The synthesis of highly substituted indoles via isonitriles

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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'

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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 Date S'Xi-ol Enemark Date C Dr. David F. O'Brien Date

I Dr. Victo

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

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

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-

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

tabcrsonine ibo^mine potential antitumor agent • 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.

acid catalyst

6 7

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 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 Intramolecular functionalization reanxmgements

Heck reaction Fecher-type Stille reactions Pd^atalyzed heteroannulation Cu-promoted Sf/vr reaction Sfl/vl reactions Reductive cycl^tions [1,31-Dipolar cycloaddition Cartianionic reactions Pd

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.

Ph PCI3 (1 eq), PhH, r.t. A 1PH^Bn a NHNHa (75% yield) Ph H 9 10

8 +

9 NH 11 12 13

OCia® 10 NH2 ©B- NHz

14

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 a CH3SCHR'C(0)R" R'> 16 17 r.0

R^C"3 Et^ f^^'V^COR"

L 19 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.

OMe Ku^COMe Cul / DMF, A yfX—

NaOA Me (80% yield) H 25 26(1.5 eq) 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 — (3eq) (26-80% yield)

25 36

[LzPdX-]

Rl = R2

a: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).

R2 36 a Pd(PPh3)^l2(20mol%). TMG(IOeq), DMF.IIOOC 41

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) R2 X = halide. OTf

RrP^X L NHC(0)CF3 44 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

1) Pd2(dba)3, CS2CO3, llgand,THF,80°C,12h

2) Pd2(dba)3,5S, 24h a:Br Hal Me^^ 48 48 55s 54 (61% yield)

P(Cy)3

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.

Pd(OAc)2(5mol%), /16U3P (20 mol%) THF, 100®C

(55-70% yield) 58

PdOAc OAc

N I 60 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.

Fe(8)(3eq), AcOH

63 67

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. 37

Scheme 1.13. Triethyl Phosphite as a Reductive Cyclization Catalyst

.Ph P(0Et)3

(50% yield)

Me Me NO

69

1J.1.13. S

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 PPha, CHaCN, A CO (4 atm) 73 (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. OAr (>80% yields)

83 "OAr 84 SOAr

,NR

.OAr 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 COR' 2) R"X J

CHO 89 90 91 (56-90% yield)

2)aq. NaOH

R' H CHO 92 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.

nBuaSnH (1.1 eq), R

AIBN(5%),CH3CN.A SnBua 94 SnBua 95 96

Pd(PPh3)4.El^.R'X.A R

SnBu3 H H 97 98 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- N=\. SSnBus R' 100 101

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 2) KHMDS, PhCH3. -TtPC -> r.t. «M to 105 Boc X

Stille Reaction OPG OPG -Br ArSnMea, Pd°, base, A 65% yield

1.3J.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) •t- K2CQ3(2eq) 109 110 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.

:0NEt2 fiBuU. lONEt2 R|

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.

115 116 117 (51-74% yield)

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. 47

Scheme 1^. a,P"Litliiuiii-Halogeii Exchange and Coupling with Electrophiles.

fiuLi, DMF

THF, -10tf>C 82% yield CHO

COzCg) CICOzMe yield 41% yield 75% yield

CO^e /TV-/ CO^e 121 CHa 122 CHa 123 CHa

U.2.5. Jackson's Indole Synthesis

In the framework of syntheses of 2,3-

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.

H HCI/EtOH

129 130 131 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

137 138 139

Me

140 141 142

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 .OMe

144 145

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 Pr radical Pr Aorhv donor

Pr Pr Pr 147 148

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.

Aorhv solvent

ISO 151 152

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 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.

PdCl2(PPh3)a AcaO.HCOOH NEtaCul. 90% yield TMSO»CH 93% yield

TMS POCI3, PrgNH,

CH2CI2 82% yield 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

S-H ccc™' 07™^ ISOa 151 152

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.

nButjSnH (2.2 eq), AIBN (10%), PhH, A;

H 150a 152a 157a 0% yield 82% yield

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. 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 PdCl2(PPh3)a NEta Cut, POCI3, PrzNH, ax RC*CH CH2CI2 • H 154

Entry R 155 Yield 155 (%) 150 Yield 150 (%;

1 IMS a 93 a 82

2 nBu b 100 b "

3 tBu c 92 e ~

4 Ph d 100 d "

5 CHeOBn e 57 e — 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

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

SnBua N^^SnBua 159

nBuaSnH

SnBus

160

nBu^nH 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.

nBuaSnH

radical trap

H 161a

radical trap = or

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 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.

nBuaSnH (2.2 eq), AIBN (10%), NuH (excess)

nBuaSnH (1 eq) AIBN (10%). NuH (excess)

H NuH s MeOH, EtsNH, BnNH2, CeHj^Hg 161a

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 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%), 82% PhH (CH3CN), 8OOC

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

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 •IMS RSH (3 eq), AIBN (15%), PhCH^ A

ISOa

170 Yield (%)

-Et a 86

•nBu 66

-Ph 49

-CH^H20H d 94

-CH^HaOTBS e 60

•CH^HaCO^e f 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. 0H

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.

COJOaEt NMea CO^t Of \ 7^ (nBu)3P(0.3eq), CHaCN.A 177 99% yield 180

O O

OEt NHAc

•HNMee H ©^COaEt H 0NMe2 178 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.

:0^e -TMS (3eq), nBioP (50%) CO^e SEt CHaCN, reflux I2h H 82% yield H 170a 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.

Nu •TMS Nudeophile (3 eq), nBuaP (50%)

SEt CH3CN,80°C SEt H 170a 181

Entry Nudeophile 181 Yield

Me02C^^C02Me 82%

EtO^C^EtOiCs^C ^COaEt

NH/4HAC

EtO^Cs^OjEl 96%

NHz

El0iC>^(0)Me 57%

Et0iC.^^(0)Ph 33% 75

Table 3.1. Cont'd.

Entry Nucleophile 176 Yield

EtOaC^N^Ph 61% NHBn after NaCNBHs 183 SEt 181f reduction

80%

SEt 184 181g

SEt 40%

SEt 182

SEt 12% EtOA.^NHAc

SEt 182

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. © © ^BusSB H •TMS -TMS PBU3 f -(TMS)SEt

170a 185 186

Nu NuH

SEt SEt H 187 181

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 (3eq) NHAc CO^e nBu^ (50%). CH3CN, reflux 12h 96% recovered starting materiai 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.

PhCHO (3 eq), nBugP (1.1 eq)

CH3CN, reflux 12h H 48% yield H 170a 188

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. 78

Scheme 3.7. One-Flask Synthesis: Indole-Formation, Alkylation.

•TMS 0^9 EtSH (3 eq), AIBN (10%), PhCHs, A; CO^e EtOaCs^C30aEt (3 eq)

NHAc 150a nBuaP (50%), CH^N, ^ 86% yield

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),

KF (0.2 eq), 18^rown-6 (0.05 eq), CH3CN, reflux 1.5h 189 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.

TBAFmiF

Si(i-Pr)3 191 192 193

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). 80

Table 3 J. Comparison of Phosphine vs. KF as Coupling Catalysts.

Nu •TMS Nudeophile (3 eq), KF (1.1 eq), 18-06 (1.1 eq)

CH3CN, 80°C SEt H H 170a 181

Entry Nudeophile 176 PBua Yield KF Yield

1 MeQA^O^e 82% 91%

SEt 181a

AcHI

EtOaCs^COaEt 98% 99% NHAc SEt 181b

EtOjCs^iO^t 96% 100%

NH2 SEt 18le

EtOiCX^N<^Ph NHBn 61% 94% after after 183 SEt NaCNBHa NaCNBHs 181d reduction reduction

Ph 80% 100% SEt 184 Ph 181a 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 ^

4- EtSH CH3CN, reflux 3h 170a

•MesSiF

NuH KF

194 182 195

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) ^

KF (1.1 eq). 18-crawn>6 (1.1 eq), CH3CN, reflux 3ti 170a 97% yield

EtSH (10 eq)

(1.1 eq), 18

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 H 40% yield H 170a 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 ;02Me )—TV MeOp^CO^e(3eq), KF/alumina (1.1 eq), C02Me "^SEt CH3CN,80°C H 37%yietd H 170a 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.

202

spirotryprostatin A 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.

4J. 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 CH2Cl2,CF^02H, 4AMS.0~>20°C

(88% yield) H3C 205:206 ^2:1 205C"H=a.R = H - H BoC20,CH3CN, 206C'®H=p,R»H 204 NEt3,A 207C"H=a.R = Boc-^ (84% yield) 89

Scheme 42, Oxidative Cyclization of a Danishefsky P-Carboline.

NBS,THF,H20.HOAe 207 MeO (46% yield) .SPh

208 209 RsBoc TFA,CHjqia 210 R>H n (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.

CHzCle, EbN; 210 + Zn.NH4CI. H2O. THF.MeOH

(68% yield) 211 / R 212 Rs SPh —I Nal04. H20, ««B_S(OPh) ^ MeOH RhCl3*3H20. EtOH.A 1 (41% yield) 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 (73% yield) Bop-CI(1J!eq),CH2Cl2, NEt3(2.5eq),0OCtor.L (90% yield)

1) UHMDS (ZZ eq), THF, 0% 2) PhSeCI (^2 eq), THF. 0«C (78% yield)

1)TFA/CH^l2(1/5), 2)NEt3.CK^l2

(86% yield) 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.

NBS(1.t8eq), f THF-AC0H-H2P (1:1:1) O^tort (68% yield) V ^ /^NFmoc IFmoc 223

20% piperidine 1)LDA (3.80 eq),-7500 inCH2Cl2.r.L 2)PtiSeBr(3.09eq),-75°C

(100% yield) (7% yield)

1)(Boc)20(5.2eq). DMAP(4.3eq). CH2CI2, r.t 2) MsCI, NEla. CH2CI^, r.t. TFA. EtaSIH. CHaCt, r.t 202 (70% yield) (74% yield)

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.

4.3J. 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)U0H 2)TB0P&CI 1) Ac^, pyridine 3) 2-iodoaniline,1-methyi> 2) MgBi2*E^; iPrzNEt AcOH 2-chlonH)yridin[um iodide

(94% yield. >20:1 £2) (78% yield) 227 94

Scheme 4j6.-CorUintted

[Pd2(dba)3]K:HCl3 1)SEM-CI,NaH (otoDsP. KOAc 2)TBAF THF, 70

3) Dess-Maitin oxtd; (72%yleld, 232:233-1:1) OTBOPS 229

231 .fiuOK

P0(0Me)2 231

Me2AICI;/PrNEt 202 (93% yield) 0:' SEM SEM 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 Ph IL 'Me [1,3]-dipolar 3XMS,PhCH3,r.t cycloaddition Xi (82% yield) 234 MeO- COaEt

1) 0-pro-06n, BOP MeCxJf NEta, MeCN H2(60psi).PdCl2. A 2) H2, Pd-C, EtOH 0 THF. EtOH 3) BOP, Et:^, MeCN

(99% yield) (70% yield)

.WJ . W

1) Lil, pyridine, A TsOH (1 eq) 2) OCO, DMAP, PhCH3,A 202 (82-89% yield) HO-fQ 'CO^t ^ B(CCl3, A 3) NaOMe, MeOH .WJ" (32% yield)

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

CO2R

244 245

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.

C02Et 02!Et

CO#t A (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

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 SEt SEt

246a 247 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

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.

c® base RCHaSR' + R"X R'

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.

P

EWG EWG RhorCu RSR' P=N2 p=M EWQ 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 A "V' RR'CHSMe +

(2) pu e CiiS04, [cfJ ^ ^ Aorhv ©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.

Rh2(OAc)4

or chiral Rh catalyst

H 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.

OEt HS^ ^ ' ^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. Ill

Scheme 5.6. Synthesis of Sulfur Ylide Precursor 260.

PhaCOH.BFa'OEta

AcOH,A 263 264 (81% yield) 2) Xk 265

..cs-JUOEt EtO' ^ss CH2Cl2/EtOH,r.t 266 (73% yield) (72% yield) 267

1) H02C-^^^^S02N3 268 CHaCN.yc 1)CH3CN,I^C03(aq),0

261

KF(1.1 eq), 18-crown-6(1.1 eq) OEt CHaCN, reflux 3h (99% yield)

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.

,0 OEt RM0Ac)4 (5 mol%), PhH, A

H 260 270

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. 113

Scheme 5.8. Proposed Mechanism of the Intramolecular Sulfiir Ylide Reaction.

5 nK)l% Rh2(OAc)4,

PhH.A (73% yield)

260 271

272 273 274

1,2-rearrangement Et gramme-type ,p firagmentation/addition

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.

48%raooverad starting matarial Rhi(0Ac)4(5mal%), PhH,d COMe 174 COMe m m minor product t2%yield

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.

278 280

COMe Rii2(OAc)4(5 mal%), PtiH, A Ts Ts (S9%yMd) Ts 281 282 283 115

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 27S MeOaCs^O^e CO^

SPh Rh^OAe)4(5mol%), KF(leq), PtiH,A CO^t 18-crowi(v6 (0.5 eq) (45%yMd) CH3CN, reflux 3h 196 2S4 285 (34%yW(l)

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.

SPh Rha(OAc)4(5mol%), PhH.A (45% yield)

•SPh COaEt

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). 118

Scheme 5.13. Intermolecular SulAir Ylide Studies.

^2

Rh2(OAc)4(5 mol%), PhH, A

(48% yield) MeOC 181b 289

Ph

SEt SEt Ph Rh2(OAc)4(5 mol%), PhH, A COaEt (42% yield)

275

OEt co^

Hh2(OAc)4(5mol%),PliH,4 (7l%y«l) a, "MeOC 181a

il CO^e OaMe MeO^II^OMe

CO^e

SEt Rh2(OAc)4 (5 mol%), PhH, A H ^CO^e 181a (95%v«/o,».u, yield) 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^

SEt Rh2(OAc)4 (5 fnol%), PhH, A

181a (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

SEt Rh2(OAc)4 (5 mol%). PhH, A SEt 181a 294

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

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)

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 6.0 5.0 4l0 3.0 1.0 0.0 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 v*.-

CC'"NHCHO 154 iR.ca,

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 llMhMMVaMNIMVNMMaMi

r" IBO 160 140 120 100 60 40 20 0 PPM

ON oo 90 i^49«.|$)^{!lN2237

85 ' V\ 80 ' 75 .

70-

6S

60 .

55-

50-

45

40

35 30 ^TMS

25

20 'NHCHO 15 lS5a : IR.CCl 10

5 0

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- "T" "T" "I I I" 180 160 140 120 100 BO 60 PPM 90 Frl Sep 18,1998 ARK2162.101

80-

75-

70-

65

60 •

55

50-

45

40

35 -

30-

25 •NHCHO

20 15Sb IR.CCI,

10

4000 3500 3000 2500 2000 1500 1000 500 ^avei^bers (cm-1) 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'" "T" IBO 160 140 120 100 80 60 40 PPM r-Bu

NHCHO

155c iR.ca«

4000 3S00 Ph

NHCHO

ISSd HNMR,2S0MHz CDQ,

D

9.0 8.0 7,0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 PPM Ph

NHCHO 15Sd "CNMR.62.5 MHz CDQ,

J u

180 160 140 120 100 80 60 40 20 PPM 95- 1/8/99, KENN2226.I01

90

85 ^ (f(f y-^J "V SO­ '\y TS - 70- 65 -

60

55 50 M 45 P 40-

35

30-

25 NHCHO 20 lS5d 15 IR.CX3, 10 3

0

4000 3500 3000 2500 2000 1500 1000 Wavenumbers (cm-1) NHCHO

]S5e 'HNMR.2S0MHZ CDCIj /

rCJu 1 )L . * ' OBn

NMCHO

ISSe "CNMR, 62.5 MHz CDOj

1 I 11

"•I '"I I I I I IBO 160 140 120 100 80 60 40 ao 0 qS PPM O 100 1/19/99, KRNN2233 105

90

80

65

60-

40

•OBn

25 NHCHO

15- lS5e IR. ca. 10

0-

4000 3500 3000 2500 2000 1500 1000 SOO Wavemimbcrs (cm-l) 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.

"I I I r 180 160 140 120 100 60 40 20 0 PPM

u>00 ^^0, 1998 ARK21S6 105 V,.v1

!

.TMS

iR.ca,

4000 3500 3000 2500 2000 Wavenumbef (cm-l) NC

150b 'HNMR.2S0MHZ CDCI,

i1

' " " I' • I • 9.0 a.o 7.0 6.0

00 Ul NC ISOb "CNMR.62.S MHz CDa,

liMltil

V" rrrj^ I "I I" IBD 160 140 120 too 80 60 PPH 40 20 as00 95 90 Sep 30 ,1998 ARK2172.101 85

BO- \-.-- 75

70 65

60

55

50

45 40

35 nBu 30

25 20 150b 15 IR-CCU 10

5

0

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

"""T" "T^ r M IBO 160 140 120 100 80 60 40 20 0 PPM

%vO 2500 2000 1500 1000 500 Wavenumbers (cm-1) ,Ph

ISOd 'H NMR, 250 MHz CDCI,

9.0 B.O 6.0 5.0 4.0 3.0 2.0 0.0 Ph

NC ISOd "CNMR,62.S MHz CDCI,

"T^ ""T" 180 160 140 120 100 80 60 40 20 PPM 1/19/99, KENN2228.10I

iR. ca.

4000 3500 OBn

NC 150e H NMR. 250 MHz CDCI,

9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 PPM I50e "CNMR.62.5 MHz CDCI,

>#<•

I I" "I" "T^ I" IBO 140 120 100 BO 60 40 ao PPM 100 95 1/21/99, KENN223S.103 90 85 80 75 70 65 60

55 50

45 40

35 30 25 ^

20 - 15 - ISOe 10^ iR.ca, 5 0

-5-1 4000 3500 SOO 2000 Wavcnuinbcrs (cm-l) NC isor 'HNMR,2S0MHz CDQ,

r

JL il

• I • I I I I I I • • I • I 9.0 8,0 7.0 6,0 5.0 4.0 3.0 2.0 1.0 0.0 PPM SO -J NC isor "CNMR.62.5 MHz CDCI,

1 m

"T^ "tt" "T" "I" "I IBO 160 140 ISO 100 60 60 40 20 PPM 75 1

70

65

60

55

50

45

40

35

30

25 -

20

15

10 IR. CCL

5

0

4000 3500 nBu

N lS2b 'H NMR, 250 MHz CDCI,

•yMM

"T" I " " • " • • I • 6.0 5.0 4.0 »o O0M ,riBu

152b "CNMR,62.S MHz CDCI, KENN22S9.QUiN 3/17/99 ^ y'

I*S fiBu LI :i :J i"

lS2b IR,CCI«

4000 3S00 3000 2S00 2000 1500 1000 Wavcnumbcfs (cm-1) N SnBu*

152c 'HNMR,500MHz CDOa

JLJUL

• t • • I • • I • • < - • I • —I— • I • —r-^ • I • • t • -T— • I • ».s 9.0 •.S S.0 7.5 7.0 6.3 60 S.S 5.0 3.J 3.0 2.} 2.0 I.S 1.0 0.S 00

N> Utio fBu

lS2c "CNMR, 125 MHz CDCI,

"I" "T" ~T" —r* "T" -"T— -r' 170 160 l» 100 90 •0 70 60 so 30 20 10 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,

Am

rrrpr, "I •""I I I I • IBO 160 140 lao 100 80 60 40 20 PPM § 1/19/99, KfiNN2229.QUIN

I

152d IR. CCI,

4000 3S00 3000 2300 2000 ISOO 1000 Wavcnumbcrs (cm-1 I52e >H NMR. 250 MHz coa, OBn

IS2e »*CNMR,62.5 MHz CDCI,

•'X" "I I" 180 160 140 BO 60 40 20 ro o 80 KENN2283 103 3/18/99 y 75 ; Mi 1,1 70 65 w 1

60

55 11 50

45

40

35

30

25 OBn 20 *N' 15 152e 10 IR.CCI,

5

0

4 0 3500 3000 2500 2000 1500 1000 500 Wavcmimbers (cm-l) -TMS

157a H NMR, 2S0 MHz CDa,

9.0 a.o 6.0 5.0 4.0 3.0 2.0 PPM

N> {3 -TMS

157a "CNMR,62.S MHz CDCI,

4

lao 160 140 120 100 BO 60 40 20 0 PPM

to u> 90. KENN2272.I05 3/5/99

85 -

•TMS

20

157a •R. CCI.

3500 3000 2500 2000 500 Wavcminibcrs (cm-l) n-penlyl OS« 157b 'H NMR. 250 MHz CDCI,

K> d '•penlyl

B lS7b *'CNMR.62.S MHz CDQ,

JLi r *

"I nrrj^ 180 160 140 120 100 BO 60 40 20 PPM N» f \ u I'l

I!

n-penty(

lS7b «

IR. CC|«

4000 3500 3(H)0 2.100 2000 Wavcnumbers (cm-1) 157c 'HNMR.250MHZ CX)Cl3

/ J s

9.0 8.0 7.0 6.0 9,0 4.0 3.0 2.'o ' ' ' ' ' ' ' ' ' ' • • ^ ffM 5S (XT'«

157c "CNMR.62.SMHz CDOj

JLJL

•"I" ""I"" "•I "T^ "T" "T" 180 160 140 120 100 80 60 40 20 to PPM 3 no -

30 -

0 _

4000 3S00 3000 2500 2000 1500 1000 500 Waveimmbcrs ^ro-1} IS7«I 'HNMR,2S0MHz CDCI, ]57d "CNMR,62.S MHz CDCI,

180 160 140 120 100 60 40 20 PPM 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,

Jd

•T^ • I • -"-r- ' • I I I I I 9.0 8.0 7.0 B.O 4.0 3.0 2.0 1.0 0.0

N) 225

ox ^a.oa

M X S

-|U Z u Mi•' I

I 11 2500 2000 1500 Wavcnumbers (cm-l) SEt

170a 'HNMR,2S0MHz CDCI3

jA Wi J

^-pr- 10 3.0 2>0 ».0 0.0 Ni -J -TMS

SEt

170a ''CNMR.62.SMHz CDCI3

JU. pM.

r to 180 160 140 120 100 80 60 40 20 0 N) PPM 00 KENNaOIO.IOI 4/29199 70 -

65 -

60 -

50

35 -

-TMS

170a 10 - JR.CCI,

4000 3500 3000 2500 2000 1500 1000 500 Wavcnumbers (cm-1) SBu -TMS

SBu

170b 'H NMR.250MHZ CDCIJ

/ 1. A A Bu -TMS

SBu

170b "CNMR.623MHZ CDa,

JiU

VfVffffrf•!*«***••**•**|fV«*«*•••!avvvvvf>*11** 180 160 140 120 100 BO 60 PPM 90

85

80

75

70

65 ^

% 60 T r a 55 T n s 50 - m i 45 I I 40 ^ a n 35 c e 30 --

25

20 170b IS IR. CCI, 10

5 -

0 - 4000 3500 3000 2500 2000 Waveinwnbcrs (cm-l) iPh -TMS

170c 'HNMR.250MHZ CDCI3

y\. J L

-ry-.- '-^r~ * I • ro 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 c>> PPM SPh -TMS

SPh

170c "CNMR, 62.5 MHz CDCI3

mm « mmfi

rTT|T»l I"' •"I "X" "T 10u> IBO 160 140 120 100 80 60 40 20 0 •p. PPM 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 80

75 -]

70

65

60

% 55 T r a 50 : n s 45 - in i 40 I I 35 - a II c 30 e TMS 25 r ir ij

20 • H'

15 ; 170(1 10 : IR, CCI,

5 ; 0 -! "T T 4000 3500 3000 2500 2000 Wavenurobers (cm-l) K> u> 00 iTBS

OTBS

170e 'HNMR,250MHz CDCI,

k Aa^Jl _/v I .JJl L J

"T^ "T^ 'I to 9.0 8.0 7.0 6.0 9.0 4.0 3.0 2.0 1.0 0.0 u> PPM NO )TBS

-TMS

OTBS

170e "CNMR, 62.5 MHz CDCIj

Ul jjj.

TTTjrrT I "T" IBO 160 140 120 100 BO 60 40 20 PPH 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 - TMS c - 25 Got^'^S ^TBS » 20 15 170e

10 iR.ca4

5 4

0 -

4000 3S00 3000 2S00 2000 Wavcnumbcrs (cm-1) -TMS

'B'

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

I'' "I" -I" • I"" ~T— ""I" •T" 190 IW 170 ISO 140 IM 120 110 100 60 20 ~9o 85 :

80 -

75 4

70 4

65

% 60 T r 55 - a n 30 s m 45 - i I 40 I a n 35 02Me c e 30 ^ •TMS 25 \n 20 r 15 170f 10 -=] IR, CCI4

5 •

0- I —r- 4000 3500 3000 2500 2000 1500 Wavemimbers (cm-i) SEt

181a 'HNMR.250MHZ CDQa

• • I • • I • ' r^r-|^ 9.0 B.O 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 PPM L/> igMa

181a "CNMR, 62.5 MHi CDQa

J 11, 11

"T^ "T™ *"I "I I I I leo 160 140 120 100 80 60 40 20 0 to PPM a\ ./

80 y' 75

70-

60-

55

50-

30

25-

20

15- 181a IR, ca<

4000 3500 3000 2500 2000 1500 iooo 500 Wavcnumbers (cm-l) AcHN C02Et

SEt

181b *H NMR,2S0MHz CDCIj

JLjw__jL X J

""T- ' I ' -r-p- ~ 9,0 e.o 7.0 6.0 S.o 4.0 3.0 2.0 1.0 0.0 PPM AcHN

SEt

181b '^CNMR. 62.5 MHz CDCI3

UL

'"•I "T" IBO 160 140 120 100 00 60 40 20 VO PPM 6/23/99. KENN3043

70

AcHI

SEI

181b IR, ca.

4000 3S00 3000 2S00 2000 ISOO 1000 300 K) Wavcmimbcri (cp-l) Ln O 181c 'HNMR.2S0MHZ coa.

s J- JUit

-T^ • I • •—T" • I I 9.0 8.0 7.0 6.0 S.O PPM -COaEt

^SEI 'Vi

181c "CNMR, 62.5 MHz CDQs

Ji An

I 1 1 I "T" T to 180 160 140 120 100 60 40 20 0 Ul PPM to 1 ' 2300 2000 Wavenumbers (cm-l) hJ L/l -SEt

181d 'HNMR.2S0MHZ CDQ,

90 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,

•WMMii •WMMM*

i'" T I T lao 100 60 60 40 20 0 ro PPM 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,

Uul

I , , 9.0 a.o 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'" "I I I I lao 160 140 120 100 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

J

TTTJTTT, '"I"" "T T' "I T leo 160 140 120 100 80 60 40 20 0 PPM 6/24/99,1 1079.102

75

70 -

60-

50

45

40

30 -

SEt

4000 3500 3000 2500 2000 1500 1000 500 Wavenumbcrs (cin-1) 263 I8lg "CNMR, 62.5 MHz CDQa

i li A mim i

"'I'" •"I"' r -rrjT^ I N> 180 160 140 120 100 80 60 40 20 PPM 2 8S K^3«JJ^7/6/99 80

75

70

65

60

55

50

45

40 H 35

30 OjEI

25 II jl "V-Ph |!| SE. 20

15 181g IB,CCI, 10

5

0

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'" "n I I I I 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 PPm to OS -J ft/

SEl OnC

182 IR. CCI,

4000 3500 2500 2000 ISOO 1000 500 Wavcraimbcfs (cm-l)

to o^ 00 SEt

'HNMR.2S0MHZ coa.

'I • I ' I K> 9.0 e.o 7.0 6.0 s.o 4 3.0 2.0 1.0 0.0 PPM 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

•r-ry —T^ •"T' -T^ • f • 'nr— • I • '-f 9.9 9.0 I4> 7.5 7.0 6.S 6j0 5.5 5.0 4^ 4.0 3.5 3i> 2.5 20 1.5 1.0 .0.5 N» -J ro co^

196 "CNMR, 125 MHz CDCI,

••I"" 190 l«0 170 160 150 140 130 120 110 100 90 70 60 SO 40 30 20 10 pfM lO U> 65

BO 75 70

65 60 % T 55 r a n 50 s m 45 i • 40 I a 35 n c 30 e 25 CQjMa 20

15 10 IR.CCI, 5 0

4000 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 85 / 80: / 75 -• 70

65

% 60 - T r 55 a n 50 ' s in ''s : i I 40 ^ I a n 35 5 c e 30 - 25 CnCSEI 20

'5 T 198 IR, CCI, 10 -3

5

4000 3500 3000 2500 2000 Wavenumbers (cm-1) 199 'HNMR.250MHZ CXKZI,

9.0 8.0 7.0 6.0 5;0 4.0 3.0 2.0 1.0 0.0 PPM 199 "CNMR.62.SMHz CDOj

»•* JLJL «MMNn

"T" •"I "T^ rrryr, "T 180 160 140 120 100 60 60 AO 20 0 PPM vO 80

75 KENN 3032.101 5/17/99 70

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