Michigan Technological University Digital Commons @ Michigan Tech Dissertations, Master's Theses and Master's Dissertations, Master's Theses and Master's Reports - Open Reports 2005 Sulfoxides as an intramolecular sulfenylating agent for indoles and diverse applications of the sulfide-sulfoxide redox cycle in organic chemistry Parag V. Jog Michigan Technological University Follow this and additional works at: https://digitalcommons.mtu.edu/etds Part of the Chemistry Commons Copyright 2005 Parag V. Jog Recommended Citation Jog, Parag V., "Sulfoxides as an intramolecular sulfenylating agent for indoles and diverse applications of the sulfide-sulfoxide redox cycle in organic chemistry", Dissertation, Michigan Technological University, 2005. https://doi.org/10.37099/mtu.dc.etds/36 Follow this and additional works at: https://digitalcommons.mtu.edu/etds Part of the Chemistry Commons SULFOXIDES AS AN INTRAMOLECULAR SULFENYLATING AGENT FOR INDOLES AND DIVERSE APPLICATIONS OF THE SULFIDE-SULFOXIDE REDOX CYCLE IN ORGANIC CHEMISTRY By PARAG V. JOG A DISSERTATION Submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY (Chemistry) MICHIGAN TECHNOLOGICAL UNIVERSITY 2005 This dissertation, “Sulfoxides as an Intramolecular Sulfenylating Agent for Indoles and Diverse Applications of the Sulfide-Sulfoxide Redox Cycle in Organic Chemistry”, is hereby approved in partial fulfillment of the requirements of the degree of DOCTOR OF PHILOSOPHY in the field of Chemistry. Department of Chemistry Dissertation Advisor: Prof. Dallas K. Bates Department Chair: Dr. Sarah A. Green Date i Acknowledgements I would like to present my sincere gratitude to my research advisor Dr. Dallas K. Bates for his patience, help and understanding during this study. His guidance both inside laboratory and in general life is invaluable and everlasting. I thank Dr. Urnezius for not only to be on my graduate advisory committee but also for all his help and some good discussions about research and life in general. I am thankful to Dr. Richard E. Brown for his guidance and time during the computational work. I would like to acknowledge Dr. Donald Lueking, Dr. Pushpa Murthy and Dr. Shiyue Fang for being on my graduate advisory committee. The help and understanding of all the staff of chemistry department which include Dean Seppala, Don Wareham, Ramona Johnson, Rita Smith, Michelle Saxton, Pamela Long, Lorri Reilly, Kelley Smith, Celine Grace, Denise Laux and Aparna Pandey is highly appreciated. Special thanks to Jerry Lutz and Shane Crist for their help with instrumental and computer related needs respectively. I also appreciate the help of David Lepse and Amanda Binoniemi (MTU Library staff) for making me knowledgeable in doing library related things. I am thankful to the Department of Chemistry for providing financial assistance throughout this study. I thank my current and former labmates (Kexue Li, Xiaofen Li, Geetha Boreddy, Anil Ekati, Jody Scheffler, Peter Klassen and Joe Lamberson) for giving some memorable years in my life. In addition, I greatly appreciate the friendship and help of all my friends including Yuth, Soumya and many others-the list of which is too long to be included. ii I would like to thank my wife Sonali for her help, patience, understanding and importantly, for her love during my graduate studies. Lastly, I pay sincere gratitude to my parents and in-laws for their support and encouragement during my life at Michigan Tech. iii Abstract This dissertation involves study of various aspects of sulfoxide chemistry. Specifically designed t-butyl and propanenitrile sulfoxides tethered to indole-2-carboxamide were used as a source of intramolecular sulfenylating agents to synthesize novel indolo[3,2-b]- 1-5-benzothiazepinones which are structurally analogous to the other biologically active benzothiazepinones. This study reveals that the intramolecular cyclization of sulfoxide follows an electrophilic sulfenylation (Sulfoxide Electrophilic Sulfenylation, SES) reaction pathway. Evidence of the absence of sulfenic acid as a transient reactive intermediate in such intramolecular cyclization is also provided. In another study, sulfoxide was used as a “protecting group” of thioether to synthesize 8-membered, indole substituted, thiazocine-2-acetic acid derivative via Ring Closing Metathesis (RCM). Protection (oxidation) of inert (to RCM) sulfide to sulfoxide followed by RCM produced cyclized product in good yields. Deprotection (reduction) of sulfoxide was achieved using Lawessons Reagent (L.R.). Application of the sulfide-sulfoxide redox cycle to solve the existing difficulties in using RCM methodology to thioethers is illustrated. A new design of a “molecular brake”, based on the sulfide-sulfoxide redox cycle is described. N-Ar rotation in simple isoindolines is controlled by the oxidation state of the proximate sulfur atom. Sulfide [S(II)] shows “free” [brake OFF] N-Ar rotation whereas sulfoxide displayed hindered [brake ON] N-Ar rotation. The semi-empirical molecular orbital (PM3) calculations revealed concerted pyramidalization of amidic nitrogen with N-Ar rotation. iv Table of Contents Thesis approval page i Acknowledgements ii Abstract iv Table of contents v Unifying Theme of Research 1 Chapter 1 Introduction 6 Part A: Sulfoxides as an intramolecular sulfenylating agent 6 Part B: Sulfoxide as a “protecting group” 22 Part C: Sulfoxide as a “molecular brake” 33 Chapter 2 Sulfoxides as an intramolecular sulfenylating agent 51 “Intramolecular Sulfoxide Electrophilic Sulfenylation (SES) of 2- and 3- Indole Carbanilides: Formation of Indolo[3,2-b]-1,5-benzothiazepinones” Introduction 54 Results & Discussion 57 Experimental Section 71 Chapter 3 Sulfoxide as a “protecting group” 89 “Simple Thiazocine-2-acetic acid Derivatives via Ring Closing Metathesis” Introduction 90 Results & Discussion 92 Experimental Section 93 Chapter 4 Sulfoxide as a “molecular brake” 95 “A Redox-Mediated Molecular Brake: Dynamic NMR Study of 2-[2- (Methylthio)phenyl]isoindolin-1-one and S-Oxidized Counterparts” Introduction 96 Results & Discussion 96 Experimental Section (see Appendix 4) - Future Directions 100 Appendix 1 Supplemental Information of Chapter 2 102 Appendix 2 Supplemental Information of Chapter 3 146 v Appendix 3 Additional Supplemental Information of Chapter 3 203 Appendix 4 Experimental Section & Supplemental Information of Chapter 4 211 Appendix 5 Step by step guide to convert and analyze NMR spectra from VNMR to gNMR (V4.1.0) 240 Step by step guide to perform PM3 Semi-empirical calculations using Gaussian™ 248 vi Unifying Theme This dissertation is a combination of efforts in understanding different aspects of sulfoxide chemistry in chemically varying substrates. The chosen sulfoxide substrates are chemically diverse in nature, however, each substrate is specifically designed to suit the requirements of the intended study. Each study is included as a separate chapter (Chapters 2, 3 and 4) and hence the chronological order of compounds and references is restricted to each chapter and is not continued from one chapter to another. Background about principles and techniques used in each study is explained in the first chapter (Chapter 1). The following brief discussion is intended to give an idea of studied aspects of sulfoxide chemistry. Sulfoxide is an important functional group in organic chemistry. To date numerous applications of sulfoxides in organic synthesis have been disclosed and further research is in progress. Our research group has an impact in specific reaction of sulfoxides, namely Sulfoxide Electrophilic Sulfenylation (SES) reaction. In the 1980’s, our research group developed SES reaction to synthesize novel N,S-heterocycles, which commonly exist as substructures of more complex biologically active compounds. In this reaction, sulfoxide is used as an intramolecular sulfenylating agent. Mechanistically, during this reaction, sulfoxide is activated thermally (heating in a high boiling solvent) or electrophilically (by an electrophilic species) to produce N,S-heterocycle. Both electrophilic and thermal activation is mechanistically different and the electrophilic activation mechanism is well- known. However, the mechanism of thermal activation is still under study mainly because it takes place in absence of any other chemical reagent. We had proposed a mechanism of thermal activation of sulfoxides involving electrophilic addition of 1 nucleophile at sulfur producing sulfonium salt as a reactive intermediate. As opposed to our proposed mechanism, other studies (discussed later) involving thermal activation of sulfoxides proposed existence of sulfenic acid (R-S-OH) as a reactive intermediate in intramolecular cyclization reactions of sulfoxides. Both sulfonium salt and sulfenic acid are extremely reactive, hence difficult to isolate species. Their presence in the reaction mixture is usually derived by the identity of by-products obtained from the reaction. However, they share one thing in common; they both originate from a sulfoxide functional group. We have shown earlier that methyl and ethyl sulfoxides follow the SES reaction pathway (sulfonium salt as reactive intermediate), for thermal activation of t- butyl sulfoxides, however, the sulfenic acid pathway is more common in literature. Synthesis of benzisothiazolones has been achieved by intramolecular cyclizations of t- butyl sulfoxides and it was argued that these proceed via sulfenic acid. However, enough evidence to prove the presence of sulfenic acid was not provided.