SYNTHESIS OF NEW HETEROCYCLE-LINKED BIS-INDOLE SYSTEMS This thesis is submitted in fulfilment of the degree of DOCTOR OF PHILOSOPHY By IBRAHIM FAZIL SENGUL 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 to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have 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. 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Date …………………………………………….............. ŝŝŝ ABSTRACT The primary aim of this project was to synthesize relatively large molecular structures derived from novel 2- and 3-indolyl compounds and to investigate their properties and reactivity. 3,6-Bis-(2-indolyl)-dibenzofurans and 3,6-bis-(2-indolyl)-carbazoles were synthesized from 3,6-diacetyldibenzofuran, 3,6-diacetylcarbazole and their derivatives via the Fischer indole synthesis. Further, the modified Bischler indole synthesis was used to generate 3,6-bis-(3- indolyl)-dibenzofurans derived from 3,6-diacetyldibenzofuran. The most reactive positions of the 2- and 3-indolyl compounds were formylated using the Vilsmeier-Haack reaction to yield the related bis-indole dicarbaldehydes in excellent yields. In addition, the dicarbaldehydes were subsequently reduced to the corresponding bis-indole dimethanols. The attempted synthesis of macrocyclic indoles from the related bis-indole dimethanols by acid catalysed reactions is described in this study. A new range of 2,3'-bis-biindolyl derivatives was synthesized using two different strategies. In the first method, the 2-substiuted bis-indoles were reacted with oxindoles in the presence of phosphoryl chloride. In the second method, the biindolyl compounds were prepared from the acid catalysed reaction of 2-substituted bis-indoles and bromoindoles. Similarly, the reaction of 3,6-bis-(3-indolyl)-dibenzofuran with oxindole generated the corresponding 2,7- bis-biindolyl ring system. ŝǀ The widespread applications of Schiff bases in medicinal chemistry are very significant. The reactivity of the 3,3'-diformyl-3,6-bis-(2-indolyl)-dibenzofurans and related carbazoles was exploited to prepare indole-containing imine macrocyclic compounds by treating the bis-indole dicarbaldehydes with 1,4-diaminobutane and 1,6-diaminohexane. The formation of macrocycles was dependent upon the size and the shape of the linker diamino compounds. The related amine macrocycles were prepared through sodium borohydride reduction of imines. The 2-indolyl compounds were acylated utilizing oxalyl chloride and trichloroacetyl chloride, and subsequently led to the generation of a new class of bis-indole esters and amides. Additionally, the construction of cyclic indolyldiamide systems from bis-gyloxyl- esters and amides and bis-trichloroacetyl indoles was investigated. Ten compounds were selected for biological testing and three compounds in particular were found to have anti-cancer activity in vitro assays ǀ ACKNOWLEDGEMENTS This is by far the most important part of my thesis. I consider myself to be very fortune to have had this opportunity to work with some wonderful people in the world. It is with great gratitude that I write these acknowledgements to show my appreciation to some of the most important people in my life. First of all, I wish to express my deepest thanks to my supervisor, Prof. David StC Black. I could not have imagined having a better advisor and mentor for my PhD degree. Thanks for giving me an opportunity to work on this great project and endless source of knowledge. I would like to thank him for the freedom to develop my own ideas and for continuous guidance and help over the years. I will be indebted to him throughout my life. I am exceptionally grateful to A/Prof Naresh Kumar for very friendly discussions, ideas and motivation throughout this project. I cannot forget to mention the tremendous help from my supervisors at the time of my post-graduate application. Without their help it would have been impossible for me to be accepted as a PhD candidate at the University of New South Wales. I wish to thank all the faculty members in the School of Chemistry, especially the professional staff namely, Jim Hook, Adelle Moore, Don Craig, Mohan Bhadbhade, Barry Ward, Ian Aldred, Joseph Antoon, Toby Jackson, Ken McGuffin, Jodee Anning, Rick Chan, Nick Roberts and Anne Ayres for their timely help. I am also grateful for the help received from Thanh, Michael, Sharif, Berta, Peta, Nancy and Sveto in the teaching labs. ǀŝ Special thanks to Marianne Dick and Ian Stewart at the University of Otago for performing microanalysis determinations and the measurement of HRMS. Thanks to all past and present members of Prof. Black’s and A/Prof Kumar’s group for their cooperation. I am very happy and proud to be a member of this friendly group. Most warmly I will remember Kasey, Samuel, Thanh, Kitty, Ren, Rick, Santosh, Eleanor, Adeline, Venty, Persefoni, Rey, Nidup, Ruth, Frank, Taj, Alam, Miga, Rui, Chris, Daniel, Ani, Yee Yee, Megan, Vishal, and seniors Dr. Able Salek, Dr. George Iskander. Special thanks to my best friends Hakan and Murat for sharing their knowledge of chemistry. They were always caring in all my matters. I am deeply grateful to my beloved parents for their continuous love, prayers and encouragement for my success. I also thank my sisters Hatice and Hacer, brother in law Ahmet and niece Esmanur. I also would like to thank my home mates Emrullah, Sefer, Cemal and Sinan for their indefinable friendship and encouragement. The financial support from the Turkish Government in the form of the Ministry of Education Scholarship during my PhD degree is gratefully acknowledged. THANK YOU, to those who have helped with this thesis. Finaly, I dedicate this thesis to my parents (Osman Nuri & Asiye SENGUL). ǀŝŝ Table of Contents COPYRIGHT STATEMENT͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ŝŝŝ ABSTRACT͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ŝǀ ACKNOWLEDGEMENTS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ǀŝ ABBREVIATIONS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘džŝ PRESENTATIONS͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘džŝǀ CHAPTER 1͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭ Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭ 1.1. General Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭ 1.2. Indole Synthesis͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯ 1.3. Indole Chemistry͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰ 1.4. Bis-Indoles and Indole Macrocycles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲ 1.5. Dibenzofurans and Carbazoles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬ 1.6. Thesis Aims͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϮ