106. Resonance of electron withdrawal. 92

Figure 1.107. Destabilization of the carbocation.

Of course, some substituents such as the halogens can have contradicting effects. For example, due to their high electronegativity, the aromatic ring is less nucleophilic and hence the rate of EAS is slower than that of unsubstituted benzene. Therefore, halogens are considered inductively electron withdrawing (Figure 1.108). However, due to their available electron lone pairs, they can donate electrons to stabilize the carbocation formed during EAS, making them ortho-/para- directing.

Figure 1.108. Inductively electron withdrawing. 93

These patterns are very predictable, to the point they are considered rules, and hence are very useful when designing synthetic pathways. However, it also makes it a great challenge to make the disfavored products.

1.8.2. Meta-substitution

As described in the previous section, in the presence of a strongly electron-withdrawing substituent such as a nitro group, electrophilic aromatic substitution is favoured on the meta-position.

However, meta substitution in the presence of electron donating groups is extremely challenging.514

Only a handful of methods have been developed to achieve this,515-518 all of which consist of multiple chemical transformations (including a metalation step), and none involve a single step electrophilic aromatic substitution.

1.8.2.1. Half-sandwich compounds

Aromatic rings can act as polyhapto ligands, coordinating with metal centers to form half- sandwich compounds. As the electrons of the aromatic ring are donating towards the metal center, the ring itself becomes electron poor. This system also becomes relatively more acidic as, on deprotonation with a strong base, the anion can be further stabilized by the electrophilic metal center (Figure

1.109).519 This anion can then act as a nucleophile in order to obtain substitution reaction products.

Figure 1.109. Deprotonation of half-sandwich compound.

94 In 1980, Card and Trahanovsky observed that a N,N-dimethylaniline chromium tricarbonyl complex could be deprotonated with butyl lithium and reacted with alkylhalides, providing a range of substitution patterns where the meta substitution was slightly favored.520 Due to the electron donating properties of nitrogen, this was seen as a potentially useful method for meta substitution on electron rich aromatic rings (Figure 1.110). Oishi et al. further developed this method, by showing that protecting the aniline with bulky substituents would block any substitution at the ortho positions, and favor the meta positons over the para position, including 100% meta selectivity with triphenylamine.521-

523 Interestingly, when t-butyldimethylsilyl group was used as a protecting group on the aniline, the selectivity for meta substitution seemed to be higher in the presence of a carbonyl electrophile than other electrophiles (meta/para 98:2 PhCHO vs 86:14 MeI). This same group also showed that tertbutyldimethylsiloxyphenyl chromium tricarbonyl would undergo the same reaction, resulting exclusively in meta substitution and brook rearrangement product (indicating deprotonation on the ortho deprotonation) in a ratio of 35:40. When a bulkier tertbutyldiphenylsilyl group was used, the ortho deprotonation was surpressed, yielding a ratio of 19:48 (Figure 1.111.). More recently, this method has also been extended to thiolated ferrocene, with great meta selectivity.524

95

Figure 1.110. meta-Substitution on aniline derivatives.

Figure 1.111. meta-Substitution on silylated phenol derivatives.

Although this method is an effective way to get meta substitution on anilines and phenols, it involves multiple steps to form the sandwich compounds, followed by cleaving off the metal after substitution, making it very wasteful and tedious procedure.

96 1.8.2.2. “Traceless” directing groups

This method is conceptually different to the other methods, as it does not directly activate the meta-position. The strategy is quite simple: add a removable temporary substituent onto the ortho position, which then directs lithiation ortho to itself (meta with respect to the original substituent).

Once substitution is achieved, the temporary group is removed, leaving behind a meta-substituted product (Figure 1.112). Two things are required for this system to work: 1) the substituent must be easily added or removed from the aromatic ring, and 2) the substituent must direct lithiation exclusively ortho to itself.

Figure 1.112. Overall mechanism for meta-substitution via traceless directing group.

This strategy was first implemented in 2005 by Weissensteiner et al., when they realized that two sequential ortho lithiation reactions on a substituted ferrocene could introduce a halogen onto both the ortho and meta position, followed by dehalogenation of the ortho halogen, giving the meta substituted product.525 In 2006 Jaouen et al., showed the same reaction sequence could be achieved with an aryl sulfoxide moiety, adding iodide exclusively onto the meta-position of the substituted ferrocene.526 Sulfoxides were ideal as they are known to be strongly ortho-lithiating,527 and are easily added or removed from an aromatic ring.528 This method was further expanded in 2008 by Brown et al., when a larger array of electrophiles were successfully added to the meta- position of anisole using an alkyl sulfoxide “ghost” substituent (Figure 1.113).529 97

Figure 1.113. meta-Substitution via traceless directing groups.

More recently, in 2011, Larossa et al. developed a relay strategy using CO2 as the traceless directing group for meta-arylation of monosubstituted arenes,530 followed by a further study extending

531 this method to unsubstituted phenols (Figure 1.114). CO2 was the perfect reagent for this sequence, as phenols are known to undergo carboxylation exclusively on the ortho position,532 and the same conditions that catalyzed arylation with a palladium catalyst also favored decarboxylation.533

Furthermore, this method introduced the possibility of using salicylic acid, and all its derivatives, as the starting material, avoiding the carboxylation step.534

98

Figure 1.114. Carbon dioxide as a traceless directing group on phenols.

Downsides to this method include the difficulty of inserting a temporary directing group to sterically hindered ortho-positions and, as with all other protecting groups, removal of the directing group could lead to the loss of wanted functionalities (ie loss of a wanted carboxylic acid on decarboxylation).

1.8.2.3. Directing scaffolds

Directing scaffold are removable structural moieties with coordinating functional groups that direct transition metal catalysts towards specific C-H bonds to gain regioselective activation at said site, overriding any intrinsic electronic or steric factors that would otherwise direct the reactivity elsewhere (Figure 1.115).

Figure 1.115. meta-Substitution via directing scaffold.

99 This method has been extensively exploited for ortho-selective reactions,535-537 directing Pd,538-

539 Rh,540-541 and Ru542 reagents exclusively to the ortho position in cyclic transition states, with a wide range of substituents.535-542 Due to the difficulty of forming rigid macrocyclic system larger than 7- membered rings makes it difficult to activate positions further than the ortho- position. However, in

2012, Yu et al. introduced elaborate scaffolds which contained a weakly coordinating nitrile group which chelated with the metal catalysts in an “end on” fashion, which extended the metals position closer to the meta- C-H (Figure 1.116).543-544

Figure 1.116. C-C bond formation at meta-position via “end-on” directing. 100

These spacing groups were conjugates with toluene derivatives, and underwent Heck coupling with very high meta-selectivity, after which the directing scaffold could be easily removed by hydrogenation. Remarkably, this method worked even with bulky ortho substituents present. Soon after, several other scaffolds were introduced. A silicon tethered scaffold was extremely efficient as it could be easily added and removed from any benzylic alcohol derivatives.545 The extended Si-O and Si-

C bonds improved the spatial orientation of the nitrile towards the meta C-H. A sulfonyl based tether that linked to indoline derivatives gave excellent meta selectivity. The sulfonamide linkage not only directed meta C-H activation, but also sequestered the nitrogen lone pair, disfavoring its intrinsic ortho-/para- directing electronic properties.546 This scaffold gave excellent meta-selectivity with olefination, arylation, and even acetoxylation on indoline derivatives. Adding a fluoride group on to a scaffold was shown to have a significant effect on meta-selectivity when olefinating tetrahydroquinoline derivatives.547 This was most likely due to an increase electron withdrawing effect of the scaffold on the amine, but also due to significant conformational change caused by the electronegativity of the fluorine atom.548 A diphenylamine backbone using an acetyl linker was also successfully used with phenols, yielding olefinated and arylated products with excellent meta- selectivity (Figure 1.117).549-550 101

Figure 1.117. Various meta-directed reactions via elaborate scaffolds. 102 1.8.2.4. The Gaunt Anomaly

In 2009, Gaunt et al. reported an unexpected result. The amido group, a known ortho-/para- directing group in electrophilic aromatic substitution and a strong ortho-director in C-H activation via cyclometallation, was shown to direct arylation on the meta-position in the presence of hypervalent iodide and a copper catalyst.551 The reaction was most efficient with acetyl and pyvaloyl groups attached to the amine, although carbamate and urea moieties also seemed to work albeit with lower yields. Meta-selectivity was extremely high except in the presence of strongly electron donating groups such as methoxide, which would override the selectivity. Even diarylation of the arylamide would occur exclusively at the meta-position as long as the position was available. This method was further extended to -aryl carbonyl compounds including esters, ketones and amides (Fig. 1.118.).552

Figure 1.118. meta-Arylations on electron rich aromatic rings.

103 The mechanism is not fully understood. A DFT study by Wu et al. suggested that the copper is in fact directed to the ortho position in an electrophilic attack, followed by a Heck-like transition state to complete arylation on the meta position (Figure 1.119),553 although further mechanistic studies are still required.

Figure 1.119. Proposed mechanism for Gaunts meta-arylation.

Interestingly, although this system has been reported to be effective with amides and -aryl carbonyl systems, no reports meta-selective substitution on O-aryl derivatives have been reported.

1.8.3. O-Aryl Carbamates

Carbamates are a carbonyl functional group with both an amide linkage and an ester linkage.

As the name suggests, O-aryl carbamates have an aromatic moiety on the ester side (Figure 1.120). 104 They are especially important in the pharmaceutical and agrochemical industries due to their pharmacological/toxic properties, mostly as acetylcholinesterase inhibitors.

Figure 1.120. General structure of O-aryl carbamate.

The enzyme acetylcholinesterase is an important enzyme in the parasympathetic nervous system, as it hydrolyzes the neurotransmitter acetylcholine (Figure 1.121).554 By hydrolyzing the neurotransmitter, it terminates the synaptic transmission, and hence the nerve signal.555 In the absence of acetylcholinesterase, once a nerve signal activates a synapse the signal would not stop. Due to the resemblance of carbamates to acetylcholine, carbamates such as O-aryl carbamates can act as reversible acetylcholinesterase inhibitors. The effect of this inhibition greatly varies with the structure or the O-aryl carbamate.

In the pharmaceutical industry, O-aryl carbamates have been used as acetylcholinesterase inhibitors to treat debilitating neurodegenerative diseases. Examples such as Neostigmine are effective to treat myasthenia gravis,556 whilst Rivastigmine is used to treat dementia due to Parkinson’s or

Alzheimer’s disease.557-559 Both drugs were developed as structural analogues of the natural alkaloid

Physostigmine, an O-aryl carbamate found in Calabar beans, which is also widely used as an antidote for anticholinergics (Figure 1.122.).560-563 Prior to their discovery by western missionaries in 1846, the pharmacological properties of Calabar beans were already being exploited by the Efik people of southern Nigeria in the form of a poison, as a test for witchcraft (if you died from consuming a bean, you had been a witch).564 The physiological effects and potential as a medicine of Calabar beans were suggested as early as 1867.565 105

Figure 1.122. O-Aryl carbamates with medicinal properties.

The toxicity of O-aryl carbamates has not gone unnoticed, and has been put to good used by the agrochemical industry in the form of insecticides, and herbicides. The development of carbamate insecticides was hailed as major breakthrough in pest control as it does not persist in the environment for long periods of time due to rapid hydrolysis of the carbamate moiety.566 It is also extremely toxic towards insects due to a high affinity towards insectoid acetylcholinesterase enzymes, whilst being only mildly toxic and rapidly metabolized by mammals and other vertebrates.567 Variations in the substitution pattern around the carbamate directly affect the biological activity of the pesticide, as well as the target organism (Figure 1.123).568 O-aryl carbamates with a small substituent, such as a methyl, on the amine are insecticidal, whilst an aromatic group on the amine make it herbicidal.569

Figure 1.123. Substitution pattern determines biological activity.

106 True to human nature, O-aryl carbamates have also been tested as chemical warfare agents.570

Although most insecticides are relatively non toxic to humans, the most potent ones, such as

Carbofuran, can be a serious health hazard to human.571 Even more potent O-aryl carbamates, such as

EA3990 and T-1123, were even tested as nerve agents (Figure 1.124).572 Due to the cationic quarternery ammonium group present in these molecules, they were inefficient at crossing the blood-brain barrier, and were deemed unweaponizable due to their inherent instability outside of crystalline form.570

Figure 1.124. O-Aryl carbamates as potential chemical warfare agents.

O-Aryl carbamates are relatively straightforward to synthesize, but require hazardous intermediates. The most effective ways are to react an isocyanate or chloroformamide, often formed in situ by reacting the corresponding amine with phosgene, with the aromatic alcohol (Figure 1.125).

107

Figure 1.125. O-Aryl carbamate synthesis via chloroformamide or isocyanate.

Alternatively, a chloroformate can be synthesized in situ by reacting the aromatic alcohol with phosgene, followed by condensation with an amine (Figure 1.126).

Figure 1.126. O-Aryl carbamate synthesis via chloroformate.

Chemicals such as phosgene and isocyanates are extremely toxic; phosgene being historically associated with chemical warfare,573 and methylisocyanate being responsible for the worst industrial disaster in history. In 1984, over half a million people were affected by a methylisocyanate leak in

Bhopal, India.574 Due to the toxicity of these chemicals, safer methods of synthesizing O-aryl carbamates are in high demand.

108 1.8.4. Stereoelectronic Chameleons

Although the title term sounds like an obscure electro music band name, it actually something even cooler. Coined by Vatsadze & Alabugin, this term refers to functional groups with electron donating or electron accepting properties than can change to the opposite properties with a change in position or spatial orientation with respect to the rest of the molecule.575 The utility of this concept is emphasized when thinking about the importance of known “umpolung” chemistry - when the polarity of a reactant is switched so that new chemical transformations can be achieved – which usually requires chemical changes, whether it be sequestering electrons with a proton or Lewis acid,576 to full chemical transformations such as oxidation or reduction.577 By controlling the spatial orientation of a functional group to change the expected reactivity, one can avoid surplus chemical transformations required in common umpolung chemistry.

Although various forms of stereoelectronic chameleons exist, the most common ones can be grouped into two categories: conformational chameleons and translocational chameleons. In conformational chameleons, electron donors are transformed into acceptors by rotational change.

Examples of this include amines,578-580 amides,581-586 carbenes,587-588 and ethers.589-590 In translocational chameleons, electron donors become acceptors by moving a substituent one bond away from the reference functionality. We have already previously encountered silicon as an example of a translocational chameleon, in the form of the β-silicon effect (see 1.3.4.1).

When discussing electrophilic aromatic substitution, the methoxy group is a quintessential electron donating group. The oxygen lone pair donates its electrons into the aromatic ring, increasing its electron density, and hence increasing the rings nucleophilicity to the point that EAS occurs x109 faster than with unsubstituted benzene.506 Unsurprisingly, the methoxy group is also exclusively ortho/para- directing. As expected, a lone pair on oxygen is aligned with the aromatic ring pi-system for maximum alignment, orienting the methoxy group planar to the aromatic ring (Figure 1.127).591

109

Figure 1.127. Electron donation by methoxy group.

However, this lone-pair-pi interaction can be disrupted in several different ways, including by decreasing lone pair availability, or increasing the electron density of the aromatic ring. For example, if the methyl group is changed into a trifluoromethyl group, the trifluoromethoxy group orients itself orthogonal to the aromatic ring.592 This is due to the lone pair no longer being able to interact with the aromatic pi-system due to strongly electron withdrawing properties of the trifluoromethyl group, as well as an increase in the electrophilicity of the σ* orbital favoring an interaction with the pi-system

(Figure 1.128).

Figure 1.128. Electronwithdrawing effect caused by σ* interaction.

Another example is observed in p-methoxy benzylic anions, where the methoxy group orients itself perpendicular to the aromatic ring. This rotation allows for stabilization of the anion by hyperconjugation, by aligning the σ* orbital with the pi-system (Figure 1.129). This inversion in electronic character has been shown to have a significant effect on the regioselectivity of an enediyne cyclization, favoring a transition state with a negative charge para to the methoxy group (Figure

1.130).589 110

Figure 1.129. Differences in stabilization of benzylic cation and anion.

Figure 1.130. Regioselectivity of enediyne cyclization.

By extrapolating from these concepts, if the oxygen lone-pair were to be physically rotated out of the plane of the ring, aligning the σ* with the pi-system, the system could be more susceptible to act as an electron withdrawing group. Our lab has shown that by varying the steric bulk of the substituent attached to oxygen, one can favor the perpendicular conformation.594 Computational studies of the relative energies of different torsion angles between the plane of the ring and an OR group showed that when R is a bulky triisopropylsilyl group, a perpendicular angle is much more favored compared to a tbutyl or methyl group (Figure 1.131). Our study also indicated an increase in substituent bulkiness led to an increase in acidity of substituted silyloxybenzoic acids. This would be consistent with an increase in the electron withdrawing properties of the oxygen (or a decrease in the electron donating properties). (For further discussion, see chapter 5) 111

Figure 1.131. Relationship between relative energy and torsion angle.

As an antithesis to this concept remains the fact that even though a methoxy group might favor a perpendicular conformation in the presence of a benzylic anion to maximize hyperconjugation, overall it is still destabilizing due to net electron donation. This is due to the oxygen having two lone pairs, and it is impossible to simultaneously misalign both from the pi-system.595 When one lone pair is orthogonal to the pi-system, the other can still contribute in donating electrons (Figure 1.132). Adding the potential of hyperconjugation of the Si-C bond makes this a fool’s errand.

Figure 1.132. Alignment of p-orbitals through complete rotation. 112

CHAPTER 2

REDUCTION OF KETONES USING 1-HYDROSILATRANE

*This chapter is adapted in part from our publication.148

2.1. Overview

1-Hydrosilatrane had previously been shown to reduce aldehydes in the presence of a Lewis base, so the method was further developed to reduce ketones. After optimizing conditions and identifying potassium tert-butoxide as the ideal activator, a relatively broad scope of aromatic and aliphatic ketones were reduced. Due to the combined bulkiness of 1-hydrosilatrane and the activator, high diastereoselectivity was observed in the reduction of menthone, a sterically hindered chiral ketone.

2.2. Introduction

The reduction of carbonyl groups is one of the most significant chemical transformations in chemistry, giving access to a plethora of products from simple starting materials.149-152 The development of chiral reducing agents has given access to asymmetric products,149 including the crucially important optically pure secondary alcohols, from prochiral ketones.231

Organosilicon hydrides, simply referred to as silanes, can act as hydride sources. Unlike borohydrides and aluminohydrides, however, silanes do not tend to directly react with weak electrophiles such as ketones and aldehydes unless the electrophilicity of the carbon center is enhanced.191 This can be achieved by adding a Lewis acid that can coordinate with the carbonyl oxygen.330,355,386 Alternatively, the Lewis acid can activate the silicon hydride bond, making the hydride much more nucleophilic.[196,596-597] In a related approach, the silicon itself can be made more Lewis acidic by adding a Lewis base whose affinity for silicon is high, such as a fluoride,54-55,396,598 or an oxide

113 anion.59,146,389,393,395 This results in a hypervalent pentacoordinate hydrosilanide anion, which can form a complex with the carbonyl oxygen and donate its hydride to the electrophilic carbon center. The increased hydride donating ability of hypervalent silicon is well known,394 and has been studied and exploited in an array of chemical transformations.38,42,599

Currently the most common silane to be used as a reducing agent is polymethylhydrosiloxane,

PMHS, due to its low toxicity, relatively high stability, and low cost.[145] However, mechanistic studies have suggested that it forms the much more volatile and dangerous MeSiH3 in situ as the active

146 species. A similar disproportionation is known to occur with (EtO)3SiH to form SiH4, which is extremely pyrophoric;147 this could create complications for large scale industrial applications.

Silatranes are caged structures in which the nitrogen atom donates its lone pair of electrons to the silicon, potentially forming a pentacoordinate silicon.94,600 Since their discovery in the 1960s,101 they have been extensively studied for myriad uses.98,106,601,602 1-Hydrosilatrane (Figure 1.27) is a promising reducing agent due to its pentacoordinate silicon atom and its relatively high stability with respect to other silanes.118,603 It is air and moisture stable, easy to handle, and cheaply synthesized from boratrane.603

Although 1-arylsilatranes are known to be toxic,95 having been commercialized as zooicides111,112 and even being portrayed as poison in movies,133 1-hydrosilatrane has a much better safety profile: the hydride derivative possesses an intraperitoneal (IP) LD50 of 100 mg/kg while the

113,132 dangerous aryl-substituted version has an IP LD50 of 0.33 mg/kg. Interestingly, 1-alkyl and 1-

95 alkoxysilatranes (with IP LD50s of 3000 and 2100 mg/kg, respectively) are practically non-toxic, and actually have pharmacological properties,109,604 and even have beneficial effects when fed to livestock.605

The application of 1-hydrosilatrane (1) as a reducing agent was published in 1976 by Eaborn et al., who reported the reduction of both acetone and 4-hydroxybenzaldehyde without an activator.127

Due to the narrow scope of Eaborn's experiments, further probing of this type of reactivity was undertaken in our lab. We previously reported the reduction of aldehydes using 1 in the presence of a

114 Lewis base activator.128 Herein we discuss the activation of 1-hydrosilatrane (1) with a Lewis base to reduce ketones in an operationally simple manner, as well as scope and stereoselectivity of the reaction.

2.3. Development of Methodology

2.3.1. Optimization

Acetophenone (2a) was reduced in N,N-dimethylformamide (DMF) at room temperature within

70 minutes using 1.1 equivalents of 1-hydrosilatrane in the presence of 1 equivalent of potassium tert- butoxide, giving 94% conversion to 1-phenylethanol (3a) (Table 2.1., Entry 1). Tests of different solvents (Table 2.1., Entries 2-4) indicated that the more polar the solvent, the greater the yield of alcohol from ketone. This is likely due to the fact that 1 is more soluble in polar solvents.

Substitution of sodium hydroxide for tert-butoxide (Table 2.1., Entry 5) induced reduction of acetophenone (2a), but with low conversion. Excess amounts of sodium hydroxide in optimized conditions gave higher yields, but these still were not as good as with tert-butoxide (see Appendix A).

Milder Lewis bases (Table 2.1., Entries 6-7) gave no conversion, indicating the need of a strong base to activate 1. Lowering the amount of tert-butoxide to 0.5 equivalents gave lower yields (Table 2.1.,

Entry 8). When 2-methoxyacetophenone (2b) was treated with 1 and 0.5 equivalents of tert-butoxide for 48 h, the yield of alcohol 3b was greater than 99%, indicating that in this case the activator acted catalytically (Table 2.1., Entry 9).

115 Table 2.1. Optimization of reaction.

ENTRY ACTIVATOR (EQ) EQUIVALENTS OF 1 SOLVENT TIME (MIN) YIELD (%)

1 tBuOK(1) 1.1 DMF 40 94

2 tBuOK(1) 1.1 DCM 40 81

3 tBuOK(1) 1.1 MeCN 40 74

4 tBuOK(1) 1.1 THF 40 15

5 NaOH(1) 1.5 DMF 70 22

6 K2CO3(1) 1.5 DMF 70 0

7 TEA (1) 1.5 DMF 70 0

8 tBuOK(0.5) 1.1 DMF 70 20

9[A] TBUOK(0.5) 1.1 DMF 2880 >99

[a] The ketone reduced in this reaction was 2-methoxyacetophenone (2b).

2.3.2. Scope of the Reaction

The scope of this reaction is broad (Figure 2.1.). Ketones can be reduced with good to excellent yields whether they are bearing electron donating groups such as methoxy, allyloxy, and phenyl as in 4-8, inductively electron withdrawing groups such as halides as in 9-10, and strong electron withdrawing groups such as nitro groups as in 11. Potentially reactive nitro (11) and allyl (7) substituents were tolerated well by the system; a trial reaction with a single α,β-unsaturated carbonyl

(chalcone) unfortunately yielded an inseparable mixture of products. Substitution at the α position is well tolerated as seen in 12-14, even when the substituent is an arene as in 15-18. The system is not limited to phenylketones, as can be seen with the reduction of cyclohexanone (19), heptanone (20),

116 and octanone (21). The isolated yields for the aliphatic alcohols may be lower due to their increased water solubility and hence lower recovery during work up.

The system appears to be limited by steric effects, as can be seen by the inability of 1- hydrosilatrane to reduce the sterically hindered carbonyl in camphor (22). However, the bulk of silatrane served useful in the reduction (-)-menthone (24), which proved to be diastereoselective: the product is almost exclusively (+)-neomenthol (23).

117

Figure 2.1. Scope of the reaction.

118

2.3.3. Diastereoselectivity

Reagents with such high selectivity for a single diastereomer in the reduction of (-)-menthone

24 are scarce, and of those, few favor the thermodynamically less stable (+)-neomenthol (23) (Table

2.2.). Commonly used commercially available L-selectride (Table 2, Entry 2) provides (+)-neomenthol but also forms a significant amount of the undesired side product (+)-isoneomenthol. Unlike reductions using certain bulky reducing agents where the diastereoselectivity is solvent dependent,606 we do not see a significant difference in our selectivity when the solvent is changed from a polar solvent, DMF

(Table 2, Entry 7), to a nonpolar solvent such as toluene (Table 2, Entry 8). This is likely due to the bulk of the 1-hydrosilatrane 1, which can only approach the (-)-menthone 24 from the less sterically hindered face in an equatorial attack (Figure 2.2.) regardless of choice of solvent.

Table 2.2. Stereoselectivity in the reduction of (-)-menthone.

ENTRY REDUCING AGENT 25:23 REFERENCE

1 NaBH4 35:65 607

2 L-selectride 0:85[a] 607

3 LiAlH4 72:28 608

4 Al(iPrO)(iBu)2H 1:99 606

5 PMHS/TBAF/Pcy 40:60 609

6 Pt/C.H2 19:81 610

7 1-Hydrosilatrane/tBuOK [b] 3:97

8 1-HYDROSILATRANE/TBUOK [C] 1:99

[a] 15% iso-neomenthol via racemization.[b] DMF as solvent.[c] Toluene as solvent.

119

Figure 2.2. Steric hindrance on (-)-menthone.

2.3.4. Mechanistic Considerations

This stereoselectivity of the reduction of menthone 2t, as well as the inability to do so with camphor, suggests that close proximity is required between the hydride donor, 1, and the carbonyl.

The increased solubility of 1 in the presence of an activator, and the inherent need of an activator for a reduction to occur, allows us to propose a mechanism (Scheme 1). The Lewis base activator coordinates with the silicon, breaking the dative bond between silicon and nitrogen, maintaining the silicon as pentacoordinate.139 The silicon then forms a hexacoordinate complex with the carbonyl, at which point the hydride is transferred to the electrophilic carbon center to reform pentacoordinate silicon.393,599 This goes on to collapse by elimination of the Lewis base activator to form the alkoxysilatrane. Support for this arises from the observation that when acetophenone is reduced in the presence of tert-butoxide activator, 1-(phenylethoxy)silatrane can be seen on the GCMS trace and in the 1H NMR spectrum after neutral workup.

120

Figure 2.3. Proposed mechanism.

The observation of intact alkoxysilatrane before workup suggests that the mechanism is different to that of PMHS or (EtO)3SiH activated by a Lewis base, in which highly unstable hydrosilanes

146 such as MeSiH3 and SiH4 are formed in situ to act as reducing agents. Avoiding such volatile and reactive intermediates renders hydrosilatrane a both safer and more operationally friendly reducing reagent than PMHS and other alkoxyhydrosilanes.

Following reaction but prior to workup, smaller amounts of tert-butoxysilatrane are also seen.

The fact that the reaction can be run with catalytic amounts of tert-butoxide supports this mechanism, and as 1-(phenylethoxy)silatrane is the main silatrane product formed (prior to workup) implies that little of the phenylethoxide acts as the activator.

2.4. Conclusion

In summary, we have reduced a broad range of ketones with 1-hydrosilatrane (1) in excellent yields. High diastereoselectivity of the reduction of (-)-menthone (2u) to (+)-neomenthol (3u) was observed, consistent with a bulky reducing intermediate. A mechanism consistent with our observations was proposed. Unlike PMHS, and (EtO)3SiH, volatile and extremely hazardous active hydrosilane species are not formed, therefore making 1-hydrosilatrane a much safer alternative for large scale reactions.

121 Further research is underway to improve enantioselectivity, as well as to explore the reduction of other significant functional groups.

2.5. Experimental and Supplementary Information

All chemicals were obtained from commercial sources and used without further purification.

Column chromatography was performed using silica gel from Macherey-Nagel (60 M, 0.04–0.063 mm). 1H

NMR, and 13C NMR were recorded on either a 300 or 500 MHz Bruker Avance III spectrometer. Chemical

1 13 shifts were reported in ppm with the solvent resonance as internal standard ( H NMR CDCl3 δ = 7.28, C

13 NMR CDCl3 δ = 77.01, C NMR (CD3)2SO δ = 39.99). The abbreviations used for the chemical shifts are as follows: s (singlet), d (doublet), t (triplet), dd (doublet of doublets), dddd (doublet of doublet of doublet of doublets), dt (doublet of triplets), td (triplet of doublets), dq (doublet of quartets), oct

(octet), m (unresolved multiplet). IR spectra were acquired using an ATI Mattson FTIR spectrophotometer on neat samples. MS data were obtained with a Shimadzu GCMS QC2010S spectrometer at 275°C. Optical rotation was obtained with a JASCO P1010 polarimeter, running a Na lamp at λ = 589 nm. Enantiomeric ratios (er) were obtained by comparing the observed optical rotation to literature precedence.

Synthesis of 1-hydrosilatrane (1) via boratrane

To a 25 mL flask was added boric acid (50 mmol) and triethanolamine (50 mmol). Water (3 mL) was added to facilitate solubility. The flask was equipped with a short path distillation apparatus and heated to 120°C until no more water condensed. The isolated boratrane was recrystallized from acetonitrile and used directly in the next step. To an oven-dried, argon-flushed 100 mL flask containing boratrane (5 mmol) in mixed xylenes (40 mL), was added triethoxysilane (6 mmol) and anhydrous AlCl3

(0.05 mmol). The reaction was refluxed over 4 h and then cooled to room temperature. The resulting solids were filtered and further recrystallized from xylene to give silatrane as white fibrous crystals.

The experimental data collected are in agreement with those described in the literature.

122

General procedure

To a 25 mL round-bottomed flask containing 5 mL N,Ndimethylformamide, was added 1- hydrosilatrane (0.263 g, 2.0 mmol), and ketone (1.0 mmol). The resulting solution was stirred for 1 minute, after which 1 M t-BuOK in THF (1.0 mmol, 1.0 mL) was added. Reaction mixture was allowed to stir for 30 min. Reaction was quenched with 25 mL 3 M HCl, and extracted with 30 mL ethyl acetate.

Organic layer was washed with brine (50 mL x 3), and dried with anhydrous sodium sulphate. After filtration, the solvent was removed under vacuum to yield product. No further steps were taken for purification

123

1-Hydrosilatrane (1)

1 13 H NMR (500 MHz, CDCl3) δ = 3.94 (s, 1 H), 3.83 (t, J = 6 Hz, 6 H), 2.89 (t, J = 6 Hz, 6 H); C NMR (125

MHz, CDCl3) 57.2, 51.2; IR (ATR) 2975, 2936, 2886, 2087, 1487, 1457, 1347, 1268, 1090, 1047, 1020,

926, 860, 748, 630, 591 cm-1.

124 (RS)-1-Phenylethanol (3)

1 H NMR (500 MHz, CDCl3): δ = 7.40 (m, 4H), 7.31 (dt, J = 2.5, 7 Hz, 1H), 4.94 (q, J = 6.5 Hz, 1H), 1.54

13 (d, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 145.8, 128.5, 127.5, 125.4, 70.5, 25.2. IR (ATR):

3348, 2971, 1665, 1451, 1203, 1076, 1010, 898, 759, 697, 606, 539 cm-1.

125 (RS)-1-(2-Methoxphenyl)ethanol (4)

1 H NMR (300 MHz, CDCl3): δ = 7.36 (dd, J = 1.5, 7.5 Hz, 1H), 7.27 (td, J = 1.2, 7.8 Hz, 1H), 6.98 (td, J =

0.9, 7.5 Hz, 1H), 6.91 (d, J = 9 Hz, 1H), 5.12 (q, J = 6.6 Hz, 1H), 3.89 (s, 3H), 1.53 (d, J = 6.6 Hz, 3H).

13 C NMR (75 MHz, CDCl3): δ = 156.6, 133.4, 128.3, 126.1, 120.8, 110.4, 66.6, 55.3, 22.9. IR (ATR): 3297,

2968, 2836, 1717, 1600, 1490, 1461, 1437, 1281, 1236, 1070, 1026, 897, 747, 731 cm-1.

126 (RS)-1-(4-Methoxyphenyl)ethanol (5)

1 H NMR (500 MHz, CDCl3): δ = 7.32 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.88 (q, J = 6.6 Hz, 1H),

13 3.82 (s, 3H), 1.50 (d, J = 6.6 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 159.0, 138.0, 126.7, 113.9, 70.0,

55.3, 25.0. IR (ATR): 3368, 2969, 2854, 1610, 1511, 1241, 1174, 1033, 896, 830, 549 cm-1.

127 (RS)-1-(3,4,5-Trimethoxyphenyl)ethanol (6)

1 H NMR (300 MHz, CDCl3): δ = 6.61 (s, 2H), 4.85 (q, J = 8 Hz, 1H), 3.88 (s, 6H), 3.84 (s, 3H), 1.50 (d, J =

13 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 153.2, 141.8, 137.0, 102.2, 70.5, 60.8, 56.1, 25.2. IR (ATR):

3438, 2968, 2938, 2837, 1561, 1507, 1457, 1417, 1326, 1232, 1122, 1004, 834, 775, 659 cm-1.

128 (RS)-1-(4-Allyloxyphenyl)ethan-1-ol (7)

1 H NMR (300 MHz, CDCl3): δ = 7.30 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 6.07 (dq, J = 5.5, 22 Hz,

1H), 5.42 (dd, J = 1.5, 17 Hz, 1H), 5.29 (dd, J = 1.5, 10.5 Hz, 1H), 4.86 (q, J = 6 Hz, 1H), 4.55 (d, J =

13 5.5 Hz, 2H), 1.49 (d, J = 6 Hz, 3H). C NMR (75 MHz, CDCl3): δ = 158.0, 138.2, 133.3, 126.6, 117.6,

114.7, 69.9, 68.9, 25.0. IR (ATR): 3363, 2972, 2885, 1608, 1510, 1238, 1174, 1086, 997, 926, 897, 829 cm-1.

129 (RS)-1-(4-Biphenylyl)ethanol (8)

1 H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 8 Hz, 4H), 7.47 (m, 4H), 7.38 (tt, J = 1, 7.5 Hz, 1H), 4.49 (q,

13 J = 1.5 Hz, 1H), 1.58 (d, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 144.8, 140.9, 140.5, 128.8,

127.3, 17.2, 127.1, 125.9, 70.2, 25.2. IR (ATR): 3306, 2973, 1485, 1403, 1072, 1005, 895, 834, 760,

727, 688 cm-1.

130 (RS)-1-(4-Bromophenyl)ethanol (9)

1 H NMR (500 MHz, CDCl3): δ = 7.49 (dt, J = 1.5, 8 Hz, 2H), 7.27 (d, J = 8 Hz, 2H), 4.89 (q, J = 6.5 Hz,

13 1H), 2.12 (s, 1H), 1.49 (d, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 14408, 131.6, 127.2, 121.2,

69.8, 25.3. IR (ATR): 3332, 2972, 1667, 1592, 1488, 1070, 1008, 897, 821, 533 cm-1.

131 (RS)-1-(4-Fluorophenyl)ethanol (10)

1 H NMR (300 MHz, CDCl3): δ = 7.63 (dd, J = 3, 5.7 Hz, 2H), 7.05 (t, J = 8.7 Hz, 2 Hz), 4.91 (q, J = 6.3 Hz,

13 1H), 1.50 (d, J = 6.6 Hz, 3H). C NMR (75 MHz, CDCl3): δ = 136.8, 160.5, 141.5, 127.1, 127.0, 115.4,

115.1, 69.8, 25.3. IR (ATR): 3355, 2974, 1604, 1508, 1221, 1157, 1080, 1012, 899, 833, 571 cm-1.

132 (RS)-1-(4-Nitrophenyl)ethanol (11)

1 H NMR (500 MHz, CDCl3): δ = 8.23 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 5.05 (q, J = 6.5 Hz, 1H),

13 1.55 (d, J = 6.5 Hz, 3H). C NMR (75 MHz, (CD3)2SO): δ = 155.8, 146.7, 126.9, 123.7, 67.9, 26.1. IR

(ATR): 3380, 2975, 1676, 1599, 1515, 1342, 1072, 853, 699 cm-1.

133 (RS)-1-Phenylpropanol (12)

1 H NMR (500 MHz, CDCl3): δ = 7.35 (m, 5H), 4.60 (t, J = 7 Hz, 1H), 1.81 (m, 2H), 0.94 (t, J = 7.5 Hz,

13 3H). C NMR (125 MHz, CDCl3): δ = 144.6, 128.4, 127.5, 125.9, 76.1, 31.9, 10.1. IR (ATR): 3359, 2965,

2875, 1700, 1452, 1222, 1011, 972, 689 cm-1.

134 (RS)-2-Methyl-1-phenylpropanol (13)

1 H NMR (500 MHz, CDCl3): δ = 7.34 (m, 7H), 4.39 (d, J = 7 Hz, 1H), 1.99 (sep, J = 7 Hz, 1H), 1.03 (d, 7

13 Hz, 3H), 0.83 (d, 7Hz, 3H). C NMR (125 MHz, CDCl3): δ = 143.1, 128.2, 127.4, 126.6, 80.1, 35.3, 19.0,

18.3. IR (ATR): 3382, 2958, 2871, 1452, 1019, 759, 699 cm-1.

135 (RS)-1,2,3,4-Tetrahydro-1-naphthalenol (14)

1 H NMR (300 MHz, CDCl3): δ = 7.45 (dd, J = 4.5, 6 Hz, 1H), 7.23 (dd, J = 3, 6 Hz, 2H), 7.13 (m, 1H), 4.81

13 (t, J = 4.8 Hz, 1H), 2.80 (m, 2H), 1.97 (m, 4H), 1.80 (m, 1H). C NMR (75 MHz, CDCl3): δ = 138.8,

137.1, 129.0, 128.7, 127.6, 126.2, 68.2, 32.3, 29.2, 18.8. IR (KBr Pellet): 3135, 2935, 1696, 1400, 1280,

1068, 740 cm-1.

136 Diphenylmethanol (15)

1 H NMR (500 MHz, CDCl3): δ = 7.42 (m, 4H), 7.37 (dt, J = 1.5, 11.5 Hz, 4H), 7.30 (m, 2H), 5.88 (s, 1H),

13 2.23 (s, 1H). C NMR (125 MHz, CDCl3): δ = 143.8, 128.5, 127.6, 126.6, 76.3. IR (ATR): 3264, 3026,

1492, 1447, 1016, 739, 698, 600, 548 cm-1.

137 (RS)-1-(4-Methylphenyl)-1-phenylmethanol (17)

1 13 H NMR (500 MHz, CDCl3): δ = 7.334 (m, 9H), 5.82 (s, 1H), 2.63 (s, 1H), 2.40 (s, 3H). C NMR (125 MHz,

CDCl3): δ = 144.1, 141.1, 137.3, 129.2, 128.5, 127.5, 126.6, 126.5, 76.1, 21.2. IR (ATR): 3276, 3025,

1657, 1451, 1016, 731, 697, 563 cm-1.

138 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (18)

1 H NMR (500 MHz, CDCl3): δ = 7.48 (dd, J = 2, 7 Hz, 2H), 7.21 (m, 6H), 6.00 (s, 1H), 3.31 (dddd, J = 4.5,

13 9, 22, 163.5 Hz, 4H), 2.24 (s, 1H). C NMR (125 MHz, CDCl3): δ = 140.5, 138.9, 130.2, 128.0, 127.1,

126.2, 76.6, 32.4. IR (ATR): 3313, 2962, 1484, 1447, 1066, 753, 599 cm-1.

139 Cyclohexanol (19)

1 H NMR (300 MHz, CDCl3): δ = 3.63 (m, 1H), 1.91 (m, 2H), 1.76 (m, 2H), 1.57 (m, 1H), 1.37 (d, J = 4.5

13 Hz, 1H), 1.25 (m, 5H). C NMR (125 MHz, CDCl3): δ = 70.3, 35.6, 25.5, 24.1. IR (ATR): 3325, 2929,

2854, 1450, 1361, 1064, 968 cm-1.

140 (RS)-2-Heptanol (20)

1 H NMR (300 MHz, CDCl3): δ = 3.81 (sext, J = 6 Hz, 1H), 1.44 (m, 8H), 1.20 (d, J = 6.3 Hz, 3H), 0.91 (t, J

13 = 6.6 Hz, 3H). C NMR (75 MHz, CDCl3): δ = 68.2, 77.0, 76.6, 68.2, 39.3, 31.9, 25.5, 23.5, 22.6, 14.0. IR

(ATR): 3333, 2959, 2928, 2859, 1461, 1376, 1110, 1062, 950, 725 cm-1.

141 (RS)-2-Octanol (21)

1 H NMR (500 MHz, CDCl3): δ = 3.81 (sext, J = 6 Hz, 1H), 1.37 (m, 10H), 1.20 (d, J = 6.3 H, 3H), 0.90 (m,

13 3H). C NMR (125 MHz, CDCl3): δ = 68.2, 39.4, 31.8, 29.3, 25.7, 23.5, 22.6, 14.1. IR (ATR): 3333, 2959,

2926, 2857, 1459, 1375, 1111, 1067, 938, 840, 724 cm-1.

142 (+)-Neomenthol (23)

1 H NMR (500 MHz, CDCl3): δ = 4.12 (m, 1H), 1.85 (dq, J = 2.4, 3.6, 13.8 Hz, 1H), 1.71 (m, 3H), 1.53 (m,

2H), 1.29 (dd, J = 3.0, 12.9 Hz, 1H), 1.14 (m, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H),

13 0.89 (d, J = 6.6 Hz, 3H). C NMR (75 MHz, CDCl3): δ = 67.7, 47.9, 42.6, 35.1, 29.2, 25.8, 24.2, 22.3,

21.2, 20.7. IR (ATR): 3427, 2947, 2916, 2869, 1712, 1456, 1367, 1242, 1153, 1026, 960, 937, 679 cm-1.

143

CHAPTER 3

ASYMMETRIC REDUCTION OF KETONES USING 1-HYDROSILATRANE

*This chapter is adapted in part from our publications.148,611

3.1. Overview

Due to the previously observed diastereoselectivity observed in the reduction of methone with

1-Hydrosilatrane, it was postulated that enantioselective reductions of prochiral ketones could be achieved using a bulky chiral Lewis base. Several chiral activators were tested, yielding relatively high enantioselectivity of up to 86% ee. Although as an initial study the results are good, more work is needed if the method is to become competitive with other current methods for enantioselective reductions of ketones.

3.2. Introduction

The asymmetric reduction of ketones is the most efficient way to synthesize chiral alcohols, which are of great importance in the pharmaceutical, agrochemical, and flavor industries.149,152,231 An immense variety of efficient methods have been developed with both transition metal catalysts and organocatalysts.232-233 Transition metal catalysts have been used in asymmetric hydrogenation and hydride transfer reactions with great success, but tend to be expensive, unstable in ambient conditions, or can contaminate the product by metal-leaking.234-237 Organocatalysts have emerged as alternatives to the transition metal catalysts without the key drawbacks.237-238 Some of the most notable organocatalytic systems include the CBS method using chiral boranes,231,293,296,300,302,408 chiral

Lewis acids with Hantzsch esters,453-455,471 and chiral Lewis base catalyzed hydrosilylations.60,398,400

144 3.2.1. Asymmetric Reduction of Ketones using Organosilicon Compounds

Hydrosilanes are popular reducing agents as they tend to be low-cost, chemically stable, easy- to-handle hydride sources, requiring an activator or catalyst for reduction to occur.191,612 The first organocatalyzed asymmetric reduction of ketones using an alkoxysilane was achieved by Hosomi et al. in 1988, using chiral lithium diolates and aminoalcoholates to activate trimethoxysilanes, forming secondary alcohols in good yields and enantioselectivity.389 Since then, several others have used chiral anionic Lewis bases to activate alkoxysilanes, with varying degrees of success, but never at the enantioselectivities achieved when using trichlorosilane and neutral chiral Lewis base activators.390-

391,393-395 The lower selectivity when using alkoxysilanes is most likely due to a competition between free achiral product alkoxide and the chiral Lewis base acting as activators.393 High enantioselectivity ensues to the greatest extent when the siloxane remains bound to the product alkoxide until workup.

3.3. Asymmetric Reduction of Ketones using 1-Hydrosilatrane

1-Hydrosilatrane 1 (Figure 1.27), a bulky alkoxysilane, has been shown to be an effective reducing agent for ketones.148 As a white crystalline solid, it is safe and much easier to handle than the most commonly used silicon hydride sources.118,603 Having observed tentative signs of the silatrane moiety preferring to remain attached to the alkoxide product, and good diastereoselectivity in the reduction of menthone due to the steric constraints of the system, it was speculated that a chiral activator could give enantioselectivity with prochiral ketones.

3.3.1. Proof of Concept

Preliminary testing of our hypothesis was done using 2-methylbenzophenone 26, as it is a sterically hindered prochiral ketone. Furthermore, by using the bulky aminoalcohol, (1S,2R)-(+)-1,2-

145 diphenyl-2-amino-1-ethanol 27, deprotonated with sodium hydride in situ, as the Lewis base activator, a respectable enantiomeric ratio of 6.7:1 was observed in the product 16 (Figure 3.1).

Figure 3.1. Enantioselectivity.

3.4. Optimization

3.4.1. Optimization of Activator

Several activators were screened for the reduction of acetophenone with varying results (Table

3.1). All activators were deprotonated in situ with sodium hydride and cooled prior to the addition of acetophenone and 1-hydrosilatrane. It was clear that activators with only one coordination site (2-4) gave much lower enantioselectivity (Table 3.1, entries 1-3) than the ones with two sites for chelation

(6, 7, 9)(Table 3.1, entries 5-7). (1S,2R)-1,2-diphenylethanolamine 7 gave the highest enantioselectivity, followed by (1R,2S)-(-)-ephedrine 9, and cinchonine 6. Surprisingly, (R)-(+)- diphenylprolinol 5 gave no enantioselectivity and very poor conversion (Table 3.1, entry 4), possibly implying that the oxygen is too hindered for effective activation of the silatrane.

146 Table 3.1. Screening of Activators

Entry Activatorb Conversion (%) (R):(S)

1 50 50:50

28

2d 28 50:50

29

3 86 50:50

30

4 10 50:50

31

5d >99 72:28

32 a Unless otherwise stated, the reaction conditions were 0.1 mmol Acetophenone, 0.11 mmol activator deprotonated in situ, 0.2-0.3 mmol 1-Hydrosilatrane, in 3mL dry THF at -30 oC for 6h. b Deprotonated in situ with NaH (2 eq wrt Activator) c ee determined by GCMS d reaction ran at

-10 oC

147

Table 3.1. (continued) Screening of Activators

Entry Activatorb Conversion (%) (R):(S)

6 99 85:15

27

7 85 18:82

33

a Unless otherwise stated, the reaction conditions were 0.1 mmol Acetophenone, 0.11 mmol

activator deprotonated in situ, 0.2-0.3 mmol 1-Hydrosilatrane, in 3mL dry THF at -30 oC for 6h.

b Deprotonated in situ with NaH (2 eq wrt Activator) c ee determined by GCMS d reaction ran at

-10 oC

3.4.2. Optimization of Solvent

Once compound 7 was identified as the best activator, a range of solvents was tested to optimize the conditions (Table 3.2). THF was observed to be the best solvent as it gave high conversion and good enantioselectivity (Table 3.2, entry 1). 2-MeTHF was close behind, but due to its relatively high freezing point, the temperature could not be lowered below 0 oC (Table 3.2, entry 2). Mixing it with benzene to allow for a slightly lower reaction temperature did not significantly improve enantioselectivity (Table 3.2, entry 3). Hexane, ether and m-xylene gave poor conversion and enantioselectivity (Table 3.2, entries 5, 6, 9 respectively), most likely due to poor dissolution of 1- hydrosilatrane.

148 Table 3.2. Solvent optimization.

Entry Solvent T (oC) Conversion (%) (R):(S)

1 THF -30 >99 85:15

2 2-MeTHF 0 98 81:19

3 C6H6/2-MeTHF(2:1) -10 98 80:20

4 C6H6 -196->r.t 99 78:22

5 Hexane -196->r.t 20 77:23

6 Et2O -30 14 76:24

7 Toluene -196->r.t >99 75:25

8 DMF -8 90 71:29

9 m-Xylene -30 21 62:38

10 MeCN -10 35 55:45

a ee determined by GCMS

3.4.3. Optimization of Temperature

The temperature dependence of enantioselectivity was tested (Table 3.3), and there was a clear pattern between decreased temperature and increased enantioselectivity to an optimal temperature of -30 oC, after which the rate of reaction was so slow that the conversion of starting material to product went down, with a slight decrease in enantioselectivity.

149 Table 3.3. Effect of temperature on enantioselectivity

Entry T (oC) Conversion (%) (R):(S) ee

1 -40 28 84:16 68

2 -30 100 85:15 70

3 -18 100 82:18 64

4 -10 100 77:23 54

a ee determined by GCMS

3.4.4. Optimization of Activator Loading

By probing the relationship between enantioselectivity and activator loading (Table 3.4), it is evident that increasing the loading of activator 27 from 1 equivalent to 2 equivalents increased the enantioselectivity (Table 3.4, entry 1 vs. 2). However, the 6% increase in ee was much less prominent than expected. Interestingly, the same amount of increase was observed when substituting activator

27 for 33 (Table 3.4, entry 3 vs 4). Increasing the activator loading of 33 to 8 equivalents gave the highest ee of 86% (Table 3.4, entry 5) indicating an interesting pattern of each doubling of activator increasing enantioselectivity by ~6%.

150 Table 3.4. Activator loading-to-enantioselectivity relationship.

Entry Activatora Activator (eq) Conversion (%) (R):(S)

1 27 1 99 85:15

2 27 2 >99 88:12

3 33 1 85 18:82

4 33 2 >99 15:85

5 33 8 >99 7:93

a Deprotonated in situ with NaH (2 eq wrt Activator) b ee determined by GCMS

Requiring superstoichiometric amounts of activator is less than ideal, but the activator can be recovered during work up with a simple acid-base wash, and reused with no loss in enantioselectivity

(Table 3.5).

Table 3.5. Recyclability of activator.

Entry Time reagent used Yield ee (%)

1 1 94 42

2 2 99 44

151 3.5. Effect of Activator Stereochemistry

The reduction was tested to see how different enantiomers and epimers affected enantioselectivity (Table 3.6). Exchanging activator 27 for its enantiomer 34 gave full inversion yet no loss in enantioselectivity (Table 3.6, entries 1 vs 2). In contrast, upon exchanging activator 33 with its epimer 35, in which the C-O stereocenter is inverted, the enantioselectivity decreases dramatically

(Table 3.6, entries 3 vs 4, 5 vs 6). Note that the enantioselectivity is also inverted, indicating that either the oxygen or the side with the phenyl group dictates the absolute stereochemistry of the product.

152 Table 3.6. Enantiomer and epimer effect on enantioselectivity.

Entry Activatora Activator (eq) Conversion (%) (R):(S)

1 2 >99 88:12

27

2 2 >99 11:89

34

3 2 >99 15:85

33

4 2 >99 76:24

35

5 33 1 85 18:82

6 35 1 >99 69:38

a Deprotonated in situ with NaH (2 eq wrt Activator) b ee determined by GCMS

3.6. Scope of Reaction

Further studies involved reducing a small range of substituted acetophenone derivatives to investigate substituent effects (Figure 3.2). Increasing the electron density of the aromatic ring (36 vs

37, 38) seemed to decrease the enantioselectivity, whilst substituting phenyl with naphthyl (36 vs 39) seemed to have no significant effect. Substitution on the position gave mixed results. A cyclic - substitution decreased the enantioselectivity and significantly decreased conversion. (36 vs 40). The addition of a chloride once again decreased enantioselectivity, but also gave a mixture of products

153 most likely due to epoxidation (36 vs 41). The addition of one methyl group showed only a small decrease in selectivity (36 vs 42), but a second methyl group, dropped the enantioselectivity dramatically down to 22% ee (36 vs 43), whilst substituting it into a cyclohexyl group reduced enantioselectivity even more down to 8% ee (36 vs 44).

Figure 3.2. Scope of asymmetric reduction of select acetophenone derivatives.

3.7. Conclusions

In summary, we have developed a method of asymmetric reduction of aromatic ketones using chiral Lewis bases as activators and 1-Hydrosilatrane as the hydride source. The enantioselectivity is good, with ees up to 86%. Further studies are underway to make the system catalytic with respect to the activator.

154 3.8. Experimental and Supplementary Infromation

General information

All chemicals were obtained from commercial sources and used without further purification.

Column chromatography was performed using silica gel from Macherey-Nagel (60 M, 0.04–0.063 mm). 1H

NMR, and 13C NMR were recorded on either a 300 or 500 MHz Bruker Avance III spectrometer. Chemical

1 13 shifts were reported in ppm with the solvent resonance as internal standard ( H NMR CDCl3 δ = 7.28, C

13 NMR CDCl3 δ = 77.01, C NMR (CD3)2SO δ = 39.99). The abbreviations used for the chemical shifts are as follows: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dddd (doublet of doublet of doublet of doublets), dt (doublet of triplets), td (triplet of doublets), dq (doublet of quartets), sept (septet), oct (octet), m (unresolved multiplet), b (broad). IR spectra were acquired using an ATI Mattson FTIR spectrophotometer on neat samples. MS data were obtained with a Shimadzu

GCMS QC2010S spectrometer at 275°C. Enantiomeric ratios were analyzed by a Shimadzu GCMS

QC2010S spectrometer equipped with a chiral column (CP-Chirasil Dex CB 25x0.25x0.25). Helium was used as the mobile phase at a column pressure of 120 kPa and varying split flow rates specified in this supporting information. The injector temperature was 230 °C, and the FID temperature was 200°C. The oven temperatures and the retention times are specified according to the substrate.

Asymmetric reduction of 2-methylbenzophenone (16*)

To a flame dried 25 mL round-bottomed flask, under argon, was added 10 mL N,N- dimethylformamide, (1S,2R)-(+)-2-amino-1,2-diphenylethanol (0.213 g, 1.0 mmol), and sodium hydride

(0.052 g, 2.2 mmol, pre-washed with hexane to remove mineral oil). Reaction mixture was stirred and gently warmed until a colour change from cream to yellow was observed. A further colour change to deep red was observed as the reaction mixture was cooled down to -18 °C using dichlorobenzene/N2 slurry. 1-Hydrosilatrane (0.526 g, 3.0 mmol) was added to the reaction mixture, followed by 2- methylbenzophenone (0.18 mL, 1.0 mmol). Reaction was allowed to stir for 3 h before it was quenched with 3 M HCl (25 mL). Extraction was done with a 1:1:1 solution of ethyl acetate/diethyl

155 ether/dichloromethane. The organic layer was washed sequentially with 3 M HCl (25 mL), and brine (25 mL x 3), before it was dried with anhydrous sodium sulphate. After filtration, the solvent was removed under vacuum to give solid product (S)-1-(2-methylphenyl)-1-phenylmethanol (3n).

General procedure for the asymmetric reduction of ketones

To a flame dried 8 mL screw cap vial, under argon, was added chiral activator (0.1 mmol, 1 eq), Sodium Hydride (60% in mineral oil) (0.22 mmol, 2.2 eq), and dry THF (3mL). The white suspension was stirred and warmed up until everything dissolved and a colour change was observed to give a clear yellow solution. The solution was allowed to cool down to room temperature, after which it was further cooled down to -30C using Nitromethane/N2 slurry. 1-Hydrosilatrane (2.0 mmol, 2 eq) was added to the reaction mixture, followed by the ketone (0.1 mmol). Reaction was allowed to stir for 6 h before it was quenched with 3M HCl (2 ml). Ethyl acetate (1ml) was added to separate layers, and an aliquot of the top layer was tested using Chiral GC to obtain enantiomeric ratio of product.

General procedure for the racemic reduction of ketones

To a 25 mL round-bottomed flask containing 5 mL N,N-dimethylformamide, was added 1- hydrosilatrane (0.263 g, 2.0 mmol), and ketone (1.0 mmol). The resulting solution was stirred for 1 minute, after which 1 M t-BuOK in THF (1.0 mmol, 1.0 mL) was added. Reaction mixture was allowed to stir for 30 min. Reaction was quenched with 25 mL 3 M HCl, and extracted with 30 mL ethyl acetate.

Organic layer was washed with brine (50 mL x 3), and dried with anhydrous sodium sulphate. After filtration, the solvent was removed under vacuum to yield product. No further steps were taken for purification.

156 (S)-1-(2-methylphenyl)-1-phenylmethanol (16*).

1 H NMR (300 MHz, CDCl3): δ = 7.54 (dd, J = 1.8, 7.2 Hz, 1H), 7.36-7.34 (m, 4H), 7.33-7.20 (m, 3H), 7.16

(dd, J = 1.8, 7.2 Hz, 1H), 6.04 (d, J = 3.9 Hz, 1H), 2.28 (s, 3H), 2.12 (d, J = 3.9 Hz, 1H); 13C NMR (75

MHz, CDCl3): δ = 142.9, 141.4, 135.4, 130.6, 128.5, 127.6, 127.5, 127.1, 126.3, 126.1, 73.4, 19.4; IR

(ATR): 3213, 3062, 3022, 2972, 2929, 2883, 2360, 2337, 1603, 1491, 1450, 1346, 1284, 1244, 1174,

-1 24 1039, 1016, 766, 739, 698, 609, 563, 536 cm ; [α]D +5.7 (c 1.98, CHCl3), 74% ee.

157 1-Phenylethanol (36)

1 H NMR (500 MHz, CDCl3): δ = 7.41-7.37 (m, 4H), 7.33-7.29 (m, 1H), 4.89 (q, J = 6.5 Hz, 1H), 2.38 (s

13 (b), 1H), 1.51 (d, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 145.9, 128.5, 127.4, 125.4, 70.3, 25.2.

IR (ATR): 3354, 2972, 2360, 1450, 1203, 1076, 1010, 899, 760, 696 cm-1.

158 1-(4-Methoxyphenyl)-ethanol (37)

1 H NMR (500 MHz, CDCl3): δ = 7.23 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.88 (q, J = 6.5 Hz, 1H),

13 3.83 (s, 3H), 1.85 (b, 1H), 1.50 (d, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 159.0, 138.0, 126.7,

113.9, 70.0, 55.3, 25.0. IR (ATR): 3377, 2970, 2835, 1612, 1585, 1512, 1302, 1242, 1174, 1086, 1034,

897, 829 cm-1.

159 1-(2-Methoxyphenyl)-ethanol (38)

1 H NMR (500 MHz, CDCl3): δ = 7.38 (dd, J = 1.5, 7.5 Hz, 1H), 7.28 (td, J = 1.5, 8.0 Hz, 1H), 7.00 (td, J =

0.5, 7.5 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.13 (q, J = 6.5 Hz, 1H), 3.88 (s, 3H), 2.78 (b, 1H), 1.53 (d, J

13 = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 156.5, 133.6, 128.3, 126.1, 120.8, 110.5, 66.4, 55.3, 23.0.

IR (ATR): 3394, 2970, 2837, 2360, 1600, 1491, 1464, 1236, 1076, 1028, 899, 752 cm-1.

160 1-(1-Naphthyl)-ethanol (39)

1 H NMR (500 MHz, CDCl3): δ = 8.13 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz,

1H), 7.69 (d, J = 7.5 Hz, 1H), 7.58 – 7.49 (m, 3H), 5.67 (q, J = 6.5 Hz, 1H), 2.02 (b, 1H), 1.69 (d, J = 6.5

13 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 141.4, 133.8, 130.3, 128.9, 127.9, 126.0, 125.6, 123.2, 122.0,

67.1, 24.4. IR (ATR): 3334, 3049, 2980, 2887, 1597, 1510, 1371, 1169, 1109, 1065, 1011, 897, 793, 775,

732 cm-1.

161 1-Tetralol (40)

1 H NMR (500 MHz, CDCl3): δ = 7.47-7.45 (m, 1H), 7.25-7.23 (m, 2H), 7.15-713 (m, 1H), 4.80 (dd, J = 4.5,

5.5 Hz, 1H), 2.89-2.73 (m, 2H), 2.06-1.96 (m, 3H), 1.95-1.91 (m, 1H), 1.85-1.78 (m, 1H). 13C NMR (125

MHz, CDCl3): δ = 138.9, 137.1, 129.0, 128.7, 127.6, 126.2, 68.1, 32.3, 29.3, 18.9. IR (ATR): 3329, 2980,

2935, 2885, 1489, 1454, 1269, 1066, 1038, 962, 910, 771, 735 cm-1.

162 2-Chloro-1-phenylethanol (41)

1 H NMR (500 MHz, CDCl3): δ = 7.43-7.34 (m, 5H), 4.94 (dd, J = 3.5, 8.5 Hz, 1H), 3.78 (dd, J = 3.5, 11.5

13 Hz, 1H), 3.68 (dd, J = 8.5, 11.5 Hz, 1H). C NMR (125 MHz, CDCl3): δ = 139.9, 128.7, 128.5, 126.1,

74.1, 51.0. IR (ATR): 3388, 3032, 2954, 1454, 1342, 1200, 1063, 1012, 764, 721, 696, 613 cm-1.

163 1-phenylpropanol (42)

1 H NMR (500 MHz, CDCl3): δ = 7.38-7.37 (m, 4H), 7.33-7.30 (m, 1H), 4.63 (t, J = 6.5 Hz, 1H), 1.90-1.74

13 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 144.6, 128.4, 127.5, 126.0, 76.1, 31.9,

10.1. IR (ATR): 3373, 2964, 2931, 2875, 1712, 1454, 1333, 1095, 1011, 974, 746, 698 cm-1.

164 2-Methyl-1-phenylpropanol (43)

1 H NMR (500 MHz, CDCl3): δ = 7.39-7.33 (m, 4H), 7.32-7.30 (m, 1H), 4.39 (d, J = 7.0 Hz, 1H), 1.99 (dq, J

13 = 6.5, 7.0 Hz, 2H), 1.03 (d, J = 6.5 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H). C NMR (125 MHz, CDCl3): δ =

143.7, 128.2, 127.4, 126.6, 80.1, 35.3, 19.0, 18.2. IR (ATR): 3386, 2958, 2872, 1468, 1452, 1201, 1018,

760, 700 cm-1.

165 Cyclohexylphenylmethanol (44)

1 H NMR (500 MHz, CDCl3): δ = 7.38-7.35 (m, 2H), 7.34-7.30 (m, 3H), 4.39 (d, J = 6.5 Hz, 1H), 2.03-2.00

(m, 1H), 1.82-1.77 (m, 1H), 1.68-1.62 (m, 3H), 1.44-1.38 (m, 1H), 1.28-0.92 (m, 4H). 13C NMR (125

MHz, CDCl3): δ = 143.6, 128.2, 127.4, 126.6, 79.4, 45.0, 29.3, 28.8, 26.4, 26.1, 16.0. IR (ATR): 3398,

2922, 2850, 1450, 1014, 758, 700, 576 cm-1.

166

CHAPTER 4

DIRECT REDUCTIVE AMINATIONS USING 1-HYDROSILATRANE

*This chapter is adapted in part from our publication.613

4.1. Overview

1-Hydrosilatrane has been shown to be very unreactive towards carbonyls in the absence of a

Lewis base activator. However, it has been shown to be an effective reducing agent towards iminium ions in direct reductive aminations of aldehydes and ketones with secondary amines to form tertiary amines. Remarkably, this reduction happens without an added activator, and in the absence of solvent, making it a green alternative pathway for direct reductive aminations. The scope of the reaction is broad.

4.2. Introduction

Due to the ubiquity of amines in important biologically active molecules in nature, and in a wide range of applications from pharmaceuticals to fine chemicals, effective syntheses are of paramount importance.405-406

Although various methods are known,417-419 direct reductive amination (DRA) is considered the most practical method for the synthesis of amines, and therefore is the most widely used.408-409 DRA involves a reaction between an amine and an aldehyde, or ketone, to form an imine or iminium ion in situ, which is then converted by a reducing agent to the corresponding amine.407 While several methods exist for the formation of secondary amines,408-409 there are few studies of direct reductive aminations that form tertiary amines due to the steric influence on enamine/iminium ion formation at equilibrium.411 Additionally, DRA using secondary arylamines to form aromatic tertiary amines has been described as challenging,411 and only a handful of procedures are known.411,413-414

167 For DRA, choosing a chemoselective reducing agent is crucial: the reductant must be able to reduce the imine or iminium ion but not the parent carbonyl compound (or other functionalities present).410 For example, catalytic hydrogenation with a metal catalyst is effective on a large scale but tends not to tolerate unsaturated substituents on the reactants.614

407 442 The most commonly used reducing agents for DRA are NaBH3CN and NaBH(OAc)3 due to their wide availability, simplicity of use, chemoselectivity, and mild reaction condition requirements.

However, NaBH3CN is toxic, forms toxic byproducts during work-up, and tends to require large excesses of amine, whilst NaBH(OAc)3 is not compatible with most aromatic ketones, or with aromatic secondary amines.406,420,442,505,615 Other borohydride derivatives overcome these issues but require more complex purification techniques.408,451

4.2.1. Direct Reductive Amination Using Organosilicon Compounds

Organosilanes have been reported as efficient alternatives to borohydrides for DRA, as they require simpler purification methods due to their good solubility in organic solvents.451 PMHS has been the silane of choice due to its non-toxicity, low price, and inertness in the absence of an activator.145

However, PMHS and other organosilanes require activating catalysts for reduction to occur.438,485,487-

488,490,500,505,616 These catalysts all have their drawbacks. For example, trifluoroacetic acid cannot be

479 411,476,482,499 used with acid–labile functionalities, Bu2SnCl2, SnCl2, and BiCl3 are toxic, and InCl3 is expensive and a known teratogen.504

4.2.2. Direct Reductive Amination Using 1-Hydrosilatrane

1-Hydrosilatrane 1 (Figure 1.27, also called silatrane) has largely been overlooked as a reducing agent since it was first synthesized by Frye et al. in 1961.101 1 has a cage structure with a lone pair of electrons on nitrogen oriented towards the silicon, rendering it effectively pentacoordinate. This has the potential to make silatrane a good reducing agent because the increase in electron density in the region of the hypervalent silicon center should make the hydride more hydridic.29,30,39 Furthermore, the hypervalent silicon center should become more Lewis acidic and therefore more likely to further

168 coordinate reducible Lewis base functionalities such as carbonyls.38 As an air- and moisture-stable solid, 1 is easy to synthesize and handle.603 Our previous work has shown that 1 is good reducing agent for aldehydes128 and ketones148 in the presence of a Lewis base, but does not readily reduce nitro, vinyl or arylhalide functional groups. To the best of our knowledge 1 has not previously been considered as a reducing agent for direct reductive aminations. We describe here our successes in accomplishing this.

4.3. Optimization

After the initial observation of para-tolualdehyde 45 reacting with diethylamine in the presence of 1 to form 46, the conditions were optimized (Table 4.1). The original reaction was performed in dichloromethane at room temperature to give 49% 3 after 45 hours (entry 1). Increasing the temperature to 60 oC and changing the solvent to chloroform gave excellent conversion to 3 within

23 hours (entry 2). Attempting to avoid halogenated solvents, but bearing in mind the solubility of 1, acetonitrile allowed a further increase in temperature to 70oC, which led to an excellent yield at slightly shorter reaction time of 18 hours (entry 3). The reaction was very slow in ethanol, giving only a fair yield after 48 hours (entry 4). Acetic acid provided an extremely rapid reaction, but reduction of the aldehyde to the corresponding alcohol was also observed (entry 5). Finally, we tested the reaction in the absence of solvent, which gave quantitative conversion to the amine and a good isolated yield

(entry 6). Exchanging the more popular PMHS for 1 under neat conditions gave a much lower yield of product (entry 7), while no reaction was observed when triethylsilane was used as the reductant (entry

8).

169 Table 4.1. Optimization of reaction conditions.

Entry Silane Temp (oC) Solvent Time (h) Yield[a] (%)

1 1 rt DCM 45 49

2 1 60 CHCl3 23 98 (84) 3 1 70 MeCN 18 99 (80) 4 1 70 EtOH 48 60 (38) 5 1 70 AcOH 3 42 6 1 70 Neat 22 99 (81) 7 PMHS 70 Neat 20 48 (32)

8 Et3SiH 70 Neat 21 n.r. [a] Yield determined by GCMS. Isolated yields in parenthesis.

4.4. Aldehydes with Secondary Amines

Figure 4.1 demonstrates the broad applicability of this method for the reaction of secondary amines with aldehydes to form tertiary amines. Benzaldehyde reacted with secondary amines to give products 47-50. A clear pattern is seen relating the steric bulk of the amine and the resulting isolated yield (compare 47 and 36 to 48 and 51, for example): this discrepancy is not related to the reaction itself, but rather due to the method of purification (acid extraction) as inspection by GCMS prior to workup indicated quantitative conversion. The reaction works well with both electron rich (46-61, 67-

70) and electron poor (62-66) aromatic aldehydes. Both aldehydes of teraphthdialdehyde were readily aminated to give bis-tertiary amine 71.

170

Figure 4.1. Scope of aldehydes and secondary amines to form tertiary amines.

171

Figure 4.1. Scope of aldehydes and secondary amines to form tertiary amines. (continued)

The α,β-unsaturated cinnamaldehyde gave high yields of the tertiary amines 72-74 with no reduction of the double bond observed. DRA of 1-naphthaldehyde gave high yields of 68 and 70 with diethylamine and pyrrolidine respectively; the relatively low isolated yield of 69 (using dibenzylamine) was due to the low solubility of the product complicating work up. The reaction is not limited to aromatic aldehydes, as the aliphatic cyclohexylcarboxaldehyde and isovaleraldehyde produced 75 and

76 in excellent yields. Picolinaldehyde formed 77 but the isolation was difficult due to enhanced solubility of the product in water. Very good functional group tolerance is observed, as reducible groups such as nitro (65), cyano (66), olefin (72-74), and ester (74) along with common protecting

172 groups such as benzyl (59) and triisopropylsilyl (60-61) remain unaffected. With respect to the amines, high yields are obtained with acyclic and cyclic aliphatic secondary amines, as well as the far less nucleophilic aromatic amines. However, the reaction was not successful with N-Boc protected amine, as it does not form the required iminium ion under our conditions.

4.5. Aldehydes with Primary Amines

We further desired to extend this method to the formation of secondary amines, however under neat conditions propylamine with para-tolualdehyde only gave the corresponding imine in quantitative yield with no observed reduction (Figure 4.2.). We postulated that protonation of the imine would facilitate reduction to the amine by 1, and this was shown to work well by other group members.613

Figure 4.2. Aldehydes with primary amines.

4.6. Ketones with Secondary Amines

Having explored the scope of tertiary amine synthesis via aldehydes, we decided to further study the possibility of reductive aminations with ketones. Formation of the enamine was observed when the reactions were attempted neat, but was avoided when small amounts of solvent were used, suggesting the importance of having silatrane available in solution as the iminium is formed. Overall,

DRA involving a range of ketones and amines was observed (Figure 4.3.).

173 Dimethylamine, pyrollidine and morpholine reacted with acetophenone to form the corresponding tertiary amines 79, 80 and 81. In contrast, diethylamine did not react with acetophenone(78) nor with the more active nitroacetophenone (82).

This seemed to be due to the inability of diethylamine to form the required iminium ion.

Potentially reducible nitro 83 group remained intact indicating some functional group tolerance. The steric effect of the bulkier isopropyl group in the reaction forming 84 did not seem to have a great negative effect on the yield. Both cyclic (85) and acyclic (86) aliphatic ketones gave good yields.

Figure 4.3. Scope of ketones and secondary amines to form tertiary amines.

4.7. Direct Reductive Amination with ammonium salts

DRA of ketones and aldehydes with ammonium salts were unsuccesful mainly due to overalkylation.

Similar obstacles have been recently noted in literature.617

174

Figure 4.4. DRA with ammonium salt.

4.8. Chemoselectivity

To study the chemoselectivity of the DRAs we ran several competition reactions with 4- acetylbenzaldehyde 87 (Figure 4.3). Under neat conditions, the aldehyde is reduced preferentially over the ketone by both N-methyl aniline to form 88 and diethylamine to form 89 with good and very good isolated yields. Aminoalcohol 90 was formed in one pot through reduction of in situ generated 89, by

1.

To test the utility and safety of this reaction, we performed the reaction on a multigram scale to produce 53 (Figure 4.4.). It must be noted that PMHS and other alkoxysilanes would not be suitable for a scaled up reaction as volatile and pyrophoric active species are potentially formed during the reaction.146-147 Although a stoichiometric amount of 1-hydrosilatrane is required, it is relatively inexpensive to synthesize. Upon aqueous work-up silatrane derivatives are hydrolysed into siloxanes and triethanolamine, which are environmentally benign waste products.

175

Figure 4.5. Chemoselectivity of DRA with 1-hydrosilatrane.

Figure 4.6. Gram scale reaction using 1-hydrosilatrane under solvent free conditions. [a] 18.6 mmol (2 equiv.). [b] 9.3 mmol (1 equiv.). [c] 18.6 mmol (2 equiv.). [d] Isolated yield.

176 4.9. Insight into the Mechanism

Preliminary data suggests that iminium ion formation is required for the reaction to proceed.

Secondary amines and aldehydes get readily reduced by 1, whilst primary amines and aldehydes form imines without reduction. However, in the presence of acetic acid, the imine can be protonated to the iminium ion, and reduction occurs to the amine. Based on our current understanding of 1 as a reducing reagent (i.e. that it requires a nucleophilic activator to transfer the hydride),128,148 we propose that a

Lewis base formed in situ acts as the activator. Alternatively, iminiums are significantly more electrophilic than either aldehydes of ketones,618 so 1 may be able to reduce such reactive compounds in the absence of an activator. Further mechanistic studies are currently ongoing.

4.10. Conclusion

We have demonstrated 1 as an efficient reducing agent in the direct reductive amination of aldehydes and ketones to form secondary and tertiary amines. This is a reasonably green procedure, as tertiary amines form readily without any solvent, catalyst, or other additives, and secondary amines form when environmentally friendly acetic acid is used as a solvent. Both alkyl and aryl amines give high yields.

The scope is broad with good functional group tolerance and chemoselectivity. The method is extremely simple, as no inert atmosphere or exclusion of water is necessary, with the added benefit of

1 being a stable, low-cost, easy to handle, and versatile reducing agent.

4.11. Experimental and Supplemental Information

General Information

All chemicals were obtained from commercial sources and used without further purification. Column chromatography was performed using silica gel from Macherey-Nagel (60 M, 0.04–0.063 mm). 1H NMR, and 13C NMR were recorded on either a 300 or 500 MHz Bruker Avance III spectrometer. Chemical shifts

177 1 13 were reported in ppm with the solvent resonance as internal standard ( H NMR CDCl3 δ = 7.28, C NMR

13 CDCl3 δ = 77.01, C NMR (CD3)2SO δ = 39.99). The abbreviations used for the chemical shifts are as follows: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dddd (doublet of doublet of doublet of doublets), dt (doublet of triplets), td (triplet of doublets), dq (doublet of quartets), sept (septet), oct (octet), m (unresolved multiplet). IR spectra were acquired using an ATI

Mattson FTIR spectrophotometer on neat samples. MS data were obtained with a Shimadzu GCMS

QC2010S spectrometer at 275°C.

General procedure for synthesis of tertiary amines (aldehydes):

In a 5 dram vial containing 1-hydrosilatrane (2 mmol) was added aldehyde (1.5 mmol) and secondary amine (1 mmol). The vial was sealed and heated at 70oC overnight. Resulting residue was dissolved in dichloromethane and extracted with 1M HCl three times. Aqueous extract was neutralized with 4M NaOH and extracted with dichloromethane three times. Organic phase was dried over anhydrous sodium sulfate and the solvent was removed under low pressure. Resulting residue was analyzed with no further purification unless otherwise stated.

General procedure for synthesis of tertiary amines (ketones):

In a 5 dram vial containing 1-hydrosilatrane (2 mmol) was added ketone (1 mmol), secondary amine (1.2 mmol) and 0.2 mL solvent. The vial was sealed and heated at 70oC overnight. Resulting residue was dissolved in dichloromethane and extracted with 1M HCl three times. Aqueous extract was neutralized with 4M NaOH and extracted with dichloromethane three times. Organic phase was dried over anhydrous sodium sulfate and the solvent was removed under low pressure. Resulting residue was analyzed with no further purification unless otherwise stated.

178 N,N-Diethyl (4-Methylbenzyl)amine (46)

1 H NMR (300 MHz, CDCl3): δ = 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 3.55 (s, 2H), 2.53 (q, J

13 = 7.0 Hz, 4H), 2.35 (s, 3H), 1.06 (t, J = 7.0 Hz, 6H). C NMR (75 MHz, CDCl3): δ = 136.8, 136.2, 128.9,

128.8, 57.2, 46.6, 21.1, 11.7. IR (ATR): 2968, 2931, 2797, 1668, 1514, 1454, 1369, 1292, 1205, 1167,

1059, 802, 756 cm-1.

179 N,N-Diethyl benzylamine (47)

1 H NMR (500 MHz, CDCl3): δ =7.37-7.32 (m, 4H), 7.26 (tt, J = 1.5, 7.0 Hz, 1H), 3.60 (s, 2H), 2.55 (q, J =

13 7.0 Hz, 4H), 1.07 (t, J = 7.0 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 140.0, 128.9, 128.1, 126.7, 57.5,

46.7, 11.8. IR (ATR): 2968, 2993, 2796, 1454, 1385, 1371, 1205, 1167, 1072, 1028, 777, 729, 696 cm-1.

180 N,N-Diisopropyl benzylamine (48)

1 H NMR (300 MHz, CDCl3): δ = 7.40 (d, J = 7.0 Hz, 2H), 7.30 (t, J = 7.0 Hz, 2H), 7.21 (t, J = 7.0 Hz, 1H),

3.66 (s, 2H), 3.04 (sept, J = 6.6 Hz, 2H), 1.04 (d, J = 6.6 Hz, 12H).

13 C NMR (75 MHz, CDCl3): δ = 143.3, 127.9, 127.9, 126.1, 48.9, 47.8, 20.8. IR (ATR): 2962, 2929, 1452,

1381, 1363, 1207, 1176, 1024, 953, 885, 750, 710, 694 cm-1.

181 Tribenzylamine (49)

1 H NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 7.0 Hz, 6H), 7.34 (td, J = 2.0, 7.0 Hz, 6H), 7.25 (tt, J = 1.5,

13 7.0 Hz, 3H) 3.59 (s, 6H). C NMR (125 MHz, CDCl3): δ = 139.7, 128.7, 128.2, 126.9, 57.9. IR (ATR): 3028,

2802, 1603, 1493, 1450, 1365, 1248, 1120, 1070, 1028, 991, 960, 741, 696 cm-1.

182 N-benzyl pyrrolidine (50)

1 H NMR (500 MHz, CDCl3): δ = 7.38-7.72 (m, 4H), 7.28-7.25 (m, 1H), 3.65 (s, 2H), 2.55-2.53 (m, 4H),

13 1.83-1.80 (m, 4H). C NMR (125 MHz, CDCl3): δ = 139.5, 128.9, 128.2, 126.9, 60.8, 54.2, 23.5. IR (ATR):

2964, 2783, 1493, 1454, 1375, 1348, 1124, 1074, 1028, 906, 876, 737, 696 cm-1.

183 N,N-Diisopropyl-(4-methylbenzyl)amine (51)

1 H NMR (500 MHz, CDCl3): δ = 7.29 (d, J = 7.5 Hz, 2H), 7.12 (d, J = 7.5 Hz, 2H), 3.63 (s, 2H), 3.04 (sept,

13 J = 6.5 Hz, 2H), 2.36 (s, 3H), 1.04 (d, J = 6.5 Hz, 12H). C NMR (125 MHz, CDCl3): δ = 140.1, 135.6,

128.7, 127.8, 48.5, 47.6, 21.1, 20.8. IR (ATR): 2962, 2927, 1512, 1464, 1381, 1361, 1207, 1176, 1115,

804 cm-1.

184 N,N-Dibenzyl (4-Methylbenzyl)amine (52)

1 H NMR (500 MHz, CDCl3): δ = 7.43 (d, J = 7.5 Hz, 4H), 7.35-7.31 (m, 6H), 7.25 (t, J = 7.5 Hz, 2H), 7.15

13 (d, J = 8.0 Hz, 2H), 3.57 (s, 4H), 3.55 (s, 2H), 2.35 (s, 3H). C NMR (125 MHz, CDCl3): δ = 139.7, 136.5,

136.4, 128.9, 128.7, 128.7, 128.2, 126.8, 57.8, 57.6, 21.1. IR (ATR): 3030, 2925, 2802, 1514, 1493,

1450, 1363, 1248, 1119, 968, 808, 746, 698 cm-1.

185 N,N-methyl(4-methylbenzyl) aniline (53)

1 H NMR (300 MHz, CDCl3): δ = 7.28-7.21 (m, 2H), 7.15 (s, 4H), 6.78 (dd, J = 0.6, 8.7 Hz, 2H), 6.73 (tt, J

13 = 7.5, 0.9 Hz, 1H), 4.52 (s, 2H), 3.02 (s, 3H), 2.35 (s, 3H). C NMR (75 MHz, CDCl3): δ = 149.8, 136.4,

135.9, 129.2, 129.1, 126.7, 116.4, 112.4, 56.4, 38.4, 21.1. IR (ATR): 2920, 1599, 1506, 1374, 1348,

1211, 1115, 796, 746, 690 cm-1.

186 N-(4-Methylbenzyl) pyrrolidine (54)

1 H NMR (300 MHz, CDCl3): δ =7.23 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 3.60 (s, 2H), 2.54-2.49

13 (m, 4H), 2.35 (s, 3H), 1.82-1.77 (m, 4H). C NMR (75 MHz, CDCl3): δ = 136.4, 128.9, 60.4, 54.1, 23.4,

21.1. IR (ATR): 2964, 2779, 1514, 1458, 1444, 1375, 1124, 879, 806, 754 cm-1.

187 N,N-Diethyl (4-Methoxybenzyl)amine (55)

1 H NMR (500 MHz, CDCl3): δ = 7.26 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 3.83 (s, 3H), 3.53 (s,

13 3H), 2.53 (q, J = 7.0 Hz, 4H), 1.06 (t, J = 7.0 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 158.5, 131.8,

130.0, 113.5, 56.8, 55.3, 46.5, 11.7. IR (ATR): 2966, 2798, 1610, 1585, 1510, 1464, 1300, 1244, 1171,

1038, 829, 771, 754 cm-1.

188 N,N-Dibenzyl (4-Methoxybenzyl)amine (56)

1 H NMR (300 MHz, CDCl3): δ = 7.44-7.41 (m, 4H), 7.36-7.31 (m, 6H), 7.24 (tt, J = 1.5 Hz, 7.0 Hz, 2H),

6.88 (td, J = 2.5 ,9.0 Hz, 2H), 3.82 (s, 3H), 3.56 (s, 4H), 3.52 (s, 2H).

13 C NMR (75 MHz, CDCl3): δ = 158.6, 139.8, 131.6, 129.9, 128.7, 128.2, 126.8, 113.6, 57.8, 57.2, 55.3.

IR (ATR): 3026, 2931, 2792, 1610, 1585, 1510, 1452, 1246, 1036, 810, 741, 696 cm-1.

189 N-(4-methoxybenzyl)-N-methylaniline (57)

1 H NMR (300 MHz, CDCl3): δ =7.24 (dd, J = 7.2, 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz,

2H), 6.78 (dd, J = 0.9, 8.7 Hz, 2H), 6.73 (td, J = 0.9, 4.2 Hz, 1H), 4.49 (s, 2H), 3.81 (s, 3H), 3.00 (s,

13 3H). C NMR (75 MHz, CDCl3): δ = 158.6, 149.8, 130.9, 129.2, 128.0, 116.5, 113.9, 112.5, 56.0, 55.3,

38.3. IR (ATR): 2899, 2833, 1599, 1506, 1244, 1171, 1034, 814, 746, 692 cm-1.

190 N,N-Diethyl (4-chlorobenzyl)amine (62)

1 H NMR (300 MHz, CDCl3): δ = 7.28 (s, 4H), 3.53 (s, 2H), 2.51 (q, J = 7.0 Hz, 4H), 1.04 (t, J = 7.0 Hz,

13 6H). C NMR (75 MHz, CDCl3): δ = 138.7, 132.2, 130.1, 128.2, 56.9, 46.7, 11.8. IR (ATR): 2968, 2933,

2800, 1489, 1454, 1385, 1205, 1167, 1086, 1014, 804, 769 cm-1.

191 N,N-Dibenzyl (4-chlorobenzyl)amine (63)

1 13 H NMR (500 MHz, CDCl3): δ = 7.42-7.31 (m, 12H), 7.25-7.22 (m, 2H), 3.56 (s, 4H), 3.53 (s, 2H). C NMR

(125 MHz, CDCl3): δ = 139.3, 138.2, 132.5, 130.0, 128.7, 128.4, 128.3, 126.9, 57.9, 57.2. IR (ATR):

3027, 2796, 1491, 1452, 1365, 1242, 1088, 1014, 972, 800, 744, 696 cm-1.

192 N,N-Diethyl (4-Nitrobenzyl)amine (65)

1 H NMR (300 MHz, CDCl3): δ = 8.18 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 3.66 (s, 2H), 2.54 (q, J

13 = 7.0 Hz, 4H), 1.05 (t, J = 7.0 Hz, 6 H). C NMR (75 MHz, CDCl3): δ = 148.7, 146.9, 129.1, 123.4 57.2,

47.1, 11.9. IR (ATR): 2970, 2808, 1599, 1518, 1342, 1107, 1063, 852, 737 cm-1.

193 N,N-Diethyl (4-phenylbenzyl)amine (67)

1 H NMR (500 MHz, CDCl3): δ = 7.63 (dd, J = 1.5, 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.48-7.43 (m, 4H),

7.36 (tt, J = 1.0, 6.5 Hz, 1H), 3.64 (s, 2H), 2.59 (q, J = 7.0 Hz, 4H), 1.10 (t, J = 7.0 Hz, 6H). 13C NMR

(125 MHz, CDCl3): δ = 141.1, 139.6, 139.2, 129.3, 128.7, 127.1, 126.9, 57.2, 46.8, 11.8. IR (ATR): 2968,

2798, 1487, 1383, 1070, 845, 754, 696 cm-1.

194 N,N-Diethyl (4-Cyanobenzyl)amine (66)

1 H NMR (300 MHz, CDCl3): δ =7.61 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 3.61 (s, 2H), 2.52 (q, J =

13 7.0 Hz, 4H), 1.04 (t, J = 7.0 Hz, 6H). C NMR (75 MHz, CDCl3): δ = 146.4, 132.0, 129.2, 119.1, 110.4,

57.4, 47.1, 11.9. IR (ATR): 2970, 2806, 2227, 1608, 1385, 1063, 814, 546 cm-1.

195 N,N-Diethyl (3-Methoxybenzyl)amine (58)

1 H NMR (500 MHz, CDCl3): δ = 7.24 (t, J = 8.0 Hz, 1H), 6.95-6.94 (m, 2H), 6.82-6.79 (m, 1H), 3.84 (s,

3H), 3.57 (s, 2H), 2.55 (q, J = 7.0 Hz, 4H), 1.07 (t, J = 7.0 Hz, 6H).

13 C NMR (125 MHz, CDCl3): δ = 159.6, 141.8, 129.0, 121.2, 114.3, 112.2, 57.6, 55.2, 46.8, 11.8. IR

(ATR): 2968, 2798, 1599, 1585, 1487, 1263, 1149, 1049, 783, 692 cm-1.

196 N,N-Diethyl (3-fluorobenzyl)amine (64)

1 H NMR (300 MHz, CDCl3): δ = 7.30-7.23 (m, 1H), 7.12-7.09 (m, 2H), 6.96-6.90 (m, 1H), 3.57 (s, 2H),

13 2.53 (q, J = 7.0 Hz, 4H), 1.05 (t, J = 7.0 Hz, 6H). C NMR (75 MHz, CDCl3): δ = 163.0 (d, J = 244 Hz, C-

1), 143.1 (d, J = 7.0 Hz, C-3), 129.4 (d, J = 7.0 Hz, C-5), 124.2 (d, J = 2 Hz, C-4), 115.4 (d, J = 13.5 Hz,

C-2), 113.5 (d, J = 21 Hz, C-5), 57.1, 46.8, 11.8. IR (ATR): 2970, 2798, 1589, 1485, 1446, 1254, 785,

746, 685 cm-1.

197 N-(4-(benzyloxy)benzyl)-N-ethylethanamine (59)

1 H NMR (300 MHz, CDCl3): δ = 7.48-7.40 (m, 3H), 7.38-7.34 (m, 2H), 7.26 (d, J = 9.0 Hz, 2H), 6.94 (d, J

= 9.0 Hz, 2H), 5.07 (s, 2H), 3.53 (s, 2H), 2.53 (q, J = 7.2 Hz, 4H), 1.06 (t, J = 7.2 Hz, 6H). 13C NMR (75

MHz, CDCl3): δ = 157.7, 137.2, 132.2, 130.0, 128.6, 127.9, 127.5, 114.5, 70.0, 56.8, 46.7, 11.7. IR

(ATR): 2968, 2798, 1610, 1508, 1234, 1024, 831, 733, 696 cm-1.

198 N,N,N’,N’-Tetraethyl-1,4-benzenedimethanamine (71)

1 H NMR (500 MHz, CDCl3): δ = 7.29 (s, 4H), 3.57 (s, 4H), 2.54 (q, J = 7.0 Hz, 8H), 1.07 (t, J = 7.0 Hz,

13 12H). C NMR (125 MHz, CDCl3): δ = 138.2, 129.1, 128.8, 126.9, 57.2, 46.7, 11.7. IR (ATR): 2968, 2798,

1456, 1383, 1059, 810, 756, 546 cm-1.

199 N,N-Diethyl-3-phenyl-2-propen-1-amine (72)

1 H NMR (300 MHz, CDCl3): δ =7.42-7.39 (m, 2H), 7.35-7.30 (m, 2H), 7.26-7.24 (m, 1H), 6.54 (d, J = 16.0

Hz, 1H), 6.32 (dt, J = 6.5, 16 Hz, 1H), 3.28 (dd, J = 1.0, 6.5 Hz, 2H), 2.60 (q, J = 7.0 Hz, 4H), 1.09 (t, J

13 = 7.0 Hz, 6H). C NMR (75 MHz, CDCl3): δ = 137.2, 132.1, 128.5, 127.8, 127.3, 126.2, 55.6, 46.7, 11.7.

IR (ATR): 2968, 2800, 1448, 1359, 1199, 1068, 966, 735, 690, 561 cm-1.

200 4-(3-phenyl-2-propen-1-yl)Morpholine (73)

1 H NMR (500 MHz, CDCl3): δ =7.39 (d, J = 7.0 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.26-7.23 (m, 1H), 6.55

(d, J = 16 Hz, 1H), 6.27 (dt, J = 7.0, 16.0 Hz, 1H), 3.75 (t, J = 4.5 Hz, 4H), 3.17 (dd, J = 1.0, 7.0 Hz,

13 2H), 2.52 (s, 4H). C NMR (125 MHz, CDCl3): δ = 137.0, 133.6, 128.8, 127.8, 126.5, 126.2, 67.2, 61.7,

53.9. IR (ATR): 2956, 2806, 1452, 1115, 868, 740, 692 cm-1.

201 1-(3-phenyl-2-propen-1-yl)-L-proline methyl ester (74)

1 H NMR (500 MHz, CDCl3): δ = 7.36 (d, J = 7.0 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.23 (tt, J = 1.5, 7.0 Hz,

1H), 6.52 (d, J = 16 Hz, 1H), 6.33 (dt, J = 7.0, 16.0 Hz, 1H), 3.66 (s, 3H), 3.44 (qd, J = 1.5, 7.0 Hz, 1H),

3.32 (qd, J = 1.5, 7.0 Hz, 1H), 3.24-3.18 (m, 2H), 2.43 (q, J = 8.5 Hz, 1H), 2.20-2.13 (m, 1H), 2.00-1.92

13 (m, 2H), 1.85-1.81 (m, 1H). C NMR (125 MHz, CDCl3): δ = 174.9, 137.1, 132.7, 128.7, 127.7, 127.1,

126.5, 65.7, 57.4, 54.0, 52.1, 29.8, 23.3. IR (ATR): 2949, 2796, 1732, 1435, 1363, 1277, 1187, 966, 744,

692 cm-1.

202 N,N-Diethyl(Naphthalen-1-yl)methanamine (68)

1 H NMR (500 MHz, CDCl3): δ = 8.38 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),

7.55-7.51 (m, 3H), 7.47-7.43 (m, 1H), 4.03 (s, 2H), 2.64 (dq, J = 2.5, 7.0 Hz, 4H), 1.12 (dt, J = 2.5, 7.0

13 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 135.8, 133.8, 132.5, 128.4, 127.5, 127.0, 125.6, 125.5, 125.2,

124.6, 56.1, 47.0, 11.6. IR (ATR): 2968, 2794, 1510, 1468, 1383, 1167, 1055, 779 cm-1.

203 N,N-dibenzyl (naphthyl)amine (69)

1 H NMR (300 MHz, CDCl3): δ = 8.13 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H),

7.62 (d, J = 7.0 Hz, 1H), 7.48-7.45 (m, 3H), 7.43-7.25 (m, 12H), 4.00 (s, 2H), 3.61 (s, 4H). 13C NMR (75

MHz, CDCl3): δ = 139.5, 135.1, 133.8, 132.4, 129.1, 128.2, 127.8, 127.3, 126.9, 125.5, 125.4, 125.1,

124.9, 58.5, 56.7. IR (ATR): 3028, 2806, 1493, 1450, 1363, 1109, 968, 804, 752, 739, 698 cm-1.

204 N-(Naphthanlen-1-yl)methyl pyrrolidine (70)

1 H NMR (500 MHz, CDCl3): δ = 8.32 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H),

7.57-7.51 (m, 3H), 7.47-7.44 (m, 1H), 4.09 (s, 2H), 2.64-1.61 (m, 4H), 1.84-1.81 (m, 4H). 13C NMR (125

MHz, CDCl3): δ = 135.5, 133.8, 132.3, 128.4, 127.6, 126.6, 125.8, 125.5, 125.3, 124.5, 58.5, 54.5, 23.6.

IR (ATR): 2962, 2789, 1508, 1346, 1120, 791, 775 cm-1.

205 N,N-Diethyl-2-pyridinemethanamine (77)

1 H NMR (500 MHz, CDCl3): δ = 8.55 (dd, J = 1.0, 4.5 Hz, 1H), 7.68-7.64 (m, 1H), 7.50 (d, J = 7.5 Hz, 1H),

7.16 (dd, J = 5.5, 7.0 Hz, 1H), 3.75 (s, 2H), 2.61 (q, J = 7.0 Hz, 4H), 1.08 (t, J = 7.0 Hz, 6H). 13C NMR

(125 MHz, CDCl3): δ = 160.7, 149.0, 136.3, 122.9, 121.7, 59.6, 47.4, 11.9. IR (ATR): 2968, 2804, 1589,

1471, 1433, 1064, 1012, 787, 752 cm-1.

206 N,N-Diethyl-(4-triisopropylsiloxybenzyl)amine (60)

1 H NMR (500 MHz, CDCl3): δ = 7.16 (t, J = 8.0 Hz, 1H), 6.92 (t, J = 2.0 Hz, 2H), 6.77 (dd, J = 1.5, 8.0 Hz,

1H), 3.54 (s, 2H), 2.52 (q, J = 7.0 Hz, 4H), 1.28 (sept, J = 7.5 Hz, 3H), 1.12 (d, J = 7.0 Hz, 18H), 1.06

13 (t, J = 7.0 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 155.9, 141.6, 128.9, 121.6, 120.4, 118.1, 57.4, 46.7,

17.9, 12.7, 11.9. IR (ATR): 2964, 2943, 2868, 2794, 1603, 1585, 1485, 1275, 881, 829, 683 cm-1.

207 N,N-methyl(3-triisopropylsilyloxybenzyl) aniline (61)

1 H NMR (500 MHz, CDCl3): δ = 7.25-7.21 (m, 2H), 7.18 (t, J = 8.0 Hz, 1H), 6.83 (dd, J = 0.5, 7.5 Hz, 1H),

6.79-6.71 (m, 5H), 4.52 (s, 2H), 3.03 (s, 3H), 1.21-1.13 (m, 3H), 1.06 (d, J = 7.5 Hz, 18H). 13C NMR (125

MHz, CDCl3): δ = 156.4, 149.6, 140.5, 129.5, 129.1, 119.4, 118.4, 118.1, 116.5, 112.4, 56.3, 38.6, 18.0,

17.9, 12.6. IR (ATR): 2943, 2866, 1599, 1506, 1277, 976, 881, 746, 688 cm-1.

208 N-((4-methylphenyl)methylene)-1-propanamine (X)

1 H NMR (500 MHz, CDCl3): δ = 8.26 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 3.59 (td, J

= 1.0, 7.0 Hz, 2H), 2.41 (s, 3H), 1.75 (dt, J = 7.0, 14.5 Hz, 2H), 0.98 (t, J = 7.0 Hz, 3H). 13C NMR (125

MHz, CDCl3): δ = 160.7, 140.7, 133.8, 129.3, 128.0, 63.6, 24.1, 21.5, 11.9. IR (ATR): 2958, 2926, 2833,

1647, 1452, 1173, 968, 812, 698 cm-1.

209 N,N-Dimethyl-(1-phenylethyl)amine (79)

1 H NMR (500 MHz, CDCl3): δ = 7.36-7.31 (m, 4H), 7.27-7.25 (m, 1H), 3.27 (q, J = 6.5 Hz, 1H), 2.23 (s,

13 6H), 1.40 (d, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ =144.2, 128.2, 127.5, 126.9, 66.0, 43.3, 20.3.

IR (ATR): 2976, 2814, 2765, 1450, 955, 756, 700 cm-1.

210 1-(1-phenylethyl)pyrrolidine (81)

1 H NMR (500 MHz, CDCl3): δ = 7.35-7.33 (m, 4H), 7.27-7.25 (m, 1H), 3.20 (q, J = 6.5 Hz, 1H), 2.57 (m,

13 2H), 2.40 (m, 2H), 1.80-1.77 (m, 4H), 1.43 (d, J = 6.5 Hz, 3H). C NMR (75 MHz, CDCl3): δ = 145.8,

128.2, 127.2, 126.8, 66.0, 53.0, 23.4, 23.2. IR (ATR): 2968, 2777, 1452, 1144, 762, 700 cm-1.

211 1-(N-Morpholino)-1-phenylethane (80)

1 H NMR (500 MHz, CDCl3): δ =7.34 (d, J = 4.0 Hz, 4H), 7.28-7.25 (m, 1H), 3.71 (td, J = 1.0, 4.0 Hz, 4H),

3.32 (q, J = 6.5 Hz, 1H), 2.5 (m, 2H), 2.41-2.37 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz,

CDCl3): δ = 144.0, 128.3, 127.7, 127.0, 67.3, 65.4, 51.3, 19.9. IR (ATR): 2962, 2856, 2808, 1450, 1117,

910, 729, 702 cm-1.

212 N-(1-(4-nitrophenyl)ethyl)pyrrolidine (83)

1 H NMR (500 MHz, CDCl3): δ = 8.19 (d, J = 9.0 Hz, 2H), 7.54 (d, J = 9.0 Hz, 2H), 3.32 (q, J = 6.5 Hz, 1H),

2.59-2.54 (m, 2H), 2.41-2.37 (m, 2H), 1.80 (dt, J = 3.0, 6.5 Hz, 4H), 1.41 (d, J = 6.5 Hz, 3H). 13C NMR

(125 MHz, CDCl3): δ = 153.8, 146.9, 127.9, 123.7, 65.4, 52.9, 23.4, 23.3. IR (ATR): 2970, 2789, 1516,

1344, 854, 756, 700 cm-1.

213 1-(2-methyl-1-phenylpropyl) (84)

1 H NMR (300 MHz, CDCl3): δ = 7.30-7.23 (m, 5H), 3,01 (d, J = 5.0 Hz, 1H), 2.46 (m, 2H), 2.40 (m, 2H),

2.19 (septd, J = 1.5, 7.0 Hz, 1H), 1.73 (m, 4H), 0.84 (d, J = 7.0 Hz, 3H), 0.77 (d, J = 7.0 Hz, 3H). 13C

NMR (125 MHz, CDCl3): δ = 139.9, 129.5, 127.3, 126.5, 52.1, 30.5, 23.2, 20.6, 16.4. IR (ATR): 2962,

2779, 1452, 1365, 1132, 889, 750, 704 cm-1.

214 N-Cyclohexylpyrrolidine (85)

1 H NMR (500 MHz, CDCl3): δ = 2.59-2.57 (m, 4H), 2.00-1.94 (m, 3H), 1.80-1.75 (m, 6H), 1.64-1.61 (m,

13 1H), 1.32-1.13 (m, 5H). C NMR (125 MHz, CDCl3): δ = 63.9, 51.6, 32.3, 26.1, 25.3, 23.2. IR (ATR):

2926, 2854, 2775, 1448, 1128, 885 cm-1.

215 1-(octan-2-yl)pyrrolidine (86)

1 H NMR (500 MHz, CDCl3): δ = 2.56 (s, 4H), 2.24-2.21 (m, 1H), 1.79-1.77 (m, 4H), 1.63-1.59 (m, 1H),

13 1.37-1.29 (m, 9H), 1.08 (d, J = 6.5 Hz, 3H), 0.90 (t, J = 6.5 Hz, 3H). C NMR (125 MHz, CDCl3): δ = 59.4,

51.5, 35.5, 31.9, 29.7, 25.9, 23.4, 22.7, 18.1, 14.1. IR (ATR): 2958, 2927, 2858, 2777, 1458, 1377,

1167, 1113, 723 cm-1.

216 1-(4-((methyl(phenyl)amino)methyl)phenyl)ethanone (88)

1 H NMR (500 MHz, CDCl3): δ = 7.94 (dd, J = 1.5, 7.0 Hz, 2H), 7.36 (d, J = 7.5 Hz, 2H), 7.25 (td, J = 2.5,

13 7.5 Hz, 2H), 6.78-6.75 (m, 3H), 4.61 (s, 2H), 3.07 (s, 3H), 2.61 (s, 3H). C NMR (125 MHz, CDCl3): δ =

197.8, 149.4, 144.9, 136.1, 129.3, 128.8, 126.8, 116.9, 112.4, 56.7, 38.8, 26.6. IR (ATR): 1680, 1599,

1506, 1265, 748, 690, 627 cm-1.

217 1-(4-((diethylamino)methyl)phenyl)ethanone (89)

1 H NMR (500 MHz, CDCl3): δ = 7.93 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 3.63 (s, 2H), 2.62 (s,

13 3H), 2.54 (q, J = 7.0 Hz, 4H), 1.07 (t, J = 7.0 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 198.0, 146.3,

135.8, 128.8, 128.3, 57.4, 47.0, 26.6, 11.9. IR (ATR): 2968, 2802, 1682, 1606, 1265, 823, 590 cm-1.

218 1-(4-((diethylamino)methyl)phenyl)ethanol (90)

1 H NMR (500 MHz, CDCl3): δ = 7.34 (s, 4H), 4.91 (q, J = 6.5 Hz, 1H), 3.58 (s, 2H), 2.54 (q, J = 7.0 Hz,

13 4H), 1.52 (d, J = 6.5 Hz, 3H), 1.06 (t, J = 7.0 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 144.3, 139.2,

129.1, 125.2, 70.3, 57.2, 46.6, 25.1, 11.7. IR (ATR): 3361, 2970, 1383, 1068, 731, 567 cm-1.

219

CHAPTER 5

SILICON PROTECTING GROUPS AS META-DIRECTING SUBSTITUENTS IN ELECTROPHILIC AROMATIC

SUBSTITUTION OF PHENOL

*This chapter is adapted in part from our publications.594, 619

5.1. Overview

The use of organosilicon protecting groups to reverse the strongly ortho para directing properties of phenol, into meta-directing species for electrophilic aromatic substitution was attempted without success. Further attempts were made in the absence of any silicon species, without improvement, leading to an ultimate termination of the project. However, an improved versatile one- pot synthesis of O-aryl carbamates was developed.

5.2. Introduction

Phenol derivatives are an important moiety in organic chemistry.620 Due to this ubiquity, regioselective functionalization of the aromatic ring is of great interest. The ortho-/para- directing properties of oxygen in electrophilic aromatic substitution are well known.620 However, the strong electron donating properties of the hydroxyl group make the synthesis of meta-substituted phenols extremely difficult. Although several different methods have been developed to circumvent the directing properties of phenols (see 1.8.2.), the methods involve multistep synthetic manipulations to temporarily add functionality that direct reactivity to the meta- positions.515 A more atom-economical, operationally simple method to obtain meta-substitution on phenols is still lacking from the synthetic repertoire, and would be highly desirable.

Interestingly, under the right conditions, the stereoelectronic properties of electron donating groups have been reversed, resulting in interesting reactivity patterns. The functional groups that have

220 been observed to have these properties have even been dubbed “stereoelectronic chameleons” (see

1.8.3).575 One such functional group is the methoxy group. Known for its electron donating properties, it has also been shown to stabilize benzylic anions on the para- position.589 By twisting orthogonal to the ring, oxygen lone pairs are twisted out of the plane of the ring, and the C-O σ* orbital is made available for hyperconjugation.

Along those lines, previous work in our group showed that varying the size of silicon protecting groups could had significant stereoelectronic effects.594 A series of silyloxybenzoic acids were synthesized and their acidity was tested in a standardized acid catalyzed reaction. The bulkier the silicon protecting group, the more acidic the silyloxybenzoic acid, with faster rate of reaction (Table

5.1).

Figure 5.1. Difference in alignment of oxygen lone pair in methoxy- and silyloxy benzoic acids.

The reasoning behind this was that the bulkier protecting group would twist the oxygen lone pair out of the plane of the ring, decreasing the oxygens ability to donate electrons into the ring. This in turn decreased the electron density at the carbonyl of the carboxylic acid, increasing the acidity.

The decrease in electron donation was supported by an observed decrease in the IR stretch of the carbonyl (Table 5.2).

221 Table 5.1. Effect of silicon bulk on catalytic ability.

Structure X Yield (%) v C=O (cm-1)

H 25 1677

OMe 14 1675

OSiMe2tBu 42 1673

OSi(iPr)3 45 1654

Table 5.2. Effect of silicon bulk on carbonyl stretch.

Structure X v C=O (cm-1)

OMe 1709

OSiMe2tBu 1715

OSi(iPr)3 1730

Computational studies supported the data, by suggesting that the lowest energy conformation for a bulky siloxy group would be orthogonal to the plane of the ring.

This led to the ideation of using bulky silicon protecting groups to change the oxygen on a phenol from a strongly electron donating, ortho-/para- directing group into an inductively electron withdrawing, meta- directing group. We decided to test the plausibility of this hypothesis by testing the regioselectivity of Friedel Crafts acylation on silicon protected phenols.

222 5.3. m-Directing Electrophilic Aromatic Substitution

5.3.1. Substrate synthesis

The study was initiated by synthesizing a series of silicon protected phenols (Table 5.3.).

Phenols were stirred in the presence of DBU, and chlorosilane was added to give protected phenols in high yields. The compounds seemed to be easy to isolate and handle. Due to free rotation around the

C-O bond, it was deemed likely that the siloxane would not remain orthogonal as it was only the theoretical minima. To favor the orthogonality of the silicon substituent, di-ortho-substituted phenols were also silylated.

Silylated resorcinol derivatives were also synthesized to take advantage of the steric hindrance of the siloxy groups (Table 5.4.). All three ortho positions should be sterically disfavored for EAS, favoring the meta position.

223 Table 5.3. Silylation of various phenol derivatives.

Entry R X Compound Yield (%)

1 H SitBu(Me)2 91 67

2 H SitBu(Ph)2 92 99

3 H Si(iPr)3 93 98

4 H Si(Et)3 94 79

5 Me Si(iPr)3 95 95

6 Me SitBu(Me)2 96 88

7 Me SitBu(Ph)2 97

8 Me Si(Et)3 98 55

9 Cl Si(iPr)3 99 84

10 Cl SitBu(Me)2 100

11 Cl Si(Et)3 101 82

Table 5.4. Silylation of resorcinol.

Entry X X Compound Yield (%)

1 Resorcinol SitBu(Ph)2 102 99

2 Resorcinol Si(iPr)3 103 89

224 5.3.2. Initial Studies

Problems arose as soon as we attempted our first Friedel Crafts acylation (Table 5.5.). Using standard acylating conditions with acetyl chloride and aluminium chloride (AlCl3) as the Lewis acid led to the formation of phenylacetate derivatives 104 and 105, indicating the cleavage of the silicon group. The conditions were changed to a less strong Lewis acid, Iron Chloride (FeCl3), which gave acylated product. However, acylation was observed exclusively on the para- position, as expected from a strongly electron donating group, with a bulky substituent sterically hindering the ortho- position.

However, these also gave para-substitution. As the rate of acylation is dependent on the electron density on the aromatic ring, it made sense that even though there would be relatively few high energy molecules with a lone pair aligned with the aromatic ring, electrophilic aromatic substitution would occur more readily via the ortho/para- directing activated parallel species.

The steric hindrance upon ortho positions in resorcinol did not seem to have much of an effect, as acylation occurred exclusively on the ortho/para- position (Figure 5.2).

225 Table 5.5. Friedel-Craft acylation on various silylated phenols.

Entry R X Compound M T (oC) t (h) Yield A B C Product

1 H Si(iPr)3 93 Al 22 24 A 104

2 Me SitBu(Me)2 96 Al 0 6 A 105

3 H Si(iPr)3 93 Fe 0 0.5 99 B 106

4 Me SitBu(Me)2 96 Fe 0 0.5 67 B 107

5 Me Si(iPr)3 95 Fe 0 0.5 99 B 108

6 Me Si(iPr)3 95 Fe -78 5 B

Figure 5.2. Friedel-Craft acylation of TIPS-protected resorcinol.

226 Whilst focusing on resorcinol derivatives, an alternative approach was devised, which took advantage of the steric bulk of the silicon protecting group instead of any electronic effects. It was conceived that making a half-sandwich chromium compound of silylated resorcinol, followed by deprotonation by a bulky lithium base like tert-butyl lithium, would lead to exclusive deprotonation at the meta-position, which could then lead to meta- substitution via electrophilic addition. However, joy of the discovery was rapidly gazumped by the unearthing of a paper from 1983 which had already done exactly what was proposed.621

Next, our focus turned towards other aromatic functionalization methods which could potentially favor meta substitution. Sanford et al. had reported a palladium catalyzed acetlyations using hypervalent iodide.622 Adapting these conditions, small amounts of meta substitution were observed with overall poor yields (Table 5.6.). The substitution pattern on the silicon did not seem to have a drastic effect on the selectivity, and due to the ortho/para- directing properties of methyl groups, it was difficult to conclude whether the meta selectivity was due to the orientation of the siloxane.

As a last-ditch effort to provide an advancement in the field of meta- directed substitution reactions, we turned our attention to work done by Gaunt et al.551-552 He had shown that ortho-/para- directing amido groups, as well as aryl carbonyl compounds, would undergo meta-arylation in the presence of a copper catalyst and hypervalent aryliodide. A screening of the literature showed that the same method had not been reported for O-aryl derivatives. An O-aryl carbamate was synthesized via an ad hoc one-pot method (see 5.4.2). This O-aryl carbamate was then subjected to the optimal reaction conditions reported by Gaunt et al., yet reaction was observed.

227 Table 5.6. meta-Acetoxylation reactions.

Entry X Yield (%) p m

1 Si(iPr)3 7 5 2

2 Si(iPr)3 25 18 7

3 SitBu(Me)2 30 20 10

Table 5.7. Arylation of O-aryl carbamates

Entry R T (oC) t(h) Yield (%)

5 H 85 48h n/r

6 NO2 80 20h n/r

7 NO2 85 48h n/r

228 As meta-substitution was only observed in small quantities and poor yields, a unanimous decision was made to terminate the project. Our one-pot synthesis for O-aryl carbamates was an improvement on the current methods reported in literature, leading us to test the scope of the method and cut our losses. In hindsight, the exclusive para- substitution during Friedel Crafts acylation of siloxybenzene could be justified by two known chemical factors which completely hindered our hypothesis. First, the β-silyl effect would stabilize any carbocation formed during EAS on the β-position via hyperconjugation (see 1.3.4.1.). The more orthogonal the Si-O bond was to the plane of the aromatic ring, the more aligned it was with the aromatic system, favoring overlap of orbitals and hence induced stability of the carbocation. Essentially, the electron donation by a lone pair was replaced by electron donation of the SI-O bond. Secondly, the ability to twist a lone pair out of the plane of conjugation to fully remove electron donation becomes practically impossible once there are more than one lone pair available (see 1.8.3.). Oxygen has two lone pairs, and once one lone pair is twisted out of the plane, the other lone pair becomes available. Although the electron donating properties are relatively lower for the second lone pair, they are still available to the aromatic ring.

5.4. O-Aryl Carbamates

O-aryl carbamates are an important class of molecules that have a wide range of uses (Figure

5.3). The pharmaceutical and medical industries have used them as acetylcholinesterase inhibitors for the treatment of debilitating neurodegenerative diseases such as Parkinsonism, myasthenia gravis, and

Alzheimer's disease (Figure 5.3 a. neostigmine b. rivastigmine).623-625 O-aryl carbamates have also been investigated as potential prodrugs for antineoplastic and antifungal drugs (Figure 5.3. c. matrix metalloproteinase-2 inhibitor).626-627 Additionally, they have been effectively used as intermediates for the synthesis of a range of antiviral, anti-infective, and antineoplastic drugs in the form of semicarbazides (Figure 5.3. d. Antifungal agent).628

229

Figure 5.3. O-aryl carbamate-containing active agents.

The agrochemical industry also has a use for O-aryl carbamates in the form of herbicides and insecticides, the difference being the substitution pattern on the O-aryl ring.568 O-aryl carbamates have also been used as synthetic intermediates for a variety of reactions using the carbamate functionality as a directing group (particularly for C-H activation at the ortho- position of the phenol) with lithium,629-630 and more recently rhodium,631 ruthenium,632 and palladium catalysts.633-636 They have also proven to be effective reagents for nickel-catalysed α-arylation of esters and amides, which can be further reacted to form -arylcarboxylic acids and -arylamines.637

An economical means of synthesising O-aryl carbamates has not been realised.628 Current methods include reaction of isolated carbamoyl chlorides with a substituted phenol,632,635,638 reaction of isolated aryl chloroformates with an amine,631,639 or copper catalysed oxidative cross-couplings of formamides and phenols.640-641 These reactions are limited by the availability of aryl chloroformates and carbamoyl chlorides, as well as the highly reactive nature of these compounds.

230 5.4.1. Methodology Development

In situ formation of the carbamoyl chloride followed by the nucleophilic attack of the aryloxide ion to yield O-aryl carbamates in good yields allows for a wide variety of substituents on the O-aryl ring and the nitrogen on the amine making the synthesis quite versatile (Figure 5.4).

The dropwise addition of pyridine to BTC (bis(trichloromethyl) carbonate, triphosgene) dissolved in dichloromethane to form pyridinium chlorocarbonyl chloride(A)642 has to be cooled down to

0°C in an ice bath as the reaction is highly exothermic and a rise in temperature releases excess amounts of toxic unreacted phosgene. For similar reasons, the selected amine (B) needs to be added in small portions whilst still cooled to 0°C. After B has displaced pyridine to form the corresponding carbamoyl chloride (C), dichloromethane and excess phosgene has to be removed under reduced pressure or the reaction will not proceed. However care must be taken in removing dichloromethane as extended periods under reduced pressure removes C and hence lower yields significantly.

Figure 5.4. Reaction route.

231 The selected phenol (D) is dissolved in pyridine and subsequently added to C and left to stir for a period of time varying from one hour to one day. Even though the reaction proceeds at ambient temperature for most of the compounds, running the reaction at 110°C generally gives higher yields and shortens the generalised reaction time to under six hours.643 After workup, the O-aryl carbamate

(E) can be easily purified via column chromatography or recrystallisation. It has been observed that the reaction does not proceed if attempted in "reverse", i.e. the in situ formation of the phenyl chloroformate (G) before the addition of B (Figure 5.5).

Figure 5.5. Formation of aryl chloroformate followed by addition of an amine is unsuccessful at

forming desired O-aryl carbamates.

5.4.2. Scope of O-aryl carbamate synthesis

A relatively large range of O-aryl carbamates were synthesized (Figure 5.6.). There seems to be no significant correlation between the identity of B and the overall yield of 112-125. Recent related work showed similar results,644 indicating that the N,N-dialkyl substituents on C do not have a significant effect on this reaction. An increase in the acidity of the phenol generally results in higher yields, as seen comparing 115 to 112, and 122 to 120. This suggests that the rate is dependent on the deprotonation of D by pyridine to give the highly nucleophilic phenoxide ion, which goes on to attack

232 C. In an effort to increase yield, the more basic triethylamine was used in place of pyridine; unfortunately this reaction did not proceed even with heating, resulting only in the generation of side- product F.

233

Figure 5.6. Scope of O-aryl carbamate synthesis. Isolated yields, b reactions run at room temperature.

234 5.5. Conclusion

The use of bulky silicon protecting groups to convert phenols from ortho-/para- directing into meta-directing groups in electrophilic aromatic substitution was unsuccessful. However, we have developed a versatile one-pot synthesis of O-aryl carbamates with a large scope of substituents providing high yields. This method is viable for a range of both phenols and disubstituted amines and does not require the isolation or handling of sensitive intermediates.

5.6. Experimental and Supplementary Information

General Infromation

Chemicals were obtained from Σ-Aldrich and Fisher Scientific. Column chromatography was performed using silica gel from Macherey-Nagel (60 M, 0.04-0.063 mm). 1H and 13C NMR data were recorded in CDCl3 on either a 300 or 500 MHz Bruker Avance III spectrometer at room temperature.

1 13 Chemical shifts are reported relative to residual CHCl3 (δ 7.24 ppm for H, δ 77.23 ppm for C). IR data was acquired using an ATI Mattson FTIR. MS data was obtained with a Shimadzu GCMS QC2010S at 275

°C.

General synthesis of O-aryl carbamates

To an oven-dried, argon-flushed 100 mL round-bottom flask was added, at 0 °C, BTC (1.5 mmol) and dichloromethane (7.5 mL) and was stirred for 5 min. Pyridine was added dropwise to form a pale yellow precipitate which redissolves after 20 min of continuous stirring. The amine was added in small portions and the mixture resulting in a red solution. This was then left to stir for 1 h at room temperature at which time the solution turned yellow. Dichloromethane was removed under reduced pressure to give a sludge. The phenol (1.5 mmol) was dissolved in pyridine (2.5 mL) and added to the sludge. The reaction was then heated at 110 °C and followed via TLC/GCMS until completion. The reaction was quenched with 25 mL ethyl acetate and washed twice with 50 mL 6 M hydrochloric acid.

235 The organic layer was dried with anhydrous granular sodium sulphate and the ethyl acetate removed under reduced pressure to give a crude product as either an oil or a solid which can then be purified by via column chromatography (9:1 hexanes/ethyl acetate) or recrystallisation from hot heptanes.

236 tertButyldimethyl(phenoxy)silane (91)

1 H NMR (500 MHz, CDCl3): δ = 7.28-7.25 (m, 2H), 6.98 (tt, J = 1.0, 2.0, 7.5 Hz, 1H), 6.89-6.86 (m, 2H),

13 1.026 (s, 9H), 0.23 (s, 6H). C NMR (125 MHz, CDCl3): δ = 155.7, 129.4, 121.3, 120.1, 25.7, 18.2, -4.4.

IR (ATR): 2955, 2919, 2859, 1595, 1491, 1259, 917, 839, 784 cm-1.

237 tertButyldiphenyl(phenoxy)silane (92)

1 H NMR (500 MHz, CDCl3): δ = 7.75 (dd, J = 1.5, 8.0 Hz, 2H), 7.45 (tt, J = 1.5, 2.5, 7.5 Hz, 2H), 7.04-

7.37 (m, 4H), 7.12 (ddd, J = 2.5, 4.5, 5.5 Hz, 2H), 6.88 (tt, J = 1.0, 7.0 Hz, 1H), 6.81-6.78 (m, 2H),

13 1.13 (s, 9H). C NMR (125 MHz, CDCl3): δ = 155.6, 135.5, 133.0, 129.8, 129.2, 127.7, 121.0, 119.7,

26.5, 19.5. IR (ATR): 3069, 2955, 2934, 2892, 2858, 1593, 1490, 1427, 1253, 1109, 914, 820, 694 cm-1.

238 Triisopropyl(phenoxy)silane (93)

1 H NMR (500 MHz, CDCl3): δ = 7.25 (t, J = 7.5 Hz, 2H), 6.97-6.88 (m, 3H), 1.33-1.17 (m, 3H), 1.12 (d, J

13 = 11.5 Hz, 18H). C NMR (125 MHz, CDCl3): δ = 156.1, 129.4, 121.0, 120.0, 18.0, 12.7. IR (ATR): 2944,

2866, 1595, 1492, 1469, 1259, 1068, 1002, 911, 883, 757, 683 cm-1.

239 Triethyl(phenoxy)silane (94)

1 H NMR (300 MHz, CDCl3): δ = 7.27-7.22 (m, 2H), 6.99-6.93 (m, 1H), 6.89-6.86 (m, 2H), 1.02 (t, J = 7.2

13 Hz, 9H), 0.76 (ddd, J = 1.2, 8.1, 19.2 Hz, 6H). C NMR (125 MHz, CDCl3): δ = 155.7, 129.4, 121.3,

120.0, 6.6, 5.1. IR (ATR): 2955, 2911, 2877, 1596, 1490, 1257, 1164, 1003, 907, 728, 690 cm-1.

240 1,3-bis((tert-butyldiphenylsilyl)oxy)benzene (102)

1 H NMR (300 MHz, CDCl3): δ = 7.61-7.58 (m, 8H), 7.42-7.37 (m, 4H), 7.33-7.27 (m, 6H), 6.81-6.76 (m,

13 1H), 6.31-6.28 (m, 3H), 1.03 (s, 18H). C NMR (125 MHz, CDCl3): δ = 156.3, 135.5, 132.9, 129.7, 129.1,

127.6, 113.0, 111.8, 26.5, 19.4.

241 1,3-bis((triisopropylsilyl)oxy)benzene (103)

1 H NMR (500 MHz, CDCl3): δ = 7.05 (t, J = 8.0 Hz, 1H), 6.51 (dd, J = 2.5, 8.0 Hz, 1H), 6.45 (t, J = 8.0 Hz,

13 1H), 1.31-1.22 (m, 6H), 1.12 (d, J = 7.0 Hz, 36H). C NMR (125 MHz, CDCl3): δ = 156.6, 129.5, 113.2,

112.0, 6.6, 5.0.

242 (2,6-dimethylphenoxy)triisopropylsilane (95)

1 H NMR (300 MHz, CDCl3): δ = 6.96 (d, J = 7.5 Hz, 2H), 6.78 (t, J = 7.5 Hz, 1H), 2.03 (s, 6H), 1.39-1.27

13 (m, 3H), 1.13 (d, J = 7.2 Hz, 18H). C NMR (125 MHz, CDCl3): δ = 153.4, 128.7, 128.1, 120.9, 18.0,

17.9, 14.2. IR (ATR): 2941, 2864, 1455, 1427, 1273, 1222, 1094, 1014, 999, 921, 884, 761, 678, 651 cm-

1.

243 tert-butyl(2,6-dimethylphenoxy)dimethylsilane (96)

1 H NMR (500 MHz, CDCl3): δ = 6.99 (d, J = 7.5 Hz, 2H), 6.82 (t, J = 7.5 Hz, 1H), 2.24 (s, 6H), 1.06 (s,

13 9H), 0.22 (s, 6H). C NMR (125 MHz, CDCl3): δ = 152.1, 128.7, 128.6, 121.2, 26.1, 18.8, 17.8, -2.9. IR

(ATR): 2954, 2931, 2858, 1593, 1469, 1437, 1263, 1215, 1096, 917, 835, 763, 678 cm-1.

244 tert-butyl(2,6-dimethylphenoxy)diphenylsilane (97)

1 H NMR (500 MHz, CDCl3): δ = 7.74 (d, J = 7.0 Hz, 2H), 7.45-7.42 (m, 2H), 7.39-7.36 (m, 4H), 6.62 (d, J

13 = 7.0 Hz, 2H), 6.80 (t, J = 7.5 Hz, 1H), 2.06 (s, 6H), 1.15 (s, 9H). C NMR (125 MHz, CDCl3): δ = 152.6,

135.1, 134.7, 129.6, 129.0, 128.1, 127.6, 121.1, 27.0, 20.3, 19.3. IR (ATR): 3070, 2957, 2932, 2858,

1593, 1471, 1426, 1272, 1218, 1107, 929, 923, 820, 763, 734, 700 cm-1.

245 (2,6-dimethylphenoxy)triethylsilane (98)

1 H NMR (500 MHz, CDCl3): δ = 7.02 (d, J = 7.0 Hz, 2H), 6.84 (t, J = 7.5 Hz, 1H), 2.29 (s, 6H), 1.07-1.00

13 (m, 9H), 0.86-0.82 (m, 6H). C NMR (125 MHz, CDCl3): δ = 152.9, 128.5, 128.3, 121.2, 17.6, 6.8, 6.5,

5.9.

246 (2,6-dichlorophenoxy)triisopropylsilane (99)

1 H NMR (500 MHz, CDCl3): δ = 7.26 (d, J = 8.0 Hz, 2H), 6.83 (t, J = 8.0 Hz, 1H), 1.48 (sept, J = 7.5 Hz,

13 3H), 1.16 (d, J = 7.5 Hz, 18H). C NMR (125 MHz, CDCl3): δ = 149.4, 128.7, 126.6, 121.7, 18.0, 14.1. IR

(ATR): 2945, 2868, 1564, 1459, 1301, 1071, 1016, 909, 883, 783, 768, 726, 713, 681, 653 cm-1.

247 tert-butyl(2,6-dichlorophenoxy)dimethylsilane (100)

1 H NMR (500 MHz, CDCl3): δ = 7.28 (d, J = 8.0 Hz, 2H), 6.53 (t, J = 8.0 Hz, 1H), 1.10 (s, 9H), 0.34 (s,

13 6H). C NMR (125 MHz, CDCl3): δ = 148.4, 128.8, 126.9, 122.0, 26.0, 18.9, -3.1. IR (ATR): 2953, 2933,

2891, 2859, 1565, 1455, 1257, 1072, 908, 785, 731 cm-1.

248 (2,6-dichlorophenoxy)triethylsilane (101)

1 H NMR (500 MHz, CDCl3): δ = 7.27 (d, J = 8.0 Hz, 2H), 6.85 (t, J = 8.0 Hz, 1H), 1.03 (t, J = 8.0 Hz, 9H),

0.96 (t, triethylsilylchloride impurity, 9H), 0.90-0.85 (m, 6H), 0.54 (q, triethylsilylchloride impurity,

13 6H). C NMR (125 MHz, CDCl3): δ = 150.0, 128.5, 126.9, 122.0, 6.8, 6.6, 6.4, 5.6.

249 4-acetylphenyl acetate (104)

1 H NMR (500 MHz, CDCl3): δ = 8.02 (dd, J = 2.0, 7.0 Hz, 2H), 7.22 (dd, J = 2.0, 6.5 Hz, 2H), 2.62 (s, 3H),

2.36 (s, 3H).

250 1-(4-((triisopropylsilyl)oxy)phenyl)ethanone (106)

1 H NMR (500 MHz, CDCl3): δ = 7.90 (ddd, J = 3.0, 6.5, 8.5 Hz, 2H), 6.92 (ddd, J = 3.0, 6.5, 8.5 Hz, 2H),

13 2.58 (s, 3H), 1.36-1.27 (m, 3H), 1.13 (d, J = 7.5 Hz, 18H). C NMR (125 MHz, CDCl3): δ = 196.9, 160.7,

130.6, 130.5, 119.7, 26.4, 17.9, 12.7.

251 1-(4-((triisopropylsilyl)oxy)2,6-dimethylphenyl)ethanone (108)

1 H NMR (500 MHz, CDCl3): δ = 7.62 (s, 2H), 2.55 (s, 3H), 2.31 (s, 6H), 1.40-1.28 (m, 3H), 1.12 (d, J = 7.5

13 Hz, 18H). C NMR (125 MHz, CDCl3): δ = 197.5, 158.3, 130.3, 129.6, 128.3, 26.4, 18.1, 17.9, 14.2.

252 4-acetyl-1,6-dimethylphenyl acetate (105)

1 H NMR (500 MHz, CDCl3): δ = 7.70 (s, 2H), 2.59 (s, 3H), 2.39 (s, 3H), 2.23 (s, 6H).

253 tert-butyl(4-acetyl-2,6-dimethylphenoxy)dimethylsilane (107)

1 13 H NMR (500 MHz, CDCl3): δ = 7.64 (s, 2H), 2.56 (s, 3H), 2.28 (s, 6H), 1.06 (s, 9H), 0.24 (s, 6H). C NMR

(125 MHz, CDCl3): δ = 197.5, 156.9, 130.6, 129.5, 128.8, 26.4, 26.0, 18.8, 17.9, -2.8.

254 2,4-bis((triisopropylsilyl)oxy)acetophenone (109)

1 H NMR (500 MHz, CDCl3): δ = 7.66 (d, J = 8.4 Hz, 1H), 6.51 (dd, J = 2.1, 8.4 Hz, 1H), 6.37 (d, J = 2.1

Hz, 1H), 2.61 (s, 3H), 2.19 (acetone impurity), 1.38-1.22 (m, 6H), 1.36-1.28 (m, 6H), 1.20-1.05 (m,

13 36H). C NMR (125 MHz, CDCl3): δ = 198.8, 160.8, 157.4, 132.0, 123.9, 113.3, 110.8, 31.3, 17.9, 17.8,

13.5, 12.7.

255 PARA: (4-acetoxy-2,6-dimethylphenoxy)triisopropylsilane (110)

1 H NMR (500 MHz, CDCl3): δ = 6.71 (s, 2H), 2.27 (s, 3H), 2.26 (s, 6H), 1.36-1.28 (m, 3H), 1.14 (d, J = 7.5

13 Hz, 9H). C NMR (125 MHz, CDCl3): δ = 169.8, 151.1, 143.9, 128.9, 121.2, 21.1, 18.0, 14.2.

256 META: (4-acetoxy-2,6-dimethylphenoxy)triisopropylsilane (111)

1 H NMR (500 MHz, CDCl3): δ = 6.97 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 2.31 (s, 3H), 2.67 (s,

13 3H), 2.09 (s, 3H), 1.37-1.31 (m, 3H), 1.14 (d, J = 7.5 Hz, 18H). C NMR (125 MHz, CDCl3): δ = 169.3,

154.1, 148.3, 128.0, 125.9, 121.0, 114.4, 20.8, 18.0, 17.9, 17.7, 14.2, 11.0.

257 Phenyl methoxy(methyl)carbamate (112)

1 H NMR (CDCl3, 500 MHz): δ = 7.40 (m; 2H), 7.25 (tt; J= 1, 7.5 Hz; 1H), 7.18 (m; 2H), 3.84 (s; 3H), 3.32

13 –1 (s; 3H). C NMR (CDCl3, 125 MHz): δ = 155.2, 150.9, 129.4, 125.7, 121.6, 61.8, 35.7. IR (cm ): v 1721,

1592, 1494, 1458, 1409, 1367, 1206, 1181, 1164, 1121, 1027, 962, 909, 838, 747, 689, 633, 600 cm–1. MS

(ESI): m/z (%) = 181 [M]+.

258 4-Acetylphenyl methoxy(methy)lcarbamate (113)

1 H NMR (CDCl3, 300 MHz): δ = 8.01 (d; J= 9 Hz; 2H), 7.28 (d; J=9 Hz; 2H), 3.83 (s; 3H), 3.32 (s; 3H),

13 2.62 (s; 3H). C NMR (CDCl3, 125 MHz): δ = 196.9, 154.6, 154.3, 134.5, 129.9, 121.7, 61.9, 35.6, 26.6.

IR (cm–1): v 1725, 1681, 1599, 1408, 1357, 1301, 1264, 1216, 1164, 1120, 1015, 958, 867 cm–1. MS (ESI): m/z (%) = 223 [M]+.

259 3-Nitrophenyl methoxy(methyl)carbamate (114)

1 H NMR (CDCl3, 500 MHz): δ = 8.14 (dt; J= 1.5, 7.5 Hz; 1H), 8.09 (t; J= 1.5 Hz; 1H), 7.59 (t; J= 8 Hz;

13 1H), 7.56 (dt; J= 1.5, 8.5 Hz; 1H), 3.85 (s; 3H), 3.35 (s; 3H). C NMR (CDCl3, 125 MHz): δ = 154.0,

151.3, 148.8, 129.9, 128.1, 120.6, 117.4, 61.9, 35.6. IR (cm–1): v 1726, 1526, 1472, 1442, 1410, 1347,

1276, 1219, 1182, 1121, 1024, 816, 735 cm–1. MS (ESI): m/z (%) = 226 [M]+.

260 4-Nitrophenyl methoxy(methyl)carbamate (115)

1 H NMR (CDCl3, 500 MHz): δ = 8.29 (d; J=15 Hz; 2H), 7.37 (d; J=15 Hz; 2H), 3.84 (s; 3H), 3.34 (s; 3H).

13 –1 C NMR (CDCl3, 125 MHz): δ = 155.7, 153.6, 145.1, 125.2, 122.2, 61.9, 35.6. IR (cm ): v 1725, 1612,

1594, 1512, 1468, 1438, 1397, 1343, 1237, 1154, 1109, 1018, 964, 862 cm–1. MS (ESI): m/z (%) = 226

[M]+.

261 2,6-Dichlorophenyl methoxy(methyl)carbamate (116)

Clear oil, Rf = 0.3 (9:1 hexanes/ethyl acetate), g, 0.132 mmol, 88%.

1 H NMR (CDCl3, 300 MHz): δ = 7.38 (d; J= 8.5 Hz; 2H), 7.16 (dd; J= 7.5, 8.5 Hz; 1H), 3.88 (s; 3H), 3.37

13 –1 (s; 3H). C NMR (CDCl3, 75 MHz): δ = 152.5, 143.9, 129.4, 128.6, 127.1, 61.9, 35.6. IR (cm ): v 1734,

1575, 1444, 1408, 1373, 1237, 1183, 1117, 1100, 1069, 1039, 1017, 956, 849, 834, 788, 773, 734, 712,

652, 610 cm–1. MS (ESI): m/z (%) = 249 (100%), 251 (64%) [M]+.

262 4-Formylphenyl dimethylcarbamate (117)

1 H NMR (CDCl3, 300 MHz): δ = 9.99 (s; 1H), 7.91 (d; J= 8.5 Hz; 2H), 7.32 (d; J= 8.5 Hz; 2H), 3.13 (s; 3H),

13 – 3.05 (s; 3H). C NMR (CDCl3, 75 MHz): δ = 191.0, 156.4, 153.9, 133.4, 131.1, 122.3, 36.8, 36.5. IR (cm

1): v 2251, 1719, 1696, 1601, 1486, 1446, 1386, 1300, 1212, 1153, 1065, 1011, 912, 859, 795, 728, 648 cm–1. MS (ESI): m/z (%) = 193 [M]+.

263 4-Acetylphenyl dimethylcarbamate (118)

1 H NMR (CDCl3, 300 MHz): δ = 7.99 (d; J= 8.5 Hz; 2H), 7.24 (d; J= 8.5 Hz; 2H), 3.13 (s; 3H), 3.05 (s; 3H),

13 2.61 (s; 3H). C NMR (CDCl3, 75 MHz): δ = 196.9, 155.3, 154.1, 134.1, 129.8, 121.7, 36.8, 36.5, 26.6. IR

(cm–1): v 1722, 1673, 1597, 1502, 1446, 1410, 1388, 1356, 1267, 1208, 1163, 1116, 1058, 1009, 958,

875, 807, 752, 587 cm–1. MS (ESI): m/z (%) = 207 [M]+.

264 4-Nitrophenyl dimethylcarbamate (119)

1 13 H NMR (CDCl3, 500 MHz): δ = 8.27 (d; J=9 Hz; 2H), 7.33 (d; J=9 Hz; 2H), 3.15 (s; 3H), 3.07 (s; 3H). C

–1 NMR (CDCl3, 125 MHz): δ = 156.4, 153.5, 144.8, 125.6, 125.2, 36.8, 26.6. IR (cm ): v 1699, 1612, 1593,

1519, 1447, 1394, 1336, 1282, 1217, 1159, 1109, 1059, 1007, 864, 745 cm–1. MS (ESI): m/z (%) = 210

[M]+.

265 2,6-Dichlorophenyl diethylcarbamate (120)

1 H NMR (CDCl3, 300 MHz): δ = 7.35 (d; J= 8.0 Hz; 2H), 7.11 (t; J= 8.0 Hz; 1H), 3.53 (q; J= 7.0 Hz; 2H),

13 3.43 (q; J= 7.0 Hz; 2H), 1.35 (t; J= 7.0 Hz; 3H), 1.24 (t; J= 7.0 Hz; 3H). C NMR (CDCl3, 75 MHz): δ =

151.8, 144.7, 129.7, 128.5, 126.5, 42.7, 42.3, 14.2, 13.3. IR (cm–1): v 1727, 1574, 1444, 1414, 1381,

1314, 1272, 1237, 1218, 1147, 1097, 1069, 1035, 952, 936, 786, 771, 746, 707 cm–1. MS (ESI): m/z (%) =

261 (100%), 263 (64%) [M]+.

266 4-Acetylphenyl diethylcarbamate (121)

1 H NMR (CDCl3, 500 MHz): δ = 7.99 (d; J=8.5 Hz; 2H), 7.25 (d; J= 8.5 Hz; 2H), 3.47 (q; J= 7, 7.5 Hz; 2H),

13 3.42 (q; J=7, 7.5 Hz; 2H), 2.62 (s; 3H), 1.29 (t; J= 7 Hz; 3H), 1.24 (t; J= 7 Hz; 3H). C NMR (CDCl3, 125

MHz): δ = 197.0, 155.4, 153.4, 133.9, 129.8, 121.7, 42.4, 42.0, 26.6, 14.3, 13.3. IR (cm–1): v 1716,

1681, 1599, 1506, 1473, 1417, 1359, 1264, 1206, 1149, 1098, 1077, 1039, 1014, 956, 864, 807, 781,

752, 589 cm–1. MS (ESI): m/z (%) = 235 [M]+.

267 4-Nitrophenyl diethylcarbamate (122)

1 H NMR (CDCl3, 500 MHz): δ = 8.27 (d; J=9 Hz; 2H), 7.33 (d; J=9 Hz; 2H), 3.47 (q; J= 7, 7.5 Hz; 2H), 3.42

13 (q; J= 7, 7.5 Hz; 2H), 1.29 (t; J= 7 Hz; 3H), 1.26 (t; J= 7 Hz; 3H). C NMR (CDCl3, 125 MHz): δ = 156.5,

152.8, 144.7, 125.0, 122.2, 42.5, 42.1, 14.26, 13.27 ppm. IR (cm–1): v 2977, 1719, 1613, 1594, 1519,

1473, 1418, 1343, 1272, 1229, 1208, 1146, 1098, 1083, 956, 861, 817, 783, 745, 688, 664 cm–1. MS (ESI): m/z (%) = 238 [M]+.

268 4-Formylphenyl 4-morpholinecarboxylate (123)

1 H NMR (CDCl3, 500 MHz): δ = 10.01 (s; 1H), 7.94 (d; J= 8.5 Hz; 2H), 7.33 (d; J= 8.5 Hz; 2H), 3.79 (t; J=

13 4.5 Hz; 4H), 3.72(br; 2H), 3.61(br; 2H). C NMR (CDCl3, 125 MHz): δ = 190.9, 156.0, 152.7, 133.6,

131.2, 122.3, 66.6, 66.5, 44.9, 44.2. IR (cm–1): v 1713, 1688, 1599, 1459, 1417, 1364, 1304, 1280, 1207,

1157, 1111, 1062, 994, 915, 859, 848, 806, 794, 647, 614, 573 cm–1. MS (ESI): m/z (%) = 235 [M]+.

269 4-Acetylphenyl 4-morpholinecarboxylate (114)

1 H NMR (CDCl3, 500 MHz): δ = 8.01 (d; J=9 Hz; 2H), 7.24 (d; J=9 Hz; 2H), 3.78 (t; J=5 Hz; 4H), 3.71 (br;

13 2H), 3.61 (br; 2H), 2.62 (s; 3H). C NMR (CDCl3, 125 MHz): δ = 196.9, 154.9, 152.9, 134.3, 129.9, 121.7,

66.6, 66.5, 44.9, 44.2, 26.6. IR (cm–1): v 1718, 1681, 1599, 1505, 1409, 1359, 1301, 1266, 1203, 1164,

1114, 1057, 1014, 989, 959, 855, 802, 749, 589 cm–1. MS (ESI): m/z (%) = 249 [M]+.

270 4-Cyanophenyl 4-morpholinecarboxylate (115)

1 H NMR (CDCl3, 300 MHz): δ = 7.69 (d; J= 9 Hz; 2H), 7.27 (d; J= 9 Hz; 2H), 3.77 (t; J= 4.5 Hz; 4H), 3.68

13 (br; 2H), 3.59 (br; 2H). C NMR (CDCl3, 75 MHz): δ = 154.6, 152.4, 133.6, 122.6, 118.3, 109.2, 66.4,

44.9, 44.2. IR (cm–1): v 2852, 2229, 1709, 1602, 1501, 1446, 1416, 1279, 1245, 1205, 1164, 1116, 1057,

1015, 990, 881, 855, 803, 749, 554 cm–1. MS (ESI): m/z (%) = 232 [M]+.

271

CHAPTER 6

CONCLUSIONS

1-Hydrosilatrane was shown to be an efficient reducing agent to convert ketones to secondary alcohols in the presence of a strong Lewis base. A large range of aromatic and aliphatic ketones were reduced in high yields. Due to the bulkiness of 1-Hydrosilatrane, high diastereoselectivity was observed when reducing sterically hindered chiral ketones. Enantioselectivity can be achieved by using a chiral Lewis base, with selectivities of up to 86% ee. However, excess chiral Lewis base is required. Furthermore, higher enantioselectivity is unlikely to be achieved with the proposed method as a less selective competing reaction is unavoidable. Further work into improving the conditions and testing a wider range of activators is necessary to obtain higher enantioselectivity.

The chemoselectivity of 1-hydrosilatrane was succesfuly exploited in the direct reductive aminations of aldehydes and ketones with secondary amines to form tertiary amines.This green process did not require an added activator, nor solvent. This made 1-hydrosilatrane a more practical candidate for direct reductive aminations than other common reducing agents.

Silicon protecting groups did not have a significant effect on changing the regioselectivity of phenol from ortho-/para- to meta- substitution in Friedel-Craft acylation. However, an efficient one-pot synthesis of O-aryl carbamates was developed that avoided tedious purification steps of hazardous intermediates.

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297

APPENDIX A

1H AND 13C NMR SPECTRA OF ALCOHOLS FROM KETONE REDUCTIONS 298 1-Hydrosilatrane (1):

299 (RS)-1-Phenylethanol (3):

300 (RS)-1-(2-Methoxphenyl)ethanol (4):

301 (RS)-1-(4-Methoxyphenyl)ethanol (5):

302 (RS)-1-(3,4,5-Trimethoxyphenyl)ethanol (6):

303 (RS)-1-(4-Allyloxyphenyl)ethan-1-ol (7):

304 (RS)-1-(4-Biphenylyl)ethanol (8):

305 (RS)-1-(4-Bromophenyl)ethanol (9):

306 (RS)-1-(4-Fluorophenyl)ethanol (10):

307 (RS)-1-(4-Nitrophenyl)ethanol (11):

308 (RS)-1-Phenylpropanol (12):

309 (RS)-2-Methyl-1-phenylpropanol (13):

310 (RS)-1,2,3,4-Tetrahydro-1-naphthalenol (14):

311 Diphenylmethanol (15):

312 (RS)-1-(2-Methylphenyl)-1-phenylmethanol (16):

313 (RS)-1-(4-Methylphenyl)-1-phenylmethanol (17):

314 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (18):

315 Cyclohexanol (19):

316 (RS)-2-Heptanol (20):

317 (RS)-2-Octanol (21):

318 (+)-Neomenthol (23):

319

APPENDIX B

GCMS, 1H AND 13C NMR SPECTRA OF ASYMMETRIC ALCOHOLS 320 4. Catalytic Experiments

Table 6.1. Catalytic Experiments.

Entry Ketone Ligand Ligand eq NaH eq Silatrane eq Solvent Solvent Amount Temperature Rxn time Conversion e:r 1 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 1.2 9.6 - THF 3 r.t 16 0 - 2 Acetophenone - - 8.5 - THF 3 r.t. 1 0 - 3 Acetophenone - - 17 0.3 THF 3 0 6 7 1:1 4 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.09 0.5 2.2 C6H6 1 -196->r.t 6 100 1:1 5 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.08 4 5.6 THF 3 r.t 1 100 52:48 6 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.08 5 3.4 THF 3 -30 6 14 61:39 7 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.1 0.6 2.2 THF 3 r.t 6 1 1:1 8 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.1 0.6 2.2 THF 3 r.t 24 2 1:1 9 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.2 1.2 2.2 THF 3 r.t 6 39 1:1 10 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.2 1.2 2.2 THF 3 r.t 24 44 1:1 11 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.3 1.8 2.4 THF 3 r.t 6 57 1:1 12 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.3 1.8 2.4 THF 3 r.t 24 64 1:1 13 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.4 2.4 2.1 THF 3 r.t 6 54 1:1 14 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.4 2.4 2.1 THF 3 r.t 24 61 1:1 15 Acetophenone (1S,2R)-2-Amino-1,2-diphenylethanol 0.6 3.4 2.1 THF 3 -30 6 34 7:3

The above table shows different experiments ran with substoichiometric amounts of Lewis base activator, in the reduction of acetophenone using 1-hydrosilatrane.

321 5. Chiral GCMS data

Table 6.2. Chiral GC/MS data.

Product Column flow Program tSM / min t(R)/ min t(S) / min (ml/min)

1.69 Ti 90°C, 0min, 16.6 28.4 30.8 0.5°C/min, Tf 112°C

1.42 Ti 130°C, 6.2 13.4 13.7 10min, 10°C/min, Tf 180°C, 15min

1.61 Ti 100°C, 19.2 31.3 32.8 0min, 1°C/min, Tf 145°C, 15min

1.77 Ti 100°C, 11.3 21.6 23.2 0min, 20°C/min, Tf 160°C, 30min

1.69 Ti 90°C, 0min, 15.0 23.2 24.1 10°C/min, Tf 134°C, 27.6min

1.42 Ti 130°C, 11.5 14.1 14.4 10min, 10°C/min, Tf 180°C, 15min

1.69 Ti 90°C, 0min, 7.1 31.2 32.9 1°C/min, Tf 114°C, 10min

1.69 Ti 90°C, 0min, 20.8 52.4 53.6 0.5°C/min, Tf 120°C, 3min

1.42 Ti 130°C, 16.4 19.3 19.5 10min, 10°C/min, Tf 180°C, 12min

322 Phenylethanol (36)

323 4-Methoxyphenylethanol (37)

324 2-Methoxyphenylethanol (38)

325 2-Naphthylethanol (39)

326 1-Tetralol (40)

327 2-Chloro-1-phenyl ethanol (41)

328 1-Phenyl propan-1-ol (42)

329 1-Phenyl-2-Methyl-Propan-1-ol (43)

330 Cyclohexylphenylmethanol (44)

331 Phenylethanol (36):

332 4-Methoxyphenyl ethanol (37): 333 2-Methoxyphenyl ethanol (38): 334 1-Naphthylethanol (39):

335 Tetralol (40):

336 2-Chloro-1-phenylethanol (41): 337 2-methyl-1-phenyl propanol (43):

338 cyclohexylphenylmethanol (44): 339 1-phenylpropanol (42):

340

APPENDIX C

1H AND 13C NMR SPECTRA OF SYNTHESIZED TERTIARY AMINES 341 N,N-Diethyl (4-Methylbenzyl)amine (46):

342 N,N-Diethyl benzylamine (47):

343 N,N-Diisopropyl benzylamine (48):

344 Tribenzylamine (49):

345 N-benzyl pyrrolidine (50):

346 N,N-Diisopropyl-(4-methylbenzyl)amine (51):

347 N,N-Dibenzyl (4-Methylbenzyl)amine (52):

348 N,N-methyl(4-methylbenzyl) aniline (53):

349 N-(4-Methylbenzyl) pyrrolidine (54):

350 N,N-Diethyl (4-Methoxybenzyl)amine (55):

351 N,N-Dibenzyl (4-Methoxybenzyl)amine (56):

352 N-(4-methoxybenzyl)-N-methylaniline (57):

353 N,N-Diethyl (4-chlorobenzyl)amine (62):

354 N,N-Dibenzyl (4-chlorobenzyl)amine (63):

355 N,N-Diethyl (4-Nitrobenzyl)amine (65):

356 N,N-Diethyl (4-phenylbenzyl)amine (67):

357 N,N-Diethyl (4-Cyanobenzyl)amine (66):

358 N,N-Diethyl (3-Methoxybenzyl)amine (58):

359 N,N-Diethyl (3-fluorobenzyl)amine (64):

360 N-(4-(benzyloxy)benzyl)-N-ethylethanamine (59):

361 N,N,N’,N’-Tetraethyl-1,4-benzenedimethanamine (71):

362 N,N-Diethyl-3-phenyl-2-propen-1-amine (72):

363 4-(3-phenyl-2-propen-1-yl)Morpholine (73):

364 1-(3-phenyl-2-propen-1-yl)-L-proline methyl ester (74):

365 N,N-Diethyl(Naphthalen-1-yl)methanamine (68):

366 N,N-dibenzyl (naphthyl)amine (69):

367 N-(Naphthanlen-1-yl)methyl pyrrolidine (70):

368 N,N-Diethyl-2-pyridinemethanamine (77):

369 N,N-Diethyl-(4-triisopropylsiloxybenzyl)amine (60):

370 N,N-methyl(3-triisopropylsilyloxybenzyl) aniline (61):

371 N-((4-methylphenyl)methylene)-1-propanamine (X):

372 N,N-Dimethyl-(1-phenylethyl)amine (79):

373 1-(1-phenylethyl)pyrrolidine (81):

374 1-(N-Morpholino)-1-phenylethane (80):

375 N-(1-(4-nitrophenyl)ethyl)pyrrolidine (83):

376 1-(2-methyl-1-phenylpropyl) (84):

377 N-Cyclohexylpyrrolidine (85):

378 1-(octan-2-yl)pyrrolidine (86):

379 1-(4-((methyl(phenyl)amino)methyl)phenyl)ethanone (88):

380 1-(4-((diethylamino)methyl)phenyl)ethanone (89):

381 1-(4-((diethylamino)methyl)phenyl)ethanol (90):

382

APPENDIX D

1H AND 13C NMR SPECTRA OF MATERIALS IN META-SUBSTITUTION PROJECT 383 tertButyldimethyl(phenoxy)silane (91):

384 tertButyldiphenyl(phenoxy)silane (92):

385 Triisopropyl(phenoxy)silane (93):

386 Triethyl(phenoxy)silane (94):

387 1,3-bis((tert-butyldiphenylsilyl)oxy)benzene (102):

388 1,3-bis((triisopropylsilyl)oxy)benzene (103):

389 (2,6-dimethylphenoxy)triisopropylsilane (95):

390 tert-butyl(2,6-dimethylphenoxy)dimethylsilane (96):

391 tert-butyl(2,6-dimethylphenoxy)diphenylsilane (97):

392 (2,6-dimethylphenoxy)triethylsilane (98):

393 (2,6-dichlorophenoxy)triisopropylsilane (99):

394 tert-butyl(2,6-dichlorophenoxy)dimethylsilane (100):

395 (2,6-dichlorophenoxy)triethylsilane (101):

396 4-acetylphenyl acetate (104):

397 1-(4-((triisopropylsilyl)oxy)phenyl)ethanone (106):

398 1-(4-((triisopropylsilyl)oxy)2,6-dimethylphenyl)ethanone (108):

399 4-acetyl-1,6-dimethylphenyl acetate (105):

400 tert-butyl(4-acetyl-2,6-dimethylphenoxy)dimethylsilane (107):

401 2,4-bis((triisopropylsilyl)oxy)acetophenone (109):

402 (4-acetoxy-2,6-dimethylphenoxy)triisopropylsilane (110):

403 (3-acetoxy-2,6-dimethylphenoxy)triisopropylsilane (111):

404

APPENDIX E

1H AND 13C NMR SPECTRA OF SYNTHESIZED O-ARYL CARBAMATES 405 phenyl methoxy(methyl)carbamate (112):

406 4-acetylphenyl methoxy(methyl)carbamate (113):

407 3-nitrophenyl methoxy(methyl)carbamate (114):

408 4-nitrophenyl methoxy(methyl)carbamate (115):

409 2,6-dichlorophenyl methoxy(methyl)carbamate (116):

410 4-formylphenyl dimethylcarbamate (117):

411 4-acetylphenyl dimethylcarbamate (118):

412 4-nitrophenyl dimethylcarbamate (119):

413 2,6-dichlorophenyl diethylcarbamate (120):

414 4-acetylphenyl diethylcarbamate (121):

415 4-nitrophenyl diethylcarbamate (122):

416 4-formylphenyl morpholine-4-carboxylate (123):

417 4-acetylphenyl morpholine-4-carboxylate (114):

418 4-cyanophenyl morpholine-4-carboxylate (115):