Synthesis of Novel Bis-Indole Systems

SYNTHESIS OF NOVEL BIS-INDOLE SYSTEMS This thesis is submitted in fulfilment of the degree of DOCTOR OF PHILOSOPHY By HAKAN KANDEMIR Supervisors Prof. David StC. Black A/Prof. Naresh Kumar School of Chemistry The University of New South Wales Kensington, Australia August, 2011 CERTIFICATE OF ORIGINALITY I hereby declare that this submission is my own work and that, to the best of my knowledge and belief, it contains no material previously published or written by another person, nor material which to a substantial extent has been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project’s design and conception or in style, presentation and linguistic expression is acknowledged. Signed……………………………………… Date ...……………………………………. i ABSTRACT The primary aim of this project was to synthesize novel 2,2′- and 7,7′-linked bis- indole systems from methoxy activated indoles, and investigate their ability to undergo electrophilic substitution reactions at C7 and C2 respectively. As an integral part of achieving this aim, the development of a new series of methoxy activated indole precursors was investigated. The construction of hydrazine bridged 2,2′- and 7,7′-linked bis-indoles was achieved from 2- and 7-glyoxylchlorides and 2- and 7- trichloroacetylindoles respectively. An efficient method was developed for the preparation of 7,7′-bis-indoles containing an oxadiazole derived spacer unit via the cyclodehydration of 7,7′- hydrazide linked bis- indoles. The preparation of a series of monomeric 1,3,4-thiadiazoles was also successfully achieved via the cyclodehydration of 2- and 7-thiosemicarbazides. Some of these 7,7′-hydrazine bridged bis-indoles showed promising antibacterial activity against both Gram positive and Gram negative bacteria. Based on these interesting biological results, some novel 7-carbohydrazides and 7-carboxamides were prepared in order to determine the effect of other substituents at the C7 position. A 7-aminomethylindole was synthesised by the reduction of the corresponding 7- cyanoindole and used as a functional precursor to prepare a range of 7,7′-bis-indoles Also, the reduction of 7-nitroethyl indoles led to the formation of 7-tryptamine analogues. These were used to generate amide and imine linked 7,7′-bis-indoles and for the construction of imine linked macrocycles, which were subsequently reduced to the corresponding amine linked macrocycles. 7-Bromoindoles are key intermediates for the synthesis of biindolyl systems. However, all attempts to synthesize 7-bromoindoles failed, but interestingly led to the generation of unexpected compounds such as 4,6-dimethoxybenzotriazole. This led to the subsequent investigation of the C7 reactivity of this system by exploring reactions such as formylation, acylation and acid catalysed dimerization. The synthesis of 7-oxotryptamines was accomplished via hydrogenation of the corresponding 7-acyl cyanides. 7-Oxotryptamines were subsequently reacted with 7- trichloroacetyindoles to form amide linked bis-indoles, which were converted to the oxazole linked bis-indoles. Some monomeric 7-methyloxazoles were also prepared ii from the 7-keto amides via cyclodehydration. However, the synthesis of 7-hydroxy tryptamine was unsuccessful and led to the formation of a dimer and an alcohol. iii ACKNOWLEDGEMENTS I would like to express my sincere gratitude to my supervisors, Prof. David Black and A/Prof. Naresh Kumar for giving me the opportunity to work on indole chemistry and I thank them for all the help, valuable advice and guidance, many helpful suggestions and ideas they have given me over the course of the project. I was impressed by their extensive knowledge in organic chemistry and their ability to overcome problems related to experiments. I was never surprised to leave David’s office with several ideas regarding my ongoing and future experiments. My thanks also go to both past and present members of the Black and Kumar group. I feel fortunate to have worked with all these people. It was a pleasure for me to work with past members Alam, Daniel, Frank and Taj, and present members from lab 336: George, Rick, Samuel, Kitty, Ren, Chris, Nicholas and Mike, from lab 333: Abel, Ibrahim, Murat, Kasey, Santosh and Nidup, and from lab 266: Ruth, Ray, Venty, Adeline and Elenor. Obviously, some of these people deserve my special thanks. Thanks to Dr. George Iskander for his suggestions related to my experiments, Rick for all his practical help, Ruth and especially Kasey for all their assistance in writing and proof reading this thesis. I also wish to thank the faculty members in the School of Chemistry, especially the professional staff, namely, Jim Hook, Donald Thomas, Adelle Moore from the NMR facility and Mohan Bhadbhade from the X-ray crystallography unit. I am thankful to my housemates in Sydney during the last three years for their friendship and support. Thanks to Ibrahim, Murat, Emrullah, Sefer, Sinan, Cemal and Gokhan. I am extremely grateful to my family, who have been so dear to me. I owe my thanks to my parents, my sisters Yıldız and Filiz, my brother Mehmet, my brothers in law Mehmet and Hakan, my sister in law Filiz, my nephew and nieces Betül, Selin, Irem, Halit, Yigit, Emir, Zeynep and Ecrin and my fiance Hacer for their love, constant iv support and moral encouragement. I also thank all my relatives and friends for their good wishes for my success. Finally, I am grateful to thank the Ministry of Education of Turkey for my scholarship. v TABLE OF CONTENTS Certificate of originality.......................................................................................... i Abstract................................................................................................................... ..ii Acknowledgements................................................................................................. .iv Table of contents.................................................................................................... .vi CHAPTER I: INTRODUCTION 1.1. Background......................................................................................................... 1 1.2. Indole Chemistry................................................................................................ 2 1.3. Bis-indoles.......................................................................................................... 4 1.4. Synthetic strategies towards bis-indoles............................................................ 6 1.5. Thesis aims..........................................................................................................11 CHAPTER II: SYNTHESIS OF BIS-INDOLES WITH HYDRAZIDE BRIDGES 2.1. Introduction......................................................................................................... 13 2.2. Synthesis of hydrazide bridged bis-indoles....................................................... 14 2.3. Synthesis of 7-carbohydrazides......................................................................... 20 2.4. Synthesis of indole-7-carbaldehydes................................................................. 23 2.5. Biological screening of bis-indoles.................................................................... 28 2.6. Conclusions....................................................................................................... 30 vi CHAPTER III: SYNTHESIS OF 7,7′-BIS-INDOLYL-1,3,4-OXADIAZOLES AND INDOLYL-1,3,4-THIADIAZOLES 3.1. Introduction...................................................................................................... 31 3.2. Synthesis of 7,7′-bis-indolyl-1,3,4-oxadiazoles............................................... 32 3.3. Synthesis of indolyl-1,3,4-oxothiadiazoles...................................................... 37 3.4. Conclusions...................................................................................................... 40 CHAPTER IV: SYNTHESIS OF 7-AMINOMETHYLINDOLE AND RELATED BIS-INDOLE DERIVATIVES 4.1. Introduction...................................................................................................... 41 4.2. Synthesis of 7-aminomethylindole.................................................................. 42 4.3. Synthesis of bis-indoles................................................................................... 45 4.4. Conclusions...................................................................................................... 48 CHAPTER V: SYNTHESIS OF 7,7′-BIS-INDOLES VIA 7-TRYPTAMINE ANALOGUES 5.1. Introduction...................................................................................................... 49 5.2. Synthesis of 7-tryptamine analogues............................................................... 50 5.3. Synthesis of bis-indoles................................................................................... 53 5.4. Synthesis of macrocyclic structures................................................................. 58 5.5. Conclusions...................................................................................................... 66 vii CHAPTER VI: STRATEGIES TOWARDS 7-BROMO-4,6- DIMETHOXYINDOLE AND REACTIVITY OF 4,6- DIMETHOXYBENZOTRIAZOLE

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