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MECHANISTIC INVESTIGATIONS OF [1 ,4]—W|TT|G
REARRANGEMENTS OF a-ALKOXYSILANES

presented by

EDITH NWAKAEGO ONYEOZILI

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MECHANISTIC INVESTIGATIONS OF
[1,4]-WITTIG REARRANGEMENTS OF a-ALKOXYSILANES
By
Edith Nwakaego Onyeozili

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Department of Chemistry

2005

ABSTRACT

MECHANISTIC INVESTIGATIONS OF
[1,4]-WITTIG REARRANGEMENTS OF ot-ALKOXYSILANES
By

Edith Nwakaego Onyeozili

The [1,4]-Wittig rearrangement pathway has remained a mechanism of many
questions. Whether it is a one step concerted process or a stepwise radical-radical anion
dissociation-recombination event and its synthetic capabilities are not fully explored.

This dissertation centers on the Wittig rearrangements of or-trimethylsilyl allyl
ethers. Key to this study was optimizing the [l,4]-Wittig rearrangement over competing
Wittig rearrangements. In the course of this study, we have demonstrated that by
employing a suitable substrate, reaction conditions could be tuned to give excellent
selectivity of the [l,4]- over the [1,2]-pathway. We have also shown that the [1,4]-Wittig
rearrangement of a-alkoxysilanes could be made efficient in terms of yield.

In pursuing our goal in understanding the mechanism of [1,4]-Wittig
rearrangement of a-alkoxysilanes, we showed that on deprotonation and bond
reorganization were separate events by generating and trapping the intermediate
carbanions prior to rearrangement. We also found that substitution at the migrating
carbon erodes the [1,4]/[1,2] selectivity, from almost exclusive (>100: 1) [1,4]-product for
the reaction of unsubstituted substrate, to approximately 2:1 [1,4]/[1,2] when a
substituent is present. Substitution at the terminal sp2 carbon of the allyl moiety also
impacts the [1,4]/[l,2] selectivity, albeit to a lower degree than substitution at the

migrating carbon, from > 100:1 [1 ,4]/[l ,2] in the absence of any substituent to

approximately 5:] [1,4]/[1,2] when the terminal sp2 carbon of the allyl moiety is
substituted.

Among the interesting observations we made is the fact that stereochemistry of
the Wittig substrate impacts the rearrangement. It was observed that for a pair of
diastereomeric or-trimethylsilyl allyl ethers, the syn diastereomer undergoes the Wittig
rearrangement readily, whereas the anti diastereomer reacts very sluggishly, requiring
severe conditions. A base such as n-BuLi allows the reactive syn-isomer to be
completely consumed with no significant transformation of the less-reactive anti-isomer,
kinetic resolution of diastereomeric ethers is feasible.

With respect to the stereochemistry, we determined that both the [1,2] and the
[1,4] pathways occurred predominantly with a retention of stereochemistry at the
migrating carbon. That said, enantiomeric ratio observed for the [1,4]-Wittig was lower
than for the [1,2]-Wittig. The [1,2]-pathway occurred with lower retention of
configuration (83% ee retention/92% er retention) than those typically found in [1,2]-
Wittig of allyl ethers (> 90%). On the other hand, the [1,4]-pathway occurred with 75%
ee (88% er) retention. In addition, the [1,4]-Wittig for both syn and anti substrates
occurred with similar levels of retention of configuration (75% and 74% respectively)
whereas there was significant difference in the levels of retention obtained for the [1,2]-
pathway (88% and 69% respectively). This result was viewed as evidence of different

mechanisms for both pathways.

To my parents
Late Clement Chukwuneke Ndubuaku
And
Paulina Nwannediuru Ndubuaku

iv

ACKNOWLEDGMENTS

I would like to express my deep appreciation to Professor Robert E. Maleczka, Jr.
for his guidance, and encouragement and patience throughout the course of my Ph.D.
studies. I also want to thank Professors Babak Borhan, Gregory Baker and John
McCracken for serving on my guidance committee.

I wish to express my gratitude to Professor Bill Wulff for the use of his
chiral HPLC instrument. My very sincere appreciation goes to Professor Babak Borhan
for his help. I wish to particularly thank Dr. William Reusch for his advice and
encouragement. I am very grateful to the NMR staff- Le Long Dinh, Kermit Johnson and
Dr. Daniel Holmes. My special thanks to Rui Huang who conducted the single crystal X-
ray diffraction analysis. Without their support my work would be impossible. I must
also thank our excellent and very supportive secretarial staff Lisa Dillingham, Nancy
Lavrik, and DeAnn Pierce. Thanks to all my colleagues in Professor Maleczka’s group
for their fiiendship and help, especially Lamont Terrell and Eric Ruggles for their
friendship and Feng Geng who started the Wittig chemistry. To my husband Ogbonna
and my children Chioma, Nwamaka and Odinaka, thanks for your unconditional love and
support. To my brother Chukwuenye, and my sisters Uzoamaka, Nwabugwu, Nkiruka
and Chika, thanks for being there for me and for loving me. To my friends Tamiika,

Glenn, Robson, Bani, Soong Hyun, Jason and Vijay, thanks for everything.

TABLE OF CONTENT

LIST OF TABLES ................................................................................... ix
LIST OF SCHEMES ................................................................................. x
LIST OF SCHEMES ................................................................................ xi
LIST OF SYMBOLS AND ABBREVIATIONS .............................................. xix
ABSTRACT ......................................................................................... xx
1
CHAPTER 1
INRTRODUCTION
1.1. Background to study ................................................................... 1
1.2. Relevant previous studies on Wittig rearrangements of ethers ................... 4
1.3. Previous synthetic studies on [1,4]-Wittig rearrangement ........................ 11
1.4. Previous mechanistic studies on [1,4]-Wittig rearrangement ................... 14
REFERENCES ............................................................................ 23
CHAPTER 2
OPTIMIZATION OF [1,4]-WITTIG REARRANGEMENT OF MODEL
SUBSTRATE
2. 1 . Introduction ............................................................................ 26
2.2. Yield Optimization ................................................................... 27
2.3. Conclusions ............................................................................ 31
EXPERIMENTAL ......................................................................... 33
REFERENCES ............................................................................. 35
CHAPTER 3
PREPARATION OF ACYLSILANES: TRAPPING OF ENOLATE
OF MODEL SUBSTRATE
3.1 . Introduction ............................................................................ 36
3.2. Electrophilic trapping of intermediate 7 enolate ................................. 37
3.3. Conclusions ............................................................................ 49
EXPERIMENTAL ......................................................................... 50
REFERENCES ............................................................................. 56
CHAPTER 4
IMPACT OF SUBSTITUTION ON WITTIG REARRANGEMENTS
OF a-ALKOXYSILYL ETHERS
4.1. Preparation of ot-alkoxysilanes ...................................................... 57
4.2. In search of new methods for accessing a-alkoxysilanes ........................ 68
4.3. Impact of substitutions on Wittig rearrangements of
a-alkoxysilanes ........................................................................ 73
4.4. Wittig rearrangements of a-alkoxysilanes: Effect of
substitution at the migrating carbon ............................................... 76

4.5. Wittig rearrangement reaction of a-alkoxysilanes: Effect of

vi

substitution at the terminal sp2 carbon of the allyl moiety ...................... 84
4.6. Wittig rearrangement reaction of a-alkoxysilanes:
Substitution at both the migrating carbon and the terminal

sp2 carbon of the allyl moiety ....................................................... 85

4.7. Conclusions ........................................................................... 91

EXPERIMENTAL ........................................................................ 93

REFERENCES ........................................................................... 124
CHAPTER 5

STEREOCHEMICAL REQUIREMENTS IN THE WITTIG
REARRANGEMENTSOF a-ALKOXYSILYL ETHERS

5.1. Stereochemical requirements for Wittig substrates ............................. 126
5.2. Derivatization of or-alkoxysilane 44 .............................................. 126
5.3. NOE experiment ..................................................................... 131
5.4. Relative reactivities of a pair of diastereomeric Wittig substrates ............ 134
5.5. Cross metathesis of a-hydroxysilanes and a—alkoxysilanes ................... 136
5.6. Conclusions ........................................................................... 141
EXPERIMENTAL ........................................................................ 143
REF RENCES .............................................................................. 151

CHAPTER 6

ON THE MECHANISM OF [1 ,4]-WITTIG REARRANGEMENT

OF a-ALKOXYSILANES
6.1. Trapping of Carbanion of model substrate 7 .................................... 153
6.2. Trapping of the carbanion of compound 40 ..................................... 158
6.3. Stereochemistry of the [1,4]-Wittig rearrangement of

a-alkoxysilyl ethers ................................................................. 1 61
6.4. Efforts towards accessing enantiopure Wittig substrate for
mechanistic studies .................................................................. 163

6.5. Accessing enantiopure a-hydroxysilane 33 .................................... 169
6.6. Asymmetric reduction of acylsilane .............................................. 174
6.7. Kinetic resolution of by or-hydroxysilane 33 Lipase ........................... 175
6.8. Stereochemistry of Wittig products ............................................... 179

6.9. Stereoselection in the [1,4]-Wittig rearrangement of
or-hydroxysilanes: Relative stereochemistry at the newly

formed adjacent stereocenters ...................................................... 183
6.10. On the mechanism of the [1,4]-alkyl shift in the Wittig
rearrangement reaction of a-hydroxysilanes ................................... 189
6. 1 1 . Conclusions ............................................... , ......................... 195
EXPERIMENTAL ........................................................................ 196
REF RENCES ............................................................................. 217
CHAPTER 7
[1,2]-WITTIG REARRANGEMENT OF a—ALKOXYSILANES
7. 1 . Introduction ........................................................................... 221

7.2. Observed [1,2]-alkyl shift/silyl migration in some a-alkoxysilanes. . . . .....222

vii

7.3. Stereochemistry of the [1,2]-Wittig rearrangement of a-hydroxysilanes. ...226

7.4. Conclusions ........................................................................... 231
EXPERIMENTAL ........................................................................ 232
REFERENCES ........................................................................... 235
CHAPTER 8
CONCLUSIONS .................................................................................. 236
APPENDICES ..................................................................................... 238
APPENDIX 1
ORTEP REPRESENTATION AND X-RAY DATA FOR COMPOUND ................ 238
APPENDIX 2
ORTEP REPRESENTATION AND X-RAY DATA FOR COMPOUND ................ 249

viii

LIST OF TABLES

Table 2.1. MeLi-mediated Wittig rearrangement reaction of 7- Effect of

Temperature ............................................................................. 28
Table 2.2. Effect of base on the selectivity of Wittig rearrangement of 7 ................... 31
Table 3.1. Allylation of the enolate of compound 7 ............................................ 37
Table 3.2. Ethylation of the enolate of 7 ......................................................... 40
Table 3.3. Methylation of the enolate of 7 ...................................................... 41
Table 3.4. Benzylation of the enolate of 7 ....................................................... 42
Table 3.5. Silylation of the enolate of 7 .......................................................... 43
Table 3.6. Acetylation of the enolate of 7 ....................................................... 44
Table 3.7. Trapping of the enolate of 7 with propyl iodide .................................... 44
Table 3.8. One-pot Electrophilic Trapping of Enolate of 7: Preparation of

Acylsilanes .............................................................................. 48
Table 4.1. Preparation of various a-alkoxysilanes ............................................. 63
Table 4.2. Wittig rearrangements of all substrates ............................................. 89

Table 6.1. Table 6.1. Buynak’s asymmeric reductions of acylsilanes using

(-)-IpczBCl ............................................................................. 1 70
Table 6.2. Lipase resolution of a-hydroxysilane 32 .......................................... 177
Table 6.3. Kinetic resolution a-hydroxysilane 32 by Amano

PS Lipase and Novozym 435 ......................................................... 178
Table 6.4. Hydrolysis of acetic acid l-trimethylsilyl ester 157 .............................. 179

ix

Figure 1.1.
Figure 4.1.

Figure 4.2.

Figure 4.5.

Figure 5.1.

Figure 5.2.

Figure 5.3.
Figure 5.4.

Figure 6.1.

LIST OF FIGURES

Substrates studied by Schlosser and Strunk ....................................... 18
Generalized Structure of a-alkoxysilanes .......................................... 59
Substrates designed to study electronic effects on the Wittig

rearrangement of a-alkoxysilanes .................................................. 79
Wittig substrates bearing various substituents at the migrating carbon ........ 82

X-ray crystal structure analysis ORTEP of 108,
2,4-dintrophenylhydrazone derivative of reactive syn 44b ..................... 128

X-ray crystal structure analysis ORTEP view of 110b,

the 3,5-dinitrobenzoyl ester derivative of reactive syn 44b .................... 130
NOSEYlD result showing relative stereochemistries in ll3a/b ............. 132
Modeling studies of the Wittig substrate 44 ..................................... 135
Formation of dianion 138 from compound 40 .................................. 161

LIST OF SCHEMES

Scheme 1.1. Representative [2,3]-Wittig rearrangement ........................................ 1
Scheme 1.2. Representative [1,2]-Wittig rearrangement ........................................ 2
Scheme 1.3. Representative [1,4]-Wittig rearrangement ........................................ 2

Scheme 1.4. Wittig rearrangement of or-alkoxysilane via the [1,2]- and
[1,4]-pathways, with a bias toward the [1,4]: formation of
acylsilanes and B-silyl ketones ...................................................... 3

Scheme 1.5. [1,4]-Wittig rearrangement/electrophilic trapping ................................ 3

Scheme 1.6. Generation of a-metalated ethers by direct deprotonation
at the or-carbon ........................................................................ 4

Scheme 1.7. Wittig-Still rearrangement: initiation by Sn-Li exchange ........................ 5
Scheme 1.8. Application of the Wittig-Still rearrangement in the

stereoselective synthesis of protected thymine polyoxin C

Wittig rearrangement initiate by [1,5]-H transfer ................................. 5
Scheme 1.9. Application of the Wittig-Still rearrangement in the total

synthesis of (+)-astrophylline Fluoride-promoted Wittig

rearrangements of a-alkoxysilanes by Maleczka ................................. 6

Scheme1.10. Wittig rearrangement of O,S-acetals initiated by lithium

Naphthalenide ........................................................................ 7
Scheme 1.11. Wittig rearrangement initiated by SmIz mediated

reduction of diallyl acetals ......................................................... 7
Scheme 1.12. Wittig rearrangement initiated by [1,5]-H transfer .............................. 7

Scheme 1.13. F luoride-promoted thermal rearrangement of a-alkoxysilanes
by Reetz and Greif .................................................................. 8

Scheme 1.14. Fluoride-promoted Wittig rearrangements of or-alkoxysilanes
prior to Maleczka’s .................................................................. 8

Scheme 1.15. F luoride-promoted Wittig rearrangements of a-alkoxysilanes
by Maleczka .......................................................................... 9

xi

Scheme1.16. Wittig rearrangement of ot-alkoxysilanes initiated by Si-Li

exchange and direct a-deprotonation manifolds ................................. 9
Scheme 1.17. Wittig rearrangement of a-alkoxysilanes initiated by Si-Li

exchange prior to Maleczka and Geng .......................................... 10
Scheme 1.18. Wittig rearrangement of a-alkoxysilanes initiated by direct

Deprotonation ...................................................................... l 0
Scheme 1.19. [1,4]-Wittig rearrangement of 4-oxa-5-hexenyllithiums mediated

by t-BuLi ............................................................................ 13
Scheme 1.20. Wittig rearrangement of allyl ethers by F elkin and Tambute ................ 14
Scheme 1.21. Wittig rearrangement of or-alkoxyalkyl allyl ethers ........................... 14
Scheme 1.22. Wittig rearrangement of bis-y,y-(dimethyl)allyl ether ......................... 15
Scheme 1.23. Wittig rearrangement of allyl a-phenylethyl ether ............................ 16
Scheme 1.24. Wittig rearrangement of cyclic allylic ether .................................... 16
Scheme 1.25. Previous studies by Schlosser and Strunk ....................................... 17
Scheme 1.26. Wittig rearrangement of stereochemically defined allyl

cyclohexenyl ether by Nakai ..................................................... 19
Scheme 1.27. Wittig rearrangement of dihydropyranyl anion via

[1 ,4]-Wittig pathway ............................................................... 20
Scheme 1.28. Wittig rearrangement of carbanions from 4-thiacyclohexenyl

systems ............................................................................... 21
Scheme 1.29. Gas-phase rearrangement of allyl methyl sulfide by Kass .................... 22
Scheme 3.1. Eletrophilic trapping of enolate of model compound 7-

formation of acylsilanes ............................................................. 36

Scheme 3.2. Allylation of enolate of compound 7 in the presence of HMPA ............... 39
Scheme 3.3. One-pot vs. two-pot Wittig rearrangement/allylation of 7 ..................... 39
Scheme 3.4. Methylation of enolate of 7 ......................................................... 41

Scheme 3.5. Schematic of envisaged [1,4]-Wittig/electrophilic trapping/coupling
reactions of model substrate 7 ..................................................... 45

xii

Scheme 3.6.

Scheme 3.7.

Scheme 3.8.

Scheme 4.1.

Scheme 4.2.

Scheme 4.3.

Scheme 4.4.

Scheme 4.5.

Scheme 4.6.

Scheme 4.7.

Scheme 4.8.

Scheme 4.9.

Scheme 4.14.

Attempted synthesis of vinyl triflate and vinyl nonaflate ...................... 46
Synthesis of the stannane coupling partner ....................................... 47

Attempted Wittig/nonaflation/Pd(0)-mediated coupling of model

Substrate 7 ............................................................................ 47
Preparation of various a-hydroxysilanes ........................................ 59
Preparation of a-(hydroxydimethylphenylallyl)silane 33 ..................... 60

Formation of a-(dimethylphenylsilyl)allyl alcohol 33 and vinyl
silyl ether 36 ......................................................................... 61

Subjection of vinyl silyl ether to deprotonation/silylation/
retro-Brook reaction conditions ................................................... 62

Etherification of a-hydroxysilane 32 with trichloroacetimidate

of cinnamyl alcohol ................................................................. 64
Preparation of substrate 58 via Rychnovsky’s protocol ........................ 65
Attempted synthesis of oc-(trimethylsilyl)allyl butyl ether ..................... 66
Attempted synthesis of a-(trimethylsilyl)allyl butyl ether-
Plausible mechanism ............................................................... 67
Independent synthesis of Wittig substrate 40 .................................... 68
Scheme 4.10. Attempted synthesis of 47 via an 3N2 displacement of a
mesylate group ..................................................................... 69
Scheme 4.11. Pd(O)-mediated stereoselective formation of C—0 bonds via
8N2 type process ................................................................... 69
Scheme 4.12. Pd-catalyzed allylic etherification using Zn(II) alkoxide as
Nucleophile ........................................................................ 70
Scheme 4.13. Attempt at accessing or-alkoxysilanes via the Williamson’s
ether synthesis ..................................................................... 71
Attempted preparation of a-alkoxysilanes by direct 3N2
Displacement ........................................................................ 71
Attempt at accessing oc-alkoxysilanes via direct 8N2 reaction ............... 72

Scheme 4.15.

xiii

Scheme 4.16. Hoffrnann and Bruckner one-pot synthesis of O—S acetals .................. 72
Scheme 4.17. Attempted adaptation of Hoffmann and Bruckner protocol .................. 72
Scheme 4.18. Wittig rearrangement of 41: expected [1,2], [1,4], and [2,3]

products ............................................................................ 74
Scheme 4.19. Wittig rearrangement of 41 mediated by n-BuLi .............................. 75
Scheme 4.20. Wittig rearrangement of 41: A Putative Mechanism ......................... 76
Scheme 4.21. Substitution at the migrating carbon: Wittig rearrangement of 44 ......... 77
Scheme 4.22. MeLi-mediated Wittig rearrangement of 42 by Maleczka and

Geng ................................................................................. 80
Scheme 4.23. Plausible pathways for the Wittig rearrangement of 42 ....................... 81
Scheme 4.24. Wittig rearrangement of metalated allyl alky ether by

Schlosser and Strunk ............................................................... 83
Scheme 4.25. Substitution at the terminal sp2 carbon: Wittig rearrangement

reaction of 55 ...................................................................... 84
Scheme 4.26. Substitution at both the migrating center and the terminal

sp2 carbon ........................................................................... 86
Scheme 4.27. Energy calculations for pre-Brook, Brook and retro-Brook

for 55 and E-56 .................................................................... 87
Scheme 4.28. Sterics in the ‘intermediate’ structures for 55 and E-56 ..................... 87
Scheme 4.29. Wittig rearrangement of compound 58/oxidation of [1 ,4] product ......... 88
Scheme 5.1. Hydroboration/oxidation of 44 ................................................... 127
Scheme 5.2. Derivatization of 44: conversion to 2,4-dinitrophenylhydrazone ........... 128
Scheme 5.3. Attempted oxymercuration/demercuration of unreactive 44 ................ 129
Scheme 5.4. Derivatization of 44: conversion to 3,5-dinitrophenylbenzoyl ester ....... 130
Scheme 5.5. Boo-glycine ester derivative of less reactive 105b ........................... 131
Scheme 5.6. Ring closing metathesis of 51 and 52 .......................................... 132

xiv

Scheme 5.7. Decomposition of metathesis product in the presence of CDC13 ............ 133

Scheme 5.8. Cross metathesis reaction of 52 in sealed tube ................................. 133
Scheme 5.9. Ring closing metathesis of 42 ................................................... 136
Scheme 5.10. Attempted Dimerization of model substrate 7 .............................. 137
Scheme 5.11. Cross-Metathesis of model substrate 7 with Styrene ....................... 137
Scheme 5.12. Metathesis Dimerization of 32 ................................................. 138
Scheme 5.13. Ruthenium Catalyzed Addition of Chloroform to Styrene ................. 139
Scheme 5.14. Mechanism of the Kharasch Addition Reaction ............................. 140
Scheme 5.15. Preparation of undecanoic acid ester of 32 ................................... 140
Scheme 6.1. Generating and trapping the carbanion of model substrate 7 ............... 153
Scheme 6.2. Trapping of carbanion of allyl ethers by Schlosser and Strunk .............. 154
Scheme 6.3. Deprotonation and Trapping of carbanion of 7 ................................. 155
Scheme 6.4. Plausible fate of compound 125 .................................................. 156
Scheme 6.5. Plausible pathway for the observed products ................................... 157
Scheme 6.6. Room temperature electrophilic trapping of carbanion of 7 .................. 158
Scheme 6.7. Attempted Wittig rearrangement reaction of 40 ............................... 159
Scheme 6.8. Electrophilic trapping of the carbanion of 40 .................................. 160
Scheme 6.9. Plausible explanation for the formation of 131 and 132 from 40 ............ 161
Scheme 6.10. Preparation of or-alkoxysilanes bearing substituent at the migrating

Carbon ................................................................................ 162
Scheme 6.11. Preparation of a-alkoxysilanes from enantiopure starting materials ...... 163

Scheme 6.12. Attempted kinetic resolution of a-hydroxysilane 34 by Kells’
Protocol ............................................................................ 164

Scheme 6.13. Epoxidation of E-3-trimethylsilanyl-prop-2-en-1 -01 with mCPBA ........ 165

XV

Scheme 6.14.

Scheme 6.15.

Scheme 6.16.

Scheme 6.17.

Scheme 6.18.

Scheme 6.19.

Scheme 6.20.

Scheme 6.21.

Scheme 6.22.

Scheme 6.23.

Scheme 6.24.

Scheme 6.25.

Scheme 6.26.

Scheme 6.27.

Scheme 6.28.

Scheme 6.29.

Scheme 6.30.

Scheme 6.31.

Scheme 6.32.

Regioselective opening of epoxide 142 ....................................... 166
Proposed derivatization and elimination reactions of 143 .................. 166
Attempted conversion of 142 to 32 mediated by Ti(IV) system ............ 167
Telluride mediated double bond transposition in primary

allylic alcohols .................................................................... 167
Telluride mediated double bond transposition in secondary

allylic alcohols .................................................................... 168
Attempted preparation of 32 via telluride ion mediated

reduction of glycidyl tosylate ................................................... 168
Attempted preparation of a,B-unsaturated a-silyl ketone 153-a

repeat of Buynak’s protocol ..................................................... 171
Oxidation of a-hydroxysilane 33 via the DeLuca protocol ................. 172
Swern oxidation of a-hydroxysilane 33 ....................................... 173
Attempted oxidation of a-hydroxysilane 33 via other routes ............... 174
Preparation of enantioenriched 45 .............................................. 175
Conversion of the [1,4]-Wittig product 82 into

3-Phenyl-pentanoic acid ......................................................... 180
Preparation of 82 via an independent route .................................... 182
Wittig rearrangement of E-56/ oxidation of [1,4]-Wittig

product 165 ........................................................................ 184
Diastereoselection in [2,3] Wittig rearrangement by Mikami et al. . . . . l 85
Proposed transition-state model for stereoselection

by Mikami et a1 ................................................................... 186
Frontal orbital representation of E-56 .......................................... 186
Proposed transition-state model for stereoselection

in the [1,4]-alky] migration in E-56 ............................................ 187
Preparation of Z-or-alkoxysilane Z-56 .......................................... 188

xvi

Scheme 6.33. Radical-radical anion dissociation-recombination in 7 ...................... 189

Scheme 6.34. Radical-radical anion dissociation-recombination in
a-alkoxysilane bearing a substituent at the migrating carbon .............. 190

Scheme 6.35. Radical-radical anion dissociation-recombination in a-alkoxysilanes
bearing a substituent at the terminal sp2 carbon of the allyl moiety ....... 191

Scheme 6.36. Carbanion formation in the [1,4]-pathway in oc-alkoxysilanes

bearing a substituent at the terminal sp2 carbon of the allyl moiety ....... 191
Scheme 6.37. Wittig rearrangement of allyl oc-phenylethyl by F elkin ..................... 192
Scheme 6.38. Stevens rearrangement of optically active allylic ammonium

salt by Jenny and Druey ......................................................... 192
Scheme 6.39. Felkin’s comparison of his and Jenny and Druey’s systems ............... 194
Scheme 6.40. Comparison of F elkin’s and our systems ...................................... 194

Scheme 7.1. Plausible pathway for the [1,2]-Wittig rearrangement/silyl
migration observed in compound 7 .............................................. 222

Scheme 7.2. Previous work by Maleczka and Geng .......................................... 223

Scheme 7.3. Present work: isolation of vinyl silyl ether 201 in the
Wittig rearrangement/electrophilic trapping of 7 .............................. 224

Scheme 7.4. Plausible mechanism of the [1,2]-Wittig rearrangement

of a-alkoxysilanes .................................................................. 225
Scheme 7.5. Wittig rearrangement reaction of 48 mediated by sec-BuLi .................. 227
Scheme 7.6. Synthesis of [1,2]-Wittig product by an independent route .................. 228
Scheme 7.7. Determination of the stereochemistry of the [1 ,2]-Wittig product .......... 228
Scheme 7.8. Comparison of the [1,2]-Wittig of (S, R)-48 and (S,S)-48 ..................... 229

Scheme 7.9. Wittig rearrangement of a pair of optically defined diastereomers
by Nakai and co-workers ......................................................... 230

Scheme 7.10. Possible racemization in the [1,2]-Wittig rearrangement
of a-alkoxysilanes as a resonance of resonance .............................. 231

xvii

Ac
acac

AIBN

aq
CI

DCC
DBU
De
DIAD
DIBAL
DMAP
DME
DMF
DMSO
EI

eq
FAB

HMPA
HRMS
HWE
KHMDS
LHMDS
mCPBA

LIST OF SYMBOLS AND ABBREVIATIONS

acetyl

acetylacetonate
2,2’-azobisisobutyronitrile
aqueous

chemical ionization

cyclohexyl
dicycloheylcarbodiimide
1,8-diazabicyclo[5,4,0]undec-7-ene
diastereomeric excess

diisopropyl azodicarboxylate
disiobutylalurninum hydride
4-(dimethylamino)pyridine
dimethoxylethane
MN—dimethylformamide

dimethyl sulfoxide

electric ionization

equivalent

fast atom bombardment

hour

hexamethyl phosphoramide

high resolution mass spectrometry
Homer—Wadsworth-Emmons reaction
potassium bis(trimethylsilyl)amide
lithium bis(trimethylsilyl)amide

m-chloroperbenzoic acid

xviii

Mes
Mesyl
min
mL
mmol
MOM
MS
NaHMDS
NBS
NMP
NOE
PMB
Py
RCM

TBAF
TBS
TCT
Tf
THF
TMS
Tosyl
Tr
TSA

2,4,6-trimethyl phenyl
methanesulfonyl

minute

milliliter

millimole

methoxyrnethyl

molecular sieves

sodium bis(trimethylsilyl)amide
N-bromosuccinimide
N-methyl prolidinone
nuclear Overhauser effect
p-methoxybenzyl

pyridine

ring closing metathesis

room temperature
tetrabutylarnmonium fluoride
t-butyldimethylsilyl
2,4,6-trichloro-[1,3,5]triazine
trifluoromethanesulfonyl
tetrahydrofuran
trimethylsilyl
toluenesulfonyl
triphenylmethyl

p-toluenesulfonic acid

xix

CHAPTER 1

INTRODUCTION

1.1. Background to study

Bond reorganizations of a-lithiated ethers to lithio alkoxides2 were first described
by Wittig and thmarrn in 1942. Termed Wittig rearrangements, these reactions have
proven to be of importance in synthetic organic chemistry. Among these rearrangements
the [2,3]-pathway (Scheme 1.1) has been most studied and has seen wide use as a tactic
in organic synthesis.3 In recent years, the [2,3]-Wittig rearrangement has been most often
employed in the stereoselective formation of homoallylic alcohols from the

corresponding a-metalated allyl ethers.4

Scheme 1.1. Representative [2,3]-Wittig rearrangement3a

2 2 2
1 \3 IB 1 \3 [2.3] 1/ 3
K\ (\e
x—\ xfl x
1 2v 1 2v 1 2v

X = heteroatom, Y = anion stabilizing group

The utility of the [2,3]-Wittig rearrangement in synthetic organic chemistry arises
from its ability to proceed with (a) regiospecific carbon-carbon bond formation and
allylic transposition of the oxygen firnction, (b) stereospecific generation of olefins (c)
the stereoselective creation of vicinal chiral centers, and (d) the transfer of chiraltyf”l

The [1,2]-Wittig rearrangement, in contrast, has received less attention. Early
studies on this isomerization pathway were mainly mechanistic in origin, with the

synthetic utility of the [1,2]-Wittig rearrangement limited by the restricted range of

substrates and the tendency toward low product yields.5 Over the past two decades,
however, chemists have made the observation that this rearrangement proceeds with high
diastereofacial selectivity.6'7 This observation has drawn more attention to the [1,2]-
Wittig rearrangement as a potential tool in forming syn-1,3-diol derivatives

preferentially.7

Scheme 1.2. Representative [1,2]—Wittig rearrngement5a

Li

. R
FLA .1. 12.). “'21 A

O Y O Y LiO Y

 

X = heteroatom, Y = anion stabilizing group

In addition to the [2,3] and [1,2]-Wittigs allylic ethers are capable of a [1,4]-
rearrangement. Even relative to the [1,2]-Wittig rearrangement, the [1,4]-pathway
remains a reaction of many questions. For example, whether the mechanism is concerted
or involves radical-radical anion dissociation-recombination is still debated.8 Some
reports suggest the [1,4]-Wittig is likely to proceed via a stepwise mechanism similar to
that of the [1,2]-rearrangement,3 while other reports describe the [1,4]-rearrangement of

3b’8 The substrate scope of the

allylic ethers as a symmetry allowed, concerted process.
[1,4]-Wittig is also not well documented and thus its potential in synthetic organic

chemistry is unclear.

Scheme 1.3. Representative [1,4]-Wittig rearrangement 3"

 

1&3 ° /3 1\

O .B /j\/+ C

17%: 902/ 4 /oe
34

In the course of ongoing research on Wittig rearrangements in our laboratory, it
was discovered9 that an or-alkoxysilane rearranged via the [1 ,2]- and [1 ,4]-pathways, with
a bias toward formation of the [1,4] derived acysilanes (Scheme 1.4). This was
interesting essentially given the synthetic utility documented for acylsilanesl and the
[1,2]-derived B-silyl ketones also .10

Scheme 1.4. Wittig rearrangement of a-alkoxysilane via the [1 ,2]- and [1,4]-pathways,
with a bias toward the [1,4]: formation of acysilanes and B-silyl ketones

1

 

10Aph 15eq 14MMeLi/EtO 4 O O
. . . 2
_ 1
4%“43 ' PhMTMS “ TMS/\/g\/Ph
3 THF, rt, 16 h 1
(60%) (21%)
via [1 ,4]-Wittig via [1 ,2]-Wittig

Since the [1,4]-Wittig proceeds via an enolate intermediate, the rearrangement
could be followed by electrophilic trapping, affording access to diversely or-
functionalized acylsilanes (Scheme 1.5). These features, if harnessed, could confer upon

the or-alkoxysilanes and the [1 ,4]-Wittig rearrangement a high level of synthetic utility.

Scheme 1.5. [1,4]-Wittig rearrangement/electrophilic trapping

 

@ o
oAPh RLi, THF 09 E ph\/\y/u\
———’ TMS
vms PhMms

E

Given the mechanistic uncertainties surrounding the [1,4]-Wittig and the yet
untapped synthetic potential of the [1,4]-Wittig, we decided to explore the [1,4]-Wittig

rearrangement of or-alkoxysilanes further.

1.2. Relevant previous studies on Wittig rearrangements of ethers

Wittig rearrangements of allylic ethers are typically initiated by the formation of
an a-metalated ether which undergoes a subsequent bond reorganization. Several
pathways for this rearrangement exist but usually come in the form of a [2,3]-, [1,2]-, or
[1,4]-shift. The process of bond reorganization involves the breaking of a C—O bond and
formation of a CC bond (Scheme 1.6).3 The [2,3]-Wittig rearrangement has long been
established as a concerted, thermally allowed sigmatropic reaction, following the
Woodward-Hoffman rules.3 As previously stated, the [1,2]-rearrangement is generally
accepted to proceed in a stepwise manner, through a radical-radical anion dissociation-
recombination process.6 Again, less is known about [1 ,4]-rearrangement, and whether its
mechanism is concerted3 or involves a radical-radical anion dissociation-recombination.8

Irrespective of the pathway, [1,2], [2,3], or [1,4], Wittig rearrangements are
generally preceded by formation of an a—metalated ether often through direct
deprotonation at the ether’s a-carbon. This process is usually facilitated by the presence
of anion stabilizing groups such as carbonyls, nitriles, as well as vinyl, phenyl, or alkynyl

moieties (Scheme 1.6).2b’”

Scheme 1.6. Generation of a-metalated ethers by direct deprotonation at the a-carbon

ji¥Rll KR"

I . 1| / / Ru

4 10 1 __.:B 10 \ _. H 3' R" w
R'VZ R'MM R' \ 20H R' \ 20H R'

M = Li+, K+, CSI, etc. [2,3]-shift [1 ,2]-shift [1 ,4]-shift

 

Generation of a-metalated ethers by direct deprotonation at the a-carbon requires the
presence of a conjugated diene or an electron withdrawing group to stabilize a-anion.

A limitation to this direct deprotonation approach is that it is only applicable to
those compounds possessing sufficiently acidic a-hydrogens. This restriction can be

overcome by generating the a-alkoxy carbanion via tin-lithium exchange4d as shown by

Still and Mitra in 1978 (Scheme 1.7).

Scheme 1.7. Wittig-Still rearrangement: initiation by Sn-Li exchange4d

1 2 3 n-BuLi,THF 3 OH
7 /

1OVSnBu3 -78 0C, 30 min
2|

 

Scheme 1.8. Application of the Wittig-Still rearrangement in the
stereoselective synthesis of protected thymine polyoxin C12f

a’SDBU3
10 - . n-BuLi 1.1 e 3'
1U THF, #13 °c -qr)t_ ©\,OH

3' :. 2
12 h N
(69%) W ‘ BOG

WN‘Boc

This Wittig-Still rearrangement has since attained the status of a useful synthetic
tool,” and has enjoyed a number of impressive applications in the area of natural product

3 For example, the Wittig-Still rearrangement was employed as a key

synthesis.l
transformation in the stereoselective synthesis of protected thymine polyoxin C12f
(Scheme 1.8).

Another example of the application of the Wittig-Still rearrangement in synthetic

organic chemistry is in the total synthesis of (+)-astrophylline by Schaudt and Blechert12b

(Scheme 1.9). In this instance the authors employed this rearrangement as a critical
transformation in the stereocontrolled generation of the 1,2-trans configuration of a key

cyclopentene intermediate.

Scheme 1.9. Application of the Wittig-Still rearrangement
in the total synthesis of (+)-astrophyllinel2b

\
3 O 3 O
2 / 0M3 n-BuLi (1.53 equiv) 2 Is“ we
1 _' THF, -78 °c - rt , .

 

 

1 O i O ; OH : b
O 2 h 0
' 740/
2 kSnBua X (excliisiveljr syn) X
1 3 \
' / O . ' 3 o
10WOMe n-BuLi (1.53 equiv) 2"“ OMe
Q. ' ' THF. -78 °c - rt OH . .
SDBU3 6 b = : b

2 h 0
X syn/agfi (2.421) x

Despite its demonstrated potential, broad application of the Wittig-Still protocol
has been governed by its call for use of relatively toxic organostannanes.l4 To get around
this limitation, several research groups have sought "tin free" alternatives to the
regioselective generation of a-ethereal carbanions. Successful solutions to this problem
include the reductive cleavage of O,S-acetals with lithium naphthalenide (Scheme
1.10);l5 Smlz mediated16 reduction of diallyl acetals (Scheme 1.11); and vinyl halides

capable of 1,5-hydrogen transfer (Scheme 1.12).l7

Scheme 1.10. Wittig rearrangement of O,S-acetals initiated by lithium naphthalenide

 

 

 

subst subst
1")qu 3 G) e OAI/ [2 3] Mt Ce L?)
. 2 Li Naphth . ' I '9 .
2 2 subst
R sen R/k Li (KS/V.
Scheme 1.11. Wittig rearrangement initiated by
SmIz mediated reduction of diallyl acetals
3 eq. 311112 I
P“ 0\/\ . 1 2 2,3 -VVltti
Y \ CH3CN [rang/0W2} l l 9 OH
OW reflux, 2 h 1 Ph 2' 3 \
(72%)

Scheme 1.12. Wittig rearrangement initiated by [1,5]-H transfer

I . Ph Ph
I Smlz (2.5 equrv) I l/ __E l r 1,5—H transfer
0v Ph > O O

rt, 10 min

 

 

OH

Ph 3 Ph
| Ql/ & | Or _, / 32%
o 2 o
1 1'

In the search for ‘tin-free’ alternatives to the regioselective generation of or-
ethereal carbanions, the possibility of replacing tin with silicon had been considered.18
However, this approach had received very limited consideration in the past. Reetz and
Greif showed that the thermal rearrangement of fluorine derivatives could be facilitated
by catalytic amounts (10 mol%) of tetrabutylarnmonium fluoride (TBAF) (Scheme

1.13).18a

Scheme1.13. F luoride-promoted thermal rearrangement
of or-alkoxysilanes by Reetz and Greif'ga

VO.TMS TBAF(10mol%) \ .TMS
22°C
(80%) O 0

Nearly a decade following Reetz’s report, Nakai reported that Wittig

 

rearrangement in a-silylallyloxy esters could be initiated by the action of the fluoride ion
(Scheme 1.14).18b Both Reetz’s and Nakai’s systems are activated (in addition to the or-

silyl group, both contain groups capable of stabilizing an anion).

Scheme1.14. F luoride-promoted Wittig rearrangements
of a-alkoxysilanes prior to Maleczka’s

 

 

Me
% 1. TBAF, -85 °C Me
0 COzMe 2.H:10+ /
TMS (100%) HO cone
E:Z=78:22
Me
(V 1. TBAF, -85 °c Me
0 002MB 2- H30+ /
TMS (100%) HO COzMe

erythro/threo = 70 : 30

Several years later Maleczka and Geng19 extended these studies and showed that

the action of fluoride could trigger the desired rearrangements even in relatively

unactivated substrates (Scheme 1.15).6°’6f

Scheme 1.15. Fluoride-promoted Wittig rearrangements
of a-alkoxysilanes by Maleczka

Ph

\/k CsF(1.5eq.) 0“ W
\ TMS ' MP“ +

 

DMF, rt, 16 h Ph H
[2,3]-mm [1,2]-Wittig
(54%) (13%)

In addition to serving as a carbanion mask, the silyl moiety in or-alkoxysilanes can
also function as an anion-stabilizing group.20 Thus there are two Wittig rearrangement
manifolds available to a-alkoxysilanes in the presence of lithium bases, with
deprotonation (e.g. by alkyl lithium bases) and Si/Li exchange being plausible ways to
initiate the Wittig rearrangements on this class of compounds. Indeed, Maleczka and
Geng9 reported the Wittig rearrangement of or-alkoxysilanes initiated by the direct
metalation of the substrates as well as by Si/Li exchange (Scheme 1.16).

Scheme 1.16. Wittig rearrangement of a-alkoxysilanes initiated
by Si-Li exchange and direct a-deprotonation manifolds

 

 

Me 3,
1o 1. ,/ MeLi,THF 0” 20H ,
3L 2 2 3' Me 3 Me
pr) \ Ph \
Ph TMS rt, 16 h TMS H
[3,2]-Wlttig (21%) [3,2]-V\fittig (75%)
ph , from deprotonation event from Si/Li exchange
3
/
\éok 1. 2. MeLi, THF AM OH
3' P -
\3 TMS rt. 16h TMS 2 \ h \ 2 3 \ Ph
[2,3]-VVIflig (60%) [2,3]-VVIttig (20%)

from deprotonation event from Si/Li exchange

While the Si/Li exchange of a-alkoxytrimethylsilanes appears to be a

straightforward alternative to the Wittig-Still rearrangement, this approach has received

little attention, despite such exchange reactions being well precedented.20b'°‘d Prior to the

work by Maleczka and Geng,9 only two examples (Scheme 1.17), both reported by

Muzler and List,20b stood alone as the only [2,3]-Wittig rearrangements triggered by Si/Li

substitution.

Scheme 1.17. Wittig rearrangement of a-alkoxysilanes
initiated by Si-Li exchange prior to Maleczka and Geng

 

 

_ 2 1 n-BuLi, THF
/“' . -5°Ct05°C
3 01 >
TMS—é, (68%)
2 n-BuLi, THF
/ 3 / 1 -5 °c to 5 °c
1' >
2(0 (78%)
ms

(<12.

2|

Scheme 1.18. Wittig rearrangement of a-alkoxysilanes initiated by direct deprotonation

 

 

Et
/ 1
$0 1' 2. 3 MeLi (1.5 equiv)
\ ;
3 TMS THF, rt, 16h
(92%)
Et 9
N [231wn' \ O
, - 1 lg
\ @/ TMS \
TMS Et
[1,4]-silyl 09
mi ration
_g__. WSW
Et

10

3|

TMS 2 \
Et
T .
“35 29
Brook \
_—_, @ \
rearrantement Et
6)
H3O
product

 

Similarly, prior to the work by Maleczka and Geng (Scheme 1.18),9 few examples
of initiating Wittig rearrangements of a-silyl ethers by direct deprotonation were
reported.21 This is surprising, in view of the fact that the deprotonation path would afford
a unique access to the synthetically malleable silanes.22 Despite the lack of precedent,
Maleczka and Geng9 showed that upon deprotonation by MeLi (Scheme 1.18), a-
alkoxysilanes underwent Wittig rearrangement via [2,3]-pathway, which was then
followed by Brook’s rearrangement and subsequent [1,4]-silyl migration to fumish a B-

silyl ketone(Scheme 1 .18).

1.3. Previous synthetic studies on [1,4]-Wittig rearrangement

As already mentioned earlier in this dissertation, relative to the [1,2]-Wittig
rearrangement, the [1,4]-rearrangement has received very little attention. The substrate
scope of the [1,4]-Wittig is not yet well documented and thus its potential in synthetic
organic chemistry is unclear.

As just discussed, Maleczka and Geng9 reported the Wittig rearrangement of an
a-alkoxysilane, initiated by cat-deprotonation (Scheme 1.4). The substrate rearranged via
the [1,2]- and the [1,4]-pathways to furnish a B-silyl ketone and an acylsilane in 1:2 ratio
in a combined 80% yield. To the best of our knowledge, this report represented the first

efficient and selective [1,4]-Wittig rearrangement of a-alkoxysilanes.

11

Scheme 1.4. Wittig rearrangement of an a-alkoxysilane

 

OAPh o o
1.5 . 1.4M M Li/Et o
v eq 8 2 > Ph\/\/u\ + /\/lK/Ph
TMS TMS TMS
THF. rt, 16h
(60%) (21%)
[1,4]-mug via [1,2]-mm

Subsequent to the reactions above, Wittig rearrangement of an a-metalated 0-
glycoside system was documented by Tomooka and co-workers.23 The authors reported
that treatment of a racemic l-ethynylated propargyl acetal (both (S)-42 and (R)-42, R’=H)
with n-BuLi (3.0 equiv) in THF at -78 °C afforded the [1 ,2] product as the major product
(78%) and only 17-19% of the [1,4] product (Scheme 1.19). However, the introduction
of a tert-butyldimethylsilyl group to the ethynyl unit at the C1 position (R’=TBDPS) led
to a reversal in product distribution, affording the [1,4]-rearrangement product as the
major product (73% yield), and the [1,2]-rearrangement product as the minor product (7-
11%). This report represents the most selective and efficient [1,4]-Wittig documented to

date.

12

Scheme 1.19. [1,4]-Wittig rearrangement of
4-oxa-5-hexenyllithiums mediated by t-BuLi23

 

 

 

\4 F ‘
H 3 é TMS
O10 \\ n-BuLi,THF o \
1O .
TMS 0L.
§ '7800 % TBS
oreopsTBS _ OTBDPS _
R TMS
E+
_. + [1,2] product
(7-11%)

    

BS

oreopsT
[1 ,4-product

E: : 383:0”gifytfifiiy'iéo'lgg/i’CHZOH (60% d.r. at c2') (60%)

Prior to the studies by Maleczka9 and Tomooka,23 Felkin and Tambute24 had
explored the Wittig rearrangements of metalated allyl aryl and allyl alkyl ethers and
found that on treatment with an excess (30%) of an equimolar mixture of propyllithium
and N,N,N, ’N’—tetramethylethylenediamine (TMEDA) in pentane (or THF in place of
TMEDA), a series of ethers afforded aldehydes and ketones (via [1,4] rearrangement),
and 1-alken-3-ol (via [1,2] rearrangement) (Scheme 1.20). The yields, however, did not
exceed 30% for either component. The authors observed that the yields of the [1,4]

products were insensitive to the substitution pattern in the allylic moiety of the ethers.

13

Scheme 1.20. Wittig rearrangement of allyl ethers by Felkin and Tambute23

0 Base 0 OH R O
I e \ R —>
R H

OBu
MeWOBu O
WoBU Me WoBU Me

 

Similarly, a-alkoxyalkyl allyl ethers have been shown to rearrange via the [1,2]
and [1,4] pathways78 to afford secondary allyl alcohols (via the [1,2]-Wittig) and
aldehydes (via the [1,4]-Wittig) respectively (Scheme 1.21). The syn [1,2] products were
obtained in 14-32% yield with 90-95% diastereoselectivity. The [1 ,4]-product was found
to predominate at low temperature, whereas at 0 °C the [1,2]-product was favored but the
absolute yield remained the same. The authors noted however, that the extent of
formation of the [1,4]-Wittig product was markedly dependent on reaction temperature

and solvent polarity.

Scheme 1.21. Wittig rearrangement of a-alkoxyalkyl allyl ethers

£1 3 Base m OR 4 H

O 1. / + W

R1 2' 1. \2/\4 R1 2 R1 1. 0
[1.2l-shift [1,4]-shift

ds = 90-95%; yield = 14-32%
syn/anti = 9:1 to 17:1

1.4. Previous mechanistic studies on [1,4]-Wittig rearrangement

As mentioned in the introductory part of this Chapter, whether the [1,4]-Wittig

involves a one-step concerted process or a two-step radical-radical anion dissociation-

14

recombination event, or both remains an open question. Indeed, there have been reports
in support of either mechanism and for both mechanisms being operative, depending on
the substrate.

Some a-metalated ether systems are capable of undergoing rearrangement via all
four Wittig pathways viz [2,3]-, [1,2]-, [3,4]-, or [1,4]-shift. However, in general such
systems (e. g. bis(allyl) and allyl 2-alkynyl ethers)3 find the 2,3-mode of rearrangement is
electronically25 and geometrically,26 favorable, and thus predominant over the 1,2-
mode26b with the 1,4368 and the 3,4-paths26b becoming competitive only in exceptional
cases. This trend is illustrated by bis-y,y-(dimethyl)allyl ether (Scheme 1.22), which

rearranges by all four pathways?“27

Scheme 1.22. Wittig rearrangement of bis-y,y-(dimethyl)allyl ether3

M W
n-BuLi 0H 0H
WOW TMEDA _ [1.21.14% [2.31.67%
ether-hexane
~80 to -25 °C
CHO
Y” Och

[1.4]. 3% [3,4], 10%

 

Felkin published the results of his mechanistic studies on the [1,4]-Wittig
rearrangement in 1977,8d in which he showed that, on treatment with excess butyl lithium
in THF at -25 °C, optically active allyl a-phenylethyl ether underwent rearrangement to
afford a mixture of anionic products via [1,2]- and [1,4]-rearrangements. Saturation of
these products afforded a mixture of [1,2] and [1,4] derived isomers in 60% overall yield

with a ratio of 16:20:64 in favor of the [1,4]-Wittig (Scheme 1.23). The authors observed

15

that all three rearrangement products favored retention of configuration with a similar
extent of racemization (30i5%) observed for all products. This was said to suggest that
reactions leading to both [1,2] and [1,4] products occurred via a non-concerted radical-

radical anion cleavage-recombination mechanism.

Scheme 1.23. Wittig rearrangement of allyl (ii-phenylethyl8d

 

 

   

 

I ..."
\ n-BuLi I’A‘~
WNZ" ————+ a W
Me THF, -25 °c W‘ph M
Me e
Ph H Ph H H,’ Ph
+ + MGM
09
1143069 Ph H Ph H H, Ph
. Mm + Mm + MeMOH
2. LIAIH4 H OH HO H
3. H2/(Pt02)
via [1,2]-Whig via [1,2]-Whig via [1 .41-Vinttig
16220264

Further support for this conclusion was derived from observations made during
the rearrangement of a cyclic allylic ether (Scheme 1.24). Despite its inability to adopt
the cisoid conformation necessary for a concerted [1,4] alkyl shifi, the compound

afforded appreciable amounts of the [1 ,4] rearrangement product.8d

Scheme 1.24. Wittig rearrangement of cyclic allylic ether8d

Bu

OBu - Bu 0
O 0% - U
THF, -25 °C

 

16

In 1989, Schlosser and Strunk28 reported that the rearrangement of metalated allyl
alkyl ethers in the presence of potassium tert-butoxide, involves preferential migration of
primary alkyl groups to the unsubstituted allylic terminus (y-position), accompanied by
alkyl migration to the a-position adjacent to the oxygen atom. This resulted in the
formation of [1,4] and [1,2] products in an approximate ratio of 9:1 (Scheme 1.25). They
obtained enolates [M=Si(CH3)3] with high (~90%) regioisomeric purity only when a
resonance inactive primary alkyl group (such as butyl, 3-methylbutyl, or nonyl) was
allowed to migrate. The migration of secondary or tertiary alkyl groups (l-ethylpropyl,
tert-butyl) or even the cyclopropylmethyl moiety led to 2:3 or 1:1 mixtures of 1-a1ken-3-

olates and enolates.

Scheme 1.25. Previous studies by Schlosser and Strunk28

,R' ,R' ,R' ,R'
' 0 R o

o RLI 0 R'-l
V 9 ‘—’ View * K2

OR. = OC4H9, OCH2CH20H(CH3) (23177); OC9H19, OCH2CPI' (75225);
OCH(C2H5)2 (50:50); OC(CH3)3 (70:30); yields = 73-85

 

 

Based on these data, they proposed a solvent caged 1-(alkoxy)-allyl radical/alkyl
radical pair as a major transient species in the Wittig rearrangement of the allyl alkyl

ethers (Scheme 1.25). They further proposed that this pair might be preceded by the

17

zwitterionic metallomer, an 0-1ithio(oxonia)-propenide, which could either collapse to
the radical pair or, in borderline cases, directly isomerize to provide the rearrangement

products.

O/\‘4 OM OM
V0 V M [XV

Figure 1.1. Substrates studied by Schlosser and Strunk28

The authors pointed out that a concerted process would imply the nucleophilic
displacement of the migrating group from the alkoxy moiety, a process that would result
in its transfer to the 01- or y-allylic carbon atom without its bonding electrons and with
retention of configuration. They argued this would be disfavored and provided the
rational why the lithiated allyl l-(7,7-dimethyl)bicyclo[2.2.1]heptyl ether (allyl 1-
apocamphyl ether) (Figure 1.1) was unable to undergo Wittig rearrangement. Additional
evidence for the radical-radical anion dissociation-recombination mechanism came from
“radical clock” experiments, namely the isomerization of the cyclopropylmethyl allyl
ether radical to a 3-butenyl (“homoallyl”) radical. In these experiments the exclusive
formation of cyclopropane derivatives (isolated as the 0—silyl ethers, M=Si(CH3)3)
(Figure 1.1) supported the radical mechanism.

In contrast to the above reports in support of the radical-radical anion
dissociation-recombination mechanism for the [1,4]-Wittig rearrangement of ethers,

Nakai has reported that this reaction pathway is likely to be a one-step, symmetry-

18

allowed, concerted process.29 In his investigation of the stereochemistry of the
sigmatropic rearrangement of stereodefined cis-allyl cyclohexenyl ethers (n-BuLi, THF,
-85 °C), he obtained a stereoisomeric mixture of secondary alcohols (via [2,3]- and [1 ,2]-
alkyl shifts) in 62% isolated yield along with 14% of a syn-aldehyde (Scheme 1.26). The
aldehyde is the result of [1,4]-rearrangement of the substrate ether, a process that
occurred with retention of stereochemistry as required by orbital symmetry
considerations. Based on the data from their stereochemical studies, the regio- and
stereochemical outcomes of the [1,4]-shift are exactly the same as those of a tandem
[2,3]-Wittig-oxy-Cope sequence of the same substrate. The authors also showed that the
proportion of the [1,4]—product varies with the type of substituent, increasing with
complexity of the substituent (Scheme 1.26).

Scheme 1.26. Wittig rearrangement of stereochemically
defined allyl cyclohexenyl ether by Nakai29

 

 

 

R2 R2 R2 OH OH R2
W0, ”43”” OHC , o / \
o o o
-85°C
R1 R1 R1 R1
[1.4] [2.3] [1.2]
R1 R2 [1,4]/[2.31412]
H H 12:24:64
CH3 H 18:54:28

C(CH3)=CH2 CH3 48 I 6 I 46

 

Despite these earlier studies, the case for either a radical-radical anion
dissociation-recombination or a concerted process cannot always be made. Indeed an

admixture of pathways may operate depending on the substrate. The rearrangement of a

19

dihydropyranyl anion was reported to occur via [1,4]-pathway to give exclusively the (Z)-
cyclopropyl enolate (Scheme 1.27).30 The [1,4]-pathway for this substrate would require
that the dihydropyranyl anion adopt a cis orientation to ensure that the two interacting
ends are in close proximity for a concerted process. This requirement is fulfilled as the
ring structure enforces a cis orientation of the allylic anion. The complete absence of
cyclopentenyl ring ([1,2]-product) was taken as evidence for a concerted pathway. On
the other hand, the analogous thioether compound did not afford the expected rearranged
product.:"1 However, on placement of resonance-stabilizing groups at C5 of this
substrate, it rearranged to afford the expected product. The fact that resonance-stabilizing
groups facilitated the bond reorganization suggested a stepwise mechanism (Scheme

1.28).

Scheme 1.27. Wittig rearrangement of dihydropyranyl anion via [1,4]-Wittig pathway30

/5\___.V/§
O 08

+ G’OG

20

Scheme 1.28. Wittig rearrangement of carbanions from 4—thiacyclohexenyl systems31

1. t-BuLi (1.1 equiv)

 

 

 

 

 

 

THF, -78 °C, 1 h Me SMe
8 then -20 °C 3 \ fl _
I i T S | + SM
2. Mel (excess), 24 h Me e
(90%, 66/33) Expected \Mttig products
Not observed
1. t-BuLi (1.1 equiv)
THF, -15 °C, 1 h Ph
D then -20 °C m
Ph 2. Mel (excess), 24 h Ph SMe
Ph (95%)

Kass and cowokers32 tried to provide a rationale for the mechanistic
contradictions and inconsistencies regarding these Wittig rearrangement pathways. They
carried out an extensive gas-phase study on the thio-Wittig rearrangement of
deprotonated allyl methyl sulfide, and found that l-thiomethylallyl anion predominantly
isomerizes to l-butenyl thiolate, a [1,4]-Wittig product. In contrast methyl deprotonation
in the gas phase leads to 3-butene-1-thiolate, a [2,3]-Wittig product. These authors found
that both [1,2] and [1,4] pathways have similar energy requirements, and are
thermodynamically accessible to allyl methyl sulfide on the basis of calculations at a high
level of theory (QCISD(T)/6-331++G(d,p)/HF/6-31+G(d)). However, by these
calculations, the [1,4] rearrangement is favored by 9 kcal mol'1 (Scheme 1.29). They also
explained that the observed selectivity for [1,2] and [1,4] could be most easily
accommodated by a concerted process, but that the stepwise radical mechanism could

also be operative.

21

Scheme 1.29. Gas-phase Wittig-rearrangement of allyl methyl sulfide by Kass32

A H0 = -23 kcaimor1 s
. AF

9

 

 

 

 

 

— _ . . - [1,2]-VVIttig
W3 CH4
@8043 ——- and/or
W8 eCi‘ig
e MSG
A H0 = -32 kcaimor1
[1,4]-Whig

22

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1. For a general review see Weber, W. P. In Silicone Reagents for Organic Synthesis;
Springer-Verlag: New York, 1983. (b) Bonini, B. F.; Comes-Franchini, M.; Fochi, M;
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2. Wittig, G.; Lohmann, L. Liebigs Ann. Chem. 1942, 550, 260-268.

3. (a) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885-902. (b) Marshal, J. A., in
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4. (a) Schulte-Elte, K. H.; Rautenstrauch, V.; Ohloff, G. Hele. Chim. Acta 1971, 54,
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Org. Chem. 1983, 48, 279-281 and references cited therein. (g) Midland, M. M.; Kwon,
Y. C. Tetrahedron Lett. 1985, 26, 5013-5016, and references cited therein. (h) Mikami,
K.; Kishi, N.; Nakai, T.; Fujita, Y. Tetrahedron 1986, 42, 2911-2918.

5. (a) Katsuhiko, T.; Yamamoto, H.; Nakai, T. Liebigs Ann. 1997, 1275-1281. (b)
Rautenstrauch, V.; Buchi, G.; Wuest, H. J. Am. Chem. Soc. 1974, 96, 2576-2580. (c) Lee,
B. H.; Biswas, A.; Miller, M. J. J. Org. Chem. 1986, 51, 106-109.

6. (a) Schafer, H.; Schdllkopf, U.; Walter, D. Tetrahedron Lett. 1968, 2809-2812, and
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3315-3318. (c) Garst, J. F.; Smith, C. D. J. Am. Chem. Soc. 1976, 98, 1526-1537. ((1)
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(e) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118, 3317-3318. (1)
Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. Chem. 1997, 1275-1281. (g)
Maleczka, R. E. Jr.; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551-8552, and references
cited therein.

7. (a) Schreiber. S. L.; Goulet, M. T. Tetrahedron Lett. 1987, 28, 1043-1046. (b) Verner,
E. J.; Cohen, T. J. Am. Chem. Soc. 1992, 114, 375-337. (c) Hoffmann, R.; Bruckner, R.
Chem. Ber. 1992, 125, 1957—1963. ((1) Tomooka, K.; Igarashi, T.; Nakai, T. Tetrahedron
Lett. 1993, 34, 8139-8142. (b) Tomooka, K.; Igarashi, T.; Nakai, T. Tetrahedron 1994,
50, 5927-5932.

8. (a) Schollkopf, U. Angew. Chem. Int. Ed. Engl. 1970, 9, 763-773. (b) Schollkopf, U.;

Fellenberger, K.; Rizk, M. Liebigs Ann. Chem. 1970, 734, 106-115. (c) Felkin, H.;
Frajerrnan, C. Tetrahedron Lett. 1977, 39, 3485-3488, and references cited therein.

23

9. Maleczka, R. E. Jr.; Geng, F. Org. Lett. 1999, I, 1111-1113.

10. For a general review see Weber, W. P. In Silicone Reagents for Organic Synthesis;
Springer-Verlag: New York, 1983. (b) Fleming, 1.; Manda], a. K. J. Chem. Soc., Chem.
Commun. 1999, 923-924. (c)Furin, G. G.; Vyazankina, O. A.; Gostevsky, B. A.;
Vyazankin, N. S. Tetrahedron 1988, 44, 2675-2749. ((1) Hsiao, C. N.; Shechter, H. J.
Org. Chem. 1988, 53, 2688-2699, and references cited therein.

11. (a) Nakai, T.; Tomooka, K. Pure Appl. Chem. 1997, 69, 595-600. (b) Nakai, T.;
Mikami, K. Organic Reactions 1994, 46, 105-209. (c) Briickner, R. In Comprehensive
Organic Synthesis, Pattenden, G., Ed.; Pergamon: London, 1991; Vol. 6, 873-908.

12. (a) Caruana, P A.; Frontier, A. J. Tetrahedron 2004, 60, 10921-10926. (b) Schaudt,
M.; Blechert, S. J. Org. Chem. 2003, 68, 2913-2920. (c) Abad, A.; Agullo, C.; Cunat, A.
C.; Jimenez, D.; Perni, R. H. Tetrahedron 2001, 57, 9727-9735. ((1) Sugimura, H.;
Hasegawa, Y.; Osumi, K. Heterocycles 2000, 52, 99-102. (e) Ghosh, A. K.; Wang, Y.
Tetrahedron 1999, 55, 13369-13376. (1) Ghosh, A. K.; Wang, Y. J. Org. Chem. 1998,
63, 6735-6738.

13. For examples, see (a) McGowan, G. Aust. J. Chem. 2002, 55, 799. (b) Marshall, J. A.;
McNulty, L. M.; Zou, D. J. Org. Chem. 1999, 64, 5193-5200 and references therein. (c)
Marshall, J. A. In Pattenden, G., Ed.; Comprehensive Organic Synthesis; Pergamon:
London, 1991; Vol. 3, pp 975-1014. (X) Mulzer, H.; Riether, D. Org. Lett. 2000, 2, 3139-
3141.

14. (a) Chemistry of Tin; Smith, P. J ., Ed.; Blackie Academic & Professional: New York,
1998. (b) Davies, A. G. In Organotin Chemistry, VCH: New York, 1997. (c) Pereyre, M.;
Quintard, J .-P.; Rahm, A. In Tin in Organic Synthesis; Butterworth: Toronto, 1987.

15. (a) Hoffmann, R.; Bruckner, R. Chem. Ber. 1992, 125, 1471-1484. (b) Kruse, B.;
Bruckner, R. Tetrahedron Lett. 1990, 31, 4425-4428. (c) Kruse, B.; Bruckner, R. Chem.
Ber. 1989, 122, 2023-2025. (d) Broka, C. A.; Shen, T. J. Am. Chem. Soc. 1989, 111,
2981-2984.

16. Hioki, K.; Kono, K.; Tani, S.; Kunishima, M. Tetrahedron Lett. 1998, 39, 5229-5232.

17. Kunishima, M.; Hioki, K.; Kono, K.; Kato, A.; Tani, S. J. Org. Chem. 1997, 62,
7542-7543.

18. (a) Reetz, M. T.; Greif, N. Chem. Ber. 1977, 110, 2958-2959. (17). (b) Takahashi,
0.; Maeda, T.; Mikami, K.; Nakai, T. Chem. Lett. 1986, 1355-1358. (c) Adam, S.
Tetrahedron 1989, 45, 1409-1414.

19. Maleczka, R. E. Jr.; Geng, F. Org. Lett. 1999, 1, 1115-1118.

24

20. (a) Carey, F. A.; Court, A. S. J. Org. Chem. 1972, 37, 939-943. (b) Mulzer, J.; List,
B. Tetrahedron Lett. 1996, 3 7, 2403-2404. (c) Magnus, R; Roy, G. Organometallics
1982, 1, 553-559. (d) For a general review see Weber, W. P. In Silicone Reagents for
Organic Synthesis; Springer-Verlag: New York, 1983.

21. For examples of the directed deprotonation and rearrangement of vinylogous 0i-
alkoxysilanes see: (a) Mikami, K.; Kishi, N.; Nakai, T. Chem. Lett. 1989, 1683-1686. (b)
Greeves, N.; Lee, W.-M. Tetrahedron Lett. 1997, 38, 6445-6448. For examples of
initiation of [1,2]-Wittig rearrangement of (aryloxy)methylsi1anes by deprotonation see:
Eisch, J. J .; Galle, J. E.; Piotrowski, A.; Tsai, M.-R. J. Org. Chem. 1982, 47, 5051-5056.
22. (a) Linderman, R. J.; Ghannam, A. J. Am. Chem. Soc. 1990, 112, 2392-2398. (b)
Brook, A. G.; Bassendale, A. R. In Rearrangements in Ground and Excited States; de
Mayo, P., Ed.; Academic Press; New York, 1980; Vol. 2, 149-227.

23. Tomooka, K.; Yamamoto, H.; Nakai, T. Angew. Chem. Int. Ed. 2000, 39, 4500-4502.
24. Felkin, H.; Tambute, A. Tetrahedron Letters 1969, 821-822.

25. (a) Woodward, R. B.; Hoffinann, R. Angew. Chem. 1969, 8, 797. (b) Woodward, R.
B.; Hoffmann, R. Angew. Chem. Int. Ed. Engl. 1969, 8, 781-852.

26. (a) Hauser, C. R.; Kantor, S.W. J. Am. Chem. Soc. 1951, 73, 1437-1441. (b)
Rautenstrach, V. J. Chem. Soc, Chem. Commun. 1970, 4-6.

27. Schlosser, M. J. Organomet. Chem. 1967, 8, 9-16.

28. Schlosser, M.; Strunk, S. Tetrahedron 1989, 45, 2649-2664.

29. Sayo, Kimura, Y.; Nakai, T. Tetrahedron Lett. 1982, 23, 3931-3934.
30. Rautenstrauch, V. Helv. Chim. Acta 1972, 55, 594-609.

31. (a) Biellmann, J. F.; Ducep, J. B.; Vicens, J. J. Tetrahedron 1976, 32, 1801-1805. (b)
Biellmann, J. F.; Ducep, J. B. Tetrahedron Lett. 1970, 11, 2899-2902.

32. Ahmak, M. R.; Dahlke, G. D.; Kass, S. R. J Am. Chem. Soc. 1996, 118, 1398-1407.

25

CHAPTER 2

OPTIMIZATION OF [1,4]-WITTIG REARRANGEMENT OF MODEL SUBSTRATE

2.1. Introduction

In the course of their study on the MeLi—promoted Wittig rearrangements of a-
alkoxysilanes, Maleczka and Gengl found that the Wittig rearrangements of or-
alkoxybenzysilanes were initiated by both direct metalation and Si/Li exchange (Scheme
1.16). For example, the rearrangement of compound 1 afforded product 3 arising from
Si/Li exchange was obtained in 75% yield while the yield for compound 2 resulting from
initiation by a-deprotonation was 21%. They further observed that on moving from or-
alkoxylbenzylsilanes to a-alkoxylallylsilanes, the extent of Si/Li exchange was
significantly diminished. This is clearly demonstrated in the second reaction of Scheme
1.16 (rearrangement of 4). Si/Li exchange afforded 6, accounting for 20% of the product
mixture and tat-deprotonation gave 60% of the corresponding B-silyl ketone product 5.

Scheme 1.16. Wittig rearrangement of a-alkoxysilanes initiated by
Si-Li exchange and direct a-deprotonation manifolds

 

 

Me 3,
1o 1. ,/ MeLi,THF 0” 20H ,
3L 2 2 3' Me 3 Me
ph \ Ph \
Ph TMS rt, 16 n TMS H
[3,2]-V\fittig (21%) [3,2]-Wittig (75%)
Ian 3, from deprotonation event from Si/Li exchange
/
10% MeLi, THF 0 OH
/\/u\3'/\/ '
\3 TMS rt, 16h TMS 2 \ Ph \ 2 3 \ Ph
[2,3]-Wittig (60%) [2,3]-Whig (20%)

from deprotonation event from Si/Li exchange

26

In addition, the Wittig rearrangements of two of their substrates were initiated
exclusively by deprotonation (Scheme 1.4 and Scheme 1.18). One of these substrates,
10, rearranged exclusively via the [2,3]-Wittig pathway to afford 11 (Scheme 1.18). The
other substrate 7 rearranged via a mixture of both [1,4]- and [1,2]-Wittig pathways, with
the [1,4]-product 81’2 favored by a ratio of 3:1 (Scheme 1.4). Given the synthetic utility
reported for both acylsilanes3 and B-silyl ketones,4 we decided to explore the Wittig
rearrangement or this substrate further, focusing on optimizing the [1 ,4]-Wittig pathway.

The reaction of Scheme 1.4 formed the basis/starting point of this dissertation.
At the start of our study we posed the following questions as a guide: (1) could the
rearrangement be made to generally to favor the [1,4]- over the [1,2]-rearrangement? (2)
Could the [1,4]-Wittig be made more efficient in terms of yield? (3) Could the synthetic
utility of the [1,4]-Wittig rearrangement be expanded? (4) What is a plausible
mechanism of this rearrangement? We believed that finding answers to the above
questions would give insight into the mechanism and synthetic utility of the [1,4]-Wittig

rearrangement of a-alkoxysilanes.

2.2. Yield Optimization
Introduction

Our initial research focused on optimizing for the [1,4]-Wittig. On the basis of
existing literature reports on the Wittig rearrangement of ethersm”4 we reasoned that
attempts at achieving selectivity of the Wittig rearrangement of a-alkoxysilanes would be
aided by a good knowledge of how reaction variables such as base (type and

concentration), reaction temperature, solvent1 and substrate structure,3 (sterics and

27

electronics) impact the reaction.

Using model compound 7, we systematically

investigated the reaction under various base, temperature, and solvent conditions.

2.2.1. Wittig rearrangement of model substrate 7: Effect of temperature

Employing MeLi as base, the effect of temperature on the Wittig rearrangement

of 7 was studied. On treatment with MeLi (1.5 eq), a-alkoxysilane 7 underwent a facile

isomerization reaction via both [1,4]- and [1,2]-pathways to afford 8 and 9. The results

obtained (Table 2.1) showed that the rearrangement of 7, mediated by MeLi, was mildly

selective for the [1 ,4]-pathway and that the selectivity is highly temperature dependent.

Table 2.1. MeLi-mediated Wittig rearrangement reaction of 7- Effect of temperature.

 

0A Ph Men 0 o
V‘TMS PhW/lLTMS + TMs/\/u\/Ph
7 THF 8 9
via [1 ,4-Wittig] via [1 ,2]-Wittig

 

Entry Base equiv Temp (°C) Time (h) Yield (°/0) [1,4]/[1,2]

 

1

2

3

1.5-2.0

3.0

3.0

3.0

4.0

4.0

18t020

-80 to ~37

~80 to -50

-80 to -50

~80 to -37

-80 to -50

1 .0 69
72 68
72 68
120 66
65 68
72 60

1.4:1 to 2:1

4:1

>12:1

>12:1

4:1

>12:1

 

Our findings can be summarized as follows: (1) the [1,2]-Wittig pathway was

effectively suppressed when the reaction temperature was kept below (-60 0C). However,

28

at this temperature, the rate of conversion of the substrate to product was very slow and
did not go to completion even after 72 h. (2) Complete consumption of the starting
material took 65 to 72 hours with 3 to 4 equivalents of MeLi respectively, and required
warming the reaction to -37 °C. Under these conditions the selectivity was 4:1 in favor of
the [1,4]-Wittig product. (3) Use of less than 3 equivalents of base at temperatures below
-60 °C resulted in less than 50% conversion of the substrate, and using more than 3
equivalents of MeLi did not give any additional advantage (compare entries 2 and 5, 3
and 6 ofTable 2.1).

Employing 3 and 4 equivalents of MeLi at different temperatures -80 to -37 °C
and -80 to -50 °C respectively for the same length of time resulted in [1,4]/[1,2] ratios of
4:1 (compare entries 2 and 3, 5 and 6 of Table 2.1), but the absolute yield of products
remained the same. It is pertinent to mention that in these experiments, reproducibility of
results was an issue. The outcome of the rearrangements varied with the rate of addition
of the base. In summary, the rearrangement of compound 7, mediated by MeLi, is
selective for the [1,4]-pathway and the degree of this selectivity is highly temperature

dependent.

2.2.2. Effect of base on the Wittig rearrangement of model substrate 7

With our initial temperature studies complete, we turned to the effect of base on
the rearrangement of model substrate 7. We tested different alkyllithium bases in the
reaction. Our results are summarized in Table 2.2. n-BuLi, unlike MeLi afforded the
[1,4]-product selectively at -78 °C (the [1,2]-product could not be detected by lHNMR).

Adding n-BuLi at -78 °C and allowing the reaction to slowly warm up to -37 °C afforded

29

the [1,2] and [1,4]-Wittig products 8 and 9. These compounds were obtained in a
combined 83% yield and 9:1 ratio in favor of the [1,4] product. However, at room
temperature, the [1,4]/[1,2] selectivity was not improved over MeLi, and the yields were
comparable. Nevertheless, n-BuLi proved to superior to MeLi. With 1.5 eq. of n-BuLi,
at -78 °C, reaction was complete in about 5 h, as compared to MeLi that gave an
incomplete reaction even beyond 72 h (compare entries 7 and 8 of Table 2.2). s-BuLi
was found to be superior to both n-BuLi and MeLi in initiating the Wittig rearrangements
of a-alkoxysilanes (results are shown in Table 2.2). Upon treatment of a cold (-78 °C)
THF solution of the substrate ether with 1.5 equiv of sec-BuLi (1.3M in cyclohexane),
Wittig rearrangement was complete in 30 min to afford the [1,4]-rearrangement product
exclusively and in good yield (79-82%). The presence of the [1,2]-Wittig product was
not detected (by using TLC, NMR and GC-MS). From these experiments, our optimum
conditions for the Wittig rearrangements of our model substrate 7 were treatment with 1.5
eq. of s-BuLi at -75 0C in THF solvent for 30 minutes, and quenching of reaction with
NII4CI (sat. aq.). Table 2.2 also illustrates the effect of temperature on the Wittig
rearrangement of our model substrate with all three bases. In general, [1,4]/[1,2]
selectivity was greatest at lower temperature, with selectivity being eroded at warmer
temperatures. To the best of our knowledge, this is the most selective and most efficient
[1,4]-Wittig rearrangement of a-alkoxysilanes in particular, and allyl benzyl ethers in

general, to be reported.

30

Table 2.2. Effect of base on the selectivity of Wittig rearrangement of 7

/\

0 Ph Base 0 O
vTMS THF Ph\/\/U\TMS + TMS/\/U\/Ph
7 8 9
via [1,4]-Wittig via [1 ,2]-Wittig

 

Entry Base Base equiv Temp (°C) Time (h) Yield (°/o) [1,4]/[1,2]

 

1 MeLi 1.5-2.0 18 to 20 1.0 59 14:1 to 2:1
2 n-BuLi 1.5 18 to 20 1.0 68 2.45:1

3 s-BuLi - - - - -

4 MeLi 3.0 -80 to -37 72 68 4:1

5 n-BuLi 1.5 -80 to -37 2 83 9.1 :1

6 s-BuLi 1.5 -50 to -37 <01 79-83 >20:1

7 MeLi 3.0 50 to -50 72 68 >12:1

8 n-BuLi 1.5 -80 to -75 <5 79-83 >100:1a
9 s-BuLi 1 .5 -80 to -75 <0.5 79-83 >1 oo; 1 a

 

a No [1,2]-Wittig product could be detected by 1H NMR

2.3. Conclusions

In summary, we have demonstrated that the [1,4]-Wittig rearrangement of simple,
unsubstituted a-alkoxysilanes, representated by 7, could be efficient in terms of yield,
and that the selectivity of the rearrangement could be improved to favor the [1,4]- over
the [1,2]-pathway. Furthermore, the differential selectivities we obtained in the Wittig
rearrangement of model substrate 7 could be an indication that [1,4-] and [1,2]-

rearrangements of a-alkoxysilanes probably have completely different mechanisms.

31

The [1,4]-Wittig of 7 results in the formation of an enolate imtermediate, which
on protonation undergoes keto-enol tautomerism to afford the resultant acylsilane 8.
Instead of protonating the enolate, the reaction could be quenched with a variety of
electrophiles, an event that would put the electophile either on the oxygen to give a vinyl
ether derivative or on or carbon to afford a-functionalized acylsilane. Chapter 2 will

discuss the electrophilic trapping of the intermediate enolate in the [1,4]-Wittig pathway.

32

EXPERIMENTAL

OAPh

vms

7

Preparation of a—alkoxysilane 7: Trichloroacetimidate of benzyl alcohol (2.0
equiv, 4.85 g, 19.20 mmol) (prepared following literature procedure)5 was added to a
stirred solution of or-(trimethylsilyl)allyl alcohol (1.0 equiv, 1.32 g (10.13 mmol) in
cyclohexane (0.2 M) at room temperature. A TMSOTf (0.055 equiv, 0.12 g, 0.55 mmol,
0.10 mL) solution in cyclohexane (0.1 mL/ 1.0 mL cyclohexane) was then added. White
precipitate formed upon addition of the Lewis acid. The reaction mixture was stirred at
room temperature overnight and filtered. The precipitate was then washed with pentane
or hexane (precipitate is soluble in ether) and the filtrate diluted with ether. The diluted
filtrate was subsequently washed with NaHCO3 (sat. aq.) (x 2), IN HCl (x 2), and lastly
with brine (x 2). The organic phase was dried over anhydrous MgSO4, filtered, and
concentrated to furnish the crude product. Note: the product was always accompanied by
an ester by-product, which was removed by base hydrolysis (usually stirring with 2M
NaOH at room temperature for about 2 h). Purification by column chromatography on
silica gel (0-1% EtOAc in hexane gradient) afforded 56% of pure 7 as a colorless oil.
[Geng Feng, Michigan State University, Ph.D. dissertation 2001]. IR (neat) 2959, 1454,
1383, 1248 cm'l. 1H NMR (300 MHz, CDC13) 8 7.37-7.24 (m, 5H), 5.89-5.77 (m, 1H),
5.12-5.04 (m, 2H), 4.71 (d, J= 12.4 Hz, 1H), 4.32 (d, J: 12.4 Hz, 1H), 3.64-3.60 (dt, J=

7.1, 1.4 Hz, 1H), 0.02 (s, 9H). 130 NMR (75 MHz, CDC13) 5 139.1, 137.2, 128.1, 127.5,

33

127.1, 112.5, 75.9, 71.8, -3.8. 7 is a known compound and has spectral data in accord
with the reported ones.la

O

PhNL'l-MS

8

Wittig rearrangement reaction of 7~ preparation of acylsilane 8. A solution of
76 mg (0.34 mmol) of silane 7 in 4.5 mL of THF was cooled to -78 °C under nitrogen. s-
BuLi (1.3 M in cyclohexane, 0.4 mL, 0.52 mmol) was added dropwise via syringe. The
reaction mixture was stirred for 30 min. at -78 oC, and then quenched with saturated
aqueous NH4Cl, diluted with diethyl ether, washed with water and brine. The organic
phase was dried over MgSO4 and concentrated. Silica gel chromatography (0 to 2%
EtOAc in hexane gradient) afforded 63 mg (82%) of 8 as a light yellow oil. IR (neat)
2955, 1717, 1643, 1497, 1454, 1250 cm". 'H NMR (500 MHz, CDC13) 5 727-14 (m,
5H), 2.62-2.59 (apparent t, J = 7.3, 6.8 Hz, 2H), 2.58-2.55 (apparent t, J = 7.8, 7.3 Hz,
2H), 1.87-1.81 (m, 2H), 0.16 (s, 9H). ‘3C (125 MHz, CDC13) 8 248.1, 141.8, 128.4,
128.3, 125.8, 47.5, 35.2, 23.6, -3.2. 8 is a known compound and has spectral data in

accord with the reported ones. "2

34

REFERENCES

1. Maleczka, R. E. Jr.; Geng, F. Org. Lett. 1999, 1, 1115-1118.
2. Yoshida, J .; Itoh, M.; Matsunaga, S.; Isoe, S. J. Org. Chem. 1992, 57, 4877-4882.

3. For a general review see Weber, W. P. In Silicone Reagents for Organic Synthesis;
Springer-Verlag: New York, 1983. (a) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.;
Mazzanti, G.; Ricci, A. J. Organomet. Chem. 1998, 567, 181-189. (b) Maleczka, R. E.,
Jr.; Geng, F. Tetrahedron Lett. 1999, 40, 3113-3114, and reference cited therein.

4. For a general review see Weber, W. P. In Silicone Reagents for Organic Synthesis;
Springer-Verlag: New York, 1983. (a) F leming,I.; Manda], A. K. Chem. Commun. 1999,
923-924. (b) Furin, G. G.; Vyazankina, O. A.; Gostevsky, B. A.; Vyazankin, N. S.
Tetrahedron 1988, 44, 2675-2749. (c) Hsiao, C. N.; Shechter, H. J. Org. Chem. 1988, 53,
2688-2699, and referenced cited therein.

5. Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. 1997, 1275-1281.

6. Maleczka, R. E., Jr; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551-8552 and references
cited therein.

7. Felkin, H.; Tambute, A. Tetrahedron Lett. 1969, 10, 821-822.

35

CHAPTER 3

PREPARATION OF ACYLSILANES:
TRAPPING OF ENOLATE OF MODEL SUBSTRATE

3.1. Introduction

In Chapter 2 of this dissertation we showed that a-alkoxysilanes, typified by
model compound 7, undergo efficient and very selective [1,4]-Wittig rearrangement to
afford affords acylsilanes via an enolate intermediate.I This discovery was made by
Maleczka and Geng,l who, during the course of their study on the Wittig rearrangements
of a-alkoxylsilanes, isolated an acylsilane [Scheme 3.1, E = H, 8], from compound 7 that
rearranged via both [1,4]- and [1,2]- pathways. This was the first time an acylsilane was
prepared via a Wittig rearrangement of a-alkoxylsilanes. The intermediacy of an enolate
offers an attractive access to a variety of novel acylsilanes by trapping the enolate with
suitable electrophiles. This was first demonstrated by Maleczka and Geng when they
generated and trapped the [1,4]-enolate with allyl bromide to obtain the 0i-allyl acylsilane
in 15% yield (Scheme 3.1, E = allyl).

Scheme 3.1. Eletrophilic trapping of enolate of model
compound 7-formation of acylsilanes
/\ . O
o ph 1. RLI, THF
_ Ph
v (.9 V \/\[/U\TMS
TMS 2' H3O E
7 (3; E = H)
1. RR A=CHCHBr
o9 (12; E = CHfCH-CH)

PhMTMS

 

36

This discovery opened the door for a new route to these useful compounds, and
we thus decided to develop viable and more efficient routes to the acylsilanes via the
Wittig rearrangement reactions of a-alkoxylsilanes (Scheme 3.1). Having gained control
of the Wittig rearrangements of our model compound, we then turned our attention on the
prospects of introducing various substituents at the a-position of the carbonyl compounds

resulting from the [1 ,4]-pathway

3.2. Electrophilic trapping of intermediate 7 enolate

We started enolate trapping studies by optimizing for the reaction illustrated in
Scheme 3.1. After generating the enolate of 7 under our optimum conditions, it was
transferred by canula into a THF solution of an appropriate electrophile. With allyl
bromide as the electrophile, we observed that the mode of addition of the electrophile and
the reaction temperature are two important factors that control the formation of as well as

the yield of product (Table 3.1).

Table 3.1. Allylation of the enolate of compound 7

 

1. s-BuLi (1.5 equiv) Ph 0
ViAph THF, -78 C, 0.5 h = TMS
\ 2. Allyl bromide /
7 TMS TEA/HMPA, THF 12

 

EntryAllyl bromide TEA‘ HMPA Temp Time Yield
(equiv) (equiv) (equiv) (°C) (M W

 

No
isolated
2 4.0 4.0 - -75 to rt 6 55

 

37

Addition of allyl bromide directly to the reaction mixture at 0 °C led to the
recovery of the rearranged products, with little or no evidence of the expected allylated
product. Use of TEA at room temperature proved advantageous, affording the desired
product, 12, in 55% yield (Table 3.1, entry 2), with just some detection of a second
product, which, from 1H-NMR and l3C-NMR, was an aldehyde. Substituting HMPA for
TEA under the prevailing reaction conditions resulted in the reverse result, the aldehyde
being obtained as the major product and 12 obtained in only 14% yield. However,
addition of the electrophile in the presence of HMPA at lower temperature (0 °C) resulted
in both 12 and this aldehyde being obtained in 2:1 ratio,2 accompanied by other by-
products. Two of these by-products (tentative structures given as 12 and 14) resulted
from multiple allylations of the enolate and one (15) a monoallylation/desilylation
compound (Scheme 3.2). These by-products could not be isolated and the NMR spectra
of the product mixture were very complex. However, we were able to at least partially
identify them by high resolution mass spectrometry3 and the tentative structures in
Scheme 3.2 suggested. As shown in Table 3.1, employing a 2:1 mixture of TEA and
HMPA resulted in a messy reaction and no product was isolated (Table 3.1, entry 1).

A two-pot Wittig rearrangement/LDA deprotonation-allylation was carried out to
compare to our one-pot process (Scheme 3.3). In this process, compound 7 was
subjected to Wittig rearrangement and 8 isolated (83%). Acylsilane 8 was then
deprotonated with LDA at low temperatures and the resulting enolate trapped with
allylbromide. Our results indicate that the one-pot process is synthetically more efficient
than the two-pot Wittig rearrangement/deprotonation-allylation route, both in terms of

time and yield.

38

Scheme 3.2. Allylation of enolate of compound 7 in the presence of HMPA

O
/ \
13
O
p
5

\

A 1. MeLi (4.0 equiv)
0 Ph THF, 0°C,6h

 

O
TMS
v . . >
TMS 2. Allyl bromide (8.0 equ1v) M
TMS

P
12
7 HMPA (8.0 equiv), THF 0 h
0 °C, 5 hr; then rt Ph H
overnight /
/ \
14 1

Scheme 3.3. One-pot vs. two-pot Wittig rearrangement/allylation of 7

2. Allyl bromide Ph

 

 

 

 

 

(4.0 equiv) O
TEA (4.0 equiv? TMS
THF, rt, 6 11 /
(55%) 12
/\
O P“ 1. s-BuLi (15 equiv) “ 1. LDA (2.1 equiv)
vms . THF, 0 °C, 2 h 10 min.
THF. -78 C. 0.5 h 2. allyl bromide (5.0 equiv)
7 TEA (5.0 equiv), THF, 0 °c
Pb 5.5 h; rt, overnight
35°/
2. NH4CI (sat. aq) u ( °)
' TMS

Column
chromatography 3
(83%)
Ethylation was achieved by use of Ed and resulted in a mixture of C- and O-

alkylated products (16 and 17) in a 3:1 ratio in favor of C -alkylation. Ethylation required

the use of an additive, and HMPA proved to be superior to TEA in this case (Table 3.2).

39

Table 3.2. Ethylation of the enolate of 7‘1l

 

 

 

Ph
1. s-BuLi (1.5 equiv) 0 Ph
oAph THF, -78 °C, 0.5 11 \|\)O\Et
4- TMS +
VTMS 2. E11 (4.0 equiv) Et / TMS
7 TEA/HMPA, THF 16 17
Entry TEA HMPA ' Temp Time Yield
(ecl-l (8Q) (°C) (11) (%)
1 4.0 - -75 to rt 3.75 48
2 - 4.0 -75 to rt 5 81

 

(a) Ratio of C—alkylation/O-alkylation was 3: l.

The methyl group was successfully installed at the a-carbon using Mel as the
electrophile (Scheme 3.4). This reaction was optimized, and the results are shown in
Table 3.3. Slow addition of the trapping mixture (Mel/TEA) to a cold (0 0C) solution of
the enolate resulted in the formation of three carbonyl compounds, one silylated
compound 18, and two aldehydes 19 and 204, respectively (Scheme 3.4). On the other
hand, slow addition of a cold (~75 oC) THF-solution of the enolate to the trapping mixture
(Mel (4.0 equiv.)/TEA (4.0 equiv.) in THF) at room temperature, and stirring for 50 min,
afforded the desired tat-methylated acylsilane as a single product in 72% yield (Table 3.3,
entry 2). Trapping at low temperatures (-75 to -45 OC) required a longer reaction time (7
h) and led to diminished yield (59%) (Table 3.3, entry 1). The feasibility of this reaction
in the absence of TEA was also investigated, and it was found that at room temperature,
and in the absence of TEA, trapping of the enolate was feasible and rate comparable to

that with TEA; however, the yield was significantly lower (56%) (Table 3.3, entry 3). It

40

is apparent from Table 3.6 that low temperatures and prolonged reaction time are
unfavorable for this reaction, and that TEA was an essential additive.

Scheme 3.4. Methylation of enolate of 7

 

1. MeLi (3.0 equiv) P” o P“ 0 Ph 0
0A ph THF, °C, overnight
v : TMS + H + H
TMS 2. Mel (8.0 equiv) Me Me Me Me
7 TEA 18 19 20

Table 3.3. Methylation of the enolate of 7

1. s-BuLi (1.5 equiv) Ph 0
0A ph THF, -78 °C, 0.5 h
v = TMS
TMS

 

 

 

2. Mel (4.0 equiv) Me

7 TEA, T °C 13
Entry TEA Temp Tlme Yield

(equiV) (°C) (1)) (%)

1 4.0 -75 to 203 7 59

2 4.0 20 0.83 72

3 - 20 1 56

 

(a)After addition at -78 °C, reaction was allowed to warm to -45 °C first. When no reaction
was observed (by GC-MS) after 1 h 25 min, it was then allowed to warm to room temperature.

Reaction of the enolate with benzyl bromide was also found to be temperature
dependent. Whereas the a-benzylated product, 21, was obtained in 66% yield in the
presence of TEA at 20 °C (PhCHzBr (4.0 equ1v)/TEA (4.0 equiv.)) (Table 3.4, entry 2),
carrying out the reaction at lower temperatures (-75 to -45 OC) resulted in an incomplete
reaction even after 24 h, affording the product in only 36% yield (Table 3.4, entry 4). It

was also determined that TEA is beneficial for this reaction, because, even though a 60%

41

yield of product was obtained in the absence of TEA (Table 3.4, compare entries 2 and
3), the reaction required 7 h to go to completion. TBAI also proved to be an effective
additive, allowing a low temperature (-75 °C) trapping and affording the product in 59%
yield. No O-alkylation was observed in these reactions. From the results in Table 3.4,
HMPA is not a requirement in this reaction (Table 3.4, compare entries 1 and 2). The use
of HMPA resulted in the formation of the desired product (in only 32% yield),

accompanied by the formation of by-products (Table 3.4, entry 1).

Table 3.4. Benzylation of the enolate of 7.

 

1. s-BuLi (1.5 equiv) P“ 0
0A ph THF, ~78 °C, 0.5 11
v > TMS
TMS 2. BnBr Bn
7 TEA, T °c 21

 

Entry BnBr TEA Temp Time Yield
(eq.) (eq.) (°C) (h) (%1

 

1a 6.0 6.0 0 to 20 4 32
2 4.0 4.0 20 1.5 66
3 4.0 - 20 7 60
4 4.0 4.0 -75 to 20 24 35w
5d 4.0 - -78 3.5 59

 

(a) 3.0 eq. of HMPA was employed. (b) The crude reaction mixture contained the rearranged and
trapped products in 122.8 ratio. (c) 22% of [1,4] product 8 was isolated. (d) 4.0 eq. of TBAI
added.

The silyl derivative 22 was prepared by trapping the enolate intermediate with
TMSCl. The trapping was investigated under various reaction conditions and the results

obtained are given in Table 3.5. The reaction afforded the O-silylated product, which was

42

expected. No C—silylation was detected. The reaction was facile at low temperatures (-75
to -45 °C), being complete in 50 minutes, and affording the desired product 22 in 85%
yield (Table 3.5, entry 4). It is also clear from the Table that TMSCl was a good enough

electrophile, so as not to require the use of any additives.

Table 3.5. Silylation of the enolate of 7.

1. s-BuLi (1.5 equiv)

/\

 

 

 

0 pr, THF, -78 °C, 0.5 h OTMS

v TMS 2. TMSCI Ph M TMS

7 TEA, T °C 22

Entry s-BuLi Time TMS.C| TEA HMPA Temp Time Yield

(equiV) (h) (equw) {equiv} (equiV) (°C) (h) 1%)
1 3.0 4 6.0 6.0 3.0 -75 to -45 1 71
2 1.5 0.5 6.0 6.0 3.0 -75 to 20 0.83 48
3 1.5 0.5 4.0 4.0 - 20 0.67 54
4 1.5 0.5 4.0 4.0 - ~75 to -45 1.33 85

 

Acetylation of the enolate was accomplished with acetyl chloride (Table 3.6).
The best conditions appeared to be addition of the cold (-75 oC) enolate solution to a
solution of CH3COC1 in THF at room temperature for 1 h 20 min. Under these
conditions, the ester (23) was obtained in 69% yield (Table 3.6, entry 2). Trapping at low

temperature was detrimental, as was the use of TBA.

43

The propyl derivatives 24 and 25 were prepared by trapping the enolate with n-
propyl iodide and the results obtained are given in Table 3.7. n-Propyl iodide proved to
be a poor electrophile, requiring the use of an additive. In this case reaction gave a 3:1
mixture of both C- (24) and O-alkylation (25) products.
significantly shortened the reaction time (from 52 h without to 24 h with TEA), but did

not give much yield enhancement (Table 3.7, entryl). However, HMPA gave better

Table 3.6. Acetylation of the enolate of 7

1. s-BuLi (1.5 equiv)

 

 

 

0A Ph THF, -78 °C, 0.5 h OAC
vTMS 2. AcCl (4.0 equiv) PhMTMS

7 TEA. T °c 23
Entry TEA Tfmp Time Yield

(equiv) < C) (h) 1%)

1 - -75 to 45 24 59

2 - 20 1.33 69

3 4.0 20 5 50

 

Use of TEA (4.0 eq)

results in terms of reaction time and product yield (Table 3.7, entries 3 and 4).

Table 3.7. Trapping of the enolate of 7 with propyl iodide.

1. s-BuLi (1.5 equiv) Ph

 

OPr

 

 

0A Ph THF, -78 «c, 0.5 h u \/\/‘\
5 Ph /
vTMS 2. Prl (4.0 equiv) TMS + TMS
7 TEA/HMPA, THF 24Pr 25
Entry TEA HMPA Temp Time Yield Ratio
(equiv) (equiv) (°C) (*0 (°/°)

1 4.0 - 20 24 39 3:1
2 - - 20 52 32 26:1
4 - 4.0 20 17 66 3:1

 

44

Benzaldehyde was also investigated as an electrophile for the trapping of the
enolate. Trapping was facile at low temperatures (-78 °C) and resulted in the formation
of 29 in 68% yield. This reaction did not require the use of Lewis acid catalysts.5

Vinyl perfluoroalkanesulfonates, e.g. vinyl triflates and vinyl nonaflates are
widely utilized in organic synthesis due to the high leaving-group ability of the
perfluoroalkanesulfonyloxy group. These compounds have often been used in transition
metal-catalyzed cross-coupling reactions.6 We envisaged that trapping the enolate
generated from the Wittig rearrangement of model compound 7 would lead to a vinyl
perfluoroalkanesulfonate, which when coupled with a suitable partner would result in a
vinyl silyl compound. This could be amenable to further transformations (Scheme 3.5).

Scheme 3.5. Schematic of envisaged [1,4]-Wittig/electrophilic trapping/coupling
reactions of model substrate 7

 

G
OAPh . . o OTf
s-BuLi 1.5 UIV
v ( eq ) > phM -----> PhM
TMS o TMS TMS
7 THF.-75 C
30 min :
R 11 R
\A/f’ /
G=an alk lchain, rin ora I Ph / - -----
y y 9 W G P“ / TMS

Attempts were also made to prepare the triflate by quenching a cold (-75 °C)
solution of the enolate with a variety of triflating agents. With triflic anhydride, only the
[1,4]-rearranged product 8 was isolated, with no evidence of the expected vinyl triflate.
The use of PhNTf2 did not allow for the isolation of the vinyl triflate 26, but gave
trimethyl-(4-phenyl-but-l-ynyl)-silane, 28 (Scheme 3.6). The formation of 28 is

envisaged to result from the expected vinyl triflate, which very likely underwent

45

elimination of the triflate and a vinyl proton to give the observed alkynylsilane (Scheme
3.6). Use of the nonaflating reagent (CF3(CF2)3SOZF) under similar reaction conditions
resulted in the formation of the vinyl nonaflate, 27 (Scheme 3.6) (lH-NMR of the crude
product was obtained). However, the nanoflate was sensitive to acidic conditions, and
attempted purification by silica gel column chromatography resulted in the elimination of
the nonaflate group to give 28. In all cases, product identification was by IH-NMR, 13C-

NMR, and high resolution GC-MS.

Scheme 3.6. Attempted synthesis of Vinyl triflate and vinyl nonaflate

Ph
PhNT2 (1.8 equiv) U" (58%)
' / TMS I
Ph

 

THF, -75 °C

0A Ph 1.3-5 h 25 (0%)
v s-BuLi (1.5 equiv) I
TMS T : TMS
THF, -75 °C, 30 min
CF3(CF2)3SOZF Ph Nf Si02
(1. 1 equiv) DI” hexanesl8
TMS
THF, -75 °C,1.3-5 h rt (58%)
(93% crude yield)

 

 

As mentioned above, vinyl triflates and nanoflates are known to be good coupling
partners in coupling reactions.9 Since our vinyl triflates (or vinyl nonaflate) were
unstable, we wanted to trap these species in situ, in a Stille or Heck coupling reaction.
This however, was not realized as the attempted Stille coupling (Scheme 3.8) (for
preparation of the stannane partner see Scheme 3.6) and Heck reaction (Scheme 3.8)

failed to occur.

46

:

Scheme 3.7. Synthesis of the stannane coupling partner

0“ t-BuMeZSiOTf (1.5 equiv)

 

lmidazole (2.0 equiv)
THF, -20°C

Bu3SnCl (1.2 equiv)

OTBS PMHS (3.0 equiv)

KF (aq) (3.0 equiv)
(Ph3P)2PdCl2 (0.5 mol%)
pentane/EtZO (2.16:1)

 

OTBS NBS (1.1 equiv)
AgNO3 (0.09 equiv)
Acetone
Bu3Sn WoTBS VOTES
SHBU3
30 31

Scheme 3.8. Attempted Wittig/nonaflation/Pd(O)-mediated coupling of model substrate 7

3. (1.06 equiv)
Pd(PPh3)4 (0.1 equiv)
LiCl (16.16 equiv)

 

 

 

 

 

 

 

rt, 15 min Decomposition
> of the substrate.
80 °C , 24 h No coupled
Bu3Sn WOTBS product isolated.
30
0A ph 1. s-BuLi (1.5 eqiv) Ph ONf
v THF, -78 °C, 30 min 1%
TMS TMS
7 2. CF3(QF2)3SOZF 27
(1.1 equ1v)
THE '73 °C' 1 h 3. (1.06 equiv)
Pd(PPh3)2C'2 Ph
(2.2 mol%) <
CH2=CHC02Me — TMS
(2.21 equiv) 23
TEA (3.5 equiv)
THF, rt, 45 h

The summary of the results of the trapping experiments is given in Table 3.8.

47

Table 3.8. One-pot Electrophilic Trapping of Enolate of 7: Preparation of Acylsilanes

1. s-BuLi (1.5 equiv)

 

 

 

. Ph Ph ,E
OAPh THF, -75 °C, 30 m: 0 + O
vms 2. Electrophile (E) TMS ms
7 TEA or HMPA E
Entry Electrophile Product(s) Yield (%)
0
Ph
1 CH2=CHCH2Br TMS 55
\ 12
0 Ph
1
2 CHacHz' Ph TMS MA (33:1)
16 / TMS 17
O
3 CH3| 73
18
O
4 PhCH Br 66
Ph 21
5 TMSCI OTMS 73
22
OAc 69
6 CH COCI 23
0 Ph /\/
Ph 0 66
24 TMS 25 ‘
ONf
\
_. \
8 CF3(CF2)2SOZF PhMTMS 27 “TMS 28 58
Ph
0
Ph
9 PhCHO I TMS 53
29
OH Ph

 

48

3.3. Conclusions

We have shown that the [1 ,4]-Wittig rearrangement of allyl ethers can be coupled
with electrophilic trapping of the resultant enolate intermediate. This procedure provides
unique access to a-functionalized acylsilanes, which are synthetically versatile building
blocks in organic chemistry. In some cases such as trapping with ethyl iodide and propyl
iodide, the vinyl silyl ether resulting from O-alkylation features a vinyl silyl group and
thus is a masked umpolung anion.

In Chapter 2 of this dissertation, we showed that for simple unsubstituted or-
alkoxysilanes such as 7 Wittig rearrangement could be very selective with careful control
of reaction conditions. We also showed that the reaction could be efficient in terms of
yield. In the present chapter, the efficiency of the [1,4]-Wittig of oc-alkoxysilanes was
effectively harnessed, establishing the utility of the [1,4]-Wittig of this class of
compounds. At this point an appropriate questions becomes “what would be the effect of
substitution on the Wittig rearrangement of a-alkoxysilanes?” This topic will be

discussed in the next chapter.

49

EXPERIMENTAL

Preparation of acylsilanes. Representative procedure: A solution of 7 in THF
(0.065 M) was cooled to -78 °C under nitrogen. s-BuLi (1.3 M in cyclohexane, 1.5
equiv) was added dropwise via syringe. The reaction mixture was stirred for 30 min. at
-78 °C. The resultant enolate solution was transferred via cannula to a THF solution of
the appropriate electrophile at the appropriate temperature. Reaction was stirred for the
required time, then quenched with saturated aqueous NH4C1 and diluted with diethyl
ether. Phases were separated and the organic phase washed with water and brine. The
organic phase was then dried over MgSO4 and concentrated. Silica gel chromatography

(0 to 2% EtOAc in hexane gradient) afforded the pure acylsilane.

0

Ph TMS
\\

12

Trapping of enolate of 7 with allyl bromide, preparation of acylsilane 12:
Applying the Representative procedure to 106 mg (0.48 mmol) of 7, 323 mg (1.92
mmol) of allyl bromide, 195 mg (1.92 mmol, 0.27 mL) of TEA at -78 °C, and allowing
the reaction to warm to room temperature for 7 h, after silica gel chromatography (0-2%
EtOAc in hexane gradient), afforded 69 mg (55%) of pure 12 as a clear oil. IR (neat)
2953, 1715, 1640, 1454, 1250 cm". 1H NMR (500 MHz, CDCl3) 5 7.31-7.11 (m, 5H),
5.70-5.61 (m, 1H), 5.01-5.61 (m, 2H), 3.03-2.97 (m, 1H), 2.53-2.43 (m, 2H), 2.39-2.33
(m, 1H), 1.98-1.89 (m, 1H), 1.62-1.55 (m, 1H), 0.16 (s, 9H). 13C NMR (125 MHz,
CDCl3) 6 250.5, 141.8, 135.8, 128.4, 128.3, 125.9, 116.6, 77.2, 54.6, 33.5, 30.6, -2.8.

HRMS (EI) m/z 259.1528 [(M-H)+; calcd for C16H230Si, 259.1518].
50

Ph OEt
\/\]/U\TMS PhM
TMS
Et
16 17

Trapping of enolate of 7 with ethyl iodide- preparation of compounds 16 and
17: Applying the Representative procedure to 121 mg (0.55 mmol) of 7, 343 mg (2.2
mmol) of ethyl iodide, and 394 mg (2.2 mmol, 0.25 mL) of HMPA, after silica gel ‘
chromatography (0-2% EtOAc in hexane gradient), afforded 84 mg (61%) of 16 as a light
yellow oil, and 28 mg (21%) of 17 as a clear oil (82% combined yield, 3:1 ratio). 16: IR
(neat) 2961, 1713, 1639, 1454, 1250 cm". 1H NMR (500 MHz CDC13) 5 7.30-7.16 (m,
5H), 2.85-2.78 (m, 1H), 2.52-2.42 (m, 2H), 1.97-1.89 (m, 1H), 1.71-1.62 (m, 1H), 1.59-
1.51 (m, 1H), 1.43-1.34 (m, 1H), 0.85 (t, J: 7.8, 6.8 Hz, 3H), 0.21 (s, 9H). l3C NMR
(125 MHz, CDC13) 5 251.2, 142.0, 128.4, 128.3, 125.8, 57.1, 33.7, 30.6, 22.3, 11.7, -2.7.
HRMS (NH3 CI) m/z 249.1676 [(M+H)+; calcd for C15H2508i, 249.1675]. 17: 1H NMR
(500 MHz, CDCl3) 5 7.33-7.16 (m, 5H), 5.10 (t, J = 7.3, 6.8 Hz, 1H), 3.67-3.62 (q, J =
7.3, 6.8 Hz, 2H), 2.39-2.25 (m, 2H), 1.86-1.78 (m, 2H), 1.20-1.17 (t, J: 7.3, 6.8 Hz, 3H),
0.12 (s, 9H). l3c NMR (300 MHz, CDC13)8 161.2, 142.2, 128.4, 128.2, 128.1, 125.6,

66.2, 35.9, 27.2, 15.8, -0.66.

0

Me
18

Trapping of enolate of 7 with methyl iodide preparation of acylsilane 18:
Applying the Representative procedure to 98 mg (0.445 mmol) of 7, 252 mg (1.78
mmol) of methyl iodide, 180 mg (1.78 mmol, 0.25 mL) of TEA for 50 min, after silica

gel chromatography (0-2% EtOAc in hexane gradient), afforded 92 mg (73%) of 18 as a

51

light yellow 611. IR (neat) 2963, 1713, 1639, 1604, 1454, 1250 cm". ‘H NMR (500MHz
CDCl3) 5 7.27-7.13 (m, 5H), 2.94-2.87 (m, 1H), 2.60—2.47 (m, 2H), 2.03-1.96 (m, 1H),
151-1.1.44 (m, 1H), 1.00 (d, J= 6.8 Hz, 3H), 0.16 (s, 9H). 13C NMR (125 MHz, 01301,)
5 250.4, 141.9, 128.3, 125.8, 49.6, 33.4, 32.6, 14.3, -2.7. HRMS (E1) m/z 233.1356 [(M-

H)*; calcd for C14H2.081, 233.1362].

0

Ph\A/HLTMS

Ph
21

Trapping of enolate of 7 with benzyl bromide-preparation of acylsilane 21:
Applying the Representative procedure to 99 mg (0.45 mmol) of 7, 307 mg (1.8 mmol)
of benzyl bromide, 182 mg (1.8 mmol, 0.25 mL) of TEA for 1.5 h, afier silica gel
chromatography (0-2% EtOAc in hexane gradient), afforded 92 mg (66%) of 21 as a light
yellow oil. IR 3026, 2951, 1713, 1639, 1603, 1496, 1454, 1250 cm". 1H NMR (300
MHz, CDCl3) 5 7.32-7.13 (m, 10H), 3.43-3.33 (m, 1H), 3.12-2.94 (dd, J= 13.7, 7.8 Hz,
1H), 2.63-2.47 (m, 3H), 2.02-1.90 (m, 1H), 1.69-1.57 (m, 1H), 0.08 (s, 9H). 13C (125
MHz, CDCl3) 5 251.8, 141.7, 139.9, 129.0, 128.4, 128.3, 126.1, 125.9, 56.3, 35.9, 33.4,

31.3, -32. HRMS (EI) m/z 309.1669 [(M-H)+; calcd for 0201125091, 309.1675].

OTMS

22
Trapping of enolate of 7 with TMSCl—preparation of vinyl silyl ether 22:
Applying the Representative procedure to 126 mg (0.572 mmol) of 7, 248 mg (2.29
mmol) of TMSCl, 231 mg (2.29 mmol, 0.32 mL) of TEA for 1.5 h, after silica gel
chromatography (hexanes neat), afforded 142 mg (85%) of 22 as clear oil. IR (neat)

52

3028,2959, 1614, 1496, 1454, 1250, 1121 cm". 1H NMR (300 MHz, CDCl;,) 8 7.29-
7.16 (m, 5H), 5.07502 (1, J= 6.7 Hz, 1H), 2.66-2.60 (t, J= 8.5, 7.4 Hz, 2H), 2.40-2.35
(m, 2H), 0.16 (s, 9H), 0.07 (s, 9H). 13C NMR (125 MHz, CDC13) 8 157.1, 142.2. 128.4,
128.3, 125.7, 124.4, 35.7, 27.6, 0.9, -1.7. HRMS (NH3 CI) m/z 293.1747 [(M+H)*; calcd

for (21611290812, 293.1757].

0A0

23

Trapping of enolate of 7 with acetyl chloride-preparation of vinyl acetate 23:
Applying the Representative procedure to 89 mg (0.404 mmol) of 7, and 127 mg (1.62
mmol) of acetyl chloride for 1.5 h, after silica gel chromatography (0-2% EtOAc in
hexane gradient), afforded 73 mg (69%) of 23 as a clear oil. IR 3086, 3026, 2955, 2922,
2849, 1745, 1603, 1496, 1454, 1369, 1230, 1089, 1039 cm“. ‘H NMR (500 MHz,
CDC13) 5 7.30-7.15 (m, 5H), 5.51-5.48 (t, J = 7.1, 6.8 Hz, 1H), 2.68-2.64 (t, J= 8.4, 7.5
Hz, 2H), 2.36-2.31 (quintet, J= 8.4, 7.5, 7.1 Hz, 2H), 2.11 (s, 3H), 0.11 (s, 9H). 13C
NMR (125 MHz, CDCl;,) 5 169.1, 155.3, 141.6, 130.5, 128.4, 128.3, 125.9, 35.0, 27.6,

20.5, -1.5. HRMS (El) m/z 262.1387 [(M); calcd for C15H2202Si, 262.1389].

0

Ph OPr
\“/\j/fi\TMS Ph\//\V¢4\
Pr TMS
24 25

Trapping of enolate of 7 with propyl iodide-preparation of compounds 24
and 25: Applying the Representative procedure to 129 mg (0.59 mmol) of 7, 398 mg

(2.34 mmol) of propyl iodide, and 420 mg (2.34 mmol, 0.41 mL) of HMPA for 17 h,

53

afier silica gel chromatography (0-2% EtOAc in hexane gradient), afforded pure 102 mg
(66%) of 24 and 25 (3:1 ratio by lHNMR) as a light yellow oil.

24: IR (neat) 2957, 1717, 1638, 1454, 1250 cm". 'H NMR (500MHz CDCl3) 5
7.29-7.12 (m, 5H), 2.92-2.86 (m, 1H), 2.52-2.44 (m, 21D, 1.95-1.88 (m, 1H), 1.65-1.51
(m, 2H), 1.32-1.17 (m, 3H), 0.86 (t, J= 6.8 Hz, 3H), 0.16 (s, 9H). 13C NMR (125 MHz,
CDC13) 5 251.2, 142.0, 128.34, 128.32, 125.8, 55.3, 33.7, 31.5, 31.0, 20.6, 14.3, -2.7.
HRMS (NH3 CI) m/z 263.1821 [(M+H)+; calcd for C16H27OSi, 263.1831].

25 was not isolated after chromatography.

Ph
LZ—JTMS

lfl45
Trapping of enolate of 7 with nonaflating agent-preparation of silyl acetylene
28: Applying the Representative procedure to 85 mg (0.39 mmol) of 7, and 128 mg
(0.43 mmol) of perfluoro-l-butanesulfonyl fluoride for about 5 h, after silica gel
chromatography (0-2% EtOAc in hexane gradient), afforded 45 mg (58%) of pure 28 as a

clear oil. IR (neat) 2959, 2175, 1603, 1496, 1454, 1250 cm". ‘H NMR (300 MHz,
CDC13) 8 7.32-7.20 (m, 5H), 2.85-2.80 (t, J= 7.7 Hz, 2H), 2.51-2.46 (t, J= 7.7 Hz, 2H),
0.13 (s, 9H). 13C NMR (75 MHz, CDC13) 8 140.6, 128.5, 128.3, 126.2, 106.6, 85.2, 35.1,

22.1, 0.1. HRMS (EI) m/z 202.1174 [(M); calcd for C13H138i, 202.1178].

Ph (3

Ph | TMS

OH Ph

29
Trapping of enolate of 7 with benzaldehyde-preparation of compound 29:

Applying the Representative procedure to 286 mg (1.3 mmol) of 7, 276 mg (2.6 mmol)

54

benzaldehyde and 3 mg (0.13 mmol) of TMSOTf for 4 h, after silica gel chromatography
(0-10% EtOAc in hexane gradient), afforded 287 g (68%) of pure 29 as a clear oil. IR
(neat) 3486, 2955, 1717, 1603, 1495, 1453, 1315, 1273, 1250 cm]. 1H NMR (500 MHz,
CDC13) 5 8.06 (d, J = 7.0 H, 2H), 7.59-7.56 (t, J = 7.5 Hz, 1H), 7.47-7.44 (t, J = 7.5 Hz,
2H), 7.39-7.26 (m, 6H), 7.23-7.20 (t, J = 7.5 Hz, 2H) 7.15-7.12 (apparent t, J = 7.5, 7.1
Hz, 1H), 6.95 (d, J = 8.0 Hz, 2H), 4.51 (t, J = 7.1, 5.7 Hz, 1H), 3.90-3.88 (dd, J= 5.7,
5.3, 3.1 Hz, 1H), 2.43-2.37 (m, 1H), 2.26-2.20 (dt, J= 12.4, 4.4 Hz, 1H), 2.06-2.03 (t, J=
7.5, 5.7 Hz, 1H), 0.06 (s, 9H). 13(3 NMR (125 MHz, CDC13) 8 168.6, 142.8, 142.2, 133.2,
129.9, 129.7, 128.5, 128.4, 128.3, 127.6, 126.8, 125.8, 74.2, 47.6, 30.4, -2.7. HRMS(E1)

m/z 415.2079 [(M+H)+; calcd for C27H3102Si, 415.2093].

55

REFERENCES

1.Maleczka, R. E. Jr.; Geng, F. Org. Lett. 1999, 1, 1115-1118.

2. 12 was obtained accompanied by a second product, which, based on 1H-NMR and 13 C-
NMR, was an aldehyde 15. Use of HMPA either alone or in combination with TEA (at 0
OC) resulted in more of this accompanying aldehyde being formed.

3. HRMS results for compounds 13, 14 and 15:

0 CM 0
Ph Ph ' Ph
SiMes S'Mea %
/
// \\ // \\
13 14 15

13: HRMS (EI) m/z 300.1911[(M); calcd for CigHzgosi, 300.1909].
14: HRMS (EI) m/z 340.2238 [(M); calcd for C22H320Si, 340.2222].
15: HRMS (E1) m/z 204.1174 [(M); calcd for C13HI602Si, 204.1150].
4. HRMS results for compounds 19 and 20:

O 0

Ph
Ph M H Wk},
Me Me Me
19 20

19: HRMS (E1) m/z 176.1207 [(M); calcd for C12H16O, 176.1201].
20: HRMS (131) m/z 162.1055 [(M); calcd for CHHMO 162.1045].

5. We sought to improve on the yield of this reaction by employing TMSOTf as catalyst
(0.01 equiv), however, this did not give any advantage.

6. For enol triflates in coupling reactions, see: (a) Li, ShengJian,; Dieter, R. K. J. Org.
Chem. 2003, 68, 969-973 and references therein. (b) Scott, J. W.; McMurry, J. E. Acc.
Chem. Res. 1988, 21, 47-54. For enol nonaflates in coupling reactions, see: (c) Lyapkalo,
I. M.; Hogermeier, J.; Reissig, H-U. Tetrahedron 2004, 60, 7721-7729 and references
therein. ((1) Lyapkalo, I.M.; Webel, M.; Reissig, H-U. Eur. J. Org. Chem. 2002, 21,
3646-3658. (e) Wada, A.; Leki, Y.; Ito, M. Synlett 2002, 7, 1061-1064. (1) Ritter, K.
Synthesis 1993, 735. (g) Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85.
(g) Stille, J. K. Angew. Chem. Int. Ed. 1986, 25, 508.

56

57

CHAPTER 4

IMPACT OF SUBSTITUTIONS ON WITTIG REARRANGEMENTS OF
a-ALKOXYSILYL ETHERS

4.1. Preparation of of a-alkoxysilanes
4.1.1. Introduction: Design of substrates

In chapter 2, we mentioned that attempts to achieve selective Wittig
rearrangement of a-alkoxysilanes would be highly dependent on understanding the
reaction variables that impact the reaction such as base (type and concentration), reaction
temperature, solvent‘ and substrate structure,2 (sterics and electronics) impact the
reaction. We then studied the effects of base, temperature and solvent and established
optimum conditions for our substrates. Employing these optimum conditions, we were
able to generate and trap the enolate of model compound 7 to functionalize the resultant

acylsilane at the a-carbon. In this chapter, we will discuss the results of our studies on

the structural requirements for (x-alkoxysilanes in the Wittig rearrangement.

Model substrate 7 rearranged selectively via the [1,4]-Witttig pathway at low
temperatures. However, as the temperature rose, there was gradual erosion in selectivity
and at room temperature, [1,4]/[1,2] selectivity reached a ratio of 2:1 (Chapter 2). This
result clearly showed that elevated temperature favors the [1,2]-Wittig. We wondered
whether we could still control the [1,4]/[1,2] selectivity if we made structural changes
(sterics and electronics) in the structure of model substrate 7.

From the beginning, we recognized that proper design of substrates was of key
importance to the study of structural requirement2 in this reaction. Tomooka and co-

workers,2f established that in general, the scope and limitations of the [1,2]-Wittig

57

rearrangement are determined principally by the migratory aptitude of the alkyl group
and the reactivity of the carbanion terminus as dictated by the nature of the carbanion
stabilizing group (Scheme 4.1). They also determined that the migratory aptitude of the
alkyl group increases in the order primary<secondary<tertiary-al1y<benzyl. This trend is
consistent with the stability order of the corresponding radicals. Previous reports have
also shown that the [1,2]-alkyl shift is promoted by a radical stabilizing migrating group
and/or a terminal radical stabilizing group (Figure 4.1).2’3 On the other hand, the yield of
[1,4]-product has been reported to be remarkably insensitive to the substitution pattern
within the allylic moiety of the ethers.l In a different study, it was shown that the
concerted pathways available to a substrate are primarily determined by the geometry of
the system and thus may be sensitive to steric effects.4 In contrast these two factors have
little or no effect on the stepwise pathways.4

Given the nature of these previous studies, we sought substrates to allow
investigations of the different factors that are most likely to control the course of the
Wittig rearrangements of a-alkoxysilanes. These factors would include the influence of
sterics, stereochemistry, and electronics and could be independently studied by the proper
choice of R) and R2 (Figure 4.1).

In investigating the structural requirements for the a-alkoxysilanes in the Wittig
rearrangement, we recognized that electronically, migrating alkyl groups that are
activated (bearing an electron donating group), deactivated (bearing an electron
withdrawing group) as well as unactivated (e.g. a simple alkyl group) would have

different impacts on the Wittig rearrangement of this class of compounds.

58

Secondly, sterics could be introduced at either the migrating carbon, the terminal
sp2 carbon of the allyl moiety, or at both. We anticipated that at whatever position,
sterics would alter the ratio of the [l,4]/[1,2]-rearrangement products, however, the
magnitude of this impact could not be estimated.

R2
A

0 Ph

R1/V\TMS

Figure 4.1. Generalized Structure of a-alkoxysilanes

4.1.2. Preparation of a-alkoxysilanes

To study a variety of Wittig substrates we first needed to prepare the precursor
silyl-alcohols. a-(Hydroxyallyl)silanes 32-34 were prepared following a procedure of
Danheiser and co-workers5 that involves the retro-Brook rearrangement6 of appropriate

alkylsilyl ethers (Scheme 4.1).

Scheme 4.1. Preparation of various a-hydroxysilanes

1. n-BuLi (1 .06 equiv),

 

THF, -78 °C, 0.5-1 h OH
R1CH20H >
2. RMeZSiCI (1.0 equiv) R1 SiMezR
THF, -78 °C, 1 n
3. t-BuLi (1.21 equiv) 32: R = Me, R1 = CHZCH-
-78 °C, 1 h 331 R = Ph, R1 = CH20H~

34: R = Me, R1 = MeCHCH-

The syntheses of 327 and 348 were uneventful, with both alcohols being obtained
in 93% and 53% yields, respectively. However, the synthesis of 33 proved to be more

complicated and was studied in some detail. Deprotonation of allyl alcohol with 1.06

59

equiv of n-BuLi in THF at -78 °C and trapping with phenyldimethylsilyl chloride
proceeded reasonably well. However, we found that this reaction was highly dependent
on the rate of addition of t-BuLi and the time following this addition. Variation in these

conditions resulted in a mixture of three products 33, 35, 36 (Scheme 4.2).

Scheme 4.2. Preparation of a-(hydroxydimethylphenylallyl)silane 33

 

OH OSiMezPh
....
vSiMezPh vSiMezPh
1n-BuLi(°1.06equiv), 35 (>10%)
v THF, -78 C 0.15- +
0H 2 THRMe;SiCI(1 1.>gequiv)
3 Ht-BuLi8 1'21 Ul PhMe Si OSiMe Ph
78 °C4 4( 0mineq W 2 W 2
36

Following addition of t-BuLi with long reaction times (1.5 h or more) gave
approximately a 1:1 to 2:1 mixture of the desired a-hydroxisilane 33 and vinyl silyl ether
36 (Scheme 4.2). Rapid addition of t-BuLi was also not favorable for formation of the
desired alcohol. Arresting the reaction five minutes after a rapid addition of base
afforded the vinyl silyl ether 36 as the only product and in near quantitative yield. As
illustrated in Scheme 4.3, the more stable resonance structure (featuring the more
substituted double bond) either abstracts a silyl group from allyl silyl ether or is trapped
by the PhMeZSiCl in the reaction mixture to give the observed product. Our best result
(11:1 alcohol to vinyl silyl ether, 71% yield) was obtained when t-BuLi was added fairly
slowly at 0.35 ml/min, with the subsequent reaction being allowed to stir at -78 °C for 40

minutes.

60

Scheme 4.3. Formation of a-(dimethylphenylsilyl)allyl alcohol

 

33 and vinyl silyl ether 36
1. n-BuLi (1 .06 equiv)
THF, -78 °C
V011 = VOSiMezPh
2. PhMezsiCI (1.0 equiv)
-78 °C

3. t-BuLi (1.21 equiv)
-78 °C 9 9
7 voswezph ‘ ' WOSiMezPh

 

VOSiMezPh

retro-Brook or
PhMeZSiCI
OH
vSiMezPh PhMeZSi WOSIMezph
33 36

It is worth mentioning that when the vinyl silyl ether 36 was subjected to the
reaction conditions of Scheme 4.2 it was recovered unchanged. Deprotonation of the
vinyl silyl ether 36 would result in the formation of an ally] carbanion stabilized by an 01-
silyl group, which could be captured by PhMeZSiCl to give 37 or result in the formation
of an a-hydroxysilane 38 bearing a vinyl silyl group (Scheme 4.4). However, none of
these products were observed. This could mean that either the deprotonation did not

happen or the a-silyl carbanion is stable toward further reaction.

61

Scheme 4.4. Subjection of vinyl silyl ether to
deprotonation/Silylation/retro-Brook reaction conditions

1. n-BuLi (1 .06 equiv),
THF, -78 °C, 0.5-1 h OH

 

 

 

PhMeZSiWOSiMeZPh ,

\ . .

36 2. RMeZSiCI (1.0 equiv) PhMezsl/VkSIMezPh
THF, -78°C, 1 h 38 (0%)
3. t-BuLi (1.21 equiv)
-78 °C, 40 min retro-Brook

PhMeZSiWOSiMezPh PhMeZSiWOSiMezPh
e e

\

PhMeZSi \ OSiMezPh

SiMezPh
37 (0%)

Our model substrate 7 and the other Wittig substrates employed in this work9
were prepared following the general method for the synthesis of or-alkoxysilanes
developed in our laboratory by Maleczka and Geng.10 Their preparation involves Lewis
acid catalyzed etherification of a-hydroxysilanes (32-34) via the trichloroacetimidatesll

of the appropriate alcohols.12 The Wittig substrates prepared are shown in Table 4.1.

62

Table 4.1. Preparation of various a-alkoxysilanesa

 

 

 

NH
|| 1R2
OH R20CCCI3 O
/|\ ' 5% TMSOTf /l\ .
R1 SiMezR = R1 SlMezR
32-34 cyclohexane
it, overnight
Entry R R1 R2 silane Yield (%)
1 Ph -CH=CH2 -CH2Ph 39 35
2 Me -CH=CH2 -CH2CH=CHSiMe3 4o 59
3 Me -CH=CH2 -CH2CH=CHPh 41 24
4 Me -CH=CH2 -CH(Ph)CH=CH2 42 22
5 Me -CH=CH2 -CH(Me)Ph 44 78
6 Ph -CH=CH2 -CH(Me)Ph 45 28
7 Ph -CH=CH2 -CH(Me)p-N02C6H4 4s 35
8 Me -CH=CH2 -CH(Me)p-MeOCeH4 47 92b
9 Me -CH=CH2 -CH(Ph)CH2Me 48 37
10 Ph -CH=CH2 -CH(Ph)CH2Me 49 38
1 1 Me -CH=CH2 -CH(Ph)CHZCH2Me 50 75
12 Ph -CH=CH2 -CH(Ph)CH2CH=CH2 51 77
13 Me -CH=CH2 -CH(Ph)CHZCH=CH2 52 80°
14 Me -CH=CH2 -CH(Ph)CHMe2 53 59
15 Me -CH=CH2 -CH(Ph)(CH2)3CH=CH2 54 15
16 Me (E)-CH=CHCH3 -CH2Ph 55 36
17 Me (E)-CH=CHCH3 -CH(Me)Ph E-56 49
18 Me (Z) -CH=CHCH3 -CH(Me)Ph Z-56 <10
19 Me (E) -CH=CHCH3 -CH(Ph)CHZCH=CH2 58 69

 

(3) Unless otherwise stated, a-alkoxysilanes were obtain in approximate ratio of 1:1 (reactive
synzless reactive anti). (b) 3.3:] ratio of less reactive:reactive diastereomeric 47 was obtained.
(c) 2.6:] ratio of less reactive:reactive diastereomeric 52 was obtained.

63

Etherification of 32 with the trichloroacetimidate of cinnamyl alcohol, catalyzed
by both TMSOTf and triflic acid, respectively, afforded a mixture of four products.‘3
These were 41 (23%), a near 1:1 pair of diastereomeric 42 (20%), and TMS-protected 32

(5%). All the compounds were fully characterized (1H NMR, 13 C NMR, DEPT) (Scheme

 

4.5).
Scheme 4.5. Etherification of a-hydroxysilane 32
with trichloroacetimidate of cinnamyl alcohol
OH /
VTMS
32 TMSOH (0 10 equiv)
" VkTMS TMS
NH cyclohexane rt
JL overnight
0130 0% OTMS
VTMS

43

Compounds 51, 52, and 58 were not accessed via the previously described route,
but rather via Rychnovsky’s protocol.9 As illustrated in Scheme 4.6, the Silylation of 34
afforded the crotyl silyl ether 57 (90% yield). This compound was employed in a three
component coupling reaction with allylsilane and benzaldehyde, catalyzed by TMSOTf
to afford 58 as a 1:1 pair of diastereomers in 68% yield. Compound 51 was a clear oil
obtained as a 1:1 pair of diastereomers in 77% yield and 52 was also a clear oil, obtained

as a 1:2.6 pair of diastereomers in 80% yield.

Scheme 4.6. Preparation of substrate 58 via Rychnovsky’s protocol

1. n-BuLi (1.08 equiv)

 

 

 

THF, -78 °C, 2 11 OH
2. TMSCI (1.0 equiv)
M011 3 /\/k + MOTMS
THF, -78 °C, 1.5 h \ TMS
3. t-BuLi (1.20 equiv) 34 (2:1)
THF, -78 °C, 2 h
0
(80 /°) WTMS
Et3N (1.0 equiv) . (1.1 equiv) Ph
TMSCI (10 equ1v) = OSIMea PhCHO (1.1 equw) > 0M
pentane, 0 °C, 2 h; \ TMS TMSOTf (0.2 equiv)
then rt. 5., 0112012, -78 °C, 2 h M TMS
(90%) (69%) 58

As illustrated in Table 4.1 we prepared a variety of a-alkoxysilanes including
those bearing activated migrating groups (e.g. benzyl and substituted benzyl), as well as
those bearing substituents at the terminal carbon of the allyl moiety. However, this first
set of compounds contained no substrates bearing unactivated migrating groups (simple
alkyls). To investigate the behavior of simple unactivated alkyl groups, we decided to
employ a-(trimethylsilyl)allyl butyl ether as a prototype. The synthesis of
a-(trimethylsily)allyl butyl ether was attempted by Lewis acid-catalyzed etherification of
a-hydroxyallylsilane, 32, with the trichloroacetimidate of n-butyl alcoholll (Scheme 4.7).
Unfortunately the target compound 59 was not observed. Nevertheless, two silylated

compounds were isolated, 40 and 60, albeit in low yields.

65

Scheme 4.7. Attempted synthesis of a-(trimethylsilyl)allyl butyl ether

 

 

OH NH TMSOTf/BFyOEtz 0M
\/|\ + | GAO/\A > vTMS
TMS C 3 cyclohexane, rt 0
32 overnight 59 (0 /°)
0M TMS
\ TMSMOM
TMS
4o 60

 

 

 

In order to explain the formation of the observed compounds, the mechanism
illustrated in Scheme 4.8 is proposed. Coordination of the Lewis acid to the acetimidate
nitrogen makes the iminium carbon more electrophilic. The incoming nucleophile (32)
would attack at the iminium carbon to form activated allylic acetimidate intermediate 61,
liberating butanol in the process. A nucleophilic attack at the terminal olefinic carbon by
another molecule of 32 would result in the formation of 40. On the other hand, a
nucleophilic attack on the terminal olefinic carbon by a butanol molecule would lead to
the formation of 60. The formation of the target compound would demand attack of a
molecule of a-hydroxysilane 32 at the a-carbon of the butyltrichloroacetimidate. This
process would require some kind of activation of the a-carbon (e.g. by resonance
stabilization), which is not possible with the butyl system. Though somewhat

disappointing this result was interesting given the unique nature of compound 40.

66

Scheme 4.8. Attempted synthesis of a-(trimethylsilyl)allyl
butyl ether-Plausible mechanism

 

 

 

69
OH Jug" NHLA
vrMs + C|3C 0M ‘—‘* cucéom _’
32
LA
/
/ a” (if
0 ON TMS o CCI3 + M014
TMS 008
81
OH /\/\
OH
\ TMS
32
OMTMS O/\/\
\ TMS TMSA/l
40 60

Considering the unique nature of compound 40, we sought further confirmation of
its structure. Independent synthesis of 40 was accomplished in 53% yield by the
BF3-OEt2 mediated etherification of 32 with the trichloroacetimidate of y-silylalcohol (3-
trimethylsilyl-Z-propen-l-ol), which was itself prepared following the method of

Denmark and Jones (Scheme 4.9).'4

67

Scheme 4.9. Independent synthesis of Wittig substrate 40

1. EtMgBr (2.78 equiv)
THF, 10 °C, overnight

 

 

 

 

: 2. TMSCI (2.78 equiv) TMS : Red-AI TMS OH
OH i '——WOH : W
5 °C to reflux, 2 h Et20, 2 to 20 °C
3. 1.4M sto, (57%)
20 °C, 5 min
(80%)
TMS OH
1. NaH (1.05 equiv)/Et20 NH / vTMS 32 OMTMS
’ /U\ T \ TMs
2. CI3CCN (1.0 eq) _ 0'30 0 BFa-OEtz, cyclohexane
3. MeOH (0.105 equ1v) overnight
pentane (53%) 4°
(86%)

4.2. In search of new methods for accessing a-alkoxysilanes

We still desired to investigate the behavior of non-activated migrating centers
under our Wittig rearrangement conditions. As the previous protocol for accessing the
Wittig substrates was not amenable to the syntheses of 01-(tn'methylsilyl)allyl alkyl
ethers,15 a nucleophilic substitution reaction between the alkoxide of l-phenyl-l-propanol
and the mesylate of 32 was considered (Scheme 4.10). The formation of 62, mesylate of
32 was very efficient, affording the desired mesylate in 96% yield.16 However, reaction
with a preformed acetimidate of l-phenylpropan-l-ol in THF resulted in an SN2'-
displacement of the mesylate group to afford 62 in 70%, with no evidence of the desired

SN2 product 47 observed.

68

Scheme 4.10. Attempted synthesis of 47 via an SN2
displacement of a mesylate group

Ph

 

NaH 0.1 uiv
0“ THF 2 0(mineq ) o L
A, +
Ph 2. OMs TMSMO
\ vTMS
TMS o o
THF, rt, 2 h 47 (0 /o) 63 (70 /o)

Kim and Lee17 reported a mild and efficient method for the stereoselective
formation of C-0 bonds via an 8N2 type process, based on Pd-catalyzed allylic
etherification using Zn(II) alkoxides as nucleophiles (Scheme 4.11). Fundamental to
their protocol was the use of allylic acetate and a wide variety of alcohols (primary,
secondary acyclic, secondary cyclic, allylic, propargylic, and aromatic). In this protocol,
EtZZn served as the source of base and counter ion.

Scheme 4.11. Pd(0)-mediated stereoselective formation
of C-0 bonds via SN2 type process

 

 

R R
Etzzn (0.5 equiv)
ph/\/I\OAC '1’ R'OH = ph/\/‘\OR'
Pd(PPh3)4 (5 mol%) R = Bn 99%
THF! " R = Me, 83%
R = i-Pr, 56%
EtZZn (0.5 equiv)
Pd(PPh3)4 (5 moi%)
C Q .. Q. LA
/ co Me * fi‘
AC0 2 0H NH4OAc (10 mol%) 0 / 002Me
1.5 equiv 1.0 equiv THF. rt. 11 h 51% (1:1)
..
P(t-Bu)2

69

The above protocol was adapted to acetyl ester of 32 and benzyl alcohol as
coupling partners. Treating a THF solution of benzyl alcohol with EtZZn at room
temperature and stirring for 50 min preformed the Zn benzyl oxide. Subsequent addition
of the allyl acetate and Pd(PPh3)4 and stirring for 2 h resulted in the complete
consumption of the allyl acetate. However, the expected coupled product was not
obtained. Instead, 65, resulting from an E2' elimination of the acetate group was isolated
in 64% yield (Scheme 4.12). This result is similar to that obtained with the
corresponding a-(trimethylsilyl)allyl mesylate (Scheme 4.10). These results are clear
indications that allylsilanes possessing substituents that are good leaving groups prefer to

react by elimination of the leaving group via an E2' mode.

Scheme 4.12. Pd-catalyzed allylic etherification using Zn(II) alkoxide as nucleophile

1. AcOH(1.0 equiv)
DCC (1.0 equiv)
DMAP (10 mol%)

 

OH CH2Cl2, 12 h 0A Ph OAPh
= '1'
vTMS 2. Ph/\OH VTMS TMSV
32 7 (0%) 65 (64%)
Et2Zn (0.5 equiv)
Pd(PPh3)4 (5 mol%)
THF, RT, 2 h

An attempt was also made to access the or-alkoxysilanes via the classical
Williamson’s ether synthesis (Scheme 4.13). The caveat of this method is that
deprotonation of the starting alcohol will very likely trigger a Brook rearrangement.
However, we reasoned that a bulky group (such as phenyl) on silicon might help slow
down this process and lead to the desired product. Thus,18 PhMe2Si- was substituted for

Me3Si- group. A catalytic amount of TBAI was also employed to facilitate benzylation.

7O

Regretably, the expected a-alkoxysilane was again not obtained. The reaction afforded
(PhMezsi)20 as the only product (quantitative crude yield). We also tried a direct 8N2
displacement of a sec-bromide with a methoxide ion (Scheme 4.14). However, the
expected allyl methyl ether was not isolated and neither was the starting sec-allyl

bromide recovered.

Scheme 4.13. Attempt at accessing a-alkoxysilanes via the Williamson’s ether synthesis

1. NaH (1.37 equiv) /\
0H 2. 15-Crown-5 (1.14 equiv) 0 Ph

\ , \ _ ‘1' (PhMGzSibO
VkSIMezph 3. BnBr (0.9 equiv) \/|\SIM62Ph

33 TBAI (0.1 equiv) 39 (0%)
THF, rt, overnight

 

Scheme 4.14. Attempted preparation of a-alkoxysilanes by direct 8N2 displacement

 

 

TMSCl (1.2 equiv) . Me
v LDA. THF \i NaOMe (12 equal) 0’
> \ :
Br -78 °C, 3 h; TMS MeOH (anhyd) VTMS
then NH4CI reflux 53
(41%) (0%)

In an attempt to get around the use of a strong base we contemplated accessing or-
alkoxysilanes via direct 8N2 reaction between 32 and l-bromoethyl benzene in the
presence of a weak base (2.0 equiv of i-PerEt, THF, rt). In the end though, this protocol

did not give the expected product (Scheme 4.15).

71

Scheme 4.15. Attempt at accessing a-alkoxysilanes via direct SN2 reaction

A

 

Br 0” iPr NEt ' O P“
- 2 (2.0 equ1v)
+ >
1311* vTMS vTMS
THF, rt
32 (0%) 44

In 1992, Hoffmann and Brucknerlg reported the synthesis of two functionalized
O-S acetals by a one-pot thioacetalization of the requisite aldehydes when they reacted
the aldehydes, (trimethylsilyl)-prenol, (trimethylsilyl)thiophenol, and 2 equiv. of
TMSOTf at -78°C in CH2C12 (Scheme 4.16). When we tried to adapt this protocol to our
system comprising crotonaldehyde, trimethylsilyl-protected crotyl alcohol, hexamethyl
disilazane, and a catalytic amound (0.05 equiv) of TMSOTf, the desired compound 67

was not observed (Scheme 4.17).

Scheme 4.16. Hoffmann and Bruckner one-pot synthesis of O-S acetals

Me3Sio/\/|\

 

R0 0 (2.0 equiv) /\/J\
Me3SiSPh (1.2 equiv) R0 0
Ph H :
TMSOTf (2.0 equiv) Ph spn
CH Cl , -78 °c
(215.21 ,0 h R = le: 52% (ds 70:30)

R = MezTexSi: 42% (ds 71 :29)

Scheme 4.17. Attempted adaptation of Hoffmann and Bruckner protocol

M83SlO/\/\
O (1.5 equiv) 0%

/\/U\ M8331-31Me3 (1.2 equiv) /\/k
\ H TMSOTf(0 05 ' 7 \ TMS
. equw)
CHZCIZ, -78 °C 6"
overnight
(0%)

 

72

In conclusion, due to our inability to access requisite substrates, we were unable
to investigate the Wittig rearrangements of tn'methylsilylallyl alkyl ethers possessing
non-activated migrating alkyl groups and which are set up to undergo [1,4]-Wittig

rearrangement.

4.3. Impact of substitutions on Wittig rearrangements of a—alkoxysilanes
4.3.1. Introduction

With substrates in hand, we started to look at their rearrangement under our
Wittig conditions. The purpose of this part of the research was to investigate the effect of
sterics on the Wittig rearrangement of ci-alkoxysilanes. Toward this end we placed a
substituent at (1) the migrating carbon, (2) the terminal olefinic carbon, and (3) both the
migrating and the terminal olefinic carbons in some of these compounds. In the first two
scenarios, if the reaction goes via both the [1,2] and the [1,4]-pathways, one stereocenter
will be formed in each of the Wittig products. Installing substituents at both sites would
in theory give a pair of diastereomeric products with two adjacent stereogenic centers. In

both cases the issue of stereoselectivity has not been well addressed to date.

4.3.2. Effect of groups on silicon on the Wittig rearrangement of a—alkoxysilanes

In Chapter 2 we presented our results on the Wittig rearrangement of our model
substrate 7 featuring iii-trimethylsilyl group. Compound 7 underwent facile bond
reorganization under our Wittig conditions. We desired to establish whether or not the
groups on silicon have any effect on the Wittig rearrangement of a-alkoxysilanes. Thus,

compound 39 (possessing PhMeZSi group) was subjected to our conditions as already

73

described for 7. We were pleased to note that the substrate reacted very readily. At low
temperatures (-78 °C) the rearrangement of 39 afforded only the [1,4]-Wittig product 68
in 69% yield (Table 4.2, entry 1). At elevated temperatures however the reaction
proceeded via both [1,4] and [1,2]-pathways to give 68 and 69. As was observed for
model substrate 7, the ratio of [1,4]/[1,2] products varied depending on the reaction
temperature. In addition both 7 and 39 had comparable reaction rates (both reactions

were done in about 30 minutes).

4.3.3. Effect of Electronics on the Wittig rearrangements of a-alkoxysilanes
4.3.3.1. Wittig rearrangement reaction of 41

Compound 41 is set up to undergo bond reorganization via the [1,2], [1,4], and
[2,3] pathways as illustrated in Scheme 4.18. Theoretically, one would expect a mixture

of some or all of the possible products.

Scheme 4.18. Wittig rearrangement of 41: expected [1 ,2], [1,4], and [2,3] products

0

 

Ph\/\/4\/lL TMS O
// TMs L\/fi\l>\\/Pn
1. 2 \
1. 3. via [1 .4l-Witti9 via [1,2]-Wittig, followed
\ . . b s' lm' at' n
10mph RLi : Y "V or Io
4%TMS Wittig
3 1 rearrangement TMS ()9 Ph I TMS O
4 . .
Ph TMS Ph
- _ - - _ - via [2,3]-Wittig, followed
v1a[2,3] Wittig Via [3,4] Wittig by silyl migration

Upon subjecting 41 to our standard Wittig conditions, it underwent facile bond

reorganization. This resulted in an inseparable mixture of two products 70 and 71

74

(Scheme 4.19). We observed however that the outcome of this reaction was dependent
upon the temperature at which the reaction was carried out. Treatment of a solution of 41
in THF with 1.5 equiv of n-BuLi (1.6 M solution in hexanes) at room temperature
resulted in a very fast reaction that was complete in approximately 5 min to afford 70 and
71 (> 1:10 ratio). At low temperatures (-78 OC), this reaction took 2.5 h to go to
completion and gave the reverse outcome, affording the [2,3] product as the major
product (70/71 >10:l). Addition of base at -78 °C, and then allowing the reaction to
warm to room temperature resulted in varying ratios of the products. Both 70 and 71
resulted from [2,3]-Wittig rearrangement of 41. No [1,2] and [1,4] products were

observed in this reaction.

Scheme 4.19. Wittig rearrangement of 41 mediated by n-BuLi

 

1, 3, TMS O TMS O
/\2/\ 3' 3'
10 Ph n-BuLi, THF 2 \ + 2 /
4%“,‘3 7‘ Ph Ph
3 41 70 71
it 5 min minor major
-78 °C 2.5 h major minor

We propose the mechanism in Scheme 4.20 to account for the products of this
reaction. a-Deprotonation at low temperatures was followed by a facile [2,3] bond
reorganization to give the [2,3] intermediate 72, which was accompanied by silyl
migration to give 73 (possibly via [1,2]-migration of the silyl moiety from carbon to
oxygen). At low temperatures, the isomerization of 70 (the kinetic product) to 71 (the
thermodynamic product) was slow, and quenching the reaction at this temperature

afforded 70 as the major product. However, at elevated temperatures, bond isomerization

75

was facile, an event driven by conjugation with the aromatic ring (Scheme 4.20),
resulting in 71 as the major product. These reactions were clean and the crude yield was
quantitative, however, upon purification by silica gel, the yield dropped significantly

(~51%), indicating sensitivity of the products to silica.

Scheme 4.20. Wittig rearrangement of 41: A Putative Mechanism.

 

 

TMS 09 TMS\O
h .
09p), RU = \ \ ------- r \ e \
\ TMs 2.3-Witti9 ph 73 pn
'earmgement 72 silyl migration 3
i
6
TMS 0 Double bond TMS O TMS O
W,“ migration W A H69 W
Ph Ph keto-enol 73 Ph
71 70 tautomerization

4.4. Wittig rearrangements of a—alkoxysilanes: Effect of substitution at the
migrating carbon

Our study of steric effects on the Wittig rearrangements of or-alkoxysilanes started
with diastereomeric a-(trimethylsilyl)allyl sec-phenethyl ethers 44a and 44b. These
compounds were synthesized as a 121.13 (anti/syn) mixture of diastereomers in 79% yield
from a-hydroxysilane 32 and the trichloroacetimidate of sec-phenethyl alcohol following
our standard method. The pair of diastereomers were not separable by column
chromatography, thus the product mixture was employed in the study. Though

inconvenient, some of the proton signals were well resolved [5 (Me3SiCH- 3.38-3.42, (td,

76

J= 6.8, 1.4 Hz, 1H); 3.77-3.81 (td, J= 5.5, 1.4 Hz, 1H) and CHZCHCHSiMey, 4.90-5.00
(tq, J = 10.4, 7.9, 1.4 Hz, 2H); 5.02-5.09 (m, J = 3.5, 1.4 Hz, 2H)], thus, it was possible to

monitor the rearrangement.

Scheme 4.21. Substitution at the migrating carbon: Wittig rearrangement of 44a/44b

 

Me Me
X /|\ O TMS O
0 Ph -B L' 1.5 ' 0 Ph Ph
v s ”" ”"3- Vt + ”‘Nws + ”Y
TMS THF, ~78 °C,8h TMS Me Me
44a/44b anti 44a 74 75
Diastereomeric 42% (8 h); [1 ,4]-Wittig product via [1,2]-Wittig

mixture 26% (overnight) 8 h 35% yield 74.75 = 1 5,1

overnight, 46% yield, 74:75 = 1.721

When a cold (-78 °C) THF solution of 44a/44b was treated with 1.5 equiv of sec-
BuLi, the clear solution turned deep purple, and after eight hours we were surprised to
find that one diastereomer was completely consumed, as evidenced by the disappearance
of one set of lH NMR signals (5 3.77-3.81 (td, J = 5.5, 1.4 Hz, 1H) and 4.90-5.0 (tq, J =
10.4, 7.9, 1.4 Hz, 2H)). Separation of the unreacted diastereomer from the Wittig
products was trivial, and afforded the [1,2] and [1,4] products (74 and 75) in a ratio of
121.5, in a combined 35% yield, with 42% recovery of the unreacted ‘less reactive’ anti
44a (Scheme 4.21) (details of determination of the relative stereochemistry of the
reactive and less reactive diastereomers will be presented in Chapter 5). We observed
that allowing the reaction to stir overnight resulted in increased yield (46%) as well as an
increase in the [1,2]/[1,4] ratio from 1:1.5 to 1:1.7, with a corresponding decrease in the
recovery of the unreacted diastereomer (26%). We were very surprised to observe the

near complete erosion of the [1,4]-selectivity (> 100:1 in the 7). Also, the introduction of

77

a substituent at the migrating carbon resulted in reduced reactivity, as evidenced by a
longer reaction time (approximately 8 h; 7 reacted completely within 30 min.).

The observed variations in product yield and percent recovery of unreacted 44a
noted in the preceding paragraph could be due to one of two reasons: either that the other
diastereomer reacted but very slowly (less reactive) or that it was undergoing some
unproductive processes. To find out which, we carried out a qualitative NMR-tube
experiment in which the pure unreactive 44a diastereomer was subjected to our Wittig
conditions and the reaction was monitored by 1H NMR. Here we observed a slow
decrease in the signal at (5 338-342), but the reaction reached a point where no further
decrease in starting material could be detected. Thus, diastereomer 44a does undergo the
Wittig rearrangement reaction under our conditions, albeit very sluggishly. This process
offers a good route to kinetic separation of the pair of diastereomers (Scheme 4.21, after
8 h reaction time, 35% yield of product mixture and 42% of less reactive isomer
recovered, compare with 46% yield of product mixture and 26% recovery of less reactive
isomer after about 20 h).

Just as with our model substrate 7 (no substituent at the migrating carbon), we
desired to establish the effect of silyl substituent on the Wittig rearrangement of a
substrate bearing a substituent on the migrating carbon. Thus compound 45a and 45b
were subjected to the Wittig conditions. The reactive diastereomer 45b readily
underwent Wittig rearrangement to afford 76 and 77 (Table 4.2, entry 5). Thus

establishing one more time that substitution on silicon was no issue on these reactions.

78

4.4.1. Wittig rearrangements of 46 and 47: Electronic factor

The presence of a substituent capable of stabilizing a negative charge (e.g., p-
N02) will lead to increased kinetic acidity of the benzylic proton, and its abstraction
could become competitive with the tertiary a-proton. This situation might be
unfavorable for the cleavage of the C-0 bond. On the other hand, the presence of an
electron-donating substituent (e.g., p-OMe) would attenuate the kinetic acidity of the
benzylic proton, and hence forestall dianion formation. To investigate this hypothesis,
substrates 46 (bearing an electron withdrawing p-NOz group) and 47 (bearing an electron
donating p-OMe group) were designed (Figure 4.2). 47 was synthesized in 92% yield as
a 3.25:1 (GC-FID) mixture of diastereomers. The minor product (reactive 47) readily
underwent the Wittig rearrangement to afford both [1,4] and [1,2] products 78 and 79 in
22% in approximately 1.8:] ratio based on total starting mixture (93% based on amount
of starting reactive isomer). On the other hand, the rearrangement of 46 was very

sluggish at low temperatures (-78 °C) and gave a complex mixture of compounds.

()—Q (9C)...

PhMeZSi 46 PhMeZSi 47

Figure 4.2. Substrates designed to study electronic effects
on the Wittig rearrangement of a-alkoxysilanes

The facile rearrangement of 47 (p-MeO-C6H4-) and the sluggish rearrangement of
47 could be indicative of a developing negative charge at the migrating center, which
would be highly stabilized in the case of 46. To a first approximation, the feasibility of

cleavage of the C—0 bond would be expected to be less for a highly stabilized migrating

group.

79

4.4.2. Wittig rearrangement of 42

Maleczka and Geng20 reported that 42 readily underwent the Wittig
rearrangement mediated by MeLi to afford the 2,3-rearrangement products selectively
(Scheme 4.22). We decided to revisit the Wittig rearrangements of this substrate under

our reaction conditions.

Scheme 4.22. MeLi-mediated Wittig rearrangement of 42 by Maleczka and Gengl

 

Ph
04% MeLi (1.7 equiv) TMS 0 0”
\J\ T MP“ + MP“
\ TMS THF, 0 °c to rt
42 °Vem'ght 80 (60%) 81 (20%)
via [2,3]-mug [2,3]-Wittig

Compound 42 is an analog of 44, with a vinyl group in place of a methyl group at
the migrating carbon. Compound 42 did not undergo the Wittig rearrangement at low
temperatures. Above -20 °C, the reaction required 4 equiv of n-BuLi and twelve hours
for the complete consumption of the starting material. The reaction however afforded an
intractable mixture of products. 42 has two acidic protons, thus, there arises the question
of regioselective deprotonation. In the event that both protons (01 and 01’) were abstracted
under the reaction condition, then one would expect each carbanion to react as an
independent entity, resulting in a mixture of products (Scheme 4.23). However, in the
event that tit-deprotonation was favored over 01'-deprotonation, it would result in a
migrating carbon that is benzylic as well as allylic. Such a structure would be expected
to lead to increased kinetic acidity of the benzylic/allylic proton and stability for a
developing negative charge, a situation that would be expected to lead to a decrease in the

migratory ability of the C-0 bond. If this was indeed the case, then moving the double

80

bond further away from the migrating center would be expected to give a different

outcome.

Scheme 4.23. Plausible pathways for the Wittig rearrangement of 42

6)
Ph 0
-H01 / Ph Ph 09/
cilgeaigggt?j MefiiM
° ‘1 " TMS
Ph [1210(14] [2 3]

cleacg\ge Ph Ph mmph
of 01' bond
via [1, 2]\ [1 ,4] [2, 3], followed by

silyl migration

This was the case with substrate 48 (R = Et; synthesized in 64% yield as a 121.2
mixture of separable diastereomers) (Figure 4.5), which underwent facile Wittig
rearrangement at low temperatures (-78 0C) to afford a mixture of both [1,4] and [1,2]
rearranged products (82 and 83) in 47-63% yield and in the ratio of 1.5:1 to 1.8:1(Table
4. 2, entry 7). Similarly, 49 (R= Et, R’3Si= PhMeZSi) (Figure 4. 5) underwent the Wittig
rearrangement to give 84 and 85 (Table 4.2, entry 7), illustrating that substitution on
silicon is no issue in the Wittig rearrangement of our substrates. Under forcing (3.0 eq of
sec-BuLi, THF, -78 °C to rt, 4 d), less reactive 48 underwent rearrangement to afford

14% of the rearranged products, with 43% recovery of the starting material.

81

f I I

0 Ph 0 Ph 0 Ph
vTMS vTMS vTMS
42 48 49
Ph Ph Ph

0&3: O/‘W O/‘W/
vTMS vSiMezR vTMS

50 R=Ph: 51 53
R=Me: 52

Figure 4.5. Wittig substrates bearing various substituents at the migrating carbon

To further investigate the effect of the proximity of olefin functionality to the
migrating center, we studied the behaviors of substrates 50 and 52 (Figure 4.5) under our
Wittig conditions. Both compounds underwent the Wittig rearrangement when treated
with of n-BuLi in THF, to give the rearranged products, along with recovery of the
unreactive diastereomers in each case. The Wittig rearrangement of 50 was facile,
requiring only 1.5 equiv of base, and at -78 °C, goes to completion within 24 h to afford
86 and 87 (Table 4.2, entry 8). On the other hand, 52 required 4 equiv of base, elevated
temperature conditions (-30 °C) and long reaction times (>24 h) to give 88 and 89 (Table
4.2, entry 9; 32% based on total 2.64:1 (unreactive anti/reactive syn) mixture of starting
material). However, at room temperature, 52 underwent complete rearrangement in less
than ten hours to afford the [1,2] and [1,4] products. The lower reactivity of 52 could be
the result of the migrating carbon being benzylic and homoallylic, situations that would
stabilize developing negative charge as well or a radical species.

Replacing the n-propyl group in substrate 50 with an isopropyl group in 53

(Figure 4.5) had a marked effect on reactivity. Compound 53 did not rearrangement at

82

low temperatures. However, at elevated temperatures (above -20 °C), the compound
underwent the Wittig rearrangement to afford the [1,2] and [1,4] products 90 and 91 in

23% yield and 1.8:] ratio (Table 4.2, entry 10).

Scheme 4.24. Wittig rearrangement of metalated allyl alkyl ether
by Schlosser and Strunk21

R' R' .R' ,R'

o’ RLi o’ R'-l 0 R 0

V e va- + k2

OR' = OC4H9, OCHZCHZCH(CH3) (23:77); OC9H19. OCHchr (75:25);
OCH(CZH5)2 (50:50); OC(CH3)3 (70:30); yields = 73-85

 

 

So far we had shown that substitution at the migrating carbon of the 01-
alkoxysilanes resulted in erosion of the [1,4]/[1,2] selectivity. The loss of selectivity in
the Wittig rearrangement of allyl ethers on placement of substitution at the migrating
carbon is precedented. Schlosser and Strunk21 reported the loss of regioisomeric purity in
the Wittig rearrangement of metalated allyl alkyl ethers upon substitution at the migrating
carbon. They observed that in the presence of potassium tert-butoxide, their substrates
afforded [1,4] and [1,2] products in an approximate ratio of 9:1 (90% regioisomeric
purity) (Scheme 4.24), but only when a resonance inactive primary alkyl group (such as
butyl, 3-methylbutyl or nonyl) was allowed to migrate. They reported that the migration
of secondary or tertiary alkyl groups (l-ethylpropyl, tert-butyl) or even the
cyclopropylmethyl moiety led to 2:3 or 1:1 mixtures of 1-alken-3-olates and enolates.

Thus our results were consistent with those of Schlesser and Strunk.2|

83

4.5. Wittig rearrangement reaction of a-alkoxysilanes: Effect of substitution at the
terminal sp2 carbon of the allyl moiety

Next, we studied the effect of a substituent at the terminal sp2 carbon of the allyl
moiety. Here we studied a-alkoxysilane 55, which was prepared following our general
protocol from a-hydroxysilane 34 and the trichloroacetimidate of benzyl alcohol in 36%

yield.

Scheme 4.25. Substitution at the terminal sp2 carbon:
Wittig rearrangement reaction of 55

 

 

/\ . .
0 Ph s-BuLi(1.5 equ1v) Me 0 TMS OH
= Ph + Ph
Me/\/I\TM6 THF. -78 °C. 30 min MTMS Me \
55 92 (421 1’3th) 93
via [1,4]-Wittig via [1,2]-rwittig
TMS O
h
MeMK/P
94(0°/0)

 

 

 

When subjected to our Wittig conditions (1.5 equiv s-BuLi, THF, -78 °C, 40
min), 55 afforded a 4:1 ratio of two new compounds 92 and 93, resulting from [1,4]- and
[1,2]-Wittig respectively, with a combined yield of 74% (Scheme 4.25). The observed
(4:1) ratio shows an erosion of the [1,4]/[1,2] selectivity. We also observed that reaction
time is significantly less than for 44a (40 min vs. 8 h). This decreased rate of reaction
with substitution at the migrating carbon could be attributed to sterics (secondary vs.
tertiary carbon). With 55 (featuring a substitution at the terminal sp2 carbon of the allyl
moiety), we did not observe the silyl migration that usually accompanies the [1,2]-Wittig

of a-alkoxysilanes bearing no such substituent (Scheme 4.25, compound 94).

From these data, we can conclude that substitution at the migrating center as well
as the terminal sp2 carbon of the allyl moiety significantly impacts the [1,4]-Wittig
rearrangement of a-alkoxysilanes but to different degrees. Our results seem to be in
disagreement with the literature report that [1,4]-alkyl shift is insensitive to the

substitution pattern in the allylic moiety of the ethers.22

4.6. Wittig rearrangement of a-alkoxysilanes: Substitution at both the migrating
carbon and the terminal sp2 carbon of the allyl moiety.

An appropriate question at this point became, “What would be the effect of
substitution at both the migrating center and the terminal sp2 carbon of the allyl moiety?”
To answer this question, ot-alkoxysilanes E-56a and E—56b were prepared from or-
hydroxysilane 34 and the trichloroacetimidate of sec-phenethyl alcohol following our
general protocol. Here though TMSOTf catalysis did not work well for this system,
giving less than 10% yield of the desired compound, BF 3-OEt2 proved to be a better
Lewis acid in this case and employing 0.15 equiv of this catalyst afforded the desired
compound as a 1:1.7 (anti E-56a/syn E-56b) pair of diastereomers in a combined 49%
yield. We studied the rearrangement of E-56a and E-56b (Scheme 4.26) under various
reaction conditions of temperature and base equivalents.

In theory, six compounds (three pairs of diastereomers) are expected from this
reaction, a pair of diastereomeric [1,4]-products, a pair of [1,2]-products, and a pair of
[1,2]-silyl migration products. On carrying out this reaction, it was found that this

substrate reacted sluggishly, requiring up to 4.0 equiv of n-BuLi base, elevated

85

temperature (-30 °C), and up to 48 h reaction time. As before only one diastereomer
underwent the Wittig rearrangement and 39% of the less reactive isomer was recovered.

All six expected compounds were formed making the product isolation very tedious. The
mixture of products 95, 96 and 97 were obtained in a combined 35-57% yield (Scheme
4.26). We were nevertheless able to obtain analytically pure samples of the products by
silica gel chromatography, followed by preparatory HPLC. It was not possible to obtain
the ratios of products from either lHNMR or HPLC, as the spectrum and chromatogram

were too complex to allow for accurate measurements.

Scheme 4.26. Substitution at both the migrating center and the terminal sp2 carbon

Me
0 Ph
Me/v TMS
E-5631E-56b
n-BuLi (4.0 eq)
THF, -78 to -30°C
48 h
J19 TMS OH TMS 0 Me 0
Ph
0 Ph Mew + Me/K/Ufi/Ph-t- PhWLTMS
Me/\/" ms + Me Me Me
anti E-563 95 96 97
less reactive via [1 ,2]-Wittig via [1 ,2]-Wittig followed via [1 ,4]-Whig
(39%) rearrangement by silyl migration rearrangement

Combined yield of products 95, 96 and 97 ranges from 35 to 57%
depending on the temperature and reaction time
The isolation of [1,2]-Wittig/silyl migration products 96 from the reaction of E-56
contrasted our earlier observation with 55, where no migration product was observed
(Scheme 4.25). We sought an explanation to these conflicting results and considered the

stability of the retro-Brook intermediate. Ab initio calculations (Geometry Optimization

86

using RHF/6-31G“ model)23 employing two models, molecular mechanics and density
functional, reveal that the Brook rearrangement of both 55 and E-56 have the same
energy requirement. However, the retro-Brook intermediate 100 from a-alkoxysilane 55
was lower in energy (6 kcal/mol) than the retro-Brook intermediate 103 from 01-
alkoxysilane E-56 (Scheme 4.27). This could explain in part the absence of silyl
migration event accompanying the [1,2]-Wittig of 55 (Scheme 4.25). One could also
argue steric difference in the pre-Brook intermediates from a-alkoxysilanes 55 and E-56
(Scheme 4.28, structures 98 and 101) was responsible for this distinction. Sterics at the
two adjacent stereogenic centers might provide enough driving force for the silyl

migration in the ‘presumed’ intermediate for E—56.

Scheme 4.27. Energy calculations for pre-Brook, Brook
and retro-Brook for 55 and E-56

OTMS OTMS
TMS o6 9
Ph / Ph
Me \ Ph Me \ 6) Me“
98 99 100
SE = 61.3 kcal/mol SE = -15.1 kcal/mol SE = 47.2 kcal/mol
TMS OE) OTMSPh e OTMSPh
M 8% Ph M 6% Me Mr
101 102 103
SE = 71.9 kcal/mol SE = -11.8 kcal/mol SE = 53.4 kcal/mol

Scheme 4.28. Sterics in the ‘intermediate’ structures for 55 and E—56

Me
H Me
O/\ Ph TMS 0A Ph LTMS
Me/V-OkTMS — Oe \ Me Me \ @TMS _ 09 \ Me
55 anion E-56 anion

87

Compound 58 required 4.0 eq. of n—BuLi, room temperature and a 7 h reaction
time to undergo the Wittig rearrangement. Like the substrates bearing a substituent at the
migrating carbon, only one diastereomer reacted to afford a complex mixture of products,
which except for the unreacted starting material proved very difficult to separate. Thus,
following the Wittig rearrangement reaction, aqueous workup, and column
chromatography on silica gel, the products were collected as a mixture. Since our main
interest was in the [1,4]-products, we decided to subject the mixture of products to

oxidation condition (3 N NaOH, 30% H202, THF, 35 to 40 °C, 2 h) (Scheme 4.29).

Scheme 4.29. Wittig rearrangement of compound 58/oxidation of [1,4] product

 

 

Ph 1. n-BuLi (4.0 equiv) g Ill/NF??? O
THF, rt, 7 h 0 o 2 2
0M 42 a P“ OH
M 2. aqueous work up THF. 35-40 °C \
\ TMS colunm chromatography 2 h
58 (32%) 104

We observed that the yield of the carboxylic acid products 104 was low (32%).
It is pertinent to mention here that the low yield of 104 was due to loss of material during
work up and isolation, and is not inherent to the reaction. We also observed that the
mixture of compounds isolated from the organic phase was intractable and upon column
chromatography, the alcohol 34 was isolated. From our results, it was obvious that the
olefin functionality in all the products was being oxidized. The summary of the Wittig

rearrangements of all the substrates is given in Table 4.2.

88

Table 4.2. Wittig rearrangements of all substratesa

 

Entry Wittig substrate

Vlflttig products

 

1 0A Ph

vSiMezPh

462 AFp-N02C5H4
47: Ar=p-MeOCGH4

Ph

0
vSiMezR

48: R=Me
49: R=Ph

RMe2Si o

68 (59%) product not observed
at low temperatures

9.

Ph

Reaction very sluggigh and was not investigated
further. However, the substrate was employed
in mechanistic experiments.

TMS o TMS 0
KM W
Ph 51%b Ph
70 (10:1 at -78 °C) 71

(1:10 at 20 °C)

Reaction gave a complex mixture of products

RMeZSi O

P“ SiMezR

1.
g

74 R=Me: 35 - 42°/o(1:1.5101>7) 75
76 R=Ph: 58.24% 77

TMS 0

Ar Ar

TMS

20
if

46: reaction sluggish; no products isolated.
47: 22% based on 3.25:1 mixture of
diastereomers, 92% based on the reactive 47

RMeZSi o

P SiMezR

i.
é

82 R=Me: 135-42% (1:1.5to 1>7) 83
84 R=Ph: 58.24% 85

 

 

Entry Wittig substrate Wittig products

 

8 Ph 0 TMS O
o/‘\/\ WTMS Viki:
vrMs
50 86 35 to 41% (~1 7:117
9 ph o TMS 0

Ph
0M .. ”1
v \ 32% based on total
TZMS

88 2.64: 1 (less reavtive/reactive)3
mixture of starting materal

10 Ph 0 TMS 0 Ph
Ph
JCT fir Vi
\
TMS
53 90 23% (1.821) 91
11 OAPh M TMS OH
Ph . Ph
MTMS S'Mea M
55 92 74% yield (4:1) 93
12 ms OH TMS O
0 Ph
95
\ TMS Ph 9635-57%
556 97. . TMS combined yield
(syn/anti 1.3)
13 Ph
The products of this reaction were not isolated.
0M The crude reaction mixture was oxidized (3N
A/k NaOH/30% H202) and the carboxylic acids
\ resulting from the [1,4]-Wittig products isolated.
58

 

(a) All reactions were carried out in THF employing s-BuLi or n-BuLi (1.5 to 4.0 equiv
depending on the substrate). Reaction temperature also depended on the substrate (see
experimental). (b) Reaction was clean and crude yield was quantitative. However, when the
compound was put on silica gel, yield decreased to 51%.

90

4.7. Conclusions

Substitution at the terminal sp2 carbon of the allyl moiety (55) does not seem to
have a significant effect on the rate of the reaction; rearrangement is complete in 40 min.
Nevertheless, selectivity is drastically eroded, with a mixture of both [1,4]- and [1,2]-
Wittig products obtained in approximately 4:1 ratio (74% yield). We observed that with
this substrate, the subsequent silyl migration that usually accompanies the [1,2]-
rearrangement of our model substrate 7 does not occur, and a tertiary alcohol [1,2]-
rearrangement product is obtained (Schemes 4.25).

Introducing sterics at the migrating carbon (44) seems to have a far more reaching
effect. We observed a longer reaction time (5-8 h), and erosion of [1,4]/[1,2] selectivity
in favor of [1,2]- rearrangement ([1,4]/[1,2] = 1.7:1). With substitution at both the
migrating and terminal sp2 carbons (E-56), Wittig rearrangement becomes sluggish, and
requires more forcing conditions (4.0 equiv of base, -30 °C, 24 h or more), and only one
diastereomer rearranges to afford a mixture of six compounds (three pairs of
diastereomers). As is observed with substitution at the migrating carbon, there is serious
erosion of [1 ,4]/[1,2] regioselectivity (approx. 3:1), accompanied by a significant drop in
yield. All the possible products were observed and isolated, amongst them the product
resulting from [1 ,2]-rearrangement/silyl migration events.

The size and nature of substituent at the migrating carbon are factors to reckon
with. The larger the group, the more difficult the reaction. Groups capable of stabilizing
a developing negative charge at the migrating carbon are not favorable since they tend to
retard the reaction. Radical stabilizing groups at the migrating carbon center, and or at

the terminal sp2 carbon of the allyl moiety promote [1 ,2]-Wittig.

91

Having established the existence of differential reactivities between a pair of
diastereomeric or-alkoxysilane (relative stereochemistry (anti) and (syn))under our Wittig
conditions, we wanted to determine which of the two diastereomers was undergoing the
Wittig rearrangement. The issue of stereochemistry of the Wittig substrates will be dealt

with in Chapter 5 of this dissertation.

92

EXPERIMENTAL

Preparation of a—(trimethylsilyl)allyl alcohols: [Danheiser, R. L.; Fink, D. M.;

Okano, K.; Tsai, Y-M.; Szczepanski, S. W. J. Org. Chem. 1985, 50, 5393-5396.]

OH

VTMS

32

Preparation of 32: Representative Procedure A. To a cold (-78 °C), stirred
solution of allyl alcohol (1.0 eq, 8.2 g, 141.18 mmol) in THF (350 mL) was added
dropwise via cannula n-BuLi (1.6 M in hexanes, 1.08 eq, 95.3 mL, 152.48 mmol). Upon
complete addition of base the reaction mixture was stirred for 1 h. Then, TMSCl (freshly
distilled over CaH, 1.0 eq, 15.34 g, 141.34 mmol, 17.92 mL) was added dropwise via
syringe. Following this addition, reaction was stirred further for 1.5 h, and then t-BuLi
(1.7 M in hexanes, 1.2 equiv, 99.66 mL, 169.42 mmol) was added dropwise via cannula.
After stirring for an additional 1.5 h, reaction was quenched by addition of sat. aq.
NH4C1, and diluted with ether. Phases were separated, and the aqueous phase extracted
with ether (150 mL x 3). Combined organic phases were washed with H20, and brine,
and dried over anhydrous Na2SO4. Distillation at atmospheric pressure afforded 17.05 g
(93%) of alcohol 32. Compound data match literature report.5 IR (neat) 3430, 2959,
1634, 1250 cm'l. 1H NMR (300 MHz, CDCl3) 5 6.06-5.95 (m, 1H), 5.08-5.01 (apparent
dt, J = 17.0, 2.2, 1.6 Hz, 1H), 4.99-4.94 (apparent dt, J = 11.0, 2.2, 1.6 Hz, 1H), 3.97-4.01
(dt, J= 5.5, 2.2, 1.6 Hz, 1H), 0.029 (s, 9H). 13C NMR (75 MHz, CDC13) 5 139.7, 109.2,
68.9, -4.2. 32 is a known compound and has spectral data in accord with the reported

ones.5"0‘24

93

0H
vSiMezPh

33

Preparation of 33: Applying the Representative Procedure A for 32 to allyl
alcohol (10.0 g, 11.7 mL, 138.7 mmol), n-BuLi (1.6 M in hexanes, 146.3 mmol, 91.44
mL), chlorodimethylphenylsilane PhMe2SiCl (15.85 g, 145.8 mmol, 18.51 mL) and t-
BuLi (1.7 M in pentane, 166.4 mmol, 97.89 mL) afforded 10.50 g (53%) of 33. IR (neat)
2959, 1642, 1493, 1452,1248, 1078, 1053 cm“. 'H NMR (300 MHz, c0013) 8 7.58-7.55
(m, 2H), 7.39-7.34 (m, 3H), 6.04-5.93 (m, 1H), 5.09-5.27 (d, J = 17.8, 1H), 5.01-4.97 (d,
J= 10.7 Hz, 1H), 4.23-4.20 (dt, J= 5.2 H, 1H), 0.35 (s, 3H), 0.33 (s, 3H). 13C NMR (75
MHz, CDC13) 5 139.2, 135.9, 134.1, 129.4, 127.7, 110.0, 68.4, -5.6, -5.9. 32 is a known

compound and has spectral data in accord with the reported ones.25‘26

Mms

34
Preparation of 34: Applying the Representative Procedure A to trans-crotyl
alcohol (10.0 g, 138.7 mmol), n-BuLi (1.6 M in hexanes, 146.3 mmol, 91.44 mL),
TMSCl (15.85 g, 145.8 mmol, 18.51 mL) and t-BuLi (1.7 M in pentane, 166.4 mmol,
97.89 mL) afforded 10.50 g (53%) of 34. IR (neat) 3395, 2959, 2856, 1452, 1248 cm".

1H NMR (500 MHz, CDC13) 8 5.61-5.43 (m, 210, 3.87 (m, 1H), 1.70-1.68 (dt, J = 6.3,

1.5 Hz, 3H), 0.01 (s, 9H). 13C NMR (125 MHz, CDC13) 5 132.3, 122.3, 68.5, 17.9, -4.2.

32 is a known compound and has spectral data in accord with the reported ones.27

94

Preparation of trichloroacetimidates: General Procedure B. [Wessel, H-P.;
Iversen, T.; Bundle, D. R. J. Chem. Soc. Perkin Trans] 1985, 2247-2250.] NaH (60%
dispersion in oil, 0.105 eq) was suspended in anhydrous ether, and a solution of the
appropriate alcohol (1.0 eq) in ether added dropwise with stirring. The reaction mixture
was stirred for 20 to 30 min, and then cooled to 0 °C with a salt-ice bath.
Trichloroacetonitrile (1.0 equiv) was added dropwise during 15 min and reaction mixture
allowed to warm to 20 °C over 60 min, then concentrated to a syrup using rotary
evaporator. A solution of anhydrous methanol (0.105 eq) in pentane (1.05 M) was then
added to the syrup and the mixture shaken vigorously, filtered and the filtrate
concentrated to afford the crude product which was used without further purification.
Yields are generally in the range 73-100%. The trichloroacetimidates were usually stored
as a solution in hexane in the freezer.

Preparation of a-alkoxysilanes: General procedure C. Trichloroacetimidate of
the appropriate alcohol (prepared according to literature procedure)” (2.0 eq) was added
to a stirred solution of the requisite a-(trimethylsilyl)allyl alcohol (1.0 equiv) in
cyclohexane (0.2 M) at room temperature. A TMSOTf (0.055 equiv) solution in
cyclohexane (usually 0.1 mL/1.0 mL cyclohexane) was then added. White precipitate
formed upon addition of the Lewis acid. The reaction mixture was stirred at room
temperature overnight and filtered. The precipitate was then washed with pentane or
hexane (precipitate is soluble in ether) and the filtrate diluted with ether. The diluted
filtrate was subsequently washed with NaHCO; (sat. aq.) (x 2), IN HCl (x 2), and lastly
with brine (x 2). The organic phase was dried over anhydrous MgSO4, filtered, and

concentrated to firr'm'sh the crude product. Purification by column chromatography on

95

silica gel (0-2% EtOAc in hexane gradient) afforded the pure product. Note: for the
synthesis of the model substrate 7 and 39, the products were always accompanied by an
ester byproduct, which was removed by base hydrolysis (usually stirring with 2 M NaOH

at room temperature for about 2 h).

OAPh
vTMS
7

Preparation of 7: Applying general procedure C to 1.32 g (10.13 mmol) of 01-
hydroxysilane 32, 4.85 g (19.20 mmol) of the trichloroacetimidate of benzyl alcohol
(prepared following General procedure B)11 and 0.12 g (0.55 mmol, 0.10 mL) of
TMSOTf afforded 1.23 g (5.59 mmol), 56% of pure 7 as a colorless oil: IR (neat) 2959,
1454, 1383, 1248 cm'l, IH NMR (300 MHz, CDC13) 5 7.24-7.37 ( m, 5H), 5.77-5.89 (m,
1H), 5.04-5.00 (dt, J = 9.3, 1.6 Hz, 2H),4.97 (m, 1H), 4.68-4.73 (d, J = 12.4 Hz, 1H),
4.30-4.34 (d, J = 12.4 Hz, 1H), 3.60-3.64 (dt, J = 7.1, 1.4 Hz, 1H), 0.02 (s, 9H). 13C
NMR (300 MHz, CDCl;) 5 139.1, 137.2, 128.1, 127.5, 127.1, 112.5, 75.9, 71.8, -3.8. 7 is
a known compound and have spectral data in accord with the reported ones. 7 is a known

compound and has spectral data in accord with the reported ones.20

OAPh
vSiMezPh
39
Preparation of 39: Applying general procedure C to 0.24 g (2.33 mmol) of 01-
hydroxysilane 33, 1.17 g (4.65 mmol) of the trichloroacetimidate of benzyl alcohol
(prepared following General procedure B)ll and 0.03 g (0.13 mmol, 0.02 mL) of

TMSOTf overnight, afforded 0.23 g (35%) of the 39. IR (neat) 2959, 1628, 1496, 1454,

96

1248 cm". ‘H NMR (300 MHz, CDC13) 8 7.55-7.21 (m, 10H), 5.84-5.72 (m, 1H), 5.10-
5.06 (apparent dt, J= 8.2, 7.7, 1.6 Hz, 1H), 5.04 (d, J: 1.4 Hz, 1H), 4.70-4.66 (d, 1H, J=
12.1 Hz, 1H),4.32-4.27(d,J=12.1 Hz, 1H), 3.84-3.81 (apparent dt, J= 7.1, 1.6, 1.1 Hz,
1H), 0.31 (s, 3H), 0.28 (s, 3H). 13C NMR (75 MHz, CDC13) 8 138.9, 136.7, 136.6, 134.2,
129.1, 128.0, 127.5, 127.5, 127.1, 113.1, 75.4, 71.9, -53, -5.6. HRMS (El) m/z 282.1433

[(M-HY; calcd for C18H220Si, 282.1440].

0M TMS

40

Preparation of 40: Applying general procedure C to 0.78 g (6.03 mmol) of 0t-
hydroxysilane 32, 2.0 g (7.24 mmol) of the trichloroacetimidate of trimethylsilylallyl
alcohol (prepared following General procedure B)11 and 0.05 g (0.36 mmol, 0.05 mL) of
BF3-OEt2 afforded 0.77 g (52%) of pure 40 as a colorless oil. IR (neat) 2957, 1624,
1248 cm". 1H NMR (300 MHz, CDC13) 8 6.07-5.98 (dt, J: 18.7, 4.9 Hz, 1H), 5.87-5.70
(m, 2H), 5.05-4.96 (m, 2H), 4.18-4.11 (ddd, J = 13.7, 4.1, 1.6 Hz, 1H), 3.82-3.75
(apparent dd, J = 11.4, 7.1, 5.2 Hz, 1H), 3.59-3.56 (dt, J = 6.9, 1.4 Hz, 1H), 0.04 (s, 9H),
0.01 (s, 9H). 13C NMR (75 MHz, CDC13) 5 143.4, 137.5, 130.9, 112.1, 76.3, 73.3, 1.31,

-3.9. HRMS (EI) m/z 242.1515 [(M);calcd for C12H26OSi2, 242.1522].

Ph

OM Ph 0V
v TMS vSiMezR
41 42

Preparation of 41 and 42: Applying general procedure C to 2.53 g (19.42 mmol)
of a-hydroxysilane 32, 10.82 g (38.84 mmol) of the trichloroacetimidate of cinnamyl

alcohol (prepared following General procedure B)11 and 0.24 g (0.19 mL, 1.07 mmol) of
97

TMSOTf overnight gave a near 1:1 mixture of 41 and 42 which was readily separable by
column chromatography on silica gel to afford 1.14 g (24%) of 41 and 1.07 g (22%) of a
1:1 diastereomeric pair of 42 as clear oils.

41: IR (neat) 2957, 1628, 1495, 1248 cm". 1H NMR (300 MHz, CDC13) 5 7.41-
7.21 (m, 5H), 6.61-6.55 (d, J= 15.9 Hz, 1H), 6.31-6.22 (m, 1H), 5.89-5.77 (m, 1H), 5.13-
5.05 (t, J = 14.3, 9.3 Hz, 2H), 4.36-4.30 (dd, J = 13.2, 4.9 Hz, 1H), 4.02-3.96 (dd, J =
12.6, 6.6, 6.0 Hz, 1H), 3.72-3.69 (d, J= 6.6 Hz, 1H), 0.07 (s, 9H). 13C NMR (125 MHz,
CDC13) 5 137.4, 137.0, 131.6, 128.5, 127.4, 127.2, 126.4, 112.3, 76.0, 70.8, -4.0. HRMS
(APCI) m/z 247.1516 [(M+H)+; calcd for C15H23OS1, 247.1518].

42: IR (neat) 2959, 1628, 1495, 1452, 1248 cm'l. 1H NMR (300 MHz, CDCl3) 5
7.40-7.20 (m, 5H), 5.84-5.66 (m, 2H), 5.30-5.22 (m, 2H), 5.07-4.98 (m, 2H), 4.85-4.82
(d, J= 8.2 Hz, 1H), 3.93-3.90 (dt, J= 7.1, 6.6, 1.6 Hz, 1H), 0.07 (s, 911). 13C NMR (125
MHz, CDC13) 5 142.4, 139.1, 137.3, 128.1, 127.0, 126.3, 117.3, 112.4, 80.81, 72.9, -3.9.

HRMS (APCI) m/z 247.1522 [(M+H)+; calcd for C1 5H23OSi, 247.1518].

Me
0 Ph

vTMS

44
Preparation of 44: Applying general procedure C to 4.01 g (30.82 mmol) of 01-
hydroxysilane 32, 15.61 g (58.57 mmol) of the trichloroacetimidate of sec-phenethyl
alcohol (prepared following General procedure B)11 and stirring the reaction overnight
afforded and 0.38 g (1.70 mmol) of TMSOTf, afforded 5.7 g (79%) of pure 1:1
diastereomeric pair of 44 as clear oils. IR (neat) 2972, 2928, 2899, 1628, 1493, 1452,

1248 cm".

98

Mixture of syn/anti 44a/44b: lH NMR (300 MHz, CDCl3) 57.36-7.10 (m, 10H),
5.83-5.68 (m, 2H), 5.06-4.87 (m, 4H), 4.56-4.46 (m, 2H), 3.82-3.80 (dt, J = 6.9, 1.4 Hz,
1H), 3.43-3.41 (dt, J = 6.9, 1.4 Hz, 1H), 1.40-1.32 (dd, 6H), 0.06 (s, 9H), 0.02 (s, 9H).
13C NMR (75 MHz, CDCl3) 5 145.3, 144.2, 137.6, 128.4, 128.0, 127.9, 127.1, 126.7,
126.6, 125.8, 112.1, 111.7, 76.0, 75.6, 74.1, 73.2, 24.8, 22.3, -3.7, -3.8. HRMS (El) m/z
234.1434 [(M); calcd for C14H22OSi, 234.1440].

Less reactive anti- 44a: lHNMR (500 MHz, CDC13) 5 7.35-7.21 (m, 5H), 5.82-
5.70 (m, 1H), 5.05-4.95 (m, 2H), 4.56-4.49 (q, J = 6.6, 6.2 Hz, 1H), 3.43-3.40 (dt, J =
7.1, 1.3 Hz, 1H), 1.39-1.37 (d, J: 6.6 Hz, 3H), -0.001 (s, 9H). 13C NMR (125 MHz,
CDCl3) 5 144.4, 137.8, 128.2, 127.2, 126.8, 112.2, 75.7, 73.3, 24.6, -3.9. HRMS (El)

m/z 234.1428 [(M); calcd for C14H22OSi, 234.1440].

Me

A

0 Ph
vSiMezPh

45

Preparation of 45: Applying general procedure C to 0.37 g (1.91 mmol) of 01-
hydroxysilane 33, 1.02 g (3.83 mmol) of the trichloroacetimidate of (S)-sec-phenethyl
alcohol (prepared following General procedure B)ll and 0.02 g (0.02 mL, 0.105 mmol) of
TMSOTf overnight afforded 0.40 g (21%) of a 1.45:1 mixture of 45 as clear oils. IR
(neat) 2972, 2928, 1628, 1452, 1248 cm"; Mixture of syn/anti 45a/45b: 1H NMR (300
MHz, CDC13) 5 7.61-7.06 (m, 20H), 5.77-5.63 (m, 2H), 5.05-5.45 (m, 4H), 4.55-4.48 (q,
J = 6.6, 6.3 Hz, 1H), 4.45-4.38 (q, J= 6.3 Hz, 1H), 4.00-3.97 (dt, J = 6.6, 1.4 Hz, 1H),
3.62-3.59 (dt, J = 6.9, 1.4 Hz, 1H), 1.37-1.34 (d, J: 6.6 Hz, 3H), 1.28-1.26 (d, J = 6.3

Hz, 3H), 0.35 (s, 3H), 0.31 (s, 3H), 0.27 (s, 3H), 0.24 (s, 3H). 13(2 NMR (125 MHz,

99

CDCl3) 8 145.2, 144.0, 137.2, 136.9, 134.3, 134.2, 129.1, 129.0, 128.1, 128.0, 127.6,
127.5, 127.1, 126.7, 125.9, 112.8, 112.3, 76.2, 75.6, 73.7, 73.7, 72.7, 24.6, 22.3, -54, -
5.4, -5.6, -59.

Less reactive anti-45a: 1H NMR (300 MHz, CDCl3) 5 7.49-7.06 (m, 10H), 5.77-
5.65 (m, 1H), 5.03-4.93 (m, 2H), 4.55-4.48 (q, J = 6.6, 6.3 Hz, 1H), 3.62-3.58 (dt, J = 6.9,
1.4 Hz, 1H), 1.35 (d, J = 6.6 Hz, 3H), 0.27 (s, 3H), 0.23 (s, 3H). 13C NMR (125 MHz,
CDC13)5143.9, 137.2, 134.3, 128.9, 128.0, 1275,1274, 127.0, 126.7, 112.8, 75.7, 72.8,

24.7, -5.3, -5.8.

PhMBzSi Me

N02
46

Preparation of 46: The trichloroacetimidate of p-nitrophenethyl alcohol was
prepared from 1.2 g (7.17 mmol) of p-nitrophenethyl alcohol, 0.03 g (0.72 mmol) NaH
0.98 g (6.81 mmol) of trichloroacetonitrile, 0.02 g (0.72 mmol) anhydrous methanol
prepared following general procedure B.ll Applying general procedure C to 0.69 g (3.59
mmol) of or-hydroxysilane 33, the in situ generated trichloroacetimidate, and 0.08 g (0.36
mmol, 0.07 mL) of TMSOTf and stirring the reaction overnight afforded 46 as a 1:1
mixture of diastereomers which were obtained in a combined 0.43 g (36%) yield as
colorless oils after purification by column chromatography on silica gel. IR (neat) 2975,
1628, 1607, 1523, 1427, 1348, 1248 cm'l. 1H NMR (300 MHz, CDC13) 5 8.19-8.16 (d, J
= 8.8 Hz, 2H), 8.15-8.12 (d, J = 8.8 Hz, 2H), 8.01-7.98 (d, J = 8.8 Hz, 2H), 7.59-7.33 (m,
10H), 7.13-7.10 (d, J = 8.8 Hz, 2H), 5.80-5.60 (m, 2H), 5.08-4.87 (m, 4H), 4.63-4.57 (q, J

= 6.6, 6.3 H, 1H), 4.53-4.47 (q, J = 6.6, 6.3 Hz, 1H), 4.0-3.98 (d, J = 6.8 H, 1H), 3.51-

100

3.49 (d, J = 6.8 Hz, 1H), 1.34 (d, J = 6.6 H, 3H), 1.27 (d, J = 6.3 Hz, 3H), 0.36 (s, 3H),
0.33 (s, 3H), 0.31 (s, 3H), 0.24 (s, 3H). ”C NMR (125 MHz, CDC13) 8 152.8, 151.8,
147.0, 146.8, 136.7, 136.6, 136.5, 136.4, 134.3, 134.2, 129.3, 127.64, 127.62, 127.2,
126.7, 126.5, 123.5, 123.4, 123.3, 113.4, 112.9, 75.4, 75.1, 74.4, 73.9, 24.5, 22.1, -54, -
5.5, -5.8, -6.6. Calculated for HRMS (FAB+) m/z 341.1445 [(M)+; calcd for

C19H23NO3Si, 341.1447].

TMS Me

0Me
47

Preparation of 47 : The trichloroacetimidate of p-methoxyphenethyl alcohol was
prepared from 2.00 g (13.14 mmol) of p-methoxyphenethyl alcohol, 0.06 g (1.38 mmol)
NaH, 1.90 g (13.14 mmol) of trichloroacetonitrile, and 0.04 g (1.38 mmol) anhydrous
methanol prepared following General procedure B.ll Then applying general procedure C
to 0.85 g (6.52 mmol) of a-hydroxysilane 32, the in situ generated trichloroacetimidate,
and 0.087 g (0.07 ml, 0.39 mmol) of TMSOTf, afforded 47 as a 3.25:1 mixture of
anti/syn diastereomers which, after silica gel chromatography (0-2% EtOAc gradient in
hexanes), was obtained in a combined 1.59 g (92%) yield as colorless oils. IR (neat)
2972, 1612, 1512, 1466, 1442, 1248 cm". Reactivesyn 47: 1H NMR (300 MHz, CDCl3)
5 7.25-7.23 (d J = 8.8 Hz, 2H), 6.84-6.82 (d, J = 8.8 Hz, 2H), 5.78-5.69 (m, 1H), 4.96-
4.94 (d, J = 11.7 Hz, 1H), 4.90-4.87 (d, J = 11.7 Hz, 1H), 4.45-4.41 (q, J = 6.8, 5.8 Hz,
1H), 3.78 (s, 3H), 3.76 (d, part of the doublet buried in the singlet at 3.78, 1H), 1.33-1.31
(d, J = 6.8 Hz, 3H), 0,03 (s, 9H). 13C NMR (75 MHz, CDCl3) 5 158.4, 137.7, 137.5,

127.1, 113.3, 111.5, 75.6, 74.0, 55.2, 22.2, -3.9. Less reactive anti 47: 1H NMR (300

101

MHz, CDCl3) 8 7.18-7.16 (d, J= 7.8 Hz, 2H), 6.85-6.83 (d, J = 7.8 Hz, 2H), 5.78-5.69
(m, 1H), 5.02-4.97 (t, J = 13.7, 10.7 Hz, 2H), 4.49-4.43 (q, J = 6.8, 5.8 Hz, 1H), 3.79 (s,
3H), 3.39-3.38 (d, J = 6.8 Hz, 1H), 1.36-1.35 (d, J = 6.8 Hz, 3H), -0.06 (s, 9H). ”C
NMR (75 MHz, CDCl3) 8 158.7, 137.7, 136.3, 127.9, 113.4, 112.0, 750,729, 55.2, 24.6,
-40. HRMS (CI) m/z 265.1617 [(M+H)*; calcd for C.5H2502Si, 265.1624].

I

0 Ph
vTMS

43

Preparation of 48: The trichloroacetimidate of a-phenylpropyl alcohol was
prepared from 1.89 g (13.84 mmol) of o-phenylpropyl alcohol, 0.033 g (1.38 mmol)
NaH, 1.90 g (13.15 mmol) of trichloroacetonitrile, and 0.044 g (1.90 mmol) anhydrous
methanol prepared following general procedure B.ll Then applying general procedure C
to 0.90 g (6.92 mmol) of a-hydroxysilane 32, the in situ generated trichloroacetimidate,
and 0.015 g (0.01 mL, 0.069 mmol) of TMSOTf overnight afforded 0.612 g ( 36%) of a
1:1 mixture anti/syn 48 as a clear oil. IR 3069, 2961, 2934, 1626, 1491, 1452, 1427,
1253,1118,1049, 1026 cm].

Less reactive anti-48a: 1H NMR (300 MHz, CDC13) 5 7.36-7.15 (m, 5H), 5.80-
5.68 (m, 1H), 5.04-4.93 (m, 2H), 4.31-4.26 (dd, J = 7.7, 7.4, 1.1 Hz, 1H), 3.42-3.39 (dt, J
= 7.4, 1.4, 1.1 Hz, 1H), 1.81-1.52 (m, 2H), 0.90-0.85 (t, J = 7.4 Hz, 3H), -0.03 (s, 9H).
13C NMR (300 MHz, CDCl3) 5 143.1, 137.8, 127.9, 127.2, 127.0, 112.6, 80.9, 72.8, 31.6,
10.6, -3.8.

Reactive syn-48b: 1H NMR (300 MHz, CDC13) 5 7.37-7.19 (m, 5H), 5.75-5.63
(m, 1H), 4.96-4.82 (m, 2H), 4.31-4.27 (t, J = 6.0, 5.8 Hz, 1H), 3.80-3.76 (dt, J = 7.1, 6.9,

102

1.6, 1.4 Hz, 1H), 1.85-1.64 (m, 2H), 0.84-0.79 (t, J= 7.1 Hz, 3H), 0.08 (s, 9H). ”C
NMR (300 MHz, CDCl3) 8 143.8, 137.9, 127.7, 126.6, 126.5, 111.53, 8.25, 75.4, 29.5,
9.5, -3.6. HRMS (APCI) m/z 249.1675 [(M+H)*; calcd for C15H240Si, 249.1674].

1

0 Ph

SiMe2Ph
49

Preparation of 49: The trichloroacetimidate of a-phenylpropyl alcohol was
prepared from 1.10 g (8.09 mmol) of a-phenylpropyl alcohol, 0.032 g (0.81 mmol) NaH,
1.11 g (7.68 mmol) of trichloroacetonitrile, and 0.03 g (0.81 mmol) anhydrous methanol
prepared following general procedure B.“ Applying general procedure C to 0.78 g (4.05
mmol) of a-hydroxysilane 33, the in situ generated trichloroacetimidate, and 0.09 g (0.40
mmol) of TMSOTf and stirring overnight afforded 0.47 g (38%) of a 1:1.2 mixture of
49a and 49b as clear oils. IR (neat) 2963, 1628, 1427, 1248 cm". Reactive syn-49b: 1H
NMR (CDCl3, 300 MHz) 5 7.60-7.16 (m, 10H), 5.68-5.56 (m, 1H), 4.92-4.78 (m, 2H),
4.16 (t, J= 6.0, 5.8 Hz, 1H), 3.95-3.92(dt, J: 6.9, 1.6, 1.4 Hz, 1H), 1.80-1.52 (m, 2H),
0.67 (t, J= 7.4 Hz, 3H) 0.36 (s, 3H), 0.31 (s, 3H). 13C NMR (300 MHz, CDC13) 5 143.5,
137.4, 136.9, 134.2, 132.9, 129.0, 127.67, 127.6, 127.5, 126.6, 126.5, 112.1, 82.39, 74.8,
29.5, 9.4, -5.1, -5.5. HRMS (CI) m/z 295.1517 [(M-CH3)+; calcd for C20H2608i,
295.1518].Less reactive anti-49a: 1H NMR (CDC13, 300 MHz) 57.50-712 (m, 10H),
5.74-5.62 (m, 1H), 5.01-4.90 (t, 2H), 4.28 (t, J = 6.9, 6.3 Hz, 1H), 3.6-3.57 (d, J = 7.4 Hz,
1H), 1.80-1.66 (m, 1H), 1.64-1.50 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H), 0.26 (s, 3H), 0.23 (s,

3H). ”C NMR (300 MHz, CDCl3) 8 142.6, 137.3, 136.8, 134.3, 128.9, 127.9, 127.3,

103

127.2, 127.0, 113.2, 80.8, 72.4, 31.6, 10.6, -5.1, -5.8. HRMS (CI) m/z 295.1521[(M-

CH3)+; calcd for C19H23OSi, 295.1518].

Ph

OM
VTMS

50

Preparation of 50: Applying general procedure C to 0.88 g (6.73 mmol) of 32,
3.96 g (13.45 mmol) of the acetimidate of l-phenylbutan-l-ol (prepared following
general procedure B)'1 and TMSOTf (catalyst) (0.07 mL, 0.04 mmol) and stirring the
reaction mixture overnight afforded 50 as a 1:1 mixture of diastereomers which were
readily separable by silica gel chromatography (0-2% EtOAc gradient in hexanes), and
obtained in a combined 1.32 g (75%) yield as colorless oils, accompanied by 0.33 g, 37%
of l-phenylbut-l-ene. IR (neat) 2959, 1628, 1454, 1248 cm".

Less reactive anti-50a: 1H NMR (300 MHz, CDCl3) 5 7.32-7.20 (m, 5H), 5.79-
5.67 (m, 1H), 5.03-4.91 (m, 2H), 4.38-4.34 (dd, J = 8.0, 7.7, 5.2 Hz, 1H), 3.40-3.37 (dt, J
= 7.4, 1.4 Hz), 1.80-1.68 (m, 1H), 1.57-1.34 (m, 2H), 1.32-1.15 (m, 1H), 0.87 (t, J= 7.1
Hz, 3H), 0.04 (s, 9H). 13C NMR (300 MHz, CDC13) 5 143.3, 137.8, 127.9, 127.2, 127.0,
112.7, 79.3, 72.8, 41.0, 19.4, 14.2, -3.8. HRMS (EI) m/z 263.1844 [(M+H)+; calcd for
C16H26OSi, 263.1831]. Reactive syn-50b: 1H NMR (300 MHz, CDCl3) 5 7.37-7.19 (m,
5H), 5.74-5.62 (m, 1H), 4.94-4.81 (ddt, J = 17.6, 13.7, 10.4, 2.2, 1.65 Hz, 2H), 4.34-4.30
(t, J= 6.0 Hz, 1H), 3.78-3,75 (dt, J= 7.1, 1.6 Hz, 1H), 1.83-1.71 (m, 1H), 1.68-1.56 (m,
1H), 1.37-1.18 (m, 2H), 0.91-0.86 (t, J= 7.7, 7.1 Hz, 3H), 0.08 (s, 911). 13C NMR (300
MHz, CDCl3) 5 144.2, 138.0, 127.7, 126.6, 126.5, 111.4, 81.4, 75.5, 39.4, 18.5, 14.3, -

3.4. HRMS (EI) m/z 263.1840 [(M+H)+; calcd for CI6H27OSi, 263.1831].

104

Ph

0M
vSiMezPh

51

Preparation of 51: General procedure D. Allyltrimethylsilane (0.12 g, 0.16 mL,
1.02 mmol), benzaldehyde (0.11 g, 0.10 mL, 1.02 mmol), and TMSOTf ((0.04 g, 0.03
mL, 0.19 mmol) were successively added to a stirred cold (-78 OC) solution of 01-
(dimethylphenylsilyl)allyl dimethylphenylsilyl ether (0.30 g, 0.93 mmol) in CH2C12 (9.3
mL). The reaction was stirred for 70 min and then quenched with NaHCO3 (aq. sat). The
aqueous phase was extracted with CH2Cl2 (10 mL x 4), and the combined organic layers
were washed with NaHCO3 (10 mL x 2), brine (10 mL x 2), and then dried (MgSO4).
Filtration and concentration afforded the crude product as a 1:1 mixture of diastereomers
which were readily separated by silica gel chromatography (0-1% EtOAc gradient in
hexanes) to give a combined 0.21 g (77%) yield of pure 51 as colorless oils.

IR (neat) 3063, 1628, 1248 cm". Reactive syn-51: 1H NMR (500 MHz, CDCl3) 5
7.59-7.56 (m, 2H), 7.38-7.32 (m, 3H), 7.27-7.18 (m, 5H), 5.64-5.53 (m, 2H), 4.90-4.79
(m, 4H), 4.27 (t, J = 6.3, 5.9 Hz, 1H), 3.98-3.96 (dt, J = 6.8, 1.5 Hz, 1H), 2.46-2.41 (m,
1H), 2.37-2.31 (m, 1H), 0.35 (s, 3H), 0.30 (s, 3H). 13'C NMR (500 MHz, CDCl3) 5 143.3,
137.4, 136.9, 134.7, 129.15, 127.8, 127.6, 126.9, 126.6, 116.8, 112.3, 81.0, 75.1, 41.5, -
5.3, -5.6. HRMS (APCI) m/z 323.1830 [(M+H)+; calcd for C21H26OSi, 323.1831]. Less
reactive anti-51: IH NMR (500 MHz, CDCl3) 5 7.50-7.02 (m, 10H), 5.81-5.73 (m, 1H),
5.70-5.63 (m, 1H), 5.00-4.91 (m, 4H), 4.43-4.40 (dd, J = 7.8, 5.8 Hz, 1H), 3.60-3.58 (dt,
J= 7.3, 1.5 Hz, 1H), 2.52-2.46 (m, 1H), 2.33-2.28 (m, 1H), 6, 0.26 (s, 3H), 0.23 (s, 3H).

”C NMR (500 MHz, CDCl3) 8 142.1, 137.1, 136.8, 135.4, 134.4, 129.0, 128.1, 127.4,

105

127.3, 127.2, 116.4, 113.5, 79.1, 72.4, 43. 1, -5.3, -6.0. HRMS (APCI) m/z 323.1834

[(M+H)+; calcd for C21H26OSi, 323.1831].

Ph

0M
vTMS

52

Preparation of 52: Applying the general procedure D described for the
preparation of 51 to allyltrimethylsilane 1.26 g, (11.0 mmol, 1.75 mL), benzaldehyde
1.67 g (11.0 mmol, 1.12 mL), and TMSOTf 0.36 mL (2.0 mmol, 0.44 g) and 01-
(trimethylsilyl)allyl trimethysilyl ether 2.0 g (10.0 mmol) in CH2C12 (100 mL), gave
a1:2.56 mixture of diastereomers. After silica gel chromatography 1.96 g (7.58 mmol)
of the pure products were obtained in a combined yield of 69%. The pair of
diastereomers is separable by column chromatography on silica gel. IR (neat) 2959,
1641, 1248, 1060 cm'l. Less reactive anti-52: 1H NMR (300 MHz, CDCl3) 5 7.35-7.22
(m, 5H), 5.88-5.69 (m, 2H), 5.05-4.95 (m, 4H), 4.46-4.42 (dd, J = 13.5, 7.7, 5.8 Hz, 1H),
3.44-3.42 (d, J = 7.4 Hz, 1H), 2.59-2.49 (quintet, J = 7.7 Hz, 1H), 2.39-2.30 (quintet, J =
6.86, 1H), .0.01 (s, 9H). ”C NMR (500 MHz, CDCl3) 8 142.5, 137.7, 135.4, 128.1,
127.4, 127.4, 116.3, 112.9, 79.3, 73.0, 43.03, -4.0. HRMS (CI) m/z 261.1664 [(M+H)+;
calcd for C (6H24OSi, 261.1675. Reactive syn-52: 1H NMR (300 MHz, CDCl3) 5 7.30-
7.20 (m, 5H), 5.79-5.60 (m, 2H), 5.01-4.80 (m, 4H), 4.39-4.35 (t, J = 6.2 Hz, 1H), 3.82-
3.78 (dt, J = 7.1, 1.3 Hz, 1H), 2.54-2.40 (m, 2H), 0.05 (s, 9H). l3C NMR (500 MHz,
CDCl3) 5143.6, 137.9, 134.9, 127.8, 126.9, 126.6, 116.8, 111.9, 81.1, 75.8, 41.5, -3.7.

HRMS (CI) m/z 261.1681 [(M+H)*; calcd for C16H240Si, 261.1675].

106

Ph
0

vTMS

53

Preparation of 53: The trichloroacetimidate of a-phenylisopropyl alcohol was
prepared from 2.88 g (19.19 mmol) of a-phenylisopropyl alcohol, 0.08 g (1.92 mmol)
NaH, 2.63 g (18.23 mmol) of trichloroacetonitrile, 0.06 g (1.92 mmol) anhydrous
methanol following general procedure B.ll Then applying general procedure C to 1.25 g
(9.59 mmol) of a-hydroxysilane 32, the in situ generated trichloroacetimidate, and 0.03
mL (0.04 g, 0.19 mmol) of TMSOTf, afforded 53 as a 1:1 mixture of diastereomers
which were readily separable by silica gel chromatography (O-2% EtOAc gradient in
hexanes), and obtained in a combined 1.47 g (5.62 mmol), 59% as colorless oils. IR
(neat) 2959, 1628, 1452, 1248 cm".

Less reactive anti-53a: 1H NMR (300 MHz, CDCl3) 5 7.31-7.19 (m, 5H), 5.77-
5.70 (m, 1H), 5.03-4.92 (dd, J = 17.2, 11.48, 10.6 Hz, 2H), 4.07-4.06 (d, J = 7.5 Hz, 1H),
3.39-3.37 (d, J= 8.0 Hz, 1H), 1.91-1.85 (m, 2H), 1.01-1.00 (d, J= 6.6 Hz, 3H), 0.72-0.70
(d, J = 7.1 Hz, 3H), -0.01 (s, 9H). 13C NMR (300 MHz, CDC13) 5 141.8, 138.0, 128.7,
128.1, 127.8, 127.1, 113.1, 84.7, 72.6, 35.0, 19.2, 19.0, -4.0. HRMS (APCI) m/z
263.1821 [(M+H)+; calcd for C16H260Si, 263.1831]. Reactive syn-53b: 1H NMR (300
MHz, CDCl3) 5 7.35-7.17 (m, 5H), 5.64-5.53 (m, 1H), 4.89-4.72 (dd, J = 16.7, 10.7 Hz,
2H), 4.01-3.99 (d, J = 6.0 Hz, 1H), 3.72-3.68 (d, J = 7.4 Hz, 1H), 1.89-1.99 (m, 1H),
0.93-0.91 (d, J = 6.9 Hz, 3H), 0.77-0.74 (d, J = 6.9 Hz, 3H), 0.05 (s, 9H). 13C NMR (300
MHz, CDCl3) 5 142.6, 138.2, 127.4, 127.3, 126.5, 111.4, 87.5, 76.6, 34.5, 18.7, -3.5.

HRMS (APCI) m/z 263.1821 [(M+H)+; calcd for C16H2gOSi, 263.1831].

107

0%
vms

54

Preparation of 54; Applying general procedure C to 0.74 g (5.68 mmol) 32, 3.46
g (10.79 mmol) of the trichloroacetimidate of l-phenyl-S-hexen-l-ol (prepared following
general procedure B)“ and TMSOTf (catalyst) (0.10 mL, 0.57 mmol) in cyclohexane and
stirring reaction overnight afforded a 1:1 pair of diastereomeric 54 as colorless oils in a
combined 0.25 g (15%) yield. IR (neat) 2941, 1641, 1454, 1248 cm". Reactive syn-54:
1H NMR (300 MHz, CDCl3) 5 7.30-7.20 (m, 105H), 5.82-5.58 (m, 4H), 5.04-4.78 (m,
8H), 4.39-4.35 (dd, 1H), 4.32-4.28 (t, 1H), 3.74-3.72 (d, 1H), 3.41-3.38 (d, 1H), 2.07-
1.97 (m, 4H), 1.81-1.51 (m, 6H), 1.42-1.24 (m, 2H), -0.33 (s, 9H), -0.05 (s, 9H). Less
reactive anti-54: 1H NMR (500 MHz, CDCl3) 5 (7.33-7.20 (m, 5H), 5.80-5.69 (m, 2H),
5.02-4.88 (m, 4H), 4.37-4.34 (dd, J = 7.8, 4.9 Hz, 1H), 3.39-3.37 (dt, J = 4.9, 2.4 Hz,
1H), 2.05-2.00 (q, J: 8 .3, 6.3 Hz, 2H), 1.79-1.70 (m, 1H), 1.62-1.48 (m, 2H), 1.37-1.27
(m, 1H), -0.05 (s, 9H). ”C NMR (300 MHz, CDCl3) 8 143.2, 138.9, 137.8, 128.1,
127.2, 127.2, 114.3, 112.8, 79.3, 72.8, 38.07, 33.7, 25.3, -4.0. HRMS (APCI) m/z

289.1983 [(M+H)+; calcd for C13H290Si, 289.1987].

OAPh
Mme

55

Preparation of 55: Applying general procedure C to 6.75 g (46.86 mmol) of 34,

17.75 g (70.29 mmol) of the trichloroacetimidate of benzyl alcohol (prepared following

108

literature procedure),” and BF3-OEt2 (catalyst) (0.65 mL, 5.15 mmol) in cyclohexane
afforded 2.11 g (34%) of 55 as a colorless oil. IR (neat) 2959, 1497, 1454, 1246 cm".
1H NMR (300 MHz, CDCl3) 5 7.35 (m, 5H), 5.55-5.39 (m, 2H), 4.69-4.65 (d, J = 12.4,
1H), 4.37-4.28 (d, J = 12.4, 1H), 3.52-3.50 (d, J = 7.1, 1H), 1.74-1.72 (d, J = 4.7, 3H),
0.01 (s, 9H). 13C NMR (75 MHz, CDCl3) 5 139.4, 129.7, 128.0, 127.5, 127.0, 125.1,
75.1, 71.3, 18.0, -3.7. HRMS (CI) m/z 252.1775 [(M+NH4)+; calcd for C14H22OSi,

252.1784].

J.

0 Ph

MTMS

E-56

Preparation of E-56: Applying general procedure C to 3.60 g (24.98 mmol) of
or-hydroxysilane 34, 13.32 g (49.50 mmol) of the trichloroacetimidate of phenethyl
alcohol (prepared following general procedure B)ll and 0.47 mL (0.53 g, 3.74 mmol) of
BF3°OEt2, afforded 3.07 g (49%) of E-56 as a 1:1 mixture of anti/syn diastereomers. IR
(neat) 2963, 1493, 1452, 1246, 1082, cm". Mixture of anti/syn E-56: Less reactive anti
E-56: 1H NMR (300 MHz, CDCl3) 5 7.34-7.21 (m, 5H), 5.43-5.33 (m, 2H), 4.55-4.49 (q,
J = 6.6, 6.3 Hz, 1H), 3.30-3.28 (d, J= 6.0 Hz, 1H), 1.72-1.70 (d, J= 4.9 Hz, 3H), 1.36-
1.34 (d, J= 6.3 Hz, 3H), -0.5 (s, 9H). l3C NMR (75 MHz, CDCl3) 5 144.5, 130.1, 128.0,
126.9, 126.7, 124.5, 75.0, 72.3, 24.8, 18.1, -3.7. HRMS (CI) m/z 248.1591 [(M); calcd

for (3151124031, 248.1596].

109

Me

Me 0 Ph
v -
SIM83

Z—56

Preparation of (2)-56: Applying general procedure C to 1.50 g (10.41 mmol) of
a-hydroxysilane (2)-34, 5.55 g (20.82 mmol) of the trichloroacetimidate of sec-phenethyl
alcohol,ll and 0.17 mL (0.14 g, 0.62 mmol) of TMSOTf afforded 0.91 g of a mixture of
products including (Z)-56. 'H NMR (300 MHz, CDCl3) 5 7.35-7.19 (m, 10H), 5.92-5.87
(apparent dd, J: 11.8, 11.0, 6.6, 5.2 Hz, 1H),5.86-5.80 (apparent dd, J= 11.8, 11.0, 6.6,
5.2 Hz, 1H), 5.71 (dd, J= 3.2, 1.1 Hz, 1H), 5.64 (dd, J= 3.2, 1.1 Hz, 1H), 4.54-4.47 (q, J
= 6.5 Hz, 1H), 4.48-4.41 (q, J= 6.5 Hz, 1H), 1.41 (d, J=6.3 Hz, 3H), 1.39 (d, J= 6.3 Hz,
3H), 1.22 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.3 Hz, 3H), 0.07 (s, 9H), -0.3 (s, 9H). 13C
NMR (75 MHz, CDCl3) 5 148.2, 147.5, 144.6, 144.2, 131.1, 129.4, 128.2, 128.1, 127.1,

127.0, 126.2, 76.1, 75.7, 75.1, 74.5, 24.8, 24.0, 21.7, 20.4, -1.1, -1.3.

Preparation of 58: Applying the general D to 0.59 g (0.82 mL, 5.18 mmol) of
allyltrimethylsilane, 0.55 g (0.53 mL, 5.18 mmol) of benzaldehyde, 0.21 g (0.17 mL, 0.94
mmol) of TMSOTf, and 1.02 g (4.71 mmol) of a-(trimethylsi1y1)allyl trimethylsilyl ether
in CHzClz (47 mL), after about 3 h reaction time afforded 58 as a 1:1 mixture of
diastereomers, which were readily separable by silica gel chromatography (0-1% EtOAc
gradient in hexanes), and obtained in a combined 0.65 g (51%) yield as colorless oils. IR

(neat) 2959, 1642, 1493, 1452,1248, 1078, 1053 cm'l. Less reactive anti-58: 1H NMR

110

(300 MHz,CDC13)5 7.34-7.17 (m, 5H), 5.85-5.64 (m, 1H), 5.42-5.20 (m, 2H), 5.01-4.93
(tm, 2H), 4.44-4.35 (m, 1H), 3.31-3.29 (01, J = 6.0 Hz, 1H), 2.55-2.38 (m, 2H), 1.71-1.69
(d, J= 5.5 Hz, 3H), —0.4 (s, 9H). 13(2 NMR (75 MHz, CDCl3) 5 142.6, 135.5, 129.9,
127.9, 127.2, 127.1, 125.1, 116.1, 78.6, 72.0, 43.1, 18.1, -3.7. Reactive syn-58: lH NMR
(300 MHz, CDCl3) 5 7.28-7.17 (m, 5H), 5.80-5.64 (m, 1H), 5.38-5.20 (m, 2H), 4.99-4.93
(t, J= 2H), 4.43-4.30 (m, 1H), 3.7 (d, J= 7.4 Hz, 1H), 2.54-2.36 (m, 2H), 1.54 (d, J= 5.5
Hz, 3H), 0.02 (s, 9H). 13C NMR (75 MHz, CDCl3) 5 143.7, 134.8, 130.4, 127.7, 126.6,
126.5, 124.1, 116.6, 80.1, 74.7, 41.3, 17.9, -3.5. HRMS (CI) m/z 275.1823 [(M+H)+;
calcd for C17H26OSi, 275.1831].

I

0 Ph
TMS/V

63

Preparation of 63: formation of mesylate of 32 - to a cold (0 0C) THF solution
of 32 (0.1 M) were added MsCl (0.87 g, 0.59 mL, 7.59 mmol), followed by Et3N (0.77 g,
1.05 mL, 7.59 mmol), and the mixture stirred for 2.5 h. Then, the reaction was quenched
with NaHCO3 (sat, aq), diluted with ether, phases separated. The organic phase was
washed with NthI (sat, aq), dried over MgSO4 and concentration with rotary evaporator
to afford 0.76 g (96%) of the crude product which was employed in the next step without
purification.

To a stirred suspension of NaH (0.02 g, 0.40 mmol) in THF (1.5 mL) at room
temperature, was added a solution of a-phenylpropyl alcohol (0.53 g, 3.9 mmol) in THF
(2.0 mL) via syringe, followed by a THF wash (1.0 ml; total volume of THF became 3.0

ml). The reaction mixture was stirred at room temperature for 30 min, and transferred via

111

syringe, to a solution of the crude mesylate in THF (7.0 mL; 0.5 M) at room temperature.
The reaction was stirred for additional 2 h, quenched with NH4C1, washed with brine,
dried over MgSO4, and concentrated to give 1.15 g of crude product. Purification on
silica gel afforded 0.61 g (2.44 mmol, 70%) of 63 as a colorless oil. IR (neat) 2963(5),
2934(m), 1622(m), 1452(5), 1248(m) cm". ‘H NMR (300 MHz, CDC13)5 7.35-7.15 (m,
5H), 6.09-6.00 (dt, J= 18.8, 5.2, 4.6 Hz, 1H), 5.87-5.80 (dt, J= 18.7, 1.5 Hz, 1H), 3.94-
3.87 (ddd, J = 4.4, 1.6 Hz, 1H), 3.80-3.74 (ddd, J = 12.9, 5.2, 1.4 Hz, 1H), 1.90-1.50 (m,
2H), 0.89 (t, J?, 3H), 0.04 (s, 9H). 13C NMR (75 MHz, CDCl3) 5 142.6, 142.4, 131.4,

128.1, 127.3. 126.7, 83.3, 71.7, 31.1,10.4, -1.2.

OAPh

Me3Si M

65

Preparation of 65: To a solution of BnOH (0.31 g (2.88 mmol) in THF at room
temperature was added dropwise EtZZn (1.0 M in heptane, 1.44 mmol, 1.44 mL) via
syringe. The resulting mixture was stirred for about 50 min, resulting in the formation of
cloudy white precipitate. To this suspension were added the acetate of 32 (0.50 g, 2.89
mmol) and Pd(PPh3)4 (5 mol%, 0.17 g, 0.15 mmol), and reaction stirred at room
temperature for 2 h. The reaction mixture was passed through a short plug of silica gel,
elute concentrated, and product purified by flash chromatography on silica gel (0 to 2%
EtOAc in hexane gradient) to afford 0.41 g (64%) of 65 as a clear oil. IR (neat) 2955,

1622, 1496.95, 1454, 1248 cm". ‘H NMR (300 MHz, CDCl3) 5 13c NMR (300 MHz,

CDCl3) 5 142.1, 138.2, 132.0, 128.3, 127.7, 127.6, 127.5, 73.1, 72.4, -1.24. 65 is a

known compound and have spectral data in accord with the reported ones.28

112

Wittig rearrangements of a—alkoxysilanes- Representative procedure E. A
solution of a-alkoxysilane (1.0 equiv) in freshly distilled anhydrous THF (0.06 — 0.07 M)
was cooled to the desired temperature under nitrogen. The required amount of s-BuLi
(1.5 — 4.0 equiv, 1.3 M in cyclohexane) was added dropwise via syringe. The reaction
mixture was stirred at the reaction temperature for the desired length of time, then
quenched with saturated aqueous NH.;C1 and diluted with ether. Phases separated and the
organic phase was washed with water and brine. The organic phase was dried over
MgSO4 and concentrated. Silical gel chromatography (0 to 2% EtOAc in hexane

gradient) afforded the rearranged products usually as a light yellow oil.

0
Ph\/\/U‘SiMe2Ph

Wittig rearrangement of 39: preparation of 68: Applying the representative
procedure E for the Wittig rearrangement of a-alkoxysilanes to 57 mg (0.20 mmol) of
silane 39, 0.37 mL (0.30 mmol) s-BuLi and THF (3.0 mL) at —78 °C for 45 min afforded,
afier silical gel chromatography (2% EtOAc in hexanes), 39 mg (69%) of pure II-05 as a
clear oil. IR cm“. ‘H NMR (500 MHz, CDCl3) 5 7.56-7.54 (m, 2H), 7.45-7.38 (m, 3H),
7.26-7.07 (m, 5H), 2.62—2.59 (apparent t, J = 7.5, 7.1 Hz, 2H), 2.51 (apparent t, J = 8.0,
7.5 Hz, 2H), 1.82-1.79 (quintet, J= 8.0, 7.5, 7.1 Hz, 2H), 0.49 (s, 6H). 13C NMR (125
MHz, CDCl3) 5 245.9, 141.8, 133.9, 129.9, 128.4, 128.3, 128.2, 128.1, 125.8, 47.9, 35.7,
23.7, -4.8. 68 is a known compound and have spectral data in accord with reported

01168.29

113

TMS 0

KM
Ph
70

Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes
to 93 mg (0.34 mmol) of 41 and 0.35 mL (1.5 equiv, 0.49 mmol) of n-BuLi (1.6 M in
hexane) at -78 °C foS 2.5 h, afforded 47 mg (51%) of 70 as a colorless oil. IR (neat)
2955, 2897, 1717, 1635, 1495, 1454, 1410, 1250 cm“. ‘H NMR (500 MHz, CDCl3) 5
7.35-7.20 (m, 5H), 6.27-6.20 (m, 1H), 5.20-5.17 (dt, J = 10.2, 1.1 Hz, 1H), 5.08-5.03 (d,
J= 17.1, 1.2 Hz, 1H), 4.41-4.39 (d, J= 8.2 Hz, 1H), 2.41-2.38 (dd, J= 10.1, 8.8 Hz, 2H),
0.73-0.66 (m, 2H), -0.09 (s, 9H). 13C NMR (125 MHz, CDC13) 5 209.7, 136.3, 128.9,

128.2, 127.3, 117.3, 62.5, 36.2, 10.2, -1.9.

TMS O

925%
Ph
71

Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes
to 153 mg (0.621 mmol) of 41 and 0.58 mL (1.5 equiv, 0.932 mmol) of n-BuLi (1.6 M in
hexane) at room temperature, after silica gel chromatography (1% EtOAc in hexanes)
afforded 80 mg (52%) of pure 71 as light yellow oil. IR (neat) 2953, 2895, 1694, 1624,
1493, 1445, 1410, 1354, 1248 cm". 1H NMR (500 MHz, CDCl3) 5 7.33-7.19 (m, 5),
6.02-5.98 (q, J = 7.2 Hz, 1H), 2.41-2.37 (dd, J= 8.7, 8.1 Hz, 2H), 1.88 (d, J = 7.2 Hz,
3H), 0.76-0.73 (t, J = 8.7, 8.1 Hz, 2H), 0.09 (s, 9H). 13C NMR (125 MHz, CDCl3) 5

208.0, 144.0, 138.1, 129.4, 128.6, 127.6, 126.8, 37.5, 15.5, 10.2, -1.9. HRMS (EI) m/z

246.1433 [(M-H)+; calcd for ClanOSi, 246.1440].

114

O TMS O

PhNTMS th

74 75

Wittig rearrangement of 44: Applying representative procedure E for Wittig
rearrangement of or-alkoxysilanes to 360 mg (1.53 mmol) of 44 and 1.8 mL (2.30 mmol)
of s-BuLi (1.3 M in cyclohexane) at -78 °C overnight, afforded 162 mg (46%) of a 1.68:1
mixture of 74 and 75 as a colorless oil. 74: IR (neat) 2957, 2899, 1643, 1603, 1495,
1452, 1410, 1375, 1250 cm". 1H NMR (300 MHz, CDCl3) 5 7.33-7.12 (m, 5H), 2.67-
2.57 (m, 1H), 2.54-2.41 (m, 1H), 1.89-1.67 (m, 2H), 124-121 ((1, J= 7.1 Hz, 3H), 0.11
(s, 9H). 13C NMR (125 MHz, CDC13) 5 248.2, 146.6, 128.4, 127.0, 126.0, 46.4, 39.3,
30.2, 22.4, -3.2. HRMS (E1) m/z 233.1358 [(M-H)+; calcd for C14HZIOSi, 233.1362].

75: IR (neat) 2955, 2895, 1717, 1601, 1495, 1452, 1414, 1373, 1248, 1180 cm'
‘. 1H NMR (300 MHz, CDCl3) 5 7.33-7.19(m, 5H), 3.82-3.75 (q, J= 7.1, 6.9 Hz, 1H),
2.34-2.28 (m, 2H), 1.38 (d, J = 6.9 Hz, 3H), 0.77-0.55 (m, 2H), -0.11 (s, 9H). 13C NMR
(500 MHz, CDCl3) 5 211.8, 140.8, 128.8, 127.8, 127.0, 52.3, 35.6, 17.7, 10.3, -1.9.

HRMS (CI) m/z 234.1466 [(M); calcd for C14H220Si, 234.1440].

0 PhMeZSi o
PhNSiMeZPh ”Pb
76 77

Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes
to 76 mg (0.25 mmol) of 45 and 0.38 mL (0.38 mmol) of s-BuLi (1.0 M in cyclohexane)
and stirring for 4 h at -78 °C afforded 37 mg (49%) of a 1.321 mixture of 76 and 77 as

light yellow oils. ‘H NMR (300 MHz, CDCl3) 5 7.49-7.02 (m, 20H), 3.75-3.68 (q, J =

115

7.1, 6.8 Hz, 1H), 2.59-2.20 (m, 4H), 1.96-1.60 (m, 2H), 1.35, d, J= 7.1, 3H), 1.16 (d, J=
6.8 Hz, 3H), 1.05-0.95 (m, 1H), 0.91-0.80 (m, 1H), 0.42 (s, 3H), 0.41 (s, 3H), 0.18 (s,
3H), 0.16, 3H). 13C NMR (75 MHz, CDCl3) 5 246, 211.3, 146.4, 140.6, 138.3, 133.8,
133.4, 129.7, 128.8, 128.7, 128.4, 128.2, 128.0, 127.7, 127.6, 126.9, 126.8, 125.9, 52.4,

46.8, 39.2, 35.6, 30.4, 22.3, 17.7, 9.5, -3.0, -3.2, -4.6.

O TMS O

p-Meoc6H4\'/\)LTMS WCGWOMe-p

78 79

Wittig rearrangement of 47: Applying representative procedure E for the Wittig
rearrangement of a-alkoxysilanes to 154 mg (0.582 mmol) of a 1:3.25 (reactive syn/less
reactive anti) mixture of 47 afforded a mixture of both [1,2]- and [1,4]-rearrangement
products 78 and 79 in approximately 1.821 ratio and in 93% yield IR (neat) 2959,
1717(w), 1643, 1613, 1515, 1456, 1248 cm". 78: 1H NMR (500 MHz, CDC13) 5 7.04 (d,
J= 8.8 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 2.62-2.55 (m, 1H), 2.52-2.46 (m,
1H), 2.43-2.37 (m, 1H), 1.82-1.75 (m, 1H), 1.72-1.65 (m, 1H), 1.20-1.18 (d, J= 6.8 Hz,
3H), 0.11 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 248.3, 157.8, 138.7, 127.8, 113.7,
55.2, 46.5, 38.5, 30.4, 22.6, -3.2. HRMS (E1) m/z 264.1542 [(M)+; calcd for C15H24028i,
264.1546].

79: IR (neat) 2953, 1715, 1611, 1513, 1456, 1250, 1178 cm". ‘H NMR (500
MHz, CDCl3) 5 7.11 (d, J = 8.3 Hz, 2H), 6.8 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H), 3.75-3.70
(q, J = 7.3, 6.8 Hz, 1H), 2.35-2.24 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 0.73-0.67 (m, 1H),

0.63-0.56 (m, 1H), -0.11 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 212.1, 158.6, 132.9,

116

128.8, 114.2, 55.2, 51.4, 35.5, 17.8, 10.4, -1.9. HRMS (El) m/z 264.1547 [(M)+; calcd

for C15H2402Si, 264.1546].

0 TMS 0

Ph

82 83

Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes
to 530 mg (2.15 mmol) of reactive 48 and 2.30 mL (3.23 mol) of s-BuLi (1.4 M in
cyclohexane) and stirring overnight at -78 °C afforded 347 mg (65%) of 82 and 83 in
approximately 2:1 ratio. IR (neat) cm'l. 82: IR (neat) 2957, 2930, 1717, 1643, 1495,
1452, 1250 cm". 'H NMR (500 MHz, CDCl3) 5 7.27-7.06 (m, 5H), 2.49-2.42 (m, 1H),
2.37-2.31 (m, 1H), 1.95-1.88 (m, 1H), 1.70-1.60 (m, 2H), 1.58-1.49 (m, 1H), 0.74 (t, J=
7.5 Hz, 3H), 0.08 (s, 9H). l3C NMR (125 MHz, CDCl3) 5 248.5, 144.9, 128.3, 128.2,
127.7, 126.0, 47.1, 46.4, 29.7, 28.4, 12.1, -3.2. HRMS (FAB+) m/z 249.1677 [(MH)+;
calcd for C15H250Si, 249.1675].

83: IR (neat) 2957, 1715, 1601, 1493, 1454, 1248 cm". 1H NMR (500 MHz,
CDCl3) 5 7.31-7.19 (m, 5H), 3.56-3.53 (t, J= 7.5, 7.1 Hz, 1H), 2.33-2.25 (m, 2H), 2.06-
2.00 (m, 1H), 1.72-1.66 (m, 1H), 1.41-0.81-0.78 (t, J = 7.5, 7.1 Hz, 3H), 0.74-0.68 (m,
1H), 0.61-0.55 (m, 1H), -0.11 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 211.5, 139.2,
128.7, 128.2, 127.0, 60.1, 36.5, 25.5, 12.2, 10.1, -1.9. HRMS (CI) m/z 248.1590 [(M)+;

calcd for C15H240Si, 248.1596].

117

O TMS C)

86 87
Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes

to 156 mg (0.60 mol) of a 1:1.35 mixture of 50 and 0.6 mL n-BuLi (1.6 M in hexane,
0.90 mol) at -78 °C for 24 h afforded 65 mg (41%) of a mixture of 86 and 87 as light
yellow oils. 86: IR (neat) 2957, 2930, 1719, 1643, 1459, 1452, 1250 cm'l. 1H NMR
(500 MHz, CDC13) 5 7.27-7.07 (m, 5H), 2.48-2.42 (m, 2H), 2.37-2.32 (m, 1H), 1.93-1.86
(m, 1H), 1.69-1.62 (m, 1H), 1.60-1.48 (m, 2H), 1.22-1.10 (m, 2H), 0.81 (t, J = 7.3 Hz,
3H), 0.08 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 248.4, 145.1, 128.3, 127.7, 126.0,
46.4, 45.0, 39.2, 28.8, 20.6, 14.1, -3.2. HRMS (CI) m/z 263.1824 [(M+H)+; calcd for
C16H27OSi, 263.1831]. 87: IR (neat) 2957, 1717, 1493, 1454, 1248 cm". ‘H NMR (500
MHz, CDCl3) 5 7.32-7.20 (m, 5H), 3.67 (t, J = 7.8, 7.3 Hz, 1H), 2.38-2.27 (m, 2H), 2.03-
1.96 (m, 1H), 1.72-1.64 (m, 1H), 1.27-1.14 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H), 0.76-0.69
(m, 1H), 0.64-0.57 (m, 1H), -0.09 (s, 9H). 13C NMR (500 MHz, CDCl3) 5 211.5, 139.4,
128.7, 128.2, 127.0, 58.1, 36.5, 34.5, 20.7, 14.0, 10.2, -1.9. HRMS (CI) m/z 262.1756

[(M)*; calcd for CI6H260Si, 262.1753].

0 TMS (3

h
Ph TMS P

\\ //
88 89

Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes
to 165 mg (0.638 mmol) of 52 and 1.6 mL (2.55 mmol) of n-BuLi (1.6 M in hexanes) at
—78 °C, allowing the reaction to warm to —30 °C and stirring at this temperature for about

30 h, after purification by column chromatography on silica gel afforded 45 mg (32%) of

118

a 4.53:1 mixture of 88 and 89 as light yellow oils. Note: the reported yield is based on
2.64:1 ratio of less reactive anti/reactive syn starting mixture of substrates.

88: IR (neat) 2955, 2926, 1717, 1643, 1495, 1452, 1248 cm". 'H NMR (500
MHz, CDCl3) 5 7.34-7.16 (m, 5H), 5.78-5.60 (m, 1H), 5.00-4.89 (m, 2H), 2.58-2.52 (m,
1H), 2.50-2.45 (m, 1H), 2.39-2.31 (m, 3H), 2.00-1.93 (m, 1H), 1.72-1.64 (m, 1H), 0.09
(6H). 13C NMR (125 MHz, CDCl3) 5 248.1, 144.4, 136.8, 128.4, 127.7, 126.2, 116.0,
46.1, 45.1, 41.4, 27.9, -3.2.

89: 1H NMR (500 MHz, CDCl3) 5 7.31-7.08 (m, 5H), 5.68-5.60 (m, 1H), 5.00-
4.91 (m, 2H), 3.72 (t, J = 7.7, 7.4 Hz, 1H), 2.81-2.75 (m, 1H), 2.65-2.59 (m, 1H), 2.09-
2.02 (m, 1H), 1.86-1.78 (m, 1H), 0.74-0.68 (m, 1H), 0.62-0.56 (m, 1H), -0.11 (s, 9H).
13C NMR (500 MHz, CDCl3) 5 210.6, 135.9, 128.8, 128.2, 128.1, 127.2, 116.6, 58.1,

36.7, 36.5, 10.1, -1.9.

O TMS O
prams Vim.
90 91

Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes
to 66 mg (0.252 mmol) of 53 and 0.39 mL (0.63 mmol) of n-BuLi (1.6 M in hexane) at —
78 °C and allowing the reaction to warm up to 4 °C for 24 h afforded 22 mg (33%) of a
1.8:] mixture of 90 and 91 as light yellow oils. 90: IR (neat)2957, 1719(w), 1643, 1493,
1452, 1250 cm'l. 1H NMR (500 MHz, CDC13) 5 7.26-7.03 (m, 5H), 2.39-2.35 (m, 1H),
2.30-2.24 (m, 1H), 2.20-2.15 (m, 1H), 2.08-2.02 (m, 1H), 1.80-1.73 (m, 1H), 1.71-1.63

(m, 1H), 0.94 (d, J= 6.8 Hz, 3H), 0.68 (d, J= 6.8 Hz, 3H), 0.06 (s, 9H). 13C NMR (125

119

MHz, CDCl3) 5 248.6, 143.8, 128.4, 128.1, 126.0, 52.4, 33.7, 25.2, 20.9, 15.3, -3.3.
HRMS (APCI) m/z 263.1840 [(M+H)+; calcd for C16H270Si, 263.1831]. 91: IR (neat)
2957, 1715, 1454, 1248 cm". 1H NMR (500 MHz, CDCl3) 5 7.29-7.20 (m, 5H), 3.3 (d, J
= 10.2 Hz, 1H), 2.42-2.25 (m, 3H), 0.94 (d, J= 6.3 Hz, 3H), 0.74-0.67 (m, 1H), 0.63 (d, J
= 6.8 Hz, 3H), 0.61-0.54 (m, 1H), -0.11 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 211.7,
138.4, 128.7, 128.6, 127.0, 66.4, 37.8, 30.7, 21.7, 20.4, 9.9, -1.9. HRMS (c1) m/z

262.1755 [(M)+; calcd for C16H2608i, 262.1753].

M TMS OH
Ph TMS MP“

92 93

Applying representative procedure E for Wittig rearrangement of or-alkoxysilanes
to 141 mg (0.60 mmol) of 55 and 0.69 mL (0.90 mmol) of s-BuLi (1.3 M in cyclohexane)
at -78 °C for for 30 min, after purification by column chromatography on silica gel,
afforded 106 mg (75%) of a 4:1 mixture of both [1,4]- and [1,2]-rearrangement products
92 (a light yellow oil) and 93 as a colorless oil.

92: 2959, 2928, 1709, 1641, 14961454, 1250 cm'l. 1H NMR (300 MHz, CDCl3)
5 7.32-7.17 (m, 5H), 2.61-2.50 (m, 2H), 2.47-2.30 (m, 3H), 0.84-0.81 (d, J = 6.6 Hz, 3H),
-0.13 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 248.59, 140.59, 129.20, 128.17, 125.91,
54.94, 43.28, 29.58, 19.90, -3.25. HRMS (EI) m/z 233.1355 [(M-H)+; calcd for

C14H210Si, 233.1362].

93: IR 3432, 2978, 2926, 1454, 1381, 1248, 1121 (neat) cm". ‘H NMR (500
MHz, CDCl3) 5 7.26-7.10 (m, 5H), 5.60-5.56 (dq, J = 15.4, 1.6 Hz, 1H), 5.19-5.12

(apparent dq, J = 15.4, 6.6, 6.0 Hz, 1H), 2.88-2.79 (apparent q, J = 13.2, 7.7 Hz, 2H),

120

1.64-1.62 (dd, J= 6.6, 1.6 Hz, 3H), 0.05 (s, 9H). l3c NMR (125 MHz, CDCl3) 5 136.2,
135.4, 130.6, 127.9, 126.3, 121.62, 70.4, 43.1, 17.8, -4.2. HRMS (E1) m/z 234.1435

[(M)+; calcd for C14H220Si, 234.1440].

TMS OH TMS O
SiMe3
95 96 97

Applying representative procedure E for Wittig rearrangement of a-alkoxysilanes
to 2.91 g (11.62 mmol) of E-56 and 29.05 mL (4.0 equiv, 46.48 mmol) of n-BuLi (1.6 M
in hexanes) at —78 °C and allowing the reaction to warm to —30 °C for 4 d, after
purification by column chromatography on silica gel, afforded 1.66 g (57%) of a mixture
95 and 96 and 97 as colorless oils.

95 (mixture of diastereomers): 1H NMR (500 MHz, CDCl3) 5 7.33-7.13 (m, 10H),
5.76-5.69 (dq, J= 15.4, 1.6 Hz, 1H), 5.62-5.57 (dq, J= 15.4, 1.6 Hz, 1H), 5.33-5.22 (dq,
J= 15.4, 6.6, 6.0 Hz, 1H), 5.18-5.06 (dq, J— 15.4, 6.6, 6.0 Hz, 1H), 3.08-3.00 (q, J = 7.1
Hz, 2H), 3.03-2.96 (q, J = 7.1 Hz, 2H), 1.73-1.70 (dd, J = 6.6, 1.6 Hz, 3H), 1.61 (dd, J=
6.0, 1.6 Hz, 3H), 1.37 (d, J= 7.1 Hz, 3H), 1.32 (d, J= 7.1 Hz, 3H), -0.3 (s, 9H), -0.09 (s,
9H). l3C NMR (125 MHz, CDC13) 5 HRMS (CI) m/z 249.1666 [(M+H)+; calcd for
C15H24OSi, 249.1675].

96: IR 2955, 1715, 1495, 1452, 1250 (neat) cm]. 1H NMR (500 MHz, CDC13) 5
7.32-7.18 (m, 10H), 3.80-3.76 (q, J= 7.3, 6.8 Hz, 1H), 3.74-3.70 (q, J= 7.3, 6.8 Hz, 1H),
2.38-2.36 (dd, J = 3.9, 3.4 Hz, 1H), 2.34-2.33 (dd, J = 3.9, 3.4 Hz, 1H), 2.10-2.06 (m,
2H), 1.39-1.36 (t, J= 6.8, 6.3 Hz, 6H), 1.35-1.10 (m, 2H), 0.82 (d, J= 7.3 Hz, 3H), 0.69
(d, J = 7.3 Hz, 3H), -0.11 (s, 9H), -0.16 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 211.4,

210.8, 140.58, 140.55, 128.81, 128.76, 127.95, 127.88, 127.03, 127.01, 53.5, 52.1, 43.4,
121

43.3, 17.5, 17.4, 15.4, 15.2, 14.6, 14.0, -3.57, -359. HRMS (E1) m/z 248.1594 [(M)+;
calcd for C15H240Si, 248.1596]. 97 was oxidized to the corresponding carboxylic acid

and data are given in Chapter 6.

Ph
OH

104

Preparation of 104: Applying representative procedure E for Wittig
rearrangement of a-alkoxysilanes to 6.66 g (2443 mmol) of E-58 and 61.10 mL (4.0
equiv, 97.74 mmol) of n-BuLi (1.6 M in hexanes) at —78 °C and allowing the reaction to
warm to —30 °C for 4 d, after purification by column chromatography on silica gel,
afforded 2.49 g (37%) of a mixture of all possible Wittig products. 0.60 g of this mixture
was dissolved in THF (4.40 mL) and 3N NaOH (0.4 mL/mmol starting material, 0.88
mL) added. The mixture was heated to 35-40 °C, and then oxidized by adding dropwise
30% H202 (0.20 mL/mmol starting material, 0.44 mL), while maintaining the reaction
temperature below 50 °C for 2 h. The aqueous phase was cooled to 0 °C, and acidified to
pH of 1-2 with 6 N HCl.. The resulting aqueous material was extracted with ether (5 x 20
mL), and the ether solution dried with MgSO4. Filtration and concentration afforded 69
mg of 104 as a thick colorless oil. Purification by column chromatography on silica gel
(hexane/EtOAc (0-10%) afforded 104a and 104b as a near 1:1 mixture of diastereomers
(ratio by lHNMR). IR (neat) 3100-2500 (vs, v br), 2973, 1709, 1642, 1495, 1452, 1414,
1296, 1250 cm". 1H NMR (500 MHz, CDCl3) 5 11.70 (br, 1H), 7.29-7.12 (m, 10H),
5.65-5.01 (m, 2H), 4.99-4.85 (m, 4H), 2.67-2.63 (m, 1H), 2.56-2.22 (m, 9H), 2.08-2.03

(dd, J= 15.1, 8.8 Hz, 1H), 1.95-1.90 (dd, J: 15.1, 9.3 Hz, 1H), 1.05 (d, J= 6.3 Hz, 3H),

122

0.83 (d, J= 6.3 Hz, 3H). 13C NMR (125 MHz, CDCl3) 5 179.9, 179.8, 142.7, 141.5,
136.8, 136.7, 128.9, 128.5, 128.3, 128.1, 126.4, 126.37, 116.1, 116.0, 51.0, 49.8, 39.7,
39.3, 37.1, 36.9, 35.0, 34.2, 17.9, 16.3. HRMS (FAB+) m/z 219.1383 [(MHY; calcd for

(3.4111902, 218.1307].

123

REFERENCES

1. Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. 1997, 1275-1281.

2. Maleczka, R. E., Jr; Geng, F. J. Am. Chem. Soc. 1998, 120, 8551-8552 and references
cited therein.

3. Felkin, H.; Tambute, A. Tetrahedron Lett. 1969, 10, 821-822.

4. Rautenstrauch, V. Helv. Chim. Acta 1972, 55, 594-609.

5. (a) Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y-M.; Szczepanski, S. W. Organic
Synthesis 1988, 66, 14-21. (b) Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y-M.;
Szczepanski, S. W. J. Org. Chem. 1985, 50, 5393-5396.

6. Brook, A. G.; Pascoe, J. D. J. Am. Chem. Soc. 1971, 93, 6224-6627. (b) Brook, A. G.
Acc. Chem. Res. 1974, 7, 77-84.

7. a-Hydroxyallylsilane 32 was obtained in 93% yield when the alcohol was isolated by
distillation at atmospheric pressure.

8. The yield of this alcohol is generally moderate. Kamimura prepared 34 in 43% yield,
see Kamimura, A.; Kaneko, Y.; Ohta, A.; Matsuura, K.; Fujimoto, Y.; Kakehi, A.;
Kanemasa, S. Tetrahedron 2002, 9613-9620.

9. Compounds 51, 52 and 58 were prepared following Rychnovsky’s protocol: Cossrow,
J.; Rychnovsky, S. D. Org. Lett. 2002, 4, 147-150.

10.Ma1eczka, R. E. Jr.; Geng, F. Org. Lett. 1999, I, 1111-1113.

11. Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans. 1 1985, 2247-
2250.

12. In the preparation of E-56 we found that BF3-0Et2 gave better results than TMSOTf.
13. Maleczka and Geng reported that this same reaction catalyzed by TMSOTf-catalyzed
afforded 67% of 42 and the formation of any other compounds was not reported.

Maleczka, R. E. Jr.; Geng, F. Org. Lett. 1999, I, 1115-1118.

14. (a) Jones, T. K.; Denmark, S. E. Org. Synth, Coll. Vol. V11, 1990, 524. (b) Denmark,
S. E.; Jones, T. K. J. Am. Chem. Soc. 1982, 104, 2642.

15. The etherification of an alcohol via the trichloroacetimidate requires for the alcohol
part of the trichloroacetimidate to be activated (benzyl or allyl).

124

16. Reaction of alcohol 32 with MsCl in the presence of 13th in THF at 0 °C afforded the
corresponding mesylate (96%).

17. Kim, H; Lee, C. Org. Lett. 2002, 4, 4369-4371.

18. Aspinall, H. C.; Greeves, N.; Lee, W-M.; Mclver, E. G.; Smith, P. M. Tetrahedron
Lett. 1997, 38, 4679-4682.

19. Hoffmann, R.; Brfickner, R. Chem. Ber. 1992, 125, 1471-1484.
20. Maleczka, R. E. Jr.; Geng, F. Org. Lett. 1999, I, 1115-1118.

21. Schlosser, M.; Strunk, S. Tetrahedron 1989, 45, 2649-2664.

22. Felkin, H.; Tambute, A. Tetrahedron Lett. 1969, No 10, 821-822.

23. Ab initio calculations (Geometry Optimization using RHF/6-31G“ Model) were
performed by Courtney Olmsted; Chemistry Department, Michigan State University.

24. Aizupurua, J. M.; Palomo, C. Science of Synthesis 2002, 4, 595-632.

25. Takai, K.; Yamada, M.; Odaka, H.; Utimoto, K.; Fujii, T.; Furukawa, 1. Chem. Lett.
1995, 4, 315-316.

26. Buynak, J. D.; Strickland, J. B.; Lamb, G. W.; Khasnis, D.; Modi, S.; Williams, D.;
Zhang, H. J. Org. Chem. 1991, 56, 7076-7083.

27. (a) Panek, J. S.; Sparks, M. A. Tetrahedron: Asymmetry 1990, I, 801-816. (b) Picard,
J. P.; Ekouya, A.; Dunogues, J .; Duffaut, N.; Calas, R. J. Organometal. Chem. 1975, 93,
51-70. (c) Dunogues, J .; Ekouya, A.; Duffaut, N.; Calas, R. J. Organometal. Chem. 1974,
66, C36-C38.

28. (a) Akira, S.; Sylke, P.; Takeo, T. Tetrahedron Lett. 1997, 38, 5537-3340. (b) Kenji,
Y.; Hideaki, 0.; Akitami, I. J. Bioscience, Biotechnology, and Biochemistry 1997, 61 ,
1038-1040. (c) Hisanaka, 1.; Toakanori, N.; Takeo, T.; Yuji, H. Tetrahedron 1995, 51,
4507-4518. ((1) Mori, M.; Watanabe, N.; Kaneta, N.; Shbasaki, M. Chem. Lett. 1991, 9,
1615-1618.

29. Fleming, 1.; Mwaniki, J. M. J. Chem. Soc., Perkin Trans. 1. 1998, 1237-1247.

125

CHAPTER 5

STEREOCHEMICAL REQUIREMENTS IN THE WITTIG
REARRANGEMENTS OF a-ALKOXYSILYL ETHERS

5.1. Stereochemical requirements for Wittig substrates

Introduction

As noted in Chapter 4, those Wittig substrates with substitution at the migrating
center were prepared as diastereomeric pairs, in near equal amounts (ratios ranging from
1:1 to 1.3:1.)I It was also noted in the same chapter that under our conditions, a pair of
diastereomers have differential reactivities, with only one diastereomer readily
undergoing the Wittig rearrangement. The appropriate question at this point became,
“Which diastereomer (syn or anti) was undergoing the Wittig rearrangement?” In an

effort to identify the two isomers we resorted to derivatization.

5.2. Derivatization of a—alkoxysilanes 44a and 44b
5.2.1. Synthesis of 2,4-dinitrophenylhydrazone derivatives of 44a and 44b

Carbonyl compounds (aldehydes and ketones) are known to form crystalline
hydrazone derivatives with 2,4-dinitrophenylhydrazine, which are ofien employed in the
identification of this class of compounds. In order to convert compounds 44a and 44b
into their corresponding 2,4-dinitrophenylhydrazones, we oxidized the double bond to

primary alcohols 105a and 105b (97% yield) by hydroboration/oxidation2 (Scheme 5.1).

126

Scheme 5.1. Hydroboration/oxidation of diastereomeric 44a/44b

 

J": 1. 9-BBN (1.0 equiv) Me
THF, 75 °C. 10 h
51:“ = 5° ..
\ 2. EtOH, NaOH 6M
TMS H202 30% HO TMS
44b (97%) 105a,b

pair of diastereomers

Diastereomeric alcohols 105a and 105b were converted into their corresponding

3 The crude aldehydes were

aldehydes 106a and 106b via a modified Swem oxidation.
subsequently converted into hydrazones by reaction with acidified 2,4-dinitrophenyl-
hydrazine at room temperature (Scheme 5.2).4

The two diastereomeric a-alkoxysilanes anti-44a and syn-44b showed different
behaviors with regard to hydrazone formation. Of the two hydrazones formed, one was
the expected product (107) and the other (108) was an elimination product in which the
benzyloxy group was lost. Since 44a could be obtained pure from the Wittig
rearrangement reaction, it was converted to the corresponding alcohol 105a, and
subsequently into the 2,4-dinitrophenyl hydrazone derivatize. We observed that the less
reactive 44a afforded the desired hydrazone 107 as an amorphous solid in 58% yield (mp
129-130 0C) (Scheme 4.31). The reactive 44b, on the other hand, formed the conjugated
hydrazone 108 in 32% yield (reaction was not optimized), bearing a vinyl silyl group
(Scheme 5.2). Recrystallization of 108 from EtOAc afforded the pure compound (m.p.

199.5-200.5 °C). NMR, and single crystal x-ray analysis5 revealed the presence of the

two double bonds (see Figure 5.1 for ORTEP of 108).

127

Scheme 5.2. Derivatization of 44a/44b: conversion to 2,4-dinitrophenylhydrazone

 

 

M M NHNH2
Xe DMSO (5.9 equiv) *6 O
O ph TCT (1.2 equiv) 0 pr. OzN N02
Ho/\/k TMS TEA (4.8 equiv) OM TMS HG)
105a/105b -35 to -30 °C 106a/106b
mixture of
diastereomers
Me
k H
Q OZN N02
OZN N02
107 108
from less reactive anti 443 from reactive syn 44b

     

N(81

J J [F
\J
N19)

Figure 5.1. Single x-ray crystal structure analysis ORTEP view

of 108, 2,4-dintrophenylhydrazone derivative of reactive syn 44b
The difficulty in recrystallizing compound 107 (hydrazone of the less reactive
anti 44a) was an impetus to explore alternatives. We hoped that the hydrazone of the
ketone derivative (rather than the aldehyde derivative) might give better crystals for
single crystal x-ray analysis. Thus, pure anti 44a was subjected to
oxymercuration/demercuration conditions for the purpose of making the secondary

alcohol. However, this venture only led to the hydrogenolysis of the ether to give sec-

128

phenethyl alcohol in 73% yield. The desired secondary alcohol 109 was not obtained

(Scheme 5.3).

Scheme 5.3. Attempted oxymercuration/demercuration of anti 44a

Me

 

 

 

 

 

Me 1. Hg(OAc)2 (1.0 equiv) /|\ Me
0 Ph Me
HZO/THF (1:1), rt
0 Ph , + 0 Ph A
v 2 3M NaOH TMS M P” OH

0

TMS ' 0.5M NaBH4 OH HO TMS (73 /°)
anti-14a 3M NaOH 109 (0%) 105 (0%)

5.2.2. Synthesis of 3,5-dinitrobenzoyl ester of a-alkoxysilanes 44a and 44b

In a further attempt towards establishing the stereochemistry of the reactive and
less reactive Wittig substrates via single crystal x-ray analysis, we converted the
diastereomeric alcohol 105a,b into the corresponding 3,5-dinitrophenyl ester6 110a,b, in
55% yield (Scheme 5.4). The ester products 110a,b were obtained as a oil/solid mixture.
Recrystallization from a 1:1 mixture of absolute ethanolzhexanes7 afford colorless
crystals of 110a (ester of the reactive 44) and an oily mother liquor containing 110b
(ester of the less reactive 44). Converting the alcohol from less reactive 44 to the
corresponding ester gave an oil. This established that the reactive diastereomer gave the
crystalline ester product (mp 745-755 °C). We obtained the single crystal X-ray
structure of this compound (Figure 5.2), which revealed the relative stereochemistry of

reactive 44 to be syn (syn with respect to TMS and Me groups).

129

Scheme 5.4. Derivatization of 44a/44b: conversion to 3,5-dinitrophenylbenzoyl ester

0
Cl e
Me 0 g/kpn
- o N =
0 Ph N02 (2.0 equ1v) 2 O/\/\SiMea

ll

 

HO/VkSiMe-a Pyridine (2.0 equiv)

DAMP (cat), CH2C12. rt
105a/105b 154-51%) N02

1 10a: anti-ester. clear oil
1 10b: syn ester. solid (mp. 74.5-75.5 '0)

(I? "5 cm ' 0‘31“

1 ‘ ‘ um ‘1
C(3) '. " ‘
. ‘ ,. :3;
. J c151 0191 ‘

" s
O . ‘ ‘4
*2 01151 cm '
01171 a ‘-
i * ‘ 01141
01211 . ”$11191 .... . \ )C1161
. 1H \ .
v, . C1181 c123 .
. i) . C(27) 4112‘. 01291
' c1221 ;1 ' 3’ “:1 " i? '
o 0126 .‘
O -. v! I \ v' o
o 1".
C(25) .

Figure 5.2. X-ray crystal structure analysis ORTEP view of 110b,
the 3,5-dinitrobenzoy1 ester derivative of reactive syn 44b
Though we had secured the relative stereochemistry of reactive 44b and could
infer the opposite relative stereochemistry for the less reactive diastereomer, we still
wished to obtain solid evidence to corroborate our results. Amino acids are known to
give crystalline ester derivatives with organic alcohols. Thus, we hoped that the ester

from N-(tert-butoxycarbonyl)glycine and the alcohol from the less reactive 44a would be

130

crystalline, enabling us get the single crystal x-ray analysis on that diastereomer. DCC
mediated esterification of 105a with N-(tert-butoxycarbonyl)glycine in the presence of a
catalytic amount of DMAP afforded the desired ester 111 in 81% yield (Scheme 5.5).
However we were unable to obtain the sought after single crystal x-ray as the ester was a

thick oil.

Scheme 5.5. Boc-glycine ester derivative of less reactive 105a

t-BocNHCHZCOZH

L (1.5 equiv) /L
DCC 1.5 uiv
0 Ph ( eq ) =

o 0 Ph
DMAP 10 w -
HOMTMS ( m° °) 'BWHNdLoNkTMs

CH2CI2, rt, overnight
(80.48%) 1 1 1

 

105a ,
from less reactive anti 44a

5.3. NOE Experiment

In a filrther attempt to establish the stereochemical requirement for the Wittig
rearrangements of a-alkoxysilanes, we reasoned that if we could tie up an acyclic Wittig
substrate into a ring, then we could use NMR experiments (NOE) to determine the
stereochemistries of the reactive and less reactive pair of diastereomers. Toward this aim
we utilized compounds 51 and 52. Compound 52, as reported in section 4.4.2 (and Table
4.2) undergoes rearrangement when its solution in THF is treated with 4.0 equiv. of n-
BuLi at temperatures above -40 °C for 48 h. Only one diastereomer reacts under these
conditions, furnishing the [1,2] and [1,4] products. We found that when a dilute solution
(0.1-0.2 M) of 51 in benzene was heated to 70-80 °C in the presence of a catalytic amount

(10-15 mol%) of Grubbs second generation catalyst, it underwent ring closing metathesis

131

(RCM) to afford six-membered cyclic ethers llZa/b in 94-96% yield (Scheme 5.6).
Diastereomeric 52 was similarly converted to the corresponding six-membered cyclic
ethers 113a/b in 97-99% yield. Then, each of the diastereomers, syn-52 and anti-52, was
subjected to the ring closing metathesis conditions. The spectral data from their
respective products were compared. Stereochemical evidence was obtained from
NOESYID experiments (Figure 5.3) that revealed NOE (1%) between Ha and Hb in the
RCM product resulting from the less reactive diastereomer (113b), an indication of syn
stereochemistry (both protons are on the same face of the molecule). On the other hand,
there was no NOE seen between Ha and Hb in the cyclic ether resulting from the RCM of

the reactive isomer (113b), indicating that the two protons are anti (Figure 5.3).

Scheme 5.6. Ring closing metathesis of 51 and 52

Ph Grubbs 2nd Generation

RMeZSi o . .
j catalyst (10-15mol%) RMGZS' U P“ RMezs'jiojmph
/ > +
I 75-80 °C, benzene, \ \

 

 

24-48 h

R=Ph: 51a/51b R = Ph: 112a 96% yield 1121:

R=Me: 523/52!) R = Me: 113a 91:-99% yield 1131:
1% NOE

65. m.

/
TMS No TMS No “.Ph
U U

113a 113a

NoNOE
Ph

”II

 

 

 

Figure 5.3. NOSEYlD result showing relative stereochemistries in 113a/b

132

Compound 113 stored well in the freezer (no evidence of decomposition was seen
after three months). However, we observed that the cyclic ether was acid sensitive,
decomposing completely within seven days when lefi in CDCl3 (from NMR analysis).
Upon isolation of the decomposition product 1148, we were able to elucidate its structure
by NMR spectroscopy, and it is as shown in Scheme 5.7. The new product is a cyclic
enol ether which features a carbonyl flmctionality (incorporation of an extra oxygen

atom). The mechanism of this reaction is not clear to us at this point.

Scheme 5.7. Decomposition of metathesis product in the presence of CDC13

 

Ph Ph
c0013
0 o
\ TMS \ o
113 114

In the course of our investigation of the ring closing metathesis reaction of 52, we
found that carrying out the reaction in a sealed tube afforded 113 (45%) and a second
product 115 (34%) yield. We elucidated the structure of 115 by 1H NMR, 13C NMR, and
DEPT experiments and is as shown in Scheme 5.8. This compound shows incorporation
of an extra oxygen atom. It also features a carbonyl group conjugated to a double bond

and a vinyl trimethylsilyl group.

Scheme 5.8. Cross metathesis reaction of 52 in sealed tube

 

Ph Grubbs 2nd Generation Ph Ph
catalyst (14 mol%)
0 \ 4 O + 0
75-80 °C, benzene
vms sealed tube, 35 h \ TMS 9 / TMS
52 113 (45%) 115 (34%)

133

5.4. Relative reactivities of a pair of diastereomeric a-alkoxysilanes

In an effort to understand the marked difference in reactivity between the syn and
anti diastereomers under our Wittig rearrangement reaction conditions, a modeling study
was undertaken. For this study, a-alkoxysilane 44 was employed for simplicity and
modeled using the Spartan Ab initio program.9

Geometry Optimization using RHF/6-31G* Model showed that the anti isomer is
lower in energy by 1.44 kcal/mol. The modeling study did not reveal much in terms of
the conformations of the pair of anti/syn diastereomeric 44a/44b. However, analysis of
the data from this study showed that the two diastereomers have slightly different
conformations (Figure 5.4). The dihedral angles were similar (C1C2C3aH of 6° in the syn
conformer and C1C2C301H of 11° in the anti conformer), thus no deductions could be
made base on it. However, the data revealed that the aromatic ring and the double bond
are on the same side of the molecule in syn 44b (Figure 5.4). This suggests a possibility
of n-stacking (C 1-C7 = 3.2 A; C2-C6 = 4.3 A) (Figure 5.4). On the other hand, in the anti
diastereomer 44a, the aromatic ring and the double bond are on opposite sides of the
molecule, with no possibility of n-stacking (C1-C7 = 4.4 A; C2-C6 = 6.1 A) (Figure 5.4).
It appears there is some steric interaction between the TMS group and the aromatic ring
that could result in the molecule being slightly out of plane. Non-planarity means that the
negative charge on the a-carbon (from deprotonation) will not be effectively delocalized
over the pi system (little or no resonance stabilization). The implication of this is that the
a-H in the less reactive anti 44a (dihedral angle C1C2C301H = 11°) will be less acidic than

in the reactive syn diastereomer (dihedral angle C1C2C3aH of 6°). It also would appear

134

that there is some crowding around the a-H that could possibly result in the alkyllithium

base having less access to that proton.

Ha
H'tg NO Mfig
Meow TMS I-bW
TMS TMS

 

Less reactive anti 44a (anti with
respect to TMS and Me groups).
TMS and phenyl ring on same face
of the molecule. Structureshows no
possibility of pi stacking. Steric
interaction betweenTMS and phenyl
groups as well as diaxial interaction
between Me and H01 are also illustrated.

654 5
O 6
W Ha 40Ha

Reactive syn 44b (syn with respect
to TMS and Me groups). Structure
shows possibility of pi stacking and
the accessibility ofHa proton to base.
Minimum steric interaction illustrated.

1
\
7 2 3 TMS %TMS
2
(syn)-44b (anti)-44a
C1CZC3Ha dihedral angle = 6° C1CZC3Ha dihedral angle = 11°

C1-C7 = 3.2 A C1-C7 = 4.4 A
C2-C6 = 4.3 A C2-Ce = 6.1 A

Figure 5.4. Modeling studies of the Wittig substrates 44a and 44b

The single crystal x-ray picture of the ester 110b show the two aromatic rings
facing each other, a conformation that would promote pi-stacking in the molecule, and
corroborates the result from the ab initio calculations for the syn isomer in the preceding
paragraph. However, we were unable to obtain the single crystal x-ray analysis of the
less reactive anti diastereomer for comparison. Nevertheless, from our NOE and single
x-ray analysis results, we can say with certainty that the reactive diastereomer is the syn

isomer (TMS and alkyl groups on same side of the molecule).

135

5.5. Cross metathesis of a-hydrosilanes and a-alkoxysilanes

We would like to point out from the start that this part of the report has little or
nothing to do with the stereochemical requirements of a-akoxysilanes in the Wittig
rearrangement. The opportunity presented itself and we could not let it pass. Following
our success with the ring closing metathesis of compounds 51 and 52, we subjected 42 to
similar metathesis reaction conditions and we were pleased to observe that this substrate
underwent cyclization to afford the expected five-membered cyclic ether 116 in 50-55%
yield (Scheme 5.9). The formation of the five-membered ring product, however, was less
efficient than the formation of six—membered counterparts 112 and 113 from the

cyclization of 51 and 52, respectively (Scheme 5.6, over 95% yield in each case).

Scheme 5.9. Ring closing metathesis of 42

Ph

 

Grubbs 2nd Generation
0V catalyst (10-15 mol%) ph O
vTMS 65-70 °C. benzene UTMS
1 - h
‘2 0 39 116 (50-55%)

We were encouraged by the above results and we wanted to apply cross
metathesis to one of the aims of this research, which was to expand the synthetic utility of
or-alkoxysilanes by developing methods for generating a wide variety of these
compounds for use in Wittig rearrangement reactions. Cross-metathesis with the terminal
olefin of monosubstituted a-silyl ethers would generate a-alkoxysilanes with internal
olefins. Several attempts were made at dimerizing our model substrate 7, as well as
cross-metathesis of this substrate with a number of partners. Dimerization using first

generation Grubbs catalyst (bis(tricyclohexylphosphine) benzylidine ruthenium (IV)

136

dichloride) did not give the expected dimer 117, instead a non-silylated, heavily
chlorinated compound 118 was isolated, the structure of which was elucidated by 1H

NMR, ”C NMR and DEPT and is as shown in Scheme 5.10.

Scheme 5.10. Attempted Dimerization of model substrate 7

Cl. 130”
Cl'R'uaPh
A 1301/3 TMS (:1
0 Ph 35 mol% A 0 Ph
v CH Cl A = Ph 0 / V Ph Cl
TMS 2 2. TMS Cl

7 42-46°C, 118 h

 

117 (0%) 118 (17%)

Cross-metathesis of compound 7 with styrenelo in the presence of second
generation Grubbs catalyst (tricyclohexylphosphine[1,3-bis(2,4,6,-trimethylphemyl)-4,5-
dihydroimidazol-Z-ylidene][benzylidine]ruthenium(IV)dichloride) resulted in the
quantitative formation of trans-stilbene. No crossed product 119 was observed (Scheme

5.11).

Scheme 5.11. Cross-Metathesis of model substrate 7 with Styrene

Mes-Nl/\N—Mes

eff

CVR'uaPh
/\ PCY3
0 Ph 35 mol%

TMS
+ /\ > mph
Ph \
vms CH2CI2. A PhMOAPh P"
7 42-46°C, 118 h

 

1 19 (0%) Quant

137

Cross-metathesis of compound 7 with acrylonitrilell was also attempted, but no
product was observed.

We thought that a good alternative route to a-alkoxysilanes possessing internal
double bonds would be to employ a-hydroxysilanes 32 in the cross-metathesis reaction to
produce new or-hydroxysilanes featuring internal double bonds, which we could then
etherify to obtain the a-alkoxysilanes. When 32 was treated with first generation Grubbs
catalyst (10 mol%, 0.005M in CHzClz, 40-44 °C), the product isolated was identical ('H-
NMR, 13'C-NMR and GC-MS) to the product (118) isolated from the attempted
dimerization of 7 (Scheme 5.12). This time, the formation of the product required less
catalyst loading (10 mol%) and shorter reaction time (78 h), than with 7 (35 mol% and
118 h).

The observation that the attempted dimerization of both a-alkoxysilane 7 and or-
hydroxysilane 32, mediated by the same catalyst, gave the same product, seemed to
indicate that the product might be either coming from the catalyst, and since the product
is heavily chlorinated (from GC-MS), the solvent, CHzClz, might be participating in the

reaction.

Scheme 5.12. Metathesis Dimerization of 32

Chg?“
CI' =\

I
P0113 P“ TMS Cl
OH 35 mol% OH

+- /
vms CH%C|2, A HO . Ph Cl
32 42-46 c, 68 h S'Mea 0'
120 (0%) 118 (17%)

 

138

A search of the literature revealed the ability of low-valent ruthenium complexes
to catalyze electron transfer reactions is known.”16 Ru(II) catalyzes the radical addition
of carbon tetrachloride or chloroform to olefins (Kharasch addition reaction).12 The first
report of this reaction employed (Ph3P)2RuC12 as the catalyst.13 Subsequently Grubbs
ruthenium catalyst,14 Cp"'Ru(Ph3P)2Cl,15 and ruthenium-carborane phosphine complexes
have been used.16 For example, Grubbs first generation catalyst has been reported to
catalyze the addition of chloroform to styrene to afford the product 121 quantitatively

(Scheme 5.13).

Scheme 5.13. Ruthenium Catalyzed Addition of Chloroforrn to Styrene

 

Cl, 130”
CI'R'uaPh
PCYa CI
©/\ (2.5%) _ CIZHC
CHCl3, 65 °c
(100%)
121

In Kharasch addition reaction, the ruthenium acts as the carrier of the halogen in a
reversible redox process. Initially, the transition metal species, M", abstracts a halogen
atom X from the organic halide, R-X, to form the oxidized species, MMIX, and the
carbon-centered radical R*. Subsequently, the radical, R*, reacts with alkene with the
formation of the intermediate radical species R-Rl“. The reaction between M"+'X and
R-R1* results in the target product R-Rl-X, and regeneration of the reduced transition-
metal species, M“, which further reacts with R-X and promotes a new redox cycle

(Scheme 5.14).

139

Scheme 5.14. Mechanism of the Kharasch Addition Reaction

R-X + Mn R. + Mn+1x

ll

 

R/\,/R1 + Mn+1 x —_ R/YR1
X

One of the coupling partners we investigated in the cross-metathesis reaction is
undec-lO-enoic acid ethyl ester. However, this too, did not undergo the desired cross-
metathesis. Following our success in the ring closing metathesis of 42, 51, and 52, we
decided to lock the two reacting olefins in one molecule and look to effect an RCM of the
resulting compound. The requisite substrate 12217 was prepared in two steps starting
from undec-lO-enoic acid ethyl ester. Hydrolysis of the ester with 10% NaOH, followed
by coupling of the resulting carboxylic acid and 32 afforded the desired ester 122 in 92%
yield (Scheme 5.15). However, when this ester was employed in the cross metathesis
reaction, the expected reaction failed to occur. A plausible explanation could be the ring
size of the expected lactone product. If the intramolecular cross metathesis occurred, the
resulting product would be a l3-membered ring lactone, which in our opinion would not

be very favorable.

Scheme 5.15. Preparation of undecanoic acid ester of 32

DCC (1.2 equiv)

 

OH O DMAP (10 mol%) Me3Si O
\/‘\ . + if v
SIMe3 HO 8 \ CHzclz, 0-23 0C O 8 \
32 4 h 122
(92%)

140

5.6. Conclusions

We have been able to establish the relatively stereochemistry of the pair of
diastereomeric a-alkoxysilanes undergoing the Wittig rearrangement. The reactive
diastereomer has the syn relative stereochemistry (or-TMS and benzylic alkyl substituent
on the same face of the molecule) while the less reactive diastereomer has the anti
relative stereochemistry. We could do this as a result of the differential reactivities of a
pair of diastereomers which we observed in the course of this research. Under our
standard Wittig conditions, the anti diastereomer undergoes the rearrangement while the
syn diastereomer does so only very sluggishly, thus affording an efficient tool for
separation of the two diastereomers. The difference in the chemical properties between
the pair of diastereomers also extends to their reactions with other compounds. In this
chapter, we noted that the reactive 44b formed a crystalline hydrazone after eliminating
the sec-phenethyl group whereas the less reactive diastereomer formed the expected
hydrazone as an amorphous solid. With regard to the formation of 3,5-dinitrobenzoate,
the reactive diastereomer (anti stereochemistry) formed a crystalline solid whereas the
ester of the less reactive diastereomer (syn stereochemistry) was a clear oil.

We were also able to accomplish the Ru-catalyzed ring closing metathesis of 01-
alkoxysilanes using Grubbs catalyst efficiently. This is an important addition to literature
considering that such cyclizations are usually difficult to effect under Ru catalysis.

At this point in our study we thought that we were ready to tackle the issue of the
mechanism of the Wittig rearrangements of a-alkoxysilanes. We were particularly
interested in the mechanism of the [1,4]-Wittig. As mentioned in Chapter 1 of this

dissertation, very little is known about the mechanism of the [1,4]-Wittig rearrangement

141

of allyl alkyl ethers as this pathway is still beclouded by many controversies. In Chapter

6 we will discuss our results in this regard.

142

EXPERIMENTAL

Me
0 Ph

HOA/kTMS

1053!!)

Preparation of 105a/b: A 100 mL round-bottomed flask equipped with a
magnetic stir bar and a N2 line was charged with 9-BBN (0.5 M solution in THF, 2.04
mL, 1.02 mmol) and the mixture refluxed. The substrate 44 (671 mg, 2.85 mmol) was
then added as a THF solution (0.57 M) and the reaction refluxed at oil bath temperature
of 90 °C, for 10 h. Reaction mixture was cooled to 55 to 65 °C and EtOH (2.0 mL),
NaOH (6 M, 0.5 mL) and H202 (30%, 1.0 mL) added. The reaction was stirred at 55 to
65 °C for 1 h and cooled to room temperature. The aqueous phase was saturated with
K2C03, phases were separated, organic phase dried over anhydrous K2CO3 and
concentrated to afford the crude product. Purification by silica gel (hexanes/EtOAc (0-
10%)) gave 702 mg of pure 105a/b in combined 97% yield. IR (neat) 3370, 2955, 2928,
1452, 1371, 1248 cm“. 1H NMR (300 MHz, CDCl3) 5 7.38-7.26 (m, 10H), 4.59-4.53 (q,
J = Hz, 1H), 4.39-4.32 (q, J = Hz, 1H), 3.89-3.75 (m, 2H), 3.52-3.44 (m, 2H), 3.20-3.20
(m, 2H), 2.21-2.09 (m, 3H), 1.68-1.59 (m, 5H), 1.43-1.41 (d, 7H), 0.09 (s, 9H), -0.07 (s,
9H). 13C NMR (300 MHz, CDCl3) 5 143.53, 143.47, 128.5, 128.2, 127.8, 127.5, 126.8,
126.7, 77.9, 76.4, 70.0, 69.0, 62.3, 61.3, 34.6, 33.7, 31.7, 27.4, 23.6, 23.5, 22.6, -2.5, -2.8.
Reactive: HRMS (EI) m/z 253.1627 [(M+H)+; calcd for C14H2502Si, 253.1624]. Less
reactive anti-105b: IR (neat) 3358, 2955, 2928, 1493, 1452, 1371, 1248 cm". 1H NMR

(500 MHz, CDCl3) 5 7.34-7.22 (m, 5H), 4.58-4.54 (apparent q, J = 6.8, 6.3 Hz, 1H),

143

3.89-3.84 (m, 1H), 3.80-3.75 (m, 1H), 3.23 (t, J = 5.4, 4.9 Hz, 1H), 2.20-2.12 (m, 1H),
1.67-1.60 (m, 1H), 1.42 (d, J = 6.8 Hz, 3H), .07 (s, 9H). 13(3 NMR (500 MHz, CDC13) 5
143.5, 128.2, 127.5, 126.8, 76.4, 70.1, 62.5, 34.6, 31.7, 23.7, -2.8. HRMS (E1) m/z

253.1618 [(M+H)+; calcd for C14H2502Si, 253.1624].

16
DEW“: DMM
02N N02 02N N02
107 108

Preaparation of hydrazone 107 and 108: To a cold (-35 to -30 °C) solution of
2,4,6-trichloro[1,3,5]-triazine(cyanuric chloride) (158 mg, 0.86 mmol) in THF, was
added DMSO (0.30 mL, 328 mg, 4.20 mmol) and the mixture stirred for 30 min. A 0.1M
THF solution of the substrate 105 (181 mg, 0.72 mmol) was added very slowly and the
reaction stirred for 30 min. Then TEA (0.48 mL, 345 mg, 3.41 mmol) was added. After
stirring for additional 20 min, the reaction was warmed to room temperature. The solvent
was removed under vacuum and B20 added to the solid formed. Reaction was quenched
by adding HCl (1 M, 2.0 mL). Phases were separated and the organic phase washed with
NaHCO3 (aq, sat), followed by brine, dried over Na2SO4 and the solvent evaporated to
yield an aldehyde intermediate, which was treated with an acidic solution of 2,4-
dinitrophenylhydrazine to afford 80 mg (25%) of a mixture of hydrazones (yellow
amorphous and orange crystals). Recrystallization from EtOAc afforded orange crystals.

107: IR (neat) 3287, 2955, 2918, 1618, 1593, 1520, 1335, 1306, 1271, 1072 cm].
1H NMR (500 MHz, CDCl3) 5 11.02 (s, 1H), 9.11 (d, J = 2.7 Hz, 1H), 8.30-8.27 (dd, J =

9.5, 2.6 Hz, 1H), 7.92-7.89 (d, J= 9.5 Hz, 1H), 7.54 (t, J = 6.0, 5.7 Hz, 1H), 7.34-7.26

144

(m, 5H), 4.54-4.50 (q, J = 6.6, 6.4 Hz, 1H), 3.24 (t, J = 5.7, 5.5 Hz, 1H), 2.89-2.83 (m,
1H), 2.62-2.56 (m, 1H), 1.39 (d, J = 6.4 Hz, 3H), -0.04. 13c NMR (125 MHz, CDCl3) 5
151.5, 130.0, 128.4, 127.7, 126.9, 123.5, 116.4, 76.6, 67.4, 33.5, 24.2, -3.1. HRMS (El)
m/z 431.1749 [(MH)+; calcd for C20H27N4OSSi, 431.1751]. (mp 1995-2005 °C ).

108: IR (neat) 3291, 1618, 1516, 1416. 1371, 1321, 1267, 1080 cm". 1H NMR
(500 MHz, CDCl3) 5 11.10 (s, 1H), 9.11 (d, J= 2.4 Hz, 1H), 8.31-8.29 (dd, J= 10.2, 8.8,
1.9 Hz, 1H), 7.94 (d, J = 9.3 Hz, 1H), 7.72 (d, J: 9.3 Hz, 1H), 6.79-6.73 (dd, J: 19.0,
18.5, 9.3, 8.8 Hz, 1H), 6.52-6.48 (d, J= 18.5 Hz, 1H), 0.15 (s, 9H). 13(3 NMR (125 MHz,
CDCl3) 5 151.0, 146.2, 144.7, 138.9,130.0, 123.4, 116.7, -1.7. HRMS (131)an 308.0935
[(M)+; calcd for C12H16N4O4Si, 308.0941]. (mp 129-130 °C)

Me

O O/k Pl‘l
02N\©/Ko/\/l\ TMS
N02

. 110a/110b
Mixture of diastereomers

Preparation of the ester 110 (mixture of diastereomers): A mixture of the
substrate alcohol, 105 (201 mg, 0.80 mmol), 3,5-dinitrobenzoyl chloride (366 mg, 1.59
mmol) in pyridine as solvent, was heated to reflux for 52-55 h. Then the solvent was
removed under reduced pressure and the crude product purified by chromatography on
silica gel (hexanes/EtOAc (0-10%) to afford 194 mg, 55% of the expected ester 110 as a
solid/oil mixture. Separation by crystallization from a 1:1 EtOH/hexane mixed solvent
afforded product as colorless crystals. IR 2961 1732, 1630, 1547, 1462, 1344, 1279,

1250, 1167 cm".

145

Reactive syn 110b: 1H NMR (300 MHz, CDCl3) 5 9.22-9.16 (m, 2H), 8.88 (d, J=
2.2 Hz, 1H), 7.33-6.96 (m, 10H), 4.59446 (m, 310, 4.37-4.29 (m, 2H), 4.19410 (m,
1H), 3.25-3.20 (dd, J= 8.2, 7.7 Hz, 1H), 3.16-3.13 (apparent t, J= 6.6, 5.0 Hz, 1H), 2.30-
2.20 (m, 1H), 2.03-1.95 (m, 1H), 1.90-1.83 (m, 2H), 1.43-1.40 (dd, J= 6.6, 6.0 Hz, 6H),
0.15 (s, 9H), 0.02 (s, 9H). 13C NMR (125 MHz, CDCl3) 5 162.2, 148.4, 143.8, 134.0,
129.2, 128.2, 127.4, 126.7, 122.0, 78.1, 66.7, 64.4, 30.6, 23.6, -2.7. (Mp. 74.5 — 75.5 °C).

Less reactive anti-110a: m.p. 74.5-75.5 °C. IR (neat) 2957, 1728, 1630,1543,
1348, 1279, 1246 cm". 1H NMR (300 MHz, CDCl3) 5 9.17 (t, J= 2.2 Hz, 1H), 8.88 (d, J
= 2.2 Hz, 2H), 7.29-6.99 (m, 5H), 4.36429 (m, 2H), 4.18410 (m, 1H), 3.25-3.20 (dd, J
= 8.0, 6.0 Hz, 1H), 1.90-1.83 (m, 2H), 1.41 (d, J= 6.3 Hz, 3H), 0.15 (s, 9H). 13C NMR
(500 MHz, CDCl3) 5 162.2, 148.4, 143.9, 134.0, 129.2, 128.2, 127.4, 126.7, 122.1, 78.1,
66.7, 64.4, 30.6, 23.6, -2.7. HRMS (Electrospray) m/z 447.1599 [(M+I-I)+; calcd for

C21H27N2O7Si, 447.1587].

0 OiPh
t-BocHNdLOA/kTMS

111
Preparation of ester 111: A solution of less reactive anti-105 (128 mg, 0.506
mmol), N-(tert-butoxycarbonyl)glycine (1.5 equiv, 133 mg, 0.758 mmol), and DMAP (10
mol%, 6 mg, 0.051) in CH2C12 57.0mL) was cooled to 0 °C. Then a solution of DCC
(1.5 equiv, 157 mg, 0.758 mmol) in CH2Cl2 (2.0 mL) was added slowly via syringe.
Following this addition, the cold bath was removed and reaction warmed to room
temperature. Reaction was stirred at room temperature overnight, then filtered to remove

the urea by-product. The filtrate was washed with 0.5 M HCl and NaHCO3 (aq. sat), and

146

dried over MgSOa. Filtration and removal of solvent in vacuo, and then purification by
column chromatography on silica gel afforded 167 mg of anti-111 as a thick colorless oil
in 81% yield. IR (neat) 3374, 2976, 2932, 1753, 1721, 1512, 1454, 1368, 1250, 1169 cm'
1. 7.31-7.24 (m, 5H), 5.00 (bs, 1H), 4.45-4.39 (q, J = 12.9, 6.6, 6.3 Hz, 1H), 4.27-4.22 (t,
J = 7.4, 7.1 Hz, 2H), 3.90 (d, J= 5.5 Hz, 2H), 3.05-3.01 (t, J= 6.3, 5.5 Hz, 1H), 2.09-
1.97 (m, 1H), l.87-1.76 (m, 1H), 1.44 (s, 9H), 1.37, (d, J = 6.6 Hz, 3H), -0.9 (s, 9H).
170.2, 155.5, 143.8, 128.1, 127.3, 126.7, 80.0, 76.5, 66.5, 63.3, 42.5, 29.6, 28.4, 23.9, -

2.9. HRMS (EI) m/z 410.2370 [(M+H)+; calcd for C21H35N058i, 410.2363].

Ph

0’
\ "’SiMezPh

112

Preparation of 112: General method F for metathesis reactions. A mixture of
less reactive anti-51 (89 mg, 0.28 mmol) and Grubbs second generation Ru catatyst (15
mol%, 35 mg, 0.04 mmol) in benzene (2.0 mL, 0.14 M) was heated to 70-77 °C for 10 h.
Reaction mixture was allowed to cool to room temperature, concentrated on the rotavap
and purified on silica gel to afford 88 mg (0.26 mmol, 94%) of trimethyl-(6-phenyl-5,6-
dihydro-2H-pyran-2-yl)-silane, 112. IR (neat) 3069, 3028, 2957, 2920, 1620, 1495,
1452, 1427, 1248, 1113 cm". lH NMR (300 MHz, CDCl3) 5 0.40, (s, 3H), 0.42 (s, 3H),
2.11-2.29 (m, 2H), 4.42-4.46 (m, 2H), 5.75-5.96 (m, 2H), 7.23-7.75 (m, 10H). 13C NMR
(300 MHz, CDCl3) 5 -5.79, -5.00, 34.10, 71.25, 75.49, 121.46, 125.54, 126.89, 127.59,
127.63, 128.03, 129.14, 134.11, 136.61, 143.76. HRMS (FAB+) m/z [(M+) 294.1441;

calcd for C19H22OSi, 294.1440].

147

Ph

(kl)
\ TMS

113
Preparation of 113: Applying general method F to 162 mg (0.63 mmol) of a
2.64:1 (cis/trans) diastereomeric 52 (ratio determined by GC-FID), and 80 mg (15 mol%,
0.094 mmol) of catalyst in 6.0 mL of benzene (0.104 M) at 75-80 0C for 10 h afforded,
after silica gel chromatography, 146 mg (quant) of 3.31:1 diastereomeric 113. IR 2957,
2774, 1604, 1493, 14521383, 1248 (neat) cm".
Less reactive anti-113a: 1H NMR (300 MHz, CDCl3) 5 7.40-7.23 (m, 5H), 5.85-
5.76 (m, 2H), 4.75-4.71 (t, J= 5.7, 5.3 Hz, 1H), 4.04-4.02 (m, 1H), 2.43-2.39 (m, H), 0.1
(s, 9H). 13C NMR (300 MHz, CDC13) 5 142.0, 128.1, 128.0, 127.1, 126.5, 119.9, 72.3,
70.1, 30.2, -2.8. HRMS (FAB+) m/z [(M-H)+ 231.1206; calcd for C14H190Si, 231.1205].
Reactive syn-113b: 1H NMR (300 MHz, CDCl3) 5 7.36-7.21 (m, 5H), 5.85-5.57
(m, 2H), 4.42-4.37 (dd, J = 9.7, 3.5 Hz, 1H), 4.19-4.15 (m, 1H), 2.28-2.10 (m,2H), 0.09
(s, 9H). 13C NMR (75 MHz, CDCl3) 5 143.9, 128.02, 127.97, 126.9, 125.5, 121.0, 75.3,

711.6, 34.2, -3.9.

Formation of 114: Allowing a CDCl3 solution of 113 to sit on the bench for
about 7 days resulted in complete conversion to decomposition product 114.8 IR 2912,
1721, 1495, 1454, 1383, 1248 (neat) cm". 1HNMR (CDC13, 500 MHz) 5 7.41-7.32 (m,

5H), 6.97-6.93 (m, 1H), 6.14-6.11 (ddd, J= 9.9, 2.5, 1.1 Hz, 1H), 5.45-5.42 (dd, J= 11.3,

148

4.7 Hz, 1H), 2.57-2.69 (m, 2H). '3(: NMR (CDC13, 125 MHz) 5 164.2, 145.1, 138.3,
128.6, 128.5, 125.9, 121.4, 79.2, 31.5. HRMS (Methane CI) m/z 174.0680 [(M)*; calcd

for C11H1002 174.0681].

Ph

0

o /TMS

115

Cyclization product 115: Applying representative procedure F to 235 mg (0.91
mmol) of 52 and 110 mg (0.130 mmol) of Grubbs second generation Ru catalyst in C6H6
in a sealed tube and heating to 80 °C for about 30 h, gave a mixture of 113 and 115 which
was readily separable by column chromatography on silica gel (hexanes/EtOAc 0-5%) to
afford 94 mg (45%) of 113 and 75 mg (34%) of 115 as colorless oils. 115: IR (neat)
2959, 1667, 1557, 1497, 1454, 1304, 1250, 1234 1070 (neat) cm'l. lHNMR (CDC13, 300
MHz) 5 7.41-7.33 (m, 5H), 5.72 (d, J= 1.0 Hz, 1H), 5.33-5.30 (dd, J= 14.6, 3.5 Hz, 1H),
2.81-2.74 (dd, J= 16.8, 14.1 Hz, 1H), 2.64-2.0 (ddd, J= 16.8, 3.5, 1.3 Hz, 1H), 0.21 (s,
9H). 13C NMR (CDCl3, 300 MHz) 5 191.7, 185.7, 139.0, 128.7, 128.4, 125.9, 114.1,

80.6, 43.4, -3.02. HRMS (El) m/z 246.1068 [(M)+: calcd for CI4H1302Si, 246.1076].

Ph

0

\
TMS

116
Preparation of 116: Applying the above representative method to 325 mg (1.32
mmol) of 42, and 112 mg (0.132 mmol) of catalyst in 7.0 mL of benzene (0.19 M) at 75-

78 0C for 36-48 h afforded 198 mg (69%) of the five-membered cyclic ether 116.

149

116a: A clear oil. IR (neat) 2957, 2929, 1599, 1493, 1449, 1250, 1097 cm". 'H
NMR (300 MHz, CDCl3) 5 7.39-7.21 (m, 5H), 5.54-5.47 (dd, J: 10.7, 7.7 Hz, 1), 5.14 (t,
J: 2.5 Hz, 1H), 3.14-3.04 (ddd, J: 11.0, 2.5 Hz, 1H), 259-250 (dd, J= 8.0, 7.7, 2.7 Hz,
1H), 0.20 (s, 9H). 13C NMR (75 MHz, CDCl3) 5 162.1, 144.1, 128.3, 127.2, 125.3,

109.9, 82.9, 39.8, -2.1. HRMS (FAB+) m/z [(M+H)+ 219.1204; calcd for C13HtoOSi,

219.1205].

116b: A shiny white fluffy solid. IR (neat) 2957, 1597, 1495, 1452, 1248, 1072
cm". 'H NMR (300 MHz, CDCl3) 5 7.37-7.27 (m, 5H), 6.05-6.01 (dt, J= 6.04, 2.0 Hz,
1H), 5.73-5.70 (dt, J= 7.1, 6.7, 2.2 Hz, 1H), 5.67-5.63 (ddd, J = 3.0, 2.7 Hz, 1H), 4.80-
4.75 (ddd, J = 3.9, 2.8, 1.9 Hz, 1H), 0.09 (s, 9H). 13C NMR (75 MHz, CDCl3) 5 137.2,

128.9, 128.3, 127.5, 126.5, 126.4, 88.6, 82.7, -3.7.

150

REFERENCES

1. Except in the case of 47 which was obtained in 3.25:1 ratio in favor of the less reactive
diastereomer.

2. Brown, H. C.; Knights, E. F .; Scouten, C. G. J. Am. Chem. Soc. 1974, 96, 7765-7770.
3. De Luca, L; Giacomelli, G; Porcheddu, A. J. Org. Chem. 2001, 66, 7907-7909.

4. (a) Karabatsos, G. J .; Graham, J, D.; Vane F. M. J. Am. Chem. Soc. 1962, 84, 753-755.
(b) Karabatsos, G. J. Shapiro, B. L.; Vane, F. M.; Fleming, J. S.; Ratka, J. S. J. Am.
Chem. Soc. 1963, 85, 2784-2788. (c) Binding N.; Muller, W.; Witting, U. Fresenius J.
Anal. Chem. 1996, 356, 315-319 (d) Behforouz, M.; Bolan, J. L.; Flynt, M. S. J. Org.
Chem. 1985, 50, 1186-1189.

5. Single crystal x-ray analysis was performed by Dr. Rui Huang of the Chemistry
Department, Michigan State University.

6. John A. Landgrebe, Theory and Practice in the Organic Laboratory. Second Edition.
D. C. Heath and Company. Lexington, Massachusetts, Toronto. P. 472.

7. Brown, H. C.; Ikegami, S.; Vander Jagt, D. L. J. Org. Chem. 1985, 50, 1165-1171.

8. (a) Tezuka, K.; Inoue, I. J. M01. Catalysis A: Chemical 1998, 129, 199-206. (b)
Sumida, S.; Ohga, M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc. 2000, 122, 1310-1313.
(c) Ghosh, A. K.; Cappiello, J .; Shin, D. Tetrahedron Lett. 1998, 39, 4651-4654.

9. Ab initio calculations were performed by Courtney Olmstead; Chemistry Department,
Michigan State University.

10. Crowe, W. B; Zhang, Z. J. J. Am. Chem. Soc. 1993, 115, 10998-10999.
11. Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 5162-5163.
12. Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001, 101, 2067-2096.

13. (a) Bland, W. J .; Davis, R,; Durrant, J. L. A.; J. Organometal. Chem. 1985, 280, 397.
(b) Matsumoto, H.; Naleano, T.; Takasu, K.; Nagai, Y. J. Org. Chem. 1978, 43, 1734. (c)
Matsumoto, H.; Nikaido, T.; Nagai, Y. Tetrahedron Lett. 1975, 899. d) Matsumoto, H.;
Nikaido, T.; Nagai, Y. Tetrahedron Lett. 1973, 5147.

14. (a) Tallarico, J. A.; Malnick, L. M.; Snapper, M. L. N. J. Org. Chem. 1999, 64, 343.
(b) Simal, F.; Dempnceau, A.; Noels, A. F. Tetrahedron Lett. 1999, 40, 5689.

15. Simal, F.; Wlodarczk, L.; Demonceau, A. Tetrahedron Lett. 2000, 41, 6071.

151

16. Simal, F.; Sebille, S.; Demonceau, A.; Noels, A. F .; Nunez, R.; Abad, M.; Teixidon,
F .; Vinas, C. Tetrahedron Lett. 2000, 41, 5347.

152

CHAPTER 6

ON THE MECHANISM OF [1,4]-WITTIG REARRANGEMENT
OF a-ALKOXYSILANES

6.1. Trapping of Carbanion of model substrate 7

In Chapter 2 of this dissertation we showed that the Wittig rearrangement of or-
alkoxysilane 7 was initiated by deprotonation of the a-proton with alkyllithium bases.
Thus we asked if deprotonation was concurrent with rearrangement? If the two events
were not concurrent, the next question would be if it were possible to hold the

intermediate carbanion 123 (Scheme 6.1) long enough to trap it with an electrophile?

Scheme 6.1. Generating and trapping the carbanion of model substrate 7

/\

 

OAPh :B OAPh o 0 Ph
7 123
E OAPh oAph

 

ll
/
+
rn
%—
...
Z
0‘)

TMS
E

To answer the question of whether or not deprotonation and rearrangement of 01-
alkoxysilanes are concurrent or separate events we searched the literature for precedence.
We found that in 1989 Schlosser and Strunkl had reported experimental conditions that
allow virtually quantitative metalation of allyl ethers without simultaneous [1,2] and [1,4]
rearrangements. This involved generating organometallic intermediates 124 [M = Li]

with sec-BuLi in THF at -75 °C for 1 h, and trapping with TMSCl (addition of TMSCl at

153

-75 °C and allowing to warm to 25 °C for 1 h) to afford alkyl 3-trimethylsilyl-1-propenyl
ethers with high yields (Scheme 6.2). They also reported that when the solutions
containing intermediate 124 were stored 2 h at -25 °C before being acidified, no allyl or
propenyl ethers remained. However in these cases only small quantities of the putative
product aldehydes or alcohols were detected. Moreover many attempts to improve the

mass balance failed.

Scheme 6.2. Trapping of carbanion of allyl ethers by Schlosser and Strunkl

R1 R2 1. sec-BuLi (1.12 equiv) R1 R2 R1 R2

0&5, -75°C,THF, 1 h > (VS/R4 TMS CVKVR‘

V R3 2. TMSCI(1.2 equiv) \M/J R3 V R3
-75 to 25 °C, 1 h 124

M = Li; R1, R2, R3, R4 = H or alkyl

 

 

Taking a lead from the above named authors, we decided to employ TMSCl as
our elecrophile. However, the rearrangement of 7 at -78 °C was very facile, being
complete in about 30 min, and attempted trapping only afforded 8. We were able to get
around this problem by initiating the Wittig rearrangement reaction in the presence of the
electrophile (Scheme 6.3). Thus, treatment of a cold (-78 oC) mixture of 7, and TMSCl
(2.0 equiv)/I‘EA (2.0 equiv) with sec-BuLi (2.0 equiv; very slow addition), stirring at this
temperature for l h, followed by an aqueous workup, resulted in the formation of three
products. The ratio of these products depended on the mode of addition of the base.

Slow addition of base (1.0 le70 min) gave a very clean reaction that resulted in
the formation of a single product 125 in 55% yield (Scheme 6.3). Formation of the

observed product could be rationalized as arising from or-deprotonation leading to a

154

resonance-stabilized allylic anion, followed by selective capture of the electrophile at the

less hindered carbon (second reaction of Scheme 6.3).

Scheme 6.3. Deprotonation and Trapping of carbanion of 7

 

 

1. TMSCI (4.0 equiv) TMS
A TEA (4.0 equiv)
0 Ph THF1'75°C TMS OAPh TMS OAPh TMS 0 Ph
% + +
\ TMS 2. s-BuLi (2.0 equiv) / TMS TMS / TMS / TMS
-75°c, 1.511
7 125 126 127
1”
0 Ph s-BuLi OAPh e o/‘Ph TMSC. TMS oAph
%TMS -Ha Vdms %ms / ms
7 123 125

More rapid addition of base (approximately 1.0 mL/35 min) resulted in the
formation of a mixture of three compounds, 125, 126, and 127 in a combined 66% yield,
with 125 as the major product. However, fast addition of the base (beyond 1.0 mL/35
min) under similar reaction conditions led to the formation of a mixture of three
compounds, with 127 as the major product, followed by 126. It is likely that on slow
addition of base, compound 125 is formed initially, and subsequently undergoes further
deprotonation to afford 126 and 127 (Scheme 6.3). Once 125 is formed, there seems to
be competition for the removal of protons Hb and He (refer to Scheme 6.4). Compound
126 could result from two pathways (Scheme 6.4): (1) selective removal of Hc followed
by Silylation (path a) or (2) selective removal of Hb, [1,5]-Hc migration, perhaps
promoted by the ability of the two silyl groups to stabilize the resulting anion followed by

Silylation (path b). It should be noted that formation of a dianion from 125 is a possibility

155

that we are not ruling out at this time. However, generation of a dianion would result in

the formation of a tetrasilylated product 128, which was not observed (Scheme 6.4).

Scheme 6.4. Plausible fate of compound 125

 

  

Hb Hb o
/\
Ki P“ '”° U P" '“b M P"
TMS / TMS patha TMS / TMS pathb TMS / TMS
125
TMSCI TMSCI
patha pathb
Hc [151-HG TMS

 

migration

1“” 1

TMS 0 Ph 0 Ph Hc 0 Ph
Jvk L‘SC' w J\/‘\

TMS / TMS TMS / TMS TMS / TMS

 

 

pathb
126 127

TMS

R
0 Ph TMS 0 Ph

9 TMSCI
TMS/\ATMS TMSMTMS
128 129(0%)

 

 

 

The selective formation of 127 following fast addition of base prompted us to
propose the intermediacy of a dianionic species 130, which could be generated if k1>k2.
Also as shown in Scheme 6.5, compound 127 could result from two possible pathways
both of which could be operative at the same time. Compounds 126 and 127 were
unexpected, but helped shed some light on the deprotonation process and that was the
possibility of dianion formation. Dianion formation could account for the problems we
had earlier in this study, which was non-reproducibility of the Wittig rearrangement
results of our model substrate 7 when the study was carried out with excess of base (in

this case MeLi).

156

We ran a parallel control experiment consisting of 7, TMSCI (4.0 eq)/T EA (4.0
eq), THF, -78 °C, but excluding sec-BuLi, and no reaction occurred, ruling out the
possibility that TEA might, in anyway, be involved/aiding the initiation of the Wittig

rearrangement reaction.

Scheme 6.5. Plausible pathway for the observed products

 

 

 

TMS
o e
Jil:/C|>\/\Ph TMSCI e OAPh TMSCI 0 Ph
TMS / TMS k2 %TMS k, \‘ykTMS
130
[1 ,5]-H TMSCI TMSCI
transfer
TMS
1°
/\ 0 Ph
TMS 0 Ph
. ,0 Ph TMSC' / TMSMKTMS
TMS “” TMS :TMS TMS
126 127

In all the above experiments, Wittig products were not evident. In addition, the
complete absence of rearranged products suggests that at low temperatures,
rearrangement was not fast enough to compete with electrophile capture, thus permitting
trapping of the deprotonated species before it can rearrange. This observation could be
interpreted to imply that the breaking of the O—C bond is the slow (rate limiting) step in
this reaction. This experiment was conclusive evidence that in the Wittig rearrangement
of our model substrate, or-deprotonation and cleavage of C—0 bond, and hence
rearrangement, are not concurrent events.

2

A pertinent question at this point then became “could rearrangement compete

favorably with electrophilic trapping at elevated temperatures?” The above experiment

157

was repeated at room temperature, and resulted in the formation of all three compounds
125, 126, and 127, in addition to the [1,4]-, [1,2]-products (8, 9), and vinylsilyl ether 22
resulting from the electrophilic trapping of the enolate from the [1,4]-Wittig pathway
(Scheme 6.6). From these results, it was apparent that at room temperature, the breaking
of the O—C bond was more facile, and Wittig rearrangement of 7 competes favorably
with electrophilic capture of the intermediate carbanion. The structures of these

compounds were assigned based on data from 1H NMR, 13 C NMR, HRMS, and DEPT.

Scheme 6.6. Room temperature electrophilic trapping of carbanion of 7

Ph Ph

11 . 11W:
1.TMSCI(2.0 equiv) TMS t K/K/Ph + / TMS

 

TEA 2. '
OAPh THF’lnoequ'V) 8 9 22
\ TMS T 1M3
2. s-BuLi 2.5e uiv /\
7 RT,1_5h( q )TMS OAPh TMS 0 P“ TMS 0 Ph
+ / +
125 126 127

8/9 = 28% (>4:1); 221125 = 6%; 126 = trace; 127 = 17%

6.2. Trapping of the carbanion of compound 40

We wanted to obtain further evidence in support of our results which showed that
deprotonation and bond reorganization of or-alkoxysilanes were separate events.
Compound 40 was employed for this purpose. Compound 40 was generated during our
attempt to prepare or-(tlimethylsilyl)-allyl butyl ether via the TMSOTf-mediated
etherification of a-hydroxysilane 32 with the trichloroacetimidate of butyl alcohol

(Scheme 4.8). Even though its formation was unexpected, 40 nevertheless is a potential

158

Wittig substrate. Considering the unique nature of 40, there is the question of the relative
acidities of protons Ha and Hb (Scheme 6.7), and of selective deprotonation by a base, or

whether, in fact, both protons could be removed simultaneously.

Scheme 6.7. Attempted Wittig rearrangement reaction of 40

 

Hb Hb
0M TMS , .
s-BuLi THF Slugglsh reaction,
\ TMS - - - - - -1- - - , formation of complex
Ha -75 °C mixture.

 

 

 

40

The rearrangement of 40 under our conditions was sluggish, even at room
temperature and produced a complex mixture of products (from 1H NMR). The
sluggishness of 40 to undergo the Wittig rearrangement may be due to the stabilization of
the resulting carbanion. We sought to understand the nature of the species undergoing
the rearrangement by trapping the carbanion with a suitable electrophile. Thus, treatment
of a cold (-78 °C) mixture of 40, TMSCl, and TEA in THF under N2 atmosphere with s-
BuLi, for 2 h afforded compounds 131 and 132 (123.44), which were isolated in a
combined 86% yield after column chromatography on AgNO3-impregnated silica gel3
(Scheme 6.8). This result reveals that 40 undergoes deprotonation under our Wittig
conditions; however, the event is not accompanied by concomitant bond reorganization.
This result thus provided further evidence that deprotonation and C—O bond breaking are

separate events.

159

Scheme 6.8. Electrophilic trapping of the carbanion of 40

 

1. TMSCI (4.0 equiv) TMS TMS
TEA (4.0 equiv)
OMTMS THF, -78 °c TMS OVTMS TMS OVTMS
= +
\ / /
TMS 2. s-BuLi (2.0 equiv) TMS TMS

 

The formation of the two observed products 131 and 132 could be explained in
two ways: (1) stepwise deprotonation-electrophilic trapping process and (2) formation of
a dianionic species, followed by electrophilic attack (Scheme 6.9). Both routes are
possible; however, dianion formation (Figure 6.1) would explain the inability of this
particular compound to undergo the Wittig rearrangement reaction readily. We speculate
that formation of a dianionic intermediate, which is resonance stabilized, would very
likely suffer from a high-energy demand for the breaking of the O-C bond following

deprotonation.

 

160

 

Scheme 6.9. Plausible explanation for the formation of 131 and 132 from 40

 

 

 

 

 

 

 

 

 

 

 

- Ha' Ha' -
/K/\ @
\‘G/Cl: / TMS -Ha OVTMS -Ha' O/‘\w/"\TMS
VI TMS \ TMS \ TMS
133 "a Hot
_ 40 135 -
1.TMsc1
2-""°‘ 1.TMSCI
2. -H01
- - - TMS - - TMS 7
e
TMS OMTMS o / TMS o \ TMS
/ TMS V TMS V TMS
_ 134 _ _ 136 _ _ 137 2
TMS TMS
TMSCI TMSCI
o \ TMS TMS o/K/‘TMS
+
/ TMS / TMS
131 132

 

_ e .
OMTMS
~.@,-
' TMS
_ 138 2

 

Figure 6.1. Formation of dianion 138 from compoun 40

6.3. Stereochemistry of the [1,4]-Wittig rearrangement of a-alkoxysilyl ethers

Having established that deprotonation and bond reorganization are not concurrent

but separate events in the Wittig rearrangement of a-alkoxysilanes, we then addressed the

next question regarding the mechanism of the [1,4]-Wittig, which was “does the [1,4]-

161

Wittig rearrangement of or-alkoxysilanes occur with retention or inversion of
configuration at the migrating center?” Answering this question would require a
substrate bearing a stereodefined migrating center which could be accessed via an
enantiomerically pure a-hydroxysilane.

Scheme 6.10. Preparation of a-alkoxysilanes bearing
substituent at the migrating carbon

OH 0 Ph 0

vrMs vTMs vTMS

32 TMSOTf X
+ = R B
cyclohexane, rt A :
f j: overnight 9 ph 9 pr.
CI3C 0 Ph VTMS VTMS

 

We already determined that the coupling of a racemic or-hydroxysilane and the
trichloroacetimidate of a secondary alcohol produces a set of diastereomers in an
approximate ratio of 1:1 to 1:1.3 in favor of the less reactive anti isomer (Scheme 6.10).
In theory, employing an enantiopure or-hydroxysilane, for instance (3)-32, and a racemic
trichloroacetimidate would result in only one pair of optically active diastereomers (SS
and S, R) (Scheme 6.11). During our earlier studies, if R = Et, Pr, i-Pr, or allyl the two
diastereomers were separable by column chromatography on silica gel. Thus we could
access enantiomerically pure substrate either by employing enantiomerically pure starting
materials (alcohol and acetimidate) or an enantiopure or-hydroxysilane and a racemic
trichloroacetimidate. Each of these two routes would in principle result in only one pair

of Optically active or-alkoxysilanes (Scheme 6.11).

162

 

Scheme 6.11. Preparation of or-alkoxysilanes from enantiopure starting materials

 

 

8
OH OAPh OH
(3)-32 (S,R)- (3)-32
TMSOTf + TMSOTf
+ = = +
cyclohexane, rt R cyclohexane, rt
overnight A overnight
1” 1 ° P“ 1“ 1
C130 0 Ph %TMS CI3C 0 Ph
racemate (S,S)- (S)-acetimidate

6.4. Efforts towards accessing enantiopure Wittig substrate for mechanistic studies
6.1.2.1. Exploratory ventures into accessing enantiopure or-hydroxysilanes

We explored a number of routes to access enantiomerically pure or-
hydroxysilanes. Kells et al4 reported the successful resolution of a-hydroxystannanes via
norephedrine carbamates in a two-phase acetonitrile-hexanes solvent system. In this
case, a-hydroxystannanes were converted into mixed carbonates with p-nitrophenyl
chloroformate. Treatment with norephedrine then afforded the carbamates which were
converted back to or-hydroxystannane by reduction with A1H3.

We carried out a model study to determine the compatibility of the trimethylsilyl
group with the above procedure. In doing so we substituted ethylchloroforrnate for p-
nitrophenylchloroformate. Thus, stirring a mixture of a-hydroxysilane 34,
ethylchloroformate, and pyridine in hexane/acetonitrile at 0 °C for 2 h, and then
quenching with water, afforded the carbonate derivative 139. The first step of this

reaction proceeded well (Scheme 6.12). However, the subsequent step, which involves

163

the replacement of the carbonate functionality with a carbamate, did not proceed, and

only 139 was recovered.

Scheme 6.12. Attempted kinetic resolution of a-hydroxysilane 34 by Kells’ protocol4

OH O

/\/k )L Pyridine (3.0 equiv)
\ TMS + /\0 >

0' Hex/MeCN (1:1)
34 0 °C, 2 h

 

O (1 S,2R)-(+)-norephedrine O E
ADA (1.3 eq) - O/lLN/VOH

‘

- . 7 H -

hexane/MeCN (1 :1 )
139 140

O

OzN—QO>=O GAO-Q—NOZ
9' MTMS

141

The failure of the second step may be due to the poor leaving ability of the
ethoxide group. To overcome this problem p-nitrophenyl chloroformate was employed in
step one of the reaction, affording the mixed carbonate 141 as a dirty white solid after 45
minutes. A mixture of this crude carbonate 141, (IS,2R)-(+)-norephedrine, and
diisopropyl amine, in hexane/acetonitrile (1 :1 v/v) was stirred at room temperature for 24
h, followed by aqueous workup to give 140 (Shemen 6.12) as an inseparable mixture of
diastereomers (Scheme 6.12). The difficulty in separation forced us to abandon this
route.

Next we explored the possibility of employing an elimination reaction to install

the terminal double bond in a-hydroxysilanes. We reasoned that elimination of a

164

suitably derivatized diol 143 could lead to the desired alcohol (Scheme 6.13). Compound
143 could be derived from the epoxy alcohol (glycidol) 142, which would come from the
epoxidation of E-3-trimethylsilanyl-prop-2-en-1-ol. Thus, silylation of propargyl alcohol
(2.0 equiv n-BuLi, B20, -20 °C, 2.2 equiv TMSCI, H2O/AcOH), followed by reduction
of the triple bond with Red-A1 afforded the requisite allyl alcohol, E-3-trimethylsilanyl-
prop-2-en-l-ols. Epoxidation of this was readily accomplished by reacting the alcohol

with 2.0 equiv of mCPBA in CH2C12 to obtain the glycidol in 66% yield (Scheme 6.13).

Scheme 6.13. Epoxidation of E-3-trimethylsilanyl-prop-2-en-l -ol with mCPBA

 

mCPBA (2.0 equiv) o
TMSMOH 7' TMS/<l/\OH
CH20l2, 0 °C, 6 h
142 (66%)
OH OH
TMS/‘V\OH vTMS
143 32

We then explored conditions for selective opening of the epoxide to furnish the
desired diol 143. Red-Al has been reported to react with epoxy cinnamyl alcohol in
dimethylethane, and open the epoxide from the less hindered side to furnish the
corresponding 1,3-diol.6 However, when a DME solution of glycidol 142 was treated
with 1.05 equiv of Red-Al at 0-25 °C for 4.5 h, 1,2-diol 144 was obtained in 60% yield
(Scheme 6.14). The expected 1,3-diol was not observed under this reaction condition.
Interestingly, an entirely different result was obtained with LiB(C2H5)3H (superhydride).
Treatment of a THF solution of 142 with 2.0 equiv of superhydride at room temperature
for l h, resulted in the opening of the epoxide from the less hindered side to afford the

desired 1,3-diol 143 in 91% yield (Scheme 6.14). The next step was tosylation of the

165

primary hydroxyl group of diol 143. However, selective tosylation was not achieved

(Scheme 6.15) and we did not pursue this procedure any further.

Scheme 6.14. Regioselective opening of epoxide 142

 

 

A?/\ LiB(C2H5)3H (2 equiv) 0H
TMS 0“ THF. 11. 1 h TMS 0“
142 (91%) 143
/<?/\ RSd-Al (1 .05 BQUIV) > TMS/\‘/\OH
TMS OH 0 OH
DME, 0-25 C, 4.5 h
142 (60%) 144

Scheme 6.15. Proposed derivatization and elimination reactions of 143

 

TsCI (1.05 equiv) OH
OH Et3N (2.5 equiv) A OH
> TM T """ ’ /
TMSMOH DMAP (3 mol%) 5M0 s rMs/|\/

The conversion of glycidols to allyl alcohols bearing terminal olefins by Ti
(IV)(C5H5)2Cl2/Zn/ZnCl2 has been reported in the literature.7 This process involves the
Ti(IV) induced homolysis of the C—0 bond of a 2,3-epoxy alcohol, with deoxygenation
occurring exclusively from the least substituted carbon end to produce terminal alkenic
alcohol in high yield. However, when this protocol was adapted to glycidol 142 (Scheme

6.16), the expected product was not obtained.

166

Scheme 6.16. Attempted conversion of 142 to 32 mediated by Ti(IV) system

(05115271sz (1.2 equiv)
/<C])/\ Zn dust (5 equiv) OH
* /
TMS 0“ 21102 (1.2 equiv) TMS/IV
142 THF, rt, overnight, 2 h 32 (0%)

 

Also documented in the literature8 is the finding that the telluride ion (generated

by in situ reduction of elemental Te by sodium hydroxymethanesulfinate dihydrate

(Rongalite) or by NaBHa) can mediate the transposition of a primary allylic alcohol to a

tertiary homochiral allylic alcohol via the tosylate ester of a homochiral glycidol obtained

by the Sharpless asymmetric epoxidation (Scheme 6.17). The site of attack of the

tellurium ion is at the carbon atom of a primary tosylate. The authors of this report also

reported successful application of this protocol to a terminal allylic alcohol8 via the

mesylate of the glycidol (Scheme 6.18)

Scheme 6.17. Telluride mediated double bond transposition in primary allylic alcohols

1. Ti(O-i-Pr)4, (+)-DIPT

 

 

\ TBHP, CH20|2, -37 °c Te (200 mesh)
OH (91%) OTs HOCH2302Na
2. TsCI, Et3N, DMAP NaOH. H20
01-12012, 15 h, -10 00 THF. 1 h

   

145 146

167

Scheme 6.18. Telluride mediated double bond transposition in secondary allylic alcohols

1 Ti(O- i- -,Pr)4 (+)- -DIPT sHb
R/Kl/ TBHP CH2CI2 -37 °c RAP (533%
+

2. chromatographic

se arat'on
p ' Te(1.1 eq)

HOCH2302N8.2H20
(3 eq, based on Te)

. . NaOH
(CH330120. Pynd'"e M59 0 (5.0 eq, based on Te. 1 N)

DMAP. (311202 R /\') 50 °C 2 h' cool to rt'
add mesylate in THF

 

 

In adapting the above protocol, the telluride ion9 was first preformed by reacting 2
equiv of Te (200 mesh) and 4 equiv of NaBH4 in DMF at 70-80 °C for 30 min. The
glycidyl tosylate 148 reacted readily with the preformed telluride complex at room
temperature. Sampling after 2 h revealed the complete absence of the starting tosylate
(Scheme 6.19). However, upon quenching (exposure to air, followed by treatment with a

few drops of H202 to to oxidize the telluride) and aqueous work up, no product was

 

isolated.
Scheme 6.19. Attempted preparation of 32 via telluride ion
mediated reduction of glycidyl tosylate
1. DMF, 70-80 °C,
Te (200 mesh) NaBH4 30 mm 0“
(2.0 equiv) t (4.0 equiv) M V

TMS
2TMS/<l/\0Ts 32 (0%)
(1. 0 equiv), 11,2 h

168

6.5. Accessing enantiopure a-hydroxysilane 33

So far, our efforts toward accessing enantiopure a-hydroxysilane 32 had proved
unsuccessful. In prior studies on asymmetric reductions of acylsilanes with chiral borane
reagents,lo‘”’12 high enantiomeric purities (95% ee or better) were obtained with
substrates in which the (it-carbon bore a phenyl ring or saturated alkyl groups. 01,13-
Unsaturated acylsilanes were reduced effectively provided they contain bulky groups on
silicon. However a,|3-unsaturated acylsilanes with small groups on silicon afforded
alcohols with lower enantiomeric purity (SO-89% ee).9’10’” Such trends are evident in the
work of Buynak and coworkers,'0 who explored the reduction of acylsilanes by (-)-
Ipc2BCl.l4 Their results are shown in Table 6.1 below (Table 6.1, compare entries 4 and
8 to entries 6, 7 and 9). or-Silyl allyl alcohols bearing a TMS group are clearly missing
from Table 6.1.

Nonetheless we were happy to find that alcohol 33 was one of the ct-
hydroxysilanes formed by Buynak (Table 6.1, entry 7).10 Although its enantiomeric
excess was not very high, it afforded us a starting point for our work. BuynakIO reported
making the a-hydroxysilane 33 in 35% yield via a sequence of reactions involving
synthesis,15 silylation, and finally acid hydrolysis"5 of allenyl ether 152 to give the 01,13-
unsaturated acylsilane 153, which was subsequently subjected to asymmetric reduction of

(Scheme 6.20).

169

Table 6.1. Buynak’s asymmeric reductions of acylsilanes using (-)-IpC2BCl10

(-)-lpczBC| (1.51 equiv)

 

 

 

 

 

 

 

o THF, rt, overnight; HQ/(H
R/lkSiRleR3 then triethanolamine (3.17 equiv) R SiR1R2R3
rt, 2.5h
Entry a-silyl alcohol % ee Entry a-silyl alcohol % ee

HO, H HO,“ HPh
1 '- _ 95 6 _ 5i : Me 89
Me SlPh3 ‘Ph
H02. H HO, H
, 96 7 \ -. 33 83
p-Tol SlPh3 SiMegPh 7
0,, H
3 WSIPM 95 8 £38- 97
O SlPh3
HO, H HQ, H
4 ’: 97 9 ’- 80
vSlPhg V5513
H04. H ,Ph
5 p-Tol Si-t-Bu 95
Ph

 

We needed alcohol 33 as a substrate in our work, thus we wanted to repeat
Buynak’s protocol. We prepared 1-(1-ethoxy-ethoxy)-propa-1,2-diene 149 by stirring a
cold (0 °C) mixture of propargyl alcohol and vinyl ether in the presence of p-
toluenesulfonic acid (pTSA) under an atmosphere of N2 for 30 min. After quenching
with a saturated solution of K2CO3, phase separation and distillation of the crude product
under reduced pressure gave the compound 149 in 60% yield. Silylation of 149 with
chloromethyldiphenylsilane (Ph2MeSiCl) was carried out in the presence of radical
inhibitor BHT (1.5 mg/mmol substrate)16 and quantitatively afforded the expected
product 150 as a thick brown oil. However, acid hydrolysis of 150 with 2N H2SO4 failed

to give the expected mL)-unsaturated or-silyl ketone. Instead, the or-silylallenyl alcohol

170

151 was isolated quantitatively (Scheme 6.20) (IR (neat) 3323 cm'l HO—C=-=C and 2178
cm'1 C=-=C). Compound 151 was subjected to chromatography on silica gel with the
expectation of possible isomerization to the a,B-unsaturated carbonyl isomer. However,
no isomerization was observed and we recorded over 90% recovery of the pure

compound. [3

Scheme 6.20. Attempted preparation of a,B-unsaturated
a-silyl ketone 153-a repeat of Buynak’s protocol

BHT (1.5 mg/mmol substrate)
-80 °C, n-BuLi (1 .06 equiv)

O O .
TSA, 0 0C 30 min;
_ \ + %o“ p = W \l/ A 7
14

 

 

OH (60%) thMeSiCI (1 .08 equiv)/THF
HMPA (1.10 equiv)/THF
-80 °C, ovenight;
TEA, -80 °C, 20 h

9

 

(80%)
thMeSi 07/0W 2N H2804 \i Ph2MeSi OH
THF, rt \ SiMePh2
(0%)
150 151(quant)

 

 

 

PhMe2Si OTOW 2N st04 0 PhMe2Si OH OH
\H/ THF.” VLSiMeZPh \H/ vSiMe2Ph

(0%) 33
152 153 154 (> 70%)

 

 

 

 

 

 

An attempt was also made at silylating the 1-(l-ethoxy-ethoxy)-propa-l,2-diene
149 with chlorodimethylphenylsilane. However, like the above case, acid hydrolysis of
152 failed to afford the desired 01,B-unsaturated or-silyl ketone 153 (Scheme 6.20). The

reaction of Scheme 6.20 afforded the l-(dimethylphenylsilanyl)-propa-l,2-dien-l-ol, 154,

171

 

 

in over 70% yield after purification by silica gel chromatography. The structures of these
compounds were elucidated by NMR (1H and 13 C), DEPT, and IR data.

With no success from the above route, we next considered making racemic a-
hydroxysilane 33, oxidizing the racemic alcohol to the acylsilane 153 and subsequently
carrying out asymmetric reduction of acylsilane 153 to obtain the requisite chiral 33. We
explored several methods to oxidize alcohol 33. DeLuca’s protocol,17 which involves the
use of cyanuric acid (TCT) in the activation of DMSO (Scheme 6.21) was first attempted.
However, this route afforded the desired enone 153 in only 6% yield, accompanied by

other by-products including 155 which was obtained in 17% yield.

Scheme 6.21. Oxidation of a-hydroxysilane 33 via the DeLuca protocol

 

DMSO (5.87 equiv) .
\/OKH TCT (1.5 equiv) ‘ 0 + OSIMezPh
\ SiMezPh TEA (4.77 equiv) \ SiMe2Ph \ SiMezPh
33 -30 °C to rt 153 (6%) 155 (17%)

a-Silyl alcohols have been shown to undergo facile Swern oxidation to afford the

18 However, Swem oxidation was not

corresponding enones in good to excellent yields.
our first choice method because of concern over how the phenyldimethylsilyl group
would behave under such conditions. Despite these reservations, our lack of progress in
this endeavor prompted us to take or-hydroxysilane 33 through the typical Swem
reaction.l9 Disappointingly this resulted in the formation of or-chloro-a,[3-unsaturated
acyl silane 156 (22%) accompanied by some disilyl ether (PhMe2Si)2O (6%). No trace of

the desired product 153 was observed (Scheme 6.22). (it-Chlorination during Swern

oxidation is documented in the literature. Smith and Leenay20 and Kende and co-

172

 

workers2| have independently reported observing 111-chlorination during the Swern

oxidation of secondary alcohols.

Scheme 6.22. Swern oxidation of racemic a-hydroxysilane 33

 

CDC 2. 0 UN
OH (DMSOzéi. O eeqquiv)) O O - ,
v VL + + (PhMeZSl)2O
SiMezPh CTEA (5. 0 eqpton iv) SiMezPh SiMe2Ph 6°/ 8
33 153 156

 

T(°C) 153:156 Yield (%)
-78 tort 156 only 223

-55 to rt 3:1 77
-50 to rt 10:1 91

 

 

(a) Reaction was accompanied by formation of (PhMe2Si)2O obtained in 6% yield

While the ct-chlorination product posed a problem, we were somewhat
encouraged by the fact that the oxidation did take place. Thus we decided to study the
reaction conditions further in an effort to make the desired alcohol without the
adventitious chlorination. Our results are summarized in Scheme 6.22. We were pleased
to observe that by simply varying the reaction temperature from -78 to -55 °C, the above
procedure afforded a 3:1 mixture of the desired product and the or-chlorinated acylsilane
in 77% yield. We obtained our best result, combined 91% yield of 153 and 156, and 10:1
ratio in favor of the desired acylsilane, by carrying out the Swern oxidation at -50 °C.

We also explored other oxidation methods, including use of FCC,22 IBX,23 and
chemical MnO224 (Scheme 6.23). The generally observed pattern with all these reagents
was that the substrate got completely consumed, but that the only isolable product was

PhMe2SiOSiMe2Ph.

173

 

 

Scheme 6.23. Attempted oxidation of or-hydroxysilane 33 via other routes

 

OH Oxidant O PhM S'OS'M Ph
> + 92 I I 82
vSiMezPh solvent VkSiMe2Ph “at.
33 Temperature 1 53 (0%) near quan ' lve

 

Oxidant Solvent Temperature

 

PCC 01-12012 rt
in EtOAc 80 °c
MnO2 CH2CI2 rt

 

6.6. Asymmetric reduction of acylsilane

Reduction of anti-unsaturated acylsilane 153 was achieved (-)-IpC2BCl by
applying literature procedure10 (treatment of an approximately 0.34 M solution of the
acylsilane in THF (at -35 °) with 1.1 equiv of (-)-IpC2BCl). The downside to this method
is the very low yield associated with it. BuynakIO reported a 25% yield of alcohol (R)-33
(83% ee). We obtained the desired alcohol 33 in 39% yield (Scheme 6.24). The alcohol
was converted to its MPA ester25 and the diastereomeric excess (84% de) was established
by 1H NMR.

Although the level of enantiomeric purity of the (-)-Ipc2BCl reduction was lower
than we would have liked for our mechanistic study, it was good enough for us to
investigate the etherification of enantioenriched a-hydroxysilane with enantioenriched

trichloroacetimidate.

174

Scheme 6.24. Preparation of enantioenriched 45

 

9 Ph
VSiMezPh
9H + NH TMSOTf (0.06 equiv) (R3145
v . M T
SlMe2Ph CI3C Ph cyclohexane, rt :
(RH-1'33 ( S)-(-) overnight 3
(1.0 equiv) [0110 -51-6 QAP"
(01.2, CHCI3) \ ‘
(2.0 equiv) \/\SiMe2Pn
(R.R)45
(1:145)

The TMSOTf catalyzed etherification of (R)-(-)-33 with the (S)-(-)-benzyl
trichloroacetimidate26 afforded a 1:1.45 mixture of diastereomeric ethers 45 (Scheme
6.24). At this point, it was clear to us that all we needed was enantiopure ct-
hydroxysilane and we could access both diastereomers of or-alkoxysilane in optically

pure form.

6.7. Kinetic resolution of a-hydroxysilane 32 by Lipase

The problems associated with the Swern oxidation of 33 and the low enantiomeric
purity offered by the asymmetric reduction of same made us look for alternative routes to
the enantioenriched Wittig substrates. This search took on a particular urgency given the
yet to be resolved problem of reducing 01,13-unsaturated acylsilane where the silicon bears
non-bulky groups such as Me, Et, and Pr.

As part of this search we considered kinetic resolution of 32. Most of the work on

kinetic resolution of or-silyl alcohols has been done with a-silyl benzyl alcohol, and 01-

175

silyl allyl alcohols in which the silicon bears bulky groups such as t-Bu, Ph, and i-Pr.10 In
addition, Lipase-mediated resolutions of secondary propargyl alcohols bearing silyl
substituents leading to high enantiomeric purity are documented in the literature.27 Even
though the substrates in these previous studies are significantly different from ours, we
thought that kinetic resolution was worth investigating since this would offer a useful
route to the less studied or-silyl alcohols. We investigated the enzymatic resolution of 01-
hydroxysilane 32 under various conditions (enzyme loading, acylating agent, and
temperature). The process involves stirring a mixture of the substrate alcohol, the
enzyme, vinyl acetate and 3A MS in pentane, and monitoring the reaction by chiral GC.
Our results are summarized in Table 6.2 below. From Table 6.2, it is clear that Amano
AK Lipase effectively resolves a-hydroxysilane 32 with synthetically useful levels of
enantiomeric differentiation. In the course of this study, we established that 1.0 wt. equiv
of Amano AK Lipase was optimal, and anything beyond this did not afford any
advantage. For instance, use of 2.0 wt. equiv of the enzyme under similar conditions
gave 81-83% ee at best. Temperature is a very important factor in this process. The
reaction is facile at elevated temperatures (33 h at 35-38 °C). It is worth noting that when

this reaction was run neat, it was slower than when run in solvent.

176

Table 6.2. Lipase resolution of a-hydroxysilane 32

 

 

Amano AK Lipase
\i‘l vinyl acetate (5 equiv) VT OAC
\ = \ t \
TMS 3 A MS, pentane TMS TMS
rec-32 rt 32 157
enanfioennched
0.5 wt. equiv 0.75 wt. equiv 1.0 wt. equiv

 

 

 

Entry Time Ratio of °/o ee Entry Time Ratio of % ee Entry Time Ratio of % ee
(h) acetates (h) acetates (h) acetates

1 47 1:8 79 1 45 1:10 82 1 23 1:6 73
2 72 1:10 82 2 72 1:9 80 2 96 1:9 81
3 120 1:10 82 3 120 1:9 80 3 120 1:9 80
4 144 1:9 80 4 144 1:9 80 4 168 1:9 80
5 192 1:10 82
6 240 1:11 84

 

Two other enzymes, Amano PS Lipase and Novozym 435, were also investigated
in the kinetic resolution of 32 (Table 6.3). Amano PS Lipase (1.0 wt equiv of Lipase, 5.0
equiv of vinyl acetate, pentane 3 A MS, rt, 168 h) afforded the desired acetate of 96% ee.
Novozym 435 proved to be the best of the three enzymes investigated. Employing 0.015
g of Novozym 435 per mmol of alcohol (5 .0 equiv of vinyl acetate,27 pentane 3A MS, rt,
168 h) gave acetic acid l-trimethylsilanyl-allyl ester of 98% ee (Table 6.3). It was
observed that very long reaction time is detrimental to the level of enantiomeric excess of
the resulting acetate, and secondly, we determined that the use of a large excess of vinyl
acetate is not necessary in the reaction. Thus, carrying out this reaction at elevated
temperatures (35-38 °C), employing 1.5 equiv of vinyl acetate afforded the desired
acetate 157 in 30% yield and 98-99% ee after 33 h (Table 6.3). The enriched alcohol was
recovered in 33% yield. On the other hand, employing only 0.01 g of Novozym

435/mmol alcohol afforded similar results in terms of enantiomeric excess (99% ee), but

177

the reaction required 84 h, and product yield was 26%, and the enriched alcohol was

obtained in 24% yield after chromatographic separation on silica gel.

Table 6.3. Kinetic resolution or-hydroxysilane 32
by Amano PS Lipase and Novozym 435

 

enzyme
vinyl acetate
OH (1.5 equiv) OH OAc
\ 4' \ + \
\ATMS 3 A MS, pentane \ATMS \ATMS
rec-32 3538 °C 32 157

enanfioennched

 

1.0 wt. equiv Amano PS Lipase 15 mg Novozym 435/mmol rac-ROH

 

 

 

Entry Time Ratio of % ee Entry Time Ratio of % ee
(h) acetates (h) acetates
1 22 1:16 88 1 8 1:166 99
2 24 1:29 93 2 13 1:172 99
3 48 1 :34 94 3 22 1 :150 99
4 96 1:25 92 4 27 1 :1 16 98
5 169 1:57 96 5 33 1:112 98

 

With the requisite chiral acetate 157 in hand, we turned our attention to finding
procedures for its hydrolysis to obtain the desired chiral alcohol. The results of this
investigation are summarized in Table 6.4 below. A variety of reagents were investigated
for the hydrolysis. Many of these led to erosion of enantiomeric excess (Table 6.4,
entries 1-6). A look at Table 6.4 reveals DIBALH as the reagent of choice, and the best
conditions for the hydrolysis of the silyl acetate to be 1.05 to 1.1 equiv of DIBALH,
hexane, -78 °C, 2 h 20 min. (entries 8 and 9). Beyond 3 h reaction times erosion of
enantiomeric excess was observed (entry 10), and it is also worth mentioning that use of
excess DIBALH resulted in erosion of % ee of the resulting alcohol (entry 11; 3.15 equiv

of DIBALH, hexane, -78 °C; 86% ee).

178

Table 6.4. Hydrolysis of acetic acid l-trimethylsilyl ester 157

 

reagent
\jfc solvent \/C|3\H
\ 7‘ \
TMS temperature TMS
(3)-(+157 time (3)-(+32

98% ee)

 

Entry Reagent Equiv Solvent T(°C) Time (h) % ee Yield (%)

 

1 K2C03 5 MeOH 20 4 85 a

2 LiOH 5 MeOH-H2O 20 5 85 a

3 LAH 1 .2 Ether reflux 2 80 a

4 LiBH(C2H5)3 2 THF 0 2 lnconclusive a

5 Red-AI 1.05 THF 0 to it 1.75 81 a

6 LiAlH(Ot-Bu)3 1.05 THF -78 to rt 48 87 a

7 DIBALH 1 .1 CH2C|2 -78 3 84 a

8 DIBALH 1 .05 Hexane -78 2.5 98 82
9 DIBALH 1 .1 Hexane -78 2.33 98 90
10 DIBALH 1 .2 Hexane -78 5 94 b
1 1 DIBALH 1.5 Hexane -78 20 94 b

 

a. The experiments in entries 1 through 7 were qualitative in nature and the yields
were not determined

b. The experiments in entries 10 and11 were carried out to determine the effect of
long reaction time on the enantiomeric excess of the chiral alcohol product

6.8. Stereochemistry of the Wittig products.

Compound (S)-(-)-32 was employed in the preparation of desired diastereopure
substrate (S,R)-48. TMSOTf-mediated etherification of enantiomerically pure (S)-(-)-32
with the trichloroacetimidate of sec-phenylpropyl alcohol afforded a 1:1 mixture of (S,R)-
48 and (S,S)-48, which were readily separable by column chromatography on silica gel.

The reactive isomer (S,R)-48, on treatment with 1.5 equiv of n-BuLi in THF at -78 °C

179

overnight, afforded the Wittig products, which were separated by column
chromatography on silica gel. We had earlier determined that the racemic [1,4]-Wittig
product rac-82 (Table 4.2, entry 7) was not resolvable by chiral GC and chiral HPLC.
However, we were pleased to observe that after oxidation of the acylsilane (Scheme

6.25), the resulting carboxylic acid 158 was resolvable by chiral HPLC.28

Scheme 6.25. Conversion of the [1,4]-Wittig product 82 into 3-Phenyl-pentanoic acid

 

 

o
P“ , TMS /

TMS / /= 30% H202 ;

; g s-BuLi (1.5 equiv) 3N NaOH HO '

VOA Ph - HI = WP“
-78 °C / MeOH, 20 min 0

9604/3 : (35%) 158

o 66 TMS :

98 er WP“
o
82

% ee retention 75%
% er retention 88%

We also subjected the less reactive anti diastereomer (S,S)-48 to our Wittig
conditions, and the reaction took about 3 days at —10 to 5 °C to go to completion. The
[1,4]-product from this reaction was also converted into the corresponding carboxylic
acid and analyzed by chiral HPLC.

For reference, we accessed the [1,4]-Wittig product via an independent route
starting from L-(-)-ephedrine (Scheme 6.26). The reaction of L-(-)-ephedrine and trans-
cinnammoyl chloride in the presence of Proton Sponge® followed by treatment of the
resulting amide with EtMgBr in ether, afforded the corresponding adduct via 1,4-
conjugate addition of the Grignard reagent to the amide. Mukaiyama29 has presented a

plausible mechanism to explain the stereoselectivity of the reaction. The reaction between

180

the amide and the Grignard reagent forms an initial internal chelate complex 159
(Scheme 6.26) that would rigidly fix the conformation of the molecule owing to the
planarity of the amide group. Excess Grignard reagent would approach the molecule
from the less sterically hindered side (i.e. opposite side of the phenyl and methyl groups
on the asymmetric carbon) by means of strong interaction with the Mg salt. Quenching
of this Mg complex with dilute acid solution afforded the addition product, and removal
of the chiral auxiliary by acid hydrolysis (H2804/AcOH, heat) furnished the carboxylic
acid, which was subsequently converted in two steps to the corresponding alkyl bromide
(Scheme 6.26). Reaction of this alkyl bromide with l-timethylsilyl-l,2-dithiane lithium
species afforded the corresponding 1,1-disubstituted 1,3-dithiane. Deprotection with
NBS and oxidation of the resulting acylsilane converted the 1,3-dithiane into the
corresponding carboxylic acid. The [1,4]-products from the two different routes were
analyzed by chiral HPLC and compared. By this analysis, we determined that the [1,4]-
Wittig product from the rearrangement of reactive (S, R)-48 was obtained with retention
of configuration at the migrating carbon ( % ee retention = 75%; % er retention = 88%).
The [1,4]-product from the less reactive (S,S)-48 was also obtained with predominant
retention of configuration (% ee retention = 74%; % er retention = 87%). Comparison of
the results obtained with both (S, R)-48 and (S,S)-48 show that both substrates afforded

[1,4] products with similar level of retention of configuration at the migrating carbon.

181

 

 

 

Scheme 6.26. Preparation of 82 via an independent route

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

O
1. EtBr (6.0 equiv)
Me PhQ/KCI 'Y'eH M90 (18 equiv)
Ph\/E\ Me (1.85 equiv) Pth ? Me Et2O, 70-80 °C
- N’ 3 I >
OH Ill Proton Sponge (2.0 equiv) 0H0 3 Ph 2. Substrate(1.0 equiv)
_ THF, 0 °C to rt, 24 h H -78 °C, Ar; then -40 °C
L (-)-ePhedrIne (92%) 48 h
FPh / me” M - P Me” - MeH
? 6 Ph N : Me -
W . \ - H+ Ph N 3 Me
k) Br,‘=O ,OiIPh m ; W I
' M9 H Mg'o - P" HO 2 Ph
Mg, I H H
- '3' - - - 160
159
CBr4 (1.25 equiv)
H2804 Ph OH LAH (2.55 equiv) P“ W0“ PPh3 (1.5 equiv)
CH3COOH f H O THF, reflux, 10 h I H CH2CI2, 0 °C
1.5 h uant
161 162 (q )
1. 1,3-Dithiane (1.0 equiv)
Ph Br n-BuLi (1.05 equiv) .
W THF, -25 °C, 45 min Ph S S NBS (6.0 equ1v)
C H > M =
2. Me3SiCl '5 H TMS acetone/H20 (8:2)
3. n-BuLi (1 .05 equiv) 0 °C, 2 h
163 -25 °C, 2 h 164 (64%)
4. RBr (1.0 equiv)
-25 °C to rt, 24 h
0 30% H202 O
Ph\_/\/U\TMS 3” N39” : Ph MOH
5 MeOH, 20 min 5
/ 32 (36%) / 155

182

 

6.9. Stereoselection in the [1,4]-Wittig rearrangement of or-alkoxysilanes: Relative
stereochemistry of the newly formed adjacent stereocenters.

We were next interested in determining the relative stereochemistry of two newly
formed stereogenic centers (Scheme 6.27) in cases where substituent was present at the
terminal sp2 carbon of the allyl moiety. or-Alkoxysilane E-56 was employed in this
investigation. The diastereomeric [1,4]-Wittig product 97 resulting from the
rearrangement reaction of E-56 was oxidized to the known30 diastereomeric carboxylic
acid 165 (Scheme 6.27). The diastereomeric acids were not separable by column
chromatography on silica gel. Nevertheless, the methyl signals were well resolved by 1H
NMR spectroscopy and by integrating the signal peaks, the anti/syn acids were formed in

a ratio of 2.8:1 to 3:1 in favor of the anti isomer.

183

Scheme 6.27. Wittig rearrangement of E-56/oxidation of [1,4]-Wittig product 165

Me
0 Ph
Me/vTMS
E-568/56b
n-BuLi (4.0 eq)
THF, -78 to -30°C
48 h
“'9 TMS OHPh TMS 0 Me 0
Me \ TMS Me Me
anti E-56 95
(39%) [1,2]-Wittig followed via [1,2]-rearrangement [1,4]-rearrangement

by silyl migration
Combined yield of products ranges from 35 to 57%, depending on the temperature and reaction time

3NNaOH
30% H202
THF, 35 to 40

M °C2h

e

TMS 0H TMS 0 Me O
0*
MM: + MAX?" 1N9?" + ”MK/KO"
Me Me Me
antiE-56 96 165

In 1983, Nakai and co-workers31 reported their efforts in acyclic
diastereoselection in the [2,3]-Wittig rearrangement of a series of isomeric crotyl ethers
(Scheme 6.28). The authors noted such general trends in terms of the sense and degree of
diastereoselection as: (1) Erythro selection by Z substrates (with low erythro selectivity
when R is Ph group) and threo selection by E substrates; (2) the dependence of the
degree of stereoselection upon the kind of substituent (R), which according to the authors
indicates that carbanion structure conferred by a given R plays a significant role in

dictating reaction stereoselectivity, and (3) the decrease in threo selectivity with

184

 

 

 

changing R for E substrates in the order: CEC>CH=CR’ (R’ = H, Ph) >CR’=CH2 (R’ =
CH3, MegSi) > Ph.

Scheme 6.28. Diastereoselection in [2,3] Wittig rearrangement by Mikami et al3 '

’43:]:
HaC?/R threo OH\ may/:1)
Twig/R

erythro

On the basis of the widely accepted postulate that the [2,3]-sigmatropic
rearrangement proceeds via envelope transition state, the authors proposed the transition-
state model shown in Scheme 6.29, which best accommodates both the sense and degree
of stereoselection described in the preceding paragraph, and which provides a logical
basis for explaining and predicting the stereoselection over a range of substrates. In their
system, they explained the observed sense of stereoselection in terms of the pseudo-1,3-
diaxial interaction between R and Hp in 167 and 168 (Scheme 6.29). The marked
dependence of the threo selectivity on the R group was rationalized by assuming an
additional RHCH3 steric parameter (gauche interaction) in the preferred transition state
166. The gauche interaction is enhanced by a bulky R group. Furthermore, based on the
postulate that the oxybenzylic carbanion possesses preferentially a pyramidal
configuration (depending largely on the solvent),32 for R = Ph, the CH3HPh gauche
interaction would be greatly enhanced, eventually leading to very low stereoselectivities

as the authors actually observed in their systems.

185

Scheme 6.29. Proposed transition-state model for stereoselection by Mikami et a131

pseudo-1 ,3-diaxial
Gauche interaction interaction

4!
’l
’0

H B, ’1:
RI

threo H [ T‘o -—I
all,

168 A

F— —

pseudo-1,3-diaxial

’A'I, interaction H3CR/ O
’ Hi3 (Z)
H
erythro H [ T‘O
cfi,
169

 

 

 

 

 

We have tried to adapt the above model to our system in an effort to explain the
observed stereochemical outcome of the [1,4]-alkyl shift in the Wittig rearrangement of
E—56 (Scheme 6.31). In doing so we presumed that the [1,4]-pathway is a one-step
concerted process, which is allowed by orbital symmetry33 as illustrated in Scheme 6.30.

The orbitals and methyl groups on silicon are left out for simplicity of presentation.

Scheme 6.30. Frontal orbital representation of E-56

i
3 4
Si _ . CH 1 WCH
W 3 2 3 3

1O;"71\

H3C Ph Lax
H3O Ph

Pseudo-1,3-diaxial interaction exists in both transitions states 170 and 171.
However, the effect is greater in 171 (PhHHB) than in 170 (CH3HHB), thus favoring 170

Now, assuming an additional R-R’ gauche interaction, this would be enhanced in 170

186

 

 

 

 

(PhHCH3) relative to 171 (CH3HCH3), making transition state 171 more favorable. The
fact that the Wittig rearrangement reaction of E-56 gives anti/syn selectivity of 2.821
would suggest that the pseudo-1,3-diaxial interaction outweighs the effect of gauche

interaction. However, the gauche effect would explain the low selectivity observed.

r.

H3CWTMS

47—0
Ph CH3

(El-55

L

Scheme 6.31. Proposed transition-state model for
stereoselection in the [1,4]-alkyl migration in E-56

—— —

Hi3

CH
H3C {)1}:ng
HPh
170

Hi3

Ph
H3C '1';ng

HCH3

 

 

171

 

Ph
threo H \AfFJMS
03;“ l
R CH3
“a (2)-56
05.1 l
erythro H [PJMS
c132
173 4

 

 

In the case of Z-56, pseudo-1,3-diaxial intearaction favors 173 (CH3HHB) over

172 (PhHHB). On the other hand, steric parameters (gauche interactions) favor 172

(CH3HCH3) over

173 (PhHCH3).

Assuming that the pseudo-1,3-diaxial interaction

outweighs the gauche interaction, then, we would expect a reversal in the outcome of the

reaction employing Z-56, that is, a reversal in anti/syn stereoselection, if the mechanism

of the [1,4]-alkyl shift were a concerted event. Thus, our next plan was to employ the

geomeric Z-56 in the Wittig rearrangement reaction.

187

 

Scheme 6.32. Preparation of Z-oc-alkoxysilane Z-56

1. n-BuLi (1 .08 equiv)

 

 

 

 

 

 

H2 (1 atm) THF -78 °C, 2 h
Me : Lindlar cat. (5 mglmmol alkyne) : Me OH 2. TMSCI (1.0 equiv) :
0” Quinoline (0.05 ml/mmol alkyne) THF, -78 °C. 2 h
EtOAc. rt, 1 h 3. t-BuLi (1.20 equiv)
-78 °C, 2 h
(71%)
OH
BF3-0Et2 (0.22 equiv) .
TMS = Me TMS Me Me Me
I c + /|\ + by-products
clohexane, rt
Z-34 Z-56 174

The synthesis of Z-56 as outlined in Scheme 6.32 started with reduction of
propargyl alcohol with Lindlar catalyst to afford the Z-crotyl alcohol (85% crude yield),
which was employed in the next step without purification. The Z-crotyl alcohol was
converted to trimethylsilyl ether by deprotonation with 1.08 equiv of n-BuLi and trapping
with TMSCI. Subsequent treatment with t-BuLi afforded the desired Z-a-hydroxysilane
Z-34 in 71% yield. Etherification with the trichloroacetimidate of sec-phenethyl alcohol,
mediated by BF3-0Et2 afforded less than 10% of the desired product Z-56, accompanied
by numerous by-products which included 174, which presumably is the result of
transacetimidation/SNZ’ by the liberated sec-phenethyl alcohol (Scheme 6.32). Given the
difficulty in accessing Z-56 no attempt was made to optimize the reaction conditions at

this point. This will be for future studies.

188

6.10. On the mechanism of the [1,4]-alkyl shift in the Wittig rearrangement reaction
of a—alkoxysilanes

Although we recognize that more work has to be done before we can make
conclusive statement on the mechanism of the [1,4]-Wittig pathway, we venture to draw
some tentative conclusions based on the results of the present research.

In the Wittig rearrangement of our model substrate 7, the [1,2]-alkyl shift is
effectively suppressed at low temperatures, and the [1,4] product is obtained as a single
product. However, at elevated temperatures, the [1,2]-pathway becomes competitive and
the [1,4]/[1,2] ratio increases to 2:1. We submit that if both rearrangement pathways
were proceeding via the radical-radical anion dissociation-recombination mechanism,
implicating a common intermediate 175 (Scheme 6.33), then complete suppression of the
[1,2]-alkyl shift at low temperatures is unlikely. The two rearrangement pathways most

likely have different mechanisms.

Scheme 6.33. Radical-radical anion dissociation-recombination in 7

TMS“ :B TMS$/\ msw TMSW
Ph Ph

7 123 175 P“ P“

On introducing a substituent at the migrating carbon, [1,2]-Wittig becomes
competitive even at low temperatures (-78 °C). This observation is in agreement with the
generally observed characteristics of this reaction pathway, which is that the [1,2]-alkyl
shift is promoted by a radical stabilizing migrating group and / or a terminal radical
stabilizing group.3'4 R 7f H implies a relatively stable secondary benzylic radical 176

which is a good intermediate and promotes [1,2]-alkyl shift (Scheme 6.34). This is

189

 

 

 

evident in the rearrangement reaction of compound 44, in which a [1,4]/[1,2] ratio of

(1.5:1 to 1.7:1) was observed, contrary to a ratio of>100:1 for 7.

Scheme 6.34. Radical-radical anion dissociation—recombination
in a-alkoxysilane bearing a substituent at the migrating carbon

TMS e TMS TMS
/
QR f \é/\0
R e R
Ph ©< 5%
176 177 P“ 178 P“

 

On introduction of a substituent at the terminal sp2 carbon of the allyl moiety as in
a-alkoxysilane 55, the [1,2]-alkyl shifi becomes competitive even at low temperatures (at
-78 °C, [1,4]/[1,2] ratio is 4:1). Even though the migrating radical intermediate is
benzylic, the allylic radical is resonance stabilized (Scheme 6.35). Theoretically, one
would expect that the radical or to TMS (180) would be the less contributing resonance
structure relative to the structure in which the radical is B to TMS (181) (B-effect of
silicon). If this argument is reasonable, then one will expect a higher ratio of [1,4]/[1,2]
than the observed 4: 1. On the other hand, if the [1,4] shift is a concerted event, then, the
reaction would involve a carbanionic intermediate (182) as shown in Scheme 6.36. 179
is expected to be the more stable resonance contributor (or-anion stabilization by silicon)
than 182 and is invariably expected to fumish more [1,2]-Wittig product. That this was
not the observation could be taken as further evidence that both [1,2] and [1,4] processes
follow different pathways. Evidently the anionic nature of the [1,4]-Wittig pathway was

supported.

190

 

 

Scheme 6.35. Radical-radical anion dissociation-recombination in or-alkoxysilanes
bearing substituent at the terminal sp2 carbon of the allyl moiety

r- '1

e TMS ' CH
TMSWCHS TMSWCHB WW3 WSW 3
O—\Ph O—\Ph 90 30

55 179 180 Ph 181 Ph

—

 

 

 

 

 

Scheme 6.36. Carbanion formation in the [1,4]-pathway in a-alkoxysilanes
bearing a substituent at the terminal sp2 carbon of the allyl moiety

TMS 9 CH3 TMS CH3 TMS CH3
W .___.. W _. ’e‘;
oj o—\ o--(

179 P“ 182 P“ 133’”h

 

Me3Si 3 CH3
2 4

c9. 1%
H3C Ph

F elkin reported in 197735 that, on treatment with excess butyl lithium in THF at
-25 °C, optically active allyl a-phenylethyl ether 184 underwent rearrangement to afford
a mixture of anionic products via [1,2]- and [1,4]-rearrangements, which were converted
to a mixture of the saturated products in 60% overall yield in a ratio of 16:20:64 (Scheme
6.37). The authors observed that all three rearrangement products 187, 188, and 189
were predominantly formed with retention of configuration and the extent of
racemization was similar (30i5%). This suggested that reactions leading to both [1,2]
and [1,4] products occurred via the non-concerted radical-radical anion cleavage-
recombination mechanism. This observation is in contrast to our results- [1,2] and [1,4]

products were formed with different levels of retention of configuration (95% ee and

191

 

97% er retention for [1,2] and 73% ee and 88% er retention for [1,4]). This too could be

interpreted as suggesting different mechanisms for both types of Wittig rearrangements.

Scheme 6.37. Wittig rearrangement of allyl a-phenylethyl by F elkin3 5

 

 

 

WO‘fiZh nBuLi ,
184 Me THF, -25 C
Ph, H
> M Me
H 09
threo-[1,2]
1. H3O@ Ph’, H
A' : Me
2. LiAIH4 H OH
3. H2(Pt02) 187

,’;\
m
I

43% o
——> H - Ph
H \O Y
T‘Ph
Me Me
185 186
Ph, H H,’ Ph
+ / 3 Me + Maw
60 H 06
erythro-[1,2] [1.4]
Pb H
3 H, Ph
+ M Me MeMOH
HO H
188 189
16220264 (187/188/189)

Scheme 6.38. Stevens rearrangement of optically active
allylic ammonium salt by Jenny and Druey

 

Me\ Me
Meq Me N NH Meq Me MN
/\/N , Ph __..a 2 MN Ph _ I . V
/ @Y'M ’ e ‘ 69 "'Me Hth
H H
190(100) 191 Me
I 192
Ph" H, Ph
+ ’I
/ MeM/NMez
NMez
193 (~100%) 194 (40-60%)

192

 

In contrast to Felkin’s system, the Stevens rearrangement of optically active
allylic ammonium salt 190, analogous to Felkin’s S-allyl a-pheneyethyl ether 184, was
studied by Jenny and Druey,36 who found that the [1,4]-shift of the phenylethyl group is
accompanied by considerable racemization, whereas the [1,2]-migration, the major
process, is stereospecific (Scheme 6.38).

Felkin35 explained that the difference in the stereochemical course of the two
reactions could be due to a difference in the configurations of the two ions 185 and 191
and hence of the radical pairs 186 and 192 (Scheme 6.39). The authors35 argued that the
preference of allylic anions for the cis configuration37 leads to a radical pair 186 in which
the migrating oc-phenylethyl radical is situated somewhere near the middle of the allylic
moiety, a situation that results in approximately equal amounts of [1,2] and [1,4]
rearrangement products and a similar racemization. The ammonium zvvitterion in the
Stevens rearrangement, on the other hand, adopts the trans configuration 191. This
scenario leads to a radical pair 192 in which the migrating radical is placed close to the
carbon atom bearing the nitrogen, and remote from the terminal carbon of the allyl
moiety, resulting in a predominance of [1,2] over [1,4] rearrangement36 and a greater
racemization in the [1,4] product. According to F elkin3 5 the migrating radical has farther

to go in order to react.

193

 

 

very different from his.

retention/97% (er) retention of configuration at the migrating carbon.

Scheme 6.39. F elkin’s comparison of his and Jenny and Druey’s systems

,A\ ”:‘1
49‘ OH

H .0 H - Ph
W‘Ph Y
Me Me
185 186
Me\ _Me
Me‘NMe Ph /,..\/N
A/
I e \ @ IuMe —. H . Ph
H Y
191 Me
192

Our system is analogous to Felkin’s (Scheme 6.40), however, we obtained results

retention/88% (er) retention and our [1,2] product with approximately 95% (ee)

argument on the position of the migrating a-phenylethyl radical held in our case, then we
could argue that the [1,2] and [14)-alkyl shifts in a-alkoxysilanes do not have the same

mechanism. This is additional evidence in support of different reaction mechanisms for

the two types of alkyl shifts.

Scheme 6.40. Comparison of Felkin’s and our systems

 

 

. A R "25‘.
.P n-BuLI / \
WO$Hh ; e H . PhO
H _.O Y
R Me THF.T°C I‘Ph M
Me e

184: R = H, T = -25 °C; Felkin's
44: R = Me3Si, T = -78 °C; ours

194

Our [1,4]-rearrangement product is obtained with 73% (ee)

If Felkin’s

6.11. Conclusions

From our electrophilic trapping experiments we obtained conclusive evidence that
in the Wittig rearrangement of or-alkoxysilanes, a-deprotonation and cleavage of C-O
bond, and hence rearrangement, are not concurrent events. Our results could also be
interpreted to imply that the breaking of the O—C bond is the slow (rate limiting) step in
the Wittig rearrangement of this class of compounds.

In the Wittig rearrangement of a stereodefined a-alkoxysilane, the [1,4]-pathway
occurred with predominant retention of configuration at the migrating carbon. We
observed that the [1 ,4]-pathway in a pair of diastereomeric a-alkoxysilanes occurred with
similar levels of retention of configuration. On the other hand, the [1,2]-Wittig in the
same pair of diastereomeric substrates occurred with different levels of retention of
configuration (details to be presented in Chapter 7). This result is evidence that the [1,2]
and the [1,4]-Wittig rearrangements of or-silyl ethers proceed via different mechanisms.

[2,3]-Alkyl migration is a concerted, thermally allowed sigmatropic process
following the Woodward Hoffmann rulezsa or the Fukui’s frontier orbital theory.33 In the
[2,3]-alkyl shifi in E substrates, the resulting [2,3] product has predominantly anti
stereochemistry at the two newly formed stereocenters. We made a similar observation
in the [1,4]-Wittig rearrangement reaction of a-alkoxysilane E—56. However, the
experiment with Z—substrate would be very necessary for an unequivocal statement on the
mechanism of the [1,4]-Wittig rearrangement of or-alkoxysilanes. This part of the study

remains on of the areas for future study.

195

EXPERIMENTAL

TMS
Are MAP“ . .h
/ /
TMS TMS TMS TMS
TMS/“\¢J‘TMS
125 126 127

Electrophilic trapping of carbanion of 7-preparation of 125, 126, and 127: A
mixture of 612 mg (2.78 mmol) of 7, 1208 mg (11.12 mmol) of TMSCI, and 1124 mg
(11.12 mmol) of TEA in 43 mL of THF, was cooled to below —78 °C. Then, 7.40 mL
(6.95 mmol) of s-BuLi (0.94 M in cyclohexane) was added slowly via syringe.
Following the addition of base, reaction was stirred at -78 °C for 3-4 h, and then
quenched by adding saturated aqueous solution of NH4C1. Phases were separated and the
organic phase was washed with water, and brine, then dried over anhydrous MgSO4.
Filtration, followed by concentration gave the crude product as a mixture, which, afier
silica gel chromatography (0 to 1% EtOAc in hexane gradient) afforded 125, 126 and 127
in a combined 82% yield. Compounds 125, 126 and 127 were readily separable by
column chromatography on silica gel (hexanes neat).

125: IR (neat) 2955, 1609 1454, 1248 cm". 'H NMR (300 MHz, CDCl3) 5 7.42-
7.25 (m, 5H), 5.25-5.21 (t, J= 8.4 Hz, 1H), 4.75 (s, 2H), l.68-1.66 (d, J= 8.4 Hz, 2H),
0.21 (s, 9H), 0.03 (s, 9H). l3C NMR (75 MHz, CDCl3) 6 159.0, 139.0, 128.3, 127.3,
127.1, 123.7, 72.3, 16.5, -0.3, -l.7. HRMS (El) m/z 292.1686 [(M)+; calcd for
C16HngSi2, 292.1679].

126: IR (neat) 2955, 1591, 1304, 1250 cm". 'H NMR (500 MHz, CDC13) 5 7.38-

7.26 (m, 5H), 5.06-5.03 (d, J= 12.7 Hz, 1H), 4.71 (s, 2H), 193-191 ((1, J= 12.2 Hz, 1H),

196

0.16 (s, 9H), 0.00 (s, 18H). 13C NMR (125 MHz, CDCl3) 8 158.0, 139.2, 128.2, 127.2,
126.9, 125.5, 72.0, 18.3, -02, -04. HRMS (131) m/z 364.2078 [(M)+; calcd for

C19H36OSi3, 364.2074].

127: A white semi solid, melting near room temperature. IR (neat) 2955, 1601,
1495, 1448, 1408, 1248 cm". ‘H NMR (300 MHz,CDC13)5 7.26-7.03 (m, 5H), 4.97-
4.91 (dd, J = 9.7 Hz, 1H), 4.70 (s, 1H), 2.07-2.00 (dd, J = 12.8, 9.7 Hz, 1H), 1.43-1.36
(dd, J= 12.4, 12.8 Hz, 1H), 0.01 (s, 9H), 0.00 (s, 9H), -0.02 (s, 9H). 13C NMR (75 MHz,
CDCl3) 8 159.0, 141.9, 127.7, 125.3, 125.2, 120.1, 76.5, 16.9, 0.2, -1.5, -3.8. HRMS (E1)

m/z 364.2078 [(M)+; calcd for C19H3éOSi3, 364.2074].

TMS TMS
O/§§/J\TMS o/L\¢¢‘TMS
TMS/\\%J\TMS TMS/“\¢A\TMS
131 132

A mixture of 187 mg (0.77 mmol) of 40, 333 mg (3.07 mmol) of TMSCI, and 310
mg (3.07 mmol) of TEA in 43 mL of THF, was cooled to below —78 °C. Then, 1.48 mL
( 1.92 mmol) of s-BuLi (1.3 M in cyclohexane) was added slowly via syringe. Follow
addition of base, reaction was stirred at -78 °C for 3-4 h, then quenched by adding
saturated aqueous solution of NH4C1. Phases were separated, the organic phase washed
with water, and brine, then dried over anhydrous MgSO4 and concentrated to give the
crude product as a mixture, which, afier silica gel chromatography (0 to 1% EtOAc in
hexane gradient) afforded the 131 and 132 in a combined 86% yield. IR (neat) 2955,
1640, 1616, 1377, 1248 cm'l.

131: 1H NMR (500 MHz, CDC13) 8 6.00 (d, J= 5.7 Hz, 1H), 5.24 (t, J= 8.8, 8.4
Hz, 1H), 4.19-4.15 (dd, J= 12.4, 5.7 Hz, 1H), 1.60-1.58 (d, J= 8.8 Hz, 2H), 1.57-1.55 (d,

197

J = 12.4 Hz, 1H) 0.11 (s, 9H), 0.03 (s, 18H), -0.01 (s, 9H). 13C NMR (125 MHz, CDCl3)
8 158.6, 142.4, 125.0, 103.2, 16.7, 15.6, -0.3, -1.1, -1.7. HRMS (EI) m/z 386.2321 [(M)+;
calcd for C13H420Si4, 386.2313].

132: 1H NMR (500 MHz, CDCl3) 8 6.0-5.94 (dd, J = 19.0, 5.7 Hz, 1H), 5.54-5.50
(dd, J = 19.0, 1.8 Hz, 1H), 4.96-4.92 (apparent dd, J = 9.3, 8.8, 7.9, 7.5 Hz, 1H), 4.19-
4.17 (dd, J= 5.7, 1.8 Hz, 1H), 1.82-1.77 (dd, J= 12.8, 9.3 Hz, 1H), 1.42-1.38 (dd, J=
13.2, 12.8, 8.0, 7.5 Hz, 1H), 0.07 (s, 9H), 0.03 (s, 9H), 0.01 (s, 9H), -0.02 (s, 9H). 13C
NMR (125 MHz, CDCl3) 5 159.4, 146.4, 125.6, 120.1, 77.9, 16.5, 0.2, -1.1, -1.5, -3.8.

HRMS (El) m/z 386.2309 [(M)+; calcd for C13H4zOSi4, 386.2313].

910A
MTMS

139

Preparation of 139: Ethylchloroformate (1.13 g, 10.41 mmol) was added to a
cold (0 °C) solution of 34 (1.0 g, 6.94 mmol) in hexane/acetonitrile (1:1 v/v, 20 mL),
followed by pyridine (1.70 mL, 20.82 mmol), and the reaction stirred at 0 °C for 2 h
(TLC showed absence of starting material). The reaction was quenched by the addition
of H20 (30 mL), diluted with CH3CN (50 mL), and then hexanes (150 mL). Layers
separated and the hexane/acetonitrile layer was washed with brine (30 mL), dried with
NaZSO4, and concentrated under reduced pressure to give the crude product, which was
employed in the second step without further purification. To a solution of the crude
carbonate in hexane/acetonitrile (1:1 v/v, 30 mL) at 0 °C, was added (1R,ZS)-(+)-
norephedrine (1.3 equiv, 1.36 g, 9.0 mmol), followed by diisopropylethylarnine (3.63

mL, 20.82 mmol). The reaction was allowed to warm to room temperature overnight,

198

then quenched by the addition of H20. Phases were separated and the organic phase
(hexane/acetonitrile) washed with brine, dried with Na2SO4, and concentrated under
reduced pressure to yield the desired product as a clear oil. The second step did not go,
and after purification by column chromatography on silica gel (3% EtOAc in hexanes),
632 mg (42%) of 139, the product of the first step, was obtained as a clear oil. IR (neat)
2961, 1744, 1451, 1370, 1277, 1252 cm'l. 1H NMR (300 MHz, CDC13) 5 5.58-5.41 (m,
2H), 4.87-4.85 (d, J = 6.3 Hz, 1H), 4.18-4.11 (q, J = 7.1 Hz, 2H), 1.67 (d, J = 5.5 Hz,
3H), 1.27 (t, J= 7.1 Hz, 3H), 0.03 (s, 9H). 13C NMR (75 MHz, CDCl3) 8 155.7, 127.1,
125,6, 74.5, 63.8, 17.9, 14.3, -4.0. HRMS (E1) m/z 216.1184 [(M+H)+; calcd for

C10H2003Si, 216.1182].

141

Preparation of carbonate 141: p-Nitrophenylchloroformate (629 mg, 3.12
mmol) was added to a cold (0 °C) solution of 34 (300 mg, 2.08 mmol) in
hexane/acetonitrile (1 :1 v/v, 11 mL), followed by pyridine (0.51 mL, 6.25 mmol), and the
reaction stirred at 0 °C for 2 h (TLC showed absence of starting material). The reaction
was quenched by the addition of H20 (5 mL), diluted'with CH3CN (10 mL), and then
hexanes (20-25 mL). Layers separated and the hexane/acetonitrile layer was washed with
brine (30 mL), dried with Na2SO4, and concentrated under reduced pressure to afford 294
mg (0.95 mmol, 46% yield) of the pure carbonate 141 (mp 58.5-59.5 °C). IR (neat)
2961, 1763, 1616, 1595, 1526, 1493, 1348, 1252, 1213 cm]. lH NMR (500 MHz,

CDCl3) 5 8.26-8.23 (d, J= 9.1 Hz, 2H), 737-734 ((1, J= 9.3 Hz, 2H), 5.68-5.61 (m, 1H),

199

5.59-5.50 (m, 1H), 4.99-4.96 (d, J: 7.7 Hz, 1H), 1.72 (d, J = 6.3 Hz, 3H), 0.09 (s, 9H).
l3C NMR (125 MHz, CDCl3) 5 155.9, 152.9, 145.2, 127.4, 126.2, 125.2, 121.8, 77.1,

17.9, -4.0. HRMS (FAB+) m/z 308.0957 [(M-HY; calcd for C14H13N05Si, 308.0955].

0

TMS/QAOH

142

Preparation of 3-trimetylsilanyl-oxiranyl)-methanol 142: To a cold (-20 0C)
solution of n-BuLi (1.6 M in hexanes, 2.0 equiv, 160.0 mmol, 100 mL) in a round-bottom
flask was added propargyl alcohol (1.0 equiv, 80 mmol, 4.66 mL) as a solution in THF (5
M, 16 mL Et20). Subsequently TMSCI (2.2 equiv, 176 mmol, 19.12 g, 22.34 mL) was
added over 30 min (-15 to -20 °C). Reaction was stirred for additional 2 h at room
temperature, poured into an excess of 1N H2S04 solution, and stirred for 2 h at room
temperature. Phases were separated and the aqueous phase was extracted with B20 (4 x
50 mL). The combined ethereal solutions were washed with NaHSO4 (sat, aq) to
neutralize the H2SO4, then dried over anhydrous MgSO4, filtered, and the solvent
removed under reduced pressure to give the crude product, (E)-3-Trimethylsilanyl-prop-
2-en-1-ol. Distillation through a 40-cm Vigreux column under reduced pressure gave
3.77 g (3 7%) of the desired allyl alcohol employed in the oxidation step.

m-CPBA (2.0 equiv, 3.0 g, 23.03 mmol) solution in CH2C12 (140 mL) was added
to a cold (0 °C), stirred solution of the E-3-trimethylsilany1prop-2-en-1-ol from step one
above (1.0 equiv, 0.22 g, 1.66 mmol) in CH2C12 (50 mL) via syringe, and the reaction
mixture stirred at 0 °C and monitored by GC-FID and TLC. After 6 h, the reaction
mixture was filtered to remove precipitated m-chlorobenzoic acid. The solvent was

removed in vacuo; the resultant massive white solid was dissolved in the minimal amount

200

 

of hexanes, filtered and washed with a minimal amount of hexanes. The solvent was
removed in vacuo to give a colorless oil, which was purified by silica gel column
chromatography using hexanes/EtOAc (20%) as eluent to give the pure epoxide 142 in
66% yield. IR (neat) 3418, 2959, 1720, 1410, 1250 cm". 'H NMR (300 MHz, CDCl3) 6
400-394 (d, J= 13.0 Hz, 1H), 3.56 (d, J= 12.1 Hz, 1H), 3.01 (m, 1H), 2.25 (d, J= 3.7
Hz, 1H) 0.05 (s, 9H). ”C NMR (125 MHz, CDCl3) 8 63.5, 56.1, 48.3, -3.8. 142 is a

known compound and has spectral data in accord with the reported ones.39

OH

TMs/L\/”\0H

143

Preparation of 1-trimetylsilanyl-propane-1,3-diol 143: To a solution of 3-
trimethylsilanyl-2,3-epoxypropan-1-ol (1.0 equiv, 220 mg, 1.50 mmol) in THF (2.0 ml)
was added dropwise via syringe, a 1.0 M solution of LiB(C2H5)3H (superhydride) (2.0
equiv, 3.01 mmol, 3.0 m1 ) in THF. The reaction was stirred at room temperature for 1 h,
at which time sampling by GC-MS revealed the complete consumption of the starting
epoxyalcohol. Then water was added to quench the reaction, followed by washing with
NaHSO4 (sat, aq), and brine. The organic phase was dried over anhydrous MgSO4,
filtered, and concentrated to furnish the crude product. Purification by silica gel column
chromatography using hexanes/EtOAc (20%) afforded 200 mg (90% yield) of 143 as a
clear 011. IR (neat) cm". 'H NMR (300 MHz, CDC13) 5 4.52-4.46 (m, 1H), 4.23420
(dd, J = 8.8, 7.5 Hz, 1H), 3.64-3.61 (dd, J = 8.8, 7.5 Hz, 1H), 1.10-1.06 (dd, J = 14.1, 7.1
Hz, 1H), 0.89-0.84 (dd, J = 14.1, 7.9 Hz, 1H), 0.02 (s, 9H). ”C NMR (300 MHz, CDC13)
6 73.0, 25.4, 7.6, -1.0. 143 is a known compound and has spectral data in accord with the

4
reported ones. 0

201

TMS/\KOH

OH
144

Preparation of 3-trimethylsilanyl-propane—l,2-diol 144: To a cold (0 0C)
solution of 3-trimethyl-silanyl-2,3-epoxypropan-1-ol (1.0 equiv, 0.10 g, 0.684 mmol) in
dimethoxyethane (DME) (3.5 ml) was added a 65+% solution of sodium bis(2-
methoxyethoxy)aluminum hydride (Red-A1) in toluene (1.05 equiv, 0.718 mmol)
dropwise under N2. Following this addition, the reaction was allowed to warm to room
temperature and stirred for 4.5 h. The reaction mixture was diluted with ether and
quenched with 5% HCI solution. Phases were separated and the aqueous phase washed
with ether. The combined organic phase was dried with anhydrous MgSO4, filtered, and
concentrated to give the crude product, which was clean (60% yield). Purification by
silica gel column chromatography using hexanes/EtOAc (20%) as eluent afforded 144 in
almost the same condition as the crude. This reaction was not optimized. IR (neat) 3358,
2952, 2919, 1420, 1250 cm". 1H NMR (300 MHz, CDCl3) 8 3.89-3.77 (m, 1H), 3.61-
3.56 (dd, J: 11.0, 2.7 Hz, 1H), 3.35-3.29 (dd, J= 11.0, 8.2 Hz, 1H), 2.58 (bs, 2H), 0.83-
0.76 (dd, J= 14.3, 8.2 Hz, 1H), 0.72-0.65 (dd, J = 14.8, 14.3 Hz, 1H). 13C NMR (300

MHz, CDCl3) 8 70.3, 69.1, 21.6, -0.8. 144 is a known compound and has spectral data in

accord with the reported ones.41

0

TMS/QAOTS

148

Preparation of toluene-4-sulfonic acid 3-trimethylsilanyl-oxiranylmethyl
ester 148: To a cold (0 °C) solution of 3-trimethylsi1anyl-2,3-epoxypropan-1-ol 1.0

equiv, 0.40 g, 2.74 mmol) in CH2C12 (5 mL) were added TsCl (1.05 equiv, 0.55 g, 2.87

202

 

 

mmol), followed by Et3N (2.5 equiv, 0.69 g, 6.83 mmol). The reaction mixture was
allowed to warm to room temperature and stirred overnight. Reaction was quenched with
NaHCO3 (sat, aq), and diluted with CH2Cl2. Phased separated and the organic phase was
washed with NH4C1 (sat, aq) and brine, then dried over MgSO4. Filtration and
concentration under reduced pressure afforded 0.73 g (89%) of tosylate 148. IR (neat)
2957, 1599, 1450, 1364, 1250, 1176 cm“. 1H NMR (500 MHz, CDCl3) 5 7.78 (d, J= 8.2
Hz, 2H), 7.33 (d, J = 7.7 Hz, 2H), 4.27-4.24 (dd, J = 11.2, 3.3 Hz, 1H), 3.90-3.87
(apparent dd, J = 11.5, 11.0, 6.6, 6.1 Hz, 1H), 3.03-3.00 (m, 1H), 2.43 (s, 3H), 2.03 (d, J
= 3.3 Hz, 1H). ”C NMR (125 MHz, CDCl3) 5 145.0, 132.8, 129.9, 127.9, 72.3, 52.4,

49.0, 21.6, -3.8.

1:>112Mt--:Si\H/o\roW

150

Preparation of [1-(1-ethoxy-ethoxy)-propa-l,2-dienyl]-methyldiphenylsilane
150: A dry 100 mL round-bottomed flask was flushed with N2, and charged with ethyl
vinyl ether (20.94 g, 0.29 mmol, 28 mL) and cooled to 0 °C. Then p-toluenesulfonic acid
(13 mg, 0.07 mmol) was added with stirring, followed by dropwise addition of propargyl
alcohol (11.63 g, 0.21 mol, 12.08 mL) over 20 min, while keeping the reaction
temperature close to 0 °C. After stirring for additional 30 min, K2C03 (sat, acfi was
added with vigorous stirring. Phases were separated and the organic phase was dried
over anhydrous K2CO3, filtered and excess vinyl ether removed by evaporation on a
rotavap. The residue was then distilled under reduced pressure (oil bath temperature

approx. 60 °C) to afford 16.02 g, 60% of the pure 1-(1-ethoxy-ethoxy)-propa-l,2-diene.

203

A solution of 1-(1-ethoxy-ethoxy)-propa-1,2-diene (10.18 g, 79.45 mmol) and BHT (1.5
mg/mmol substrate, 0.12 g, 0.54 mmol) in 320 mL THF in a 1 L round bottom flask was
cooled to —80 °C, with stirring, and n-BuLi (1.5M solution in hexanes, 84.22 mmol,
56.15 mL) was added dropwise via a syringe over 1.5 h. After stirring for additional 30
min, a solution of Ph2MeSiCl (19.98 g, 85.81 mmol, 18 mL) in THF (30 mL) was added
dropwise via a syringe, followed by addition of a solution of HMPA (15.66 g, 87.40
mmol, 15.2 mL) in THF (30 ml). The reaction mixture was stirred at —80 °C overnight,
then Et3N (12 mL) was added and the mixture stirred vigorously for 10 min, then poured
into NaHCO3 (sat, aq) (200 mL) and ether/pentane (1:1 v/v) added. Phases were
separated and the aqueous phase washed with ether/pentane (1 :1) (x 2). The combined
organic phases were subsequently washed with H20 and brine, passed through anhydrous
Na2SO4, and then dried over K2C03. Filtration, evaporation of solvent with a rotavap,
and removal of the rest of the volatile components by distillation gave quantitative yield
(29.22 g) of the product 150 as a thick brown oil. IR: (neat) 2978, 2178, 1589, 1429,
1385, 1254 cm". 1H NMR (500 MHz, CDCl3) 5 7.64-7.34 (m, 10H), 4.90-4.87 (q, J =
5.3 Hz, 1H), 4.35-4.27 (q, J= 5.0 Hz, 2H), 3.70-3.63 (m, 1H), 3.53-3.47 (m, 1H), 1.35-
1.34 (d, J= 5.3 Hz, 3H), 1.20-1.17 (t, J= 7.1 Hz, 3H), 0.70 (s, 3H). 13C NMR (75 MHz,

CDCl3) 8 135.0, 134.5, 129.7, 127.9, 105.4, 98.8, 87.1, 61.1, 53.4, 19815.2, -2.1.

thMeSiWOH

151
Preparation of 1-(methyldiphenylsilanyl)-propa-l,2-dien-l-ol 151: [1-(1-

ethoxy-ethoxy)-propa-1,2-dienyl]-dimethylphenylsilane 150 (28.58 g, 88 mmol) was

204

added to 2N H2804 (13.2 mL in 88 mL THF) and stirred at room temperature overnight.
Reaction was poured into H20 and extracted with ether/pentane (1:1). The combined
organic fractions were washed with H20 (x 3) and brine (x I), poured through anhydrous
Na2SO4, dried over Na2SO4 and concentrated under reduced pressure to give the crude l-
(diphenylmethylsilany1)-propa-1,2-dien-1-ol 151, which was purified by chromatography
on silica gel (0-5% EtOAc in hexane gradient) to give a quantitative yield of the pure
product. IR (neat) 3327, 2961, 2178, 1429, 1254, 1115, 1041 cm". 1H NMR (300 MHz,
CDCl3) 8 7.70-7.40 (m, 10H), 4.34 (s, 2H), 2.23 (bs, 1H), 0.76 (s, 3H). 13C NMR (300
MHz, CDCl3) 8 134.74, 134.42, 129.73, 127.93, 107.17, 86.94, 51.55, -2.24. HRMS (BI)

m/z 252.0959 [(M)+; calcd for C16H16OSi, 252.0970].
PhMe2Si\H/OT07
152

Preparation of [1-(1-ethoxy-ethoxy)-propa-l,2-dienyl]-dimethylphenylsilane,
152: A dry 100 ml round-bottomed flask was flushed with N2, and charged with ethyl
vinyl ether (20.94 g, 0.29 mol, 28 mL) and cooled to 0 °C. Then p-toluenesulfonic acid
(13 mg, 0.07 mmol) was added with stirring, followed by dropwise addition of propargyl
alcohol (11.63 g, 0.21 mol, 12.08 mL) over 20 min, while keeping the reaction
temperature close to 0 °C. After stirring for additional 30 min, K2C03 (sat, aq) was
added with vigorous stirring. The organic phase was dried over anhydrous K2CO3,
filtered and excess vinyl ether removed by rotavap. The residue was then distilled under
reduced pressure (oil bath temperature approx. 60 °C) to afford 16.02 g, 60% of the pure

1-(l-ethoxy-ethoxy)-propa-1,2-diene. A solution of 1-(1-ethoxy-ethoxy)-propa-1,2-diene

205

(5.10 g, 39.73 mmol) and BHT (1.5 mg/mmol substrate, 0.06 g, 0.27 mmol) in 160 mL
THF was cooled to —80 °C, with stirring, and n-BuLi (1.5 M solution in hexanes, 42.11
mmol, 28.1 mL) was added dropwise via a syringe over 1 h. After stirring for additional
30 min, a solution of PhMe2SiCl (7.33 g, 42.90 mmol, 7.20 mL) in THF (15 mL) was
added dropwise via a syringe, followed by addition of a solution of HMPA (7.831 g,
43.70 mmol, 7.6 mL) in THF (15 mL). The reaction mixture was stirred at —80 °C
overnight, then EI3N (6 mL) was added and the mixture stirred vigorously for 10 min,
then poured into NaHCO3 (sat, aq) (100 mL) and ether/pentane (1:1 v/v) added. Phases
were separated and the aqueous phase washed with ether/pentane (1:1) (x 2). The
combined organic phases were subsequently washed with H20 and brine, passed through
anhydrous Na2S04, and then dried over K2C03. Filtration, removal of solvent by
rotavap, and removal of the rest of the volatile components by distillation gave 8.35 g
(80%) of the product 152 as thick brown oil. IR (neat) 2974, 2176, 1428, 1384, 1251,
1116, 1056 cm'l. ‘H NMR (300 MHz, CDCl3) 8 7.63-7.35 (m, 5H), 4.89-4.83 (q, 1H),
4.24 (s, 2H), 3.71-3.43 (m, 2H), 1.34-1.32 (d, 3H), 1.21-1.17 (m, 3H), 0.41 (s, 6H). 13C
NMR (75 MHz, CDCl3) 8 136.6, 133.62, 129.45, 127.84, 103.60, 98.61, 88.64, 60.88,

53.32, 19.71, 15.21, -1.05. 152 is a known compound.”a

PhMefiim/OH

154
Preparation of l-(dimethylphenylsilanyl)-propa-l,2-dien-l-ol 154: [1-(1-
ethoxy-ethoxy)-propa-1,2-dienyl]-dimethylphenylsilane was added to 2N H2S04 (4.7 mL

in 31 mL THF) and stirred at room temperature overnight. Reaction was poured into

206

H20 and extracted with ether/pentane (1:1). The combined organic fiactions were
washed with H2O (x 3) and brine (x 1), poured through anhydrous Na2SO4, dried over
Na2SO4 and concentrated under reduced pressure to give 6.65 g (88%) of the crude 1-
(dimethylphenylsilanyl)-propa-1,2-dien-l-ol, which was purified by chromatography on
silica gel (0-5% EtOAc in hexane gradient) to give the product 154 in 71% yield. IR
(neat) 3324, 2961, 2178, 1492, 1250 cm]. 1H NMR (300 MHz, CDCl3) 8 7.63-7.36 (m,
5H), 4.28 (s, 2H), 1.78 (bs, 1H), 0.42 (s, 6H). ‘3 C NMR (75 MHz, CDC13) 8 136.4, 133.6,
129.5, 127.9, 105.4, 88.7, 51.7, -1.1. HRMS (E1) m/z 190.0817 [(M)+; calcd for

CHHMOSi, 190.0814].

OSiMezPh

SiMezPh
155

Preparation of 153 and 155-oxidation of oxidation of a-hydroxysilane 33: To
a cold (-35 to -30 0C) solution of 2,4,6-trichloro[1,3,5]-triazine (cyanuric chloride) (8.23
g, 44.65 mmol) in THF (150 mL), was added DMSO (12.4 mL, 174.74 mmol) and the
mixture stirred for 40 min. A 0.1 M THF solution of 1-(dimethylphenylsilany1)-prop-2-
en-l-ol (5.72 g, 29.76 mmol) was added very slowly and the reaction stirred for 2 h,
followed by the addition of TEA (19.80 mL, 142 mmol). After stirring for an additional
1 h, the reaction was warmed to room temperature. The solvent was removed under
vacuum and B20 added to the resulting solid residue. Reaction was quenched by adding
HCl (1M, 2.0 mL). Phases were separated and the organic phase washed with NaHCO;
(aq, sat), followed by brine, dried over Na2SO4 and the solvent evaporated to give the

oxidation products 153 (371 mg, 6% yield) and 155 (1.61 g, 17% yield). 155: IR (neat)

207

2959, 1630, 1427, 1252 cm". 'H NMR (300 MHz, CDC13)8 7.55-7.31 (m, 10H), 5.87-
5.80 (m, 1H), 5.04-5.00 (d, J= 17.8 Hz, 1H), 4.91-4.88 (d, J= 10.3 Hz, 1H), 4.18 (d, J=
2.4 Hz, 1H), 0.27 (s, 3H, 0.26 (s, 6H), 0.23 (s, 3H). ”C NMR (75 MHz, CDCl3) 5 138.8,
134.3, 133.6, 129.3, 129.1, 127.7, 127.6, 110.5, 69.3, -1.1, -12, -59, -6.0. HRMS

(FAB+) m/z 326.1521 [(M)*; calcd for C19H260Si2, 326.1522].

o
VLSiMeZPh

153

Preparation of 153: Swern oxidation of 33: To a cold (-50 OC) solution of
oxalyl chloride (1.32 mL, 15.06 mmol) in CH2Cl2 (18.30 mL) was added via syringe,
DMSO (2.15 mL, 30.13 mmol) solution in CH2C12 (4.56 mL) and the reaction stirred for
20 min. Then, the substrate alcohol 33 (2.63 g, 13.70 mmol) solution in CH2C12 (4.56
mL) was added via syringe and the reaction stirred at -50 °C for 20 min. Et3N (7.63 mL,
54.79 mmol) was added by syringe (reaction turned yellow and massive precipitate
formed). The cold bath was removed and the reaction allowed to warm to room
temperature over 1 h. Aqueous workup, and purification by column chromatography on
silica gel (0 to 2% EtOAc in hexane gradient) afforded 153 and 155 (10:1) in 91% yield.
IR (neat) 2961, 1726, 1640, 1601. 1429, 1252 cm“. lH NMR (300 MHz, CDCl3) 5 7.54-
7.35 (m, 5H), 6.44-6.38 (dd, J= 18.0, 11.0 Hz, 1H), 5.95 (d, J= 17.2), 5.81 (d, J= 11.0,
1H), 0.52 (s, 6). 13C NMR (75 MHz, CDCl3) 8 235.5, 141.1, 135.2, 133.9, 129.8, 128.9,
128.2, -3.7. 153 is a known compound and have spectral data in accord with the reported

01165.10

208

0

SiMezPh
Cl
156

156: IR (neat) 2963, 1699, 1626,1429, 1252, 1111 cm". 1H NMR (300 MHz,
CDCl3) 8 7.53-7.36 (m, 5H), 6.25 (d, J= 2.2 Hz, 1H), 6.11 (d, J= 2.2 Hz, 1H), 0.57 (s,

6H). ”C NMR (75 MHz, CDCl3) 5 224.5, 144.4, 134.5, 133.9, 130.2, 128.4, 127.8, -32.

0A0

\ TMS
157

Enzymatic resolution of 1-trimethylsilanyl-prop-Z-en-l-ol 32-preparation of
(S)-(-)-32: To a solution of racemic a-hydroxysilane 32 (7.71 g, 59.27 mmol) in pentane
(20 mL, 4.0 M) were added Novozym 435 (0.015 g/mmol racemic alcohol, 0.89 g) and
vinyl acetate (1.5 equiv, 7.65 g, 88.90 mmol, 8.2 mL). The reaction was stirred at to 38
0C and monitored by chiral GC (BETA DEX TM 325 capillary column, 30 m x 0.25 mm
x 0.25 um film thickness, Catalog No. 24308; Program 30 to 100 °C, at 5 °C/min, hold at
100 °C for 2 min). Then reaction mixture was filtered through a pad of Celite 503,
concentrated, and purified by silica gel column chromatography. Optical rotation IR
(neat) 2961, 1742, 1636, 1370, 1235 cm". ‘H NMR (300 MHz, CDCl3) 5 5.84-5.77 (m,
1H), 5.26-5.14 (dt, J = 6.0, 2.0 Hz, 1H), 4.98-4.93 (m, 1H), 2.05 (s, 3H), 0.02 (s, 9H).

13C NMR (75 MHz, CDCl3) 8 170.6, 134.9, 111.2, 70.6, 20.9, -4.1. 157 is a known

compound and has spectral data in accord with the reported ones.42

./

HO\n/\/:\Ph
O 158

209

Preparation of 4-phenyl-hexanoic acid 158. 30% H202 (1.0 mL) and 3N NaOH
(0.50 mL) were added to a solution of 4-pheny1-l-trimethylsilanyl-hexan-l-one (0.32
mmol, 0.08 g) in MeOH (3.0 mL) and the mixture turned cloudy, which dissipated on
stirring at room temperature for 20 min. The mixture was extracted with ether, and
concentrated. Purification by column chromatography on silica gel (hexane/EtOAc (0-
10%) gave 0.022 g (0.116 mmol, 36%) of 4-phenyl-hexanoic acid 158. IR (neat) cm".
1HNMR (CDC13, 300 MHz) 8 0.76 (t, 3H), 1.50-1.72 (m, 2H 3H), 1.75-1.88 (m, 1H),
1.95-2.07 (m, 1H), 2.15 (t, 2H), 2.37-247 (m, 1H). ”CNMR (CDC13, 125 MHz) 5 179.1,
144.2, 128.4, 127.7, 126.3, 47.1, 32.0, 31.1, 29.6, 12.1. 158 is a known compound and

have spectral data in accord with the reported ones.43

Ph OH

O
/ 161

Preparation of 3-phenyl-pentanoic acid 161. N-(2-Hydroxy-1-methyl-2-
phenyl-ethyl)-N—methyl-3-phenyl-acrylamide: A solution of cinnamoyl chloride (1.15
equiv, 22.80 mmol, 3.8 g) in THF (8.0 mL, 2.85 M) was added via cannula over 10 min
to an ice-cold solution of L-(-)-ephedrine-HC1(1.0 equiv, 19.83 mmol, 4.0 g) and proton-
sponge in THF (47 M, 0.42 M L-(-)-ephedrine). Reaction was stirred at 0 °C and allowed
to warm to rt for 24 h. The reaction mixture was partitioned between EtOAc (79 mL) and
brine (6.0 mL). Phases were separated and the aqueous phase extracted with EtOAc to
afford 6.95 g of the crude product, which was passed through silica gel column to give
6.03 g (18.17 mmol, 92%) of and excess phenylacetyl N-(2-Hydroxy-1-methyl-2-phenyl-

ethyl)-N-methyl-3-pheny1-acrylamide. This amide was employed in the following step.

210

Alkylation of N-(2-hydroxy-l-rnethy|-2-phenyl-ethyl)-N-methyl-3-phenyl-
acrylamide: A 3-necked round-bottomed flask equipped with a condenser (carrying a
drying tube), an addition funnel, and a magnetic stir bar was charged with Mg (7.95 g,
327.12 mmol) and ether (80 mL). The flask was immersed in an oil bath and a solution
of EtBr (11.88 g, 109.04 mmol) in ether (50 mL) added slowly. Reaction was stirred at
reflux for 3 h and transferred via cannula to a cold (-78 °C) solution of N-(2-hydroxy-l-
methyl-2-phenyl-ethyl)-N-methyl-3-phenyl-acrylamide (from step one above) (6.03 g,
18.17 mmol) in ether/T HF (1:1.5 v/v, 280 mL). Following the transfer, reaction was
allowed to warm from -78 to -40 °C and stirred at this temperature for 48 h. The reaction
was filtered (to remove insoluble materials), residue washed with EtOAc. The aqueous
phase was extracted with EtOAc, combined organic extract dried over MgSO4, filtered,
concentrated, and purified by column chromatography on silica gel (hex/EtOAc (0-40%)
to afford 160 in >100% yield. Acid hydrolysis: Compound 160 was dissolved in AcOH
(43 mL) and 6N H2804 (86 mL), and refluxed for 3 h. The reaction mixture was cooled
to room temperature, diluted with ether, and phases separated. The aqueous phase was
extracted with ether (40 mL x 3) and the combined ethereal extracts was washed with
brine, and dried over MgSO4. Filtration and concentration under reduced pressure
afforded 2.63 g of the crude 161. Purification by column chromatography on silica gel
(hexanes/EtOAc (0-50%) afforded 1.87 g (10.52 mmol, 58% yield) of the pure acid (yield
was over 2 steps). IR (neat) 3400-2500, 1709, 1933, 1605, 1495, 1452, 1412, 1285 cm".
1H NMR (300 MHz, CDC13) 8 11.31 (bs, 1H), 7.32-7.16 (m, 5H), 3.04-2.94 (m, 1H),

2.71-2.56 (m, 2H), 1.80-1.53 (m, 2), 0.78 (apparent t, J= 7.7, 7.1 Hz, 3H). ”C NMR (75

211

MHz, CDCl3) 8 178.7, 143.4, 128.3, 127.3, 126.4, 43.5, 41.2, 29.1, 11.9. 161 is a known

compound and have spectral data in accord with the reported ones.44

Ph W011
/ 162
Preparation of 3-phenyl-pentan-1-ol 162. To a solution of LAH (0.98 g, 25.87
mmol) in THF (80 mL) was added a solution of 3-phenyl-pentanoic acid 161 (1.80 g,
10.14 mmol) in THF (50 mL), and the reaction refluxed for 18-20 h. The reaction was
quenched by very careful addition of H20. Phases were separated and the aqueous phase
was extracted with ether (50 mL x 3). The combined ethereal layer was washed with
H20 and brine, dried over MgSO4, filtered and concentrated to give 1.88 g of crude 3-
phenyl-pentan-l—ol as a light yellow, thick oil. Purification by column chromatography

on silica gel (hexanes/EtOAc (0-10%) afforded 1.28 g (7.81 mmol, 74%) of alcohol 162

as a thick colorless oil. [a]:+11, (c. 1.21, PhH). IR (neat) 3331, 2963, 2930, 1603,

1495, 1452, 1372 cm". 'H NMR (300 MHz, CDCl3) 5 7.30-7.12 (m, 5H), 3.54-3.39 (m,
2H), 2.62-2.51 (m, 1H), 1.99-1.87 (m, 1H), 1.83-1.72 (m, 1H), 1.70-1.50 (m, 3H), 0.77 (t,
J= xx Hz, 3H). ”C NMR (125 MHz, CDC13) 5 144.8, 128.3, 127.5, 126.0, 61.2, 44.3,
39.3, 29.8, 12.2. 162 is a known compound and have spectral data in accord with the

reported ones.45

Preparation of (3-Bromo-l-ethyI-propy1)-benzene 163. A 100 mL 2-necked
round-bottomed flast was charged with 3-phenyl-pentan-1-ol 162 (1.0 equiv, 3.05 mmol,

212

0.50 g), CBr4 (1 .25 equiv, 3.81 mmol, 1.26 g) and CH2Cl2 (to make a 0.1 M solution of 3-
phenyl-pentan-l -01. The flask was capped under N2 and cooled to 0 °C. Then, a solution
of PPh3 (1.5 equiv, 4.57 mmol, 1.2 g) in CH2C12 (10 mL, 0.45 M) was added at the rate of
0.86 ml/min, and reaction stirred at 0 °C for 1.5 h. Reaction mixture was allowed to
warm to room temperature, and diluted with ether. White precipitates formed. Filtration,
concentration of the filtrate, and purification by column chromatography on silica gel
afforded 0.69 g (3.04 mmol, 99.80%) of (3-Bromo-1-ethyl-propyl)-benzene 163.46 IR
(neat) 2961, 2926, 1603, 1493, 1452, 1254 cm". 'H NMR (300 MHz, CDCl3) 5 7.30-
7.13 (m, 5H), 3.31-3.23 (m, 1H), 3.14-3.05 (m, 1H), 2.7-2.60 (m, 1H), 2.24-2.01 (m, 2H),
1.73-1.51 (m, 2H), 0 78 (t, J= 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) 8 143.5, 128.4,

127.6, 126.3, 46.1, 39.5, 32.3, 29.4. 122- M”

Q.

1311\/\)<Sime3

164

\....

Preparation of trimethyl-[2-(3-phenyl-pentyI)-[l,3]dithian-2-yl]-silane 164.
To a cold (-25 °C) THF solution of 2-silyl-1,3-dithiane (0.5 M, 1.0 equiv, 2.55 mmol,
0.49 g, 0.5 M in THF) was added dropwise over 20 min, n-BuLi (1.6 M solution in
hexane, 1.05 equiv). Reaction was stirred for 2 h, and transferred to a THF solution of 3-
bromo-l-ethyl-propyl)-benzene 163 (1.0 equiv, 2.55 mmol, 0.58 g, 0.5 M in THF).
Reaction was stirred at -25 °C for 5 8 h, and allowed to warm to room temperature for 10
h, and quenched by the addition of ether/water (4:3 v/v). Phases were separated, and the
organic layer washed with brine (x 2), dried over MgS04 and concentrated on the rotavap
to give crude trimethyl-[2-(3-phenyl-pentyl)-[1,3]dithian-2-yl]-silane 164. Purification

213

by column chromatography on silica gel (hexanes/EtOAc (0-1%) delivered 0.68g (2.03
mmol, 80%) of the pure product. IR (neat) 2959, 1603, 1493, 1452, 1423, 1250 cm]. IH
NMR (300 MHz, CDCl3) 8 7.30-7.14 (m, 5H), 2.84-2.74 (m, 1H), 2.66-2.56 (m, 1H),
2.41-2.21 (m, 3H), 2.10-2.00 (m, 2H), 1.90-1.57 (m, 6H), 0.78 (t, J = 7.7, 7.1 Hz, 3H),
0.13 (s, 9H). 13C NMR (125 MHz, CDCl3) 8 145.3, 128.2, 127.8, 125.9, 48.3, 38.8, 34.6,
34.3, 29.8, 25.5, 23.1, 22.9, 12.2, -2.6. HRMS (EI) m/z 338.1544 [(M)+; calcd for

C13H3082Si, 338.1558]. [a]:

Preparation of 4-phenyl-1-trimethylsilanyl-hexan-l-one 82. A solution of
trimethyl-[2-(3-phenyl-pentyl)[1,3]- dithian-2-y1]-silane 164 (1.0 equiv, 0.88 mmol, 0.30
g) in acetone (8.0 mL) was added slowly to a cold (0 °C) stirred suspension of N-
bromosuccinimide (6.0 equiv, 5.29 mmol, 0.94 g) in 80% aqueous acetone. Reaction was
stirred at 0 °C for 2 h. The ice bath was removed and N328 solution wa rapidly added,
and product extracted with ether. The combined organic layers were washed with H2O,
brine, dried with MgSO4, and concentrated on the rotary evaporator. Purification by
column chromatography on silica gel (hexanes/EtOAc (0-1%) afforded 0.14 g (0.56
mmol, 64%) of 4-Phenyl-1-trimethylsilanyl-hexan-1-one 82. IR (neat) cm'l. lHNMR
(CDC13, 300 MHz) 8 7.29-7.06 (m, 5H), 2.49-2.42 (m, 1H), 2.38-2.31 (m, 2H), 1.95-
1.88(m, 1H), 1.70-1.61 (m, 2H), 15801.49 (m, 1H), 0.76-0.73 (t, J = 7.5 Hz, 3H), 0.08 (s,

9H). ”CNMR (CDC13, 125 MHz) 5 248.5, 144.8, 128.3, 127.7, 126.0, 47.1, 46.4, 29.8,

28.4, 12.1, -32. [a]”

214

0
4.71/10H
158

Preparation of 158: The [1,4]-Wittig product 97 from the Wittig rearrangement
of a-alkoxysilane of E-56 (217 mg, 0.87 mmol) was dissolved in THF (0.24 M, 3.6 mL),
and 3N NaOH (0.83 mL/mmol starting material, 0.72 mL) added. The mixture was
heated to 35-40 °C, and then oxidized by adding dropwise 30% H202 (0.42 mL/mmol
starting material, 0.36 mL), while maintaining the reaction temperature below 50 °C for 2
h. The aqueous phase was cooled to 0 °C, and acidified to pH of 1-2 with 6 N HCl.. The
resulting aqueous material was extracted with ether (5 x 20 mL), and the ether solution
dried with MgS04. Filtration and concentration afforded 158 mg (94% yield) of 158a
and 158b as thick colorless oils. Purification by column chromatography on silica gel
(hexane/EtOAc (0-10%) afforded 158a and 158b as a 2.8:] mixture of diastereomers
(ratio by lHNMR). IR (neat) 3100-2500 (s, v br), 2967, 1707, 1495, 1452, 1412, 1290
cm'].

Major anti-158a: 1H NMR (500 MHz, CDC13) 8 11.49 (br s, 1H), 7.31-7.18 (m,
5H), 2.72-2.65 (quintet, J = 7.1, 6.6 Hz, 1H), 2.53-2.48 (dd, J = 14.8, 4.4 Hz, 1H), 2.28-
2.18 (m, 1H), 2.14-2.09 (dd, J= 15.1, 9.1 Hz, 1H), 1.28-1.26 (d, J= 7.1 Hz, 3H), 0.88 (d,
J: 6.6 Hz, 3H). l3C NMR (125 MHz, CDCl3) 8 179.8, 144.8, 128.2, 127.6, 126.2, 44.4,
38.9, 36.2, 18.3, 17.5. HRMS (El) m/z xxx.yyyy [(M-H)+; calcd for C12H1602,
xxx.yyyy].

Minor syn-158b: 1H NMR (500 MHz, CDCl3) 8 11.49 (br s, 1H), 7.33-7.18 (m,
5H), 2.63-2.56 (quintet, J = 7.1, 6.6 Hz, 1H), 2.35-2.31 (apparent dd, J = 15.4, 14.8, 4.4,

3.8 Hz, 1H), 228-2.18 (m, 1H), 2.04-1.99 (dd, J = 14.8, 9.3 Hz, 1H), 1.27-1.24 (d, J= 7.1

215

Hz, 3H), 1.04 (d, J= 6.6 Hz, 3H). l3’C NMR (125 MHz, CDCl3) 8 179.8, 145.7, 128.2,

127.5, 126.1, 44.7, 39.8, 36.4, 18.3, 17.2. Anti 158a and syn 158b are known compounds

and have spectral data in accord with the reported ones.47

216

REFERENES

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23. (a) Surendra, K.; Krishnaveni, N. S.; Reddy, M. A.; Nageswar, Y. V. D.; Rao, K. R.
J. Org. Chem. 2003, 68, 9119-9121. (b) Surendra, K. ; Krishnaveni, N. S.; Reddy, M.A.;
Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68, 2058-2059. (c) Yadav, J. S.;
Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Tetrahedron 2004, 60, 2131-2135. (d)
Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem. Int. Ed. 2003, 42,
4077-4082.

24. (a) Abul-Haj j, Y. J. J. Steroid Biochem. 1984, 21, 621-622. (b) Gorlitzer, K.; Bartke,
U. Pharmazie 2002, 10, 679-681. (c) Brimble, M. A.; McEwan, J. F. ARKIVOC 2000, 1,
909-916. (d) Aoyama, T.; Sonoda, N.; Yamaguchi, M.; Toriyama, K.; Anzai, M.; Ando,
a.; Schioiri, T. Synlett, 1998, 35-36. See also refs. 4-8 therein for former work by these
authors. (e) Hirano, M.; Yakabe, S.; Hikamori, H.; Clark, J. H.; Morimoto, T. J. Chem.
Res. Synop. 1998, 308-309. (I) Hirano, M.; Yakabe, S.; Hikamori, H.; Clark, J. H.;
Morimoto, T. J. Chem. Res. Synop. 1998, 310-311. (g) Hirano, M.; Yakabe, S.; Hikamori,
H.; Clark, J. H.; Morimoto, T. J. Chem. Res. Synop. 1998, 770-771.

25. (a) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.;
Baldwin, J. J .; Christy, M. E.; Ponticello, G. S.; Varga, S. L.; Springer, J. P. J. Org.
Chem. 1986, 51 , 512- (b) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M. J. Org. Chem. 1986, 51, 2370-2374. (c) Latypov, S. K.; Seco, J. M.;
Quinoa, E.; Riguera, R. J. Org. Chem. 1996, 61 , 8569. (d) Latypov, S. K.; Seco, J. M.;
Quinoa, E.; Riguera, R. J. Am. Chem. Soc. 1998, 120, 877-

26. Resolution of sec-phenethyl alcohol was done by stirring a mixture of the racemic
alcohol, 1.0 equiv of acetic anhydride and Amano AK Lipase in benzene at room

temperature for 55 h [( 2° —51.6 ° (c 1.294, CHCl3); Lit 2’ -41.0 ° (neat)).] This
[0].. [0]..

218

 

 

 

reaction also afforded 45.81 of (R)-(+)-1-phenylethanol acetate [0]: +94.4 ° (c 1.104,
CHC13); Lit. [a]: +106 °, (c l, ether)). The trichloroacetimidate of (S)-(-)-phenethyl

alcohol was prepared following literature procedure and obtained in 88% enantiomeric
excess ([a]: —51.6 ° (c 1.2, CHC13)).

27. Marshall, J. A.; Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001, 3, 3369-3372.
28. ProStar particulars

29. Mukaiyama, T.; Iwasawa, N. Chemistry Letters 1981, 913-916.

30. (a) Darcel, C.; Flachsmann, F.; Knochel, P. Chem. Commun. 1998, 205-206. (b)
Boudier, A. ; Darcel, C.; Flachsmann, f. Micouin, L. Oestreich, M.; Knochel, P. Chem.
Eur. J. 2000, 6, 2748-2760.

31. Mikami, K.; Kimura, Y.; Kishi, N.; Nakai, T. J. Org. Chem. 1983, 48, 279-281.

32. Cram, K. J. Fundamentals of Carbanion Chemistry; Academic Press: New York,
1965; Chapters III, IV.

33. (a) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry;
Academic: New York, 1970. (b) Nakai, T.; Mikami, K. Chem. Rev. 1986, 86, 885-902.

34. Felkin, H.; Tambute, A. Tetrahedron Lett. 1969, 10, 821-822. (b). Tomooka, K.;
Yamamoto, H.; Nakai, T. Liebigs Ann. 1997, 1275-1281.

35. Felkin, H.; Frajerman, C. Tetrahedron Lett. 1977, 3485, and references cited therein.
36. Jenny E. F.; Druey, J. Angew Chem. 1962, 87, 152.

37. Broaddus, C. D. J. Am. Chem. Soc. 1965, 87, 3706.

38. (a) F ukui, K. Theory of Orientation and Stereoselection; Springer-Verlag: Berlin,
1971. (b) Fleming, 1. Frontier Orbitals and Organic Chemical Reactions; Wiley: New
York, 1976.

39. Kobayashi, Y.; Ito, T.; Yamakawa, 1.; Urabe, H.; Sato, F. Synlett 1991, 11, 813-815.
40. Paetow, M.; Ahrens, H.; Hoppe, D. Tetrahedron Lett. 1992, 33, 5323-5326.

41. (a) Mehltretter, G. M.; Bhor, S.; Klawonn, M.; Dobler, C.; Sundermeier, U.; Eckert,

M.; Militzer, H.; Beller, M. Synthesis 2003, 2, 295-301. (b) Soderquist, J. A.; Rane, A.
M.; Lopez, C. J. Tetrahedron Lett. 1993, 34, 1893-1896.

219

42. (a) Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727-10737. (b) Lorsbach,
B. A.; Prock, A.; Giering, W. P. Organometallics 1995, 14, 1694-1699. (c) Aicher, T. D.;
Keith, R.; Fang, F. G.; F orsyth, C. J .; Jung, S. H.; Kishi, Y.; Scola, P. M. Tetrahedron
Lett. 1992, 33, 1549-1552.

43. (a) Brienne, M. J .; Quannes, C.; Jacques, J. Bulletin de la Societe Chimique de
France 1967, 32, 613-623. (b) Din, L. B.; Meth-Cohn, Otto; Walshe, N. D. A.
Tetrahedron Lett. 1979, 49, 4783-4786. (c) Reinheckel, H.; Sonnek, G.; Gendike, R.
Journal fuer Praktische Chemie (Leizig) 1975, 317, 273-283.

44.[(a) Chiacchio, U,; Corsaro, A.; Gambera, G.; Rescifina, A.; Pipemo, A.; Romeo, R.;
Romeo, G. Tetrahedron: Asymmetry 2002, 13, 1915-1921. (b) Alexakis, A.; Benhairn, C.
Tetrahedron: Asymmetry 2001, 12, 1151-1157. (c) Mani, N. S.; Wu, M. Tetrahedron
Asymmetry 2000, 11, 4687-4691. ((1) Sekio, M.; Yoshihiro, K. Chemistry & Industry
(London, United Kingdom) 1965, 9, 381-382.

45. (a) Sekio, M.; Yoshihiro, K. Chemistry & Industry 1965, 9, 381-382. (b) Soeta, T.;
Kuriyama, M.; Tomioka, K. J. Org. Chem. 2005, 70, 297-300.

46. Giovannini, R.; Studemann, T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org.
Chem. 1999, 64, 3544-3553. Compound employed, however no spectral data were
provided.

47. (a) Boudier, A.; Darce;. C.; Flachsmann, F.; Micouin, L.; Oestreich, M.; Knoechel, P;

Chem. Eur. J. 2000, 6, 2748-2761. (b) Darcel, C.; Flachsmann, F.; Knochel, P. Chem.
Commun. 1998, 205-206.

220

CHAPTER 7

[1,2]-WITTIG REARRANGEMENT OF or-ALKOXYSILAN ES

7.1. Introduction

As reported in previous chapters of this dissertation, the Wittig rearmgements of
a-alkoxysilanes studied in this work were initiated by deprotonation or to the silyl
group and afforded [1,2] and [1,4] products. Product distribution depended largely on
the structure of the starting alkoxy ether and the temperature of the reaction. We
showed that for a simple a-alkoxysilane 7 bearing no substituent at the migrating
carbon center and at the terminal sp2 carbon of the allyl moiety, product formation
could be controlled simply by careful control of reaction temperature and that the [1 ,2]-
rearrangement pathway could be effectively suppressed. We also showed that
compounds featuring a substituent either at the migrating center or at the terminal sp2
carbon, or at both sites, afforded the [1,2] and [1 ,4] products in approximately 1:2 ratio,
regardless of the reaction temperature.

As reported in Chapter 4, substitution at the migrating carbon resulted in a pair
of diastereomeric compounds with different reactivities. We also reported that the
Wittig products formed a new chiral center. We reported the determination of the
relative stereochemistries of the reactive and less reactive diastereomer pair of or-
alkoxysilanes in Chapter 5 and in Chapter 6 we discussed the mechanism of the [1,4]-
Wittig. At this point we were poised to investigate further the [1,2]-Wittig reaction of

a-alkoxysilanes.

221

7.2. Observed [1,2]-alkyl shift/silyl migration in some a—alkoxysilanes

Maleczka and GengI first showed that the Wittig rearrangement of our model
substrate 7 afforded the products 8 and 9 via the [1,4] and [1 ,2] pathways (Scheme 7.1).
A close look at this Scheme reveals that while 8 is the [1,4]-Wittig product, 9 is not the
expected [1,2]-product, but is obtained via the [1,2]-pathway.

Scheme 7.1. Plausible pathway for the [1 ,2]-Wittig
rearrangement/silyl migration observed in compound 7

G \O TMSh TMS\:/
Brook rearrangement:

Direct [13] sil I 196
migration y [1 ,4]-silyl
[1 2]-shift migration

H‘ TMS
OAPh RLi / Ph Ph

\ TMS \ e TMS 197 9

7 123 [1,4]-shift
o6 H- o

PhMTMS —’ F'h\/\/lLrMs

 

Scheme 7.1 shows our explanation of the observed [1,2]-products from the
Wittig rearrangement of compound 7. The [1,2]-Wittig pathway for the carbanion of 7
(123) via radical-radical anion dissociation-recombination event would afford the
tertiary alkoxide 195, which could undergo a subsequent silyl migration via two
possible routes. First, the silyl group could do a 1,2-Brook rearrangement, placing the
negative charge on the carbon, and a subsequent 1,4-shifi to give an enolate

intermediate 197. The second route would involve a direct [1,3]-sily1 migration, also

222

 

 

 

giving the enolate 197. Looking at these two scenarios more closely, the first route
involves breaking a weaker Si—C bond (Si—C bond in Me4Si is 318 kJmol'l/75.967
kcalmol", bond length 0.189 nm) and making a stronger O—Si bond [approximate bond
dissociation energies: Si—O bond in Me3SiOMe is 531 kJmol'l/126.851 kcalmol'l; in
(M28020 812 kJmol-1/193.98 kcalmol'l; bond length in (H3Si)20 is 0.163 1<.Itno1"/)].2
However, this process would result in going from an alkoxide anion to a carbanion.
The question here is whether the gain in energy (AE) could offset the loss in going from
an alkoxide to a carbanion. In the second route, there is breaking of a C—C bond and
making of a new C—C bond, a process that is energetically neutral, but maintains an

alkoxide anion throughout.

In their previous work, Maleczka and Gengl reported isolation of an alkyl silyl
ether 199, which would arise from a [1,2]-Brook rearrangement on deprotonation of the
tertiary alcohol 198 (Scheme 7.2). This result seems to support the first pathway as the

operative mechanism.

Scheme 7.2. Previous work by Maleczka and Geng

HO :TMS

 

(cat) MeLi H “(OTMS HCI :
9936 THF .. 99% FF P9545
Me H then H20 Me H Me H
198 (14:1) 199 200

In the present work, we isolated a vinyl trimethylsilyl ether 201 from the Wittig
rearrangement/electrophilic trapping of 7 (Scheme 7.3). The formation of compound
201 could be explained by either Brook rearrangement/[l,4]-silyl migration or direct

[1,3]-si1yl migration, as both routes result in the requisite enolate intermediate 197

223

(Scheme 7.1). Thus, this result does not give information as to which mechanism is

operative.

Scheme 7.3. Present work: isolation of vinyl silyl ether 201
in the Wittig rearrangement/electrophilic trapping of 7

A 1. s-BuLi (1.5 equiv)

0 Ph THF, -75 °c, 30 min OTMS OTMS
\ > Ph / + / P“
\/‘\TMS 2. TMSCI (4.0 equiv) MTMS WSW
7 THF, -75 to 45 c 22 (51%) 201 (3%)
3.5 h (via enolate 197

 

In Chapter 4, we reported the Wittig rearrangement of 55, featuring a
substitution at the terminal sp2 carbon of the allyl moiety. Here, we did not observe the
silyl migration that usually accompanies the [1,2]-Wittig of or-alkoxysilanes bearing no

such substituent (Scheme 4.26).

Scheme 4.26. Substitution at the terminal sp2 carbon:
Wittig rearrangement reaction of 55

 

 

/\ . .
0 Ph s-BuLI (1.5 equw) Me 0 TMS OH
/\/|\ 4 13th t M V9141
Me \ TMS THF, -73 °c, 30min TMS e
55 92 (421 1‘8th) 93
via [1 ,4]-rearrangement via [1 ,2]-rearrangement
TMS O
Me/K/lk/Ph
94
Not observed

 

 

 

The isolation of 92 from the Wittig rearrangement of 55 seems to support the
second route. If Brooks rearrangement precedes silyl migration, and if substitution at

the terminal sp2 carbon of the allyl moiety suppresses silyl migration, then one would

224

expect the formation of the allyl trimethylsilyl ether 202 (Scheme 7.4), which we did
not observe. Although we have no direct evidence of any O-silyl products, we are not
completely ruling out the possibility that the [1 ,3]-si1yl migration could occur via Brook
rearrangement of 195 (Scheme 7.1).3
Scheme 7.4. Plausible mechanism of the [1,2]-Wittig
rearrangement of a-alkoxysilanes

/\ radical-radical anion
0 Ph SOC-BUU (15 6(1) 0A Ph dissociation-recombination

Me/\/k - : MeMSiMea :

TMS THF, -78 °c, 30 mm

 

 

55 179
Deal-LP], . TMS Qe OTMS
[Me/\r/QTMS MeWh [we/W Ph

202 (0%)

In the Wittig rearrangement of E-56 (Scheme 4.26), we isolated two products
arising from [1,2]-rearrangement 95 and [1,2]-rearrangement/silyl migration 96. Steric
congestion at the two vicinal stereocenters could be the driving force for the silyl

migration leading to 96.

225

Scheme 4.26. Substitution at both the migrating center and the terminal sp2 carbon

Me

A

0 Ph
Me/\/" TMS

anti E-56a
(39%)

Me
0 Ph
MeNkTMS
E-56a/E-56b
n-BuLi (4.0 eq)
THF, -78 to -30°C
48h
TMS 0H TMS 0 Me 0
Ph
“new + MeMkfph + PhNTMS
+ Me Me Me
95 96 97
via [1,2]-Wittig via [1 ,2]-VVIttig followed via [1,4]-Wittig

by silyl migration

Combined yield of products 95, 96 and 97 ranges from 35 to 57%
depending on the temperature and reaction time

7.3. Stereochemistry of the [1,2]-Wittig rearrangement of a—alkoxysilanes

For an a-alkoxysilane bearing an alkyl substituent at the migrating center, there

arises the question of stereochemistry at the newly formed stereocenter of the [1,2]-

Wittig product. The Wittig rearrangement of enantiodefined substrate 48 afforded 82

and 83, arising from [1,4] and [1,2]-Wittig pathways respectively (Scheme 7.5).

Unlike the [1 ,4]-Wittig product 82, 83 was amenable to analysis by chiral HPLC.4 The

racemic [1,2] product was analyzed first to determine the retention times for the two

enantiomers (for reference purposes).

226

Scheme 7.5. Wittig rearrangement reaction of 48 mediated by sec-BuLi

 

_/ 0
IMS ./ sec-BuLi (1.5 equiv) TM S s + * Ph
: = > TMS
Ph
VOAPh -78 0C \g/m
48 82 83
96% ee/98% er °/o ee retention 75%

% er retention 88%

Next enantiomerically enriched [1,2] product 83 was prepared by an
independent route as illustrated in Scheme 7.6. The preparation started with the
formation of the amide 2035 (81% yield), by the reaction between pseudoephedrine and
phenylacetyl chloride, in the presence of TEA. Deprotonation of this amide by LDA,
trapping with EtI, and removal of the chiral auxiliary by acid hydrolysis afforded the
expected 2-phenyl-butyric acid (42%). This compound was subsequently converted to
the corresponding 2-pheny1-butyryl chloride. Lewis acid mediated acetylation of 2-
phenyl-butyryl chloride‘5 followed by catalytic hydrogenation afforded the expected
[1,2]-Wittig product 83 (81% yield, 87% ee). The HPLC traces of the [1,2]-Wittig
products (from both sources) were obtained and compared. It was found that the [1,2]-
pathway proceeded with retention of configuration at the migrating carbon (% ee

retention = 83%, % er retention = 92%) (Scheme 7.7).

227

Scheme 7.6. Synthesis of [1,2]-Wittig product by an independent route

 

 

Me
Ph ' ,H Me O 1. LDA
YW' Et3N (1.3 equiv) ph = kph THF, -75 °c, 1 h
OH Me > $171 =
... CH2Cl2, rt, 2 h OH Me 2. warm to 0 °C
A (80%) Etl (1.5 equiv), 7 h
Ph COCI

0 1. SOCI2 (2.0 equiv)
6N H2SO4/AcOH (2:1) /U\/Ph benzene, 80 °C, 48 h>

Me O
PhYxNsz/Ph ei-io

 

 

 

 

: reflux, 2Me;,Si : SiMe3
OH Me \ \ (1.12 eqiuv)
203 204 AICI3 (1.12 equiv)
CHZCIZ, 10 h
0 H 10°/ Pd /0 0
Ph 2' ° _ /\/U\/Ph
// 2 V TMS :
TMS : EtOAc, rt, 24 h =
205 \ (81 %. 86% ee) 83 \

Scheme 7.7. Determination of the stereochemistry of the [1,2]-Wittig product

TMS ,/ sec-BuLi (1.5 equiv) 5 g

? : TMS '1' TMS
VOA Ph -78 cc WP“ WP“

 

O O

48 82 83
96% ee/98°/o er % ee retention 75% % ee retention =83%
% er retention 88% % er retention = 92%)

We subjected the less reactive (S,S)-48 to the Wittig conditions and it reacted
completely in about three days to give the [1,2] and [1,4] rearranged products. On
analysis by chiral HPLC, we found that the [1,2]-Wittig product was obtained with a

lower level of retention of stereochemistry (69% ee retention/85% er retention) than the

228

level obtained with the reactive diastereomer (S,R)-48 (83% ee retention/~92% er

retention).

Scheme 7.8. Comparison of the [1,2]-Wittig of (S, R)-48 and (S,S)-48

/
TMS -.-/ TMS ./ TMS :/ TMS ;
r : ? : \ t
(S) (R) (R) (R) O
(S,R)-48 (S,R)-206 207 (S)-83
TMS TMS TMS
\; f__,\; (“w @( ___TMs\/\"/L/Ph
V\o Ph \/e\o Ph 0e Ph
(3) (S) (R) (S) 0
(S,S)-48 (S,S)-206 208 (R)-83

[1,2]-Wittig rearrangement of allyl alkyl ethers is known to occur with inversion
of configuration at the metal bearing center and with retention of configuration at the
migrating carbon.7 In the Wittig rearrangement of a-alkoxysilanes investigated in this
study, we observed predominant retention of configuration at the migrating carbon.
Following deprotonation, there is weakening and breaking of the C—0 bond. With the
breaking of the C-0 bond there is inversion of configuration at the or carbon (metal-
bearing center) from (S) to (R) in both the reactive and less reactive diastereomers. It
would appear that recombination between (R)-207 and (R)-benzylic radical is more
rapid in the reactive (S, R)-48 than recombination between (R)-208 and (S)-benzy1ic
radical in less reactive (S,S)-48. This is evident in the different levels of retention of
configuration observed for both cases. This observation is in contrast to the results

obtained by Nakai (Scheme 7.9).8

229

Wittig rearrangement of compound 209 was studied by Nakai and co-workers
who found that the (S, R)-209 afforded 211 with lower level of retention at the migrating
center (90%) and lower level of inversion at the metal-bearing center (74%) than (S, S)-
209 that afforded 213 with 98% retention at the migrating center and 90% inversion at
the metal-bearing center.8 According to the authors, the difference in stereospecificity
means that a substantial level of mutual recognition of radical enantiomers takes place
during the recombination process.

Scheme 7.9. Wittig rearrangement of a pair of optically
defined diastereomers by Nakai and co-workers

: H :
: SnBu3 : 9; ; 90% Ret.
PhAOA Et 9 ’ A622, lnv.
(S) (R) (3) (S) OH
(S,R)-209 210 211
_ H : 98% R81.
Pit/\o Et Ph/Q 90 E Ph/\5/;i°/I
(S) (S) (S) (R) OH 0 nv.
(S,S)-209 212 213

The lower degree on retention of configuration at the migrating carbon observed
for a-alkoxysilanes relative to Nakai’s results could be explained by resonance
(Scheme 7.10). Resonance in the carbanion could result in partial racemization, and
thus lower level of retention. The metal-bearing center in Nakai’s study is resonance

inactive.

230

Scheme 7.10. Possible racemization in the [1,2]-Wittig rearrangement
of a-alkoxysilanes as a resonance of resonance

TMS TMS
(RPe V 09
207 207

7.4. Conclusions

[1,2]-Wittig rearrangement of a-alkoxysilanes occurred with predominant
retention of configuration at the migrating center. We obtained 83% ee/92% er
retention with the reactive syn diastereomer and 69% ee/85% er retention with the less
reactive anti diastereomer. The lower level of retention we obtained with the syn 48b
compared to literature reports8 for allyl alkyl ethers could be accounted for by the
significant difference in the structures studied. The metal-bearing center in the
literature subtrates were resonance inactive in contrast to our systems that were
susceptible to resonance. The significant difference in stereoselectivity observed for
the syn 48b and anti 48a was in disagreement with Nakai’s results.8 Whereas his
system showed mutual recognition of radical enantiomers during the recombination,

our system gave the opposite outcome.

231

EXPERIMENTAL

O

HOJK/pn

K
204

Preparation of 2-phenyl-butyric acid 204: A 3-necked round-bottomed flask
(500 mL) equipped with a mechanical stirrer was charged with LiCl (6.0 equiv, 132.98
mmol, 5.63 g), iPerH (2.25 equiv, 49.87 mmol, 5.04 g, 7.0 ml), and THF (27 mL, 0.8 M
substrate). The resulting suspension was cooled to -78 °C, and n-BuLi (1.6 M in hexane,
2.08 equiv, 46.10 mmol, 30.73 mL) was added via syringe. The reaction was warmed
hriefly to 0 °C and cooled back to -78 °C. An ice-cold solution of N-(2-hydroxy-l-
methyl-2-phenyl-ethyl)-N-methyl-2-phenyl-acetamide (1.0 equiv, 22.16 mmol, 6.28 g) in
a minimal amount of THF was added to the reaction via cannula. The reaction mixture
was stirred at -78 °C for 1 h, at 0 °C for 15 min, and at room temperature for 5 min, and
cooled back to 0 °C. Then EtI (1.5 equiv, 33.24 mmol, 5.18 g, 2.66 mL) was added and
the reaction stirred at -78 °C for 7 h.

The crude product was taken up in 10 M H2804 (50 mL) and 1,4-dioxane (50
mL). The biphasic mixture was heated at reflux (oil bath temperature 130 °C) for 3 h and
then cooled to 0 °C. The mixture was adjusted to pH _>_ 10 by the slow addition of 50%
aqueous NaOH solution, and the resulting mixture was portioned between H20 and
CH2C12 (2 x 100 mL). The aqueous layer was acidified to pH 5 2 by the slow addition of
6 N H2S04 (aq) and then extracted with CHzClz (100 mL x 3). The combined organic
extract was concentrated to about 50 mL, the concentrate washed with 1 N HCl (aq) to

remove residual dioxane, dried over Na2S04, and concentrated to afford crude 2-phenyl-

232

 

butyric acid. Purification by column chromatography on silica gel, eluting with
hexanes/EtOAc (100-90%) afforded 0.92 g (5.62 mmol, 25%) of the pure acid. Note: A

repeat of this reaction starting from (+)-norephedrine afford the pure acid 204 in 42%

starting from (+)-norephedrine. [a]: +54.5 (c. 1.63, CHCl3). IR (neat) 3400-2400,

2969, 1707, 1601, 1497, 1456, 1414, 1287, 1223 cm". IHNMR(CDC13, 300 MHz) 5
11.54 (bs, 1H), 7.34-7.21 (m, 5H), 3.46-3.41 (t, J= 7.7 Hz, 1H), 2.16-2.01 (m, 1H), 1.87-

1.72 (m, 1H), 0.91-0.86 (t, J= 7.4 Hz, 3H). 'HNMR (CDC13, 75 MHz) 5 180.3, 138.2,

128.5, 128.0, 127.3, 53.3, 26.3, 12.2. [a];0 +55 (0.1.63, CHCl3). 204 is a known

compound and has spectral data in accord with the reported one.9

0

Ph
//§

TMS \
205

Preparation of 205: A mixture of 2-phenyl-butyric acid (1.0 equiv, 3.20 mmol,
0.52 g) and SOC12 (2.0 equiv, 6.39 mmol, 0.76 g, 0.47 mL) in benzene was stirred at 80
°C for 48 h, and excess solvent removed under reduced using a rotavap. The resulting 2-
phenyl-butyryl—chloride was taken up in CHzClz and bis(trimethylsilyl)acetylene (1.12
equiv, 3.58 mmol, 0.61 g, 0.81 mL) added. This mixture was cooled in ice water and
anhydrous AlCl3 (1.12 equiv, 3.58 mmol, 0.48 g) added in portions. After stirring for
about 5 .0 min, the cold bath was removed, and reaction stirred at RT for 10 h. The
reaction mixture was poured into 20 ml of ice-cold water, and extracted with ether (50
mL x 4). The ethereal extract was dried over anhydrous MgSO4, filtered and
concentrated on a rotary evaporator to five the 0.60 of crude product. Purification by

silica column chromatography on silica gel (2% EtOAc in hexanes) afforded 0.60 mg

233

_J .

 

 

(77%) of pure 205. [a]: +450 (0. 1.092, CHCl3). IR (neat) 2964, 2151, 2093, 1676,

1454, 1254 1140 cm“. ‘H NMR (CDC13, 300 MHz) 5 7.34-7.21 (m, 5H), 3.63-3.57 (t, J
= 7.7, 7.4 Hz, 1H), 3.24-2.09 (m, 1H), 1.88-1.73 (m, 1H), 0.90-0.85 (t, 7.4 Hz, 3H), 0.14
(s, 9H). l3C NMR (CDC13, 75 MHz) 8 187.6, 137.3, 128.6, 128.5, 127.3, 101.4, 99.9,
62.5, 24.6, 12.1, -O.8. on +45 (c. 1.0925, CHClg). HRMS (CI) m/z 244.1279 [(M)+;

calcd for ClstoOSi, 244.1283].

0

TMS/\/u\/Ph

83

/....

Preparation of 83: 10% Pd/C was added to a solution of 4-phenyl-l-
trimethylsilanyl-hex-l-yn-3-one (1.73 mmol, 0.42 g) in EtOAc at RT. The flask was
evacuated, and filled with H2 gas at 1 atm (H2 balloon). The flask was evacuated and this
process repeated 4 times. The reaction was then stirred under H2 atmosphere for 36 h.
The reaction was filtered on Celite 503, the Celite thoroughly washed, and the combined

organic phases concentrated to give the crude product. Purification by column
chromatography on silica gel (hexanes/EtOAc (0-1%) afforded 0.30 g (1.35 mmol, 78%)
of pure product 4-phenyl-1-trimethylsilanyl-hexan-3-one 83. IR (neat) 2957, 1715, 1601 ,
1493, 1454, 1248 cm". ‘H NMR (500 MHz, CDCl3) 8 7.31-7.19 (m, 5H), 3.56-3.53 (t, J
= 7.5, 7.1 Hz, 1H), 2.33-2.25 (m, 2H), 2.06-2.00 (m, 1H), 1.72-1.66 (m, 1H), 1.41-0.81-
0.78 (t, J = 7.5, 7.1 Hz, 3H), 0.74-0.68 (m, 1H), 0.61-0.55 (m, 1H), -0.11 (s, 9H). 13C
NMR (125 MHz, CDCl3) 5 211.5, 139.2, 128.7, 128.2, 127.0, 60.1, 36.5, 25.5, 12.2, 10.1,

-l.9.

234

| “J

U)

REFERENCES
1. Maleczka, R. E. Jr.; Geng, F. Organic Letters 1999, 1, 1115-1118.
2. Silicon in Organic Synthesis by E. Colvin. 1981. Publishers: Butterworths.

3. (a) Kuwajima, I. J. Organomet. Chem. 1985, 285, 137-148. (b) Still, W. C. J. Org.
Chem. 1976, 41, 3063-3064.

4. Information on chiral HPLC.

5. Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J .; Gleason, J. L. J.
Am. Chem. Soc. 1997, 119, 6496-6511.

6. Newman, H. J. Org. Chem. 1973, 38, 2254-2255.

7. (a) Verner, E.J.; Cohen, T; J. Am.Chem. Soc. 1992, 114, 375-377. (b) Hoffman, R.;
Brukner R. Chem. Ber.l992, 125, 1957-1963. (c) (a) Tumooka, K.; Igarashi T.; Nakai, T.
Tetrahedron Lett. 1993, 34, 8139-8142. (b) Tumooka, K.; Igarashi T.; Nakai, T.
Tetrahedron 1994, 50, 5927-5932.

8. Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann. 1997, 1275-1281.
9. (a) Fujiwara, T.; Sasaki, M.; Omata, K.; Kabuto, C.; Kabuto, K.; Takeuchi, Y.
Tetrahedron: Asymmetry 2004, 15, 555-563. (b) Nieuwenhuijzen, J. W.; Grimbergen, R.

F. P.; Koopman, C.; Kellogg, R. M.; Vries, T. R,; Pouwer, K.; van Echten, E.; Kaptein,
B.; Hulshof, L. A.; Broxterman, Q. B. Angew. Chem. Int. Ed. 2002, 41, 4281-4286.

235

 

 

 

 

CHAPTER 8

CONCLUSIONS

We have demonstrated that the [1,4]-Wittig rearrangement of simple,
unsubstituted a-alkoxysilanes, representated by 7, could be efficient. The selectivity of
the rearrangement was improved to favor the [1,4]- over the [1,2]-pathway. We also
showed that the [1,4]-Wittig rearrangement of allyl ethers could be coupled with
electrophilic capture of the resultant enolate intermediate. This procedure provides
unique access to a-functionalized acylsilanes, which are synthetically versatile building
blocks in organic chemistry.

The relative stereochemistries of a pair of diastereomeric a-alkoxysilanes
undergoing Wittig rearrangement were established employing such techniques as 1H
NMR (NOE) experiments and single crystal x-ray analysis. We determined that the
reactive diastereomer has the syn relative stereochemistry and the less reactive has the
anti relative stereochemistry. We also showed that a pair of diastereomeric 0t-
alkoxysilanes have different chemical properties with regard to the formation of
hydrazone and ester derivatives.

Efficient ring closing metathesis of a-alkoxysilanes using Grubbs second
generation Ru catalyst was achieved. We made five and six-membered cyclic ethers and
observed the formation of six-membered silyl ethers to be more efficient than the
formation of five-membered ones. This is an important contribution to the field

considering that cyclization of a-alkoxysilanes is not trivial.

236

In the area of mechanism of the Wittig rearrangement, we found that on
deprotonation and cleavage of C—0 bond in the Wittig rearrangement of oz-alkoxysilanes
are not concurrent but separate events. That the [1,2]-pathway could be effectively
suppressed at low temperatures was evidence that the [1,4-] and the [1,2]-rearrangements
of a-alkoxysilanes have different mechanisms. The [1,4]-Wittig rearrangement of
stereochemically defined a-alkoxysilanes occurred with predominant retention of
configuration (75% ee ret.) at the migrating carbon as required by orbital symmetry
considerations. The [1,4]-Wittig rearrangement of a-alkoxysilanes bearing substituents
at the migrating center and the terminal olefinic carbon formed acysilanes with
approximately 3:1 anti selectivity. This result is in agreement with Nakai’s results for
the [2,3]-Wittig rearrangement of E allyl ethers. This could interpreted as implying the
concertedness of the [1,4]-Wittig of a-alkoxysilanes. That [1,4]-pathway for the syn and
the anti substrates acylsilanes occur with similar levels of retention of configuration (75%
and 74% respectively) on one hand and [1,2]-products with significantly different levels
of retention of configuration (83% and 69%) on the other hand is conclusive evidence
that these two rearrangement pathways have different mechanisms. At low temperatures,
the less reactive anti diastereomer was undergoing deprotonation as evidenced by the
formation of yellow reaction mixture, however, at this temperature, no rearrangement
occurred. This provided further conclusive evidence that the breaking of the C—0 bond is

the limiting step of this reaction.

237

APPENDIX 1

ORTEP REPRESENTATION AND X-RAY DATA FOR COMPOUND 108

238

Table 1. Crystal data and structure refinement for p1

 

Identification code p1

Empirical formula C24 H32 N8 08 Si2
Formula weight 616.76

Temperature 173(2) K
Wavelength 0.71073 A

Crystal system Triclinic

Space group P1

Unit cell dimensions a = 6.2212(12) A

b = 11.574(2) A

c = ll.576(2) A

alpha = 110.73(3) deg.
beta = 99.03(3) deg.
gamma = 95.56(3) deg.

Volume 759.3(3) A"3
gensity (calculated) 11.349 Mg/mA3
Absorption coefficient 0.176 mmA-l
F(000) 324

Crystal size ? x ? x ? mm
Theta range for data collection 1.91 to 28.26 deg.
Index ranges -8<=h<=8, -15<=k<=11, -14<=l<=l4

Reflections collected / unique 4723 / 4022 [R(int) = 0.0117]
Completeness to theta = 28.26 90.1%

Refinement method Full-matrix least-squares on F"2
Data / restraints / parameters 4022 / 3 / 411

Goodness-of-fit on F"2 0.779

Final R indices [I>25igma(l)] R1 = 0.0329, wR2 = 0.0951

R indices (all data) R1 = 0.0436, wR2 = 0.1029
Absolute structure parameter 0.0(3)

Largest diff. peak and hole 0.235 and -0.253 e.A"-3

239

Table 2. Atomic coordinates ( x 10"4), equivalent isotropic
displacement parameters (A02 x 10"3), and occupancies for p1

 

 

x y z U(eq) Occ.

Si(l) 14281(2) 1821(1) 6722(1) 28(1) 1
C(2) 16559(12) 3071(7) 7870(7) 44(2) 1
C(3) 15381(10) 442(6) 5784(7) 39(2) 1
C(4) 12257(10) 1311(7) 7571(6) 38(2) 1
C(5) 12733(1 1) 2481(6) 5600(6) 28(1) 1
C(6) 10638(10) 2144(6) 5161(6) 28(1) 1
C(7) 9430(9) 2568(6) 4199(5) 20(1) 1
N(8) 7416(9) 2102(5) 3717(5) 29(1) 1
N(9) 6428(9) 2544(5) 2806(5) 27(1) 1
C(10) 4352(9) 2091(6) 2212(5) 23(1) 1
C(11) 3183(9) 2536(5) 1361(5) 22(1) 1
N(12) 4187(9) 3545(5) 1036(5) 27(1) 1
0(13) 6158(8) 3937(5) 1437(4) 37(1) 1
0(14) 3014(8) 4008(5) 419(4) 35(1) 1
C(15) 977(9) 2062(5) 741(5) 23( 1) 1
C(16) -74(9) 1067(6) 1019(5) 23(1) 1
N(17) -2367(8) 580(5) 395(5) 28( 1) 1
0(18) -3264(8) 976(5) -357(5) 46(1) 1
0(19) -3299(7) -256(5) 646(5) 39(1) 1
C(20) 987(10) 613(6) 1865(6) 27( 1) 1
C(21) 3159(10) 1117(6) 2436(5) 26(1) 1
Si(22) 2166(2) 7036(1) -2327(1) 26(1) 1
C(23) 4177(13) 7492(9) -3160(8) 52(2) 1
C(24) -149(12) 5842(8) -3417(7) 45(2) 1
C(25) 1 1 18(10) 8467(6) -l372(6) 34(1) 1
C(26) 3605(10) 6389(6) -1239(6) 28(1) 1
C(27) 5840(9) 6686(5) -725(6) 27(1) 1
C(28) 6959(10) 6280(6) 168(6) 31(1) 1
N(29) 9044(8) 6733(5) 681(5) 26(1) 1
N(3 0) 9950(8) 6286(5) 1549(5) 24(1) 1
C(31) 12122(9) 6778(6) 2181(5) 22(1) 1
C(32) 13294(10) 6330(5) 3076(5) 24(1) 1
N(3 3) 12289(8) 5316(5) 3342(5) 26(1) 1
0(34) 1345 l (8) 4870(5) 3991(5) 41(1) 1
0(35) 10249(8) 4920(5) 2941(5) 41(1) 1
C(36) 15483(9) 6839(6) 3636(5) 24(1) 1
C(37) 16525(9) 7745(6) 3408(5) 24(1) 1
N(3 8) 18822(9) 8301(5) 4032(5) 32(1) 1
0(39) 19772(8) 91 16(5) 3739(5) 38(1) 1
0(40) 19732(8) 7879(6) 4799(5) 49(2) 1
C(41) 15428(10) 8254(6) 2569(5) 25(1) 1

240

C(42) 13293(10) 7782(6) 1964(6) 26(1) 1

 

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

Table 3. Bond lengths [A] and angles [deg] for pl

 

Si(1)-C(3) 1.848(7)

Si(1)-C(2) 1.876(7)

Si(1)-C(4) 1.885(6)

Si(1)-C(5) 1.911(6)

C(5)-C(6) 1.289(9)

C(6)-C(7) 1.498(7)

C(7)-N(8) 1.268(8)

N(8)-N(9) 1.412(6)

N(9)-C(10) 1.323(8)
C(10)-C(l 1) 1.404(7)
C(10)-C(21) 1.412(8)
C(11)-C(15) 1.402(7)
C(1 1)-N(12) 1.463(7)
N(12)-C(13) 1.220(7)
N(12)-C(14) 1.230(6)
C(15)-C(16) 1.428(7)
C(16)-C(20) 1.378(7)
C(16)-N(17) 1.451(7)
N(17)-O(18) 1.207(7)
N(17)-O(19) 1.225(7)
C(20)-C(21) 1.377(8)
Si(22)-C(23) 1.840(8)
Si(22)-C(24) 1.840(8)
Si(22)-C(26) 1.843(6)
Si(22)-C(25) 1.878(6)
C(26)-C(27) 1.382(8)
C(27)-C(28) 1.398(8)
C(28)-N(29) 1.310(8)
N(29)-N(30) 1.357(7)
N(30)-C(31) 1.390(7)
C(31)-C(42) 1.430(8)
C(31)-C(32) 1.445(7)
C(32)-C(36) 1.386(8)
C(32)-N(33) 1.427(7)
N(33)-C(34) 1.236(6)
N(33)-C(35) 1.260(7)
C(36)-C(37) 1.308(8)
C(37)-C(41) 1.425(7)

241

 

 

 

 

C(37)-N(38)
N(38)-O(40)
N(38)-O(39)
C(41)-C(42)
C(3)-Si(l)-C(2)
C(3)-Si(1)-C(4)
C(2)-Si(1)-C(4)
C(3)-Si(1)-C(5)
C(2)-Si(1)-C(5)
C(4)-Si(1)-C(5)
C(6)-C(5)-Si(l)
C(5)-C(6)-C(7)
N(8)-C(7)-C(6)
C(7)-N(8)-N(9)
C(10)-N(9)-N(8)
N(9)-C(10)-C(l 1)
N(9)-C(10)-C(21)
C(1 1)-C(10)-C(21)
C(10)-C(11)-C(15)
C(10)-C(1 1)-N(12)
C(15)-C(l 1)-N(12)
O(l3)-N(12)-O(14)
0(1 3)-N(12)-C(1 1)
O(14)-N(12)-C(1 1)
C(1 1)-C(15)-C(16)
C(20)-C(16)-C(15)
C(20)-C(16)-N(17)
C(15)-C(16)-N(17)
0(18)-N(17)-O(19)
O(l8)-N(l7)-C(16)
O(19)-N(17)-C(16)
C(16)-C(20)-C(21)
C(20)-C(21)-C(10)
C(23)-Si(22)-C(24)
C(23)-Si(22)-C(26)
C(24)-Si(22)-C(26)
C(23)-Si(22)-C(25)
C(24)-Si(22)-C(25)
C(26)-Si(22)-C(25)
C(27)-C(26)-Si(22)
C(26)-C(27)-C(28)
N(29)-C(28)-C(27)
C(28)-N(29)-N(30)
N(29)-N(30)-C(3 1)
N(30)-C(3l)-C(42)
N(30)-C(31)-C(32)

1.466(7)
1.246(7)
1.239(7)
1.360(8)
1 1 1.2(3)
109.0(3)
1 10.8(4)
108.7(3)
108.9(3)
108.2(3)
121.7(5)

122.4(5)
1 18.9(5)
1 14.8(5)

1 19.9(5)

124.0(5)
120.2(5)
115.8(5)
123.9(4)
122.4(4)
113.7(4)
122.1(5)
118.4(5)
119.4(5)
115.9(5)
122.4(5)
121.2(5)
116.4(5)
122.7(5)
120.3(5)
117.0(5)
118.6(5)
123.3(5)
112.2(4)
108.0(3)
108.6(3)
109.2(4)
110.3(3)
108.4(3)
124.8(4)
126.3(5)
120.3(6)
115.2(5)
118.3(5)
119.8(5)
123.1(5)

242

C(42)-C(31)-C(32)
C(36)-C(32)~N(33)
C(36)-C(32)-C(31)
N(33)-C(32)-C(31)
O(34)-N(33)-O(3 5)
O(34)-N(33)-C(32)
O(35)-N(33)-C(32)
C(37)-C(36)-C(32)
C(36)-C(37)-C(41)
C(36)-C(37)-N(38)
C(41)-C(37)-N(38)
O(40)-N(3 8)-O(39)
O(40)-N(38)-C(37)
O(39)-N(38)-C(37)
C(42)-C(41)-C(37)
C(41)-C(42)-C(31)

117.1(5)
118.7(4)
119.8(5)
121.5(5)
121.8(5)
118.6(5)
119.6(5)
121.9(5)
120.7(5)
121.5(5)
117.7(5)
123.8(6)
117.0(5)
119.1(5)
120.6(5)
119.9(5)

 

Symmetry transformations used to generate equivalent atoms:

243

Table 4. Anisotropic displacement parameters (A02 x 10"3) for pl

 

 

U11 U22 U33 U23 U13 U12
s1(1) 27(1) 28(1) 27(1) 13(1) 1(1) 3(1)
C(2) 43(4) 31(3) 38(3) 2(3) -19(3) -6(3)
C(3) 29(3) 37(3) 46(4) 17(3) 2(3) -9(2)
C(4) 32(3) 64(4) 32(3) 30(3) 17(2) 15(3)
C(5) 35(3) 28(3) 24(3) 18(2) -3(2) 3(2)
C(6) 28(3) 35(3) 25(3) 20(2) -2(2) 11(2)
C(7) 20(2) 25(3) 20(3) 15(2) -1(2) 7(2)
N(8) 36(3) 34(3) 24(3) 20(2) 2(2) 9(2)
N(9) 32(2) 28(3) 28(3) 19(2) 2(2) 3(2)
C(10) 22(3) 23(3) 23(3) 6(2) 6(2) 6(2)
C(11) 23(2) 17(3) 24(3) 6(2) 7(2) -5(2)
N(12) 31(3) 24(3) 29(3) 15(2) 3(2) 1(2)
0(13) 27(2) 41(3) 44(3) 25(2) -3(2) -6(2)
0(14) 34(2) 37(3) 43(3) 30(2) 1(2) -1(2)
C(15) 24(2) 18(2) 22(3) 7(2) 1(2) -3(2)
C(16) 25(3) 18(2) 26(3) 8(2) 8(2) -2(2)
N(17) 23(3) 28(3) 27(3) 10(2) -1(2) -4(2)
0(18) 30(2) 54(3) 56(3) 36(3) -11(2) -11(2)
0(19) 23(2) 38(3) 56(3) 25(2) 3(2) 4(2)
C(20) 26(3) 26(3) 31(3) 13(3) 9(2) 1(2)
C(21) 30(3) 29(3) 20(3) 11(2) 4(2) 13(2)
Si(22) 23(1) 31(1) 25(1) 13(1) 0(1) 6(1)
C(23) 48(4) 69(5) 51(4) 39(4) 0(3) 15(4)
C(24) 45(4) 44(4) 45(4) 19(3) -2(3) 13(3)
C(25) 38(3) 28(3) 40(3) 12(3) 11(3) 19(2)
C(26) 22(2) 30(3) 34(3) 12(3) 9(2) 3(2)
C(27) 30(3) 19(3) 31(3) 10(2) 9(2) -3(2)

244

C(28)
10(29)
14(30)
C(31)
C(32)
14(33)
0(34)
0(35)
(:(36)
(:(37)
14(38)
(3(39)
0(40)
C(41)
C(42)

35(3)
19(2)
17(2)
26(3)
29(3)
27(3)
38(2)
28(2)
28(3)
21(2)
31(3)
37(3)
35(3)
32(3)
27(3)

25(3)
28(3)
27(3)
24(3)
26(3)
25(3)
35(3)
45(3)
29(3)
29(3)
29(3)
31(2)
61(4)
20(3)
23(3)

31(3)
31(3)
29(2)
21(3)
24(3)
25(3)
54(3)
55(3)
22(3)
21(3)
38(3)
43(3)
55(3)
27(3)
36(3)

7(2)

12(2)
14(2)
12(2)
16(2)
12(2)
30(3)
37(3)
15(2)
9(2)

14(2)
17(2)
37(3)
13(2)
20(2)

9(3)
2(2)
-1(2)
5(2)
3(2)
0(2)
-9(2)
-6(2)
6(2)
0(2)
8(2)
4(2)

-13(2)

9(2)
8(2)

0(2)
2(2)
2(2)
4(2)
12(2)
1(2)
2(2)
-9(2)
13(2)

7(2)
7(2)

-10(2)

1(2)
5(2)
1(2)

 

The anisotropic displacement factor exponent takes the form:

-2 pi"2 [1102 a*"2 U11 + +2hka* b* U12]

245

 

Table 5. Hydrogen coordinates ( x 1004), isotropic displacement
parameters (AA2 x 1003), and occupancies for p1

 

x y z U(eq) Occ.

 

H(2A) 15943 3772 8349 66

1
H(2B) 17543 3336 7417 66 1
H(2C) 17358 2744 8431 66 1
H(3A) 14186 -175 5194 58 1
H(3B) 16141 93 6337 58 1
H(3C) 16388 691 5334 58 1
H(4A) 1 1 100 677 6968 56 1
H(4B) 1 1635 2017 8035 56 1
H(4C) 13005 980 8144 56 1
11(5) 13630(110) 2870(70) 5420(60) 50(20) 1
H(6) 9750(80) 1710(50) 5430(40) 15(13) 1
H(7) 10550(90) 3090(60) 3990(50) 56(19) 1
11(9) 6980(150) 3160(90) 2570(80) 150(30) 1
H(15) 243 2377 183 27 1
H(20) 252 -21 2046 32 1
H(21) 3875 800 2997 31 1

78

H(23A) 5339 8125 -2560 1
H(23B) 3455 7814 -3749 78 1
H(23C) 4788 6773 -3607 78 1
H(24A) -1180 5652 -2948 68 1
H(24B) 399 5096 -3859 68 1
H(24C) -873 6154 -4014 68 1
H(25A) 2344 9092 -827 52 1
H(25B) 178 8249 -872 52 1
H(25C) 297 8791 -l928 52 1
H(26) 2810(80) 5690(50) -920(40) 26(12) 1
H(27) 6790(100) 7520(60) -860(50) 79(19) 1

H(28)

6330(60) 5640(40) 420(30) 7(8) 1

H(30) 9150(50) 5730(30) 1680(30) 0(6) 1
H(36) 16234 6526 4192 29 1
H(41) 16179 8914 2434 30 1
H(42) 12594 8113 1410 32 1

 

Table 6. Torsion angles [deg] for p1

 

246

H
OZN N02
108

 

247

APPENDIX 2

ORTEP REPRESENTATION AND X-RAY DATA FOR COMPOUND 110b

248

 

Table 1. Crystal data and structure refinement for pl

 

Identification code
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group

Unit cell dimensions

Volume

Z

Density (calculated)
Absorption coefficient
F(000)

Crystal size

p1

C21 H26 N2 07 Si
446.53

293(2) K

0.71073 A

?

?

a = 8.3919(17) A

b = 12.006(2) A

c = 12.492(3) A

alpha = 112.9l(3) deg.
beta = 9378(3) deg.
gamma = 91 .95(3) deg.
1154.3(4) A"3

2

1.285 Mg/m"3

0.145 mmA-l

472

?x?x?mm

Theta range for data collection 1.85 to 28.28 deg.

Index ranges

-8<=h<=l 1, -15<=k<=15, -15<=l<=16

Reflections collected / unique 7332 / 6098 [R(int) = 0.0095]

Completeness to theta = 28.28 90.4%

Refinement method F ull-matrix least-squares on F"2
Data / restraints / parameters 6098 / 3 / 559

Goodness-of-fit on F02 0.925

Final R indices [l>2sigma(I)] R1 = 0.0326, wR2 = 0.1051

R indices (all data) R1 = 0.0390, wR2 = 0.1119
Absolute structure parameter 0.0(2)

Largest diff. peak and hole 0.247 and -0.221 e.A"-3

Table 2. Atomic coordinates ( x 10"4), equivalent isotropic

displacement parameters (AA2 x 10"3), and occupancies for p1

 

x y z U(eq) Occ.

 

C(1) -336(6) 3490(4) 6289(5) 31(1) 1
C(2) -82(6) 4535(4) 6081(4) 28(1) 1

C(3) 906(6) 5540(4) 6853(4) 26(1) 1
C(4) 1613(6) 5471(4) 7830(4) 26(1) 1
C(5) 1382(6) 4417(4) 8061(4) 28(1) 1
C(6) 408(6) 3467(4) 7271(4) 28(1) 1

N(7) 205(6) 2347(3) 7498(4) 34(1) 1
0(8) -831(6) 1594(3) 6887(4) 49(1) 1

0(9) 1050(6) 2273(3) 8306(4) 46(1) 1

250

N(IO)
0(11)
0(12)
C(13)
0(14)
0(15)
C(16)
C(17)
C(18)
Si(19)
C(20)
C(21)
C(22)
0(23)
C(24)
C(25)
C(26)
C(27)
C(28)
C(29)
C(30)
C(31)

C(32)

-847(5)
-796(5)
-1508(6)
2608(5)
3266(5)
2676(4)
3582(6)
3615(6)
4553(6)
4224(1)
2025(7)
4837(8)
5453(8)
6232(4)
7189(6)
8921(7)
6819(6)
6000(7)
5633(8)
6050(8)
6849(7)
7222(7)

1832(6)

4645(4)
5615(3)
3692(3)
6504(4)
6528(3)
7460(3)
8571(4)
9378(4)
8843(4)
9629(1)
9450(6)
1 1267(5)
8916(5)
8973(3)
7987(4)
8514(5)
6847(3)
5853(4)
4797(5)
4686(5)
5712(5)
6739(5)

6640(4)

5044(3)
4953(3)
4262(4)
871 1(4)
9628(3)
8385(3)
9156(4)
8465(4)
7381(4)
6312(1)
5805(5)
7061(5)
5040(4)
7796(3)
7086(5)
7439(7)
7290(4)
6369(5)
6517(6)
7566(7)
8513(5)
8315(5)

2757(5)

251

35(1)
37(1)
51(1)
27(1)
34(1)
30(1)
26(1)
26(1)
23(1)
28(1)
43(1)
48(1)
40(1)
28(1)
34(1)
52(2)
27(1)
36(1)
52(2)
47(1)
42(1)
38(1)

31(1)

1

l

C(33)
C(34)
C(35)
C(36)
C(37)
N(38)
0(39)
0(40)
N(41)
0(42)
0(43)
C(44)
0(45)
0(46)
C(47)
C(48)
C(49)
Si(SO)
C(51)
C(52)
C(53)
0(54)

C(55)

1045(6)
79(6)
-146(6)
603(6)
1544(6)
1304(6)
440(5)
2315(5)
2337(5)
3005(6)
2264(5)
-1 177(5)
-1799(5)
4224(4)
-2171(6)
-2179(6)
-3083(6)
-2756(1)
-621(7)
-3863(7)
-3408(7)
-4768(4)

-5689(6)

6676(4)

5706(4)

4666(4)

4624(4)

5576(4)
7789(4)
7892(3)
8577(3)
5534(3)
6431(4)
4528(3)
3591(3)
3599(3)
2706(3)
1591(4)
795(4)
1299(4)
525(1)
699(5)

1280(5)

-1 126(4)

1187(3)

2123(4)

1739(4)
935(4)
1 148(4)
2188(4)
2926(4)
1518(4)
738(4)
2150(4)
4016(4)
4723(4)
4088(3)
282(4)
-595(3)
642(3)
-106(4)
576(4)

1672(4)

2713(1)

3243(5)

4042(4)
1954(5)
1243(3)

1910(4)

252

30(1)
28(1)
25(1)
29(1)
29(1)
37(1)
43(1)
48(1)
34(1)
56(1)
40(1)
25(1)
34(1)
30(1)
31(1)
27(1)
26(1)
28(1)
41(1)
36(1)
36(1)
29(1)

30(1)

C(56)
C(57)
C(58)
C(59)
C(60)
C(61)

C(62)

-7424(7)
-531 1(6)
5731(7)
-5346(7)
4591(8)
4139(7)

4514(7)

1654(5)
3309(4)
3388(5)
4495(5)
5416(6)
5372(4)

4290(5)

1556(7)
1768(4)
677(5)
583(6)
1420(7)
2482(6)

2639(5)

49(2)
30(1)
34(1)
47(1)
51(2)
43(1)

37(1)

 

U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

253

Table 3. Bond lengths [A] and angles [deg] for p1

 

C(1)-C(6)
C(1)-C(2)
C(2)-C(3)
C(2)-N(10)
C(3)-C(4)
C(4)-C(5)
C(4)-C(13)
C(5)-C(6)
C(6)-N(7)
N(7)-O(9)
N(7)-O(8)
N(10)-O(1 1)
N(10)-O(12)
C(13)-0(14)
C(13)-0(15)
0(15)-C(16)
C(16)-C(17)
C(17)-C(18)
C(18)-0(23)
C(18)-Si(19)
Si(19)-C(21)
Si(19)-C(20)
Si(19)-C(22)
C(23)-C(24)
C(24)-C(26)
C(24)-C(25)
C(26)-C(31)
C(26)-C(27)
C(27)-C(28)
C(28)-C(29)
C(29)-C(30)
C(30)-C(31)
C(32)-C(37)
C(32)-C(33)
C(33)-C(34)
C(33)-N(38)
C(34)-C(35)
C(35)-C(36)
C(35)-C(44)
C(36)-C(37)
C(37)-N(41)
N(38)-0(40)
N(38)-0(39)

1.350(8)
1.390(7)
1.412(6)
1.462(7)
1.355(7)
1.413(6)
1.480(6)
1.378(7)
1.485(6)
1.229(7)
1.215(6)
1.213(6)
1.260(5)
1.227(6)
1.361(5)
1.456(5)
1.529(6)
1.538(6)
1.451(6)
1.924(4)
1.855(6)
1.888(6)
1.881(5)
1.474(5)
1.512(7)
1.530(8)
1.359(7)
1.412(6)
1.378(8)
1.392(10)
1.439(8)
1.379(7)
1.390(7)
1.410(8)
1.393(7)
1.477(6)
1.384(6)
1.426(7)
1.516(6)
1.342(7)
1.495(6)
1.230(6)
1.225(7)

254

N(41)-0(42)
N(41)-O(43)
C(44)-0(45)
C(44)-C(46)
O(46)-C(47)
C(47)-C(48)
C(48)-C(49)
C(49)-0(54)
C(49)-Si(50)
Si(50)-C(51)
Si(50)-C(53)
Si(50)-C(52)
0(54)-C(55)
C(55)-C(56)
C(55)-C(57)
C(57)-C(62)
C(57)-C(58)
C(58)-C(59)
C(59)-C(60)
C(60)-C(61)
C(61)-C(62)
C(6)-C(1)-C(2)
C(1)-C(2)-C(3)
C(l)-C(2)-N(10)
C(3)-C(2)-N(10)
C(4)-C(3)-C(2)
C(3)-C(4)-C(5)
C(3)-C(4)-C(13)
C(5)-C(4)-C(13)
C(6)-C(5)-C(4)
C(l)-C(6)-C(5)
C(1)-C(6)-N(7)
C(5)-C(6)-N(7)
O(9)-N(7)-O(8)
O(9)-N(7)-C(6)
O(8)-N(7)-C(6)
0(1 1)-N(10)-O(12)
0(1 1 )-N(10)-C(2)
0(12)-N(10)-C(2)
O(14)-C(13)-O(15)
O(14)-C(13)-C(4)
O(15)-C(13)-C(4)
C(13)-0(15)-C(16)
O(15)-C(l6)-C(l7)
C(16)-C(17)-C(18)
O(23)-C(18)-C(17)

1.186(6)
1.245(5)
1.186(6)
1.304(6)
1.467(5)
1.507(7)
1.529(7)
1.462(6)
1.883(5)
1.845(6)
1.877(4)
1.878(5)
1.404(6)
1.516(8)
1.527(6)
1.368(7)
1.425(7)
1.408(7)
1.297(9)
1.377(10)
1.416(7)
1 17.1(4)
122.3(5)
120.9(4)
1 16.8(4)
1 18.1(4)
120.9(4)
121.5(4)
1 17.6(4)
1 18.2(5)
123.4(4)
1 18.4(4)
1 18.1(5)
125.4(4)
1 17.9(4)
1 16.7(5)

123.0(4)
120.1(4)
116.9(4)

123.4(4)
125.9(4)
110.7(4)

118.6(3)
105.1(3)
112.1(4)
106.8(4)

255

O(23)-C(18)-Si(19)
C(17)-C(18)-Si(19)
C(21)-Si(19)-C(20)
C(21)-Si(l9)-C(22)
C(20)-Si(l9)-C(22)
C(21)-Si(19)-C(18)
C(20)-Si(19)-C(18)
C(22)-Si(19)-C(18)
C(18)-O(23)-C(24)
O(23)-C(24)-C(26)
O(23)-C(24)-C(25)
C(26)—C(24)-C(25)
C(31)-C(26)-C(27)
C(3 1)-C(26)-C(24)
C(27)-C(26)-C(24)
C(28)-C(27)-C(26)
C(29)-C(28)-C(27)
C(28)-C(29)-C(30)
C(31)-C(30)-C(29)
C(26)-C(31)-C(30)
C(37)-C(32)-C(33)
C(34)-C(33)-C(32)
C(34)-C(33)-N(38)
C(32)-C(33)-N(38)
C(35)-C(34)-C(33)
C(34)-C(35)-C(36)
C(34)-C(35)-C(44)
C(36)-C(35)-C(44)
C(37)-C(36)-C(35)
C(36)-C(37)-C(32)
C(36)-C(37)-N(41)
C(32)-C(37)-N(41)
O(40)-N(38)-O(39)
O(40)-N(38)-C(33)
O(39)-N(38)-C(33)
O(42)-N(41)-O(43)
O(42)-N(41)-C(37)
O(43)-N(41)-C(37)
O(45)-C(44)-O(46)
O(45)-C(44)-C(35)
O(46)-C(44)-C(35)
C(44)-O(46)-C(47)
O(46)-C(47)-C(48)
C(47)-C(48)-C(49)
O(S4)-C(49)-C(48)
O(54)-C(49)-Si(50)

110.0(3)
113.1(3)
109.0(3)
109.7(3)
110.7(3)
109.8(2)
108.6(2)
109.2(2)
114.5(3)
110.5(4)
104.1(4)
114.9(4)
118.6(5)
123.3(4)
118.0(5)
120.0(5)
121.3(5)
118.5(5)
118.0(5)
123.4(5)
115.4(4)
122.9(4)
119.4(5)
117.7(5)
118.9(5)
119.1(4)
120.1(4)
120.8(4)
119.7(4)
124.1(5)
119.9(4)
116.1(4)
123.6(4)
119.0(5)
117.3(5)
125.3(4)
118.8(4)
115.9(4)
127.6(4)
122.1(4)
110.4(4)
117.1(3)
105.8(4)
113.5(4)
105.1(4)
111.2(3)

256

C(48)-C(49)-Si(50)
C(51)-Si(50)-C(53)
C(51)-Si(50)-C(52)
C(53)-Si(50)-C(52)
C(51)-Si(50)-C(49)
C(53)-Si(50)-C(49)
C(52)-Si(50)-C(49)
C(55)-O(54)-C(49)
O(54)-C(55)-C(56)
O(54)-C(55)-C(57)
C(56)-C(55)-C(57)
C(62)-C(57)-C(58)
C(62)-C(57)-C(55)
C(58)-C(57)-C(55)
C(59)-C(58)-C(57)
C(60)-C(59)-C(58)
C(59)-C(60)-C(61)
C(60)-C(61)-C(62)
C(57)-C(62)-C(61)

114.8(3)
109.8(3)
105.9(3)
111.5(2)
109.9(2)
109.6(2)
110.1(2)
115.2(4)
106.3(4)
112.5(4)
113.2(4)
118.3(5)
122.2(5)
119.4(4)
117.4(5)
123.3(6)
121.2(5)
118.2(5)
121.5(5)

 

Symmetry transformations used to generate equivalent atoms:

257

Table 4. Anisotropic displacement parameters (AA2 x 10"3) for p1

 

 

U11 U22 U33 U23 U13 U12
C(1) 32(2) 21(2) 36(3) 7(2) 6(2) -6(2)
C(2) 26(2) 26(2) 28(2) 5(2) 0(2) -1(2)
C(3) 27(2) 21(2) 26(2) 5(2) 0(2) -1(2)
C(4) 27(2) 20(2) 31(2) 10(2) 8(2) -1(2)
C(5) 32(2) 27(2) 27(2) 12(2) 7(2) 6(2)
C(6) 30(2) 21(2) 37(3) 13(2) 11(2) 0(2)
N(7) 35(2) 25(2) 44(2) 15(2) 10(2) -3(2)
0(8) 60(3) 30(2) 55(3) 16(2) 5(2) 42(2)
0(9) 48(2) 39(2) 64(3) 35(2) 6(2) 5(2)
N(10) 34(2) 38(2) 24(2) 2(2) -2(2) -3(2)
0(11) 45(2) 31(2) 35(2) 13(2) 2(2) 5(2)
0(12) 63(3) 39(2) 42(2) 11(2) -18(2) -10(2)
C(13) 28(2) 31(2) 33(2) 23(2) 7(2) 8(2)
0(14) 42(2) 34(2) 28(2) 16(1) 4(2) 0(2)
0(15) 40(2) 26(2) 27(2) 15(1) -6(2) -11(1)
C(16) 30(2) 21(2) 26(2) 10(2) 4(2) -6(2)
C(17) 32(2) 23(2) 22(2) 9(2) 7(2) 1(2)
C(18) 27(2) 19(2) 24(2) 10(2) 2(2) -2(2)
Si(19) 35(1) 25(1) 28(1) 14(1) 3(1) 0(1)
C(20) 36(3) 58(3) 38(3) 25(2) -5(2) 2(2)
C(21) 56(4) 49(3) 47(3) 27(2) 6(3) 5(2)
C(22) 59(3) 36(2) 33(2) 21(2) 10(2) 10(2)
0(23) 25(2) 23(1) 34(2) 8(1) 4(1) 4(1)
C(24) 36(3) 30(2) 37(3) 12(2) 14(2) 16(2)
C(25) 29(3) 44(3) 88(5) 29(3) 17(3) 3(2)
C(26) 27(2) 18(2) 32(2) 4(2) 1(2) 1(2)
C(27) 37(3) 27(2) 33(2) 1(2) 4(2) 4(2)
C(28) 48(3) 28(2) 60(4) 4(2) 0(3) 2(2)
C(29) 44(3) 23(2) 78(4) 21(2) 13(3) 4(2)
C(30) 36(3) 51(3) 47(3) 26(2) 3(2) 2(2)
C(31) 35(3) 34(2) 42(3) 13(2) 2(2) 4(2)
C(32) 30(2) 30(2) 31(2) 8(2) 2(2) 4(2)
C(33) 28(2) 27(2) 37(3) 14(2) 4(2) 4(2)
C(34) 25(2) 30(2) 34(2) 17(2) 4(2) 0(2)
C(35) 23(2) 30(2) 25(2) 12(2) 1(2) 2(2)
C(36) 31(2) 31(2) 31(2) 18(2) 7(2) 4(2)
C(37) 31(2) 32(2) 28(2) 15(2) 4(2) 4(2)
N(38) 39(2) 29(2) 48(3) 18(2) 11(2) 9(2)

258

0(39)
0(40)
N(41)
0(42)
0(43)
C(44)
0(45)
0(46)
C(47)
C(48)
C(49)
Si(50)
C(51)
C(52)
C(53)
0(54)
C(55)
C(56)
C(57)
C(5 8)
C(59)
C(60)
C(61)
C(62)

44(2)
46(2)
35(2)
72(3)
41(2)
26(2)
39(2)
36(2)
35(2)
26(2)
24(2)
33(1)
44(3)
39(2)
50(3)
28(2)
36(3)
39(3)
28(2)
36(3)
49(3)
42(3)
35(3)
35(3)

40(2)
31(2)
32(2)
47(2)
44(2)
20(2)
32(2)
28(2)
32(2)
23(2)
24(2)
25(1)
37(2)
39(2)
16(2)
25(1)
24(2)
30(2)
33(2)
36(2)
47(3)
45(3)
27(2)
39(2)

53(2)
65(3)
37(2)
39(2)
39(2)
22(2)
34(2)
28(2)
21 (2)
32(2)
30(2)
29( 1)
42(3)
32(2)
40(3)
33(2)
35(2)
85(4)
35(2)
34(2)
66(4)
83(4)
64(3)
38(3)

26(2)
19(2)
18(2)
12(2)
23(2)
0(1)
15(2)
14(1)
7(2)
10(2)
9(2)
14(1)
16(2)
15(2)
1 1(2)
9(1)
15(2)
26(3)
19(2)
19(2)
43(3)
41(3)
14(2)
17(2)

5(2)
1(2)
-2(2)
-22(2)
-4(2)
2(2)
-4(2)
-3(1)
3(2)
-1(2)
1(2)
4(1)
3(2)
1 1(2)
5(2)
1(1)
6(2)
25(3)
7(2)
-4(2)
1 1(3)
20(3)
10(2)
5(2)

7(2)
-7(2)
3(2)
-19(2)
3(2)
-5(1)
-1(1)
-6(1)
-7(2)
-1(2)
0(2)
2(1)
8(2)
-5(2)
-7(2)
1(1)
0(2)
10(2)
11(2)
3(2)
21(2)
13(2)
-2(2)
7(2)

 

The anisotropic displacement factor exponent takes the form:
-2 pi"2 [h"2 a*"2 U11 + + 2 hk a* b" U12]

259

 

Table 5. Hydrogen coordinates ( x 10"4), isotropic displacement
parameters (AA2 x 10"3), and occupancies for p1

 

U(eq)

 

x y z Occ.
H( 1) -991 2834 5773 37 1
H(3) 1066 6230 6695 3 1 l
H(5) 1875 4366 8728 33 l
H(16A) 4659 8403 9355 31
H(16B) 3064 8957 9869 31
H(17A) 4101 10171 8965 31
H(17B) 2526 9480 8223 31
H(18) 4228 7979 6974 27 1
H(20A) 1694 8604 5429 64 1
H(20B) 1845 9832 5264 64
H(20C) 1419 9824 6464 64
H(21A) 5950 11365 7334 72
H(21B) 4210 11627 7711 72
H(21C) 4668 1 1656 6525 72
H(22A) 6566 9018 5313 60
H(22B) 5283 9300 4499 60 1
H(22C) 513 8 8068 4657 60 1
H(24) 6930 7821 6259 41 1
H(25A) 9050 9235 7287 78 1
H(25B) 9629 7930 6996 78
H(25C) 9170 8709 8255 78
H(27) 5707 5910 5662 43 1
H(28) 5097 4146 5903 62 l
H(29) 5817 3965 7654 57 1
H(30) 7106 5684 9237 51 1
H(31) 7779 7392 8914 45 1
H(32) 2498 7284 3279 38 1
H(34) -407 5757 266 34
H(36) 441 3940 2355 34 1
H(47A) -1690 1 195 -834 37
H(47B) -3253 1769 —280 37
H(48A) -1082 695 802 33 l
H(48B) -2663 1 76 33
H(49) -2755 2162 2086 32 1
H(S l A) -298 1544 3640 61
H(5 l B) 7 342 2594 61
H(S 1C) -463 301 3772 61 1

260

 

 

H(52A)
H(52B)
H(52C)
H(53A)
H(53B)
H(53C)
H(55)

H(56A)
H(56B)
H(56C)

-3494
-3672
-4989
-2814
-4530
~3215

-5455

-7595
-7672
-8104

H(58)
H(59)
H(60)
H(61)
H(62)

-6241
-5648
-4350
-3601
-4213

2119
889
1218
-1487
-1212
-1523
2265
919
1495
2250
2734
4570
6118
6036
4245

4416
4574
3815
1286
1708
2480
2733
1679
747
2020
52
-115
1300
3081
3351

55
55
55
54
54
54
36
74
74
74
41
56
61
52
44

 

Table 6. Torsion angles [deg] for p1

 

261

 

I“:
0

o
02" O/\/LTMS

110b

 

 

 

262