SYNTHESIS AND REACTIONS OF BICYCLO[1.1.0]

575 Pages·2009·4.3 MB·English

by  Prema C. Iyer

SYNTHESIS AND REACTIONS OF BICYCLO[1.1.0]BUTANES

by
Maciej Andrzej Aleksander Walczak
B. S. (maxima cum laude), A. Mickiewicz University, 2003

Submitted to the Graduate Faculty of
Arts and Sciences in partial fulfillment
of the requirements for the degree of
Doctor of Philosophy

University of Pittsburgh
2009
UNIVERSITY OF PITTSBURGH
FACULTY OF ARTS AND SCIENCES

This dissertation was presented

by

Maciej A. A. Walczak

It was defended on
August 31, 2009
and approved by
Scott G. Nelson, Professor, Department of Chemistry
Craig S. Wilcox, Professor, Department of Chemistry
Billy W. Day, Professor, Department of Pharmaceutical Sciences
Dissertation Advisor: Peter Wipf, Distinguished University Professor, Department of Chemi-
stry

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Copyright © by Maciej A. A. Walczak
2009
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SYNTHESIS AND REACTIONS OF BICYCLO[1.1.0]BUTANES
Maciej A. A. Walczak, Ph. D.
University of Pittsburgh, 2009

This dissertation describes methods for the synthesis of bicyclo[1.1.0]butanes and their
reactions. The bicyclo[1.1.0]butyl skeleton was first assembled by intramolecular, amide directed
Simmons-Smith cyclopropanation of propargyl amides and cyclopropenes. However, a more
general approach applicable to the synthesis of amines, alcohol, esters, and amides was devel-
oped. This method is based on the generation of bicyclo[1.1.0]butyllithium from gem-
dibromocyclopropanes via sequential transmetallation reactions with alkyllithium reagents and
addition to electrophilic acceptors.
Studies on the reaction of bicyclo[1.1.0]butanes were focused on thermal and metal-
catalyzed transformations. Bicyclo[1.1.0]butanes activated by an aromatic group underwent
highly chemo- and diastereoselective intramolecular pericyclic reactions under mild conditions.
The outcome of these processes was controlled by the selection of the allylating reagents, and N-
allyl amides gave exclusively formal ene products. On the other hand, cinnamyl amides partici-
pated in an intramolecular cycloaddition reaction. The postulated presence of radical in the me-
chanism of these reactions was supported by chemical and spectroscopic (ESR) studies.
In the metal-catalyzed cycloisomerization reactions, an intramolecular cyclopropanation
of allyl amides catalyzed by complexes of Rh(I) is described. These reactions proceeded via
metal carbene intermediates, which were selectively generated by applying phosphine additives
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with different steric and electronic properties. Based on the mechanistic proposal, the synthesis
of pyrroles from bicyclo[1.1.0]butanes was achieved using a Rh(I)/bidentate ligand catalytic sys-
tem and hindered amides. Finally, cycloisomerization reactions of propargyl amides and ethers
as well as electron-deficient bicyclo[1.1.0]butanes catalyzed by Pt(II) are described. These reac-
tions proceeded via a series of carbene intermediates to give polycyclic nitrogen- and oxygen-
containing heterocycles, which could be of utility in research and development.
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS .............................................................................................. XXIV
ACKNOWLEDGEMENTS .............................................................................................. XXVIII
1.0 SYNTHESIS OF BICYCLO[1.1.0]BUTANES ......................................................... 1
1.1 INTRODUCTION ............................................................................................... 2
1.1.1 Fundamental Properties of Cyclopropanes ................................................ 2
1.1.2 Structure of Bicyclo[1.1.0]butane ................................................................ 4
1.1.3 Bicyclo[1.1.0]butane in Nature .................................................................... 8
1.1.4 Synthesis of Cyclopropanes .......................................................................... 9
1.1.4.1 Halomethylmetal-Mediated Cyclopropanations .............................. 10
1.1.4.2 Transition Metal-Catalyzed Decomposition of Diazo Compounds 14
1.1.4.3 Nucleophilic Addition - Ring Closure ............................................... 15
1.1.5 Synthesis of Bicyclo[1.1.0]butane .............................................................. 15
1.1.5.1 Synthesis of the Lateral Bond ............................................................ 16
1.1.5.2 Construction of the Central C C Bond ............................................ 18
1 3
1.1.5.3 Simultaneous Formation of Central and Lateral Bonds ................. 19
1.1.5.4 Addition of Carbene to Cyclopropene .............................................. 20
1.1.5.5 Simultaneous Formation of Two Lateral Bonds .............................. 22
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1.1.6 Halogen-Metal Exchange Reactions .......................................................... 23
1.1.7 Acidity of Bicyclo[1.1.0]butane .................................................................. 26
1.2 RESULTS AND DISCUSSION ........................................................................ 28
1.2.1 Synthesis of Imines ...................................................................................... 28
1.2.2 Synthesis of Bicyclo[1.1.0]butane via Double Carbene Addition ........... 31
1.2.3 Synthesis of Bicyclo[1.1.0]butanes by Carbene Additions to
Cyclopropenes ............................................................................................................ 39
1.2.4 Synthesis of Bicyclo[1.1.0]butane by Addition of
Bicyclo[1.1.0]butyllithium ......................................................................................... 42
1.2.5 Synthesis of Enantiomerically Enriched Bicyclo[1.1.0]butanes ............. 49
1.2.5.1 Enantioselective Addition ................................................................... 50
1.2.5.2 Diastereoselective Addition to Sulfinyl Imines ................................. 51
1.2.6 Synthesis of 2-Substituted Bicyclo[1.1.0]butanes ..................................... 55
1.2.7 Synthesis of gem-Disubstituted Bicyclo[1.1.0]butanes ............................. 58
1.2.8 Cross-Coupling Reactions of Bicyclo[1.1.0]butylstannane ..................... 59
1.2.9 Reaction of Zinc Carbenoids with Allenyl Amides .................................. 60
1.2.10 Diversity-Oriented Synthesis of Azaspirocycles ....................................... 62
1.3 CONCLUSIONS ................................................................................................ 63
2.0 PERICYCLIC REACTIONS OF BICYCLO[1.1.0]BUTANES ............................ 64
2.1 INTRODUCTION ............................................................................................. 64
2.1.1 Ene Reaction ................................................................................................ 64
2.1.2 [2+2] Cycloaddition Reactions ................................................................... 74
2.1.3 Ene Reactions of Strained σ-Bonds ........................................................... 79
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2.2 RESULTS AND DISCUSSION ........................................................................ 83
2.2.1 Tandem Allylation-Ene Ractions of Bicyclo[1.1.0]butanes ..................... 83
2.2.2 Ene Reactions of Propargyl Amides .......................................................... 89
2.2.3 [2+2] Reactions of Bicyclo[1.1.0]butane and Cinnamyl Bromides ......... 93
2.2.4 Reactions of Unactivated Bicyclo[1.1.0]butanes ...................................... 97
2.2.5 Mechanistic Analysis of Ene and [2+2] Reactions ................................. 102
2.2.6 ESR Studies ............................................................................................... 109
2.2.7 The Effect of Conjugation on the Reactivity and Selectivity ................ 114
2.2.8 Studies towards Novel Benzannulation Methodology ........................... 120
2.3 CONCLUSIONS .............................................................................................. 123
3.0 METAL-CATALYZED REACTIONS OF BICYCLO[1.1.0]BUTANES .......... 125
3.1 INTRODUCTION ........................................................................................... 125
3.1.1 Transition Metals and Strained Molecules ............................................. 126
3.1.2 Rh-Catalyzed Isomerization of Cyclopropanes...................................... 128
3.1.3 Rhodium-Catalyzed Isomerization Reactions of Cyclobutanes ........... 132
3.1.4 Metal-Catalyzed Isomerization Reactions of Bicyclo[1.1.0]butanes .... 134
3.1.4.1 Rhodium ............................................................................................. 136
3.1.4.2 Nickel and Palladium ........................................................................ 138
3.1.4.3 Platinum ............................................................................................. 140
3.1.4.4 Silver ................................................................................................... 142
3.2 RESULTS AND DISCUSSION ...................................................................... 144
3.2.1 Rhodium-Catalyzed Cycloisomerization Reactions of
Bicyclo[1.1.0]butanes ............................................................................................... 144
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3.2.2 Synthesis of Pyrroles via Carbene Insertion into NH Bonds ................ 155
3.2.3 Platinum-Catalyzed Cycloisomerization Reactions of
Bicyclo[1.1.0]butanes ............................................................................................... 164
3.3 CONCLUSIONS .............................................................................................. 173
4.0 EXPERIMENTAL SECTION ................................................................................ 175
APPENDIX A ............................................................................................................................ 428
APPENDIX B ............................................................................................................................ 434
APPENDIX C ............................................................................................................................ 442
APPENDIX D ............................................................................................................................ 448
APPENDIX E ............................................................................................................................ 457
APPENDIX F ............................................................................................................................ 467
APPENDIX G ............................................................................................................................ 476
APPENDIX H ............................................................................................................................ 484
APPENDIX I ............................................................................................................................. 502
APPENDIX J ............................................................................................................................. 510
BIBLIOGRAPHY ..................................................................................................................... 520
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LIST OF TABLES

Table 1. Structural parameters for bicylo[1.1.0]butane. ................................................................. 4
Table 2. Comparison of the regioselectivity of metal carbenoids. ............................................... 12
Table 3. Reactions of α-substituted propargyl amides with (CH I) Zn in CH Cl . ...................... 33
2 2 2 2
Table 4. Reactions of propargyl amides with (CH I) Zn. ............................................................. 34
2 2
Table 5. Optimization of reaction conditions for double addition of (CH I) Zn to 112b. ........... 37
2 2
Table 6. Scope of the synthesis of bicyclo[1.1.0]butanes via double carbene addition. .............. 38
Table 7. Scope of the synthesis of bicyclo[1.1.0]butanes via addition to cyclopropenes. ............ 41
Table 8. Synthesis of bicyclo[1.1.0]butanes via direct addition of bicyclo[1.1.0]butyllithium to
imines. ........................................................................................................................................... 44
Table 9. Trapping of bicyclo[1.1.0]butyllithium with carbonyl electrophiles. ............................. 47
Table 10. Enantioselective addition of bicyclo[1.1.0]butyllithium to P,P-diphenylphosphinyl
imine 83a. ..................................................................................................................................... 51
Table 11. Optimization studies on the addition of organolithium reagents to chiral imine 144a. 52
Table 12. Diastereoselctive addition of bicylo[1.1.0]butyllithium reagents to sulfinyl imines. ... 53
Table 13. Synthesis of 2-substituted bicyclo[1.1.0]butanes. ........................................................ 57
Table 14. Reaction of allenyl amide 159 with (CH I) Zn. ........................................................... 61
2 2
x