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The synthesis of highly substituted indoles via isonitriles
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Authors Kennedy, Abigail Rose
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THE SYNTHESIS OF HIGHLY SUBSTITUTED INDOLES VIA ISONTTRILES
By
Abigail Rose Kennedy
A Dissertation Submitted to the Faculty of the
DEPARTMENT OF CHEMISTRY
In Partial Fulfillment of the Requirements For the Degree of
DOCTOR OF PHILOSOPHY
In the Graduate College
THE UNIVERSTTY OF ARIZONA
2001
UMI Number. 3023479
UMI' UMI Microfomt 3023479
Copyright 2001 by Bell & Howell Infomiation and Learning Company. All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
Bell & Howell Information and Learning Company 300 North Zeeb Road
P.O. Box 1346 Ann Arbor, Ml 48106-1346
2
THE UNIVERSITY OF ARIZONA « GRADUATE COLLEGE
As members of the Final Examination Committee, we certify that we have
read the dissertation prepared by Abigail Rose Kennedy
entitled The Synthesis of Highly Substituted Indoles via IsnnifWIpg
and recommend that it be accepted as fulfilling the dissertation
requirement for the Degree of Doctor of Philosophy
Dr. Rqbect B.iBates
Enemark
Date
S'Xi-ol Date
C Dr. David F. O'Brien O'Brien
Dr. Victo
Date
I
Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copy of the dissertation to the Graduate College.
I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement.
Diaeeftation Director
3
STATEMENT BY AUTHOR
This dissertation has been submitted in partial fulfillment of the requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library.
Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgements of source are made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the head of the major department or the Dean of the Graduate College when in his or her judgement the proposed used of material is in the interests of scholarship. In all other instances, permission must be obtained from the author.
SIGNED:
4
ACKNOWLEDGEMENTS
I would like to thank my advisor Dr. Jon Rainier for training me in organic
synthesis, and for his enthusiastic support of my chemistry and my career. He
challenged me to become the chenust that I am today.
I would also like to acknowledge my committee; Dr. Robert Bates, Dr. John
Enemark, Dr. David O'Brien, and Dr. Victor Hruby for critiquing this dissertation. They
have been wonderful teachers both inside and outside of the classroom.
Furthermore, I would like to acknowledge my labmates; Dr. Shawn Allwein,
Jason Cox, Jason Imbriglio, and Qing Xu for creating a fiin workplace and for all of their
support. I wish the best of chemistry to the youngest Rainier group members, as well as
the undergraduates that have worked with me on this project (Eric Chase and Michael
Taday.)
I would like to especially thank good friends that have supported me throughout
this ride; Dr. Michele Cosper, Anne McElhaney, Danielle Wehle, Rachel and Danny
LaBell and Brooke Schilling. Also, thanks to Dr. Jeffrey Anthis who has shown me the
definition of true friendship. I wouldn't have made it this far without all of you.
Finally, I would like to thank my parents, Sarah, Dougie, Ruthie and Molly for
their unconditional support and for being my biggest cheering section over the past 28
years.
DEDICATION
For Liebehaber,
I love you.
6
TABLE OF CONTENTS Page
LIST OF ABBREVUTIONS 11
LISTOFnGURES 13
LIST OF SCHEMES 14
LIST OF TABLES 19
ABSTRACT 20
CHAPTER 1. THE SYNTHESIS OF 2 -DISUBSTITUTED INDOLES
1.1. Indole Containing Products; A Rationale for Indole Synthesis 21
1.2. An Overview of the Synthesis of 2,3-Disubstituted Indoles 22
1.3. The Synthesis of 2,3-Disubstituted Indoles 25
1.3.1. Functionalization of C-2 and C-3 During Indole Assembly 25
1.3.1.1. Baccolini's Indole Synthesis 25
1.3.1.2. Gassman's Indole Synthesis 26
1.3.1.3. Suzuki's Indole Synthesis 27
1.3.1.4. Blechert's Indole Synthesis 28
1.3.1.5. Larock's Indole Synthesis 29
1.3.1.6. Smith's Indole Synthesis 30
1.3.L7. Cacchi's Indole Synthesis 31
1.3.1.8. Edmondson's Indole Synthesis 32
1.3.1.9. Yamanaka's Indole Synthesis 33
7
TABLE OF COmEmS-CotiHnued
1.3.1.10. Yamamoto's Indole Synthesis 34
1.3.1.11. Suh's Indole Synthesis 35
1.3.1.12. Sundberg's Indole Synthesis 36
1.3.1.13. Soderberg's Indole Synthesis 37
1.3.1.14. FQrstner's Indole Synthesis 38
1.3.1.15. Thyagarajan's Indole Synthesis 39
1.3.1.16. Ito's Indole Synthesis 40
1.3.1.17. Fukuyama's Indole Syntheses 41
1.3.2. Functionalization of C-2 and C-3 After Indole Assembly 43
1.3.2.1. Smith's Indole Synthesis 43
1.3.2.2. M^debielle's Indole Synthesis 44
1.3.2.3. Knight's Indole Synthesis 45
1.3.2.4. Cribble's Indole Synthesis 45
1.3.2.5. Jackson's bidole Synthesis 47
1.3.2.6. Greci's Indole Synthesis 48
1.3.2.7. Anthony's Indole Synthesis 49
1.3.2.8. Nakazaki's Indole Synthesis 49
1.3.2.9. Raucher's Indole Synthesis 50
1.4. Conclusions 51
8
TABLE OF CONTENTS-Cottiinued
CHAPTER 2. THE SYNTHESIS OF SUBSTITUTED INDOLES VIA ISONTTRILE RADICALS
2.1. Introduction 52
2.2. Isonitriles as Geminal Radical Donors/Acceptors 52
2.3. Bergman Cycloaromatization Approach to Substituted Quinolines 54
2.4. Tin-Mediated konitrile-Alkyne Cascade to Substituted Indoles 58
2.5. Sulfiir-Mediated Isonitrile-Alkyne Cascade to Substituted Indoles 65
2.6. Conclusions 67
CHAPTER 3. 2,10-DITHIOINDOLES AS VERSATILE INDOLE INTERMEDUTES
3.1. Genera] Approaches to Functionalization of 2,10-Dithioindoles 69
3.2. Addition of Carbon Nucleophiles at C-IO 70
3.3. Addition of Sulftir Nucleophiles at C-10 82
3.4. Addition of Cyanide Ion as a Nucleophile at C-10 83
3.5. Addition of an Amine Nucleophile at C-10 84
3.6. Elimination of the C-10 Thioether Exclusively 84
3.7. Conclusions 85
TABLE OF COmEmS-Continued
CHAPTER 4. PROGRESS IN THE SYNTHESIS OF SPIROTRYPROSTATIN A
4.1. Biological Activity of Spirotryprostatin A
4.2. Danishefsky's Synthesis of Spirotryprostatin A
4.3. Reported Syntheses of Spirotryprostatin B
4.3.1. Danishefsky's Synthesis of Spirotryprostatin B
4.3.2. Ganesan's Synthesis of Spirotryprostatin B
4.3.3. Overman's Synthesis of Spirotryprostatin B
4.3.4. William's Synthesis of Spirotryprostatin B
4.3. Our First General Approach to the Core of Spirotryprostatins A
4.3.1. An "Interrupted" Pictet-Spengler Cyclization
4.3.2. Elaboration of the Thioimidates
4.4. N-Acyl Iminium Ion Approach to Spirotryprostatin A
4.5. Conclusions
CHAPTER 5. DERIVATIZATION OF 2,10-DITHIOINDOLES VU SULFUR YLIDES
5.1. Formation and Structure of Sulfur Ylides
5.2. Common Reactions of Sulfur Ylides
5.3. Intramolecular Sulfur Ylide Reactions
5.3.1. Proposal for an Asymmetric Gramine Reactions via Sulfiir Ylides
10
TABLE OF CONTENTS-Coimnueif
5.3.2. Synthesis of an Intramolecular Sulfur Ylide Precursor 110
5.3.3. fotramolecular Sulfur Ylide Results 111
5.4. Intermolecular Sulfur Ylide Reactions 113
5.4.1. Sulfur Ylides from C-10 Thioindoles 113
5.4.2. Sulfur Ylides from 2,10-Dithioindoles 115
5.4.3. Sulfur Ylides from 2-Thioindoles 117
5.4.4 Attempted Sulfur Ylide Formation from Vinyl Carbenes 119
5.5. Conclusions 123
CHAPTER 6. CONCLUSIONS 124
CHAPTER 7. EXPERIMENTAL
7.1. General Methods 125
7.2. Experimental Procedures 126
APPENDICES
1. Permissions 162
2. Spectra 163
REFERENCES 356
11
LIST OF ABBREVUTIONS
AIBN 2,2'-Azobisisobutyronitrile
BocjO Di-reit-butyl dicaibonate
t-BuOH ferr-Butyl alcohol
18-C-6 l8-Crown-6
DCC 1,3-Dicyclohexylcarbodiimide
DMAP 4,-Diinethylaininopyridine
DMDO Dimethyl dioxirane
DMF MiV-Dimethylformamide
DMSO Methyl sulfoxide
EWG Electron-withdrawing group
EtOH Ethyl alcohol
LDA Lithium diisopropylamide
LiHMDS Lithium bis(trimethylsilyl)amide
LiTMP Lithium tetramethylphosphoramide
KHMDS Potassium bis(trimethylsilyl)aniide
MCPBA m-Chloroperbenzoic acid
MeCN Acetonitrile
MeOH Methyl alcohol
MS Molecular sieves
NHS N-Bromosuccinamide
NOB Nuclear Overhauser effect
12
LIST OF ABBREVUTIONS-Contfiiiietf
BOP Benzotriazol-l-yloxy-tris(dimethylainino)phosphonium hexafluorophosphate
BOP-Cl Bis(2-oxo-3-oxazolidinyl)phosphinic chloride
SCE Saturated calomel electrode
Sem-Cl 2-(Trimethylsilyl)ethoxymethyl chloride
TBAF TetrabuQrlammonium fluoride
TBDPS-Cl Tributyldimethylsilyl chloride
TIPS Triisopropylsilyl
TFA Trifluoroacetic acid
TFAA Trifluoroacetic anhydride
THF Tetrahydrofiiran
TLC Thin layer chromatography
TMG Trimethylene glycol
TsOH p-Toluenesulfonic acid
W-2 Ra-Ni Raney nickel
13
LISTOFnCURES
Figure Page
1.1. Some Natural Products Containing Indole Derivatives 21
1.2. A Framework for the Synthesis of 2,3-Disubstituted Indoles 24
2.1. The Changing Description of the Structure of Isonitriles 52
2.2. Isonitriles as Genunal Radical Donors and Acceptors S3
3.1. Proposed Chemistry of Novel 2,10-Dithioindoles 69
4.1. Spirotryprostatins A and B 86
4.3. Determination of the Relative Stereochemistry of 246a 100
14
LIST OF SCHEMES
Scheme Page
1.1. The Fischer Indole Synthesis 23
1.2. A ModiHed Fischer Indole Synthesis 26
1.3. Gassman's Synthesis of 2,3-Disubstituted Indoles 27
1.4. Suzuki's Synthesis of 2,3-Disubstituted Indoles 28
1.5. A Nitrone-Cyanoallene Coupling Approach to Indoles 29
1.6. Larock's Heteroannulation of Internal Alkynes 30
1.7. Solid Phase Synthesis of 2,3-Disubstituted Indoles (Smith) 31
1.8. Cacchi's Palladium-Catalyzed Indole Synthesis 32
1.9. Edmondson's Hartwig-Buchwald-Heck Reaction to Form Indoles 33
1.10. Yamanaka's Pd°-Catalyzed Synthesis of 2,3-Disubstituted Indoles 34
1.11. Yamamoto's Pd°-Catalyzed Indole Synthesis 35
1.12. Reductive Cyclization of o-Nltrostyrenes by Suh et al 36
1.13. Triethyl Phosphite as a Reductive Cyclization Catalyst 37
1.14. Pd°-Catalyzed Reductive Cyclization to Form Indoles 38
1.15. FQrstner's Ti-Catalyzed Reductive Cyclization to Form Indoles 39
1.16. 2,3-Disubstituted Indoles via Amine Oxides 40
1.17. Ito's Synthesis of 2,3-Disubstinited Indoles via Isonitriles 41
1.18. Fukuyama's Indole Synthesis via Isonitrile Radicals 42
1.19. Fukuyama's Free Radical Cyclization of 2-Alkenyl Thioanilides 43
1.20. A Solid Phase Synthesis of 2,3-Disubstituted Indoles 44
15
LIST OF SCHEMES-Contfrnieif
1.21. An Electrochemical Approach to 2,3-Disubstitute(i Indoles 45
1.22. a-Deprotonation and Reaction with Electrophiles 45
1.23. P-Deprotonation and Coupling with Electrophiles 46
1.24. Simultaneous a,p-Deprotonation and Coupling with Electrophiles 47
1.25. Rearrangement of Indolenines to Form Substituted Indoles 48
1.26. Rearrangement of 2-Hydroxyindolenines to 2,3-Disubstituted Indoles 48
1.27. Indole Synthesis via Rearrangement of 3-a-Epoxyoxindoies 49
1.28. A Two-fold Wagner-Meerwein Type Rearrangement 50
1.29. Rancher's Ortho Ester Claisen Rearrangement to Indoles 51
2.1. The Bergman Cycloaromatization 55
2.2. Proposed Isonitrile-Alkyne Cycloaromatization 55
2.3. Synthesis of Isonitrile 150a 56
2.4. Anticipated Bergman-Type Reaction vs. Observed Isomerization 56
2.5. The First Isonitrile-Alkyne Cascade to 2,3-Disubstituted Indoles 57
2.6. Proposed Mechanism for the Isonitrile-Alkyne Cascade 60
2.7. Wang Cycloaromatization via TMS-stabilized Intermediate 165 61
2.8. Attempted Trapping of the Proposed Vinyl Radical Litermediate 159a 62
2.9. Attempted Trapping of the Proposed Indolenine Intermediate 160a 63
2.10. Proposed Mechanism of Sulfur-Mediated Indole Formation 67
16
LIST OF SCHEMES-CofUiinued
3.1. Attempted Alkylation of 3-(Alkylthio)methylindoles 71
3.2. Somei's Gramine Fragmentation-Addition via nBujP 72
3.3. Phosphine-Catalyzed Alkylation of 2,10-Dithioindoles 73
3.4. Proposed Mechanism of Phosphine-Catalyzed Alkylation 76
3.5. Attempted Coupling of 2,10-Dithioindole 182 76
3.6. Coupling Reaction in the Presence of Benzaldehyde 77
3.7. One-Flask Synthesis: Indole-Formation, Alkylation 78
3.8. Belsky's Fluoride-Catalyzed Michael Addition 78
3.9. A Fluoride-Catalyzed Gramine Coupling 79
3.10. Proposed Alkylation Mechanism with KF as Catalyst 82
3.11. Synthesis of Differentially-Substituted 2,10-Dithioindoles 82
3.12. Coupling of Cyanide Ion to 2,10-Dithioindoles 83
3.13. Addition of an Amine Nucleophile to 2,10-Dithioindoles 84
3.14. KF/Alumina as a 2,10-Dithioindole Coupling Catalyst 85
4.1. The Danishefsky Synthesis of Spirotryprostatin A 88
4.2. Oxidative Cyclization of a Danishefsky p-Carboline 89
4.3. Completion of the Total Synthesis of 1 by Danishefsky 89
4.4. Total Synthesis of Spirotyprostatin B by Danishefsl^ et al 90
4.5. Ganesan's Approach to the Synthesis of Spirotryprostatin A 92
4.6. The Overman and Rosen Synthesis of Spirotryprostatin A 93
17
LIST OF SCHEMES-Cofi<jiiii«<f
4.7. The Synthesis of Spirotiyprostatin B by Williams and Sebahar 95
4.8. Pictet-Spcnglcr Cyclization to Fonn ^-Carbolines 97
4.9. Retro-Mannich Reaction of Spirocyclic Thioimidates 100
4.10. Elaboration of the Spirocyclic Thioimidates 101
4.11. "Interrupted" Pictet-Spengler Cyclization of a Secondary Amine 102
4.12. N-Acyl Iminium Ion Approach to Spirotryprostatin A 103
4.13. Alkylation of 2,10-Dithioindole with a Diketopiperazine Nucleophile 104
5.1. The "Salt Method" of Synthesizing Sulfur Ylides 105
5.2. Sulfur Ylides via a SulHde-Carbene Reaction 106
5.3. Common Reactions of Sulfur Ylides 108
5.4. A Sulfur Ylide Approach to Asymmetric Gramine Reactions 109
5.5. Retrosynthesis of the Sulfur Ylide Precursor 110
5.6. Synthesis of Sulfiir Ylide Precursor 264 111
5.7. Rhodium-Catalyzed Intramolecular Sulfur Ylide Formation 112
5.8. Proposed Mechanism of the Intramolecular Sulfur Ylide Reaction 113
5.9. Sulfur Ylide Reaction with 3-[(Ethylthio)methyll-lH-indole 279 114
5.10. Sulfur Ylide Formation with N-Protected Indole Species 114
5.11. Intermolecular Sulfur Ylide Formation/Rearrangement 116
5.12. Proposed Mechanism of Intermolecular Sulfur Ylide Chenustry 117
5.13. fotermolecular Sulfur Ylide Studies 118
5.14. Reaction of Vinyl Carbenoid Species with 2-Thioindoles 119
18
LIST OF SCHEMES*Coii/sfitiie<f
5.15. A Demonstration of Conjugate Additions to Vinyl Carbenoids 120
5.16. Proposed Mechanism for Formation of 294 122
19
LIST OF TABLES
Table Page
2.1. Synthesis of a Series of o-Alkynyl Isonitriles 58
2.2. Tin-Mediated Isonitrile-Alkyne Cascade to 2,3-Disubstituted Indoles 59
2.3. Thermal and Lewis Acid-Mediated Isonitrile-Alkyne Cascades 64
2.4. Sulfiir-Mediated Isonitrile-Alkyne Cascade 66
3.1. Scope and Limitations of 2,10-Dithioindoles 74
3.2. Comparison of Phosphine vs. KF as Coupling Catalysts 80
4.1. An "Interrupted" Pictet-Spengler Cyclization 98
5.1. Reaction of Vinyl Diazo Compounds with 2-Thioindole 121
20
ABSTRACT
A highly efHcient approach to 2,3-<lisubstituted indoles has been presented. The
indole precursors, isonitriles, were used as powerful geminal radical donors/acceptors.
The novel isonitrile-alkyne free radical cascade has been efficiently mediated by tin and
sulfur. In the case of sulfur, interesting 2,3-dithioindoles were formed. This new class of
compounds has exhibited great promise as versatile indole intermediates. In particular,
nucleophilic additions at C-10 of the 2,10-dithioindoles were achieved using carbon,
sulfur and amine nucleophiles.
The versatility of 2,10-dithioindoles was further demonstrated using rhodium-
mediated sulfur ylide chemistry. We achieved an intramolecular sulfur yiide reaction
which led to a gramine-type addition product 270. Furthermore, sulfur ylides were
formed intermoleculariy and rearranged to give highly substituted indoles.
In studies aimed at the synthesis of the spirotryprostatins, our 2,10-dithioindoles were
used in the synthesis of both a simple C-3 spiro-oxindole compound 249 and a
diketopiperazine-containing indole derivative 256. This demonstrated the exciting
potential of our indole-forming reaction and elaboration methodologies in natural product
synthesis.
21
CHAPTER 1. THE SYNTHESIS OF 2^-DISUBSTmJTED INDOLES
1.1. Indole*G>ntai]iing Natural Products; A Rationale for Indole Synthesis
Indole derivatives are abundant in natural products. This has led to a wealth of
methodologies targeting the synthesis of indoles. Indole-containing natural products
range from compounds incorporating simple tryptophan subunits to others consisting of
highly functionalized indole skeieta. Our research has addressed the continuing need for
novel syntheses of highly substituted indoles with the hope of accessing biologically
interesting natural products.
Figure 1.1. Some Natural Products Containing Indole Derivatives.
tpirotryprottaHn A • inhibits mammalian cell cyde npcn^ne
• leul(emia selective cytotoxicity
potential antitumor agent tabcrsonine ibo^mine
• halludnogen and muscle relaxant
5 talaoeidin
•tumor promoter
22
Several biologically active indole-derived natural products are shown in Figure 2.1.
Spirotryprostatin A (1) belongs to the spirotryprostatins, a class of compounds which
have been shown to possess potential anti-tumor activity.' The biological activity of
Spirotryprostatin A, as well as progress made toward its total synthesis is described in
Chapter 4. Asperazine (2) is an intriguing indole-derived natural product with a core
structure consisting of an indoline skeleton coupled to another indole moiety.* This
natural product exhibits leukemia selective cytotoxicity. Tabersonine (3) is another
potential anti-tumor agent also containing an indole derivative.^ Its pentacyclic structure
contains an indoline moiety. Ibogamine (4), another indole-derived natural product,
elicits hallucinogenic properties in humans. In fact, it has been used for centuries as a
muscle relaxant in traditional spiritual rituals in western Africa. In western medicine, it
has shown potential "anti-addictive" action in combination with opioid analgesics.*
Teleocidin (5) is a known tumor promoter.^ Its core structure contains an indole moiety,
with a dipeptide-derived linkage between C-3 and C-4 of the indole ring. We believe that
the methodology described herein to access highly substituted indoles should lend itself
to the total syntheses of these provocative natural products.
1 An Overview of the Synthesis of 2,3-Disubstituted Indoles
Fischer and Jourdan' first published their classic indole synthesis well over 100 years
ago, yet it remains an efficient approach to the synthesis of substituted indoles. It is
commonly considered to be the most versatile and widely applicable indole synthesis to
date. In the Fischer indole synthesis, an aromatic hydrazone, 6, reacts under acidic
23
conditions to give indole skeleton 7 (Scheme l.l). Since its introduction in 1883,
numerous variations of the Fischer indole synthesis have been reported, thus broadening
access to highly substituted indoles. The best conditions for the Fischer Indole synthesis
are highly substrate dependent, and have been reviewed extensively elsewhere.^
Scheme 1.1. The Fischer Indole Synthesis.
In addition to the Fischer indole synthesis, several other methods have been studied
extensively. These include the Bischler, Madelung, Reissert, and Nenitzescu indole
syntheses, to name a few.^ Despite the wealth of methods that are known today, there
remains a need for general, mild syntheses of highly substituted indoles. This need is
accentuated by the wealth of indole-containing biologically active natural products that
have been identified.
When considering the utility of our indole synthesis, it is important to compare it
against other methods. The synthesis of substituted indoles can be conveniently
categorized into two main classes (Figure 1.2). It is possible to assemble the indole core,
as in the Fischer synthesis, while setting the functional groups at C-2 and C-3 during the
ring assembly step. Alternatively, it is possible to synthesize a relatively simple indole
skeleton, and in a second series of transformations, to fiinctionalize at C-2 and/or at C-3.
It is also possible to use a combination of these two main strategies; that is, to
functionalize only at C-2 or at C-3 during the indole-assembly step, followed by further
acid catalyst
6 7
24
functionalization to install the remaining substitution. The strategies can be further
branched into sub-categories involving intramolecular or intermolecular methods. This
provides a convenient organization of the synthesis of 2,3-disubstituted indoles and
reactions exemplifying these strategies are described (yide infra).
Figure 1.2. A Framework for the Synthesis of 2^*Disubstituted Indoles.
Syntheses of 2,3-0isut>stitiited
Indoles
Functionalize C>2 Functionalize and C-3 during indole C-2 and/or C-3
synthesis after indole synthesis
7\ '^x Intermolecular Intramolecular
Intermolecular functionalization
Intramolecular reanxmgements
Fecher-type Cu-promoted Sf/vr reaction [1,31-Dipolar cycloaddition Pd<atalyzed heteroannulation
Heck reaction Pd^atalyzed heteroannulation Reductive cycl tions Oxidative routes Lewis acid-mediated cydizations Isonitrile couplings Thioimidate couplings
Stille reactions Sfl/vl reactions Cartianionic reactions
Heck reaction Pd^atalyzed heteroannulation Reductive cycl tions Oxidative routes Lewis acid-mediated cydizations Isonitrile couplings Thioimidate couplings Indolenines
Wagner-Meeiwein Ortho^erClaisen
25
13. The Synthesis of 23-Disubstituted Indoles
U.l. Functionalization of C-2 and C-3 During Indole Assembly
13.1.1. Baccolini's Indole Synthesis
There are numerous examples of the synthesis of 2,3-disubstituted indoles which
involve setting C-2 and C-3 during the ring assembly step. The key advantage of this
method is that there may be no need to further fiinctionalize at those centers subsequent
to indole formation. In 1981 Baccolini^ published an example of a modified Fischer
indole synthesis (Scheme 1.2). Baccolini showed that arylhydrazine S> when reacted with
ketone 9 in the presence of phosphorus trichloride, gave an 80% yield of 2,3-disubstituted
indole 10. Baccolini proposed that this reaction proceeds via the Robinson and
Robinson' mechanism for the Fischer indole synthesis. That is, arylhydrazone 11 forms,
which then tautomerizes to ene-hydrazine 12. Ene-hydrazine 12 then undergoes a [3,3]
sigmatropic rearrangement to give 13. Amine addition to the pendant iminium ion 14
produces intermediate 15, which loses ammonia to form the 2,3-disubstituted indole 10.
It has been proposed^ that the main function of the catalyst is to facilitate the
transformation of the arylhydrazone 11 to the ene-hydrazine 12. Through the use of
milder reaction conditions, this synthesis improves upon the classic Fischer indole
synthesis.
26
Scheme 12, A Modified Fisher Indole Synthesis.
a NHNHa 1 PH^Bn
9
PCI3 (1 eq), PhH, r.t.
(75% yield)
A Ph
Ph H 10
8
+
9
11
OCia® NH2
14
12
©B- NHz
NH
13
10
U.1J. Gassman's Indole Synthesis
Gassman and coworkers'" reported a synthesis of 2,3-disubstituted indoles that was
also reminiscent of the Fischer indole synthesis. In their synthesis, 3-
thiomethylindolenines rearranged upon reductive desulfiirization to provide 2,3-
disubstituted indoles in good to excellent yields (Scheme 1.3). Aniline 16 reacted with
various acyl chlorides, followed by p-carbonylsulfides to give aza-sulfonium salt 18. In
the presence of base, 18 was converted to the corresponding ylide which presumably
27
underwent a Sommelet-Hauser type rearrangement, followed by an intramolecular
condensation to give 3-thiomethylaminol intermediate 22. Upon loss of water, 3-
thiomethyl indolenine 23 was formed, which subsequently underwent reductive
desulfiirization in the presence of Raney nickel to afford the desired 2,3-disubstituted
indoles 24.
Scheme 1 J. Gassman's Synthesis of 2^Disubstituted Indoles.
(CH; 3C0CI
16
a 17
CH3SCHR'C(0)R" R'>
r.0
Et^
L 19
R^C"3
f^^'V^COR"
20 21
iMe iMe
W-2 Ra-Ni
U.U. Suzuki's Indole Synthesis
In 1984, Suzuki " published a novel synthesis of 2,3-disubstituted indoles from the
condensation of amline derivatives and stable enolates. lodoaniline 25 was subjected to
stable sodium enolates such as 26 in the presence of a Cu(I) salt, DMF, and heat.
28
Disubstituted indole 29 was formed in 80% yield during the one-flask procedure. The
proposed mechanism involves a copper-promoted nucleophilic aromatic substitution of
the enolate onto iodoaniline. The resultant keto group of intermediate 27 reacts with the
ortho-amno function to provide intermediate 28. Upon loss of water, the indole skeleton
forms. This represented the Hrst copper-promoted aromatic nucleophilic substitution
route to substituted indoles.
Scheme 1.4. Suzuki's Synthesis of 2^Disubstituted Indoles.
25
Ku^COMe
A NaO Me
26(1.5 eq)
Cul / DMF, A yfX— OMe
(80% yield)
H 29
H OMe
OH
H
28
1J.1A Blechert's bdole Synthesis
Dt 1994, Blechert et al. published a novel synthesis of 2,3-disubstituted indoles from
the cycloaddition reaction of aromatic nitrones with activated allenes (Scheme 1.5).
Aromatic nitrone 30 reacted with cyanoallene 31 in heated ethanol to give a 71% yield of
the desired 2,3-disubstituted indole 35. The reaction involves a 1,3-dipolar cycloaddition
29
of the nitrone to the activated double bond of the allene to provide 32. Oxazoline 32
undergoes hetero-Cope rearrangement followed by a retro-Michael reaction to give 34>
Condensation of the amine gives indole 35.
Scheme 1 . A Nitrone-Cyanoallene Coupling Approach to Indoles.
OEl
CN 35
OEt •CN
33
1.3.1.5. Larock's Indole Synthesis
There exist several examples of intermolecular reactions that access 2,3-disubstituted
indoles via palladium catalysts. In 1998, Larock'^ published the synthesis of 2,3-
disubstituted indoles using palladium catalysis in which internal alkynes 36 coupled to
iodoaniline 25 in the presence of Pd(0Ac)2 (Scheme 1.6). The proposed mechanism of
Larock's indole synthesis involves oxidative insertion of Pd(0) to the aryl iodide to give
37, followed by syn insertion of the internal alkyne into the aryl-palladium bond. When
unsymmetricai internal alkynes were used, indoles containing the bulkier alkyne
substinient at C-2 were formed. Thus, in the insertion reaction, the bulky group ends up
30
being adjacent to palladium. Reductive elimination gives 2,3-disubstituted indoles 40 in
very good yields.
Scheme 1.6. Larock's Heteroannulation of Internal Alkynes.
Pd(OAc)2(5 mol%),
LiX, base (5 eq),
PPh3(5mol%). DMF + Ri —
25
(3eq)
36
(26-80% yield)
[LzPdX-]
a: Rl = R2
NH2
37 38 39
U.1.6. Smith's Indole Synthesis
Smith'* showed that Larock's palladium-catalyzed heteroannulation could be applied
to solid-phase synthesis. By simply changing the conditions of the heteroannulation.
Smith's group was able to perform the indole-forming reaction on Ellman's THP resin
(Scheme 1.7).
31
Scheme 1.7. Solid Phase Synthesis of 23«Disubstituted Indoles (Smith).
a 41
Pd(PPh3) l2(20mol%).
TMG(IOeq), DMF.IIOOC
R2 36
13.1.7. Cacciii*s Indole Synthesis
In recent years, other groups have achieved syntheses of 2,3-disubstituted indoles
using palladium catalysis. In 1992, Cacchi et al.'^ successfully reacted trifluoroacetamide
43 with aryl halides and vinyl triflates in the presence of palladium to obtain the desired
2,3-disubstituted indoles 47 in good yields (Scheme L8). The presumed reaction
mechanism involves oxidative insertion of Pd(0) into the aryl halide or vinyl triflate. A
7C-palladium complex 45 then forms, followed by intramolecular addition of the nitrogen
onto the coordinated alkyne to give the a-palladium species 46. Finally, reductive
elimination releases the desired 2,3-disubstituted indole.
32
Scheme 1.8. Cacchi's PaHadium-Catalyzed Indole Synthesis.
NHC(0)CF3 Ri = aryl, vinyl (50-89% yield) X = halide. OTf
RrP^X
L NHC(0)CF3
44
R2
45
1.3.1.8. Edmondson's Indole Synthesis
The prevalence of palladium catalysis in the synthesis of indoles is a tribute to the mild
conditions used in these efficient reactions. In a Hnal example of an intermolecular
indole synthesis in which C-2 and C-3 are set during indole formation, Edmondson et
al.'^ successfully employed palladium to catalyze the coupling of a vinylogous anude to
an aryl halide (Scheme 1.9). Aryl dibromide 48 reacted with vinylogous amide 49 in the
presence of palladium and amino-phosphine ligand 55. The Hrst step presumably
involves a Hartwig-Buchwald coupling to give 52. Intramolecular Heck cyclization then
gives the desired 2,3-disubstinited indole 54.
33
Scheme 1.9. Ediiioiidsoii*s IIartwig-Buchwald<Heck Reaction to Fonn Indoles.
a: Br Hal
48 48
1) Pd2(dba)3, CS2CO3, llgand,THF,80°C,12h
2) Pd2(dba)3,5S, 24h
Me^^ 55s
P(Cy)3
54 (61% yield)
H
53
co6< H
52
U.1.9. Yamanaka's Indole Synthesis
Palladium has also been used extensively as a catalyst in intramolecular syntheses of
indoles in which the C-2 and C-3 centers are functionalized during the key indole-
forming step. In 1990, Yamanaka" transformed vinylogous amides into indoles (Scheme
1.10). Aromatic vinylogous amides 56, substituted with an ortho-iodo group, reacted
with Pd(0) under basic conditions to give moderate yields of the desired 2,3-disubstituted
34
indoles 57. In a similar fashion to the Edmondson indole synthesis, this cyclization
presumably proceeds via an intramolecular Heck reaction.
Scheme 1.10. Yamanaka's Pd"-Catalyzed Synthesis of 2^Disubstituted Indoles.
Pd(OAc)2(10mol%),
NEt3(1.2eq),DMF
120%, sealed tube, 6h
(35-71% yield)
U.1.10. Yamamoto's Indole Synthesis
Yamamoto'^ effected the cyclization of aryl imines onto pendant alkynes using
Pd(0Ac)2 (Scheme 1.11). Aromatic imine 58 (R, = aryl) cyclized onto pendant,
substituted alkynes to produce indoles 62 in good yield. The proposed mechanism
involves formation of palladacycle 60, followed by reductive elimination to give
indolenine 61. Alternatively, imine 58 could be thought of as undergoing
carbopalladation and ^-hydride elimination to form 61. Elimination gives the 2,3-
disubstituted indole 62.
35
Scheme 1.11. Yaiiiamoto*s Pd'-Catalyzed Indole Synthesis.
58
PdOAc
I
Pd(OAc)2(5mol%), /16U3P (20 mol%)
THF, 100®C
(55-70% yield)
60
OAc
N
61
U.1.11. Suh's Indole Synthesis
bi a similar fashion to the aforementioned intramolecular reactions, the C-2 and C-3
centers can be established during indole synthesis using reductive cyclizations. In
general, reductive cyciization routes to indoles have several advantages. First, readily
available aryl nitro compounds are often precursors to the indoles. Second, reductive
cyclizations are flexible, as they can be effected thermally or through the use of transition
metals.
In 1965 Suh et al." first introduced the reductive cyciization of 2-(4,5-dimethoxy-2-
nitrophenyOacrylonitriles in the presence of iron and acid (Scheme 1.12). Nitrostyrene 63
underwent reductive cyciization in the presence of an excess of iron shavings and acetic
36
acid. The proposed mechanism involves the initial reduction of the nitro group to give
hydroxyiamine 64. Intermediate 64 presumably undergoes intramolecular Michael
addition and subsequent dehydration followed by tautomerization to provide indole 67.
Scheme 1.12. Reductive Cyclization of o-Nitrostyrenes by Suh et al.
1 J.1.12. Sundberg's Indole Synthesis
Sundberg and KotchmaH° published another variant of the reductive cyclization to
form the indole core (Scheme 1.13). Nitrostyrene 68 underwent deoxygenation in the
presence of trivalent phosphorus to give 2,3-disubstituted indole 72 in 50% yield. One
proposed mechanism for this reaction involves the formation of an electrophilic nitrogen-
containing intermediate, such as nitroso intermediate 69. The pendant alkene presumably
cyciizes onto the electrophilic nitrogen species to give carbocation 70. Migration of the
C-2 phenyl group and aromatization gives indole 72.
Fe(8)(3eq), AcOH
63 67
37
Scheme 1.13. Triethyl Phosphite as a Reductive Cyclization Catalyst
.Ph P(0Et)3
(50% yield)
Me
NO
69
Me
1 J.1.13. S<klerberg*s Indole Synthesis
Soderberg et al.^' improved upon the previous routes to 2,3-disubstituted indoles by
using palladium as a catalyst to induce reductive cyclizations (Scheme 1.14).
Nittostyrene 73 underwent reductive cyclization to form 2-methyl-3-methylindole 78 in
excellent yield. The proposed mechanism for this transformation involves the initial
reduction of the nitro group. The resultant aniline 74 is thought to then undergo a Pd(II)-
catalyzed cyclization.
38
Scheme 1.14. Pd'-Catalyied Reductive Cyclization to Form Indoles.
Pd(OAc)2(6mol%)
oc 73
PPha, CHaCN, A CO (4 atm)
(97% yield)
74 77
,Me
Me
75
U.1.14. Fiirstner's Indole Synthesis
Fiirstner et al. have also been major players in the field of indole-forming reductive
cyclizations. In 1994, they reported the use of low-valent titanium catalysts to effect the
reductive cyclization of oxo-amides to indoles (Scheme I.IS).^ From amide 79, the
activated titanium species presumably induces highly reactive intermediates leading to
82. Fiirsmer proposed that the highly reactive intermediates were dianions such as 81
formed from the two electron reduction of carbonyl compound 79 and the cyclization of
80. The high oxophilici^ of titanium was thought to drive this reaction.
39
Scheme 1.15. Ffirstner's Ti-Catalyzed Reductive Cyclization to Form Indoles.
[Ti]
(45-90% yield)
0-[T.l
U.1.15. Thyaganuan's Indole Synthesis
In addition to the aforementioned reductive cyclizations yielding indole skeletons,
there exist oxidative routes to form 2,3-disubstituted indoles. For example, Thyagarajan^
utilized the oxidation of anilines to substitute the C-2 and C-3 centers during an
intramolecular indole-forming reaction (Scheme 1.16). Aniline derivative 83 reacted
with mCPBA to produce high yields of 2,3-disubstituted indoles 88. Presumably, this
reaction involves the rearrangement of amine-oxide 84 to 85." Allene 85 then undergoes
a [3,3] sigmatropic rearrangement to give 86. Aromatization and cyclization gives 87
and an acid-catalyzed allylic rearrangement ensues to provide 2,3-disubstituted indole 88.
40
Scheme 1.16. 2,3-Disubstituted Indoles via Amine Oxides.
nCPBA(1 eq), CH I& r.t.
(>80% yields)
83 "OAr 84 S OAr
OAr
OAr
,NR
.OAr
86 88
U.1.16. Ito's Indole Synthesis
Ito et al.^ reported a very efHcient alkylation/hydrolysis procedure using formamides
as indole precursors (Scheme 1.17). They showed that aromatic isonitriles 89, having a
pendant acyl group, could be deprotonated by NaH, and alkylated with alkyi halides to
give 90. Acidic hydrolysis of isonitrile 90 gave formamide 91. Upon treatment with
aqueous base, 91 cyclized and aromatized to give 2,3-disubstituted indoles 93 in good
yields.
41
Scheme 1.17. Ito's Synthesis of 23-Disubstitutcd Indoles via Isonitriles.
1)NaH/DMS0
2) R"X J COR'
89 90 (56-90% yield)
91 CHO
2)aq. NaOH
R'
92 CHO
H
93 (53-90% yield)
1.3.1.17. Fukuyama's Indole Syntheses
Fukuyama has provided several elegant examples of the use of substituted aromatic
isonitriles as precursors to highly substituted indoles in a free radical process. Ortho-
alkenyl aromatic isonitriles 94 underwent tin-mediated free radical cyclization and
subsequent Stille couplings to give 2,3-disubstituted indoles 98 in very good yield over
two steps (Scheme 1.18)." The proposed mechanism involves formation of a stannyl-
imide radical intermediate 95, which presumably undergoes a 5-exo-dig cyclization to
give alkyi radical 96. Reduction of 96 provides a 2-stannyl indole 97. This efficient free
radical approach to highly substituted indoles was highlighted in Fukuyama's synthesis
of the natural product discorhabdin A."
42
Scheme 1.18. Fukuyama's Indole Synthesis via IsonitrUe Radicals.
AIBN(5%),CH3CN.A
nBuaSnH (1.1 eq),
SnBua
R
94 95 SnBua
96
Pd(PPh3)4.El .R'X.A R
SnBu3 H H
98 97
43^2% yield (2 steps)
Complementary to the isonitrile free radical approach to indoles, Fukuyama and co
workers recently demonstrated that 2,3-disubstituted indoles could be generated from the
free radical cyclization of thioanilides (Scheme 1.19).^ In this approach, Fukuyama
successfiilly coupled an alkyl-thioanilide 99 with a pendant, substituted oleHn using tin
free radical conditions. The proposed mechanism involves the cyclization of imide
radical 101 onto the pendant alkene to give indole precursor 102. Reduction of
intermediate 102 gave very good yields of the desired 2,3-disubstituted indoles 103 after
aromatization. This free radical indole synthesis complemented Fukuyama's previous
indole methodology (Scheme 1.18) because he was able to synthesize indoles having
both sp^-substitution at C-2 via Stille couplings (isonitrile route), and sp^-substitution
(thioanilide route).
43
Scheme 1.19. Fukuyama's Free Radical Cyclization of 2-Alkenyl Thioanilldes.
nBuaSnH (1.1 eq), AIBN (5%), PhCHa, A
(36-93% yield)
oa-SSnBus
100
N=\.
101 R'
U.2. Fimctionalization of C-2 and C-3 After Indole Assembly
U.2.1. Smith's Indole Synthesis
Within the framework of synthetic methods to 2,3-disubstituted indoles, the second
major strategy includes cases in which C-2, C-3 or both centers are fiinctionaiized after
the key indole-forming step. For example. Smith et al.^ recently reported the solid phase
synthesis of 2,3-disubstituted indoles using a bromination, Stille coupling protocol
(Scheme 1.20). In this synthesis, simple N-Boc indoles containing an alkyl chain at C-3
were depiotonated at C-2 and brominated at low temperature to give 2-bromoindole 105.
After removal of the Boc carbamate, bromoindole 105 was attached to the Wang resin. A
subsequent StiUe reaction between 106 and an aryl stannane was then carried out in
moderate yield to obtain the desired 2,3-disubstituted indoles 107. The resin was then
44
hydrolyzed using acid. Using this chemistry, Smith et al. were able to synthesize novel,
high-affinity hS-HTjA antagonists, some of which are currently in clinical trials for the
treatment of chronic schizophrenia.
Scheme 1.20. A Solid Phase Synthesis of 2 -Disubstituted Indoles.
1)NaOMe,MeOH OPG
2) BtCF^FaBr
«M to 105 Boc
2) KHMDS, PhCH3. -TtPC -> r.t.
X OPG
Stille Reaction OPG
ArSnMea, Pd°, base, A
-Br
65% yield
1.3 J.2. MMebielle's Indole Synthesis
Another method for fiinctionalizing a C-3 substituted indole at C-2 was reported by
M^debielle and coworkers.^' This method involved the indirect electrochemical
reduction of perfluoroalkyl halides in the presence of indolyl anions (Scheme 1.21). It
was proposed that this reaction proceeded through an SknI mechanism.^^ This
methodology will be applied to the synthesis of F-alkylated analogues of plant hormones,
which are, as yet, not accessible by other methods.
Scheme Ul. An Electrochemical Approach to 2^Disubstituted Indoles.
DMSO/0.1M Et4NBF4 E=-1.457 vs. SCE cartxxi felt cathode PhNOs (mediator) 109 110 •t- K2CQ3(2eq)
45
1J.13. Knight's Indole Synthesis
Another general method for fiinctionalizing at C-2 and C-3 of the indole skeleton
involves deprotonation and subsequent reaction with electrophiles. An example of
deprotonation at C-2 to form 2,3-disubstituted indoles was reported by Knight et al.^^ in
1993 (Scheme 1.22). The C-3 substituent was critical, and the diethylamide derivative
ill gave the best results. As shown, 111 was deprotonated at low temperature and then
trapped with various alkyl halides to obtain 113. Alternatively, the a-lithio-indole
intermediates were trapped with aldehydes to give hydroxy indoles 114. Both of these
processes gave good yields, although the reaction failed to give coupled products when
ketones were used as the electrophiles.
Scheme 1.22. Deprotonation at C-2 and Reaction with Electrophiles.
fiBuU. lONEt2 R| :0NEt2
H THF. -78'»C
^OP
P=CH3,TOS (86-91% yield)
RCHO
IH
(66-82% yield)
13.2.4. Gribble*s Indole Synthesis
Similarly, Gribble reported that it is possible to effect the deprotonation of N-
protected indoles at C-3 by utilizing a pyridine directing group at C-2 (Scheme 1.23). He
46
postulated that the coordination of the lithium counter-ion to the adjacent pyridine
nitrogen was critical to the success of this reaction. Upon quenching of the carbanionic
intermediate 116 with various electrophiles, good yields of the desired 2,3-disubstituted
indoles 117 were obtained.
Scheme 1.23. Deprotonatkm at C-3 and Coupling with Electrophiles.
Gribble has also utilized a dianion to synthesize 2,3-disubstituted indoles. As shown
in Scheme 1.24, N-methyl-2,3-diiodoindole 118 underwent lithium-halogen exchange
using rBuLi at low temperature to produce di-lithio intermediate 119. This intermediate
was quenched with DMF to provide di-aldehyde 120, or with COjCg) to give the di-acid
indole product 121. The di-lithio intermediate 119 also condensed with phthalic
anhydride to give 122 in 41% yield, and with methyl chloroformate to give a 75% yield
of di-ester 123.
115 116 117 (51-74% yield)
47
Scheme 1 . a,P"Litliiuiii-Halogeii Exchange and Coupling with Electrophiles.
fiuLi,
THF, -10tf>C
121 CHa
DMF
82% yield
122 CHa
CHO
CICOzMe 75% yield
COzCg) yield 41% yield
CO^e /TV-/
CO^e
123 CHa
U.2.5. Jackson's Indole Synthesis
In the framework of syntheses of 2,3-<lisubstituted indoles, the final strategy to be
considered also involves the introduction of the C-2 and C-3 functionality after indole
formation. Several groups have investigated the use of indolenine rearrangements to
form 2,3-disubstituted indoles. In 1967 Jackson and coworkers^ reported the use of
Lewis acids to mediate the intramolecular rearrangement of indolenines 124 to
substituted indoles 125 (Scheme 1.2S). These rearrangements followed the normal
migratory aptitude patterns seen in cationic-induced rearrangements. The indolenines
were prepared via ali^lation of C-3 indolyl anions, or were formed in situ in the presence
48
of acid as in the example shown. As shown, indole 126 reacted with a strong Lewis acid
to obtain the indoles 128a/b in 60% yield.
Scheme 1JS. Rearrangement of Indolenines to Form Substituted Indoles.
or Lewis add
126 127 1281
+
128b * stritrfum label
1 J.2.6. Greeks Indole Synthesis
In 1980, Greci and coworkers^ utilized an acid-catalyzed rearrangement to induce the
formation of 2,3-disubstituted indoles (Scheme 1.26). This reaction involved an
intramolecular rearrangement of 3-hydroxyindoline 129 under acidic conditions to give
the corresponding 2,3-disubstituted indole 131. The migratory aptitude of the
substituents at C-2 of 130 determined the position of the substituents at C-2 and C-3 in
the product 131.
Scheme 1J6. Rearrangement of 2-Hydroxyindolines to 2^Disubstituted Indoles.
131 130
H HCI/EtOH
129
49
U.2.7. Anthony's Indole Syntiiesis
Anthony and coworkers ^ reported an indole-forming rearrangements involving 3- a-
epoxyoxindoles (Scheme 1.28). Oxindoles 132 were epoxidized using basic peroxide
conditions to give the desired 3-a-epoxyoxindoles 133. Oxindole 133, when treated with
base, presumably undergoes a fragmentation and subsequent epoxide opening to give
indoline 135. Intermediate 135 then rearranges through a mechanism similar to the
aforementioned acid-catalyzed rearrangement of 3,3-disubstituted indolines to 2,3-
disubstituted indoles.
Scheme 1.27. Indole Synthesis via Rearrangement of 3-a-Epoxyoxindoles.
mHzQ.
base H
132 133 136
-tR,
Rz 134 135
U.2.8. Niakazald's Indole Synthesis
In 1960, Nakazaki and coworkers^ used a Wagner-Meerwein rearrangement to form
2,3-disubstituted indoles. In this reaction, 2-methyl-3-phenylindole 137 reacted at high
50
temperature in the presence of aluminum trichloride to give the rearranged 3-methyl-2-
phenylindole 142 in 60% yield (Scheme 1.28). This two-fold Wagner-Meerwein type
rearrangement presumably involves electrophilic attack of the Lewis acid at the 3-
position of the indole ring, giving cationic intermediate 139. The C-3 phenyl substinient
then migrates to C-2, leading to a new cationic intermediate 140. The methyl group then
migrates to C-3, and upon loss of the Lewis acid, the indole ring is reformed.
Scheme 1.28. A Two-fold Wagner-Meerwein Type Rearrangement
N^Me
139 137 138
140
Me
141 142
U J.9. Rancher's Indole Synthesis
Raucher et al.^ have synthesized 2,3-disubstituted indoles via ortho ester Claisen
rearrangements (Scheme 1.29). In these reactions, 3-indolylglycolic acid derivatives
such as 143 underwent ortho ester Claisen rearrangements to give 146. The researchers
demonstrated the utility of this methodology in their total synthesis of vindorosine.
51
Scheme 1^9. Raucher*s Ortho Ester Claisen Reairangement to Indoles.
Mei
143 Ts 146 Ts COaMeCOsMe
iMe
144
.OMe
145
1.4. Conclusions
In conclusion, several strategies exist to form 2,3-disubstituted indoles. These
strategies install C-2 and C-3 functional groups either during the key indole-forming step,
or after the indole skeleton has been formed. In general, some limitations of the
aforementioned strategies include the use of precursors that can be cumbersome to
synthesize, harsh reactions conditions that will not tolerate sensitive functionality, and a
lack of selectivity for substitution. Due to the wealth of indole-containing natural
products that are known today, more indole syntheses that are both mild and general are
warranted. Our research has adopted the challenge of synthesizing highly substituted
indole compounds in the hopes of accessing biologically active indole natural products.
52
CHAPTER 2. THE SYNTHESIS OF SUBSTITUTED INDOLES VUISONITRILE RADICALS
2.1. Introduction
In our research, we have synthesized indoles from aromatic isonithles. During the
indole-forming reaction, the isonitriles presumably react as geminal radical donors and
acceptors (vide infra). In this chapter, a brief outline of the initial Bergman
cycloaromatization experiment leading to the serendipitous indole methodology is
presented. The development of an isonitrile-alkyne cascade to form 2,3-disubstituted
indoles is discussed, including tin- and sulfiir-mediated methodologies. A mechanism for
indole formation is proposed, and mechanistic studies follow. The discovery and careful
optimization of a novel free radical cascade to 2,3-disubstituted indoles is presented.
2.2. Isonitriles as Geminal Radical Donors/Acceptors
Isonitriles were first discovered in the late nineteenth century. Lieke'*' unknowingly
synthesized the first isocyanide from the reaction of allyl isocyanide with silver cyanide.
Several other reports documented the appearance of isonitriles prior to their identiHcation
as a new class of compounds. Finally in 1868 Gautier^^ recognized that a new class of
compounds had been created.
Figure 2.1. The Changing Description of the Structure of Isonitriles.
• 1892 Net Structure *1930 Undemann-Wiegrebe structure
© 0 R—N=c: R—l>^C
53
Since their discovery, the structure of isonitriles has primarily been described in two
different fashions. In 1892, Nef" proposed that the structure of isonitriles consisted of a
divalent carbon atom with a double bond between the nitrogen and carbon atoms. In
1930, Lindemann and Wiegrebe^ proposed a more polar structure of isonitriles, where a
formal C,N triple bond exists. This description has since been proven via microwave
studies to be a more accurate general description of isonitriles.
In an attempt to symbolize their reactivity with free radicals, Curran*^ proposed yet
another way of depicting isonitriles in 1991 (Figure 2.2). In a similar fashion to Nef, the
isonitrile contained a formal double bond between nitrogen and carbon. By drawing one
of the electrons on the divalent carbon as an "open" radical, the synthon signified the
radical-accepting capability of isonitriles, while the "closed" electron denoted the radical-
donating capability, bi this way, Curran used the synthon to symbolize the geminal
radical-accepting and -donating capability of isonitriles.
Figure 22. konitriles as Geminal Radical Donors and Acceptors.
1991 Curran synthon
N=:Co
' r ^ EWG
54
Because the temiinal carbon atom has the capabiliQr of forming two sequential
geminal bonds, isonitriles can be used efficiently in multi-component free radical
couplings (Figure 2.2). In general, a radical can add to the isocyanide to produce an
imide radical. The imide radical can react with some other radicalphile, such as an
activated alkene, to produce another alkyl radical intermediate. The new alkyl radical
can react with yet another coupling component, or the radical can be quenched to end the
free radical chain process. The resultant imine of the isonitrile multi-component coupling
provides a useful functional group to be further manipulated. Therefore, isonitriles have
been useful tools in multi-component radical couplings aimed at the synthesis of complex
natural products.
The geminal radical donor/acceptor capability of isonitriles lies at the foundation of
our work. One of our goals was to harness the power of isonitriles to form two geminal
bonds at the carbon center of isonitriles in order to access novel compounds. This idea
was applied to a free radical isonitrile-alkyne cascade in which 2,3-disubstituted indoles
were formed in a very efHcient fashion.
2.1. Bergman Cycloaromatization Approach to Substituted Qumolines
The Bergman^ cycloaromatization (Scheme 2.1) is an efHcient method of synthesizing
aromatic compounds. For example, ene-diyne derivative 147 cycloaromatizes to form a
biradical intermediate 148 under thermal or photolytic conditions.*" Upon quenching of
the biradical intermediate 148 with a radical donor, highly substituted naphthalenes 149
are obtained.
55
Scheme 2.1. The Bergman Cycloaromatization,
Pr
Aorhv Pr radical
donor Pr
Pr Pr
147 Pr
148
Due to an interest in the chemistry of isonitriles in cycloaromatization reactions, we
initially explored Bergman-type cycloaromatization reactions of aromatic isocyanides
having a pendant alkyne, such as phenyl isocyanide derivative 150 (Scheme 2.2). Upon
thermal or photolytic cycloaromatization of isocyanide 150, a biradical intermediate 151
would be formed, and upon quenching with a radical donor, substituted quinoline 152
would be obtained. This methodology would not only provide access to highly
substituted quinoline compounds, but it would also extend the scope of the Bergman
cycloaromatization protocol.
Scheme 2.2. Proposed Isonitrile-Alkyiie Cycloaromatization.
To this end, phenyl isocyanide 150a, having a pendant, TMS-capped alkyne in the
ortho position, was synthesized. Isocyanide 151a was obtained from commercially
available iodoaniline 153 (Scheme 2.3). Formylation'*' of 153 using acetic-formic
anhydride gave 154. Sonogashira coupling^ of trimethyisilylacetylene and o-
iodoformanilide 154 provided a 93% yield of desired alkyne 155a. Dehydration with
Aorhv solvent
ISO 151 152
56
phosphoros oxychloride" and iPrNH provided the desired isocyanide 150a in an 82%
yield. While 150a is acid-sensitive, it can be puriHed via distillation or chromatography
on a neutral alumina column. Furthermore, a neat solution of 150a can be stored at
-20°C for several months widiout notable decomposition.
Scheme 2 J. Synthesis of Isonitrile 150a.
AcaO.HCOOH
90% yield
POCI3, PrgNH,
CH2CI2
82% yield
PdCl2(PPh3)a
NEtaCul.
TMSO»CH
93% yield
TMS
155a 150a
The results from our study of a Bergman-type cycloaromatization of 150a are depicted
in Scheme 2.4. Disappointingly, 150a was stable at temperatures below ISOT. At
180°C or above, isomerization to nitrile 156 occurred.
Scheme 2.4. Anticipated Bergman*type Reaction vs. Observed Isomerization.
/TMS
ISOa
ccc™' 151
S-H 07™
152
TMS
57
Undaunted by the lack of cycloaromatization of ISOa under thermal conditions, we
decided to focus our attention on the use of free radical conditions to initiate the
cycloaromatization. Presumably, this would also allow us to access the desired
substituted quinolines. While deciding upon the exact free radical conditions to use,
intriguing reports from Fukuyama et al. were considered. As was mentioned In Scheme
1.18 (Chapter 1), these reports described the synthesis of 2,3-disubstituted indoles
through the cycloaromatization of aromatic isonitriles containing pendant alkenes.^
Based on Fukuyama's precedence, isocyanide ISOa was subjected to free radical
cyclization conditions and acidic work-up. Indole product lS7a was the exclusive
product in 82% yield (Scheme 2.5). None of the corresponding quinoline lS2a was
observed. Although this did not constitute the initially anticipated cycloaromatization, it
was a first step toward understanding the chemistry of alkynyl aromatic isonitriles in a
free radical-mediated cycloaromatization.
Scheme 2.5. The First Isonitrile-Alkyne Cascade to 2 -Disubstituted Indoles.
hi order to determine the scope of this free radical cascade reaction, a series of
isonitriles having various substituents on the pendant alkyne were synthesized. As shown
(Table 2.1), it was possible to perform an efGcient Sonogashira coupling of substituted
alkynes with o-iodoformanilide to yield aromatic compounds 155 in good yield.
nButjSnH (2.2 eq), AIBN (10%), PhH, A;
H 157a
82% yield
150a 152a
0% yield
58
Isocyanide ISOf was obtained via TBAF-induced hydrolysis of ISOa, leading to the
desired terminal alkyne. Because of their inherent instability to puriHcation, isonitriles
150b, 150c, 150d, 150e and 150f were used in crude form.
Table 2.1. Synthesis of a Series of o-Alkynyl Isonitriles.
'R .R
POCI3, PrzNH, ax • H
PdCl2(PPh3)a
NEta Cut,
RC*CH
154
CH2CI2
Entry R 155 Yield 155 (%) 150 Yield 150 (%;
IMS a 93 a 82
nBu b 100 b "
tBu c 92 e ~
Ph d 100 d "
CHeOBn e 57 e —
1
2
3
4
5
6 H
2.4. Tin*niediated Isonitrile*Alkyne Cascade to Substituted Indoles
With isonitriles 150a-f in hand, the proposed free radical-induced
cycloaromatizations were examined. Isonitriles 150b-f were exposed to two equivalents
of tributyltin hydride and AIBN in refluxing benzene. Protodestannylation of the
products upon work-up gave quinoline and/or indole products (Table 2.2)" In the case
of an n-butyl-substituted alkyne 150b (Entry 2, Table 2.2), quinoline 152b was the
predominant product. In the case of t-butyl alkyne 150c (Entry 3, Table 2.2), indole
59
157c was the predominant product. The yields for the reaction decreaed with R = Ph
(150d) and R = CHjOBn (150e) and in both instances, mixtures of indole and quinoline
were obtained (Entries 4 and S, Table 2.2). With terminal alkyne 150f (Entry 6, Table
2.2), exclusive formation of quinoline 152f occurred, albeit in low yield (18%).
Table 2J2. Tin-Mediated Isonitrile-Alkyne Cascade to 2 -Disubstituted Indoles.
iiBU3<siin yc.e _ nBuaSnH (2.2 eq), AIBN (10%), PhH, A;
H3O ©
Entry R 152 Yield 152 (%) 157 Yield 157 (%)
1 IMS a 0 a 82
2 nBu b 53 b 10
3 tBu 0 10 c 55
4 Ph d 13 d 28
5 CHaOBn e 4 e 7
6 H f 18 f 0
Our proposed mechanism for the formation of indole and quinoline products, based
upon Fukuyama's mechanism, is illustrated in Scheme 2.6. We proposed that tribu^ltin
radical adds to the carbon atom of isocyanide 150, which gives stannylated imide radical
intermediate 158. The imide radical can undergo a 6^ndo-dig fiee radical cyclization to
60
give quinoline radical intermediate 162, and the quinoline skeleton 163 after hydrogen
atom abstraction.
Scheme 2.6. Proposed Mechanism for the IsoiiitrUe*Alkyne Cascade.
nBu^n
N^^SnBua SnBua
159
nBuaSnH
nBu^nH
SnBus
160
nBu^nH
SnBus
163
Alternatively, the stannylated imide radical 158 underwent a S-exo-dig free radical
cyclization to provide exocyclic vinyl radical 159. This led to indolenine intermediate
160 upon hydrogen atom transfer from tribu^ltin hydride. In the presence of nBujSnH,
the indolenine intermediate is reduced to 2-stannyl indole 161. Tribu^ltin hydride has
been reported to act as both" a hydrogen atom donor^' and hydride donor^ in certain
cases. Acidic hydrolysis leads to the observed indoles 157.
61
Several important details concerning the proposed mechanism warrant discussion.
First, two different hypotheses can be used to account for the exclusive formation of
indole when the alkyne is substituted with a trimethylsilyl group (Entry 1, Table 2.2). It
is possible that silicon's ability to stabilize a-radicals" might favor S-exo-dig cyclization
of imide radical 158. In 1999, Wang et al.^' demonstrated a similar phenomenon
(Scheme 2.7). In their thermally-initiated cyclization of ketenimine 164, a TMS group
was proposed to stabilize intermediate 165, causing complete formation of indole 166.
Scheme 2.7. Wang Cycloaromatization via TMS-stabilized Intermediate 165.
TMS
(89%yfeld)
It is also possible that non-bonded interactions between the bulky TMS group and the
BusSn substituent destabilized the transition state leading to 162. In support of this
notion, the cyclization of bull^ rBu-alkyne 150c gave primarily indole 157c, while
cyclization of nBu alkyne 150b gave predominantly quinoline 152b. From these
experiments, we concluded that steric destabilization of intermediates along the quinoline
pathway was largely responsible for the prevalence of S-exo-dig cyclization in the case of
R s TMS, although a-radical stabilization by TMS cannot be completely overlooked.
62
In order to gain an understanding of the proposed mechanism, a series of experiments
to trap the proposed intermediates were carried out. We initially attempted to trap the
proposed intermediates 159a and 160a. In an effort to trap the proposed vinyl radical
intermediate 159a we conducted reactions in the presence of dimethyl fiimarate and
methyl acrylate (Scheme 2.8). Unfortuntately, the only product obtained was 2-
stannylated indole 161a.
Scheme 2.8. Attempted Trapping of the Proposed Vinyl Radical Intermediate 159a.
Similarly, we attempted to trap the proposed indolenine intermediate 160a with
nucleophiles other than hydride (hydrogen atom) (Scheme 2.9). To this end, the
isonitrile-alkyne cyclization was run using two equivalents of tributyltin hydride in the
presence of amine nucleophiles (diethylamine, benzylamine, and aniline). The product
obtained in these reactions was 2-stannylated 161a. We also ran the reaction in the
nBuaSnH
radical trap
H
161a
radical trap = or
63
presence of methanol as a potential nucleophile. Despite the fact that we used methanol
as the solvent, no incorporation of a methoxy group into the indole skeleton was
observed.
Scheme 2.9. Attempted Trapping of the Proposed Indolenine Intermediate 160a.
In the aforementioned experiments, we used 2.2 equivalents of nBu^SnH. With the
notion that /iBujSnH was selectively delivering hydride even in the presence of excess
nucleophile, we examined the cyclization in the presence of amines and methanol using
just one equivalent of nBujSnH (Scheme 2.9). Disappointingly, the only material
obtained from this experiment was 161a, as well as recovered starting material 150a.
These results neither validated nor disproved the proposed mechanism, and so the novel
isonitrile-all^e cascade was explored further.
We shifted the focus of our cycloaromatization smdy to include the exploration of
various initiators. In an effort to initiate the reaction at lower temperatures (AIBN
requires an initiation temperature > 60i°C) a triethylborane/Oj initiator system was
employed. These reactions proceeded as expected at room temperature, however, they
nBuaSnH (2.2 eq), AIBN (10%), NuH (excess)
nBuaSnH (1 eq) AIBN (10%). NuH (excess)
NuH s MeOH, EtsNH, BnNH2, CeHj Hg H
161a
64
generally gave lower yields than when AIBN was used (Table 2.3). Also, thermal and
Lewis-acid-induced free radical cyclizations were explored. Interestingly, even in the
absence of AIBN (Entry 3, Table 2.3), we isolated 157a, albeit in low yield (12%). In the
presence of MgBrj'EtjO, the reaction also proceeded to yield the desired indole lS7a
(34%; Entry 4, Table 2.3). While these yields were appreciably lower than in the
optimized case (82%; Entry 1, Table 2.3), it was still of interest that both the thermal and
Lewis acid-mediated isonitrile-alkyne cascades did proceed in the absence of a free
radical initiator.
Table 2 J. Thermal and Lewis Acid-Mediated Isonitrile-Alicyne Cascades.
conditions
Entry Conditions Yield 157a
BuaSnH (2.2 eq). AIBN (10%), PhH (CH3CN), 8OOC
82%
2 BusSnH (2.2 eq), BEta^Oa, PhH. 80< 32%
3 BuaSnH (2.2 eq), PhH, 80°C 12%
4 BusSnH (2.2 eq), MgBrs'EtaQ (10%), 34% PhH (CH3CN), 8OOC
While pleased with the tin-mediated isonitrile-alkyne cascade of 150a, we became
interested in exploring other free radical sources. We thought it might be interesting to
65
add radicals other than tin (i.e. carbon or sulfur) to the isonitriles in order to initiate the
free radical cascade. The impems for this study stemmed, in part, from the disadvantages
associated with working with tributyltin hydride as a free radical source. First, tin
reagents are inherently toxic, thus it is not a particularly desirable free radical source in
the reaction. Second, tin byproducts from the reaction were often difficult to eliminate,
even after an aqueous work-up using a saturated KF solution to remove tin salts. Hence
other sources of free radicals were investigated.
2,5. Sulfur-Mediated IsonitrUe<Alkyne Cascade to Substituted Indoles
Saegusa,'' Bachi,^ and Nanni^' have performed comprehensive studies involving the
addition of sulfur radicals to isonitriles. Based on this precedence, we felt that thiols
might not only serve to initiate the isonitrile-alkyne free radical cascade, but that they
might also act as nucleophiles and react with the proposed indolenine intermediate 160.
With these possibilities in mind, experiments using thiols in the isonitrile-alkyne
cyclization to form substituted indoles were conducted. When aryl isonitrile 150a was
subjected to AIBN and thiols, 2,10-thioindole species 170 were formed in moderate to
high yields (Table 2.4).^ Included among the thiols were alkyi, aryl, and substituted
alkyl mercaptans. We were gratiHed to achieve our novel isonitrile-alkyne firee radical
cascade using the new free radical source—sulfur.
66
Table 2.4. Sulfiir-Mediated Isonitrile-Alkyiie Cascade.
TMS
ISOa
RSH (3 eq), AIBN (15%), PhCH A
-Et
•nBu
-Ph
-CH^H20H
-CH^HaOTBS
•CH^HaCO^e
a
d
e
f
•IMS
170 Yield (%)
86
66
49
94
60
72
Hie 2,10-ditiuoindole products 170 were the first compelling evidence reinforcing our
proposed mechanism of the indole-forming reaction (Scheme 2.10). Presumably, the first
step of the reaction involves addition of a thiol radical to the carbon atom of the
isocyanide in 150a to form imide radical 171. The imide radical undergoes a S-exo-dig
cyclization to give vinyl radical 172. The vinyl radical then abstracts a hydrogen atom
from the thiol to provide the proposed indolenine intermediate 173. We postulated that
the thiol then reacts as a nucleophile with indolenine 173, providing 2,10-dithioindole
170.
67
Scheme 2.10. Proposed Mechanism of Sulfiir-Mediated Indole Formation.
TMS
SR
150a
RSH RS • ' 17
The new sulfur-mediated free radical cascade to 2,3-disubstituted indoles was
extremely gratifying not only because the reaction was general for a number of thiols, but
it also provided indirect evidence for a previously elusive intermediate (the proposed
indolenine 173). Furthermore, highly substituted 2,10-dithioindoIes were formed, thus
creating a novel class of compounds, which would later prove to be versatile indole
intermediates (Chapter 3).
2.6. Conclusions
In sunmiary, experiments that were aimed at a Bergman cycloaromatizau'on of
aromatic isonitriles led to the discovery of a novel synthesis of indoles. Since this
discovery, a highly efGcient indole methodology, involving a free radical cascade and an
indolem'ne intermediate, has been developed to access 2,3-disubstinited indoles. This
isonitrile-alkyne cascade was mediated efficiently by tin and sulfiir. Mechanistic studies
involving attempts to trap proposed intermediates were performed; however, the first
68
compelling evidence in support of an indolenine intermediate stemmed from the use of
sulfur to mediate the reaction. In the event, novel 2,10-dithioindoles were formed.
Outlined in the next chapter are our preliminary studies toward using the 2,10-
dithioindoles as versatile organic intermediates.
69
CHAPTER 3. 2,10-DITHIOINDOLES AS VERSATILE INDOLE INTERMEDUTES
3.1. General Approaches to Functionalization of 2,10-Dithioindoles
After the successful formation of novel 2,10-dithioindoles, our attention turned to their
use in synthesis. Purified 2,10-dithioindoles are stable, yellow solids that can be stored at
-20°C for extended periods of time with no appreciable decomposition. We believed the
interesting functionality of the 2,10-dithioindoles would allow us to access a variety of
organic reactions leading to more highly substituted indoles, as illustrated in Figure 3.1.
Hence, we felt that 2,10-dithioindoles were potentially valuable indole intermediates.
Figure 3.1. Proposed Chemistry of Novel 2,10-DitiiioindoIes.
• susceptible to elimination and coupling with nucleophiles
• Julia coupling with electrophiles
• Peterson olefinations
H
• malces C-3 nucleophilic
• displacement with nucleophiles
• thio-Qaisen rearrangements
70
We proposed several interesting transformations for the 2,10-dithioindoles (Figure
3.1). For example, we felt that conditions might be found to form and carry out
nucelophilic additions to indolenine intermediates via elimination of the C-10 thioether.
This would permit the formation of a carbon-carbon bond at C-10; these substrates had
been inaccessible from our isonitrile-alkyne cascade thus far. We also believed that the
C-10 thioether and trimethylsilyl groups would allow us to access to Julia and Peterson
type couplings with electrophiles respectively. Thus, we believed the C-10 thiol and
trimethylsilyl functionality had great synthetic promise.
The C-2 thioether was also intriguing and several reactions were proposed to unleash
its reactivity (Figure 3.1). We believed that the C-2 thioether would render C-3 more
nucleophilic relative to indoles lacking such a group. In addition, we thought it should be
possible to displace the 2-thioether under appropriate nucleophilic conditions. Also,
indoles substituted with a C-2 allyl-thioether have been shown to undergo thio-Claisen
rearrangements onto the C-3 position of the indole ring.^^ This could be utilized as a new
method for selectively fiinctionalizing C-3 of the indole nucleus. Studies of the novel
2,10-dithioindoles that follow have included, but were not limited to, the chemistry
illustrated in Figure 3.1.
3 . Addition of Carbon Nucleophiles at C>10
CXir preliminary e^orts to harness 2,10-dithioindoles as versatile organic
intermediates focused on the formation of carbon-carbon bonds at C-10 using gramine
fragmentation-addition chemistry. In the 19S0's, Popplesdorf and Holt^ showed that
71
alkylthio groups could be displaced from 3-(alkylthio)methylindole using amine
nucleophiles (Scheme 3.1). However, they were unsuccessful in their attempts to add
carbon nucleophiles under similar conditions. They concluded that thiomethyl indole
derivative 174 is less reactive toward fragmentation-addition than gramine. This lack of
reactivity was likely due to the poorer leaving group ability of the alkylthio group relative
to related amine groups. Undaunted by this precedent, we hoped that the 2-thioether of
the 2,10-dithioindoles would add sufficient electron density to the indole system to allow
us to use the C-10 thioether group in nucleophilic coupling reactions.
Scheme 3.1. Attempted Alkylation of 3-(Alkylthio)iiiethylindoles.
H
0 KOH(cat.).A
49% yield
EtO^Cs^O t CO t T /r- /—^^CO#t NHAc
KOH(cat.).A // [j
172
An approach to gramine fragmentation-addition was reported by Somei^ using tri- n-
butylphosphine to catalyze the coupling of gramine (177) with malonate nucleophiles in
quantitative yields (Scheme 3.2). A problem associated with the traditional
fragmentation-addition conditions is double allQrlation. Somei's conditions, however,
effected exclusive mono-alkylation of gramine.
72
Scheme 32, Soinei*s Gramine Fragmentation-Addition via nBujP.
Of NMea
OaEt CO t
177
H 0NMe2
178
(nBu)3P(0.3eq), CHaCN.A 99% yield
O O
OEt
NHAc
•HNMee
COJ
\ 7 180
H ©^COaEt
AcHN COzEt 179
Alkylphosphines have relatively low basicities (pK 6.00 in ethanol-water, 2:1 v/v),^
but they have strong nucleophilicities. Hence, Somei proposed that tri-n-butylphosphine
was acting as a nucleophile to directly displace the dimethylamine group of granune
(177) in the first step in this coupling. A phosphonium ion intermediate 178 was thus
implicated, which could be displaced by the carbon nucleophile. Somei proposed that the
carbanion nucleophile would be associated with the phosphorus atom in intermediate
179. Furthermore, he postulated that the bulkiness of the phosphorus ligands on the
phosphonium ion intermediate 179 served to prevent dialkylation through steric
repulsion. Based upon this precedence, and other examples" of using tributylphosphine
as an efficient gramine addition catalyst, this protocol was applied to 2,10-dithioindoles.
73
Scheme 33. Phosphine-Catalyzed Alkylation of 2,10'Ditliioiiidoles.
SEt
-TMS (3eq), nBioP (50%)
CHaCN, reflux I2h
82% yield
CO^e
:0^e
H
170a
H
181a
Gratifyingly, when 2,10-dithioindole 170a was treated with an excess of dimethyl
malonate and 50% tri-n-butylphosphine in refluxing acetonitrile, coupled product 181a
was isolated in 82% yield (Scheme 3.3). This product had lost not only the benzylic
thioether group as expected, but also the benzylic trimethylsilyl group. Based on this
result, the scope and limitations of the phosphine-catalyzed coupling were explored
(Table 3.1). Other malonate-derived nucleophiles (i.e. diethylacetamidomalonate and
diethylaminomalonate) coupled to 170a, as did P-ketoesters (Entries 4 and S, Table 3.1).
Nucleophiles containing less acidic protons (i.e. glycine and cyciohexanone) did not
couple with 170a. In these cases, the only product obtained was a low yield of 2,10-
dithioindole 182. In contrast, protected glycine derivatives (i.e. benzaldehyde and the
benzophenone Schiff base derivatives 183 and 184) successfully coupled with the 2,10-
dithioindole 170a. As shown in Entry 6 (Table 3.1), the highest yields for the coupling of
aldimine derivative 178 were obtained when the product was reduced in situ using
NaCNBH} to give benzhydrylamine derivative 176f in 61% yield over two steps.
74
Table 3.1. Scope and Limitations of 2,10-Dithioindole Couplings.
•TMS
SEt
Nudeophile (3 eq), nBuaP (50%)
CH3CN,80°C
170a
Nu
SEt H
181
Entry Nudeophile 181 Yield
Me02C^^C02Me
EtOiCs^C
NH/
EtO^C ^COaEt
4HAC
EtO^Cs^OjEl
NHz
El0iC> (0)Me
Et0iC. (0)Ph
82%
96%
57%
33%
75
Table 3.1. Cont'd.
Entry Nucleophile 176 Yield
EtOaC^N^Ph
183
184
NHBn
SEt 181f
SEt 181g
61% after
NaCNBHs reduction
80%
EtOA. NHAc
SEt
SEt
SEt
SEt
40%
182
182
12%
We believe that the flrst step in the mechanism for the coupling reactions involves the
displacement of the C-10 thioether group by PBuj to create phosphonium ion 185
(Scheme 3.4). We believe that the phosphonium intermediate then loses trimethylsilyl
cation to give ylide intermediate 186. Protonation of the ylide leads to reduced
phosphonium ion 187. Whether the thiolate ion acts as a proton shuttle to deprotonate
the carbon nucleophile and deliver it to ylide intermediate 186, or ylide 186 directly
deprotonates the nucleophile is not clear. The carbanion then displaces the C-10
phosphonium ion of 187, giving coupled product 181. Presumably, with glycine and
76
cyclohexanone, (Entries 8 and 9, Table 3.1), the nucleophile was not sufficiently acidic to
be deprotonaied by the ylide intermediate 186, The thiolate ion generated in the reaction
displaces the benzylic phosphonium ion to give product 182.
Scheme 3.4. Proposed Mechanism of Plio5phine*Catalyzed Coupling.
•TMS PBU3
© © ^BusSB
-TMS f -(TMS)SEt
H
170a
NuH
185 186
Nu
SEt SEt
187
H
181
Interestingly, no coupling occurred in the absence of the C-10 TMS group. When 182
was subjected to tri-n-butylphosphine and diethylacetamidomalonate, none of the desired
coupled product 181b was obtained, and 96% of starting material 182 was recovered
(Scheme 3.5). This suggests that the C-10 trimethylsilyl group is necessary in order for
the coupling to succeed.
Scheme 3.5. Attempted Coupling of 2,10-Ditliioindole 182.
Et02CsX0#l
NHAc (3eq)
nBu (50%). CH3CN, reflux 12h
96% recovered starting materiai
CO^e
77
fo an effort to prove the feasibility of the proposed ylide intermediate 186, we ran the
coupling in the presence of benzaldehyde. When 2,10-dithioindole 170a was reacted
with benzaldehyde in the presence of one equivalent of tri-n-butylphosphine, a 48% yield
of styryl derivative 188 was isolated (Scheme 3.6). This served as indirect evidence of
the proposed ylide intermediate. Attempts to generalize this reaction for aliphatic
aldehydes failed, perhaps due to the presence of acidic a-protons on the aldehyde.
Similarly, trimethylacetaldehyde did not react with the 2,10-dithioindole 170a, possibly
due to steric encumbrance of the aldehyde.
Scheme 3.6. Coupling Reaction in the Presence of Benzaldehyde.
The prospect of performing the indole-forming reaction and alkylation in a one-flask
process was considered (Scheme 3.7). The greatest advantage of a one-flask process
would be the ability to form highly substituted indole products without the need to isolate
and purify the 2,10-dithioindole. Isocyanide ISOa was subjected to the free radical
cyclization conditions and upon completion of the reaction (TLC), the reaction mixture
was concentrated. The residue was taken up in CHjCN and subjected to the phosphine
coupling reaction with diethylacetamidomalonate. The one-flask process provided a
gratifying 86% yield over two steps after chromatography of 181b.
PhCHO (3 eq), nBugP (1.1 eq)
CH3CN, reflux 12h
48% yield H
170a H
188
78
Scheme 3.7. One-Flask Synthesis: Indole-Formation, Alkylation.
•TMS EtSH (3 eq), AIBN (10%), PhCHs, A;
EtOaCs^C
150a
30aEt (3 eq)
NHAc
nBuaP (50%), CH^N, 86% yield
0^9
CO^e
We have also explored other methods of carrying out carbon-carbon bond forming
reactions at C-2 of 2,10-dithioindole 170a. As the tri-n-butylphosphine conditions are
capricious (possibly due to the tendency for PBu, to oxidize to its non-reactive oxide
even after scrupulous purification), we sought other catalyst systems that would promote
the same couplings. To this end, fluoride ion has been shown to be an efficient catalyst
in Michael additions. In particular, Belsky*^ showed that potassium fluoride is an
efficient source of fluoride ion in the presence of 18-crown-6. He performed the Michael
addition of nitromethane to styryl derivative 189 using a catalytic amount of KF and
crown ether to obtain Michael adduct 190 in 94% yield (Scheme 3.8).
Scheme 3.8 Belsky's Fluoride*Catalyzed Michael Addition.
MeNOa (20 eq),
189
KF (0.2 eq), 18^rown-6 (0.05 eq),
CH3CN, reflux 1.5h
94% yield 190
In I99S, Iwao and Motoi ^ repotted the application of fluoride ion as a gramine-
addition catalyst (Scheme 3.9). Treatment of gramine methiodide derivative 191 with
79
TB AF presumably induced attack of fluoride ion on the TIPS group, causing formation of
indolenine intermediate 192. Fluoride ion could then act as a base catalyst in the
coupling of carbon nucleophiles with indolenine 192 to give 193 in very good yields (79-
97%).
Scheme 3.9. A Fluoride-Catalyzed Gramlne Coupling.
Based on this precedence, coupling reactions were carried out with 2,10-dithioindole
170a using KF, 18-crown-6, and acidic hydrogen-containing compounds (Table 3.2). In
each case, the yields for these transformations exceeded the yields of the PBuj couplings.
The most striking example of this improvement was observed with glycine derivatives
183 and 184, in which the yields improved from 61% and 80% to 94% and 100%
respectively (Entries 4 and 5, Table 3.2).
TBAFmiF
Si(i-Pr)3
191 192 193
80
Table 3 J. Comparison of Phosphine vs. KF as Coupling Catalysts.
•TMS Nudeophile (3 eq), KF (1.1 eq), 18-06 (1.1 eq)
CH3CN, 80°C
H 170a
Nu
SEt H
181
Entry Nudeophile 176 PBua Yield KF Yield
1 MeQA^O^e
EtOaCs^COaEt
NHAc
EtOjCs i
NH2
O t
EtOiCX^N<^Ph
183
184 Ph
Ph
SEt 181a
AcHI
SEt 181b
SEt 18le
NHBn
SEt 181d
SEt 181a
82% 91%
98% 99%
96% 100%
61% 94% after after
NaCNBHa NaCNBHs reduction reduction
80% 100%
81
The fluoride-induced reactions are advantageous for several reasons including the
enhanced yields and the enhanced stability of KF and 18-crown-6 when compared to
PBU3. In addition, the reaction proceeded much faster. With KF, the reaction was
typically complete after three hours, while the corresponding tri-n-butylphosphine case
usually required twelve hours or longer to ensure completion. One major disadvantage
associated with the KF conditions was the occurrence of double alkylation unless a large
excess of nucleophile was used. This problem was compounded because
chromatographic separation of the excess nucleophile from the product was often
problematic.
It was possible to follow the KF-mediated reaction by TLC. The first change noted
was almost immediate transformation of starting 2,10-dithioindole 170a into desilylated
2,10-dithioindole 182. Then, more slowly, 182 proceeded to the desired products 181.
From the available precedent, it would appear to be likely that KF was acting as a base to
convert 182 into coupled product 181 via an indolenine intermediate (Scheme 3.10).
Indeed, when 2,10-dithioindole 182 was independently reacted under the KF conditions,
coupled products 181 were obtained. The successful coupling of 182 illustrates the
power of the KF catalyst system, as 182 was unreactive during attempted couplings using
PBU3 (vu/e supra).
82
Scheme 3.10. Proposed Alkylation Mechanism with KF as Catalyst
;Et
-tms
CH3CN, reflux 3h 170a
•MesSiF
194
NuH KF
182
4- EtSH
195
3.3. Addition of SulAir Nucieophiles at C*10
In order to fully harness the reactivity of the 2,10-dithioindoles, we became interested
in the differential substitution of thioethers at C-2 and C-10. When 170a and 197 were
exposed to methyl ^-mercaptopropionate and ethanethiol, KF, and 18-crown-6, we
isolated 196 and 198, respectively (Scheme 3.11).
Scheme 3.11. Synthesis of Differentially-Substituted 2,10-Dithioindoles.
„gX>^C02Me (Seq) ^
170a
KF (1.1 eq). 18-crawn>6 (1.1 eq),
CH3CN, reflux 3ti
97% yield
EtSH (10 eq)
(1.1 eq), 18<rown-6 (1.1 eq)
CH3CN, reflux 3ti 89% yield
83
It is important to note the practicality of differentially substituting 2,10-dithioindoIes
in this manner. Thiols containing functionalities which are sensitive to free radicals (i.e.
allyl mercaptan and benzyl mercaptan) gave intractable mixtures when used in the sulfiir-
mediated isonitrile alkyne cascade; however, they have the potential to add at C-IO as
depicted (Scheme 3.11). Theoretically, this allows a great range of thioethers to be
installed at C-10. We demonstrated this versatility by coupling a diazo-containing thiol,
with 170a. This will be discussed in Chapter 5.
3.4. Addition of Cyanide Ion as a Nucleopiiile at C-10
We have also coupled 2,10-dithioindole 170a with cyanide by subjecting 170a to
KCN^** in DMF at SO°C for several hours (Scheme 3.12). These conditions provided a
40% yield of 3-cyanomethyl indole 199. In this reaction, not only was the benzylic
thioether removed as expected, but also the benzylic TMS group was lost. The 3-
methylcyano group of indole 199 should prove to be an interesting handle for further
reactions, because the cyano group can be transformed to several useful functional
groups.
Scheme 3.12. Coupling of Cyanide Ion to 2,10-Ditliioindoles.
KCN(IOeq),
DMF, 50®C
40% yield H 170a
H
199
84
3 . Ad tionofan AmineNucleopliileatC-lO
We also examined the coupling of amines with 170a. Dithioindole 170a was
subjected to KF, 18-CT0wn-6 in refluxing acetonitrile and dimethylamine (Scheme 3.13).
This provided a 92% yield of the desired dimethylamino-substituted thioindole 200. In
turn, we envision that 19S can be further reacted in a gramine fragmentation-addition
process. The presence of the C-2 thioether of 200 should aid in the gramine reaction,
possibly allowing for the advantageous use of lower temperatures or milder conditions
for the gramine coupling.
Scheme 3.13. Addition of an Amine Nucleopliile to 2,10-Dithioindoles.
$Et
HNMe2(g) (excess), !f y^NMe2
KF (1.1 eq), 18-06 (1.1 eq), CH3CN, 80°C J^SEt
92% yield 200
3.6. Elimination of the C-10 Thioether Exclusively
During experiments designed to address the scope of the KF catalyst system, other
sources of fluoride ion were considered. One such commercially available source, KF
adsorbed on alumina, has seen success comparable to KF/18-crown-6 in Michael addition
reactions.^' Dithioindole 170a was subjected to dimethyl maionate and KF/alumina in
refluxing acetonitrile (Scheme 3.14). Surprisingly, rather than obtaining maionate
derivative 181a as anticipated, maionate derivative 201 was obtained in an unoptimized
37% yield. As illustrated, the C-10 TMS group remained.
85
Scheme 3.14. KF/Alumimi as a 2,10-Ditliioiiidole Coupling Catalyst
Et
)—TV
"^SEt
MeOp^CO^e(3eq), KF/alumina (1.1 eq),
CH3CN,80°C
37%yietd
C02Me
;02Me
H 170a
H 201
Presumably, the alumina was simply reacting as a base to displace the benzylic
thioether in a gramine-Qrpe fragmentation-addition process.^ An attempt to carry out this
reaction using basic alumina resulted in a nearly quantitative recovery of 2,10-
dithioindole 170a. This was the Hrst example seen in this coupling chemistry in which
the benzylic TMS group was not removed during the elimination-addition.
3.7. Conclusions
In summary, numerous ways to functionalize 2,10-dithioindoles have been presented.
It was possible to add carbon, sulfur, and amine nucleophiles at C-10 under catalytic
phosphine or fluoride conditions. It was also possible to perform a more traditional
gramine-type coupling using KCN. An anomalous coupling reaction was discovered
using KF on alumina in which the C-10 thioether of the 2,10-dithioindoles was removed,
while the benzylic TMS group remained. These investigations will be of fundamental
importance in the use of 2,10-dithioindoles in the generation of highly fiinctionalized
indole natural products.
86
CHAPTER 4. PROGRESS IN THE SYNTHESIS OF SPIROTRYPROSTATIN A
4.1. Biological Activity of Spirotryprostatin A
Spirotryprostatin A (1) is an oxindole-containing natural product with a spiro-center at
C-3 in a tryptoplian-proHne-deriveddiketopiperazine unit (Figure 4.1). This compound
exemplifies the unique architecture found in a relatively new class of compounds, the
spiroindolinones, which were first reported in 1991.' A methoxydehydrocongener of 1,
spirotryprostatin B (202), is another prominent member of this class of compounds. Both
spirotryprostatins have gained signiHcant attention from synthetic chemists in the past
few years. This is due, in part, to their proposed medicinal application as anti-cancer
chemotherapeutic agents.
Figure 4.1. Spirotryprostatins A and B.
J.
spirotryprostatin A
202
spirotryprostatin B
The spirotryprostatins were isolated fn>m the fermentation broth of a fungus,
Aspergillus fimigatus. Thus far, they have been shown to inhibit the mammalian cell
cycle at the G2/M phase.^ This was determined by inhibition of the cell cycle
progression of mouse tsFT210 cells. While spirotryprostatin B (ICjo of 14.0 ^M) shows
87
stronger inhibitory activity than spirotryprostatin A (IC50 of 197.5 ^M), ICjo values for
both compounds are within the micromolar range. It was posmlated that the methoxyl
group in spirotryprostatin A is responsible for the higher inhibitory activity of
spirotryprostatin B, although the mechanism of action of the spiroindolinones is currently
unknown.
Spirotryprostatins A and B show promise as cancer chemotherapeutics functioning as
cell cycle inhibitors, or as molecular probes to be used to elucidate the regulatory
mechanisms of the cell cycle. Based on the promising biological data and the poor yield
of the spirotryprostatins through fermentation (400 L of culture medium produced I mg
of spirotryprostatin A and 11 mg of spirotryprostatin B)/^ an efficient synthesis of this
class of compounds has been warranted. The formidable challenge of stereoselectively
synthesizing the spirotryprostatins would undoubtedly lead to the discovery of new
reactions and provocative methodologies. One of our goals has been to employ our
efficient indole methodology toward the synthesis of the spirotryprostatins. This would
not only serve as an important "proof of concept" that our indole methodology is
practical for natural product synthesis, but it also might allow access to novel
spiroindolinone analogues possessing significant anti-tumor activity.
4 J. Danishefsky's Synthesis of Spirotryprostatin A
Several groups have targeted the synthesis of the spiroindolinones. Danishefsky et
al.^^ reported the Hrst total synthesis of spirotryprostatin A in 1998. Since then, the
research groups of Overman,^' Williams,^' and Ganesan" have reported syntheses of the
88
spirotryprostatins. Outlined herein is a discussion of their strategies toward the
spiroindolinones.
The Danishefsky and Edmondson synthesis of Spirotryprostatin A, first reported in
1998/^ involved a Pictet-Spengler cyclization to form a P-carboline intermediate,
followed by an oxidative rearrangement in order to install the C-3 spiro center (Scheme
4.1). The acid-mediated Pictet-Spengler cyclization of thio-substituted aldehyde 203
with 6-methoxytryptophan derivative 204, gave a 2:1 mixture of ^-carbolines 205 and
206 in 88% yield. Because the 18 a-epimer (205) provided the desired C-9, C-18 trans
stereochemistry, 205 was then protected as an N-Boc derivative to produce 207 in 84%
yield. In a critical step, protected p-carboline 207 was oxidized using acidic NBS
conditions to give spiro oxindole 209 (Scheme 4.2). Presumably, bromohydrin
intermediate 208 was initially formed. In situ rearrangement led to 209 in 46% yield.
From 209, removal of the Boc group gave 210 in 93% yield.
Scheme 4.1. The Danishefsky Synthesis of Spirotryprostatin A.
203
H3C
205C"H=a.R = H -206C'®H=p,R»H 207C"H=a.R = Boc-
BoC20,CH3CN, NEt3,A
(84% yield)
CH2Cl2,CF^02H, 4AMS.0~>20°C
(88% yield) 205:206 2:1
H 204
89
Scheme 42, Oxidative Cyclization of a Danishefsky P-Carboline.
207 NBS,THF,H20.HOAe
(46% yield) MeO .SPh
208 209 RsBoc 210 R>H nTFA,CHjqia
(93% yield)
With the desired oxindole and C-3 spiro center in place, Danishefsky installed the
diketopiperazine moiety of spirotryprostatin A (Scheme 4.3). This was accomplished by
coupling Troc-protected proline unit 211 with the secondary amine 210. Zinc-induced
reductive cleavage of the Troc group gave 212 in 68% yield. Upon oxidation to the
corresponding sulfoxide 213, elimination provided an 80% yield of 214 over two steps.
The olefm in 214 was isomerized to 202 in 41% yield to complete the first total synthesis
of spirotryprostatin A in 12% overall yield. The key step in this total synthesis involved
the installation of the desired stereochemical relationship of C3 and C18 during the
oxidative rearrangement to form the C-3 spirocenter.
Scheme 43. Completion of the Total Synthesis of 1 by Danishefsicy.
210 +
CHzCle, EbN; Zn.NH4CI. H2O.
THF.MeOH
(68% yield) 211 / R
212 Rs SPh ««B_S(OPh)
RhCl3*3H20. EtOH.A
(41% yield)
—I Nal04. H20, MeOH
1
90
43. Reported Syntheses ( SpirotryprostatinB
4J.1. Danishefsky's Synthesis of SpirotryprostatinB
Several groups have synthesized spirotryprostatin B, including Danishefsky, ^
Williams,Overman,^^ and Ganesan.^ Spirotryprostatin B is an inviting target molecule
due to its strong inhibition of the mammalian cell cycle. Also, the absence of the C-9
stereocenter simplifies the complex scaffold relative to spirotryprostatin A. Not
surprisingly, Danishefsky approached the total synthesis of spirotryprostatin B in a
manner similar to his reported synthesis of spirotryprostatin AJ* In order to improve
upon their previous synthesis, a Mannich reaction of an oxindole was substituted for the
Pictet-Spengler cycltzation. This enabled them to directly install the required prenyl
group.
Scheme 4.4. Total Synthesis of Spirotryprostatin B by Danishefsky et al.
NEt}3AMS, 'OMe pyridine, 0"C to r.t
NH24CI Bop-CI(1J!eq),CH2Cl2, NEt3(2.5eq),0OCtor.L
(90% yield)
(73% yield)
1) UHMDS (ZZ eq), THF, 0% 2) PhSeCI ( 2 eq), THF. 0«C
(78% yield)
(86% yield)
1)TFA/CH^l2(1/5), 2)NEt3.CK l2
91
As shown in Scheme 4.4, oxindole 215 (from the commercially available ethyl ester of
L-tryptophan), was subjected to a Mannich reaction with isoprenyl aldehyde 216, which
gave spirooxindole 217 in 73% yield of four isomers; (35,185), (3/?, 18/?), (3/?, 185) and
(35,18/?). The mixture of 217 was then coupled to N-Boc proline 218 to give a 90%
yield of a single product, 219. Next, a phenylselenyl group was installed to give 220.
Crude selenide 220 was then photolyzed in the presence of dimethyl dioxirane to give the
desired unsaturated ester 221 as a mixture of three compounds (desired 221, 3-epi-221,
and 18-epi-221). After separation of the desired unsaturated ester 221 by
chromatography, the Boc group was removed using TFA. By subjecting the resulting
amine to NEt,, they isolated spirotryprostatin B (202) in 7% yield over five steps.
43.2. Ganesaii's Synthesis of Spirotryprostatin B
Wang and Ganesan ^ recently reported a total synthesis of spirotryprostatin B. In a
manner similar to the approach of Dantshefsky,^^ Ganesan incorporated an oxidative
rearrangement to install the spiro oxindole skeleton. In contrast to the Danishefsky
oxidative rearrangement, Ganesan*s key transformation involved the rearrangement of a
relatively highly fiinctionalized |3-carboline, which would then simply be cyclized to
form the diketopiperazine portion of spirotryprostatin B (Scheme 4.5).
92
Scheme 4 J. Ganesan's Approach to the Synthesis of Spfax>tryprostatiii B.
f
V / NFmoc
NBS(1.t8eq), THF-AC0H-H2P (1:1:1)
O tort
(68% yield)
IFmoc 223
20% piperidine inCH2Cl2.r.L
(100% yield)
1)LDA (3.80 eq),-7500 2)PtiSeBr(3.09eq),-75°C
(7% yield)
1)(Boc)20(5.2eq). DMAP(4.3eq). CH2CI2, r.t
2) MsCI, NEla. CH2CI , r.t.
(70% yield)
TFA. EtaSIH. CHaCt, r.t
(74% yield) 202
Accordingly, ^-carboline 222 underwent oxidative cyclization using NBS to give
oxindole 223 in 68% yield (Scheme 4.5). Ganesan highlighted the signiHcance of being
able to perform the oxidative rearrangement with NBS in the presence of the prenyl unit,
which Danishefsky previously masked^^ while performing the oxidative rearrangement.
Wang noted that the rearrangement occurred with satisfactory stereoselectivity.
Presumably, oxidation occured on the less hindered face of the indole (opposite the
prenyl group), and the subsequent pinacol-Qrpe rearrangement occured with inversion at
the spiro center, while the migrating carbon exhibited retention of configuration.
93
The Fmoc group of spirooxindole 223 was then removed, and spontaneous cyclization
to the diketopiperazine skeleton gave 219 quantitatively. Selenylation provided hydroxy
compound 225 in 7% yield. Protection of 225 as an N-Boc derivative, followed by
elimination of the C-10 hydroxy group via a mesylate, gave 226. Finally, exposure of 226
to acid revealed spirotryprostatin B, 202. This synthesis reinforced Danishefsky's
previous assertion that substitution of P-carboline 222 plays an important role in the
stereochemical outcome of the oxidative rearrangement.
4.3 J. Overmaii's Synthesis of Spirotryprostatin B
In contrast to the syntheses of spirotryprostatin B by Danishefsky and by Ganesan,
Williams and Overman reported syntheses that neither started from tryptophan
derivatives, nor did they involve oxidative rearrangements to access the C-3 spirocenter.
In his approach. Overman's^' key transformations involved a palladium-catalyzed Heck
reaction and palladium-catalyzed n-allyl chenustry.
Scheme 4.6. The Overman and Rosen Synthesis of Spirotryprostatin B.
1) Ac , pyridine 2) MgBi2*E ; iPrzNEt AcOH
1)U0H 2)TB0P&CI 3) 2-iodoaniline,1-methyi>
2-chlonH)yridin[um iodide
(94% yield. >20:1 £2) (78% yield)
227
94
Scheme 4j6.-CorUintted
229
OTBOPS
231
3) Dess-Maitin oxtd;
1)SEM-CI,NaH 2)TBAF
.fiuOK
(72%yleld, 232:233-1:1)
[Pd2(dba)3]K:HCl3 (otoDsP. KOAc
THF, 70<t
P0(0Me)2 231
0:' SEM SEM
Me2AICI;/PrNEt
(93% yield) 202
232 233
Allylic alcohol 227 was first acetylated and reacted with MgBrj^EtjO, followed by
base to give £-dienoate 228. Dienoate 228 was converted to the corresponding
siloxycarboxylic acid, which subsequently coupled with iodoaniline to give 229 in 78%
yield. After protection of anilide 229 as a SEM ether, deprotection of the TBDPS group
and oxidation gave an intermediate aldehyde. The aldehyde was then reacted with
diketopiperazine-derived phosphonate 230 to give 231 in 61% yield. In the key step in
the synthesis, 231 cyclized under palladium-catalyzed ic-allyl conditions to provide a
72% yield of the desired pentacycle product as a 1:1 mixture of the desired compound
233 and the C-3, C-18 bis-epimer 232. Removal of the SEM group of 233 provided
spirotryprostatin B (202) in 93%yield. Thus spirotryprostatin B was synthesized by the
Overman group in an overall yield of 9%.
95
4J.4. William's Synthesis of SpirotryprostatinB
Scheme 4.7. The Synthesis of Spirotryprostatin B by Williams and Sebahar.
Ph
Xi 'Me
3XMS,PhCH3,r.t
IL
234
Ph
MeO-
. W J
COaEt
[1,3]-dipolar cycloaddition
(82% yield)
MeCxJf H2(60psi).PdCl2. A
0 THF. EtOH
(99% yield)
. W
1) 0-pro-06n, BOP
NEta, MeCN 2) H2, Pd-C, EtOH 3) BOP, Et: , MeCN
(70% yield)
. W J "
'CO t
TsOH (1 eq) PhCH3,A
(82-89% yield)
1) Lil, pyridine, A
2) OCO, DMAP,
HO-fQ
^ B(CCl3, A
3) NaOMe, MeOH
(32% yield)
202
Williams and Sebahar also recently completed a total synthesis of spirotryprostatin
B. They envisioned that the core pyrrolidine ring could be installed via an asymmetric
[l,3]-dipolar cycloaddition using a chiral azomethine 237 (Scheme 4.7). In the Hrst step
of their synthesis, oxazinone 234 was subjected to aldehyde 236, oxindole 23S« and
molecular sieves in toluene. This protocol led to the formation of ylide 232, [1,3] Dipolar
96
cycloaddition with oxindole 235 gave pyrrolidine 238 in 82% yield. An £-P-exo
transition state of the dipolar cycloaddition was thought to be responsible for the
cycloaddition stereoselectivity.
Hydrogenolysis of 238 led to 234 in quantitative yield. Diketopiperazine formation
gave the spirotryprostatin B skeleton 240 in 70% yield. Elimination of the 3° methyl
ether under acidic conditions gave 241. Treatment of 241 with Lil in refluxing pyridine
hydrolyzed the carboxylic ester to the corresponding acid. Decarboxylation using
Barton's conditions gave the C-12-epimer of spirotryprostatin B. Epimerization with
NaOMe in methanol gave a 2:1 ratio of spirotryprostatin B (202), and its C-12 epimer.
4 J. Our First General Approach to the Core of Spirotryprostatiii A
4 J.l. An "Interrupted'* Pictet-Spengler Cyclization
On the heels of our success in indole-formation and alkylation at C-10 of novel 2,10-
dithioindoles, we believed that our indole methodology would provide access to the
spirotryprostatin core skeleton (i.e. would serve as a "proof of concept" for the
applicability of our indole synthesis). In our proposed synthesis of the spirotryprostatins,
we initially envisioned an "interrupted'* Pictet-Spengler cyclization strategy to form the
core C-3 spiro structure of the spirotryprostatins.
97
Scheme 4.8. Pictet'Spengler Cyclization to Fonn P-Cariralines.
CO2R
243
244
CO2R
245
A prototypical example of the Pictet-Spengler cyclization is presented in Scheme 4.8.
Tryptophan derivative 242 condenses with an aldehyde to form imine 243 in situ. The
indole nitrogen can then donate electron density to the aromatic system, thereby
imparting nucleophilic character at C-3, which reacts with the pendant imine of 243. The
Pictet-Spengler cyclization is generally considered to proceed via transient spirocyclic
intermediates such as 244." If C-2 of the indole nucleus is unsubstituted, as in the
Danishefsley synthesis of spirotryprostatin A, the spirocyclic intermediate 244 then
rearranges to provide the p-carboline skeleton 245. Typically, the Pictet-Spengler
reaction requires an acid catalyst and a means for removing water, such as a Dean-Stark
trap or molecular sieves.
98
We theorized that the 2-thioether tryptamine derivatives, prepared through our C-10
coupling protocol, would undergo a Pictet-Spengler cyclization. We believed the
possibility existed that the cyclization would stop at the spirocyclic intermediate stage
due to substitution at C-2 of the indole. Delightfully, this cyclization proceeded as
expected (Table 4.1).
Table 4.1. An "Interrupted" Pictet-Spengler Cyclization.
02!Et
CO#t A C02Et
(3eq)
4A molecular sieves CH2CI2,24h, r.t.
246
Entry R 246 Yield (%) d.r.
1 -Et a 82 5:1
2 -Me b 80 2:1
3 -Ph 0 55 3:1
Tryptamine derivative 181c, which was previously synthesized in the alkylation of
2,10-dithioindoles (Chapter 3), was subjected to propionaldehyde and 4A molecular
sieves in dichloromethane at room termperature. Gratifyingly, the anticipated spirocyclic
thioimidate 246a was obtained in 86% yield (Table 4.1).^ Although trifluoroacetic acid
was initially used to catalyze this reaction, the cyclization acnially proceeded to a higher
yield in the absence of an acid catalyst. This can perhaps be attributed to the
99
nucleophiliciQr imparted to C-3 from the 2-thioether of 181c. The use of acetaldehyde
and benzaldehyde also gave good yields (80 and 55% respectively) of the desired
corresponding spirocycles 246b and 24<ic.
In each case, a diastereomeric mixture of products was formed, with the best
diastereomeric ratio (5:1) obtained in the case of propionaldehyde (Table 4.1). After
separation of the diastereomeric mixture of 246a using both alumina preparative thin-
layer chromatography and reverse-phase HPLC, a sufHcient amount of the major
diastereomer of 246a was obtained to determine its relative stereochemistry. After
assignment of the 'H NMR peaks using 2D COSY data, 2D NOE studies were performed
to determine the stereochemistry of 246a. It was determined (Figure 4.2) that aromatic
proton H, interacted with pseudo equatorial proton H(, from the five-membered
pyrrolidine ring. Similarly, aromatic proton H, showed an NOE with methylene protons
Hg. Furthermore, interaction between and Hd was observed, and H, showed an NOE
with thioether protons Hf. One-dimensional NOE studies confirmed these interactions.
Fortuitously, the relative stereochemistry of the major diastereomer of 246a is the same
relative stereochemistry required for spirotryprostatin A.
100
Figure 4 J. Determination of the Relative Stereociieniistry of246a.
NH
248* sptrotryprostatin A1
4.3.2. Elaboration of tlie Thioimidates
Scheme 4.9. Retro*Mannich Reaction of SpirocycUc Thioimidates.
SEt
246a
SEt
247
SEt
181e
The spirocyclic thioimidates 246 were somewhat unstable compounds, prone to
undergo a retro-Mannich reaction (Scheme 4.9). This was catalyzed by both acid and
base, which may explain why the addition of acid as a catalyst during the "interrupted"
Pictet-Spengler reaction gave low yields. The retro-Mannich susceptibility of 246 also
impeded fiirther transformation of the thioimidate. Hydrolysis of thioimidate 246 to the
corresponding oxindole was attempted; however, these attempts resulted in either
recovery of the starting material 246, or in the letro-Mannich product 181c. In the face of
101
this difficulty, we hypothesized that protection of the pyrrolidine ring nitrogen with an
electron-withdrawing group might inhibit the undesirable retro-Mannich reaction
(Scheme 4.9).
To this end, attempts were made to place several protecting groups ( Boc, methyl, and
acetate) onto the pyrrolidine nitrogen. In these cases, the retro-Mannich reaction of 246a
prevailed. In the event, secondary amine 246a was successfully protected with a
trifluoroacetate group, albeit in low yield (Scheme 4.10). With trifluoroacetate-protected
compound 248 in hand, we explored the hydolysis of the thioimidate to the corresponding
oxindole. Hydrolysis of the thioimidate using a large excess of silver nitrate" gave the
desired oxindole 249 in 32% unoptimized yield.
Scheme 4.10. Elaboration of the Spirocyclic Thioimidates.
PO#t COiEl TFAA(4.4eq), AgNOadOeq). '°2* ncOCF3
pyridine (6.6 eq) J J u (9;l)lBu0H:H20 - J 1 •"H
CH2aa r.t. \ L Xf' (17% yield) (32% yield)
246a 246
Due to difficulty in protecting the secondary amine of 246b, it was envisioned that
the "interrupted" Pictet-Spengler cyclization could be performed on a secondary amine.
The Mannich cyclization of secondary amines have been reported.^'-^ In these cases,
however, only highly reactive aldehydes were used to effect the cyclizations. Taking this
into account, benzhydrilamine derivative 181f was subjected to paraformaldehyde and
sodium sulfate in refluxing acetonitrile, which gave 30% yield of desired spirocyclic
thioimidate 250 (Scheme 4.11). Our previous decision to protect the pyrrolidine nitrogen
was validated, as 250 was found to be more stable than its unprotected counterpart.
102
Scheme 4.11. 'Interrupted'* Pictet-Spengler Cyclization of a Secondary Amine
OsMe yC02Et
(CH20)h. Na2S04 NHBn // ^—r^^NBn
CH3CN,A
(30% yield) 250
While this general method to access the spirotryprostatin A core skeleton suffered
from low to moderate yields, as well as a low diastereomeric ratio in the key
"interrupted" Pictet-Spengler cyclization, we were able to access the core oxindole
structure of the spirotryprostatins from our 2,10-dithioindoles. Indeed, our first
generation approach to the spirocyclic oxindole core of 1 highlighted the potential of our
novel indole forming/alkylation methodology in nahiral product synthesis.
4.4. N-Acyl Iminium Ion Approach to Spirotryprostatin A
While the "interrupted" Pictet-Spengler cyclization of 2,10-dithioindole derivatives
showed promise in accessing the core of the spirotryprostatins, we realized that a new
approach was warranted. With the goal of utilizing a highly diastereoselective, efficient
cyclization methodology, we explored the possibility of harnessing N-acyl iminium ion
chemistry in the synthesis of the spirotryprostatins.
103
Scheme 4.12. N*Acyl Iminium Ion Approach to Spirotryprostatin A.
KF, 18<rown-6, CH3CN, A H SEt
acidic cond's
Our second generation approach involving N- acyl iminium ion chemistry began with
2,10-dithioindole 170a (Scheme 4.12). We proposed the coupling of diketopiperazine
unit 251 to 2,10-dithioindole 170a to provide N-acyl iminium ion precursor 252. Upon
treatment of alkoxy-substituted hemi-aminal 252 with acid, the N-acyl iminium ion
intermediate 253 would form. We also proposed that 253 might then undergo a
diastereoselective cyclization of C-3 onto the pendant N-acyl iminium ion to give
spirocyclic thioimidate 254. We were hopeful that the C-12 stereocenter present in the
diketopiperazine moiety 251 would control the stereochemistry of the cyclization.
In order to consider the new N- acyl iminium ion approach, it was critical to assess the
feasibility of adding a diketopiperazine-containing nucleophile to the 2,10-dithioindoles.
Hence, the addition of diketopiperazine-containing nucleophile" 255 to 2,10-dithioindole
104
proceeded in good yield (80%) using our KF/18-C-6 conditions to give a 1:1
diastereomeric mixture at C-9 of 256 (Scheme 4.13). With 256 in hand, we are prepared
to carry out cyclization reactions. This will be the subject of future studies in our
laboratory.
Scheme 4.13. Alkylation of 2,10-Ditliioindole with a Diketopiperaziiie Nucleophile.
J/ HN
255
KF(l.leq). 18-C-6 (1.1 eq)
CHaCN, reflux 3h
(83% yield)
4.5. Conclusioiis
In conclusion, the spirotryprostatins are intriguing oxindole compounds that are
potential anti-cancer chemotherapeutics. Our research has addressed the continuing need
for a general synthesis of the spirotryprostatins. An "interrupted" Pictet-Spengler
cyclization was developed and employed to form spirocyclic thioimidates en route to a
functionalized oxindole skeleton. Our next approach to the synthesis of the
spirotryprostatins will involve the use of N-acyl iminium ion chemistry. These studies
will ultimately serve as a "proof of concept' of the applicability and versatility of novel
2,10-dithioindoles as organic intermediates in naniral product synthesis.
105
CHAPTER 5. DERIVATIZATION OF 2,10-DITHIOINDOLES VIA SULFUR YLIDES
5.1. Fonnation and Structure of SulAur Ylides
The increasing popularity of sulfur ylides in synthesis is due to their expanding
versatility, as well as the improving techniques to obtain sulfur ylides. Thermal,
photochemical and catalytic methods have been developed to access sulfur ylides. Sulfur
ylides have been used extensively in the synthesis of p-lactam antibiotics, pyrrolizidine
alkaloids, as well as other namral products. The chemistry of sulfur ylides has been
reviewed extensively."-"
To date, there are primarily two methods to access sulftir ylides. The first and most
widespread method involves the deprotonation of a sulfonium salt (Scheme 5.1). A
suMde reacts with an alkyl halide to give a sulfonium salt. An appropriate base can then
be used to deprotonate the a-proton of the sulfonium salt to provide the desired sulfur
ylide.
Scheme 5.1. The ''Salt Method" of Synthesizing Sulfiir Ylides.
RCHaSR' + R"X R' c® base
f
106
The second common method to fonn sulfur ylides is through the reaction of a
thioether with a carbene. The carbene can be formed from the decomposition of a diazo
compound under thermal, photolytic, or catalytic conditions.^ The catalytic transition
metal method of carbene formation is a relatively simple approach involving neutral
conditions, hence it is widely applicable in synthesis. In the formation of sulfur ylides
firom the decomposition of diazo compounds, the first step is most likely formation of a
metal carbenoid intermediate which has the same electrophilic character as a free singlet
carbene (Scheme S.2). Copper- and rhodium-stabilized carbenes are the most prominent
in the literature. Once the metal carbenoid intermediate is formed, a thioether reacts as a
good Lewis base by donating a non-bonding pair of electrons to the electrophilic carbene,
resulting in the formation of a sulfur ylide. When the diazo starting material is
substituted with electron-withdrawing groups, stable sulfur ylides can be formed, some of
which are isolable salts.
Scheme 5.2. Sulftir Ylides via a Sulfide>Carbene Reaction.
RhorCu P=N2
EWQ
EWG
EWG p=M
RSR'
P
EWG
EWG
107
The carbene method of forming sulfur ylides is very practical today thanks to the
numerous ways to simply generate organic diazo compounds." Using the transition-
metal catalyzed formation of sulfur ylides, researchers have been able to not only form
sulfur ylides intermolecularly, but also, four, five, six and seven-membered cyclic sulfur
ylides have been prepared.
5 J. Coimnon Reactions of Sulfur Ylides
The reactions that are accessible via sulfur ylides can be categorized into three main
types; a,p-eliminations, Steven's rearrangements ([1,2] rearrangements), and [2,3]-
sigmatropic rearrangements. When there is a P-hydrogen available for elimination on
the sulfur ylide, a,P-elimination can occur. This process (Reaction (1), Scheme 5.3) is
facilitated by large alkyl groups on the sulfur atom, as well as high temperatures. The
a,P-elimination decomposition pathway most likely proceeds through cis-elimination and
a five-membered cyclic transition state. The second major reaction pathway of sulfur
ylides is a Stevens-type or [1,2] rearrangement (Reaction (2), Scheme S.3). The 1,2-shift
of sulfur ylides was first reported by Stevens in 1932." According to kinetic analysis, as
well as CIDNP NMR spectroscopy, this occurs through homolytic dissociation followed
by recombination to give the observed products. Sulfur ylides can also undergo a [2,3]-
sigmatropic rearrangement when there exists an appropriately substituted n-system
(Reaction (3), Scheme 5.3). According to orbital symmetry control, the [2,3]-sigmattopic
rearrangement must proceed with complete allylic inversion to give the observed
108
products. We have considered these reaction pathways of sulfur ylides with the goal of
functionalizing our novel 2,10Klithioindoles.
Scheme SJ. Common Reactions of Sulfiir Ylides.
(1)
1 "V'
A RR'CHSMe +
(2)
pu e CiiS04,
Aorhv [cfJ
©9
^Ph —
Ph
(3)
" 1 1 1 1 fCHg
53. Intramolecular Sulfiir Yllde Reactions
5J.1. Proposal for an Asymmetric Gramine Reaction via Sulfiir Ylides
It would be extremely valuable to develop an asymmetric version of the coupling at C-
10 of our 2,10-dithioindoles (i.e., an asymmetric gramine-type reaction). Although some
of our initial thoughts toward controlling the stereochemistry of alkylation at C-10
involved the use of chiral phosphine catalysts,^ as well as chiral cinchona alkaloid
109
catalysts " the notion of using intramolecular sulfur ylide fragmentation-rearrangements
to access stereospecific allqrlation at C-10 was intriguing.
We hypothesized that a diazo functionality tethered through a C-10 thioether might
lead to carbene formation, which would in turn form a cyclic sulfur ylide (Scheme S.4).
The sulfur ylide would then undergo rearrangement and result in the substitution at C-10
of the indole. Furthermore, we hoped that the sulfur ylide rearrangement could be
performed in a stereospecific manner, either through the use of a chiral thioether or
through the use of a chiral catalyst. As illustrated in Scheme 5.4, diazo decomposition of
257 would lead to the formation of sulfur ylide 258. A subsequent rearrangement might
be directed by chiral centers R, and R2 to form 259 in an asymmetric fashion.
Alternatively, chiral catalysts such as those that have been popularized by Doyle,''
McKervey,^ and Davies,'^ (Scheme 5.4) could be utilized to effect this asynmietric
transformation.
Scheme 5.4. A Sulfur Ylide Approach to Asymmetric Gramine Reactions.
H or chiral Rh catalyst
Rh2(OAc)4
H
2S9
Z=CH2.0
110
5 Synthesis of an Intramolecular Sulfiir YUde Precursor
With the hope of developing an asynunetric gramine reaction through sulfur ylide
rearrangements, we decided to study the chemistry of sulfur ylide precursor 260 (Scheme
5.5). As depicted in Scheme 5.5, we felt that indole 260 could be synthesized from a
gramine derivative 261 and a diazo-containing thiol 262. By first using a gramine
derivative rather than our 2,10-dithioindoles, we hoped the generality of this
methodology would be demonstrated.
Scheme SS. Retrosynthesis of the Sulfur Ylide Precursor.
HS ' OEt
OEt
12 H
260 261 262
To this end, the synthesis of diazo-containing thiol^ 262 was accomplished from 3-
mercaptopropionic acid 267 (Scheme 5.6). Mercaptopropionic acid 263 was first
protected as the corresponding trityl thioether 264 under acidic conditions. Acid 264 was
activated and reacted with the magnesium chelate of hydrogen ethyl malonate (265) to
provide ^-ketoester 266 in 73% yield. Next, the trityl group was removed and the desired
dithiane 267 was formed using iodine. Diazo-group transfer was effected using diazo
transfer reagent 268 to give a 77% yield of the diazo-substituted dithiane 269. Finally,
the disulHde was reduced using dithioerythritol to give thiol 262 in five steps and 23%
overall yield. Coupling of thiol 262 with gramine methosulfate 261 gave the desired
thioether 260 in 99% yield.
I l l
Scheme 5.6. Synthesis of Sulfur Ylide Precursor 260.
263
PhaCOH.BFa'OEta
AcOH,A
(81% yield)
..cs-JU 266 (73% yield)
264 2) Xk
265
OEt EtO' CH2Cl2/EtOH,r.t
(72% yield)
^ss
267
1) H02C- ^^^S02N3
268 CHaCN.yc
2)NEt3
(77%yieW)
1)CH3CN,I C03(aq),0<C
2)
OEt
OH
262
(69% yield)
261
KF(1.1 eq), 18-crown-6(1.1 eq)
CHaCN, reflux 3h
(99% yield)
OEt
SJ.3. Intramolecular Sulftir Ylide Results
With the desired sulfur ylide precursor in hand, our attention turned to the formation
of the anticipated sulfur ylide. Upon heating thioether 260 in benzene at 80°C in the
presence of S mol% of dirhodium tetraacetate, P-ketoester 270 formed in 70% yield^
(Scheme 5.7).
112
Scheme 5.7. Rhodium-Catalyied Intramolecular Sulfor YUde Formation.
Mechanistically, the Hrst step in this reaction is believed to be formation of the
rhodium-stabilized electrophilic carbenoid 275 (Scheme 5.8). Carbenoid intermediate
271 then reacts with one of the lone electron pairs of the tethered sulfur atom to give
sulfur ylide 272. Sulfur ylide 272 presumably undergoes a 1,2-rearrangement to give
keto ester product 270. Alternatively, sulfur ylide 272 could undergo a gramine-type
fragmentation in which the a-thio carbanion 274 is extruded and an indolem'ne
intermediate 273 ensues. The carbanion 274 can recombine with indolenine 273 to give
the observed product 270.
OEt RM0Ac)4 (5 mol%), PhH, A
H 270
,0
260
113
Scheme 5.8. Proposed Mechanism of the Intramolecular Sulfiir Ylide Reaction.
5 nK)l% Rh2(OAc)4,
PhH.A
(73% yield)
260 271
274 273 272
Et 1,2-rearrangement gramme-type firagmentation/addition ,p
270
5.4. Intermolecular Sulfur Ylide Reactions
5.4.1. Sulfiir Ylides from C-10 Thioindoles
We also became interested in the use of sulfur ylides to fiinctionalize thioindoles in an
intermolecular fashion. We flrst considered the action of simple diazo compounds on C-
10 thioether analogues of gramine. Along these lines, 3-[(ethyithio)methyl]-lH-indole"
174 was subjected to ^-ketoester diazo compound*" 275 and 5 mol% Rh2(OAc)4 in
refluxing benzene (Scheme S.9).
114
Scheme 5.9. Sulfur Ylide Reactton with 3-[(Ethylthio)iiiethyl]-lH-liiidole 279.
In this reaction, 48% of starting material 174 was recovered. As well, 12% of indole
276 was isolated, corresponding to C-H bond insertion at C-7 by the metal carbene from
275. Also, preliminary data suggested that a minor amount (» 3%) of indole 277,
corresponding to C-H bond insertion at C-2, was detected. Apparently, the indole
nitrogen was directing the C-H bond insertion process at C-2 and C-7 in preference to
sulfur ylide formation. To confirm this hypothesis, N-methyl- and N-tosyl-protected 3-
[(ethylthio)methyl]-lH-indole were prepared and subjected to diazo compound 275 in the
presence of rhodium (Scheme S.IO).
Scheme 5.10. Sulfiir Ylide Formation with N-Protected Indole Species.
48%raooverad starting matarial
Rhi(0Ac)4(5mal%), PhH,d COMe
COMe
m t2%yield
174 m minor product
278 280
COMe
Ts 281
Rii2(OAc)4(5 mal%), PtiH, A
(S9%yMd) Ts Ts 283 282
115
Per our hypothesis, N-protected indoles 278 and 281 gave products 280 and 283,
respectively. Presumably, the products are derived from the formation of sulfur ylides
279 and 282. No C-H bond insertion products about the aromatic core were isolated.
These reactions provide a method to functionalize N-protected indoles at C-10, which is
problematic using traditional gramine fragmentation/couplings.
5.4.2. Sulfiir Ylides from 2,10-Ditliioindoles
As was mentioned, we hoped to harness sulfur ylides as a means to functionalize 2,10-
dithioindoles. In this regard, we hoped to overcome a potentially problematic
chemoselectivity issue by using a differentially substituted 2,10-dithioindole. Hence, we
synthesized di^erentially-substituted 2,10-dithioindole 198. We believed that the C-2
thioether of 198 would be less reactive than the C-10 thioether, because the lone pairs of
electrons on the C-2 thioether are delocalized through both the indole ring as well as the
phenyl ring, thus rendering the C-2 thioether less Lewis basic than the C-IO thioether.
We subjected to 198 to diazo compound 275 under rhodium catalysis (Scheme 5.11).
Surprisingly, compound 284 was obtained in 47% yield. Di order to conflrm the identity
of the product, 284 was subjected to dimethyl malonate and KF/l8-crown-6, which gave
285 in an unoptimized 34% yield. We believe that the relatively low yield of this
fragmentation/coupling sequence speaks to the special reactivity that the 2-thioether
imparts during couplings of our 2,10-dithioindoles.
116
Scheme 5.11. IntermolecuUir Sulfur Ylide Formatioii/Rearrangeiiient
OEt SEt
SPh Rh^OAe)4(5mol%), PtiH,A
(45%yMd) 196
27S
196 2S4
MeOaCs^O^e
KF(leq), CO t 18-crowi(v6 (0.5 eq)
CH3CN, reflux 3h (34%yW(l)
CO
285
During the C-2 thioether insertion reaction, we believe a sulfur ylide intermediate
222 is formed, which undergoes subsequent 1,2-reaTrangement (Scheme S.12). No
evidence of carbene reaction at the C-10 thioether of 198 was found. Based on our above
Hnding that carbene additions to gramine derivative 174 gave C-H insertion at C-7 and C-
2, it seemed plausible that in this reaction, the indole nitrogen was playing a similar
directing role. We felt that the nitrogen was coordinating to the electrophilic carbene in
order to form a coordinated intermediate 286.
Thus, a novel and potentially useful way of derivatizing 2,10-thioindoles at C-2 was
discovered. We believe this method might allow efHcient access to natural products
containing substitution at C-2, such as ibogamine (Chapter 2). Therefore, the scope and
limitations of intermolecular sulfur ylide reactions of the 2,10-dithioindoles were
explored.
117
Scheme 5.12. Proposed Mechanism of Intermolecular Sulfur Ylide Chemistry.
5.4.3. Sulfur Ylides from 2*Thioindoles
To continue our studies, we essentially reversed the order of reactions (i.e. performed
coupling at C-10 Hrst, followed by carbene addition) in order to Hrst harness the special
coupling reactivity imparted to the 2,10-dithioindoles by the C-2 thioether. Hence, a
series of previously coupled indoles 181b, 181g, and 181a (synthesized from 2,10-
dithioindole 170a) were subjected to diazo compounds 275 and 288^^ in refluxing
benzene in the presence of a catalytic amount of dirtiodium tetraacetate (Scheme 5.13).
SPh Rha(OAc)4(5mol%), PhH.A
(45% yield)
•SPh
COaEt
118
Scheme 5.13. Intermolecular SulAir Ylide Studies.
181b
SEt Ph
181a
^2
Rh2(OAc)4(5 mol%), PhH, A
(48% yield)
275
OEt
il OaMe MeO II OMe
CO^e
SEt Rh2(OAc)4 (5 mol%), PhH, A
(95% yield)
289 MeOC
Ph
Rh2(OAc)4(5 mol%), PhH, A
(42% yield)
SEt
COaEt
co
Hh2(OAc)4(5mol%),PliH,4
(7l%y«l) a, "MeOC
CO^e
H ^CO^e 181a v«/o,».u, 292 CO^e
2-ThioindoIe 181b reacted with P-ketoester-derived diazo compound 275 to give the
corresponding sulfur ylide rearrangement product 289 in 48% yield (Scheme S.12)>
Similarly, 2-thioindole 181g reacted to give the anticipated ^-ketoester 290 in moderate
yield (42%). The yield improved to 61% when the simple malonate-derived indole 181a
119
reacted under the same conditions to give P-ketoester 291. Substituted indole 292 formed
in 95% yield from the reaction of 181a with malonate-derived diazo compound 288.
While these reactions await further optimization, this new method of forming a carbon-
carbon bond at C-2 of the thioindole derivatives appears promising.
5.4.4. Attempted Sulfur Ylide Formation from Vinyl Carbenes
We have also examined the use of vinyl diazo compounds in the intermolecular
reaction of carbenes with the thioindoles. When indole 181a was subjected to P-methyl
vinyl diazo compound 293a" we were surprised to note a new product being formed
(Scheme S.14). Rather than isolating the C-2 sulfur ylide rearrangement product 296, we
isolated 3,3-disubstituted thioimidate 294a.
Scheme 5.14. Reaction of Vinyl Carbenoid Species with 2-Tliioindoles.
;o^e
co
Rh2(OAc)4 (5 fnol%), PhH, A
181a
SEt Rh2(OAc)4 (5 fnol%), PhH, A
(45% yield) 294a
CO^e
120
Davies" has shown that rhodiuin(II)-stabilized vinyl carbenoid species exhibit
electrophilic character at both the carbene site as well as at the ^-position of the alkene.
In his studies, vinyl diazo compound 297 was subjected to Rh2(OAc)4 and butyl vinyl
ether (Scheme S.IS). He isolated 24% of cyclopentene 298, as well as 37% of
vinylcyclopropane 299.
Scheme 5.15. A Demonstration of Conjugate Additions to Vinyl Carbenoids.
Rh.(OAcU Q ^
BUOCH=CH2 BUO COsMe /
297 CH2CI2 298 299
(24% yield) (37% yield)
Davies proposed that cyclopentene 298 was a result of conjugate nucleophilic addition
of butyl vinyl ether to die rhodium-carbenoid derivative of 297. Based on this precedent,
we believe that in our system, C-3 of indole 181a is adding in a nucleophilic, conjugate
fashion to the vinyl metal carbene species. In order to see if this anomalous reaction was
general, two other vinyl diazo compounds 293b' and 293c'' were synthesized and
reacted with 2-thioindole 181a (Table S.l). In these cases, the corresponding
thioimidates 294b and 294c were obtained in 88 and 82% yield, respectively. That we
observed conjugate addition to vinyl carbenes having ^-substitution is particularly
interesting, because in Davies' work, ^-substitution of vinyl carbenes apparently
precluded conjugate addition.
121
Table 5.1. Reaction of Vinyl Diazo Compounds with 2*Tliioindole.
OR' 293
Rh2(OAc)4 (5 mol%). PhH, A SEt
294
SEt 181a
Entiy 293 R R' 294 Yield (%)
1 a Me Et a 93
2 b H IBu b 88
3 c CO^t Et c 82
In order to determine if the presumed conjugate addition was occurring by
nucleophilic addition to a metal carbenoid, the reaction was run in the absence of Rh(II),
and in that case, 99% of starting material was recovered. This suggests that the rhodium
is indeed playing a critical role to activate the vinyl compound towards nucleophilic
conjugate addition. Hence, C-3 of 181a presumably attacks the rhodium carbene formed
from 293 to give 300. Cyclization to 301, P-hydride elimination to 302, and reductive
elimination gives the observed products 294.
122
Scheme 5.16. Proposed Mechanism for Formation of 294.
CO^e CO
Rh2(OAc)4(5tnol%).PhH,A
We believe that the conjugate addition of 2-thioindoles to vinyl metal carbenoids will
provide access to interesting indole derivatives containing a spiro center at C-3. As was
discussed, we have previously encountered difficulties in stereoselectively forming a C-3
spiro center intramolecularly through the use of Pictet-Spengler reactions (Chapter 4).
While this conjugate addition methodology is in its preliminary stages, we feel that this
new method of forming 3,3-disubstituted indoline derivatives has potential for the
synthesis of biologically active natural products containing a C-3 spiro center.
123
SS. Conclusioiis
It is clear that our 2,10-dithioindoles are beginning to fulfill their promise as versatile
intermediates in organic synthesis. Sulfur ylides were used to selectively fiinctionalize
C-10 and C-2 of the 2,10-dithioindoles, as well as simpler thioether analogues of
gramine. A better understanding of these reactions will lead to further optimization of
the intermolecular sulfur ylide chemistry. Intramolecular sulfur ylides show promise in
asymmetric gramine-type reactions. This may ultimately allow us access to biologically
active indole-containing natural products in an asymmetric fashion.
124
CHAPTER 6. CONCLUSIONS
We have developed a highly efficient synthesis of 2,3-disubstituted indoles. From
isonitriles, both tin and sulfur mediate the free radical cyclization leading to the indole
skeleton. In the case of sulfur, novel 2,iO-dithioindoles are formed. The 2,10-
dithioindoles have proven to be versatile organic intermediates. In particular, we have
been able to couple the 2,10-dithioindoles with several nucleophiles (i.e. carbon, sulfur,
and nitrogen nucleophiles) at C-10. This alkylation is mediated efficiently by PBuj and
KF/18-crown-6. One of our goals has been to perform this coupling stereoselectively.
To this end, we believe that we can access coupled products stereoselectively through the
use of intramolecular sulfur ylide formation and rearrangement. Furthermore, we have
shown that sulfur ylides formed intermolecularly from thioindoles are an efflcient means
to functionalize the indole skeleton.
Finally, w e have used deriva tives from our indole synthesis/ coupling protocol in
studies directed toward the synthesis of Spirotryprostatin A. It is our ultimate hope that
our indole-forming methodology and elaboration sequences will lead to the synthesis of
biologically active indole-containing natural products.
125
CHAPTER 7. EXPERIMENTAL
7.1. General Methods
NMR spectra were recorded on either a Bruker AM-250 or a Bruker DRX-SOO NMR
at 250 MHz and 500 MHz respectively. Chemical shifts were reported in 5, parts per
million (ppm), relative to chloroform (S = 7.24 ppm) as an internal standard. Coupling
constants, 7, were reported in Hertz (Hz) and refer to apparent peak multiplicities and not
true coupling constants. Mass spectra were recorded at the Mass Spectrometry Facility at
the Department of Chemistry of the University of Arizona on either a Jeol HX-1 lOA GC
or a Hewlett-Packard 5988A GC/MS. IR spectra were recorded on a Nicolet Impact 410
spectrophotometer. Purification with deactivated silica gel refers to silica gel which had
been stirred with 5% NEtj and the eluting solvent for 15 min. Ether and THF were
distilled from sodium/benzophenone. Benzene, toluene, CHjCIj, CHCI3, CH3OH,
pyridine, i-PrNEt, EtjN, and EtjNH were distilled from CaHj. CH3CN was distilled from
K2CO3. BujP was distilled before use. Cul and benzaldehyde were both puriHed before
their use. All other reagents were used without puriHcation. Unless otherwise stated, all
reactions were run under an atmosphere of argon in flame-dried glassware.
Concentration refers to removal of solvent under reduced pressure (house vacuum at ca.
20 mm Hg) with a BQchi Rotavapor.
126
7 J. Experimental Procedures
iV-(2-iodo<phenylHonnainide 154. To 2.1 mL (49 mmol) of formic acid (88%)
at o'c was added acetic anhydride (1.8 mL, 8.3 mmol). The solution was allowed to
warm to room temperature and after l.Sh, 2-iodoaniline (2.0 g, 9.1 mmol) was added.
After stirring the dark brown, opaque mixture overnight at room temperature, the pH was
adjusted to 8-10 using saturated KjCO, (aq). Light brown crystals were obtained upon
filtration of the mixture, and were subsequently washed several times with cold water.
Flash chromatography (neutralized silica gel, 10:1 hexanes:ethyl acetate) provided 2.0 g
(87%) of 154 as a white solid. m.p. 118-119»C 'H NMR (250MHz,CDCl3 8 8.63 (d, J =
11.1 Hz, 0.5H), 8.46 (s, 0.5H), 8.26 {dj = 8.2 Hz, 0.5H), 7.77 (d, J « 8.0Hz, 0.5H), 7.51
(bs, IH), 7.33 (m, IH), 7.18 (d, J = 8.0 Hz, 0.5H), 6.88 (m, IH); NMR (62.5MHz,
CDClj) 8 162.0,159.0,139.8, 138.9,129.5,129.1,127.0,126.3, 122.3, 119.5; DKCCU)
3384, 3228, 1721 cm '; MS (EI, 70 eV) 247 (M*), 120; HRMS (EI, 70 eV) calcd for
CrHglNO (M^) 246.9494, found 246.9500.
Representative procedure for the Sonogashira coupling 150 with substituted
alkynes. i\r-[2-(triniethyl*silanyiethynyl)-phenyl]-fomuunide 154a. To a solution of o-
iodo-N-formanilide (0.31 g, 1.3 nmiol) and THF (13 mL) at rt was added EtjN (0.53 mL,
3.8 mmol) and PdCl2(PPh3)2 (0.027 g, 0.038 mmol). At 0.25 hr intervals, Cul (0.024 g,
0.13 mmol) and trimethylsilylacetylene (0.27 mL, 1.9 mmoi) were added. Over this time
period, the color of the solution changed from dark amber to dark green. After stirring
for an additional 1.5 hr, the reaction mixture was Hltered through a short pad of alumina
127
(eluted with THF (20 mL)), and concentrated. Flash chromatography (neutralized silica
gel, 10:1 hexanesrethyl acetate) gave 0.26 g (93%) of 155a as a dark orange solid. ni.p.
78-80"C 'H NMR (250MHz, CDClj) 8 8.78 (d, / = 11.3 Hz, IH), 8.44 (d, 7 = 1.6 Hz,
2H), 8.36 (d, /s 8.3 Hz, IH). 7.93 (bs, 2H), 7.43 (m, 2H), 7.24 (m, 2H), 7.02 (m, 2H),
0.25 (s, 18H); "C NMR (62.5MHz, CDC^S 161.1,158.8, 133.0, 131.9, 129.8, 124.1,
123.6,119.7,115.6, -0.17, -0.25; IR (CCI4) 3389,2963,2906,2153, 1712 cm '; MS (EI,
70 eV) 217 (MO, 202, 143; HRMS (EI, 70 eV) calcd for C.^H.jNOSi (M^) 217.0923,
found 217.0917.
iV-[2*(hex-l-ynyl)-phenyl]-formaniide 155b. Prepared according to the
procedure outlined for the formation of 155a using o-iodo-N-formanilide 154 (0.50 g, 2.0
mmol), EtsN (0.43 mL, 3.0 mmol), PPhj (0.013 g, 0.051 mmol), Cul (0.005 g, 0.02
mmol), Pd(PPh3)Cl2 (0.071 g, 0.10 mmol), l-hexyne (0.35 mL, 3.1 mmol) and THF (5
mL). Flash chromatography (neutralized silica gel, 10:1 hexanes:ethyl acetate) gave 0.45
g (100%) of 155b as a brown solid. m.p. 39-41"'C 'H NMR (250MHz, CDCI3) 8 8.76 (d,
11.0 Hz, 0.5H), 8.43 (d, J ~ 1.4 Hz, 0.5H), 8.34 (d, / = 8.3 Hz. 0.5H), 8.04 (bs, IH),
7.34 (m, IH), 7.18 (m, 1.5H), 6.99 (m, IH), 2.42 (q, J = 6.9 Hz, 2H), 1.50 (m, 4H), 0.90
(t, / = 7.1 Hz, 3H); "C NMR (62.5MHz, CDCI3) 8 161.7, 159.3, 138.2, 137.9, 133.2,
132.1,129.1,129.0,124.6,124.0,120.0,116.0,114.4,113.2,98.5,75.9,75.6,31.0,22.4,
19.6,13.9; IR (CCI4) 3389,2958,2228, 1712 cm-l; MS (EI, 70 eV) 201 (M^), 172,144;
HRMS (EI, 70 eV) calcd for CjaH.jNO (M*) 201.1154, found 201.1152.
128
iV-[2-(3>3-dimethyl-buM-ynyl)-plienyl]-roiinaiiiide 155c. Prepared according
to the procedure outlined for the formation of 155a using o-iodo-N-fomoianilide 154 (1.0
g, 4.0 inmol), EtaN (1.69 mL, 12.1 nunol), Cul (0.077 g, 0.41 mmol), Pd(PPh3)2Cl2
(0.085 g, 0.12 mmol), t-butylacetylene (0.75 mL, 6.1 mmol), and THF (40 mL). Flash
chromatography (neutralized silica gel, 5:1 hexanes:ethyl acetate) gave 0.74 g (92%) of
155c as a pale orange solid. m.p. 73-75'C 'H NMR (250MHz, CDCI3) 8 8.76 (d, J -
11.0 Hz, 0.3H), 8.45 (d, / = 1.5 Hz, 0.7H), 8.36 (d, J = 8.3 Hz, 0.7H), 7.78 (bs, IH), 7.36
(m, IH), 7.23 (m, 1.3H), 7.04 (m, IH), 1.35 (s, 6H), 1.33 (s, 3H); "C NMR (62.5MHz,
CDCl3) 8 161.1, 158.6, 137.6, 137.4, 132.8, 131.6, 128.9, 124.3, 123.7, 119.7, 115.6,
114.0,112.6,106.4,74.0,73.8,31.0, 30.9,28.4; IR (CCI4) 3389,2958,2228, 1712 cm ';
MS (EI, 70 eV) 201 (M*), 172, 144; HRMS (EI, 70 eV) calcd for C.aH.jNO (M')
201.1154, found 201.1152.
Ar-(2*phenylethynyl-phenyl)-formaiiude 155d. Prepared according to the
procedure outlined for the formation of 155a using o-iodo-N-formanilide 154 (0.30 g, 1.2
mmol), EtjN (0.25 mL, 1.8 mmol), PPhj (0.008 g, 0.031 mmol), Cul (0.003 g, 0.01
mmol), Pd(PPh3)2Q2 (0.043 g, 0.061 mmol), phenyl acetylene (0.20 mL, 1.8 mmol), and
THF (5 mL). Flash chromatography (neutralized silica gel, 10:1 hexanes:ethyl acetate)
gave 0.32 g (100%) of 155d as a brown solid. 'H NMR (250MHz, CDCI3) 8 8.80 (d, J s
11.3 Hz, 0.5H), 8.48 (s, 0.5H), 8.43 (d, 8.3 Hz, IH), 8.02 (bs, IH), 7.52 (m, 3H), 7.32
(m, 3H), 7.13 (m, 2H); "C NMR (62.5MHz, CDQj) 8 161.2,158.9,138.8, 137.8,137.5,
132.9,131.9, 131.6,131.4,129.7,129.6,129.0,128.9,128.6,128.5,128.4,124.5,123.9,
123.4, 122.3, 122.2, 120.0, 119.3,116.1, 112.0,96.5, 83.8; IR (CCI4) 3398, 1717 cm ';
129
MS (EI, 70 eV) 221 (M*), 193; HRMS (EI, 70 eV) calcd for C,5H„N0(M*) 221.0841,
found 221.0843.
Ar-[2>(3-beiizyloxy-prop-l-ynyl)«plienyl]-fomiaiiiide 15Se. Prepared according
to the procedure outlined for the formation of 155a using o-iodo-N-formanilide 154 (O.SO
g, 2.0 mmol), EtjN (0.85 mL, 6.1 mmol), Cul (0.038 g, 0.20 nunol), Pd(PPh3)2Cl2 (0.043
g, 0.061 mmol), benzyl-protected propargyl alcohol (0.44 g, 3.1 mmol), and THF (20
mL). Flash chromatography (neutralized silica gel, 10:1 hexanesrethyl acetate) gave 0.30
g (57%) of 155e as a light orange solid. m.p. 42-54°C 'H NMR (250MHz, CDCI3) 8
8.77 (d, y = 11.3 Hz, 0.5H), 8.40 (m, 1.5H), 8.05 (bs, IH), 7.37 (m, 7H), 7.10 (m, IH),
4.65 (s, 1.4 H), 4.64 (s, 0.6H), 4.45 (s, 1.4 H), 4.41 (s, 0.6H); "C NMR (62.5MHz,
CDCI3) 8 161.3, 159.0, 138.0, 137.8, 137.0, 135.0, 133.1, 132.0, 130.1, 129.7, 128.4,
128.2, 127.9, 127.9, 127.8, 127.6, 127.5, 124.3, 123.7, 119.9, 116.2, 112.7, 111.2,92.4,
92.3,81.2,80.9,71.8,57.7,57.6; IR (CCI4) 3394,3327,3072,2863,2224 cm '; MS (EI,
70 eV) 265 (M*), 159; HRMS (EI, 70 eV) calcd for CnH.jNOj (M*) 265.1103, found
265.1095.
Representative procedure for the dehydration of fonnamides. (2-isocyano-
phenytethynyl)-triniethybiiane 150a. To a solution of 155a (0.34 g, 1.6 mmol) and
CHiQ^ (10 mL) at 0°C was added iPriNH (1.3 mL, 9.4 mmol). Phosphoryl chloride,
(0.32 mL, 3.4 mmol) was added dropwise. After 0.25 h, the reaction mixture was
quenched at 0°C with 1 mL 20% NajCO, (aq). The reaction mixture was diluted with 25
mL CH2CI2 and washed with 25 mL 20% Na2C03 (aq) and brine (50 mL), dried over
K2CO3 and concentrated. Bulb-to-bulb vacuum distillation (50-65°C, ca. 5 mm Hg)
130
provided 0.25 g (82%) of 150a as a green liquid. Alternatively, isocyanide 150a can be
chromatographed (neutral alumina, 50:1 hexanesiethy! acetate). 'H NMR (250MHz,
CDCI3) 8 7.50 (m, IH), 7.32 (m, 3H), 0.27 (s, 9H); "C NMR (62.5MHz, CDCI3) 6 167.5,
132.5, 129.0,128.8, 126.5,121.5,102.9,99.4, -0.3; IR (CCI4) 3076,2967, 2901,2167,
2115 cm '; MS (EI, 70 eV) 199 (M^) 184, 154; HRMS (EI, 70 eV) calcd for CpH^NSi
(M^) 199.0817, found 199.0812.
l-(hex-l*ynyl)*2-isocyanobeiizene 150b. Prepared according to the procedure
outlined for the formation of 150a using formamide 155b (0.13 g, 0.64 mmol), iPrjNH
(0.54 mL, 3.1 nrniol), POCI3 (0.13 mL, 1.4mmol), and CHjClj (4.3 mL). Crude
isocyanide 150b was taken into the radical reactions, although a sample for
characterization was obtained via flash chromatography (neutral alumina, 50:1
hexanes:ethyl acetate). 'H NMR (250MHz, CDCI3) 8 7.16 (m, IH), 7.30 (m, 3H), 2.50 (t,
/ = 6.9 Hz, 2H), 1.44 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H); "C NMR (62.5MHz, CDCI3) 8
123.3, 128.8,128.0, 126.4, 123.0,98.5, 30.5, 21.9; IR (CCI4) 3062, 2958, 2934, 2873,
2234, 2124 cm '; MS (EI, 70 eV) 183 QA*) 167; HRMS (EI, 70 eV) calcd for CijH.aN
(M^) 183.1048, found 183.1003.
l-(but>l-ynyl«3,3*diiiiethyl)-2*isocyanobeiizene 150c. Prepared according to
the procedure outlined for the formation of 150a using formamide 155c (O.IO g, 0.50
nunol), iPrjNH (0.42 mL, 3.0 mmol), POCI3 (0.10 mL, 1.1 nrniol), and CHjClj (3 mL).
Flash chromatography (neutral alumina, 50:1 hexanes:ethyl acetate) gave 0.092 g
(>100%) of isocyanide 150c. 'H NMR (250MHz, CDCI3) 8 7.47 (m, IH), 7.33 (m, 3H),
131
1.39 (s, 9H); "C NMR (62.5MHz, CDCI3) 8 166.0, 132.1, 128.8, 128.0, 126.3, 123.0,
106.7, 74.6, 53.5, 31.6, 30.8, 28.3,22.6, 14.1; IR (CCI4) 2979, 2936,2875, 2243. 2122
cm '; MS (FAB*) 184 (MH+) 154; HRMS (FAB*) calcd for C^H^N (MH*) 184.1126,
found 184.1126.
l*(2-phenylethynyl)-2*isocyanobenzene ISOd. Prepared according to the
procedure outlined for the formation of 150a using formamide 155d (0.49 g, 2.2 mmol),
iPr2NH (1.8 mL, 13 mmol), POCI3 (0.45 mL, 4.9 mmol), and CH2CI2 (15 mL). Crude
isocyanide 150d was taken into the radical reactions, although a sample for
characterization was obtained via flash chromatography (neutral alumina, 50:1
hexanesrethyl acetate). 'H NMR (250MHz, CDCl,) 8 7.64 (m, 2H), 7.40 (m, 7H); "C
NMR (62.5MHz, CDCI3) 8 132.2,131.9,129.1,129.0,128.7,128.4,128.3,126.5,122.2,
121.8,96.8,84.4; IR (CCI4) 3076,3034,2224,2119 cm '; MS (EI, 70 eV) 203 (M*) 126;
HRMS (EI, 70 eV) calcd for CjjH^ (M*) 203.0735, found 203.0726.
l-(3«benzyloxyprop-l-ynyl)-2-isocyanobenzene 150e. Prepared according to
the procedure outlined for the formation of ISOa using formamide 155e (0.11 g, 0.40
mmol), iPriNH (0.34 mL, 2.4 mmol), POQj (0.083 mL, 0.89 mmol) and CHjCli (3 mL).
Flash chromatography (neutral alumina, 50:1 hexanes:ethyl acetate) gave 0.034 g (34%)
of isocyanide 150e. 'H NMR (250MHz, CDCI3) 8 7.37 (m, 9H). 4.74 (s, 2H), 4.46 (s,
2H); ''C NMR (62.5MHz, 0X^3) 8 137.2, 132.7, 129.1, 129.0, 128.4, 128.3, 127.9,
127.7,127.1,126.6,92.6,81.4,76.5,73.2,71.7,68.6,57.6; IR {CO,) 3071,3034,2934,
2863 cm"'.
132
l-ethynyl-2*isocyanobeiizene 150f. To a solution of isocyanide 150a (0.061 g,
0.31 mmol) and THF (1 mL) at 0»C was added TBAF (l.O M in THF, 0.37 mL, 0.37
mmoi) dropwise. The volatile isocyanide was chromatographed directly (neutral
alumina, pentane) and concentrated to give 0.039 g (100%) of isocyanide ISOf NMR
(250MHz, CDClj) 5 7.44 (m, IH), 7.24 (m, 3H), 3.34 (s, IH); ' C NMR (62.5MHz,
CDClj) 5 133.1, 129.4, 128.9, 128.3, 126.6, 84.4; IR (CCIJ 3300, 2252, 2131 cm ';
HRMS (EI, 70 eV) calcd for (M^) 127.0422, found 127.0424.
Representative procedure for the tin*inediated indole formation. 3>
(triniet!iyl«siIanylniethyl)-lH-indole 157a. To a solution of isocyanide 150a (0.048 g,
0.24 mmol) and benzene (3.5mL) in a pressure tube, were added tributyltin hydride (0.15
g, 0.53 mmol) and AIBN (0.004 g, 0.024 mmol). The mixture was heated using an oil
bath (100°C) for 1 h. The crude reaction mixture was diluted with ether (25 mL), washed
with 3M HCl (50 mL) and saturated KF (aq) (2 x 50 mL), dried over MgS04 and
concentrated. Flash chromatography (10:1 hexanes/ethyl acetate) gave 0.040 g (82%) of
indole 157a. 'H NMR (250MHz. CDCI3) 5 7.74 (bs, IH), 7.59 (d, J = 7.7 Hz, IH), 7.33
(d, J = 7.8 Hz, 2H), 7.19 (m, 2H), 6.84 (s, IH), 2.17 (s, 2H), 0.08 (s, 9H); ''C NMR
(62.5MHz, CDCI3) 8 136.1, 128.1, 121.5, 120.1, 119.2, 118.7, 113.5, 110.8, 13.8, -1.4;
IR (CCI4) 3488,3422,3057,2953,2882 cm '; MS (EI, 70 eV) 203 (M*) 130; HRMS (EI,
70 eV) calcd for CiiH^NSi (M+) 203.1130, found 203.1137.
3-pentyl-U7-indole 157b and 3-butyl-qiiinoline 152b. Prepared according to
the procedure outlined for the formation of 157a using 150b, (0.030 g, 0.16 mmol),
133
nBusSnH (0.097 mL, 0.35 mmol), AIBN (0.002g, 0.016mmol), and benzene (I mL).
Flash chromatography (neutralized silica gel. 10:1 hexanes-.ethyl acetate) gave 0.0031 g
(10%) of indole 157b and 0.016 g (53%) of quinoline 152b. 'H NMR (250MHz, CDCl,)
(157b) 8 7.86 (bs. IH), 7.61 (d, J = 7.7 Hz. IH), 7.34 (d. J = 8.9 Hz. IH). 7.16 (m. 2H),
6.95 (s, IH), 2.74 (t, J = 7.6 Hz, 2H). 1.71 (m, 2H), 1.36 (m, 4H), 0.87 (t, / = 6,4 Hz,
3H); "C NMR (62.5MHz. CDClj) 8 136.3,127.6,121.8,121.0,119.0,117.2, 111.0,31.8,
29.8, 25.1, 22.6, 14.1; IR (CCI4) 3489, 3420, 3057, 2962, 2927, 2857, 1455 cm*'; MS
(EI, 70 eV) 187 (M*) 130; HRMS (EI. 70 eV) calcd for C.aH.vN (M^) 187.1361, found
187.1352. 'H NMR (250MHz, CDCl,) (152b) 8 8.77 (d, J = 2.0 Hz, IH), 8.06 (d, J - 8.4
Hz, IH), 7.90 (s, IH), 7.75 (d, J = 8.2 Hz, IH). 7.64 (dt. J = 6.3,1.4 Hz, IH), 7.50 (t, 7 =
7.0 Hz, IH), 2.79 (t, J s 7.7 Hz. 2H). 1.69 (m. 2H). 1.39 (m. 2H), 0.94 (t, / = 7.3 Hz,
3H); "C NMR (62.5MHz, CDCI3) 8 151.0,143.8, 129.3, 127.7, 125.8, 36.5, 35.6,22.8,
14.0: IR (CCI4) 3068,2956,2931,2863,1548, 1462 cm '; MS (EI, 70 eV) 185 (M*) 128;
HRMS (EI, 70 eV) calcd for C.aH.jN (M+) 185.1204, found 185.1201.
3-(2^*dimethyl-propyl)-liSr'indole 157c and 3-r*butyl-2-(tributylstaimyl)-
quinoline 152c. Prepared according to the procedure outlined for the formation of 157a
using 150c, (0.092 g, 0.50 mmol), nBujSnH (0.30 mL, 1.1 mmol), AIBN (0.0083 g,
0.050 mmol), and benzene (6 mL). Flash chromatography (neutralized silica gel. 10:1
hexanes:ethyi acetate) gave 0.052 g (56%) of indole 157c as a pale yellow solid. m.p. 36-
38''C and 0.0097 g (4%) of quinoline 152c as a colorless oil. 'H NMR (250MHz. CDCI3)
(157c)87.91 (bs. IH).7.63(d.7=7.5Hz, IH).7.34(d,7= 7.3Hz. IH).7.19(1,7=6.9
134
Hz, IH), 7.12 (t, / = 7.0 Hz, IH), 6.94 (d, /=2.2 Hz, IH), 2.66 (s, 2H), 0.98 (s, 9H); "C
NMR (62.5MHz, CDQj) 8 135.9, 128.9, 123.0, 121.4, 119.7, 119.1, 114.2, 110.8, 39.0,
32.2, 29.7; IR (CCI4) 3489, 3429, 3056, 2962, 2901, 2858, 1464 cm '; MS (FABO 187
(MH*); HRMS (FAB*) calcd for C.jHnN (MH*) 187.1361, found 187.1360. 'H NMR
(500MHz, CDCI3) (152c) 8 9.00 (s, IH), 8.04 (dd, J = 8.3, 1.2 Hz, IH), 7.99 (d, J s 7.9
Hz, IH), 7.59 (dt, J = 7.5, 1.2 Hz, IH), 7.46 (dt, J = 7.7, 1.5 Hz, IH), 1.49 (s, 9H), 1.45
(m, 6H), 1.28 (m, 12H), 0.83 (t, /= 7.3 Hz, 9H); "C NMR (125MHz. CDCI3) 8 152.9,
150.0, 147.6, 145.9, 134.2, 130.1, 129.3, 127.7, 125.2, 35.7, 32.7,29.0, 27.2, 16.1, 13.5;
IR (CCIJ 2970, 2927, 2866 cm '; MS (FAB*) 476 (MH*) 289; HRMS (FAB*) calcd for
C2sH42NSn (MH*) 476.2344, found 476.2358.
3-beiizyUlH-indole lS7d and 3-phenyl>quinoline lS2d. Prepared according to
the procedure outlined for the formation of lS7a using 150d, (0.030 g, 0.16 mmol),
nBusSnH (0.097 mL, 0.35 mmol), AIBN (0.002 g, 0.016 mmol), and benzene (1 mL).
Flash chromatography (neutralized silica gel, 10:1 hexanes:ethyl acetate) gave 0.0031 g
(28%) of indole 157d and 0.016 g (13%) of quinoline 152d. 'H NMR (250MHz, CDCI3)
(157d) 8 7.94 (bs, IH), 7.52 (d, / = 8.1 Hz, IH), 7.35 (d, / = 6.3 Hz, IH), 7.26 (m, 6H),
7.13 (m, IH), 6.90 (s IH), 4.11 (s, 2H); ' C NMR (62.5MHz, CDCI3) 8 141.2, 137.0,
128.7, 128.3, 127.4, 125.9, 122.3, 122.0, 119.3, 119.1, 115.8, 111.0, 31.6; IR (CCI4)
3488, 3062, 3028 cm '; MS (EI, 70 eV) 207 (M*) 130; HRMS (EF) calcd for C,5H,3N
(M*) 207.1048, found 207.1048. 'H NMR (250MHz, CDCI3) (152d) 8 9.17 (d, J s 2.2
Hz, IH), 8.29 (d, /= 2.1 Hz, IH), 8.13 (d, 8.4Hz, IH), 7.87 (d, / = 7.8 Hz, IH), 7.71
135
(m, 3H), 7.55 (m. 3H), 7.46 (in, IH), 7.34 (s, IH); "C NMR (62.5MHz, CDCI3) 8 150.0,
147.4,137.9,133.9,133.2, 129.4,129.3,129.2,128.3,128.1,128.0,127.4, 127.0, 119.1;
IR (CCI4) 3066, 3028, 1560, 1498 cm '; HRMS (EI, 70 eV) calcd for C,5H„N (M*)
205.0891, found 205.0888.
3-(2-benzyloxy*ethyl)-lH*indole 157e and 3*beiizyloxyiiiethyl«quinoline 152e.
Prepared according to the procedure for the formation of 157a using 150e (0.092 g, 0.45
mmol), /iBujSnH (0.27 mL, 1.0 mmol), AIBN (0.008 g, 0,04 mmol) and benzene (2 mL).
Flash chromatography (neutralized silica gel, 10:1 hexanes:ethyl acetate) gave 0.027 g
(7%) of indole 157e and 0.012 g (4%) of quinoline 152e. 'H NMR (250MHz, CDCI3)
(lS7e) 8 7.95 (bs, IH), 7.61 (d, / = 7.0 Hz, IH), 7.31 (m, 3H), 7.12 (m, 4H), 7.03 (d, J =
1.1 Hz, IH), 4.55 (s, 2H), 3.77 (t, J =• 12 Hz, 2H), 3.09 (t, / s 7.0 Hz, 2H); "C NMR
(62.5MHz, CDClj) 8 138.4,136.0,128.2, 127.6, 127.5,127.4, 121.8,119.1,118.7,113.0,
110.9,72.9, 70.5; IR (CCI4) 3489, 3412, 3066,3031,2927, 2858, 1456, 1101 cm '; MS
(EI, 70 eV) 251 (M*) 130; HRMS (EI, 70 eV) calcd for CpHnNO (M^) 251.1310, found
251.1315. 'H NMR (250MHz, CDCI3) (152e) 8 8.31 (s, IH), 8.00 (d, J = 8.1 Hz, IH),
7.83 (d, /s 8.2 Hz. IH), 7.68 and 7.51 (m, 2H), 7.51 (m, IH), 7.37 (m, 5H), 4.76 (s, 2H),
4.74 (s, 2H); "C NMR (62.5MHz, CDCI3) 8 136.5, 130.1, 128.6, 128.2, 128.0, 127.8,
127.6,127.1,73.3,68.6; IR (CQ^) 3068,3031,2956,2926,2851,1209,1040 cm '.
quinoline 152f. Prepared according to the procedure for the formation of lS7a
using 150f, (0.039 g, 0.31 mmol), nBu3SnH (0.18 mL, 0.67 nraiol), AIBN (0.005 g, 0.03
nmiol) and benzene (2.0 mL). Flash chromatography (neutralized silica gel, 10:1
136
hexanes:ethyl acetate) gave 0.007 g (18%) of quinoline 152f. 'H NMR (250MHz, CDClj)
8 8.66 (d, y = 4.1 Hz, IH), 8.01 (d, J = 8.4 Hz, IH), 7.60 (m, 2H), 7.45 (m, 2H), 7.14 (s,
IH).
Representative procedure for the thiol-mediated formation of 2,3-
disubstituted indoles. 2-ethylsulfany!*3-[etiiylsulfanyl-(trinietliyi-silanyI)-niethyl]>
IH-indoie 170a. A solution of isocyanide ISOa (1.13 g, 5.69 mmol), ethanethiol (2.10
mL, 28.4 mmol), AIBN (0.14 g, 0.85 mmol) and toluene (142.0 mL) was heated to teflux
for 15 min. After removal of toluene, the reaction mixture was filtered through a pad of
alumina (10:1 hexanes:ethyl acetate) to yield 1.57 g (86%) of 2,10-dithioindole 170a as a
light yellow solid. m.p. 94-960C 'H NMR (250MHz, CDClj) 8 8.04 (bd 7 = 8.0 Hz, IH),
7.92 (bs, IH), 7.26 (d, / = 8.0 Hz, IH), 7.17 (dt, J = 7.5,1.2 Hz, IH), 7.05 (dt, J = 8.0,
1.0 Hz, IH), 3.97 (bs, IH), 2.77 (m, 2H), 2.25 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H), 1.12 (t, /
= 7.4 Hz, 3H), 0.08 (s, 9H); "C NMR (62.5MHz, CDClj) 8 137.0, 126.7, 125.0, 122.8,
122.2,120.5,118.9,110.4,31.0,29.7,25.9,15.4,14.3, -1.5; IR (CCI4) 3472,2961,2920
cm '; MS (FAB*) 323 OA*), 294, 262; HRMS calcd. for C.sH^jNSiSi (M*) 323.1198,
found 323.1192.
2-butylsuifanyl-3-[butyisiiifanyi-(triniethyl-silanyl)-niethyl]>li7-indole 170b.
Prepared according to the procedure outlined for the formation of 170a using isocyanide
150a (0.036 g, 0.18 mmol), butanethiol (0.058 mL, 0.54 mmol), AIBN (0.005 g, 0.03
mmol), and toluene (4.5 mL). Flash chromatography (neutral alumina, 10:1 hexanes:ethyl
acetate) gave 0.045 g (66%) of 170b as a pale yellow oil. 'H NMR (250MHz, CDQ,) 8
8.03(bd 7=8.0 Hz, IH), 7.90 (bs, IH), 7.26 (d, 7 = 9.6 Hz, IH), 7.16 (dt, 7= 7.5,1.1 Hz.
137
IH), 7.04 (dt, J = 7.7, 1.1 Hz, IH), 3.93 (s, IH), 2.74 (t, J = 7.2 Hz, 2H), 2.23 (m, 2H),
1.23-1.62 (m, 8H), 0.89 (t, J-1.1 Hz, 3H), 0.78 (t, J - 7.1 Hz, 3H), 0.08 (s, 9H); "C
NMR (62.5MHz. CDClj) 8 137.0, 127.0, 122.7, 122.1, 120.3, 118.9, 110.3, 36.7, 32.3,
31.8,31.2,30.0,22.0,21.9,13.7,13.6, -1.5; IR (CCI4) 3472,3402,3056,2961 cm '; MS
(FAB*) 379 (M*), 322, 290; HRMS calcd. for (M*) 379.1824, found
379.1820.
2-phenylsulfanyN3-[phenylsiilfanyl<(triiiiethyl-silanyl)-iiietiiyl]-li7-indole
170c. Prepared according to the procedure outlined for the formation of 170a using
isocyanide 150a (0.055 g, 0.28 mmol), thiophenol (0.085 mL, 0.83 mmol), AIBN (0.007
g, 0.04 mmol), and toluene (7.0 mL). Flash chromatography (neutral alunima, 10:1
hexanes:ethyl acetate) gave 0.057 g (49%) of 170c as a pale yellow oil. 'H NMR
(250MHz, CDClj) 6 8.18 (bd / = 6.4 Hz, IH), 7.85 (bs, IH), 7.16 (m, 8H), 6.99 (m, 5H),
4.41 (s, IH), 0.15 (s, 9H); "C NMR (62.5MHz, CDCI3) 8 137.5, 136.3, 129.8, 129.1,
128.5,127.2,126.0,125.7,123.2,122.7,122.0,121.4,119.2,110.6,33.7, -1.5; 1R{CCI)
3463, 3411, 3057, 2953 cm '; MS (FAB*) 419 (M*), 347, 342, 310; HRMS calcd. for
C24HMNS2Si (M*) 419.1198, found 419.1188.
2-([2-(2*hydroxy«ethylsulfanyl)-lJ7-indol*3-yl]-(triiiiethyl-silanyl)-
methylsulfanyl]«ethanol 170d. Prepared according to the procedure outlined for the
formation of 170a using isocyanide ISOa (O.ll g, 0.54 mmol), 2-mercaptoethanol (0.19
mL, 2.7 mmol), AIBN (0.014 g, 0.081 mmol), and toluene (14 mmol). Flash
chromatography (neutral alumina, 25:1 CH2Cl2:CH30H) gave 0.18 g (94%) of 170d as a
pale yeUow soUd. m.p. 90-92"C 'H NMR (250MHz, CDCI3) 8 8.94 (bs, IH), 7.97 (bd, /
138
s 7.9 H2, 1H), 7.24 (d, J - 7.2 Hz, IH), 7.14 (t, /=7.5 Hz, IH), 7.03 (t, J = 7.5 Hz, IH),
3.91 (s, IH), 3.78 (m, 2H), 3.52 (m, 2H), 3.10 (bs, IH), 2.89 (m, 3H), 2.41 (m, 2H), 0.08
(s, 9H); "C NMR (62.5MHz, CDCI^) 8 137.2, 126.3, 125.1, 122.7, 121.7, 119.0, 118.5,
110.7,61.6,60.3,41.2,38.8,34.9,29.8, -1.6; IR (CC1«) 3463,3316 (br), 2953 cm '; MS
(FAB*) 355 (M*), 278, 154; HRMS calcd. for C.fiHjjNOiSjSi (M*) 355.1096, found
355.1079.
2«[2-(terr-butyl*dimethyl-silanyloxy)<«Uiylsiilfanyl]*3«[[2-(/erf*butyl-dimethyU
silanoxy)-ethylsulfanyl]-(triinethyl-silanyl)-inethyl]-lH-indole 170e. Prepared
according to the procedure outlined for the formation of 170a using isocyanide 150a
(0.31 g, 1.6 nmiol), 2-(t-butyldimethylsiloxy)ethyl mercaptan (0.91 g, 4.7 nraiol), AIBN
(0.039 g, 0.24 mmol) and toluene (47 mL). Flash chromatography (neutral alumina, 20:1
hexanes:ethyl acetate) gave 0.56 g (60%) of 170e as a pale yellow oil. 'H NMR
(250MHz, CDCIj) 8 9.17 (bs, IH), 7.96 (bd, / = 7.9 Hz, IH), 7.22 (d, /= 9.2 Hz, IH),
7.08 (t, / = 7.5 Hz, IH), 7.00 (t, / = 7.4 Hz, IH), 4.00 (m, 3H), 3.55 (m, 2H), 2.93 (bt, /=
5.2 Hz, 2H), 2.37 (m, 2H), 0.99 (s, 9H), 0.80 (s, 9H), 0.20 (s, 6H), 0.07 (s, 9H), -0.06 (s,
6H); "C NMR (62.5MHz, CDClj) 8 137.0, 126.7, 126.6, 122.1, 121.9, 118.6, 116.8,
110.3,64.2,62.5,39.3,38.9,33.9,30.2,26.1,25.9,23.4,18.7, 18.3, -1.5, -5.2, -5.3, -5.3,
-5.3; IR (CCI4) 3472, 3359, 2962, 2927, 2857 cm:'; MS (FAB*) 583 (M*), 392, 424;
HRMS calcd. for CjgHjjNOjSiSij (M*) 582.2747, found 582.2745.
3*[[2«(2-iiiethoxycarbonyl'eUiylsulfany)«lfl-indoU3-yKtriiiiethyl-silanyl)*
methylsulfanyll'propionic add methyl ester 170f. Prepared according to the procedure
outlined for the formation of 170a using isocyanide 150a (0.088 g, 0.44 mmol), 2-
139
mercaptopropionate (0.24 mL, 2.2 mmol), AIBN (0.011 g, 0.067 mmol) and toluene (II
mL). Flash chromatography (neutral alumina, 10:1 hexanesrethyl acetate) gave 0.14 g
(72%) of ITOf as a pale yellow oil. 'H NMR (250MHz, CDClj) 8 8.63 (bs. IH), 7.97 (bd,
/ = 7.9 Hz, IH), 7.30 (d, J- 8.1 Hz, IH), 7.17 (t, / = 7.2 Hz, IH), 7.03 (t, J = 7.5 Hz,
IH), 3.92 (s, IH), 3.74 (s, 3H), 3.57 (s, 3H), 3.00 (m, 2H), 2.65 (t, 7 = 6.8 Hz, 2H), 2.48
(bs, 4H), 0.06 (s, 9H); NMR (62.5MHz, CDCI3) 8 172.7, 172.5, 137.2, 126.3, 124.3,
123.0, 122.1, 119.9, 119.0, 110.7,52.1,51.6,34.9,34.2,32.0,31.6,29.9, -1.5; ^(CCU)
3368, 2961, 2900, I74I cm '; MS (FAB^) 439 (M*), 320, 352; HRMS calcd. for
CjoHaN04S2Si (M*) 439.1307, found 439.1299.
Representative procedure for the phosphine-mediated alkylation of 2,10-
dithioindoles. 2*(2-ethylsulfanyl*UMndol-3-ylmethyl)-maloiiic acid dimethyl ester
181a. A solution of 2,10-dithioindole 170a (0.053 g, 0.16 mmol), dimethyl malonate
(0.094 mL, 0.82 mmol), Bu^P (0.021 mL, 0.082 mmol), and acetonitrile (2.4 mL) was
heated to reflux for 9h. The reaction mixture was concentrated after cooling to rt. Flash
chromatography (neutralized silica gel, 3:1 hexanesrethyl acetate) gave 0.042 g (82%) of
indole 181a as a colorless oil. 'H NMR (250MHz, CDCI3) 8 8.10 (bs, IH), 7.54 (d, J -
8.0Hz, IH), 7.26(d, J-8.0Hz, IH), 7.17 (dt,7^7.0,1.2Hz, IH), 7.10(dt,/ = 7.1,1.l
Hz, IH), 3.83 (t, 7 = in Hz, IH), 3.64 (s, 6H), 3.48 (d, 7 « 7.8 Hz, 2H), 2.76 (q, 7 = 7.3
Hz, 2H), 1.22 (t, 7 = 7.4 Hz, 3H); ' C NMR (62.5MHz, CDClj) 8 169.5, 136.4, 127.5,
126.2, 122.9, 119.8, 118.9, 117.4, 110.6, 52.6, 52.5, 30.7, 24.4, 15.3; IR (CQJ 3469,
3389, 2953, 1736 m '; MS (FAB*) 321 (M*), 190; HRMS calcd. for C,sHjoN04S (MH")
322.1113, found 322.1128.
140
2-acetylainino-2-(2-ethylsulfanyMJ7-indol*3-yliiiethyl)-iiialoiiic add dimethyl
ester 181b. Prepared according to the procedure outlined for the formation of 181a,
using 170a (0.060 g, 0.19 mmol), diethylacetamido malonate (0.041 g, 0.19 mmol), BU3P
(0.023 mL, 0.093 mmol) and acetonitrile (1.2 mL). Flash chromatography (neutralized
silica gel, 1:2 hexanes:ethyl acetate) gave 0.042 g (98%) of 181b as a pale yellow oil. 'H
NMR (250MHz, CDCI3) 8 8.15 (bs, IH), 7.44 (d, J = 7.9 Hz, IH), 7.25 (d, / = 6.5 Hz,
IH), 7.14 (dt, J = 7.5, 1.1 Hz, IH), 7.04 (dt, J = 7.5, l.l Hz, IH), 6.46 (s, IH), 4.23 (m,
4H), 3.87 (s. 2H), 2.70 (q, J - 7.3 Hz, 2H), 1.92 (s, 3H), 1.26 (t, / = 7.1 Hz. 6H), 1.15 (t,
y = 7.3 Hz, 3H); "C NMR (62.5MHz, CDCI3) 8 169.3,167.9,136.4, 128.8, 127.3,122.9,
119.7,119.0, 114.9,110.6,66.7,62.5,30.8,28.1,23.3,15.1,13.9; IR (CCI4) 3469,3413,
2982, 1740, 1664 cm '; MS (FAB*) 407 (M*), 246, 190; HRMS calcd. for CjoH^NAS
(MH") 407.1641, found 407.1631.
2-aiiiino«2-(2-ethylsulfanyMH-indol>3-yliiiethyl)-nialonic acid diethyl ester
181c. Prepared according to the procedure outlined for the formation of coupling product
181a, using 170a (0.13 g, 0.39 mmol), diethylamino malonate (0.082 g, 0.47 nunol),
BuaP (0.049mL, 0.19mmol) and acetonitrile (12.4 mL). Flash chromatography
(neutralized silica gel, 5:1 hexanes'.ethyl acetate) gave 0.14 g (96%) of 181c as a pale
yellow oil. 'H NMR (250MHz, CDCI3) 8 8.15 (bs, IH), 7.57 (d, J - 7.8 Hz, IH), 7.26 (d,
J = 7.7 Hz, IH), 7.16 (t, J = 6.9, Hz, IH), 7.06 (t, /= 7.5 Hz, IH), 4.20 (m. 4H), 3.62 (s,
2H), 2.75 (q, / s 7.3 Hz, IH), 2.03 (bs 2H), 1.24 (t, / = 7.2 Hz, 6H), 1.18 (t. / = 7.8 Hz,
3H); "C NMR (62.5MHz, CDCI3) 8 171.6, 136.5, 128.4, 127.7, 122.9, 119.7, 119.5,
114.5,110.6,66.3,61.9,30.8,30.5,15.1,13.9; ^(Caj 3377,3212,2979,2927,1741
141
cm '; MS (FAB^) 365 (NT), 729 [2M*H], 190; HRMS calcd. for C.gHjjNAS (MH*)
365.1535, found 365.1542
2-(2-ethylsulfanyl-lffMndol-3*ylmethyl)-3-oxo-butyric acid diethyl ester
181d. Prepared according to the procedure outlined for the formation of coupling
product 181a, using 170a (0.035 g, 0.11 mmol), ethyl acetoacetate (0.068 mL, 0.53
mmol), BU]P (0.014 mL, 0.053 mmol) and acetonitrile (1.0 mL). Flash chromatography
(neutralized silica gel, 10:1 hexanesrethyl acetate) gave 0.020 g (57%) of 181d as a pale
yellow oil. 'H NMR (250MHz, CDCI3) 5 8.02 (bs, IH), 7.54 (d, 7 = 8.0 Hz, IH), 7.27 (d,
/= 8.0 Hz, IH), 7.17 (dt, /= 7.5,1.2 Hz, IH), 7.09 (dt, / = 7.4,1.3 Hz, IH), 4.08 (q, 7 =
7.1 Hz, IH), 3.93 (t, J = 7.5 Hz, IH), 3.41 (d, J = 7.5 Hz, 2H), 2.76 (q, J = 7.4 Hz, 3H),
2.12 (s, 3H), 1.22 (t, / = 7.4 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H); "C NMR (62.5MHz,
CDCl3)6 203.1,169.6,136.4,127.6, 125.9,123.0, 120.0,119.1,118.0,110.6,61.4,60.2,
30.8, 29.5, 23.6, 15.3, 13.9; IR (CCI4) 3469, 3394, 2963, 1736, 1717 cm '; MS (FAB*)
319 (M*), 246,190; HRMS calcd. for CpHjiNOjS (MH*) 320.1320, found 320.1306.
2-(2*ethyisiilfanyi-Lff-indol-3-ylmethyl)-3H>xo-3-plienyl-propioiuc acid ethyl
ester 181e. Prepared according to the procedure outlined for the formation of coupling
product 181a, using 170a (0.023 g, 0.072 mmol), ethyl benzoylacetate (0.062 mL, 0.34
nmiol), BujP (0.009 mL, 0.04 mmol) and acetonitrile (1.0 mL). Flash chromatography
(neutralized silica gel, 5:1 hexanes:ethyl acetate) gave 0.009 g (33%) of 181e as a pale
yeUow oil. 'H NMR (250MHz. CDQa) 8 7.91 (m, 2H), 7.60 (d, 7.8 Hz, IH), 7.50 (m,
IH), 7.37 (m, 2H), 7.24 (m, 2H), 7.16 (dt, / = 7.3, 1.4 Hz, IH), 7.08 (dt, J = 7.4,1.3 Hz,
IH), 4.80 (t, 7=7.4 Hz, IH), 4.01 (q, J-7.1 Hz, 2H), 3.56 (m, 2H), 2.75 (q, 7= 7.4 Hz,
142
2H), 1.20 (t, J - 7.3 Hz. 3H). 1.02 (t, 7 - 7.1 Hz. 3H); "C NMR (62.5MHz, CDCI3) 8
195.1,169.6. 136.4, 136.3. 133.3. 128.6, 128.5, 127.8,125.9, 122.9, 119.8, 119.2, 118.3,
110.5,61.3,55.0, 30.8, 24.3, 15.3, 13.8; IR (CCI4) 3481, 3377,3074, 2987, 1741, 1698
cm '; MS (FAB*) 381 (M*). 307; HRMS calcd. for CJ2H23NO3S (MH*) 381.1399, found
381.1394
3-beiizylaiiiino*3*(2-ethylsiilfanyl-lH-indole-3-yl)-propionic acid ethyl ester
ISlf. Prepared according to the procedure outlined for the formation of coupling product
181a, using 170a (0.051 g. 0.16 mmol), benzaidehyde Schiff base 183 (0.036 g. 0.19
nmiol), BujP (0.020 mL, 0.079 mmol) and acetonitrile (1 mL). Following concentration
of the reaction mixture, the resulting residue was taken up in methanol (3 mL) and
acidifled to pH 4.0 using HCl (O.IM in MeOH). Sodium cyanoborohydride (0.15g,
0.24mmol) was added in two portions (0.015 g, 0.24 mmol followed by 0.010 g. 0.16
mmol) while the pH of the reaction mixture was maintained at 4.0. The reaction mixture
was concentrated and the resuhing residue was taicen up CHCI3, washed with water, dried
(MgSOJ. and concentrated. Flash chromatography (neutralized silica gel, 3:1
hexanes:ethyl acetate) gave 0.037 g (61% from 170a) of 181f as a pale yellow oil. 'H
NMR (250MHz, CDCI3) 8 7.98 (bs. IH). 7.43 (d, 7.9 Hz, 2H), 7.10 (m. 7H). 6.95 (t. J
= 6.9 Hz. IH). 3.89 (q. J = 7.1 Hz. 2H). 3.69 (d. J = 13.2 Hz, IH). 3.53 (t, / = 7.1 Hz.
IH), 3.51 (d, J = 13.1 Hz, IH), 3.12 (m, 2H), 2.60 (q. /=7.2 Hz, 2H), 1.75 (bs. IH). 1.06
(t, J = 7.4 Hz, 3H). 0.94 (t. / = 7.1 Hz, 3H); "C NMR (62.5MHz, 003) 8 175.0,139.8,
136.4, 128.3, 128.2. 128.0, 126.8, 126.4. 122.9, 119.6, 119.2, 117.6, 110.5, 61.6, 60.6,
143
52.1, 30.9, 29.4, 15.3,14.0; IR (CCIJ 3474, 3360, 3034, 2982, 1731 cm '; MS (FAB*)
383 (MO, 190; HRMS calcd. forCzjH^NAS (MHO 383.1793, found 383.1799.
3-(beiizhydryUdene-aiiiino)-3*(2-ethylsiilfanyl>l^>indol-3-yl)-propionic acid
ethyl ester 181g Prepared according to the procedure outlined for the formation of
coupling product 181a, using 170a (0.25 g, 0.77 mmol), benzophenone Schiff base 184
(0.62 g, 2.3 mmol), BujP (0.097 mL, 0.39 mmol) and acetonitrile (4.8 mL). Flash
chromatography (neutralized silica gel, 20:1 hexanes:ethyl acetate) gave 0.28 g (80%) of
181g as a pale yellow oil. 'H NMR (250MHz, CDClj) 8 7.84 (bs, IH), 7.42 (d, 7= 6.7
Hz, 2H), 7.12 (m, 6H), 6.99 (m, IH), 6.78 (dt, J « 7.0,0.9 Hz, IH), 6.37 (d, J = 7.1 Hz,
2H), 4.32 (dd, J = 9.1,4.8 Hz, IH), 4.04 (m, 2H), 3.43 (dd, J = 13.9,4.7 Hz, IH), 3.33
(dd,y= 13.9,9.0Hz, IH),2.48(m,2H), 1.10(t,/ = 7.1 Hz,3H),0.96(t,y = 7.3Hz,3H);
"C NMR (62.5MHz, CDCI3) 8 172.1, 170.3, 139.4, 136.1, 135.9, 130.0, 128.9, 128.3,
128.2, 128.0, 127.9, 127.8, 127.6, 126.4, 122.7, 119.5, 119.4, 118.0, 110.2, 66.1,60.9,
30.9, 28.9, 15.2, 14.1; IR (CCI4) 3469, 3370, 3057, 2967, 1735 cm '; MS (FABO 457
(MO, 395,267,190; HRMS calcd. for CjgHjsNAS (MHO 457.1950, found 457.1939.
2-ethylsuiranyl-3^thylsulfanylinethyl-lA-indole 182. 'H NMR (500MHz,
CDCI3) 8 7.99 (bs, IH), 7.71 (d, 7 = 8.0 Hz, IH), 7.29 (d, J = 8.1 Hz, IH), 7.20 (dt, J =
7.6, 1.1 Hz, IH), 7.12 (dt, J s 7.5,1.0 Hz, IH), 4.05 (s, 2H), 2.79 (q, / = 7.3 Hz, 2H),
2.49 (q, J = 7.4 Hz, 2H), 1.27 (t, /= 7.4 Hz, 3H), 1.23 (t, / = 7.4 Hz, 3H); ' C NMR (125
MHz, CDClj) 8 136.5, 127.4, 126.3, 123.2, 119.8, 118.5, 110.6, 31.2, 26.0, 25.8, 15.4,
14.7; IR (CCI4) 3481, 3412, 2979 cm '; MS (FABO 251 (MO, 190; HRMS calcd. for
CijHigNSz (MHO 251.0802, found 251.0796.
144
2-ettiylsuiranyl>3>styryMJ7-indole 188. A solution of 170a (0.03S g. O.ll
mmol), benzaldehyde (0.033 mL, 0.33 mmol), BU3P (0.030 mL, 0.12 mmol) and
acetonitrile (1 mL) was heated to reflux. After 8h, the reaction mixture was cooled and
concentrated. Flash chromatography (neutralized silica gel, 10:1 hexanes:ethyl acetate)
gave 0.015 g (49%) of styrene 188 as a pale yellow oil. 'H NMR (250MHz, CDCI3) 8
7.89 (bs, IH), 7.78 (d, J = 7.4 Hz, IH), 7.30 (m, 2H), 7.07 (m, 4H), 6.97 (m, 4H), 2.56 (q,
J = 7.3 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H); ''C NMR (62.5MHz, CDClj) 5 138.7, 136.7,
128.6, 128.5, 127.1, 126.8, 126.0, 125.9, 123.4, 121.9, 120.7, 120.4, 119.5, 110.9, 31.2,
15.4; TR (CCI4) 3469, 3408,3057, 3034,2972,2924 cm '; MS (FAB*) 279 (M*); HRMS
calcd. for C.gHnNS (MH*) 279.1082, found 279.1080.
2-ethylsulfanybiiethyl-2-phenylsiilfanyl-Uf-indole 198. To a solution of 197
(0.58 g, 1.4 mmol) and acetonitrile (9.0 mL) was added EtSH (1.0 mL, 14 mmol), KF
(0.12 g, 2.1 mmol), and 18-crown-6 (0.55 g, 2.1 mmol). After being heated to reflux for
7h the mixture was concentrated. Flash chromatography (neutralized silica gel, 20:1
hexanes:ethyl acetate) provided 0.37 g (88%) of 198 as a pale yellow oil. 'H NMR (500
MHz, CDCI3) 5 8.06 (s, IH), 7.84 (m, IH), 7.13-7.34 (m, 8H), 4.10 (d, / s 4.5 Hz, 2H),
2.49 (m, 2H), 1.26 (m, 3H); "C NMR (125 MHz, CDCI3) 8 226.0, 137.1, 136.6, 129.2,
127.2,127.1,126.1,123.8,123.1,120.1,120.0,111.0,25.8,25.7,14.6; ^(CCU) 3481,
3420, 3039, 2979, 2927 cm '; HRMS calc'd for C^HnNSj (M*) 299.0802, found
299.0800.
3-(2-ethylsttlfanyl-li7-indol>3-yliiiethylsiilfanyl)-propioiiic acid methyl ester
196. To a solution of 182 (0.033 g, 0.13 mmol) and acetonitrile (12 mL) was added
145
methyl mercaptopropionate (0.043 mL, 0.33 mmol), KF (0.0083 g, 0.14 mmol), andl8-C-
6 (0.038 g, 0.014 mmol). A Dean Stark trap was used and the reaction mixture was
refluxed for 3h and concentrated. Flash chromatography (neutralized silica gel, 5:1
hexanesrethyl acetate) gave 0.039 g (97%) of 196 as a yellow oil. 'H NMR (5(X) MHz,
CDCI3) 8 8.03 (s, IH), 7.70 (d, J - 7.9 Hz, IH), 7.29 (d, / = 8.1 Hz, IH), 7.20 (t, J = 7.6
Hz, IH), 7.12 (t, /= 7.5 Hz, IH), 4.05 (s, 2H), 3.65 (s, 3H), 2.78 (q, / = 7.3 Hz, 2H), 2.71
(t, J = 7.3 Hz, 2H), 2.63 (t, J = 7.3 Hz, 2H), 1.23 (t, 7 = 7.3 Hz, 3H); "C NMR (125
MHz, CDCI3) 8172.5, 136.6, 127.2, 126.6, 123.3, 119.9, 119.6, 117.8, 110.7,51.7,34.7,
31.2, 26.5, 26.3, 15.4; IR (CCIJ 3472, 3377, 2936, 1750 cm '; HRMS calc'd for
C,jH„NSA (M*) 309.0857, found 309.0854.
(2-eUiylsulfiBnyMi7-indol-3*yl)<acetoiiitrile 199. A solution of 170a (0.030 g,
0.093 mmol), finely powdered KCN (0.060 g, 0.93 mmol), and aqueous DMF (l.OmL)
was heated with an oil bath (50°C) overnight. The reaction mixture was poured into HjO
(10 mL), extracted with CH2CI2 (3 x 10 mL). The combined organic layers were dried
(Na2S04) and concentrated. Flash chromatography (neutralized silica gel, 3:1
hexanes:ethyl acetate) gave 0.008 g (40%) of 199 as a pale yellow oil. 'H NMR
(250MHz, CDCl^) 8 8.21 (bs, IH), 7.66 (d, / = 8.2 Hz, IH), 7.34 (d, J=7.5 Hz, IH), 7.26
(dt, J = 6.9,1.2 Hz, IH), 7.19 (dt, J = 7.4,1.4 Hz, IH), 3.94 (s, 2H), 2.79 (q, / = 7.3 Hz,
2H), 1.23 (t, 7 = 7.3 Hz, 3H); "C NMR (62.5MHz, CDCI3) 8 136.3,126.8,126.6,123.8,
120.7, 118.6, 117.9, Ul.O, 110.7, 31.1, 15.4,13.8; IR (CCI4) 3469, 3346, 2967, 2252
cm '; MS (FAB^) 217 (M*), 185; HRMS calcd. for C^HoNiS (MHO 217.0799, found
217.795.
146
(2<«diylsulfanyl-Ur*iiidol>3-ylmethyl)-dimethyl-aiiiine 200. Dimethyl amine
(large excess) was bubbled through a refluxing solution of 170a (0.15 g, 0.46 mmol), KF
(0.030 g, 0.52 mmol), 18-C-6 (0.061 g, 0.23 nunol) and acetonitrile (3.0 mL) for l.5h.
The reaction mixture was concentrated and flash chromatography (silica gel, 1:2
hexanesrethyl acetate) gave 0.10 g (93%) of 200 as an offwhite solid, m.p. 97-99°C. 'H
NMR (250MHz, CDClj) 8 8.15 (s, IH), 7.70 (d, J = 7.8 Hz, IH), 7.26 (d, J - 8.0 Hz,
IH), 7.16 (dt, J = 7.5, 1.1 Hz, IH), 7.07 (dt, J = 8.0, 1.1 Hz, IH), 2.75 (q, J = 7.3 Hz,
2H), 2.24 (s, 6H); "C NMR (62.5MHz, CDCI3) 8 136.3, 128.5, 127.1, 122.8, 119.9,
118.7, 110.4, 53.9, 45.4, 30.9, 15.3; IR (CCI4) 3481, 2970, 2936, 2832, 2771 cm ';
HRMS calcd. for C.jH.jNiS (MH*) 235.1269, found 235.1273.
2-[(2*ethylsulfanyl-lH-indol>3-yl)-(trimethyl-silanyl)*methyl]-nialonic acid
dimethyl ester 201. A solution of 170a (0.042 g, 0.13 mmol), dimethyl malonate (0.018
mL, 0.16 nrniol), 40% by weight KF/alumina (0.038 g, 0.26 mmol) and acetonitrile (1.5
mL) was refluxed. In 6h intervals, additional KF/alumina (0.050 g, 0.34 mmol) was
added twice. After 18h reflux total, the mixture was Altered (CH2CI2) and concentrated.
Flash chromatography (neutral alumina, 10:1 hexanes:ethyl acetate) gave 0.019 g (37%)
of 201 as a colorless oil. 'H NMR (250MHz, CDCI3) 8 8.02 (s, IH), 7.50 (d, / = 7.5 Hz,
IH), 7.23 (d, J = 8.0Hz, IH), 7.13 (t, 7«7.4 Hz, IH), 7.03 (t, J-7.0 Hz, IH), 4.37 (d, J
= 12.4 Hz, IH), 3.78 (s, 3H), 3.67 (d, /= 12.6 Hz, IH), 3.27 (s, 3H), 2.88 (m, 2H), 1.28
(t, 7 = 7.1 Hz, 3H), -0.03 (s, 9H); "C NMR (62.5MHz, CDCI3) 8 169.7, 169.4, 136.5,
126.6, 125.7,122.4, 120.8, 119.9, 119.1, 110.6, 53.0, 52.6, 52.0, 30.6, 27.4, 15.5; IR
147
(CCU 3481, 3402, 3100, 3039, 2962, 1745, 1741 cm '; MS (FAB*) calcd. for
C„HMNSiS04, found (M*) 294.5.
Representative procedure for tiie formation of spirocyclic tiiioiniidates.. 2'-
ethyl-2'etiiylsulfanyl*spfro[indole-3,3'«pyrrolidine]-5',5'*dicarboxylic acid diethyl
ester 246a. A solution of 181c (0.18 g, 0.49 mmol), propionaldehyde (0.10 mL, 1.4
mmol), 4A molecular sieves (0.14 g), and dichloromethane (5.0 mL) was stirred
overnight at rt and concentrated. The sieves were filtered off and washed scrupulously
with dichloromethane. Chromatography (neutral alununa, 5:1 hexanes:ethyl acetate)
gave 0.17 g (86%) of a 5:1 diastereomeric mixture of spirocyclic thioimidates 246a. 'H
NMR (250MHz, CDClj) 8 7.44 (d, J = 7.6 Hz, IH), 7.32 (m, 2H), 7.08 (q, / = 7.8 Hz,
IH), 4.29 (m, 4H), 3.47 (m, IH), 3.23 (m, 3H), 2.88 (dd, /s 35.4,15.0 Hz, 2H), 2.84 (dd,
/= 64.4, 14.6 Hz, 2H), 1.22-1.43 (m, 8H), 1.06 (m, IH), 0.87 (m, IH), 0.66 (m, 3H); "C
NMR (62.5MHz, CDCI3) 8 184.9,183.4,171.9,171.8,170.0,169.4, 154.8, 154.7,141.6,
140.6,128.2,127.9,124.3,124.0, 123.6,121.4,118.6,118.3,71.5,70.9,70.0,69.3,67.7,
67.2,62.3,62.2,62.1,43.5,42.8, 25.7, 25.2, 23.3, 22.1, 14.1, 14.1, 14.0,11.9, 11.0; IR
(CCI4) 2970, 2936,2884, 1750 cm '; MS (FAB*) 405 (M*), 365, 331, 190; HRMS calcd.
for C21H29N2SO4 (M*) 405.1848, found 405.1859.
2-ethylsulfanyl-2'-niethyl>spiro[indole<3 ''Pyrroiidine]-5',S'-dicarboxylic
acid diethyl ester 246b. Prepared according to the procedure outlined for the formation
of 246b using amine 181c (0.036 g, 0.097 mmol), 4A molecular sieves (0.050 g),
dichloromethane (l.OmL), and acetaldehyde (0.027 mL, 0.49 mmol). The reaction
mixture was stined for 3h at rt, using a reflux condenser to prevent loss of aldehyde.
148
Flash chromatography (neutral alumina, S:1 hexanes:ethyl acetate) gave 0.031 g (80%) of
spirocyclic thioimidate 241a as a mixture of inseparable diastereomers (2:1). 'H NMR
(250MHz, CDClj) 5 7.42 (t, / = 7.9 Hz, IH), 7.29 (m, 2H), 7.09 (m, IH), 4.30 (m, 4H),
3.62 (m, IH), 3.23 (m, IH), 3.07 (d, /= 14.7 Hz, IH), 2.75 (d, 7 = 15.0 Hz, IH), 2.68 (d,
J = 14.6 Hz, IH), 1.43-1.19 (m, 9H), 0.85 (d, / = 6.4 Hz, IH), 0.57 (d, J = 6.2 Hz, 3H);
' C NMR (62.5MHz, CDClj) 6 184.4, 182.7, 171.6, 171.5, 170.1, 169.5, 154.7, 141.1,
140.1,128.3, 128.0, 124.3, 124.0,123.3, 121.4, 118.3,71.9, 71.4,68.6,68.2,63.9,63.6,
62.4,62.3,62.1,43.1,42.7,25.6,25.2,14.2, 14.1,14.0, 13.8, 13.2, l.O; IR (CCI4) 3342,
3316, 2970, 1741 cm '; MS (FAB*) 391 (M*), 365, 190; HRMS calcd. for CjoHrN204S
(MH*) 391.1692, found 391.1697.
2-ethyisulfanyI>2'-phenyl-spiro[indole*3^'-pyrrolidine]>5'^'-dicarboxylic
acid diethyl ester 246c. Prepared according to the procedure outlined for the formation
of 246a using 181c (0.090 g, 0.25 mmoi), 4A molecular sieves (0.16 g), dichloromethane
(2.5 mL), and benzaldehyde (0.037 mL, 0.37 mmol). The reaction mixnire was refluxed
for two days and concentrated. Flash chromatography (neutral alumina, 5:1
hexanes:ethyl acetate) gave 0.058 g (52%) of spirocyclic thioimidates 246c as a mixture
of inseparable diastereomers (3:1). 'H NMR (250MHz, CDCI3) 5 7.44 (d, / = 7.1 Hz,
2H), 7.28 (s, IH), 6.94-7.14 (m, 18H), 4.82 (d, J = 4.5 Hz, 2H), 4.34 (m, lOH), 3.33 (m,
5H), 3.00 (m, 5H), 1.47 (t, J = 7.4 Hz, 5H), 1.30 (m, 17H), 1.90 (t, J = 7.3 Hz, 3H); "C
NMR (62.5MHz, CDQj) 8 184.6,181.4,172.1,171.9,169.6,169.3,155.1,154.1,141.2,
140.5,135.9,135.0,128.5,128.3,127.7,127.4,126.3,125.8,124.3,123.6,121.6, 118.3,
118.0,70.7,70.1,69.9,68.1,67.9,62.4,62.1,42.0,41.8,25.4,25.3,14.3,14.1,13.8,1.0;
149
IR (CCI4) 3342, 3065, 3031, 2979, 2927, 1745 cm '; MS (FAB*) 453 (M*), 190; HRMS
calcd. for C25H29N2O4S (MH") 453.1848, found 453.1831.
l'beiizyl-2-ethylsulfanyl-spiro[indole-3^'*pyrrolidine]-S'*dicarboxylic acid
diethyl ester 250. A solution of benzhydrylamine 181f (0.024 g, 0.063 mmol),
paraformaldehyde (0.006 g, 0.20 mmol), Na2S04 (0.088 g, 0.62 mmol) and acetonitrile (I
mL) was refluxed for Ih and concentrated. Flash chromatography (neutralized silica gel,
5:1 hexanes:ethyl acetate) gave 0.(X)78 g (31%) of 250 as a colorless oil. 'H NMR
(250MHz, CDCI3) 8 7.69 (d, J = 6.9 Hz, IH), 7.38 (m, 3H), 7.46 (m, 4H), 7.11 (t, / = 7.5
Hz, IH), 4.71 (m, 3H), 4.08 (d, / = 13.1 Hz, IH), 3.72 (dd, J = 9.3,6.1 Hz, IH), 3.61 (d,
y = 13.1 Hz, IH), 3.23 (q, J = 7.5 Hz, 2H), 3.07 (d, J = 9.3 Hz, IH), 2.76 (d, J = 9.3 Hz,
IH), 2.62 (m, 2H), 2.25 (dd, J - 13.7, 6.1 Hz, IH), 1.40 (t, J = 7.4 Hz, 3H), 1.28 (t, J -
7.0 Hz, 3H); ' 'C NMR (62.5MHz, CDCI3)
185.5,173.0,154.0,144.0,138.2,128.8,128.2,127.9,127.1,124.5,122.6, 118.1,64.5,6
2.2, 61.6, 60.8, 57.1, 40.2, 25.2,; l«BMS4.fcalc'd. for C23H27N2OS (M+)
295.1793, found 295.1797.
2''ethyl<2-ethylsulfanyl-l'-trifluoroacetyl«spiro[indole-3^''pyTroiidiiie>
S'^'^dicariioxylic acid diethyl ester 248. To a cooled solution of 246a (0.11 g, 0.28
mmol), pyridine (0.068 mL, 0.84 mmol) and CHjCl; (2.1 mL) was added trifluoroacetic
anhydride (0.087 mL, 0.62 mmol). The reaction mixture was stirred overnight at rt and
concentrated. Flash chromatography (neutral alumina, 10:1 hexanes:ethyl acetate) gave
0.033 g (23%) of248 as a colorless oil. 'H NMR (250MHz, CDQ,) 8 7.42 (d, J = 7.7 Hz,
IH), 7.32 (m, IH), 7.26 (m, IH), 7.10 (t, / = 7.5 Hz, IH), 4.36 (m, 2H), 4.28 (m, 3H),
150
3.25 (m, 2H). 3.10 ((!./= 14.5, IH), 2.95 (d, / = 14.5, IH), 1.90 (s, IH), 1.70 (s, IH),
1.40 (t, J = 7.5 Hz, 3H), 1.31 (m, 6H), 0.23 (t, J = 7.2 Hz. 3H); NMR (62.5 MHz,
CDCI3) 185.5, 168.5, 166.6,154.9,137.5,129.2,124.3,123.8,119.1,73.9,67.7,65.9,63.
1, 63.0, 27.8, 25.7, 14.0, IQ.JIRMS calc'd. for CjHaNiOjSFj (M*) 501.1671, found
501.1670.
2'*ethyU2*oxo-l''trifluoroacetyl-l^-dihydro>spiro[indole-33'-pyrroiidine]'
5'^'«dicarboxylic acid diethyl ester 249. A solution of spiro thioimidate 248 (0.015 g,
0.030 mmol), silver nitrate (0.025 g, 0.14 mmol) and (9:1) /BuOH-HjO (1.5 mL) was
stirred at rt for 5h. Additional silver nitrate (0.025 g, 0.14 mmol) was added. After 17h
stirring at rt, the reaction mixture was filtered (ethyl acetate), washed with brine, dried
(NajSOJ and concentrated. Flash chromatography (neutralized silica gel, 3:1
hexanes;ethyl acetate) gave 0.0045 g (32%) of 249 as a colorless oil. 'H NMR (250 MHz,
CDCI3) 8 7.48 (s, IH), 7.27 (m, 2H), 7.04 (t, J = 7.6 Hz, IH), 6.87 (d, J = 7.7 Hz, IH),
4.30 (m, 5H), 3.17 (d, J = 13.2 Hz, IH), 2.89 (d, J = 13.7 Hz, IH), 1.80 (m, 2H), 1.29 (m,
6H), 0.52 (m, 3H); NMR (62.5 MHz, CDCI3) 8 178.9, 168.7, 166.5, 140.8, 130.0,
125.7, 122.7, 117.2, 115.0, 110.0, 73.4, 67.4, 63.0, 29.7, 13.8, 10.9; LRMS calcd for
Q,H„N205F3(M+H*) 457.1.
3-(2*ethyisulfanyl*l£Mndol-3-yliiietiiyl)-l,4*dioxoH)ctahydro-pyrroio[l^]-
pyrazine>3-carboxyUc acid ethyl ester 256. A solution of 170a (0.28 g, 0.87 nunol),
255 (0.20 g, 0.088 nmiol), KF (0.056 g, 0.96 mmol), 18-C-6 (0.25 g, 0.95 mmol) and
acetonitrile (5.5 mL) was lefluxed for 2h. At intervals of Ih, additional KF (0.030 g, 0.52
mmol) and 18-C-6 (0.10 g, 0.38 mmol) were added. After tefluxing 5h total, the reaction
151
mixture was concentrated. Flash chromatography (neutralized silica gel, 1:2
hexanes:ethyl acetate) gave 0.30 g (83%) of 256 as a 2:1 mixture of diastereomers. 'H
NMR (250 MHz, CDClj) 8 9.33 (s, 2H), 8.88 (s, IH), 7.46 (d, J = 7.8 Hz, 3H), 7.22 (m,
3H), 7.04 (dt, / = 7.4, l.l Hz, 3H), 6.93 (t, J = 6.9 Hz, 3H), 6.71 (s, 2H), 6.23 (s, IH),
4.22 (m, 2H), 3.99 (m, 6H), 3.85 (d, /= 14.5 Hz, 2H). 3.53 (m, 6H), 3.40 (d, /= 14.5 Hz,
2H), 2.90 (m, 2H), 2.60 (m, 6H), 2.34 (m, 4H), 1.54-1.98 (m, 9H), 1.23 (t, / = 7.1 Hz,
6H), 1.03 (m, 12H); "C NMR (62.5 MHz, CDCI3) 8 170.3, 168.5, 168.0, 167.9, 162.5,
162.3,136.8,136.4,129.2, 128.2, 127.7,127.4, 123.0,119.8, 119.1, 113.0,112.8, 111.0,
110.7, 69.0, 67.0, 63.0, 59.1, 57.8, 46.2, 45.4, 32.9, 30.8, 30.2, 29.3, 28.8, 28.6, 22.5,
21.2, 15.0,14.9, 13.9, 13.7; IR (CCI4) 3455, 3377, 3282, 3057,2988, 2936, 1750, 1689
cm'; HRMS calc'd for C2,Hj6N304S (M") 416.1644, found 416.1631.
2-diazo^(lJ7-indol-3>yliiiethylsulfanyl)-3-oxo-pentanoic add ethyl ester 260.
To a solution of gramine methosuifate 261 (0.060 g, 0.21 mmol) and acetonitrile (1.0
mL) at 0°C was added K2CO3 (0.029g, 0.21 mmol) and Bu4NBr (0.068 g, 0.21 mmol.)
followed by thiol 262 (0.046 g, 0.21 mmol) and acetonitrile (2.0 mL). The yellow
mixture was allowed to warm to room temperature over 7 h and then poured into
HjO/EtjO (1:1,50 mL). The aqueous phase was extracted with EtjO (2 x 25 mL), dried
(Na2S04), and concentrated. Flash chromatography (neutralized silica gel, 3:1 hexanes:
ethyl acetate) provided 0.070g (100%) of 260 as a colorless oil. 'H NMR (250 MHz,
CDCI3) 8 8.05 (s, IH), 7.71 (dd, /= 7.7,0.55 Hz, IH), 7.33 (d,/= 7.7 Hz, IH), 7.15 (m,
3H), 4.27 (q, J ^ 7.1 Hz, 2H), 3.96 (s, 2H). 3.13 (t, / = 7.2 Hz, 2H), 2.74 (t, J = 7.1 Hz.
2H), 1.30(t,/-7.1 Hz,3H); "CNMR(62.5MHz,CDCl,)8 191.1,161.2,136.4,126.7,
152
123.0, 122.3, 119.2, 112.1, 111.2, 61.5, 40.0, 27.0, 25.7, 14.3; IR (CCIJ 3412, 3048,
2979, 2148, 1733, 1664 cm '; HRMS calc'd for C.sHnNjOjS (M^) 331.0991, found
331.0999.
2-(lA*indol-3«ylniethyl)-3H>xo-tetrahydro-thiophene-2-carboxylic acid ethyl
ester 70. A solution of thioether 260 (0.035 g, 0.11 mmol), Rh2(OAc)4 (0.0023 g, 0.0052
nunol), and benzene (2.0 mL) was heated to reflux. After 5b the reaction mixture was
concentrated. Flash chromatography (neutralized silica gel, 2:1 hexanes:ethyl acetate)
gave 0.023 g (70% yield) of270 as a colorless oil. 'H NMR (250 MHz, CDCI3) 5 8.05 (s,
IH), 7.65 (d, / = 7.0 Hz, IH), 7.31 (dd, J = 6.9, 1.8 Hz, IH), 7.14 (m, 2H), 7.04 (d, J =
2.4 Hz, IH), 4.22 (m, 2H), 3.53 (q, 7 = 15.1 Hz, 2H), 3.00 (ddd, J = 10.9, 8.8, 7.0 Hz,
IH), 2.73 (ddd, J = 17.7, 7.0, 3.2 Hz, IH), 2.56 (ddd, J = 17.7, 7.0, 3.2 Hz, IH), 2.25
(ddd, J - 17.6,8.7,8.7 Hz, IH), 1.27 (t, 7 = 7.1 Hz, 3H); "C NMR (62.5 MHz, CDCI3)
210.6, 170.8, 135.6, 128.3, 124.5, 122.0, 119.5, 119.5, 110.9, 109.9, 64.0,62.1,40.
2, 28.3, 23.9, ; l«0(CCl4) 3481, 3420, 2979, 1759 cm '; HRMS calc'd for
CigHigNOjS (M") 303.0929, found 303.0931.
3*ethylsiilfanyliiMthyl-lir-indole 174. To an ice-cooled solution of gramine (4.0
g, 23.0 mmol), EtSH (8.50 mL, 115 mmol) and MeOH (46 mL) was added dimethyl
sulfate (2.2 mL, 23 mmol). The reaction mixture was refluxed for 6h and poured into
ice-cold H20. The mixture was extracted using EtjO (3 x 50 mL). The combined
organic layers were washed successively with 10% HCl(aq) (100 mL), HjO (lOOmL),
NaHC03(aq) (100 mL); dried (MgSOJ; Hltered and concentrated. Flash chromatography
(neutralized silica gel, 3:1 hexanes:ethyl acetate) gave 2.5 g (57%) of 174 as an off-white
153
solid. in.p. 45-47T. 'H NMR (250 MHz, CDCIj) 8 7.94 (s, IH), 7.77 (d, J - 7.8 Hz,
IH), 7.33 (d, / = 8.1 Hz, IH), 7.18 (t, / = 7.4 Hz, IH), 7.06 (s, IH), 3.98 (s, 2H), 2.52 (q,
J - 7.3 Hz, 2H), 1.29 (t, J = 7.4 Hz, 3H); "C NMR (62.5 MHz, CDCI3) 8136.3, 126.7,
122.7, 122.1, 119.5, 119.1, 112.4, 111.1, 26.3,25.4, 14.4; IR (CCI4) 3489, 3420, 2074,
2970,2936, cm'; HRMS calc'd for C„H,3NS (M^) 191.0769, found 191.0766.
2-(3*ethylsiilfanyliiiethyMJ7-ind0l-7-yl)-3'0X0-butyric acid ethyl ester 276.
Rh2(OAc)4 (0.0046 g, 0.010 mmol) and 275 (0.039 g, 0.25 mmol) were added to a
solution of 3-ethylsulfanylmethyl-l^-indole (0.040 g, 0.021 mmol) and benzene (5.0
mL). The mixture was heated to reflux over 3h and then concentrated. Flash
chromatography (neutralized silica gel, 5:1 hexanes.ethyl acetate) provided 0.0080 g
(12%) of C-7 insertion product 276 as a pale yellow oil. 'H NMR (250 MHz, CDCI3) 8
12.70 (s, IH), 7.72 (d, J = 7.0 Hz, IH), 7.17 (dt, / = 7.7, 1.5 Hz, IH), 7.08 (dt, / = 7.8,
1.3 Hz, IH), 6.86 (s, IH), 4.13 (m, 2H), 2.44 (q, /=7.4 Hz, 2H), 1.74 (s, 3H), 1.22 (t, J =
7.4 Hz. 3H), 1.08 (t, / = 7.1 Hz, 3H); "C NMR (62.5 MHz, CDCI3) 8 176.3, 170.8,
138.1,128.2, 127.2, 122.5,119.8,119.4,112.7,109.9,103.7,61.2,26.2,25.2,17.7,14.5,
14.1; IR (CCI4) 2979, 2927, 1655, 1620 cm '; HRMS calc'd for CnHi.NOjS (M^)
319.1242, found 319.1239.
2-ethylsiilfanylmethyM-methyl-indole 278. To a cooled solution of EtSH
(0.055 mL, 0.74 mmol) and CH3OH (3.85 mL) was added Na(s) (0.017 g, 0.74 mmol)
followed by a solution of 1-methylgramine (0.12 g, 0.64 nrniol) and CH3OH (1 mL). The
resulting mixture was then heated to reflux for 12 h. The mixture then poured into HjO,
extracted with EtjO (4 x 20 mL), dried (MgS04), and concentrated. Flash
154
chromatography (neutralized silica gel, 10:1 hexanes:ethyl acetate) provided 0.017g
(13%) of 278 as a colorless oil. 'H NMR (250 MHz, CDCI3) 8 7.69 (d, /= 7.9 Hz, IH),
7.27 (d, 7 = 7.8 Hz, IH), 7.21 (dt, /= 8.1,1.2 Hz, IH), 7.11 (dt,7= 7.3,1.3 Hz, IH), 6.97
(s, IH), 3.93 (s, 2H), 3.74 (s, 3H), 2.48 (q, 7 = 7.4 Hz, 2H),1.24 (t, 7 = 7.4 Hz, 3H); "C
NMR (62.5 MHz, CDCI3) 8 137.2,127.5,127.4,121.8, 119.3, 119.0, 111.1, 109.2,32.7,
26.7, 25.6, 14.5; IR (CCI4) 3048, 2970, 2936, cm '; HRMS calc'd for C.jH.jNS (M*)
205.0925, found 205.0928.
2*ethylsulfanyliiiethyl-l*(toluene-4*sulfonyl)-indole 281. To a mixture of 3-
[(ethylthio)methyl1-lH-indole (0.13 g, 0.68 mmol), BU4NHSO4 (0.023 g, 0.068 mmol),
0.7 mL of 50% KOH(aq.), and benzene (2.7 mL) was added TsCl (0.13 g, 0.68 mmol).
The mixture was stirred vigorously for Ih and then poured into H2O (15 mL). The
aqueous phase was extracted with CH^CI^ (3 x 30 mL). The organic extracts were dried
(K2CO3) and concentrated. Flash chromatography (neutralized silica gel, 3:1
hexanes:ethyl acetate) provided 0.23 g (98%) of 281 as an off white solid, mp 72-73°C;
'H NMR (250 MHz, CDCI3) 8 7.97 (d, 7 = 8.6 Hz, IH), 7.73 (d, 7=8.3 Hz, 2H), 7.60 (d,
7 = 7.8, IH), 7.45 (s, IH), 7.25 (m, 4H), 3.78 (s, 2H), 2.35 (q, 7 = 7.4 Hz, 2H), 2.30 (s,
3H),1.19 (t, 7 = 7.3 Hz, 3H); "C NMR (62.5 MHz, CDCI3) 8 144.9,135.5,135.0,130.0,
129.8, 126.7, 124.9, 124.1,123.2, 120.0, 119.3, 113.8,25.7,25.3,21.5, 14.2; IR(CCl4)
2979, 2927, 1378, 1188 cm '; HRMS calc'd for QgHisNOjSi (M*) 345.0857, found
345.0853.
2-ethylsiilfanyl-2-(l-methyl-indol>3-yliiiethyl)*3M>xo-butyric acid diethyl ester
280. A solution of 278 (0.017 g, 0.083 mmol), 275 (0.026 g, 0.17 nunol), and
155
Rh2(OAc)4 (0.0037 g, 0.0084 mmol) and benzene (1.7 mL) was heated to reflux. An
additional 0.026 g of 275 (0.17 mmol) was added after Ih and the mixture was heated to
reflux for an additional Ih. Following concentration, flash chromatography (neutralized
silica gel, 3:1 hexanes:ethyl acetate) provided 0.016 g (58%) of280 as an off white solid,
mp 64-66X; 'H NMR (250 MHz, CDClj) 8 7.53 (d, / = 7.9 Hz, IH), 7.24 (d, J = 7.9 Hz,
IH), 7.16 (dt, J = 7.3, 1.1 Hz, IH), 7.06 (dt, J = 7.9, 1.2 Hz, IH), 7.06 (s, IH), 3.98 (m,
2H), 3.72 (s, 3H), 3.61 (d, 15.6 Hz, IH), 3.38 (d, 7= 15.5 Hz, IH), 2.43 (m, 2H), 2.30
(s, 3H), 1.21 (t, / = 7.5 Hz, 3H). 1.05 (t, / = 7.1 Hz, 3H); ' C NMR (62.5 MHz,
CDClj) 8199.5, 169.3,136.3,128.5,128.3,121.4,118.8,118.7, 109.1,107.4,68.3,62.1,
32.8, 27.7, 26.1, 23.2, 13.7, 13.5; IR (CCI4) 2979, 2936, 1715 cm '; HRMS calc'd for
CijHaNOjS (M^) 333.1399, found 333.1402.
2-ethylsiilfanyl-3*oxo-2-[l-toluene<4'Sulfonyl)'indol-3-ylniethyl]-butyricacid
ethyl ester 283. To a solution of 281 (0.037 g, 0.11 mmol), Rh2(OAc)4 (0.0041,0.0093
mmol), and benzene (2.2 mL) at reflux was slowly added a solution was 275 (0.044 g,
0.28 mmol) and benzene (1.0 mL) over 45 min. An additional 0.030 g (0.19 mmol) of
275 and benzene (1 mL) was added via syringe pump to the refluxing solution over 45
min. Concentration of the reaction mixture and flash chromatography (neutralized silica
gel, 3:1 hexanes:ethyl acetate) yielded 0.026 g (50%) of 283 as a colorless oil. 'H NMR
(250 MHz, CDCI3) 5 7.61 (d, / = 8.0 Hz, IH), 7.34 (d, J = 8.3 Hz, 2H), 7.19 (m, 2H),
7.12 (d, / = 6.6 Hz, IH), 7.02 (m, 3H), 5.49 (s, IH), 5.27 (d, / «1.5 Hz, IH), 5.07 (d, J s
1.0 Hz, IH), 3.47 (m, 2H), 2.84 (m, IH), 2.32 (s, 3H), 2.28 (s, 3H), 2.17 (m, IH), 1.24 (t,
/ = 7.4 Hz, 3H), 0.93 (t, / = 7.2 Hz, 3H); "C NMR (62.5 MHz, CDQj) 8197.7,166.6,
156
143.9, 141.7, 133.8, 132.7, 129.3, 129.2, 127.6, 125.9, 120.6, 120.0, 110.3, 71.8, 66.1,
62.3,27.7,24.3,21.5,13.4,12.8; IRCCCIJ 2988,2927, 1733,1707 cm'; HRMS calc'd
forQ^HaNOjSi (M^) 474.1409, found 474.1393.
2-{3-[2-(beiizhydrylidene-aiiiino)-2-eUtoxycarbonyl<«thyl]-lff-indol-2>yl}-2-
eUiylsulfanyN3-oxo*butyric add ethyl ester 290. A solution of Schiff base 181g (0.053
g, 0.12 ramol), diazo compound 275 (0.027 g, 0.17 mmol), Rh2(OAc)4 (0.0026 g, 0.0059
mmol) and benzene (2.6 mL) was refluxed for 7h and concentrated. Flash
chromatography (neutralized silica gel, 3:1 hexanesiethyl acetate) gave 0.028 g (40%) of
290 as 2:1 mixture of diastereomers. 'H NMR (250 MHz, CDClj) 8 11.10 (s, 3H), 7.49
(m, 6H), 7.26 (m, 27H), 6.98 (m, 6H), 6.17 (d, / = 6.6 Hz, 3H), 4.47 (t, J = 6.7 Hz, 2H),
4.33 (m, 4H), 4.21 (m, 13H), 4.06 (q, J = 7.2 Hz, 2H), 3.72 (m, 6H), 3.30 (dd, J = 14.2,
7.1 Hz, IH), 3.00 (m, 3H), 2.52 (s, 6H), 2.50 (s, 3H), 1.24 (m, 18H), 1.07 (t, J - lA Hz,
3H), 0.97 (t, / = 7.4 Hz, 6H); ' C NMR (62.5 MHz, CDClj) 8 194.0, 171.2, 166.5, 139.2,
138.9,137.1,135.2,130.4,128.9,128.7,128.5,128.2, 127.9, 127.8, 127.0, 126.1, 125.5,
125.2, 121.7, 121.2, 120.7, 120.3, 120.0, 119.6, 112.2, 66.0,61.2,61.0,59.6,59.5, 36.9,
36.7, 29.6, 28.3, 27.9, 14.7, 14.6, 14.2, 9.7; IR (CCU) 3256, 3057, 2979, 2926, 1741,
1680 cm '; HRMS calc'd for C34H37N2O5S (M*) 585.2423, found 585.2432.
2-acetylaiiiino-2-[2*(l-ethoxycarbonyM*ethylsiilfanyl-2*oxo-propyl)-li7-
indol>3-yliiiethyl]-nialoiiic acid diethyl ester 289. A solution of acetamide 181b (0.050
g, 0.12 mmol), diazo compound 275 (0.020 g, 0.13 mmol), Rh2(OAc)4 (0.0027 g, 0.0061
mmol) and benzene (2,5 mL) was refluxed for 12h and concentrated. Flash
chromatography (neutralized silica gel, 1:2 hexanes:ethyl acetate) gave 0.030 g (47%) of
157
289 as a pale yellow oil. 'H NMR (250 MHz. CDCI3) 8 11.28 (s, 3H), 7.57 (d, / = 8.1 Hz,
IH), 7.35 (d, J = 8.2 Hz, IH), 111 (m, IH), 7.10 (rn, IH), 6.93 (s, IH), 4.49 (m, IH),
4.01-4.32 (m, 9H), 3.99 (s, 3H), 3.26 (m, IH), 2.45 (s, 3H), 1.01-1.35 (m, 12 H); "C
NMR (62.5 MHz, CDClj) 6 193.6,169.6,168.1,166.9,137.2,127.3,125.5, 122.5,120.6,
120.4, 116.8,112.4,66.4,62.6,62.5,59.9,37.0,29.7,28.2,22.9,14.6, 13.9,13.8,9.9; IR
(CCI4) 3420, 3290, 2988, 2944, 1741, 1681 cm '; HRMS calc'd for CjgHajNiOgS (M*)
535.2114, found 535.2103.
2-(3*ethylsulfanyliiiethyM£r-indol-2-yl)>3-oxo-2*phenyisulfanyl-butyric acid
ethyl ester 284. A solution of 198 (0.10 g, 0.33 mmol), Rh2(OAc)4 (0.0077 g, 0.017
mmol), 275 (0.072 mL, 0.52 nunol), and benzene (6.9 mL) was heated to reflux for 5h.
Concentration of the reaction mixture and flash chromatography (neutralized silica gel,
5:1 hexanes:ethyl acetate) provided 0.067 g (47%) of 284 as a viscous yellow oil. 'H
NMR (250 MHz, CDCI3) 5 10.94 (s, IH), 7.67 (d, 7 = 8.1 Hz, IH), 7.20 (m, 5H), 7.08
(m, 3H), 4.08 (m, 4H), 2.38 (m, 5H), 1.19 (t, / = 7.1 Hz, 3H), 1.08 (t, J s 7.4 Hz, 3H);
"C NMR (62.5 MHz. CDQj) 5 192.5, 166.7, 137.5, 131.0,129.6, 126.1, 125.7, 125.5,
123.6, 120.8, 120.5, 118.7, 112.8, 59.9, 29.7, 26.3, 25.1, 14.7, 14.4; IR (CCI4) 3238,
2988, 2936, 1741, 1689 cm '; HRMS calc'd for CjaHjeNOjSi (M*) 428.1354, found
428.1357.
2-[2-(l-iiietlioxycarbonyl-2-oxo-l-phenylsulfanyl-propyl)-li7-indol-3-
ylmethyll-maloiiic acid dimethyl ester 285. A solution of 284 (0.030 g, 0.070 mmol),
dimethyl malonate (0.016 mL, 0.14 nrniol), KF (0.0020 g, 0.034 mmol), 18-crown-6
(0.0092 g, 0.035 mmol), and acetonitrile (1.5 mL) was heated to reflux. After 2h,
158
additional KF (0.0020 g, 0.034 mmol) and 18-crown-6 (0.0092 g, 0.035 mmol), were
added. The reaction was allowed to proceed for 10 additional hours. Concentration of
the reaction mixture and flash chromatography (neutralized silica gel, 3:1 hexanes:ethyl
acetate) provided 0.012 g (34%) of 285 as a viscous yellow solid. 'H NMR (250 MHz,
CDCI3) 8 11.09 (s, IH), 7.67 (d, / = 8.1 Hz, IH), 7.37 (m, 4H), 7.21 (m, 4H), 4.23 (m,
2H), 3.91 (dd, J = 9.2,6.1 Hz, IH), 3.76 (partially obscured m, I H), 3.69 (s, 3H), 3.68
(m, 1 H), 3.60 (dd, J = 14.5, 6.0 Hz, I H), 3.46 (s, 3H), 2.49 (s, 3H), 1.32 (t, J = 7.1 Hz,
3H); "C NMR (62.5 MHz, CDCI3) 5 168.9, 168.8, 137.5, 131.1, 130.2, 129.6, 126.0,
125.7, 125.6, 122.3, 120.8, 120.1, 118.9, 112.9, 59.9, 52.8, 52.6, 29.6, 23.8, 14.6; IR
(CCU 3238, 3091, 3039,, 2953, 1751, 1750, 1689 cm '; HRMS calc'd forCMHMN07S
(M*) 498.1586, found 498.1579.
Representative Procedure for tiie Intermolecular Rhodium-Catalyzed SulAir
Ylide Reaction with 181a. 2-[2-(l-ethoxycarbonyM-ethylsulfanyl*2-oxo-propyl)>lH-
indol-3-ybnethyl]-nialonic acid dimethyl ester 291. To a solution of 181a (0.032 g,
O.IO mmol), Rh2(OAc)4 (0.0041 g, 0.0093 mmol), and benzene (2.0 mL) was added a
solution of 275 (0.051 g, 0.33 nunol) and benzene (1.0 mL) over 45 min. Concentration
of the reaction mixture and flash chromatography (neutralized silica gel, 1:2
hexanesrethyl acetate) yielded 0.028 g (61%) of 291 as a pale yellow oil. 'H NMR (250
MHz, CDQj) 6 11.22 (s, IH), 7.59 (d, /= 8.1 Hz, IH), 7.37 (d, / = 8.2 Hz, IH), 7.29 (t,
/= 7.6, Hz, IH), 7.13 (t, / = 7.5 Hz, IH), 4.17 (m, 4H), 3.89 (dd, /= 10.2,5.2 Hz, IH),
3.73 (s, 3H), 3.73-3.53 (m, 3H), 3.57 (s, 3H), 3.45 (dd, /= 14.5, 5.3 Hz), 2.50 (s, 3H),
1.28 (t, J - 7.3 Hz, 3H); "C NMR (62.5 MHz, CDCI3) 8 193.9, 169.1, 169.0, 166.7,
159
137.2,125.5, 125.4, 121.5, 120.6, 119.8,119.1, 112.6,59.7, 52.8, 52.5,52.2, 37.0,29.6,
23.8,14.6,10.0; IR (CCI4) 3282,3014,2962,1741, 1745, 1689 cm '; HRMS calc'd for
CjjHmNOtS (M*) 450.1586, found 450.1589.
2*[3-(2^*diethoxycarbonyl-ethyl)-l£r-indoK2-yl]-2*ethylsiilfanyl-maloiiicacid
dimethyl ester 292. As described for the synthesis of 291, indole 181a (0.074 g, 0.23
mmol), 288 (0.085 g, 0.54 mmol), Rh2(OAc)4 (0.0070 g, 0.016 ramol) and benzene (2.0
mL) were used. Flash chromatography (neutralized silica gel, 1:5 hexanesiethyl acetate)
provided 0.098 g (94%) of 292 as a colorless oil. 'H NMR (250 MHz, CDCI3) 8 10.88
(s, IH), 7.61 (d, J = 8.0 Hz, IH), 7.34 (d, J = 8.3 Hz, IH), 7.31 (t, J = 7.6, Hz, IH), 7.15
(t, J = 7.3 Hz, IH), 4.08 (m, IH), 3.90 (dd, /= 10.3, 5.0 Hz, IH), 3.75 (s, 3H), 3.74 (s,
6H), 3.75-3.41 (m, 4 H), 3.56 (s, 3H), 1.30 (t, J - 7.4 Hz, 3H); "C NMR (62.5 MHz,
CDCl3)8 169.1,169.0, 137.3, 125.7,125.4,121.9, 120.8, 120.0,119.1,112.5,60.3,52.9,
52.6, 52.1, 51.4, 38.0, 23.8, 9.8; IR (CCI4) 3230, 2979, 2962, 1755, 1750, 1689 cm ';
HRMS calc'd for QtHajNOgS (M*) 452.1379, found 452.1379.
Representative Procedure for the Conjugate Addition of Indole 181a to Vinyl
Diazo Compounds. 2-[3-(3-butoxycarbonyl-allyl)-2-ethylsulfanyl>3ff-indol-3*
ylmethyll-malonic acid dimethyl ester 294b. To a solution of 181a (0.019 g, 0.059
mmol), Rh2(OAc)4 (0.0023 g, 0.0052 mmol) and benzene (1.2 mL) at reflux was added
293b (0.040 g, 0.24 nmiol) and benzene (1.0 mL) over 45 min. Concentration and flash
chromatography (neutralized silica gel, 2:1 hexanes:ethyl acetate) provided 0.024 g
(88%) of 294a as a pale yellow oil. 'H NMR (250 MHz, CDCI3) 8 7.43 (d, J = 7.7 Hz,
IH), 7.26 (m, IH), 7.09 (m, 2H), 6.14 (ddd, IH), 5.64 (dd, /= 15.4,1.0 Hz, IH), 3.63 (s.
160
3H), 3.16 (s, 3H), 3.11-3.88 (m, 2H), 2.73 (m, 3H), 2.48 (m, 2H), 1.40 (partially obscured
t, / = 7.4 Hz, 3H), 1.36 (s, 9H); "C NMR (62.5 MHz, CDClj) 8 183.2, 169.3, 169.0,
165.0,155.4, 140.0,138.3,128.7,126.8, 124.0,123.2, 118.9,80.2,61.4,52.7,52.3,47.4,
41.2, 35.2, 28.0, 25.1, 14.3; IR (CCU 3100, 3039, 2988, 2953, 1759, 1755.0, 1724.0
cm'; HRMS calc'd for C24H32NOjS (MH*) 462.1950, found 462.1953.
2>[3.(3^tiioxycarbonyM-iiiethyl*allyl)>2-ethylsulfanyl«3£fMndol-3-yliiiethyl]-
malonic acid dimethyl ester 294a. As described for the synthesis of 294b, indole 181a
(0.042 g, 0.13 mmol), Rh2(OAc)4 (0.0039 g, 0.0088 mmol), 293a (0.080 g, 0.52 nunol)
and benzene (2.6 mL) were used. Flash chromatography (neutralized silica gel, 2:1
hexanes:ethyl acetate) provided 0.054 g (93%) of thioimidate 294a as a colorless oil. 'H
NMR (250 MHz, CDClj) 6 7.42 (t, J = 6.7 Hz, 3H), 7.27 (m, 3H), 7.06 (m, 7H), 6.41
(dd, J = 15.5,9.3 Hz, IH), 5.93 (d, J = 15.6 Hz, 2H), 5.80 (d, J = 15.6 Hz, IH), 4.21 (q, J
= 7.1 Hz, 4H), 4.09 (q, 7 = 7.1 Hz, 2H), 3.62 (s, 12H), 3.26 (m, 6H), 3.14 (s, 4H), 3.10 (s,
6H), 2.74 (m, lOH), 2.36 (ra, 2H), 1.42 (t, / = 7.4 Hz, 6H), 1.36 (t, / = 7.6 Hz, 3H), 1.31
(t, / = 7.1 Hz, 6H), 1.20 (t, J = 7.1 Hz, 3H), 1.02 (d, J - 6.8 Hz, 3H), 0.49 (d, J = 6.7 Hz,
6H); "C NMR (62.5 MHz, CDClj) 8 183.5, 183.2, 169.4, 169.2, 169.1, 166.0, 165.9,
156.1,155.8,147.4,147.1, 137.5, 136.4, 128.8, 128.7, 124.5, 123.9, 123.8, 123.7, 123.1,
118.9, 118.8, 64.8, 60.5, 60.2, 52.7, 52.3, 52.2, 47.6,47.5, 44.4, 44.3, 34.6, 33.9, 25.3,
25.1, 14.7, 14.2, 14.1,13.9; DKCCU 3100, 3039, 2953,2927,1759,1755, 1724 cm-';
HRMS calc'd for CaHjjN OgS (M*) 447.1716, found 447.1713.
4-[3*(2^-diiiiethoxycarbonyl«ethyl)*2-ethylsulfanyl«3H-indoI-3-yl]-pent-2-
enedioic acid diethyl ester 2iMc. As described for the synthesis of 294b, indole 181a
(0.041 g, 0.13 mmol), Rh2(OAc)4 (0.0046 g, O.OlO mmol), 293c (0.11 g, 0.52 mmol), and
benzene (2.5 mL) were used. Flash chromatography (neutralized silica gel, 2:1
hexanesrethyl acetate) provided 0.053 g (82%) of thioimidate 294c as a colorless oil.
Thioimidate 294c proved to be somewhat unstable to chromatographic purification. 'H
NMR (250 MHz, CDCI3) 8; 7.41 (t, J = 7.2 Hz, 3H), 7.31-7.01 (m, 7H), 6.33 (dd, J =
15.5, 9.9 Hz, IH), 6.02 (d, J « 15.6 Hz, 2H), 5.86 (d, J = 15.7 Hz, IH), 4.14 (m, 12H),
3.76 (m, 6H), 3.58 (m, lOH), 3.33 (m, 6H), 3.14 (s, 3H), 3.13 (s, 3H), 2.71 (m, 6H), 2.31
(dd, J ~ 13.8,1.8 Hz, 2H), 1.29 (m, 18H), 0.86 (t, J - 7.1 Hz, 6H), 0.78 (t, J - 7.1 Hz,
3H); ' C NMR (62.5 MHz, CDCI3) 8 182.3, 181.4, 170.7, 169.1, 169.0, 168.8, 167.8,
165.2,165.1,155.8,155.7,139.6,139.1,136.3,135.6, 134.7,129.2, 129.1, 127.2,126.0,
125.4, 124.5,123.9, 123.4, 119.0, 118.9, 118.7,63.9,63.2,62.6,61.6,61.1, 61.0,60.8,
60.6,60.4,56.0,55.1,52.8,52.7,52.3,47.3,47.0,46.8,35.1,34.1,34.0,33.4,25.5,25.3,
14.2,14.1,14.0,13.5; IR (CCI4) 3091,3039,2988,2962,1750,1655 cm '; HRMS calc'd
for CjjHaNOgS (M*) 506.1849, found 506.1857.
162
APPENDIX 1
PERMISSIONS
Portions of this dissertation were reprinted with permission from:
(1) "An Isonitrile-alkyne cascade to di-substituted indoles," by Jon D. Rainier,
Abigail R. Kennedy and Eric Chase published in Tetrahedron Letters 1999,40,
6325-6327. Copyright 1999, Elsevier Science Ltd.
(1) "Cascades to Substituted Indoles," by Jon D. Rainier and Abigail R. Kennedy
published in the Journal of Organic Chemistry 2000,65, 6213-6216. Copyright
2000, American Chemical Society.
(1) "The Use of Sulfur Ylides in the Synthesis of Substituted Indoles," by Abigail R.
Kennedy, Michael H. Taday and Jon D. Rainier, submitted to Organic Letters,
2001.
APPENDIX 2
SPECTRA
NHCHO 154
'HNMR.250MHZ CDCI,
a
9.0 7 , 0 5 . 0 3 . 0 6 . 0 4 l 0 0 . 0 1 . 0 PPM
OC' 154
"CNMR,62.S MHz CDCI,
4.
""I I I I I I I I 180 160 140 120 100 80 60 40 20
PPM
Tue Sep 15. 1998 ARK21.SS.101
CC' "NHCHO
154 iR.ca,
v*.-
4000 3500 3000 2500
JMS
NHCHO
155a H NMR.2S0MHZ
coa.
9 ,0 S.O 4 .0 2 . 0 0 . 0 PPM
NHCHO
ISSa
"CNMR, 62.5 MHz CDCI,
mirn i-iL
r" IBO 160 140 120 100
PPM
llMhMMVaMNIMVNMMaMi
60 40 20 0
ON oo
90 i^49«.|$)^{!lN2237
85
80 '
75 .
70-
6S
60 .
55-
50-
45
40
35
30
25
20
15 lS5a : IR.CCl
10
5
0
' V\
^TMS
'NHCHO
4000 3S00 3000 2S00 2000 1500 1000 Wavenurobcrs (cm-l)
NHCHO
15Sb H NMR.250MHZ
CDCK
I I W a
I I I i I I 9.0 8.0 7.0 6.0 S.O 4.0 3.0 2,0 1.0 0.0
PPM
NHCHO
155b "CNMR.623MHZ
CDQ,
i
I-180
"T" 160
"T" 140 120
"I I I" 100 BO 60
PPM
Frl Sep 18,1998 ARK2162.101 90
80-
75-
70-
65
60 •
55
50-
45
40
35 -
30-
•NHCHO 25
20 15Sb IR.CCI,
10
4000 3500 3000 2500 2000
^avei^bers (cm-1)
1500 1000 500
I-Bu
NHCHO
9.0 a .o 7.0 6.0 s .o 3.0 1.0 0 .0 PPM
fBu
NHCHO
ISSc "CNMR, 62.5 MHz
CDQ,
liU
I'" IBO 160 140
"T" 120 100 80 60 40
PPM
r-Bu
NHCHO
155c iR.ca«
4000 3S00
Ph
NHCHO
ISSd HNMR,2S0MHz
CDQ,
D
8 . 0 3 .0 9 .0 7 ,0 6.0 5 .0 4 .0 2 . 0 1 .0 0 . 0 PPM
Ph
NHCHO 15Sd
"CNMR.62.5 MHz CDQ,
J u
180 160 140 120 100 80 PPM
60 40 20
M P
95-
90
85
SO
TS -
70-
65 -
60
55
50
45
40-
35
30-
25
20
15
10
3
0
1/8/99, KENN2226.I01
'\y y-^J
NHCHO
lS5d IR.CX3,
4000 3500 3000
( f ( f
"V
2500 2000 1500 1000 Wavenumbers (cm-1)
NHCHO
]S5e 'HNMR.2S0MHZ
CDCIj
rCJu
/
1 )L . * '
OBn
NMCHO
ISSe "CNMR, 62.5 MHz
CDOj
1 IBO 160
"•I 140 120
I 11
'"I I I I I 100 80 60 40 ao 0 qS
PPM O
100 1/19/99, KRNN2233 105
90
80
65
6 0 -
40
•OBn
25 NHCHO
lS5e IR. ca.
15-
10
0 -
4000 3500 3000 2500 2000 Wavemimbcrs (cm-l)
1500 1000 SOO
TMS
NC
150a 'HNMR.2S0MHZ
coa.
J
> I I I ^ 9.0 B.O 7 ,0 6 .0 S.O 4.0 3 .0 8 .0 1.0 0 ,0
ppH S; NJ
150a "CNMR.62.S MHz
coa.
180 160 140 120 100 PPM
"I I I r 60 40 20 0
00 u>
^^0, 1998 ARK21S6 105
iR.ca,
.TMS
V,. v1
!
4000 3500 3000 2500 2000
Wavenumbef (cm-l)
NC
150b 'HNMR.2S0MHZ
CDCI,
i 1
' " " I' 9 .0 a .o
• I • 7 .0 6 . 0
00 Ul
NC
ISOb "CNMR.62.S MHz
CDa,
liMltil
V" IBD 160
rrrj^
140 120 too PPH
"I I" 40 20 80
I 60
00 as
95
90
85
BO-
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
Sep 30 ,1998 ARK2172.101
\ - . - -
nBu
150b IR-CCU
4000 3500
NC
150c 'HNMR,2S0MHz
CDO,
9.0 B.O 7.0 6 . 0 5.0 4.0 2 .0 0.0 PPM
ISOc
"CNMR,62.5 MHx CDCI,
JU ILi
IBO """T" 160
"T 140 120 100
PPM 80
r 60 40 20
M 0
% vO
2500 2000
Wavenumbers (cm-1)
1500 1000 500
,Ph
ISOd 'H NMR, 250 MHz
CDCI,
B . O 6 . 0 2 . 0 0.0 5 . 0 4 . 0 3 . 0 9 . 0
Ph
NC
ISOd "CNMR,62.S MHz
CDCI,
180 160 140 120 100 PPM
"T 80 60
""T" 40 20
1/19/99, KENN2228.10I
iR. ca.
4000 3500
OBn
NC
150e H NMR. 250 MHz
CDCI,
9 . 0 8.0 7 . 0 2 .0 6.0 5 . 0 4 . 0 3 . 0 1.0 PPM
I50e
"CNMR.62.5 MHz CDCI,
>#<•
I I" IBO
"I" 140 120
"T 100 PPM
BO 60 I"
40 ao
100 95
90
85
80
75
70
65
60
55
50
45
40
35
30
25 ^
20 -
15 -
10^
5
0
-5-1
1/21/99, KENN223S.103
ISOe iR.ca,
4000 3500 SOO 2000 Wavcnuinbcrs (cm-l)
NC
isor 'HNMR,2S0MHz
CDQ,
• I • I I I I 9.0 8,0 7.0 6,0 5.0
PPM
r
JL il
I I • 4.0 3.0
• I • 2 .0 1 . 0
I 0.0
SO -J
NC
isor "CNMR.62.5 MHz
CDCI,
1 m
"T 160
"tt" 140
"T" ISO 100
PPM 40
"I 20 IBO 60
"I" 60
75 1
70
65
60
55
50
45
40
35
30
25 -
20
15
10
5
0
4000
IR. CCL
3500
nBu
N
lS2b 'H NMR, 250 MHz
CDCI,
•yMM
"T" 6.0
I " " • " 5 . 0
O0M • • I • 4 . 0 »o
,riBu
152b "CNMR,62.S MHz
CDCI,
KENN22S9.QUiN 3/17/99 ^ y'
fiBu
LI :i :J i"
lS2b IR,CCI«
I* S
4000 3S00 3000 2S00 2000 1500 1000 Wavcnumbcfs (cm-1)
N SnBu*
152c 'HNMR,500MHz
CDOa
JLJUL
• t • 9.0 •.S
• I • S.0
• I • 6.3
• < -
60 S.S 5.0 • I • <S
—I— 4J>
• I • 3.J
—r- 3.0
• I • 2.}
• t • 2.0
-T— I.S
• I • 1.0 ».s 7.5 7.0 0.S 00
N> o Uti
fBu
lS2c "CNMR, 125 MHz
CDCI,
170 160 l» "I" 90
"T" •0
~T" 60
—r* so
"T" 30
-"T— 20
-r' 10 100 70
to 2
M ^SnBua
152c iR. ca.
4000 3300 3000 2300 2000
Wavenumbcrs (cm-1)
'IDQD zfflVOSZ'HI^N Hi
PZSl
Ph
152d *>CNMR.62.S MHi
CDCI,
"I •""I I I I • IBO 160 140 lao 100
PPM
Am
20 80 60 rrrpr, 40
§
1/19/99, KfiNN2229.QUIN
152d IR. CCI,
4000 3S00 3000
I
2300 2000 Wavcnumbcrs (cm-1
ISOO 1000
I52e >H NMR. 250 MHz
coa,
OBn
IS2e »*CNMR,62.5 MHz
CDCI,
•'X" 180
"I I" 160 140 BO 60 40 20
ro o
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
4
KENN2283 103 3/18/99
w y
; Mi 1 , 1 1
11
*N'
152e IR.CCI,
OBn
0 3500 3000 2500 2000 Wavcmimbers (cm-l)
1500 1000 500
-TMS
157a H NMR, 2S0 MHz
CDa,
a . o 9.0 6.0 5.0 2 .0 3 .0 4 .0 PPM
N> {3
-TMS
157a "CNMR,62.S MHz
CDCI,
lao 100 BO PPM
160 140 120
4
60 40 20 0
to u>
90. KENN2272.I05 3/5/99
85 -
•TMS
20
157a •R. CCI.
3500 3000 2500 2000 Wavcminibcrs (cm-l)
500
OS « n-penlyl
157b 'H NMR. 250 MHz
CDCI,
K> d
B
'•penlyl
lS7b *'CNMR.62.S MHz
CDQ,
JLi
180 160 140 120 100 PPM
r *
"I BO 60
nrrj
40 20 N»
f \
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lS7b
IR. CC|«
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4000 3500 3(H)0 2.100 2000 Wavcnumbers (cm-1)
157c 'HNMR.250MHZ
CX)Cl3
/
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9.0 8.0 7.0 6.0 9,0 4.0 3.0 2.'o ' ' ' ' ' ' ' ' ' ' • • ^ f f M 5S
(XT' « 157c
"CNMR.62.SMHz CDOj
JLJL
180 160 •"I" 140
""I"" 120
"•I 100
PPM
"T 80 60
"T" 40
"T" 20 to
3
no -
30 -
0 _
4000 3S00 3000 2500 2000
Waveimmbcrs ro-1}
1500 1000 500
IS7«I 'HNMR,2S0MHz
CDCI,
]57d "CNMR,62.S MHz
CDCI,
180 160 140 120 100 PPM
60 40 20
N> to fo
1/22/99, KENKI223(5.J04 •\'\l
K lS7d IR. CCI,
4000 3300 3000 2S00 2000 Wavcnuinbers (cm-1)
,OBn
I57e H NMR,250MHz
CDCI,
•T 9.0
• I • 8 .0 7.0
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Jd
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N)
225
M X S
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ox oa ^a.
Mi •' I
I 11 2500 2000 1500
Wavcnumbers (cm-l)
SEt
170a 'HNMR,2S0MHz
CDCI3
jA Wi
J
3.0 ^-pr-2>0 ».0 0.0
10 Ni -J
-TMS
SEt
170a ''CNMR.62.SMHz
CDCI3
180 160 140 120 100 PPM
JU. pM.
80 60 20 40 r 0 to N)
00
KENNaOIO.IOI 4/29199
70 -
65 -
60 -
50
35 -
-TMS
170a JR.CCI,
10 -
4000 3500 3000 2500 2000 Wavcnumbers (cm-1)
1500 1000 500
SBu -TMS
SBu
170b 'H NMR.250MHZ
CDCIJ
/
1. A A
Bu -TMS
SBu
170b "CNMR.623MHZ
CDa,
JiU
V f V f f f f r f • ! * « * * * • • * * • * * | f V « * « * • • • ! a v v v v v f > * 1 1 * * 180 160 140 120 100 BO 60
PPM
% T r a n s m i I I a n c e
90
85
80
75
70
65 ^
60
55 T
50 -
45
40 ^
35
30 --
25
20
IS
10
5 -
0 -
4000
170b IR. CCI,
3500 3000 2500 2000
Waveinwnbcrs (cm-l)
iPh -TMS
170c
'HNMR.250MHZ CDCI3
y\.
L
9.0 8.0 7.0 6.0
J
5.0 4.0 PPM
-ry-.-3.0
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ro c>>
SPh -TMS
SPh
170c "CNMR, 62.5 MHz
CDCI3
mm «
I"' IBO
rTT|T»l
160 140 120
mmfi
•"I 100
PPM
"X" 80
"T 0
10 u> •p. 60 40 20
2SOO 2000
Wavenumbers (cm-1)
170d H NMR.2S0MHZ
CDQ,
B.O 7.0 6.0 S.O 4.0 3.0 2.0 0.0 PPM
-TMS
I70il "CNMR,62.5MHi
CiXlb
1 11 L
'"I I I I I I I I I I' 180 160 140 120 100 80 60 40 20 0
PPM
% T r a n s in i I I a II c e
80
75 -]
70
65
60
55
50 :
45 -
40
35 -
30
25 r
20 •
15 ;
10 :
5 ;
0 -!
4000
ir ij
H'
170(1 IR, CCI,
TMS
3500 3000 "T T
2500 2000
Wavenurobers (cm-l) K> u> 00
iTBS
OTBS
170e 'HNMR,250MHz
CDCI,
k Aa^Jl _/v I .JJl L
J
"T 9.0
"T 8.0
'I 7.0 6.0 9.0 4.0
PPM 3.0 2.0 1.0 0.0 to u>
NO
)TBS
-TMS
OTBS
170e
"CNMR, 62.5 MHz CDCIj
Ul jjj.
TTTjrrT IBO
I 160
"T" 140 120 100
PPH BO 60 40 20
90 ~
85
80 -•
75
70 -f
65 4
% 60 -T z. r 55 ~ a n 50 -s -
III 45 1 -
t 40 1 a 35 -n -
c 30 -c -
25
20
15
10
5 4
0 -
4000
Got »
170e iR.ca4
TMS
' S^TBS
3S00 3000 2S00 2000 Wavcnumbcrs (cm-1)
'B'
-TMS
i7or 'HNMR.250IVfHz
CDCI,
kiL k1
9t0 8 .0 7 .0 6 .0 S.O^^^ 4 .0 3 .0 2 .0 t .O 0 .0
-TMS
I70f "CNMR, 125 MHz
CDCU
WW
~T— 140
•T" 120
-I" 170
• I"" ISO
" " I "
IM I''
190 " I " IW 60 20 100 110
% T r a n s m i I I a n c e
~9o
85 :
80 -
75 4
70 4
65
60
55 -
30
45 -
40
35
30 ^
25
20
15
10 -=]
5 •
0 -
4000
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\n r 170f IR, CCI4
•TMS
3500 3000 I
2500 2000
Wavemimbers (cm-i)
—r-1500
SEt
181a 'HNMR.250MHZ
CDQa
9 . 0 B . O 7 . 0 6.0 • • I • • 5 . 0
PPM
I • ' 4 . 0 3 . 0
r^r-|
2 . 0 1 .0 0 . 0 L/>
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181a
"CNMR, 62.5 MHi CDQa
leo "T 160 140
"T™ 120
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PPM 80
J 11, 11
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80 y'
75
70-
6 0 -
55
50-
30
25-
20
181a IR, ca<
15-
4000 3500 3000
./
2500 2000 1500 iooo 500 Wavcnumbers (cm-l)
AcHN C02Et
SEt
181b *H NMR,2S0MHz
CDCIj
JLjw__jL X
""T-9,0 7.0
' I ' e.o
-r-p-6.0 S.o
PPM 4.0
J
3.0 2.0 1.0 ~ 0.0
AcHN
SEt
181b
' CNMR. 62.5 MHz CDCI3
UL
IBO 160 140 120 '"•I 100
PPM 00
"T" 60 40 20 VO
6/23/99. KENN3043
70
AcHI
SEI
181b IR, ca.
4000 3S00 3000 2S00 2000 Wavcmimbcri (cp-l)
ISOO 1000 300 K) Ln O
181c 'HNMR.2S0MHZ
coa.
s J-
JUit
-T 9.0
• I • 8.0
•—T" 7.0
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PPM
-COaEt
'Vi ^SEI
181c
"CNMR, 62.5 MHz CDQs
I 1 1 I 180 160 140 120 100
PPM
Ji An
60 40 "T" 20
T 0
to Ul to
1 ' 2300 2000
Wavenumbers (cm-l)
hJ L/l
-SEt
181d 'HNMR.2S0MHZ
CDQ,
9 0 B . O 7 . 0 6 . 0 5 . 0 4 . 0 3 . 0 2 . 0 1 . 0 0 . 0 PPM
i(0)Ma
SEt
181d •^CNMR, 62.5 MHz
CDQ,
i'"
lao T
•WMMii •WMMM*
20 T 0 100
PPM 60 60
I 40 ro
6/23/99, K»iN3077
C(0)Me
181d IR, CCI4
4000 3 3000 iOO 2000 Waveaumbera (cm-l)
,C(0)PH
^C02Et
^SEt
181e 'HNMR,2S0MHZ
CDQ,
9 .0 a .o
Uul I , ,
4 . 0 3 . 0 2 . 0 1 , 0 0 . 0
181e "CNMR, 62.5 MHz
CDCI,
»»i)i»iii'i>#iiwiiiiiiiiw ILpi
'"I"" I I I'" lao 160 140 120
"I I I I 100 80 60 40 20 K> PPM S5
MO)Ph
Q--jI CO,E,
181c iR-ca,
4000 3500 3000 2500 2000
Wavenumbers (cm-1)
to vO
NHBn
SEt
i8ir HNMR,2S0MHz
CDCIa
9.0 8.0 7.0 6.0 S.O 4.0 3.0 2.0 0.0 PPH
NHBn
SEt
181f
''CNMR,62^MHz CDCI3
leo TTTJTTT, 160 120 100
PPM
'"I"" 140
J
"T 80
T' 60
"I 40 20
T 0
6/24/99,1 1079.102
75
70 -
60-
50
45
40
30 -
SEt
500 4000 3500 3000 2500 2000 Wavenumbcrs (cin-1)
1500 1000
263
I8lg "CNMR, 62.5 MHz
CDQa
i li A mim i
180 "'I'" 160
•"I"' 140
r 120 100
PPM 80 60
-rrjT^ 40
I 20
N> 2
H
8S
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
K^3«JJ^7/6/99
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181g IB,CCI,
4000 3500 3000 2500 2000 Wavcnumbcrs (cin-1)
266
182 "CNMR, 125 MHz
CDOj
J uJJl
•I I I I \ 1 1 1 1 1 1 1 1'" 190 180 170 160 150 140 130 120 110 100 90 80 70
"n I I I I 60 50 40 30 20 PPm to
OS -J
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182 IR. CCI,
4000 3500 2500 2000
Wavcraimbcfs (cm-l) ISOO 1000 500
to o 00
SEt
'HNMR.2S0MHZ coa.
'I 9.0 e .o 7.0 6.0 s.o 4
PPM
• I ' 3.0 2.0
I 1.0 0.0
K> VO
188 "CNMR, 125Mlfa
CDCb
-» , , , - - , , , , , , 1 - - , 190 lao 170 160 190 140 190 120 110 100 90 80 70 60 90 40 90 20 pfn 10
6/2^m{| NN3076. 103
188 IR. ca.
4000 3500 2500 2000 Wavenumbers (cm-l)
196 'H NMR, SOO MHz
CDCI,
/
JUL jUl
9.9 9.0 •r-ry
I4> 7.5 —T 7.0
•"T' 6.S 6j0
-T 5.5 5.0 4
• f • 4.0 3.5
'nr— 3i> 2.5
• I • 2 0 1.5 1.0
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N» -J ro
co
196 "CNMR, 125 MHz
CDCI,
190 l«0 170 160 150 140 130 ••I"" 120 110 100 90 70 60 SO 40 30 20 10 pfM
lO U>
% T r a n s m i • I a n c e
65
BO
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
0
4000
IR.CCI,
CQjMa
3500 3000 2500 2000
Wavenumbers (cm-1)
275
198 ''CNMR, 125 Mm
COCI,
190 lU 170 l«0 ISO 140 130 120 110 100 W 80 70 60 M 40 30 20 IV* 10
% T r a n s in i I I a n c e
85
8 0 :
75 -•
70
65
60 -
55
50 '
''s :
40 ^
35 5
30 -
25
20
'5 T
10 -3
5
/ /
CnC SEI
4000
198 IR, CCI,
3500 3000 2500 2000
Wavenumbers (cm-1)
199 'HNMR.250MHZ
CXKZI,
9 . 0 8.0 7 . 0 4 . 0 6.0 5 ; 0 3 . 0 2 . 0 1 . 0 0.0 PPM
199 "CNMR.62.SMHz
CDOj
»•* JLJL
180 160 "T" 140 120
«MMNn
•"I 100
PPM 60 60
"T^ AO
rrryr, 20
"T 0
vO
* T r a n s m i I I a n c e
80
75
70
65
60
55
SO
45
40
35
30
2S
20
15 {
10 ~
5 -
KENN 3032.101
>-4000
5/17/99
199 iR.CCl4
3500 3000 2S00 2000
Wavenumbcra (cm-1)
ISOO 1000 500
N> oo o
200 'H NMR, 250 MHz
CDQ,
J
-T-r-4.0
-,-pr-3.0 2.0
' I ' 1.0 0 . 0
K> 00
200 "CNMR.62.S MHz
CDCI,
.Ji
"'I I I "I I'" IBO 160 140 120 100 60 40 SO
to oo ro
% T r a n s in
85
80
75
70
65
60
55 -
50
45
40 -
35
30 -
25
20
15
10
5
4000
R 200 IR. CCI«
'• "\,.r •'VJ" yv'VY
NMej
SEt
3500 3000 I ' I •
2500 2000
Wavenumbers (cm-l)
1500 1000 500
TMI
SEt
201 *H NMR,2S0MHz
CDCI,
'" " I' 9 . 0 8.0 7 . 0
AJIA J
n
' • I • " o n
K> A n
' • I • • n
SEI
201 "CNMR,62.5 MHz
CDCI,
.jjul i L Ji L
"I" teo 160 140 120 100 80 60
M 40 20 Iv)
00 Ut
COgMe
2SOO 2000
Wavenuinbers (cm-l)
246a IHNMR,2S0MHz
CBa,
9 . 0 r-T-pr-,
e . o 7 . 0 • • I " 6.0
I 5 . 0
PPM
K> 00 -J 4 . 0 3 . 0 2 , 0 1 .0 0 . 0
EI04CL ,1 cCOaEl
NH
'- SEI
246a
"CNMR,62.SMHz CDQ,
m W fNMWV J i •* 1 •••i I I I I 1 I I I" IBO 160 140 120 100 80 60 40 20
PPM
T* 0
T VA
EtOjC CO2EI
246a IR, ca.
4000 3S00 3000 -r T"
2500 2000
Wavenumbcfs (cm-l)
KJ 00 NO
lOaCL .P ..Wt
NH
Cd 246b
*H NMR.250MHZ CDOa
it
' I I I 9.0 8.0 7.0 6.0 S.O
PPM
J L
4.0 "T' 3.0
' I I ' 2.0 1.0 0.0
fOdEt
m
cx? Me
246b "CNMR, 62.5 MHz
CDCI3
pll m ,1. ll|iM|«|!#liHl ¥*
180 ' T" 160
"T" 140 120 «00
PPH 80 60 40 20
ro vO
80
•'s
70 -i;
65
60 f
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25
20 -
15 :
10 :
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4000
246b iR, ca«
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3500 3000 T T
2500 2000
Wavenumbcrs (cm-1) ro NO N>
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246c 'H NMR, 250 MHz
CDCI,
1
9,0 8.0 7.0 6.0 5.0 PPM
il
•T" 4.0
"T' 3.0 2.0 1.0
n^sei
246c "C NMR. 62.S MHz
CDQ,
|M>MMII| | | HIH
180 160 140 120 100 80 PPM
60 40 20 0
.COjEI
IR. CCI,
4000 3SOO
Vu \
III
2500 2000
WavenumbcTs (cm-l)
1300 1000 SOO
to VO
248 'HNMR,500MHz
CDCI,
eo VO OS
248 "CNMR, 125 MHz
CDQ,
mm iwPMiL mm I JMhi JI tfrnm 0m
180 160 140 120 100 BO 60 40 20 PPH
249 'H NMR.250MHZ
coa.
249 "C NMR, 125 MHz
CDCI,
I ' I r-180 160 140
mm
120 —I— 100
—T" 80
-T-60
—f—
40 "T— 20
1 ppm
to vo NO
300
250 "CNMR. 62.5 MHz
coa,
4m mm i 1
180 160 140 120 I
100 PPM
80 60 40 20
HN.
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256 'HNMR.250MHZ
CDCI,
6.0 5 . 0 4 . 0 PPM
SEi
256 "CNMR,62.S MHz
CDCI,
J I li itt I. II
IBO 160 140 120 100 80 60 40 so
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85
Wavenunibers (cm-1)
260 'HNMn,2S0MHz
CDO,
[
9 . 0 8 . 0
1
3 . 0 2 . 0 1.0 0 . 0
260 'H^NMR, 62,5 MHz
CDCI,
LJj.
rnr* 160 160 140 120 100
PPM 60 60
r 40 20
Lk>
2S00 2000
Wavenumhcrs (cm-H
oJV> 270
*HNMR.2S0MHz CDCi,
aJLJI_
9.0 B.O 7.0 6.0 S.O PPM
j|_AMiULJL.
3.0 2.0 r-pr-
1 .0 ~ 0 . 0
o oo
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270 '»CNMH, 62.5 MHz
CDCI,
1-1 III ll i l . . 1 . 1 I 1
200 180 160 - y -140 120
PPM
'T" 100
"T" 80 60 40
"T" 20
u> s
2500 2000
Wavenumbers (cm-l)
-SEt
174 •H NMR.SOOMHZ
CDa,
I • • • • I » ' - I • I I > ' ' ' I ' • ' • « ' ' ' ' I ' ' ' ' I • • ' ' I • • I • - , , - J • . • . ; I • • • , , I I , I 9.5 90 %,5 10 7.5 7.0 6.9 6.0 5.5 5.0 43 4.0 3.5 3i> 2.5 20 1.5 tJO 0.5 0.0
174 "CNMR, I2SMHZ
CDCI,
1 ' I I I f I I f 80 70 60 SO 40 30 20 ppm 10
U» to
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CK" 174
iR.ca
4000 3500 3000 2500 2000
Wavenumbers (cm-1)
ei02C^C(0)Me
276 *HNMR,2S0MHz
CDO,
Ou
12.0 11.0 10,0 • f •
9 .0 r
a . o 7 .0
99^ e«0aC^C(O)Me
116
'*CNMR, 62.5 MHz CDCI,
"1 1 I 1 I I I" 180 160 140 120 100 BO 60 40 20
PPM
HS
80
7S
70
65
% 60
T r 55 a n SO s m 45 1 1 40 1 a 35 n c e 30
25
20
15
10
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4000
59" ElC) ^C(0)Me
276 IR.CCU
3S00 3000 2500 2000
Wavcreimbcrs (cm-1) SOO
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PPM
a
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•I«in iM» i
180 160 140 120 100 PPH
80 60 40 20
SOO 2000
Wavcnunibcfs (cm-H
2.0 9 .0 7 .0 5 .0 4 .0 3 .0 8.0 6 .0 1.0 0.0 PPM
280 **CNMn, 62.5 MHz
COO,
. I II ii
I I I I I I"' 180 160 140 ISO 100
PPM
U l J I
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80 80 40 SO
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% T r a n s m i I I a n c e
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75 -
70
65
60
55
50
45
40
35
30
25
20
15
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5
I'l
CXJ^ 280
IR, CCI4
4000 3500 3000 2500 2000
Wavenumbers (cm-l)
281 **CNMR, 62.5 MHz
CDO,
I "I I I I I I 160 160 140 120 100 80 60 40 20
PPM
Ui
cx^"' Ts
281 IR.CCI,
4000 3500 3000 2500 2000 1500 1000 500 Wavcnumbcfs (cm-1)
OJ
p)f*e
% 283
'HNMR.2S0MHZ CDCta
/ JULL f *•*, _JL11
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PPM
Ui K>
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•V." ™
283 •*CNMR. 62.5 MHz
coa.
Ji JL ill i/W 111, I,
lao 160 nrrjTTT 140 120 100
PPM ao 60
'T" 40 20
\\ V
.C(0)Me
IS
283 IR.CCI,
4000 3300 3000 300 2000
Wavenumbcfs (cin-1)
OL JL P(0)Me
284 *HNMR,2S0MHz
CDCIi
J
I I I ' • • I I 4.0 3.0 2,0 1.0 0,0
U> to vo
SEt
284 "CNMR, 62.5 MHz
CDCI,
"I I I I I I I I «" lao 160 140 lao 100 so 6o 40 ao
PPM
% T r a II s m i I I a n c e
85
80
75
70
65 {
60
55 •:
50
45 ^
40
35 4
30 ^
25 -*
20
15 -
10 £
5 "
7 -.
4000
SEt
f j ~ X C ( 0 ) M e
284 iR.ca
3500 3000 2500 2000
Wavcnumbcrs (cm-1)
u> ui
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285 'H NMR,2S0MHz
CDCI,
1
"I . • 11 .0 10 .0 9 .0 B.O
LA
C(0)Me
285 "CNMR, 62.5 MHz
CDCI,
•M I I I I I I I IBO 160 140 120 100 80 60 40 20
PPM
U>
«*Arjw~,,/s,yv(-v -
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285 iR, cx:i«
4000 3500 3000 2300 2000
Wavcnumbefs (cni-1)
AcHN .COsEt
CXJgEt COMe
289
'H NMR. 2S0 MHz CDCI,
X
L JUlwU.
7 . 0 11.0 10.0 9 .0 8.0 6 . 0
COijEI COMe
289 "CNMR.62.S MHz
CDCI,
mm ji J\ u M^«MK
""I" ' 180 160
I" 140
•""T" 180
- • - } • • •
100 oou "I V . , T
BO 60 40 ao
U» U> ON
% T r
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• a n c e
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5 •
0
4000
AcHN .COjEl
COjEl COMe
289 IR. CCI,
3500 3000 I . '
2500 2000
Wavenumtxra (cm-1)
j:. Pti
#1 3Et
290 'H NMR. 2S0 MHz
CDO,
—jj » A_ Hi i K
'I I I I 4. 0 3 . 0 2 .0 1 .0 0 . 0
Ut u> 00
COMe
290 ''CNMR,62.S MHz
CDCI,
ilu idijLi
IBO 160 140 lao too PPM
•tVM J l i I Ji l i„J
80 60 40 'T" 20
OJ u>
% T r a
I " |s m i I 1 a n
ic e
80
75 •
70
65
60
55
50
45
40
35
30
25
20
15
to -1
5
0
COgEl
COMa
IR, ca.
4000 3500 3000
Wavenumbefs (cm-1)
.SEI
Me(0)Cf CQ2EI
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MeOzCf CQzMe
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Wavenumbcrs (cm-1)
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80 60 40 20
00
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IR, CCI<
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Wavcnumbers (cm-1)
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Wavenumbers (cm-1)
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MeOjC
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Wavemmibcrs (cm-l)
356
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