Synthesis of New Heterocycle-Linked Bis-Indole Systems

SYNTHESIS OF NEW HETEROCYCLE-LINKED BIS-INDOLE SYSTEMS

This thesis is submitted in fulfilment of the degree of

DOCTOR OF PHILOSOPHY

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.

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.’

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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-gyloxylesters 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 CHAPTER 2͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϰ Synthesis of New 3,6-Bis-(2-Indolyl)-Dibenzofurans and Carbazoles via Fischer Indole Synthesis͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϰ 2.1. Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϰ 2.1.1. 2-Substituted Bis-Indoles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϰ 2.1.2. Fischer Indole Synthesis͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϲ 2.2. Synthesis of 3,6-Bis-(2-Indolyl)-Dibenzofurans and Carbazoles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϴ 2.3. Attempted Synthesis of Tetrakis-Linked Indoles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϰ 2.4. Attempted Cyclisation of Linked Bis-Indole Systems͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϵ 2.5. Conclusions͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϲ CHAPTER 3͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ Synthesis of New 3,6-Bis-(3-Indolyl)-Dibenzofurans via the Modified Bischler Indole Synthesis ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ 3.1 Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ 3.1.1. 3-Substituted Bis-Indoles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϳ

ǀŝŝŝ 3.1.2. Synthetic Routes to 3-Substituted Bis-Indoles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϯϵ 3.2. Synthesis of 3,6-Bis-(3-Indolyl)-Dibenzofuran͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϭ 3.3. Attempted Cyclisation of 3-Substituted Bis-Indole Systems͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϰϳ 3.4. Conclusions͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϯ CHAPTER 4͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϰ Extension of Bis-Indoles to Bis-Biindolyls͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϰ 4.1. Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϰ 4.2 Synthesis of Biindolyl Systems from Indolin-2-one͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϱϱ 4.3. Synthesis of Biindolyl Systems from 2-Bromoindoles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϮ 4.4. Attempted Synthesis of Cyclic 2,3'-Biindolyl Systems.͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϱ 4.5. Conclusions͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϲϵ CHAPTER 5͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ Bis-Indole Macrocycles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ 5.1. Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ 5.1.1. Schiff Bases͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϬ 5.2. Synthesis of Imine Macrocycles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϯ 5.2.1. Bis-Indole Macrocycles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϳϱ 5.2.2. Bis-Biindolyl Macrocycles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϮ 5.3. Synthesis of Amine-Based Macrocycles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϯ 5.4. Synthesis of Bis-Indole Azomethine Macrocycles͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϱ 5.5. Conclusions͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϴϵ CHAPTER 6͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϬ Electrophilic Reactivity Studies͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϬ 6.1. Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϬ 6.1.1. Reaction with Oxalyl Chloride͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϬ 6.1.2. Reaction with Trichloroacetyl Chloride͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϯ 6.2. Synthesis of Bis-Indolylglyoxyloyl Chlorides͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϰ 6.3. Synthesis of Bis-Glyoxylic Esters and Amides͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϵϲ 6.4. Synthesis of Bis-Indole Carboxamides͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϭ 6.5. Synthesis of Macrocyclic Indolyl-Diamides͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϯ 6.6. Conclusions͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϲ

ŝǆ CHAPTER 7͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϳ Biological Activity͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϳ 7.1. Introduction͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϳ 7.2. Anti-Cancer Screening͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϬϳ 7.3. Conclusions͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϬ CHAPTER 8͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϭ Experimental͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϭ 8.1. General Information͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϭ 8.2 Experimental Details͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϯ 8.2.1 General Synthetic Procedures:͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϭϯ ,WdZϵ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϵϳ WWE/y͗yͲZĂǇƌǇƐƚĂůůŽŐƌĂƉŚǇĂƚĂ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϵϳ CHAPTER 10͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϮϬϰ References͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϮϬϰ

ABBREVIATIONS

Ac2O acetic anhydride

AcOH acetic acid

AlCl3 aluminum chloride

Ar Aryl

Br2 Bromine

BF3 boron trifluoride

CCl4 carbon tetrachloride

CHCl3 Chloroform

CH3CO2K potassium acetate

(COCl)2 oxalyl chloride

Conc. concentrated

CS2 carbon disulfide

DCM dichloromethane

DMF dimethylformamide

DMSO dimethylsulfoxide

ESI electroscopy ionization

Et Ethyl

Et2O diethyl ether

Et3N triethylamine

EtOH Ethanol

ǆŝ h hour(s)

HCl hydrochloric acid

HCHO formaldehyde

HRMS high resolution mass spectrometry

IR infrared spectroscopy i-PrOH Isopropanol

KOH potassium hydroxide

Me Methyl

MeCN Acetonitrile

MeO Methoxy

MeOH Methanol

Min Minute mL milliliter(s) mmol milli mol

μM micro molar

NaBH4 sodium-borohydride

NaHCO3 sodium-bicarbonate

NH3 Ammonia

NMR nuclear magnetic resonance p-TsOH p-toluenesulfonic acid ppm parts per million

POCl3 phosphoryl chloride

PPA polyphosporic acid

ǆŝŝ PCl3 phosphorus trichloride

THF tetrahydrofuran

TFA trifluoroacetic acid

TLC thin layer chromatography

TFAA trifluoroacetic anhydride

TiCl4 titanium tetrachloride

UV ultraviolet spectroscopy

ZnCl2 zinc chloride

ǆŝŝŝ

PRESENTATIONS

A part of this research has been presented at the following conferences.

1. Ibrahim Fazil Sengul, Naresh Kumar, David StC. Black, Synthesis of Di-Indolyl

Substituted Dibenzofurans and Carbazoles, RACI Natural Group Annual One-Day

Symposium, Newcastle University, NSW, October 2009, (Poster Presentation).

2. Ibrahim Fazil Sengul, Naresh Kumar, David StC. Black, Synthesis of Di-Indolyl

Substituted Dibenzofurans and Carbazoles, The Royal Australian Chemical Institute

30th Annual One-Day Symposium, Sydney University, NSW, December 2009,

(Poster Presentation).

3. Ibrahim Fazil Sengul, Naresh Kumar, David StC. Black, Synthesis of 2,2'-Linked

Bis-Indole Macrocycles, RACI Natural Product Group Annual One-Day

Symposium, Macquarie University, NSW, October 2010, (Poster Presentation).

4. Ibrahim Fazil Sengul, Naresh Kumar, David StC. Black, Synthesis of Bis-Indole

Macrocycles, 23th International Congress on Heterocyclic Chemistry, Glasgow,

Scotland, August 2011, (Poster Presentation).

ǆŝǀ CHAPTER 1

Introduction

1.1. General Introduction

Indole heterocyclic systems are biologically important scaffolds that occur widely in many natural products including plants,1 fungi2 and marine organisms.3 Over the past 130 years, the chemistry of indole 1 has been the subject of intense study and considerable effort has been devoted to the synthesis of complex and pharmacologically active indole alkaloids.4

Some of the more commonly known indole compounds include the neuro-transmitter serotonin (5-hydroxytrptamine) 2,5 the halucinogen lysergic acid diethylamide6 (LDS) 3 and the anti-inflammatory agent indomethacin 4.7,8

2 &+ &22+ 0H 1 0H 0H2 1+ 1 0H +2 0H 1 1 & 2 + 1 VHURWRQLQ + &O O\VHUJLF DFLG GLHWK\ODPLGH /6' LQGRPHWKDFLQ

ϭ 1.2. Indole Synthesis

Since the first synthesis of indole in 1866, a variety of synthetic methods for the construction of indoles have been explored.9,10 The most commonly used methods for the preparation of indoles are the Fischer and Bischler indole syntheses.11,12,13,14

Emil Fischer reported his method for the synthesis of indole in 1883.11,12 According to the

Fischer method, an N-aryl-hydrazone 5 undergoes acid-catalysed or thermal sigmatropic rearrangement to generate the indole skeleton 6 after the elimination of ammonia (Scheme

1.1).15

Scheme 1.1

Alternatively, the Bischler rearrangement method involves the cyclisation of amino- ketones, prepared from the condensation of aniline with phenacyl bromides, to give 2- substituted indoles (Scheme 1.2).16 The classical problem with the Bischler technique is the rearrangement that occurs during the cyclization of the secondary phenacylaniline, in the presence of a trace amount of aniline hydrobromide, to give the corresponding 2- phenylindole.

Scheme 1.2 Reagents and conditions: a) EtOH, NaHCO3, reflux, 2 h b) aniline

hydrobromide, silicone oil, inert gas, 130 oC, 3 h

By comparison, a modified Bischler method has been used to generate 3-substituted-4,6- dimethoxyindoles.17 This approach involved treatment of 3,5-dimethoxyaniline 7 with halogenated ketones 8 in the presence of an inorganic base such as sodium bicarbonate to afford the substituted phenacyl aniline intermediates 9. The anilino-ketones 9 are subsequently N-protected with acetic anhydride to give the corresponding amides 11 which are then cyclised in the presence of trifluoroacetic acid to generate N-acetylindoles 12.

Deprotection via treatment with methanolic potassium hydroxide affords the desired 3- substituted-4,6-dimethoxyindoles 13 (Scheme 1.3).17

Scheme 1.3 Reagents and conditions: a) NaHCO3, EtOH, reflux 2 h b) Ac2O, r.t., overnight

c) TFA, 100 oC, under argon, 2 h, d) MeOH, KOH, r.t., 1 h

A large number of activated 2-substituted, 3-substituted and 2,3-disubstituted indoles bearing methoxy groups at the C4 and C6 positions have been produced by our group via the Bischler rearrangement and modified Bischler indole synthesis methods.

1.3. Indole Chemistry

In general the most reactive site of the indole nucleus with respect to electrophilic substitution is the C3 position. N-Substitution can be obtained in cases where a nitrogen anion is the reactive intermediate. In the event that C3 is blocked by a substituent, electrophilic substitution is diverted to the C2 position.18,19

ϰ 20H ( 5 ( 1 1 0H2 1 + + + (

Figure 1.1

Further substitution patterns on the indole ring divert reactivity to other sites. This is

illustrated in one case by the development of a range of 4,6-dimethoxyindoles where

the reactivity at the C7 position can be increased by the two electron donating methoxy

groups at the C4 and C6 positions.20 Studies of various electrophilic substitutitons such

as formylation of 3-substituted-4,6-dimethoxyindoles 16a-c showed that 7-substituted

products 17a-c are obtained in preference to 2-substituted indoles 18a-c (Scheme

1.4).21

o Scheme 1.4 Reagents and conditions: POCl3, DMF, 0 C

Indole based imine formation is one of the significant methods for the preparation of indolo-macrocyclic compounds, which have been generated by the condensation of indole dialdehydes and various diamines.22 For example, the monoindolyl macrocyclic have been

ϱ obtained in the form of their metal complexes 2323 from template reactions of the dialdehyde 22 and selected diamino compounds 19-21.

20H 20H 0H 0H +

0H2 1 2 0H2 1 1 + 0 + 1 1 2

0 1L &X

+ 1 + 1 +1

+1 +1 +1 +1 +1 +1 2 2 2

1.4. Bis-Indoles and Indole Macrocycles

Bis-indole alkaloids are an important and prolific structural class and possess interesting biological properties. For example, nortopsentins 24a-c are bis-indole alkaloids, isolated from the Caribbean deep-sea sponge Spongosorites reutzleri, and show cytotoxicity and antifungal activity.24,25 2,4-Bis-(3-indolyl)-pyrazine 25 also displays a broad spectrum of cytotoxic activity.26

Furthermore, bis-indole systems may be readily exploited for the development of novel macrocyclic systems. Macrocyclic bis-indolylmaleimides 26a-d and 27 are examples of biologically active macrocyclic compounds, which show good selectivity for protein kinase

C (PKC) and glycogen synthase kinase-3 (GSK-3).27

+ + 2 1 2 2 1 2

1 1 1 1

0H 2 2 0H 1 1 1 1 5 0H DG D 5 (W E 5 0H F 5 L3U G 5 +2&+&+

Numerous methods can be used to synthesise bis-indole macrocylic compounds. For example, Rajakumar et. al. reported that the preparation of macrocyclic indolophane

ϳ compounds 29a-c from indolophane dialdehydes 28a-c utilizing intramolecular McMurry coupling methodology (Scheme 1.5).28

Scheme 1.5 Reagents and conditions: TiCl4, Zn, THF, pyridine, reflux, overnight

Our group has previously synthesized bis-indole based imine macrocycles 3029 and 3130 via condensation of the corresponding 2,2'-biindolyl-7-dialdehyde with diamines in benzene in the presence of molecular sieves.

7,7'-Biindolyl-2-dialdehydes 32 and 33 were also utilized by our group to generate bis- indole imine systems. The dialdehydes 32 and 33 were heated under reflux overnight with two diamino compounds in isopropanol to yield the imine macrocyclic compounds 34 and

35 as free ligands (Scheme 1.6).31,32,22

Scheme 1.6 Reagents and conditions: 1,2-diaminoethane and 1,3-diaminopropane, i-

PrOH, reflux

As an alternative approach, the macrocyclic biindolylmethanediamides 38 have been prepared in moderate yields through treatment of 7-trichloroacetylindoles 36 at room temperature with diamines in acetonitrile followed by condensation with formaldehyde or an aryl aldehyde in methanol containing acetic acid (Scheme 1-7).33

ϵ 20H 20H 0H2 $U $U $U D

0H2 1 0H2 1 1 20H + + + 1+ &O& 2 +1 2 2

20H 0H2 $U 5 $U

20H 0H2 1 1 + + 1+ +1 2 2

Scheme 1.7 Reagents and conditions: a) diamines, MeCN, r.t.,1 h. b) con. HCl, RCHO,

MeOH

Overall, bis-indole based macrocycles such as 30, 31 and 38 are of interest due to their potential use as molecular receptors for the inclusion of metal cations, anions or neutral molecules.29,30,33

1.5. Dibenzofurans and Carbazoles

Dibenzofuran 39, carbazole 40 and their derivatives are rigid heterocyclic systems that have been a source of great interest for chemists due to the wide spectrum of their biological properties.34,35

ϭϬ

Carbazole 40 and its derivatives are an important class of nitrogen containing aromatic heterocyclic compounds, having long attracted attention from researchers due to their valuable properties.36 Carbazole-based compounds are attractive as photoelectrical materials and dyes, as well as for supramolecular recognition and medicinal chemistry.36

The carbazole family of compounds presents a variety of biological activities. For example, the carbazomycins 41a and 41b are antibiotics with a carbazole framework, while the interesting indolo carbazole microbial alkaloid K-252a 42 is a broad-spectrum protein kinase inhibitor.36

+ 1 2 52 20H ; ;

0H 1 1 1 + 0H 0H &2 0H 2+ D &DUED]RP\FLQ $ 5 0H E &DUED]RP\FLQ % 5 +

Certain dibenzofuran derivatives also show biological activity, including inhibition of the clotting of thrombin and inhibition of serotonin.35 Usnic acid 43 is an example of a biologically active dibenzofuran derivative which shows anti-bacterial activity.37

ϭϭ

Another significant feature of carbazole and dibenzofuran in the field of synthetic chemistry is that these compounds are easily functionalized and can be covalently linked to other molecules.38,39

1.6. Thesis Aims

The general aim of the work described in this thesis was to develop dibenzofuran and carbazole linked bis-indole compounds (Figure 1.2) and explore their potential as building blocks to larger macrocyclic structures. Specifically, 3,6-bis-(2-indolyl)-dibenzofuran and carbazoles and 3,6-bis-(3-indoly)-dibenzofurans which could undergo electrophilic substitutions and additions at the vacant C3 or C2 position respectively were targeted. 4,6-

Dimethoxyindoles were also exploited in order to provide additional reactivity at the C7 position.

Figure 1.2

Chapter 2 of this thesis describes the preparation of a range of 3,6-bis-(2-indolyl)- dibenzofuran and carbazole derivatives via the Fischer indole synthesis. The attempted

ϭϮ development of 3,3'-diindolylmethane based macrocycles from these systems is also presented.

In Chapter 3 the preparation of new 3,6-bis-(3-indolyl)-dibenzofurans by the modified

Bischler indole synthesis is described. The C2 and C7 reactivity of these systems is also explored towards the development of novel diindolylmethane based macrocycles.

Chapter 4 discusses the construction of new bis-biindolyl structures from the 2- and 3- susbtituted bis-indoles through treatment with a number of oxindole derivatives.

Chapter 5 of this thesis investigates the preparation of imine based macrocycles from the

2- and 3-substituted bis-indole dicarbaldehydes and bis-biindolyl dicarbaldehydes. The reduction of these imine based macrocycles to the corresponding diamino macrocycles is also reported.

Chapter 6 presents the reactivity of the 3,6-bis-(2-indolyl)-dibenzofurans and carbazoles and 3,6-bis-(3-indolyl)-dibenzofurans towards electrophilic substitutions and additions with oxalyl chloride and trichloroacetyl chloride. The use of bis-trichloroacetylindoles in the preparation of the new macrocyclic diamide system is also discussed.

Chapter 7 of this thesis shows the preliminary anti-cancer screening results of selected bis- indole derivatives.

ϭϯ CHAPTER 2

Synthesis of New 3,6-Bis-(2-Indolyl)-Dibenzofurans and

Carbazoles via Fischer Indole Synthesis

2.1. Introduction

2.1.1. 2-Substituted Bis-Indoles

Bis-indole alkaloids are compounds consisting of two indoles connected to each other, often via heterocyclic units.40,41 Bis-indole derivatives are an important structural class due to their interesting biological properties and are therefore an important target for drug design.42-44 Nortopsentin 24 is one example of a bis-indole, and shows interesting anti- inflammatory activity as mentioned in Chapter 1. In connection with this, bis-indole derivatives are an interesting target for synthetic developments.45

Owing to the structural diversity of this class of compounds, numerous synthetic methods for the synthesis of bis-indoles are reported in the literature.46,47 Gu et. al.48 have reported the synthesis of 2,4-bis-(3-indolyl)-thiazoles 46-49 using the Hantzsch reaction. This entailed a mixture of thioamides 44 and Į-bromoketones 45 being heated under reflux in absolute ethanol to give the bis-(3-indolyl)-thiazole products in excellent yield. The thiazole nortopsentin analogues 46-49 were afforded upon removal of the toluenesulfonyl group and showed important cytotoxic activities against a variety of human cancer cell lines in vitro.48 ϭϰ

Scheme 2.1 Reagents and conditions: a) EtOH, reflux, 1 h b) NaOH, MeOH, reflux

Another example, reported by Blades and Wilds, utilises the reaction of diazo ketones with aniline salts. p-Bis-(2-indolyl)-benzene 50 was prepared from the diazo ketone and

49 terephthaloyl chloride in the presence of BF3 in 10 % yield.

In general, the reported synthetic strategies to bis-indoles involve the introduction of the heterocyclic unit to substituted indoles. The preparation of bis-indoles from substituted heterocycles using well known indole synthesis methods therefore represents a less common synthetic approach.

ϭϱ 2.1.2. Fischer Indole Synthesis

Although many methods have been developed for the synthesis of indoles,50,51 the Fischer indole synthesis is the most reliable and commonly used method.52-55 This reaction entails the two step synthesis of C2 substituted indoles starting from phenylhydrazine and an aromatic ketone.56-58

Mechanistically, the Fischer indole synthesis proceeds via the reaction of phenylhydrazine

51 with an aldehyde or a ketone 52 to form a phenylhydrazone 53, which subsequently undergoes [3,3]-sigmatropic rearrangement, ring closure and aromatization to give the

59,60 indole 54 (Scheme 2.2). A range of acid catalysts including Brønsted acids (H2SO4,

HCl, PPA, AcOH), Lewis acids (ZnCl2, TiCl4, PCl3) and solid acids (zeolite, montmorillonite clay), have been used to facilitate the cyclisation of the arylhydrazone.59

Although aldehydes can be used in this reaction, they have been noted to undergo unexpected side reactions such as aldol or aromatic substitution under the harsh Fischer conditions.61

Scheme 2.2 The mechanism for Fischer indole synthesis

ϭϲ The Fischer indole synthesis has been successfully employed, for example, to give good yields of 2-(4-bromophenyl)-indole 57. Heating phenylhydrazine 51 at reflux with 4- bromoacetophenone 55 afforded phenylhydrazone 56 which was subsequently cyclised upon treatment with polyphosphoric acid (Scheme 2.3).62

Scheme 2.3 Reagents and conditions: a) EtOH, reflux, 2 h b) polyphosphoric acid, 110 oC

The versatility of this synthetic methodology was anticipated to lend itself towards the synthesis of a new range of 2-substituted bis-indoles. In particular, 2-substituted bis-indole systems 58, based on dibenzofuran, carbazole and carbazole derivatives were targeted along with the tetrakis structure 59. The reactivity of these systems was subsequently explored for the development of macrocyclic systems such as compound 60.

ϭϳ

2.2. Synthesis of 3,6-Bis-(2-Indolyl)-Dibenzofurans and Carbazoles

Dibenzofuran, carbazole and their derivatives were chosen as linkers to synthesise 3,6-bis-

(2-indolyl)-dibenzofurans and carbazoles 58. As already mentioned, the carbazole and dibenzofuran ring systems are easily functionalized and covalently linked to other molecules.38,39 In particular, dibenzofuran and carbazole undergo Friedel-Crafts acetylation at the C3 and C6 positions using aluminium trichloride as the catalyst.63,64 This reaction therefore provides a facile route to suitable ketone precursors for the Fischer indole synthetic method.

Bruce et. al.63 have reported acetylation of dibenzofuran 39 using Friedel-Crafts reaction conditions. According to the reported procedure, acetylation of dibenzofuran 39 occurred readily by heating at 50 °C in the presence of acetyl chloride and aluminium trichloride for

15 h to generate the corresponding 3,6-diacetyl compound 63 in 90% yield (Scheme 2.4). It was also found in the literature64 that when carbon disulfide was employed as a solvent, the reaction was completed after 6 h. Therefore, using the above methodology in the presence

ϭϴ of carbon disulfide as solvent, carbazole 40, N-methylcarbazole 61 and N-ethylcarbazole 62

were acetylated to afford the corresponding 3,6-diacetyl compounds 64-66 in high yields.

o Scheme 2.4 Reagents and conditions: AlCl3, CH3COCl, CS2, 50 C, 6 h

Aromatic ketones 63-66 were subsequently reacted with phenylhydrazine 51 in order to

produce the corresponding phenylhydrazone intermediates 67-70 (Scheme 2.5).

0H 0H 1+ +1 1 1

; 2 2 ; 2 0H 0H ; 1+ 1+ 1 ; 10H ; + ; 1(W

; 2 2 ; 1+ 0H ; 10H +1 1 0H ; 1(W

1 0H

Scheme 2.5 Reagents and conditions: EtOH, HOAc, reflux, 3 h

ϭϵ When aromatic ketone 63 was condensed with phenylhydrazine in the presence of absolute ethanol and a few drops of glacial acetic acid, phenylhydrazone 67 was produced as a single product in 80% yield. Similar treatment of ketones 64-66 afforded the corresponding phenylhydrazone derivatives 68-70 in comparable yields.

However, two products were obtained when N-methyldiacetyl carbazole 65 was reacted with phenylhydrazine 51. The major product, obtained in 78% yield, was identified as the desired phenylhydrazone 69, while the minor product was identified as the mono-reacted compound 71 in 13% yield.

The molecular weights of the compounds 67-71 were determined by ESI mass spectrometry, which revealed the anticipated molecular ions at m/z 433, 432, 446, 460, 356

(M+1) respectively.

The 1H NMR and 13C NMR spectra of compound 67 were characteristic for compounds 68-

70. The 1H NMR spectrum of compound 67 showed the presence of a singlet at 2.39 ppm corresponding to the two sets of C-methyl protons. The spectrum also showed the presence of additional 12 protons at 6.88 ppm and 7.22-7.36 ppm along with 10 phenylhydrazone protons and 2 NHs. Additionally, the dibenzofuran protons of compound 67 appeared at

7.57, 7.97 and 8.33 ppm.

The 1H NMR spectrum of compound 71 in DMSO displayed three singlets at 2.40, 2.68 and 3.90 ppm which corresponded to the acetyl group, C- and N-methyl protons, respectively. The spectrum also showed one broad singlet at 9.02 ppm corresponding to one

NH proton. The DEPT 135 and 13C spectrum supported the structure 71 with the carbonyl and methyl carbons of the acetyl group appearing at 197.4 ppm and 27.1 ppm respectively.

ϮϬ Acid catalysed cyclisation of the phenylhydrazone 67 in the presence of methanesulfonic acid produced a mixture of two compounds which were separated by column chromatography. The major product, isolated in 75% yield was identified as the desired

3,6-bis-(2-indolyl)-dibenzofuran 72 while the minor product was determined to be the mono-indole product 76 which was produced in 12% yield (Scheme 2.6). The structure of compound 76 was determined through NMR spectroscopy with the 1H NMR spectrum showing a singlet at 2.71 ppm corresponding to the acetyl methyl proton and the indole NH proton appeared at 11.62 ppm. The 13C NMR spectrum showed a methyl carbon resonance at 27.1 ppm and a carbonyl carbon at 197.3 ppm, which are characteristic peaks for the acetyl group.

Scheme 2.6 Reagents and conditions: methanesulfonic acid, 110 oC, 1.5 h

The related cyclisation of phenylhydrazones 68 and 70 in the presence of methanesulfonic acid also gave two products, with the major products being identified as the target 3,6-bis-

(2-indolyl)-carbazoles 73 and 75 (Scheme 2.7). In contrast to the previous reaction, however, the minor products were identified as the mono-indoles 77-78 which were obtained in low yields (Table 2.1). Interestingly, the methyl substituted analogue 69 afforded only the bis-indole compound 74 in 73% yield.

Ϯϭ

Scheme 2.7 Reagents and conditions: methanesulfonic acid, 110 oC, 1 h

Table 2.1 Yields of 2-substituted indoles 72-78.

X Bis-indole Yield (%) Mono-indole Yield (%)

O 72 75 76 12

NH 73 67 77 14

NMe 74 73 - -

NEt 75 75 78 18

The structures of compounds 72-75 were supported by 1H NMR and 13C NMR spectroscopic data. The 1H NMR spectrum of the compound 72 in DMSO (Figure 2.1), as a typical example of the 2-substituted bis-indole derivatives, displayed a doublet at 6.95 ppm

ϮϮ corresponding to the indole H3 and H3' protons and the indole NH protons appeared as a broad singlet at 11.67 ppm. The disappearance of the two C-methyl protons as compared to spectrum of the starting material indicated that cyclisation had taken place. The 13C NMR spectrum revealed the presence of the C3 and C3' carbon peaks at 98.9 ppm. The loss of the

C-methyl signals as compared to 67 again indicated that cyclisation had occurred. Further structural verification was obtained via mass spectrometry, with the ESI mass spectra revealing (M+1) peaks at m/z 399, 398, 412 and 426, consistent for compounds 72-75 respectively.

Figure 2.1: 1H NMR spectrum of the compound 72

Identification of compounds 77 and 78 was performed through 1H and 13C NMR spectra and mass spectrometry data. The 1H NMR spectrum of compound 77 in DMSO showed the

H3 proton as a singlet at 6.86 ppm and presented two singlets at 11.35 and 11.49 ppm

Ϯϯ corresponding to the carbazole and indole NH respectively. The 13C NMR spectrum displayed the C3 carbon peak at 97.5 ppm. In addition to this, the ESI mass spectrum revealed a (M+1) peak at m/z 283. In contrast, the 1H NMR spectrum of compound 78 in

DMSO exhibited a triplet at 1.34 ppm corresponding to the methyl protons and a quartet at

4.40 ppm corresponding to the methylene proton. Additionally, the ESI mass spectrum showed the molecular ion at m/z 311 (M+1).

2.3. Attempted Synthesis of Tetrakis-Linked Indoles

The Fischer indole synthetic method proved highly effective in the preparation of carbazole linked bis-indoles. It was therefore of interest to determine whether the methodology could be extended to the development of a tetrakis system in which two carbazole units are linked.

The xylyl linkers 79-81 were chosen for this study in order to generate N,N'-linked carbazoles. Alkali metal salts of carbazoles are known to undergo N-alkylation with alkyl halides.65 Thus, carbazole was reacted with Į,Į'-dibromo-p-xylene 79 in the presence of potassium hydroxide in DMSO to give compound 82 in 74% yield. Similar treatment of carbazole with Į,Į'-dibromo-m-xylene 80 and Į,Į'-dibromo-o-xylene 81 gave the corresponding meta- and ortho- substituted analogues 83 and 84 in good yields.66

Ϯϰ S/LQNHU P/LQNHU R/LQNHU

&+ %U &+ %U &+ %U 1 &+%U 5 5 5 5 &+%U 1 &+%U

Figure 2.2 Symmetrically linked carbazoles

N,N'-linked carbazoles 82-84 were then acetylated using Friedel Crafts reaction conditions.

Treatment of bis-carbazoles 82-84 for 6 h at 50 oC with acetyl chloride and aluminium chloride in carbon disulfide gave the corresponding 3,3',6,6'-tetraacetyl compounds 85-87 in 48-53% yields (Scheme 2.8).

o Scheme 2.8 Reagents and conditions: AlCl3, CH3COCl, CS2, 50 C, 6 h

Ϯϱ The chemical shifts of the methyl and N-methylene protons in the 1H NMR spectra of compounds 85-87 were characteristic for the 3,3',6,6'-tetraacetyl compounds 85-87, as shown in Table 2.2. In particular, the 1H NMR spectrum of compound 85 showed a singlet at 2.67 ppm corresponding to the twelve methyl protons and the N-methylene protons appeared at 5.44 ppm. In compound 85 containing the aromatic ring substituted at the para position, it was observed that the protons corresponding to aromatic ring appeared as a singlet at 6.94 ppm. However, in the spectra of compounds 86 and 87 which possess the aromatic nucleus linked at meta- and ortho- positions, the aromatic ring protons were coupled and appeared as doublets and multiplets. The 13C NMR spectrum further supported the structure, with a carbonyl resonance appearing at 201 ppm and the mass spectrum revealed a peak at m/z 627 (M+Na) which was consistent for compound 85.

Table 2.2 Selected 1H NMR spectral data (į, ppm) of tetra-acetyl compounds 85-87.

ǻ 85 86 87

CH2N 5.44 5.49 5.51

CH3 2.67 2.67 2.67

The next stage of the Fischer indole synthesis was to generate the tetra-hydrazones by condensation of the 3,3',6,6'-tetra-acetyl compounds 85-87 with phenylhydrazine in ethanol containing a drop of acetic acid at reflux. However, the desired tetra-hydrazone compounds

88 could not be isolated. Therefore, the subsequent step of cyclisation was attempted in the presence of methanesulfonic acid (Scheme 2.9). Unfortunately, after work up the reaction

Ϯϲ failed to yield any pure product for characterization. However, the crude product from the reaction mixture showed a m/z peak at 911 (M+Na) corresponding to the tetrakis-indole 89.

2 2 0H 0H 0H 0H 1 1 1 1 + + 1 1 5 D 1+ 5 1 + 1 1 + + 1 0H 0H 1 1 1 2 2 0H 0H E

+1 1 +

+ 1 +1

Scheme 2.9 Reagents and conditions: a) EtOH, HOAc, reflux, 2 h b) methanesulfonic acid,

110 oC, 2 h

An alternate approach to the tetrakis system was to investigate the N-alkylation of the already prepared bis-indole system with Į,Į'-dibromo-p-xylene 79. Initially, the reaction of

2-indolyldibenzofuran 72 and Į,Į'-dibromo-p-xylene 79 were performed at room

Ϯϳ temperature for 3 h in DMSO in the presence of potassium hydroxide in order to examine the reactivity of the indole NH groups which could lead to the generation of side product.

However, the reaction gave polymers or complex mixtures, however, either at room temperature or when the reaction was repeated at reflux (Scheme 2.10). It was thought that unfavourable steric interactions were most likely inhibiting the reaction.

With the observed lack of reactivity at the indole NH in compound 72, the related alkylation of the corresponding 2-indolylcarbazole 73 was subsequently explored for the generation of the target tetrakis system. Carbazole 73 was heated at room temperature with

Į,Į'-dibromo-p-xylene 79 in DMSO in the presence of potassium hydroxide for 12 h.

However, the desired tetrakis-linked indole was not obtained (Scheme 2.10). It was thought that either tetrakis-linked indole was again not formed due to steric hindrance or the reaction gave a mixture of polymeric product.

Scheme 2.10 Reagents and conditions: a) DMSO, KOH, r.t., 3 h or b) DMSO, KOH, 100

oC, 12 h

Ϯϴ 2.4. Attempted Cyclisation of Linked Bis-Indole Systems

The acid catalysed cyclisation of dimethanols is a versatile method for the preparation of novel macrocyclic systems, particularly from bis-indoles. According to the literature,22 indole macrocycles 91 can be prepared in 60% yield through treatment of diindolyldimethanol 90 with a catalytic amount of p-toluenesulfonic acid in dry acetone

(Scheme 2.11).

2+ +2 1 1

1 1

Scheme 2.11 Reagents and conditions: acetone, p-TsOH , r.t., 1 h

It was anticipated that this methodology could be applied to the 3,6-bis-(2-indolyl)- dibenzofurans and carbazoles to generate a novel range of macrocylic systems. In particular, the required dimethanol precursors could be readily accessed via the bis-indole dicarbaldehydes.

It is well known that C3 is the most reactive indole position for electrophilic aromatic substitution reactions such as formylation,67 which can be readily achieved through a variety of methods. In this instance, Vilsmeier-Haack conditions were selected due to its simplicity, convenience, ability to achieve high yields and applicability to bis-indole

Ϯϵ systems. For example, work done by our group22 has shown that the N-alkylated indole-

3,3'-dicarbaldehydes 93 can be produced from the 1,1'-diindolyl compound 92 in reasonable yield using two equivalents of Vilsmeier-Haack formylating reagent at 0 oC

(Scheme 2.12).

o Scheme 2.12 Reagents and conditions: POCl3, DMF, 0 C

Therefore, the preparation of 2-substituted bis-indole dicarbaldehydes under Vilsmeier-

Haack reaction conditions was investigated. The reaction of the dibenzofuran 72 with five equivalents of phosphoryl chloride in DMF at 0 oC gave the corresponding 3,3'-diformyl-

3,6-bis-(2-indoly)-dibenzofuran 94 in 90% yield. In a similar manner, compounds 95-97 were prepared from the corresponding 3,6-bis-(2-indolyl)-carbazole derivatives 73-75 under Vilsmeier-Haack reaction conditions in 85, 90 and 80% yield respectively (Scheme

2.13).

ϯϬ

o Scheme 2.13 Reagents and conditions: POCl3, DMF, 0 C, overnight

The spectroscopic data of bis-indole dicarbaldehyde 94 was characteristic for compounds

94-97. The 1H NMR spectrum showed the disappearance of the H3 and H3' signal at 6.96 ppm and the appearance of a new sharp singlet at around 10.08 ppm which corresponded to the aldehyde protons. Similarly, the carbonyl groups appeared as a new resonance at 186.1 ppm in the 13C NMR spectrum and showed a stretching mode frequency at 1583 cm-1 in the

IR spectrum.

Unfortunately, compounds 94-96 were found to be poorly soluble in a range of organic solvents. Attention therefore turned to the preparation of the corresponding N-alkyl derivatives in an effort to improve the solubility of these compounds. It is well known that alkali metal salts of pyrrole and indole can be N-alkylated with alkyl halides.65 In particular,

N-methylation of indole can be achieved in DMSO with methyl iodide in the presence of

KOH.68 Thus 3,6-bis-(2-indolyl)-dibenzofuran and carbazoles 72-74 were treated with an excess of potassium hydroxide and methyl iodide in DMSO for 2 h at room temperature to

ϯϭ generate the corresponding N-methyl analogues 98 and 99 in good yield (Scheme 2.14). In the case of carbazole 73, alkylation occurred at the carbazole NH in addition to the indole

NH to yield the trimethyl compound 99.

Scheme 2.14 Reagents and conditions: DMSO, KOH, methyl iodide, r.t.. 2 h

The 1H NMR spectrum of compound 98 showed the disappearance of the two NH protons at 11.6 ppm and the appearance of a new singlet at 3.82 ppm correlating to the methyl groups, which similarly apparent at 31.5 ppm in the 13 C NMR spectrum. Compound 99 showed the corresponding indole N-methyl groups at 3.73 ppm and 29.8 ppm in the 1H and

13 C NMR spectra respectively, in addition to a second set of signals at 3.90 ppm and 31.5 ppm owing to the carbazole N-methyl group. Further structural confirmation was provided by the ESI mass spectra which showed peak at m/z 427 and 440 (M+1) for compounds 98 and 99 respectively.

With the N-substituted bis-indoles 98 and 99 in hand, preparation of the corresponding N- substituted dicarbaldehydes under Vilsmeier-Haack conditions was undertaken. Treatment of compounds 98 and 99 with an excess of phosphoryl chloride in DMF at 0 oC gave the

ϯϮ more soluble bis-indole dicarbaldehydes 100 and 101 in 86 and 77% yield respectively. The

1H and 13C NMR spectra of compound 100 and 101 were consistent with the related analogues 94 and 96.

o Scheme 2.15 Reagents and conditions: POCl3, DMF, 0 C, overnight

Attention subsequently turned to the reduction of the dicarbaldehydes 94-97 and 100-101 to the corresponding alcohols. Previous work has shown that hydroxymethyl indoles can be readily obtained in good yields from the carbaldehydes upon treatment with sodium

69 borohydride as a reducing agent. Therefore, reduction of bis-indole dicarbaldehyde 94 by sodium borohydride was investigated in a number of solvents, such as methanol, ethanol and isopropanol to optimise the yield of product 102. It was found that when ethanol was employed as a solvent, the reaction gave the maximum yield of 78%. Similar treatment of compounds 95-97 and 100-101 with sodium borohydride in absolute ethanol gave the corresponding bis-indole dimethanols 103-107 in good yields (Scheme 2.16).

ϯϯ

Scheme 2.16 Reagents and conditions: EtOH, NaBH4, r.t., 6 h.

The generation of rigid 22-membered ring macrocyclic systems via acid catalysed condensation of bis-indole dimethanols 102-107 with p-toluensulfonic acid in dry acetone was finally explored. Treatment of bis-indole dimethanol 102 for 1 h at room temperature with p-toluenesulfonic acid in the presence of dry acetone was found to give a mixture of compounds which could not be separated by column chromatography. To determine whether the solubility of the starting material was influencing the reaction outcome, compound 105 was also reacted with acetone and p-toluenesulfonic acid but was found to produce a similar result.

ϯϰ

Scheme 2.17 Reagents and conditions: acetone, p-TsOH, r.t., 1 h

The related cyclisation of bis-indole dimethanols 102-107 with acetic acid at room temperature was then investigated. After stirring at room temperature for 3 days, however, complex polymeric materials were produced in preference to the desired indole macrocycles.

Scheme 2.18 Reagents and conditions: HOAc, r.t., 3 days

Attention subsequently turned to the acid catalysed cyclisation of these compounds in the presence of a benzaldehyde in an attempt to reduce the formation of polymeric products.

Bis-indole 102 was therefore reacted at reflux with benzaldehyde in methanolic

ϯϱ hydrochloric acid for 12 h but no significant reaction was observed. Similarly, the desired

22-membered macrocyclic compounds 109 and 110 were not produced from the corresponding condensation of the N-substituted bis-indole derivatives 106 and 107.

Scheme 2.19 Reagents and conditions: MeOH, benzaldehyde, HCl, reflux, 12 h

Overall, the preparation of indole macrocycles from bis-indole dimethanols under acid catalysed conditions proved to be problematic with either no reaction occurring or polymeric materials being produced.

2.5. Conclusions

A new range of 3,6-bis-(2-indolyl)-dibenzofuran and carbazole derivatives have been successfully prepared from starting dibenzofuran and carbazoles via Fischer indole synthesis. In addition to this, the indoles were successfully formylated at the C3 positions, and the aldehyhydes subsequently reduced to the related methanols.

ϯϲ CHAPTER 3

Synthesis of New 3,6-Bis-(3-Indolyl)-Dibenzofurans via the

Modified Bischler Indole Synthesis

3.1 Introduction

3.1.1. 3-Substituted Bis-Indoles

As already mentioned, bis-indole alkaloids are an important class of compounds due to their high degree of biological acitivity.42-44 Of this class, the 3-substituted bis-indoles are perhaps the most prolific owing to the C3 position being the most reactive indole site.

Examples include the bis-indole demethylasterriquinone B1 111 which is a selective activator of the insulin receptor70 and bromodeoxytopsentin 112 and isobromodeoxytopsentin 113 which showed moderate cytotoxicity against a human leukemia cell-line.71

ϯϳ Additionally, the bis-indole derivatives hamacathins 114a-b, isolated from marine sponges

Hamacantha and Rhaphisia, have been found to possess significant antimicrobial activity against C. albicans, C. neoformans and Bacillus subtilis.72,73

With the successful preparation of new 3,6-bis-(2-indolyl)-dibenzofuran and carbazoles described in Chapter 2, it was of interest to extend this work to the generation of the related

3-indolyl systems. In contrast to the 2-indolyl compounds which possessed N1, N1' and C3,

C3' active sites, 3-indolyl derivatives based on methoxy activated indoles would be susceptible to electrophilic substitution reactions at N1, N1', C2, C2', C7 and C7' (Figure 3-

1). It was anticipated that the activation of the C7 and C7' positions in particular would provide sufficient steric space for the subsequent development of novel macrocyclic systems.

+ + + E E E+ E H H N N OMe MeO

R MeO OMe

Figure 3.1

ϯϴ 3.1.2. Synthetic Routes to 3-Substituted Bis-Indoles

As with the 2-substituted bis-indoles, the synthetic strategies towards of 3-substituted bis- indoles can be based upon the use of either substituted indoles or substituted heterocycles as the starting material. For example, Black and co-workers have utilized the first strategy for the preparation the 3-substituted bis-indole system 116.74The 3-(4-bromophenyl)-4,6- dimethoxyindole 115 underwent one-pot Suzuki coupling with bis-(pinacolato)-diboron in the presence of PdCl2 (dppf) and potassium acetate in dry DMF. This was followed by the addition of another equivalent of indole 115, Pd(PPh3)4 and NaOH solution to generate compound 116 in 37% yield.74

Scheme 3.1 Reagents and conditions: bis-(pinacolato)-diboron, PdCl2 (dppf), CH3CO2K,

DMF, Pd(PPh3)4, NaOH.

The second strategy is represented by the adoption of the Nordlander indole synthesis for the preparation of bis-indolyl benzene 122.30 Treatment of 3,5-dimethoxyaniline with Į,Į'- dibromo-1,4-diacetylbenzene 118 afforded the phenacylaniline 119 in 80% yield. This compound was then reacted with trifluoroacetic anhydride to give the N-protected intermediate 120, which was not isolated, but rather underwent cyclisation to the N- protected bis-indole 121 in 80% yield upon continued stirring in trifluoroacetic acid at room temperature for another 3 days under an inert atmosphere. ϯϵ Scheme 3.2 Reagents and conditions: a) 3,5-dimethoxyaniline, EtOH, NaHCO3, reflux 6 h

b) TFAA, under N2 c) TFA, 3 days d) MeOH, KOH.

The final step involved the use of methanolic potassium hydroxide solution to give the desired benzenoid-indole 122 in 95% yield.30 It was anticipated that the most efficient

ϰϬ approach to the target 3,6-bis-(3-indolyl)-dibenzofuran was to begin with the substituted dibenzofuran. Instead of the Fischer method used previously in Chapter 2, the modified

Bischler indole synthesis17 method discussed in the introduction was selected as the basic approach to the desired 3-substituted indoles.

3.2. Synthesis of 3,6-Bis-(3-Indolyl)-Dibenzofuran

The modified Bischler indole synthetic strategy required the initial synthesis of the dibromoacetylbenzofuran starting material.17 Bruce et al.63 have reported that p-bis-

(bromoacetylbezene) 118 can be readily prepared by dissolving 1,4-diacetylbenzene 117 in glacial acetic acid followed by the dropwise addition of two stoichiometric equivalents of bromine at 40 o C and stirring for 4 h at room temperature.

%U 0H 2 2

2 0H 2 %U

Scheme 3.3 Reagents and conditions: Br2, HOAc, r.t, 4 h

Therefore, 3,6-diacetyldibenzofuran 63, whose synthesis is described in Chapter 2, was reacted with two equivalents of bromine in glacial acetic acid at 40 oC over 20 min.

Surprisingly, the reaction generated two products upon workup and these were separated by column chromatography.

The first product was isolated in 54% yield and identified as the desired bromoketone 123.

The 1H NMR spectrum showed a sharp singlet that integrated for 4H at 4.57 ppm and was

ϰϭ therefore assigned as the methylene protons. Similarly, the CH2 groups were apparent at

30.47 ppm in the DEPT 13C NMR spectrum and the ESI mass spectrum showed the molecular ion peak at m/z 410 (M+1) which was consistent with the expected structure of compound 123.

The second product was identified as the overreacted compound 124. In this case, the 1H

NMR spectrum exhibited a sharp singlet that integrated for 2H at 6.79 ppm which

13 corresponded to the CHBr2 protons. In addition, the CH group appeared in the C NMR spectrum at 39.4 ppm and the mass spectrum revealed a peak at m/z 568 (M+1) which is consistent with compound 124. Reaction optimization indicated that the formation of compound 124 was dependent upon the reaction temperature during the dropwise addition of bromine, with temperatures slightly over 40 oC favouring its production.

2 2 2 2 2 %U 2 %U %U %U 0H 0H %U %U 2 2 2

Scheme 3.4 Reagents and conditions: Br2, HOAc, r.t., 4 h.

The next step of the Bischler method entailed the condensation of 3,6- di(bromoacetyl)benzofuran 123 with two equivalents of 3,5-dimethoxyaniline in the presence of sodium bicarbonate in absolute ethanol. Heating at reflux for 6 h afforded the corresponding phenacyl-dianiline 125 as a yellow powder in 90% yield (Scheme 3.5).

ϰϮ

Scheme 3.5 Reagents and conditions: EtOH, 3,5-dimethoxyaniline, NaHCO3, reflux, 6 h.

1 The H NMR spectrum of the intermediate phenacyl-dianiline 125 in CDCl3 showed the presence of a broad singlet at 5.02 ppm corresponding to the NH protons, while the twelve methoxy protons appeared as a sharp singlet at 3.80 ppm. The new NH groups were also apparent in the IR spectrum at 3389 cm-1 and the ESI mass spectrum showed the expected peak of m/z 555 (M+1) for compound 125.

Phenacyl-dianiline 125 was subsequently treated with trifluoroacetic anhydride in an attempt to furnish the N-protected bis-indole in one pot as used in the Nordlander procedure. However, neither the N-protected intermediate 126 nor the cyclised product were produced. The reaction was therefore undertaken in two steps, treatment of phenacyl- dianiline 125 with acetic anhydride at room temperature for 12 h successfully gave the protected anilino ketone 126 in 83% yield.

ϰϯ Scheme 3.6 Reagents and conditions: acetic anhydride, r.t., 12 h

1 The H NMR spectrum of N-protected intermediate 126 showed the new acetyl protons at

2.06 ppm as a sharp singlet. The 13C NMR spectrum similarly showed the new methyl groups at 21.9 ppm and carbonyl carbons at 170.8 ppm. Finally, the mass spectrum revealed the anticipated peak at m/z 639 (M+1).

The N-protected anilino-ketone 126 was readily cyclised in 3 h at 100 oC to the N-protected bis-indole 127 in the presence of trifluoroacetic acid under argon. In the 1H NMR spectrum of the C3-symmetric compound 127, the H5 and H5' indole protons appeared as a doublet at

6.53 ppm, H7 and H7' appeared at 7.70 ppm and the H2 and H2' protons were observed at

7.73 ppm due to deshielding by the N-protecting group. Furthermore, the CH2 peak was no longer present in the 13C NMR spectrum and the ESI mass spectrum showed the expected peak at m/z 603 (M+1).

Scheme 3.7 Reagents and conditions: TFA, 100 oC, 3 h.

ϰϰ Deprotection of bis-indole 127 was carried out at room temperature for 3 h using potassium hydroxide in methanol to afford the desired 3,6-bis-(3-indolyl)-dibenzofuran 128 as a white solid in 69% yield after purification by column chromatography (Scheme 3.8).

Scheme 3.8 Reagents and conditions: MeOH, KOH, r.t., 3 h

Confirmation of the 3-substituted bis-indole 128 structure was obtained by 1H NMR spectroscopy. The acetyl protons at 2.68 ppm in the starting material 127 had disappeared and the NH protons appeared at 11.11 ppm. Three doublets at 6.21, 6.54 and 7.24 ppm corresponded to H5, H7 and H2 protons of the pendant indole respectively and two singlets at 3.73 and 3.76 ppm corresponded to methoxy group protons (Figure 3.2). The 13C NMR spectrum also showed the loss of the carbonyl peak and the ESI mass data revealed the expected molecular ion peak at m/z 519 (M+1). The X-ray crystal structure of the bis-indole

128 structure (Figure 3.3) showed the dibenzofuran ring in the centre flanked by the two indole units on either side at positions 3 and 6. In addition, it was also found that the NH groups in both indole units were pointing in the same directions while the dibenzofuran ring was pointing in the opposite direction.

ϰϱ

Figure 3.2: 1H NMR spectrum of the bis-indole 128

Figure 3.3 ORTEP diagram of compound 128 ϰϲ 3.3. Attempted Cyclisation of 3-Substituted Bis-Indole Systems

Activated 3-substituted indoles 129 have been found to undergo condensation with aromatic aldehydes in the presence of HCl to give 2,2'-di-indolylmethanes 130a-d.75 In contrast, condensation with the same aryl aldehydes in the presence of phosphoryl chloride afforded the macrocyclic calix[3]indoles 131a-d. These compounds 131a-d could also be formed from the related condensation of di-indolylmethanes 130a-d with indole 129 and phosphoryl chloride in chloroform (Scheme 3-9).75

Scheme 3.9 Reagents and conditions: a) aromatic aldehydes, MeOH, HCl, r.t., overnight

b) POCl3, CHCl3, reflux, 2 h c) aromatic aldehydes, POCl3, CHCl3,reflux, 1 h.

It was postulated that the more complex 3,6-bis-(3-indolyl)-dibenzofuran 128 could possibly undergo similar electrophilic aromatic substitution reactions at the indole C2 and ϰϳ C7 positions to generate a new range of macrocyclic systems. One ambitious aim was to form a cylindroid structure with calix[3]indoles at each end of the cylinder. When 3- substituted bis-indole 128 was reacted at reflux in chloroform for 4 h with benzaldehyde in the presence of phosphoryl chloride, either complex mixtures or polymeric materials were obtained. Similarly, no significant reaction occurred when compound 128 was treated with

40% formaldehyde in methanol in the presence of hydrochloric acid for 3 h (Scheme 3.10).

Scheme 3.10 Reagents and conditions: a) benzaldehyde, CHCl3, POCl3, reflux, 4 h b)

formaldehyde, HCl, MeOH, reflux, 3 h.

In order to reduce the probability of forming polymeric materials, the blockage of one of the C2 and C7 reactive sites was investigated. Black and co workers have reported the synthesis of the 3-substituted bis-indole macrocyclic system 133 by refluxing the bis- formyl indole 132 with formaldehyde in glacial acetic acid for 12 h (Scheme 3.11).30 This encouraged us to generate the related diformyl analogue of 3,6-bis-(3-indolyl)-dibenzofuran

128 and explore its cyclisation.

ϰϴ

Scheme 3.11 Reagents and conditions: HOAc, HCHO, reflux, 12 h

Vilsmeier-Haack formylation of the bis-indole 128 in the presence of two equivalents of

Vilsmeier-Haack reagent at 0 oC for 6 h produced bis-indole dicarbaldehyde 134 in 77% yield. The 1H NMR spectrum of the product, when compared to bis-indole 128, showed the disappearance of H7 and H7' at 6.20 ppm and appearance of a sharp singlet at 10.36 ppm which integrated for 2H and corresponded to the new aldehyde groups. The H5 and H5' protons appeared as a singlet at 6.47 ppm instead of a meta-coupled doublet and the H2 and

H2' protons remained at 8.23 ppm which further confirmed the substitution at the C7 and

C7' indole positions. Similarly, the 13C NMR spectra displayed a resonance at 186.8 ppm corresponding to the new carbonyl functionalities and the ESI mass spectrum showed a peak at m/z 575 (M+1), which further supported the formation of compound 134.

Treatment of the compound 128 with an excess of the Vilsmeier-Haack formylation reagent under the same reaction conditions led to formylation at C2 and C2' as well as the C7 and

C7' positions to produce the bis-indole-carbaldehyde 135 as a yellow solid in 68 % yield. In

ϰϵ this instance, the 1H NMR spectrum showed the absence of H2, H2' and H7, H7' protons at

6.20 and 7.24 ppm respectively, and the appearance of two sharp doublets at 9.60 and 10.30 ppm corresponding to the aldehyde groups. Compound 135 was found to be less soluble than analogue 134 which inhibited the acquisition of a 13C NMR spectrum but the ESI mass spectrum of the compound 135 revealed the peak at m/z 653 (M+Na)+.

o Scheme 3.12 Reagent and conditions: a) DMF, two equiv. of POCl3, 0 C 6 h. b) DMF, an

o excess of POCl3, 0 C, 6 h.

The bis-formyl indole compound 134 which possesses only two nucleophilic sites, namely

C2 and C2', was subsequently examined as a precursor to novel cyclic structures.

Compound 134 was heated at reflux with formaldehyde in glacial acetic acid for 1 h, however, only polymeric materials or complex mixtures were once again formed (Scheme

3.13). It was thought that unfavourable steric hindrance and the ridigity of the dibenzofuran linker were preventing the formation of the desired macrocyclic system. ϱϬ

Scheme 3.13 Reagents and conditions: HOAc, HCHO, reflux, 12 h.

As another alternate approach, it was anticipated that the carbonyl groups could be reduced to the corresponding alcohols which could then undergo acid catalysed cyclisation. For example, the reaction of dialcohols 136 with a 3-substituted 4,6-dimethoxyindole 137 in acetic acid has been reported to give the unsymmetrically linked calix[3]indoles 138

(Scheme 3.14).76

Scheme 3.14 Reagents and conditions: HOAc, r.t, 1 h

Bis-formyl indole carbaldehyde 134 and dicarbaldehyde 135 were therefore reduced to the corresponding alcohols 139 and 140 by treatment with sodium borohydride at room temperature in ethanol. The corresponding bis-dihydroxymethyl indole 139 and bis-

ϱϭ tetrahydroxymethyl indole 140 were obtained in 77% and 65% yields respectively (Scheme

3.15).

Scheme 3.15 Reagents and conditions: EtOH, NaBH4, r.t., 6 h

The 1H NMR spectrum of the compound 139 displayed a sharp singlet at 4.80 ppm corresponding to the methylene protons, with supporting information from the DEPT 135

13C NMR spectrum showing the methylene carbon at 53.9 ppm. The ESI mass spectrum showed a peak at m/z 601 (M+Na)+ and a strong absorption at 3411 cm-1 in the IR spectrum was attributed to the OH stretching mode absorption. In comparison, the 1H NMR spectrum of the compound 140 in DMSO displayed two methylene signals at 4.53 and 4.78 ppm as broad singlets. Solubility problems again prevented a 13C NMR spectrum from being obtained but the ESI mass spectrum showed a peak at m/z 661 (M+Na)+.

The 3-substituted bis-indole dimethanols 139 and 140 were then subjected to acid catalysed condensation in acetic acid as described in the literature,76 but only a complex mixture of compounds was produced after 1 h. Variation of the reaction conditions was performed, however, the use of p-toluensulfonic acid in dry acetone, dry THF or isopropanol did not generate the desired macrocyclic systems (Scheme 3.16).

ϱϮ

Scheme 3.16 Reagents and conditions: various acid catalysed reaction conditions

3.4. Conclusions

A synthetic route to 3,6-bis-(3-indolyl)-dibenzofuran has been developed using the modified Bischler indole synthesis method and a number of derivatives were prepared. The preparation of macrocyclic indoles via acid catalysed reactions was investigated but complex mixtures of polymeric materials were obtained. These results suggested that 3,6- bis-(3-indolyl)-dibenzofuran methanols are unstable under acid-catalysed reaction conditions and undergo uncontrolled reaction to yield a mixture of polymeric compounds.

ϱϯ

CHAPTER 4

Extension of Bis-Indoles to Bis-Biindolyls

4.1. Introduction

Biindolyl systems have received significant attention in recent literature, particularly in connection with their structural features and potential therapeutic applications.77 For example, the 2,2'-biindolyl-derived indolocarbazole alkaloid rebeccamycin 143 and staurosporine 144 display antitumor activity,77 with the former being an inhibitor of DNA topoisomerase I78 and the latter targeting protein kinase C.79 2,2'-Biindolyl compound 145 is another example of a biologically active biindolyl system and is implicated in the biosynthesis of eumelanine.80 Due to their wide range of biological activities, biindolyl systems continue to be an important synthetic target.81,82

ϱϰ

This chapter describes our investigation of the reactivity of the 3,6-bis-(2-indolyl)- dibenzofurans and carbazoles 72-75 described in Chapter 2 and 3,6-bis-(3-indolyl)- dibenzofuran 128 discribed in Chapter 3 towards the development of novel biindolyl compounds. In particular, the reactive 3 and 3'-positions of 2-indolyl systems were anticipated to lead to 2,3'-bis-biindolyl systems while the reactive C2, C2', C7 and C7' positions of 3-indolyl systems would lead to the related 2,7'-bis-biindolyl and 2,2'-bis- biindolyl systems.

E+ E+ + E+ E H E+ E+ H MeO N N OMe

HN NH OMe OMe

X O

2-indolyl system 3-indolyl system

Figure 4.1

4.2 Synthesis of Biindolyl Systems from Indolin-2-one

As mentioned, bis-indole alkaloids are compounds consisting of two indoles connected to each other, often via heterocyclic units.40,41 The biindolyl systems are a particular group of bis-indoles, in which the two indole units are directly linked either by C-N or C-C bonds.83

Numerous synthetic methods have been reported in the literature for the preparation of biindolyl structures possessing a range of different linkages.84-86 The majority of reported biindolyls possess C-C linkages, though C-N and N-N linkages are also known.83

ϱϱ

One of the most versatile synthetic approaches to C-C linked biindolyls entails the reaction of an indole with an oxindole in the presence of phosphoryl chloride. For example,

Bergman and Eklund have achieved the synthesis of 2,3'-biindolyl 148 by heating N- methylindole 146 at reflux for 2 h with N-methyloxindole 147 in the presence of phosphoryl chloride in dichloromethane.87

Scheme 4.1 Reagents and conditions: DCM, POCl3, reflux, 2 h.

In a similar fashion, Black and co-workers used this Vilsmeier-Haack type reaction to prepare 2,3'-biindolyl 151 in 60% yield from 2-phenylindole 149 and indolin-2-one 150.

The overreacted terindolyl 152 was also produced in 19% yield. (Scheme 4.2).88,89

Scheme 4.2 Reagents and conditions: anhydrous CHCl3, POCl3, reflux, 4 h

ϱϲ Our research group has extended this methodology to the preparation of 2,7’-biindolyls.89

Treatment of 4,6-dimethoxyindole 153 with indolin-2-one 150 was found to give 2,7'- biindolyl 156 in 75% yield. Through use of 4,6-dimethoxy-indolinone 155, the reaction was extended to the synthesis of 2,7'-biindolyl 157 and terindolyl 158 in 55% and 30% yield respectively (Scheme 4.3).89

Scheme 4.3 Reagents and conditions: anhydrous CHCl3, POCl3, reflux, 4-12 h

Bis-indoles 72-75, with reactive C3 and C3' indole sites, are suitable substrates to undergo

Vilsmeier-Haack type reaction with indolin-2-one 150 to generate novel 2,3' bis-biindolyl systems. The reaction of 3,6-bis-(2-indolyl)-dibenzofuran 72 with indolin-2-one 150 was initially investigated. Phosphoryl chloride was added dropwise to an ice cold solution of dibenzofuran 72 and indolin-2-one 150 and the reaction was then stirred in an oil bath at 60 oC for 3 h. before base work up. Column chromatography of the crude material afforded the desired bis-biindolyl 159 in 56% yield. In light of this result, carbazole derivatives 73-75 were similarly reacted with indolin-2-one 150 to generate 2,3' bis-biindolyl systems 160,

161 and 162 in 57, 53 and 64% yields respectively (Scheme 4.4).

ϱϳ

o Scheme 4.4 Reagents and conditions: POCl3, 60 C, 3 h

The key 1H NMR spectral data for bis-indolyl compounds 159-162 are presented in Table

4.1 for which bis-biindolyl compound 161 was characteristic. The indole H3 proton of the starting material 74 at 6.90 ppm disappeared and a new sharp singlet appeared at 6.38 ppm corresponding to the new indole H3'. Two broad singlets integrating for 2H each were present at 10.96 and 11.67 ppm corresponding to the new indole NH and the bis-indolyl

NH respectively. In addition to this, 22 aromatic protons were presented as multiplets at

6.97 and 7.19 ppm, three doublets at 7.29, 7.48 and 7.65 ppm and two singlets at 7.57 and

8.39 ppm. Finally, a sharp singlet appeared at 3.87 ppm corresponding to the carbazole N- methyl group. The formation of compounds 159-162 were further supported by mass spectra, which revealed the peaks at m/z 629, 628, 642 and 656 (M+1).

ϱϴ Figure 4.2: 1H NMR spectrum of the biindolyl 161.

Table 4.1: Selected 1H NMR spectral data (į, ppm) of bis-biindolyl compounds 159-162.

Compound New indole Parent indole H3' Number NH NH

159 6.44 10.94 11.66

160 6.37 10.93 11.64

161 6.38 10.96 11.67

162 6.40 10.98 11.67

ϱϵ The related reaction with 4,6-dimethoxyindolin-2-one 155 was subsequently of interest as the C7 position is activated for the later development of macrocyclic systems. 4,6-

Dimethoxyindolin-2-one 155 has been prepared in 95% yield by Clemmensen reduction of the hydroxyester 154 (Scheme 4.5).90

Scheme 4.5 Reagents and conditions: SnCl2, HCl, NaOH

Reaction of 3,6-bis-(2-indolyl)-dibenzofuran 72 with two equivalents of 4,6- dimethoxyindolinone 155 in the presence of phosphoryl chloride afforded the corresponding 2,3'-bis-biindolyl compound 163 in 60% yield as a yellow powder (Scheme

4.6).

Scheme 4.6 Reagents and conditions: POCl3, 60 C, 3 h

The 1H NMR spectrum of compound 163 in DMSO showed three broad singlets at 6.13,

6.27 and 6.44 ppm corresponding to the H5, H7 and H3 respectively. In addition, two NH

ϲϬ signals appeared at 10.80 and 11.71 ppm for the parent indoles and the new indoles, respectively. The introduced methoxy groups were present as two singlets at 3.71 and 3.79 ppm, which were similarly reflected by resonances at 55.2 and 55.5 ppm in the 13C NMR spectrum. Furthermore, the ESI mass spectrum of compound 163 showed the expected molecular ion peak at m/z 749.

With the targeted 2,3'-bis-biindolyls in hand, attention subsequently turned to the preparation of 2,7'- and 2,2'-bis-biindolyl systems from 3,6-bis-(3-indolyl)-dibenzofuran

128 and indolin-2-one 150. The previously described 2,7'-biindolyls (Scheme 4.3) used 2,3- disubstituted indoles so it was of interest to determine the selectivity of the reaction for the

C7 or C2 position. Treatment of the compound 128 with two equivalents of indolin-2-one

150 and phosphoryl chloride gave no significant reaction or it gave complex mixtures which could not be separated. Similarly, when the 3-indolyl compound 128 was reacted with indolin-2-one 150 in chloroform in the presence of trifluoromethanesulfonic anhydride at room temperature for 1 h, it also gave an inseparable mixture.

o Scheme 4.7 Reagents and conditions: POCl3, 60 C, 3 h

ϲϭ 4.3. Synthesis of Biindolyl Systems from 2-Bromoindoles

Black and co-workers have reported91 an alternative method for the synthesis of biindolyl systems from brominated indoles. Treatment of diphenylindole 153 with 3-bromoindole

165 in the presence of trifluoroacetic acid at room temperature produced 2,7'-bi-indolyl 166 in 80% yield.91 This strategy was found to be faster than the corresponding reaction with indolin-2-one, reaching completion within 5 min.

Scheme 4.8 Reagents and conditions: DCM, TFA, r.t., 30 min.

This synthetic strategy was therefore utilized for the development of 2,3'-bis-biindolyls related to compound 163 where the indole C3 position is blocked. Such systems were anticipated to be superior precursors to macrocylic systems than bis-biindolyl 163 as they possess only one reactive site, C7, instead of two reactive sites, C2 and C7.

3-Substituted indoles undergo C2-bromination with N-bromosuccinimide in the presence of a bulky, deactivating N-substituent. Our group has previously prepared4 2-bromo-3- phenylindole 170 from 4,6-dimethoxy-3-phenyl-1H-indole 167. Indole 167 was reacted with benzenesulfonyl chloride in dry tetrahydrofuran to give N-protected indole 168, which was subsequently treated with 1.1 equivalents of N-bromosuccinimide. 2-Bromo-N-

ϲϮ phenylsulfonylindole 169 was then deprotected to give 2-bromoindole 170. However, indole 170 was found to decompose instantly on attempted recrystallisation from dichloromethane, probably due to traces of acid present.

Scheme 4.9 Reagents and conditions: a) THF, n-butyllithium, benzensulfonyl chloride b)

N-bromosuccinimide, CCl4 c) KOH, MeOH.

Due to the instability of 2-bromoindole 170, the related 2-bromo-4,6-dimethoxy-3-(p- tolyl)-1H-indole 171 was selected for coupling to the bis-indoles. The reaction of 4,6- dimethoxy-3-(p-tolyl)-1H-indole 171 with benzenesulfonyl chloride in tetrahydrofuran produced the N-phenylsulfonylindole 172 in 75% yield. The N-protected indole 172 was then reacted with 1.1 equivalents of N-bromosuccinimide to give the corresponding 2- bromo-N-phenylsulfonyl indole 173, which upon deprotection afforded the corresponding

2-bromoindole 174 in 66% yield. It was found that the compound 174 is more stable than the compound 170.

ϲϯ

Scheme 4.10 Reagents and conditions: a) THF, n-butyllithium, benzensulfonyl chloride b)

N-bromosuccinimide, CCl4 c) KOH, MeOH.

Coupling of 3,6-bis-(2-indolyl)-dibenzofuran 72 with 2-bromoindole 174 was performed in dichloromethane in the presence of one drop of trifluoroacetic acid and gave the corresponding 2,3'-bis-biindolyl system 175 in 67% yield within 30 min. In accordance with the literature example (Scheme 4-10), the reaction time was significantly faster than the phosphoryl chloride method which took 3 h. The corresponding carbazole analogue 75 was subsequently reacted with 2-bromo-3-phenylindole 174 under the same reaction conditions to afford the corresponding 2,3'-bis-biindolyl 176 in 72% yield.

ϲϰ

Scheme 4.11 Reagents and conditions: DCM, TFA, r.t., 30 min

The 1H NMR spectrum of compound 175 in DMSO showed the characteristic H5, H5' and

H7, H7' peaks at 6.19 and 6.48 ppm respectively and displayed twelve methoxy protons at

3.66 and 3.80 ppm (6H each). The spectrum also showed the six p-methyl protons at 2.26 ppm and the two NH signals at 11.21 and 11.74 ppm. Furthermore, three sets of doublets appeared at 7.87, 8.12 and 8.72 ppm corresponding to the dibenzofuran protons. In a similar fashion, the 13C NMR spectrum displayed the p-methyl carbons at 21.1 ppm and exhibited the new methoxy carbon resonances at 55.3 and 55.5 ppm.

4.4. Attempted Synthesis of Cyclic 2,3'-Biindolyl Systems.

It was anticipated that the free 3- and 3'-positions of the 2,3-biindolyl systems could undergo further substitution to generate novel cyclic systems via acid catalysed dimerisation. To this end, formylation of compounds 158 and 161 was carried out at 0 oC with an excess of phosphoryl chloride in dimethylformamide. The corresponding products

ϲϱ 177 and 178 were obtained as bright orange-yellow solids in 90 and 85% yields respectively.

o Scheme 4.12 Reagents and conditions: DMF, POCl3, 0 C, 12 h

The 1H NMR spectra of compounds 177 and 178 exhibited sharp singlets that integrated for

2H and corresponded to the aldehyde protons at 9.57 and 9.58 ppm respectively. The supporting data from 13C NMR similarly displayed aldehyde resonances at 185.7 and 185.8 ppm respectively and the ESI mass spectra of the compounds 177 and 178 revealed peaks at m/z 707 and 734 (M+Na) respectively.

2,3'-Bis-biindolyl compound 176 was also formylated in order to obtain the corresponding

2,3'-bis-biindolyl dicarbaldehyde 179. When the compound 176 was reacted with excess phosphoryl chloride in dimethylformamide at 0 oC for 12 h, it gave 2,3'-bis-bindolyl dicarbaldehyde 179 in 80% as a yellow solid. The bis-biindolyl dicarbaldehyde 179 was synthesized as a precursor to generate imine macrocyclic systems through condensation reactions with amines, and this is described in Chapter 5. The 1H NMR spectrum of compound 179 showed the presence of the aldehyde protons as a singlet at 10.30 ppm .

Similarly, the 13C NMR spectra displayed the new carbonyl resonance at 186.4 ppm. ϲϲ

o Scheme 4.13 Reagents and conditions: POCl3, DMF, 0 C, 12 h

Reduction of 2,3'-bis-biindolyl dicarbaldehyde 177 and 178 with excess sodium borohydride in absolute ethanol at room temperature for 6 h gave the corresponding 2,3'- bis-biindolyl dimethanols 180 and 181 in 54 and 59% yield. The 1H NMR spectrum of compound 181 in DMSO displayed the absence of aldehyde protons at 9.50 ppm, along with the presence of hydroxymethyl protons at 4.40 ppm. The spectrum also showed two signals at 10.91 and 11.74 ppm corresponding to the NH protons. The 13C NMR spectrum further supported the structures, with the hydroxymethyl carbon being present at 55.4 ppm and the carbonyl resonance being absent.

ϲϳ Scheme 4.14 Reagents and conditions: EtOH, NaBH4, r.t., 6 h

Attempts were subsequently made to synthesize a macrocyclic indole system from 2,3'-bis- biindolyl dimethanols 180 and 181. Acidic treatment of the bis-indolyl dimethanol 180 was carried out with p-toluenesulfonic acid as the catalyst in acetone at room temperature for 3 h, but the reaction gave either polymers or complex mixtures which could not be separated.

The same result occurred when compound 180 was treated with glacial acetic acid for 12 h.

Similarly, when dibenzofuran 180 was replaced by the bis-biindolyl benzocarbazole 181, no significant reaction was observed. Presumably, the geometry was not suitable for the formation of the 15-membered ring system.

&+2+ +2+& 1+ +1 FRPSOH[ PL[WXUHV RU SRO\PHUV 1 1 + + ;

; 2 ; 1(W Scheme 4.15 Reagents and conditions: a) p-TsOH, acetone, r.t., 3 h, b) glacial acetic acid,

r.t., 12 h

ϲϴ 4.5. Conclusions

A new range of 2,3'-bis-biindolyl derivatives was successfully prepared from 3,6-bis-(2- indolyl)-dibenzofurans and carbazoles. Two methods were successfully investigated for the synthesis of 2,3'-bis-biindolyl compounds, namely the treatment of 2-susbtituted bis-indoles with oxindoles in the presence of phosphoryl chloride and the acid catalysed coupling of the 2-substituted bis-indoles with bromoindoles.

ϲϵ CHAPTER 5

Bis-Indole Macrocycles

5.1. Introduction

Macrocyclic compounds are important targets in the area of drug discovery due to the fact that naturally occurring macrocycles often show diverse and remarkable biological activities. Macrocycles have proved useful in treating disease and providing a basic pre- organized scaffold that can optimally present functional binding domains. However, these compounds rarely function as classic enzyme inhibitors. Another structural advantage of macrocycles is that these compounds are very effective as ligands when the ring has a significant effect in restricting structural flexibility.92 The natural macrocycles therefore provide valuable inspiration for the design of new macrocyclic structures and the aim of this current work was to generate indole based imine macrocyclic systems using Schiff base and hydrazone chemistry.

5.1.1. Schiff Bases

Compounds comprising the –N=CH- moiety are known as Schiff bases.93,94 They are generally synthesised by the condensation of a primary amine and a carbonyl functionality, with the elimination of water.93,95 Schiff bases are an important class of compounds due to their broad pharmacological effects, which include antibacterial,96,97 antifungal,98,99 and antitumor activity.100 For example, compounds 182a-d are examples of biologically active bis-Schiff bases, which exhibit good analgesic and anti-inflammatory activities.101

ϳϬ

According to the literature,102 indole-3-carboxylidene derivatives 183-185 are biologically active Schiff bases which have been synthesised by the condensation of indole-3- carbaldehyde with glycine, DL-alanine and DL-valine respectively. These indole-3- carbaldimines 183-185 showed antimicrobial activity against Staphylococcus aureus,

Escherichia coli and Bacillus polymyxa.102

The advantages of the imine moiety include the availability of donor lone electron pairs on the nitrogen atom, the capability for conjugation and the ability to provide a valuable

30 degree of conformational flexibility required by a potential host. For example, Kyoung-Jin et al. have reported that indoles containing macrocyclic imine systems can act as a class of receptors for anions.103

ϳϭ 5.1.2. Hydrazones

Hydrazones and their derivatives are an important class of compound in organic chemistry and show interesting biological properties such as anti-convulsant, anti-tuberculosis, antitumor, anti-HIV, anti-inflammatory, and anti-microbial activity.104-107 For example; nifuroxazide 186 is a biologically active hydrazone, which shows an intestinal antiseptic activity and isoniazid 187 displays very high activity against M. tuberculosis H37Rv.104

The structure –NH-N=CH-, commonly known as an hydrazone, is generally synthesised by the reaction of a substituted hydrazine or hydrazide with aldehydes and ketones in a suitable solvent such as ethanol, methanol, tetrahydrofuran or butanol.104 Recently,

Shirinzadeh et al.108 reacted 1-methyl-1H-indole-3-carbaldehyde 188 with several hydrazines in ethanol to give the corresponding hydrazone derivatives 189a-c which were shown to possess strong antioxidant activity.

Scheme 5.1 Reagents and conditions: EtOH, several hydrazine hydrates, reflux ϳϮ 5.2. Synthesis of Imine Macrocycles

It has been reported22 that the monoindolyl macrocyclic compounds 191-194 can be synthesised by the condensation of 3,7-diformyl-4,6-dimethoxyindole 190 and 2,7- diformyl-4,6-dimethoxy-3-methylindole 22 with commercially available diamino compounds such as 1,10-diaminodecane and 1,12-diaminododecane as shown in Scheme

5.2.

Scheme 5.2 Reagents and conditions: i-PrOH, NH2(CH)nNH2, reflux, overnight

In a similar fashion, Black and co-workers have reported the synthesis of new bis-imine macrocycles. Reaction of N,N'-diindolylxylene-3,3'-dicarbaldehyde 93 with 1,2- diaminoethane in anhydrous toluene and catalysed by p-toluenesulfonic acid gave the

ϳϯ seventeen-membered ring compound 195 in 50% yield as a yellow solid after purification by column chromatography.22

Scheme 5.3 Reagents and conditions: toluene, p-TsOH, 1,2 diaminoethane

Imine-based bis-indole macrocycles 3029 and 3130 have also been prepared through condensation of the parent 7,7'-diformyl-2,2'-biindolyl and 7,7'-diformyl-2,2'-biindolyl- methane compounds with 1,2-diaminoethane and 1,3 diaminopropane.

The formation of imine macrocycles from mono- and di-indolyl dialdehydes and diamino compounds is therefore a versatile route to novel macrocyclic systems22 which encouraged the use of this strategy to generate macrocycles from the bis-indoles and bis-biindolyl systems described in Chapters 2-4.

ϳϰ 5.2.1. Bis-Indole Macrocycles

The reaction of 3,3'-diformyl-3,6-bis-(2-indolyl)-dibenzofruan 94, whose synthesis is described in Chapter 2, with 1,2-diaminoethane was initially investigated. However, no reaction occured after heating the reagent in absolute ethanol at reflux for 12 h and only starting materials were recovered upon workup. Similarly, no reaction was observed upon treatment of dibenzofuran 94 with 1,4-diaminobenzene. These results indicated that a two carbon spacer was insufficient to bridge the two indoles, presumably due to the rigid nature of the dibenzofuran.

Scheme 5.4 Reagents and conditions: a) EtOH, 1,2-diaminoethane, reflux, 12 h, b) EtOH,

1,4-diaminobenzene, reflux, 12 h

ϳϱ Therefore, the linker was extended to four carbons, with compound 94 being reacted with

1,4-diaminobutane. After 12 h at reflux, the new bis-indole based imine macrocycle 198 was isolated in 73% yield. The 1H NMR spectrum of compound 198 showed the replacement of the aldehyde protons at 10.07 ppm by the new imine protons at 8.62 ppm.

Two singlets also appeared at 1.87 and 3.67 ppm which corresponded to the methylene protons. The 13C NMR spectrum showed the methylene protons at 28.0 and 61.8 ppm respectively and the imine carbon at 156.3 ppm. Furthermore, the IR spectrum showed an imine stretching frequency at 1632 cm-1 and the mass spectrum revealed a peak at m/z 507

(M+1).

In the same manner, bis-indole dicarbaldehydes 95 and 96 were condensed with 1,4- diaminobutane to produce 18-membered macrocycles 199 and 200 in yields of 67% and

75% respectively. Selected NMR data for the compounds 198-200 are summarized in Table

5.1.

1 &+2 2+& 1 1+ +1 1+ +1

; ; ; 2 ; 2 ; 1+ ; 1+ ; 10H ; 10H

Scheme 5.5 Reagents and conditions: EtOH, 1,4-diaminobutane, reflux, 12 h

ϳϲ

Table 5.1: Selected NMR data (į, ppm) for compounds 198-200.

Compound CH2 N-CH2 N=CH

Number 1H 13C 1H 13C 1H 13C

198 1.87 28.0 3.67 61.8 8.62 156.3

199 1.87 27.9 3.68 61.9 8.47 156.7 200 1.87 27.9 3.49 61.9 8.50 156.8

Further extension of the linker was subsequently investigated, with compounds 94-96 being treated with 1,6-diaminohexane to generate the corresponding 20-membered ring macrocyclic imines. These reactions were facile, reaching completion after 12 h and producing compounds 201-203 in 68, 55 and 63% yields respectively.

&+2 2+& 1 1 1+ +1 1+ +1

; ; ; 2 ; 1+ ; 2 ; 10H ; 1+ ; 10H

Scheme 5.6 Reagents and conditions: EtOH, 1,6-diaminohexane, reflux, 12 h

ϳϳ As shown in Table 5.2 the 1H NMR spectra of the compounds 201-203 displayed the imine proton resonances around 8.37 ppm, while aldehyde resonances at around 10.08 ppm were absent, and the 13C NMR spectra showed the new imine carbon at 156.5 ppm. The IR spectra of the compounds 201-203 displayed absorptions at 1627, 1632 and 1626 cm-1 respectively corresponding to the imine stretching frequencies. The structure of compounds

201-203 were further confirmed by high resolution ESI mass spectrometry, wherein the ESI mass spectra displayed peaks at m/z 535, 534 and 548 (M+1) respectively.

Table 5.2: Selected 1H NMR spectral data (į, ppm) of the compounds 201-203.

Compound CH2 N-CH2 N=CH

Number 1H 13C 1H 13C 1H 13C

201 1.54, 1.80 24.1, 28.5 3.63 61.4 8.37 156.5

202 1.50, 1.76 23.9, 28.5 3.57 61.4 8.28 156.8

203 1.87, 1.76 23.9, 28.4 3.56 61.5 8.33 156.7

ϳϴ

Figure 5.1: 1H NMR spectrum of 1,6-diamino linked bis-indole macrocycle 202.

In a similar fashion, the formation of imine macrocyclic systems from the related 7,7'- diformyl-3,6-bis-(3-indolyl)-dibenzofuran 134, whose synthesis is reported in Chapter 3, was explored. The 7,7'-diformyl-3,6-bis-(3-indolyl)-dibenzofuran 134 is an important intermediate and can also serve as a precursor for a variety of ligand synthesis. Since Schiff base reaction of bis-indole dicarbaldehyde 94 gave the bis-indole imine macrocycle 198, the reaction of 7,7'-diformyl-3,6-bis-(3-indolyl)-dibenzofuran 134 with diamino compounds under Schiff base reaction condition would generate the corresponding imine macrocycles

204-206. However, none of these desired macrocycles 204-206 could be generated and,

ϳϵ only the starting metarials were recovered when the reactions were attempted in isopropanol or ethanol under reflux. Based on these results, it was concluded that iso-propanol or ethanol was not suitable solvent to generate bis-indole macrocycles 204-206.

Conversely, it was found that the reaction of bis-indole dicarbaldehyde 134 with 1,2- diaminobutane in iso-propanol and in the presence of dichloromethane afforded the diamine 207 in good yield, together with what appears to be a dimeric compound 210 which could not be separeated, instead of the desired monomeric cyclic product. The 1H

NMR spectrum of the compound 207 exhibited an indicative CH proton at 8.26 ppm. The

DEPT 135 and 13C NMR spectrum supported this structure, indicating the loss of two CHO carbons as a result of imine formation. The spectrum also showed the presence of two characteristic peaks at 65.2 and 44.2 ppm corresponding to the N=CH2 and N-CH2 methylene carbons respectively. The high resolution mass spectrometry showed that the diamine 207 was the major compound at m/z 659 (M+1), and also showed the formation of the minor dimeric compound 210 at m/z 1197 (M+1).

ϴϬ

Scheme 5.7 Reagents and conditions: EtOH or i-PrOH, DCM, various diamines, reflux,

overnight

The initial reaction of the compound 134 with 1,2-diaminoethane suggested that the chain length was inadequate to allow formation of the target monomeric macrocyclic compound

204. Therefore, the size of diamino compounds were subsequently increased, utilising 1,4- diaminobutane and 1,12-diaminododecane in an attempt to bridge the two indole units.

However, when bis-indole 134 was reacted with 1,4-diaminoethane in iso-propanaol and in the presence of dichloromethane, the bis-indole diamine 208 was formed instead of the ϴϭ desired macrocycle 205. Formation of the open chain compounds appeared to be the preferred product as similar treatment of bis-indole 134 with longer carbon chain 1,12- diaminobutane yielded the bis-indole diamine 209 rather then macrocycle 206. The stability of the imines can be attributed to the presence of hydrogen bonding between indole NH and the imines. This introduces rigidity and stability into the system.

5.2.2. Bis-Biindolyl Macrocycles

It was envisaged that bis-biindolyls 177 and 178, whose synthesis is described in Chapter 4, would also serve as suitable precursors for Schiff base reactions with a range of primary amines. To this end, 2,3'-bis-biindolyl compound 177 was reacted with 0.5 equivalent of

1,4-diaminobutane under Schiff base reaction conditions, however, the reaction resulted in a complex inseparable mixture (Scheme 5.8). Similarly, when 2,3'-bisbiindolyl 178 and

1,4-diaminobutane were heated for 12 h in absolute ethanol, the reaction again gave a complex inseparable mixture. It was thought that the size of diamino compound was not suitable to the macrocyclic ring size and shape.

Scheme 5.8 Reagents and conditions: EtOH, 1,4-diaminobutane, reflux, 12 h

ϴϮ Attention subsequently turned to the corresponding 7-carbaldehyde derivative 179 in the hope that the geometry of the macrocyclisation would be more favourable. Treatment of compound 179 with 1,4-diaminobutane for 6 h in absolute ethanol was found to give successfully the corresponding indole based imine macrocyclic compound 211 in moderate yield as a yellow powder (Scheme 5.9).

Scheme 5.9 Reagents and conditions: EtOH, 1,4-diaminobutane, reflux, 6 h

5.3. Synthesis of Amine-Based Macrocycles

While the macrocyclic imines showed adequate flexibility for their generation, the related amine analogues would be expected to display more flexibility and stability.30 Hence the reduction of imine macrocycle 198, through treatment with sodium borohydride in ethanol at room temperature for 6 h, afforded a diamine macrocycle 212 in 58% yield . Similarly, the reduction of compounds 199-203 under the same reduction conditions gave the corresponding diamino macrocycles 213-217 in 56-62% yields respectively. ϴϯ

Scheme 5.10 Reagents and conditions: EtOH, NaBH4, r.t., 8 h

The 1H NMR spectrum of compound 214 was characteristic for a diamino macrocycle and showed the absence of the imine resonance at 8.62 ppm and the appearance of the methylene signal at 3.81 ppm. This was also supported by a 13C NMR and DEPT 135 experiment, wherein the spectra showed the characteristic N-CH2 peak at 48.8 ppm. The

ESI mass spectral data of diamino macrocycles 212-217 revealed peaks at m/z 511, 510,

524, 539, 538 and 552 (M+1) respectively.

ϴϰ

Figure 5.2 1H NMR spectrum of 1,6-diamino linked bis indole macrocycles 214.

5.4. Synthesis of Bis-Indole Azomethine Macrocycles

As already mentioned, hydrazones and their derivatives are generally synthesised by the condensation of appropriate substituted hydrazines with aldehydes in a suitable solvent such ethanol, methanol, tetrahydrofuran and butanol.104 This method therefore formed the basis for the synthesis of hydrazone macrocycles. 3,3'-Diformyl-3,6-bis-(2-indolyl)- dibenzofuran 94 was treated with hydrazine hydrate in ethanol at reflux for 3 h to generate the corresponding indole hydrazone derivative 218 in 84% yield. In a similar manner, compounds 95-97 were condensed with hydrazine hydrate in ethanol to generate indole hydrazone derivatives 219-221 in good yields of 78, 78 and 82% respectively.

ϴϱ

Scheme 5.11 Reagents and conditions: EtOH, hydrazine hydrate, reflux, 2 h

The 1H NMR spectrum of compound 218 was characteristic for these compounds 219-221.

The aldehyde proton at 10.08 ppm was replaced by a sharp singlet at 8.15 ppm which indicated the presence of the CH=N moiety. Similarly, the 13C NMR spectrum displayed the absence of the carbonyl peak at 186.1 ppm and the appearance of the CH=N peak at

137.4 ppm and the IR spectrum showed an absorption band at 1616 cm-1 corresponding to the CH=N functional group. Further structural determination of the compounds 218-221 was obtained by mass spectrometry which revealed peaks at m/z 483, 482, 496, 510 (M+1) respectively.

The 7,7'-diformyl bis-indole 134 was then similarly condensed with hydrazine hydrate by heating under reflux in ethanol for 3 h, to give compound 222 in 74% yield as a yellow solid. The 1H NMR spectrum of compound 222 showed the absence of aldehyde peaks and the appearance of a singlet at 8.27 ppm integrating for 2H which corresponds to N=CH peaks. The ESI-mass spectrum of compound 222 revealed a peak at 603 (M+1)

ϴϲ 1+ 1+ &+2 &+2 1 1 + + 0H2 1 1 20H +& &+ + + 0H2 1 1 20H

20H 20H 20H 20H 2 2

Scheme 5.12 Reagents and condtions: EtOH, hydrazine hydrate, reflux, 3 h

Indole hydrazones 218-222 were then used as substrates for Schiff base condensation with a number of bis-indole dicarbaldehydes to produce novel azine systems. Hence, treatment of bis-indole hydrazone 221 with one equivalent of the carbaldehyde 97 in ethanol at reflux for 3 h yielded the crude derivative 223 in 48% yield. However, the 1H NMR spectrum of compound 223 was unclear and a 13C NMR spectrum could not be obtained due to poor solubility, which also hindered the purification of the compound. The mass spectrum of compound 223 revealed a peak at m/z 955 (M+1) which is consistent with

C64H46N10.

ϴϳ

Scheme 5.13 Reagents and conditions: EtOH, reflux, 12 h

Unfortunately, no reaction occurred when compounds 218-220 were combined with appropriate bis-indole carbaldehydes 94-96 in ethanol for 3 h. Similarly, no reaction was apparent when bis-indole hydrazone 222 was reacted with 3-substituted bis-indole carbaldehyde 134 under reflux for 12 h in an attempt to form the corresponding azine system 224.

ϴϴ

Scheme 5.14 Reagents and conditions: EtOH, reflux, 12 h

5.5. Conclusions

The synthesis of indole based imine macrocyclic ligands from bis-indole carbaldehydes has been successfully accomplished using Schiff base chemistry. It was found that the formation of the macrocycles was dependent upon the size and the shape of the linker compounds, with longer and more flexible linkers being favoured. The related amine macrocycles were also prepared through sodium borohydride reduction. The preparation of bis-hydrazone derivatives was also examined by condensation of bis-indole carbaldehydes with hydrazine hydrate.

ϴϵ CHAPTER 6

Electrophilic Reactivity Studies

6.1. Introduction

6.1.1. Reaction with Oxalyl Chloride

The reaction of indole with oxalyl chloride was first reported by Guina in 1924.109 The product indol-2-ylglyoxyloyl chloride was incorrectly assigned and the structure was confirmed to be the indol-3-ylglyoxyloyl chloride, which was shown to react readily with alcohols and amines to give the corresponding glyoxylic esters and amides. Amide derivatives, in particular, have been used in crystal engineering due to their susceptibility to form hydrogen bonding.110-113

3-Aryl-4,6-dimethoxyindole 225 undergoes reaction with oxalyl chloride to give both 2- and 7-indolylglyoxyloyl chlorides, and the regioselectivity of the reaction was found to be solvent-dependent. For example, the use of dichloromethane or tetrachloromethane as solvent resulted in the formation of the 7'-isomer and 2'-isomer in a 70:30 ratio. This ratio was reversed when diethyl ether was employed as the solvent.114 Use of diethyl ether as a solvent has an additional advantage in that the 2'-glyoxyloyl chloride 226 precipitates out of the reaction mixture as a red solid while the 7'-glyoxyloyl chloride 227 remains in solution, thereby eliminating the need for chromatography. Both indolylglyoxyloyl chlorides 226 and

ϵϬ 227 have been converted directly into glyoxylic acids 228a and 229a, glyoxylic esters 228b and 229b, and glyloxylamides 228c-h and 229c-h in quantitative yields (Scheme 6.1).114

Scheme 6.1 Reagents and conditions: a)(COCl)2, solvents b)YH, solvents

The primary and secondary indol-2-ylglyoxylamides 230a and 230b were reported in the literature as networks of complementary intra- and intermolecular hydrogen bond motifs.115,116

ϵϭ &O

0H2 2 + 1 0H2 1 + 2 5

D 5 + E 5 0H

Figure 6.1

Oxalyl chloride has also been reacted with the bis-indole compounds to give glyoxyloyl chlorides which can further be used for the generation of the corresponding glyoxylic esters and amides. For example, the bis-glyoxylic esters and amides 231 were synthesized from diindolylbenzene 92 in moderate yields as shown in Scheme 6.2.22

Scheme 6.2 Reagents and conditions: a) (COCl)2, Et2O b) YH, Et2O

ϵϮ 6.1.2. Reaction with Trichloroacetyl Chloride

Purwono et. al. reported33 the use trichloroacetyl chloride as a reagent for the formation of trichloroacetylindoles. According to this approach, the reaction of 3-(4-chlorophenyl)-4,6- dimethoxy-1H-indole 225 with trichloroacetyl chloride in chloroform under reflux gave the corresponding 7-trichloroacetylindole 232 and 2-trichloroacetylindole 233 in 66 and 17% yields respectively. These were then reacted with water, amines and alcohols to give the corresponding acids 234a and 235a, esters 234b and 235b and amides 234c-f and 235c-f as shown (Scheme 6.3).33

Scheme 6.3 Reagents and conditions: a) CHCl3, trichloroacetyl chloride b) CHCl3, YH

ϵϯ Bis-indole carboxamide derivatives can also be generated by the reaction of trichloroacetylindoles with ammonia or primary amines in acetonitrile at room temperature.

Black and co-workers produced the bis-indole carboxamide 237 from trichloroacetyl indole

236, by stirring it with ammonia at room temperature for 1 h in acetonitrile in the presence of triethylamine (Scheme 6.4).33

Scheme 6.4 Reagents and conditions: MeCN, NH3, r.t., 1 h

6.2. Synthesis of Bis-Indolylglyoxyloyl Chlorides

In the previous chapters, it has been shown that 3,6-bis-(2-indolyl)-dibenzofurans and carbazoles were susceptible towards electrophilic substitution at C3 and C3' while 3,6-bis-

(3-indolyl)-dibenzofurans were reactive at the C2, C2' and C7, C7' positions. It was of interest to explore this reactivity further for the preparation of bis-indolylglyoxyloyl chlorides and the corresponding glyoxylic esters and amides.

The reaction of 3,6-bis-(2-indolyl)-dibenzofuran 72 with oxalyl chloride as an acylation reagent was initially investigated in order to generate bis-glyoxylic chloride 238.

Performing the reaction in anhydrous diethyl ether at room temperature was found to give the corresponding bis-glyoxylic acid chloride 238 in 80% yield as a brown solid.

ϵϰ

Scheme 6.5 Reagents and conditions: (COCl)2, Et2O, r.t., 3 h

The 1H NMR spectrum of the bis glyoxylic acid chloride 238 showed the disappearance of the H3 and H3' protons at 6.96 ppm, which proved that the starting material 72 had completely been converted to the bis-glyoxlic acid chloride 238. This was further supported by the 13C NMR spectrum in which two carbonyl resonances were evident at 167.2 and

184.8 ppm.

Bis-indoles 73-75 were subsequently reacted with oxalyl chloride to generate bis-indole glyoxylic acid chlorides 239-241 in 67, 75 and 77% yields respectively. Interestingly, the bis-glyoxylic acid chloride 239 was found to be unstable and readily underwent decomposition. This problem with stability was overcome by replacing the parent indole 73 with N-substituted indole 99. Hence, treatment of N-methylated bis-indole 99 with oxalyl chloride afforded the corresponding N-methyl derivative 242 in 46% yield.

ϵϱ

Scheme 6.6 Reagents and conditions: (COCl)2, Et2O ,r.t., 3 h.

In contrast to the above results, similar treatment of 3,6-bis-(3-indolyl)-dibenzofuran 128 with oxalyl chloride gave an inseparable mixture.

Scheme 6.7 Reagents and conditions: (COCl)2, Et2O, r.t.

6.3. Synthesis of Bis-Glyoxylic Esters and Amides

Treatment of bis-glyoxyloyl chloride 238 at reflux with absolute ethanol for 1 h, gave the corresponding bis-glyoxylic acid ester 243 in 64% yield. The product precipitated out from the reaction mixture and did not require any further purification. The 1H NMR spectrum showed the methyl protons as a triplet and the methylene protons as a quartet at 1.10 and

ϵϲ 3.57 ppm respectively while the 13C NMR spectrum showed the methyl and methylene carbon resonances at 13.6 and 56.3 ppm respectively. The mass spectrum showed a peak corresponding to bis-glyoxylic ester 243 at m/z 621 (M+1).

Scheme 6.8 Reagents and conditions: EtOH, reflux, 1 h

Attention subsequently turned to the generation of bis-glyoxylic acid amides, with the reaction of bis-glyoxyloyl chloride 238 with ammonia being initially investigated.

Treatment of bis-glyoxyloyl chloride 238 with concentrated ammonia at room temperature for 2 h gave the corresponding bis-glyoxylamide 244 in 74% yield. The 1H NMR spectrum of compound 244 in DMSO displayed the glyoxylamide moiety as two broad singlets at

7.83 and 7.93 ppm while the NH proton of the indole appeared as a singlet at 11.30 ppm.

The ESI mass spectrometry results revealed peaks at m/z 541 (M+1) corresponding to bis- amide 244. Similar reaction of bis-glyoxyloyl chlorides 240 and 241 with ammonia gave bis-glyoxylamides 245 and 246 in 68 and 65% yields respectively.

ϵϳ

Scheme 6.9 Reagents and conditions: conc. ammonia, r.t., 2 h

Similarly, bis-glyoxyloyl chloride 238 was stirred in 40% aqueous methylamine solution at room temperature for 2 h to yield compound 247 in 73% yield. Similarly, bis-glyoxyloyl chlorides 240 and 241 were reacted with methylamine to give the corresponding bis- glyoxylamides 248 and 249 in 64 and 70% yields respectively.

Scheme 6.10 Reagents and conditions: methylamine solution, r.t., 2 h

The 1H NMR spectrum of bis-glyoxyloyl amide 248 displayed the methylene proton signal for NH-methyl as a doublet at 2.16 ppm, showed the NH proton of the secondary amide

ϵϴ peak at 8.40 ppm and the NH proton of the indole appeared as a singlet at 12.53 ppm. In addition, the methyl carbon signal appeared at 25.2 ppm in the 13C NMR spectrum.

The synthesis of novel bis-glyoxyloyl amides was further continued using 3,5- dimethoxyaniline and p-toluidine. The bis-glyoxyloyl chlorides 238, 240 and 241 were treated with 3,5-dimethoxyaniline in anhydrous ether at room temperature for 3 h which gave the corresponding bis-glyoxylamides 250-252 in 78, 75 and 63% yields respectively

(Scheme 6.11). Similarly, the treatment of bis-glyoxyloyl chloride 238 with p-toluidine under similar conditions, afforded the corresponding ketoamide derivative 253 in 77% yield as a yellow solid (Scheme 6.11). The mass spectra of compounds 250, 252 and 253 revealed the molecular ions at m/z 813, 840 and 721 (M+1) respectively, and the ESI spectrum of compound 251 showed a peak at m/z 848 (M+Na).

Scheme 6.11 Reagents and conditions: a) Et2O, 3,5-dimethoxyaniline b) Et2O, p-toluidine

The successful synthesis of the bis-glyoxylamide derivatives so far encouraged the generation of compound 255 as a precursor to the biindolyl-glyoxyloyl system 256.

According to the standard procedure, treatment of bis-glyoxyloyl chloride 238 with anilino

ϵϵ ketone 254 in the presence of anhydrous diethyl ether gave the corresponding compound

255 which precipitated out as a white solid in 83% yield.

Scheme 6.12 Reagents and conditions: a) Et2O, r.t., 3 h b) various cyclisation reaction

conditions

The structure of the bis-glyoxylamide 255 was supported from its 1H NMR spectrum which demonstrated methylene protons at 5.32 ppm. The spectrum also displayed twelve methoxy protons at 3.38 ppm as a singlet. Furthermore, the 13C NMR spectrum illustrated the methylene resonances at 55.1 ppm and showed the methoxy signals at 55.3 ppm. The ϭϬϬ supporting data from the ESI mass spectroscopy revealed a peak at m/z 1227 (M+Na) corresponding to C64H46N4NaO11.

A number of acid-catalysed reaction conditions were investigated for the cyclization of compound 255 to 256 including trifluoroacetic acid at room temperature and at 100 o C and methanesulfonic acid at room temperature. However, the reactions were unsuccessful and only polymeric materials were obtained. A probable reason for this observation is the stability of this keto-amide 255 under acidic conditions.

6.4. Synthesis of Bis-Indole Carboxamides

Treatment of 3,6-bis-(2-indolyl)-dibenzofuran 72 with trichloroacetyl chloride in 1,2- dichloroethane at reflux for 3 h gave the bis-trichloroacetyl indole 257 in 68% yield.

Similarly, the reaction of 3,6-bis-(2-indolyl)-N-ethyl carbazole 75 with trichloroacetyl chloride under similar conditions gave the corresponding bis-trichloroacetyl indole 258 in

57% yield. However, bis-trichloroacetyl indole 258 was found to be an unstable product and readily underwent decomposition.

Scheme 6.13 Reagents and conditions:1,2-dichloroethane, trichloroacetyl chloride

ϭϬϭ The 1H NMR spectrum of compound 257 showed the disappearance of the H3 and H3' protons at 6.99 ppm from which it was determined that the starting material was completely converted to bis-trichloroacetyl indole 257. The supporting data from the 13C NMR spectrum showed the characteristic carbonyl resonance at 180.1 ppm. The ESI mass spectroscopy revealed a peak at m/z 686 (M+1).

The first attempt to synthesise bis-indole carboxamide derivatives entailed treatment of bis- trichloroacetyl indole 257 with ammonia in acetonitrile in the presence of triethylamine and afforded carboxamide 259 in 60% yield. Similar treatment of bis-trichloroacetyl indole 257 with methylamine in acetonitrile for 1 h afforded the corresponding compound 260 in 73% yield (Scheme 6.14).

Scheme 6.14 Reagents and conditions: a) MeCN, Et3N, ammonia, r.t., 1 h b) MeCN, Et3N,

methylamine, r t, 1 h.

1 The H NMR spectrum of compound 259 in DMSO displayed the carboxamide NH2 protons as a broad singlet at 7.94 ppm while the NH proton of the indole appeared as a broad singlet at 11.88 ppm. The 13C NMR spectrum showed a carbonyl carbon resonance at

ϭϬϮ 167.7 ppm while the ESI mass spectrum revealed a peak at m/z 485 (M+1). Meanwhile, the

1H NMR spectrum of compound 260 in DMSO exhibited the methyl proton signal as a doublet at 2.84 ppm and the NH proton of the secondary amide appeared at 7.81 ppm. In addition, the methyl carbon resonance appeared at 27.5 ppm in the 13C NMR spectrum and the molecular formula was confirmed by the ESI mass spectrum peak at 513 (M+1).

6.5. Synthesis of Macrocyclic Indolyl-Diamides

In the previous chapter the synthesis of imine macrocycles has been described. It was anticipated that this methodology could be extended further to develop a new range of macrocyclic indolyl-diamides from bis-indolylglyoxyloyl chlorides and bis- trichloroacetyindole derivatives and would potentially enhance the metal binding capacity of these systems. For example, it has been reported that indoline-2,3-dione 261 can be acylated utilizing oxalyl chloride in dichloromethane in the presence of pyridine, followed by the addition of alcohols and amines to give bis-glyoxylic esters and amides 262.117,118

Subsequent cyclisation of these bis-glyoxylic compounds 262 with diamines in the presence of nickel (II) acetate and triethylamine gave the corresponding amido macrocyclic complexes 263 as shown in Scheme 6.15.

ϭϬϯ

1 Scheme 6.15 Reagents and conditions: a) (COCl)2, pyridine, CH2Cl2, R H

2 b) NH2-R -NH2, Ni(OAc)2, Et3N

The Schiff base condensation of bis-glyoxylic ester and amide derivatives 243, 244 and 250 with 1,2-diaminobutane was examined in an attempt to produce the indole based bis- glyoxlic macrocylic imines 264. The reaction of bis-glyoxlic ester 243 with 1,4- diaminobutane in acetonitrile in the presence of triethylamine at room temperature for 6 h failed to generate the corresponding bis-glyoxlic macrocylic system 264. Similarly, no reaction took place when bis-glyoxylic amides 244 and 250 were reacted with 1,4- diaminobutane under the same reaction conditions. The use of other solvents such as diethyl ether instead of acetonitrile and higher reaction temperatures also failed to generate bis-glyoxlic macrocylic imines 264. Overall, attempts to synthesise compounds 264 from bis-glyoxylic ester and amide derivatives 243, 244 and 250 were not successful. One probable reason could be the oxalyl functionality on the indole ring systems providing steric hindrance, thus inhibiting imine formation. ϭϬϰ 5 5 5 5 &+ 2 Q 2 2 2 1 2 2 1 1 1 + 1 1 + + +

2 2 5 (W2 5 1+ Q 5 GLPHWKR[\DQLOLQH

Scheme 6.16 Reagents and conditions: EtOH, 1,2-diaminoethane, 1,4-diaminobutane

Since 3,6-bis-(2-indolyl)-dibenzofuran 72 react with trichloroacetyl chloride in 1,2- dichloroethane to form bis-trichloroacetyl indole 257, it was of interest to examine the reactivity of trichloroacetyl indole 257 towards diamino compounds, such as 1,2- diaminoethane, 1,4-diaminobutane and 1,12-diaminododecane. A possible outcome could be the formation of a new class of macrocyclic diamides such as compounds 265-267 containing amide linkages (Scheme 6.17). To check this possibility, indole 257 was reacted with 1,2-diaminoethane at room temperature. The crude 1H NMR spectrum showed the presence of compounds 265 and 268 which could not be separated for characterization.

Similarly, the treatment of bis-trichloroacetyl indole 257 with 1,4-diaminobutane and 1,12- diaminododecane under similar conditions gave the corresponding macrocyclic diamides

266 and 267, together with the diamides 269 and 270. However, none of the compounds could be purified for characterization even after extensive chromatography or by recrystallization in different solvents. Even the 1H NMR spectra of partially purified mixtures were extremely complicated to analyze. The ESI mass spectrometry showed peaks

ϭϬϱ at m/z 511, 539 and 651 (M+1) corresponding to compounds 266-267 respectively, and also revealed peaks at m/z 571, 627 and 851 corresponding to compounds 268-270.

Scheme 6.17 Reagents and conditions: MeCN, diamino compounds, r.t., 1 h

6.6. Conclusions

3,6-Bis-(2-indolyl)-dibenzofuran and carbazole derivatives were acylated using oxalyl chloride and trichloroacetyl chloride, and subsequently led to the generation of new bis- indole ester and amide derivatives. However, it was observed that some of the bis- gyloxylesters and amides were unstable and failed to generate the macrocyclic indolyldiamides. On the contrary, it was found that cyclisation reaction of the bis- trichloroacetyl indoles with appropriate diamines afforded the corresponding inseparable cyclic diamides and uncyclised diamines.

ϭϬϲ CHAPTER 7

Biological Activity

7.1. Introduction

Throughout this thesis the biological activity of bis-indoles and related analogues separated in the literature has been mentioned. A selection of the new bis-indole derivatives synthesised during this work was therefore preliminarily screened for anti-cancer activity.

7.2. Anti-Cancer Screening

3,6-Bis-(2-indolyl)-dibenzofuran 72, carbazole 73, 3,6-bis-(3-indolyl)-dibenzofuran 128,

7,7’-dialdehyde derivative 134 and hydrazone derivative 222 were selected for anti-cancer screening along with the bis-biindolyls 169 and 177 and imine macrocycles 198, 200 and

201. The currently available anti-proliferative drug DFO was used as a control and the ability of the selected bis-indole compounds to inhibit cellular proliferation on SK-N-MC neuroepithelioma cells was performed using a standard MTT Assay. The maximum compound concentration tested in this initial study was 12.5 μM due to the solvent

(DMSO), and potentially the compounds possessing toxicity at higher concentrations, which would hence lead to inaccurate results.

The anti-proliferative activity of the compounds was assessed by calculating the concentration that inhibited cellular proliferation by 50% (IC50) and the results are shown in table 7.2.

ϭϬϳ Table 7.2: Anti-cancer screening of bis-indole derivatives

Product Average IC50 Value (μ M)

DFO 21.29

72 > 12.5

73 > 12.5

128 9.85

134 >12.5

198 7.00

201 > 12.5

177 > 12.5

200 > 12.5

160 5.41

222 > 12.5

The results indicated that the bis-indoles possessed anti-proliferative activity, with 3,6-bis-

(3-indolyl)-benzofuran 128, imine macrocycles 198 and bis-biindolyls 160 in particular showing better activity that the positive control, DFO which had an IC50 value of 21.29

μM.

ϭϬϴ

The 3-indolyl analogue 128 showed an IC50 value of 9.85 μM, while the corresponding 2- indolyl compounds 72 and 73 exceeded the maximum concentration tested 12.5 μM. This potentially suggests the subtle geometry difference between these structures influences the binding of these compouds to the active site in the cells.

The addition of 7,7’-substituents to compound 128 resulted in a decrease in activity, with compounds 134 and 222 possessing an IC50 value above the maximum concentration tested.

A similar trend was observed with the bis-biindolyl compounds 160 and 177, with the unsubstituted analogue 160 showing a potent antiproliferative activity (IC50 = 5.42 μM) and the formyl substituted anlogue 177 being above the intended range.

Of the macrocycles 198, 200 and 201, the less flexible benzofuran derivative 198 showed the best activity, with an IC50 value of 7.00 μM. Increasing the flexibility of the alkyl linker

ϭϬϵ in compound 201, or changing from a benzofuran to a carbazole 200 led to an IC50 value above the tested concentration range.

Interestingly, no preference between the benzofuran and carbazole moiety was evident, with the benzofuran derivatives of the parent 3,6-bis-indolyls and macrocycles showing stronger activity and the carbazole derivative of the bis-biindolyls showing superior activity.

7.3. Conclusions

A preliminary screening of the selected bis-indole derivatives developed throughout this body of work show reasonable anti-cancer activity. The preliminary anti-cancer results show promise for further development with selected analogues being more potent than the control.

ϭϭϬ CHAPTER 8

Experimental

8.1. General Information

All reactions requiring anhydrous conditions were performed under an argon atmosphere and dry solvents were prepared as follows. MeOH, EtOH and EtOAc were obtained from commercial sources. Light petroleum (hexane) was distilled and the fraction 60-80 °C was used for chromatography and recrystallization. Anhydrous THF, DCM and CH3CN were obtained using a PureSolv MD Solvent Purification System.

Melting points were measured using a Mel-Temp melting point apparatus, and are uncorrected.

High resolution mass spectra (HRMS) reported to 4 decimal places were recorded on either a Bruker FT-ICR MS (EI) or a Micromass ZQ2000 (ESI) mass spectrometer in the School of Chemistry, UNSW and the School of Chemistry University of Otago, New Zealand.

Microanalysis was performed on a Carlo Erba Elementel Analyzer EA 1108 at the

Campbell Microanalytical Laboratory, the University of Otago, New Zealand.

Infrared spectra were recorded with a Thermo Nicolet 370 FTIR spectrometer as KBr disks.

Ultraviolet-visible spectra were measured using a Varian Cary 100 Scan spectrometer, and the absorption maxima together with the molar absorptivity (İ) are reported͘

NMR spectra were recorded in the designated solvents on a Bruker Avance DPX300 (300

MHz) at the designated frequency and were internally referenced to the solvent peaks. 1H

NMR spectral data are reported as follows: chemical shift measured in parts per million

(ppm) downfield from TMS (į); multiplicity; observed coupling constant (J) in Hertz (Hz); ϭϭϭ proton count; assignment. Multiplicities are recorded as singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q), quintet (p), multiplet (m), doublet of doublets (dd), and combinations of these. 13C NMR chemical shifts are reported in ppm downfield from TMS

(į), and identifiable carbons are given. Acid-free deuterated chloroform was obtained by passing the solvent through a short column of anhydrous K2CO3 prior to use.

Column chromatography was carried out using Merck 230-400 mesh ASTM silica gel.

Suction column chromatography was carried out using Merck 60H silica gel. Gravity column chromatography was carried out using Merck 70-230 mesh ASTM silica gel.

Preparative thin layer chromatography was carried out on 3 x 200 x 200 mm glass plates coated with Merck 60GF254 silica gel. Reactions were monitored using thin layer chromatography, performed on Merck DC aluminium foil coated with silica gel GF254.

Compounds were detected by short and long wavelength ultraviolet light, charring with vanillin or permanganate solutions and iodine vapour.

ϭϭϮ 8.2 Experimental Details

8.2.1 General Synthetic Procedures:

GP-1: General procedure for acetylation

To a solution of the appropriate substrate (1 equiv) in carbon disulfide (30 ml) was added aluminium chloride (2 equiv), followed by slow addition of acetyl chloride (2 equiv). The reaction mixture was stirred for 6 h at 50 oC, and the solvent was evaporated off. The crude mixture was recrystallized from dichloromethane and light petroleum to give the desired acetyl derivatives.

GP-2: General procedure for the preparation of hydrazones

To a solution of the appropriate 3,6-diacetyl compound (1 equiv) in ethanol (20 ml) was added phenylhydrazine (2 equiv) in the presence of glacial acetic acid and the mixture was heated to at reflux for 2 h. The precipitate that formed was filtered and washed with dilute

HCl (10 ml) followed by cold 95 % cold ethanol (20 ml). The product was recrystallized from ethanol to yield the desired hydrazones as yellow crystals.

GP-3: General procedure for the preparation of 2-indolyl compounds

A mixture of the appropriate hydrazone (1 equiv) and methanesulfonic acid (10 ml) was stirred for 1 h at 110 oC. Ice water (50 ml) was added and the mixture was stirred for further

30 min. The precipitate was filtered and washed with water. The crude product was purified using gravity column chromatography using dichloromethane as an eluent to give the title compounds.

ϭϭϯ GP-4: General procedure for the preparation of N,N'-linked carbazoles

Carbazole (2 equiv) was added to a suspension of potassium hydroxide (4 equiv) in dimethylsulfoxide (15 ml). The mixture was stirred for 1 h after which the appropriate xylenedibromide (1 equiv) was added. The reaction was stirred for another 6 h. Addition of water (20 ml) caused precipitation of the crude product. The solid was filtered, dissolved in dichloromethane (100 ml) and washed with brine. Column chromatography over silica gel

(1:1 dichlromethane-light petroleum) yielded the title compounds as colorless solids.

GP-5: General procedure for the formylation of indoles

Dimethylformamide (5 ml) was cooled in an iced water bath, treated with phosphoryl chloride (2 equiv or excess) and stirred for 20 min. This solution was then added dropwise over 8 min, to a solution of the appropriate indole (1 equiv) in dimethylformamide (5 ml) with stirring. The resulting solution was stirred overnight at ambient temperature. Ice cold water (5 ml) was added and the mixture was basified to high pH with 5M sodium hydroxide. The mixture was then stirred at ambient temperature for 30 min. The resulting precipitate was filtered, washed with water and dried to give the desired formyl indoles.

GP-6: General procedure for the reduction of formyl indoles and imines

To a solution of the appropriate formyl indole or imine (1 equiv) in ethanol (20 ml) was added the excess sodium borohydride. The reaction mixture was stirred at room temperature for 6 to 12 h. The excess borohydride was quenched with the slow addition of distilled water (40 ml). The mixture was then extracted several times with ethyl acetate.

The combined extracts were dried over anhydrous sodium sulphate, concentrated under

ϭϭϰ reduced pressure and recrystallized from dichloromethane/light petroleum to afford the desired compounds.

GP-7: General procedure for the preparation of bis-biindolyl compounds

To a solution of the appropriate bis-indole (1 equiv) in phosphoryl chloride (5 ml) was added the indolin-2-one or 4,6-dimethoxyindolin-2-one (2 equiv). The reaction mixture was then stirred in an oil bath at 60 oC for 3 h. After cooling, the mixture was poured onto crushed ice and basified to high pH with 5M NaOH. After stirring further for another 10 min. with cooling, the resulting precipitate was filtered, yielding the desired bis-biindolyl compounds.

GP-8: General procedure for the preparation of imine macrocycles

To a solution of the appropriate bis-indole dicarbaldehyde (1 equiv) in ethanol (30 ml) was added 1,4-diaminobutane or 1,6-diaminohexane (0.5 equiv) and the mixture was stirred at reflux overnight. The mixture was brought to room temperature and the precipitate was filtered and air dried to yield the desired macrocyclic compounds.

GP-9: General procedure for the preparation of indole hydrazones

A mixture of the appropriate bis-indole dicarbaldehyde and excess hydrazine hydrate was refluxed for 2 h in ethanol. Then, the mixture was cooled to room temperature and the resulting precipitate was filtered, recrystallized from dichloromethane/light petroleum to yield the indole hydrazones.

GP-10: General procedure for the preparation of bis-glyoxyloyl chlorides

ϭϭϱ A solution of the appropriate bis-indole (1equiv) and excess oxalyl chloride in anhydrous diethyl ether (20 ml) was stirred at room temperature for 3 h. The resulting precipitate was filtered, washed with ether and dried to yield the desired bis-glyoxyloyl chlorides.

GP-11: General procedure for the preparation of bis-glyoxylamides

Method A

Concentrated ammonia (10 ml) was added to the appropriate bis-glyoxyloyl chloride and the solution stirred at room temperature for 2 h. Water (5 ml) was then added and extracted with ethyl acetate. The organic layer was washed with water until neutral pH, and dried

(Na2SO4). The solvent was removed under reduced pressure to yield the corresponding amides.

Method B

To a solution of the appropriate bis-glyoxyloyl chloride was added excess of 40 % aqueous methylamine. The reaction mixture was stirred at room temperature for 2 h. The resulting precipitate was filtered, washed with water until neutral pH and air dried to yield the desired amides.

Method C

The appropriate bis-glyoxyloyl chloride (1 equiv) in anhydrous diethyl ether (20 ml) was treated with 3,5-dimethoxyaniline (2 equiv) in anhydrous ether (20 ml) at room temperature for 3 h. The resulting precipitate was filtered, washed with water and air dried to afford the corresponding amide.

ϭϭϲ 1,1'-(Dibenzo[b,d]furan-2,8-diyl)diethanone (63)

This compound was prepared as described in general O O Me Me procedure 1 using dibenzofuran 39 (1.00 g, 5.95 mmol) and aluminium chloride (1.58 g, 11.90 mmol) in carbon disulfide O

(30 ml) in the presence of acetyl chloride (0.90 ml, 11.90 mmol). The title compound 63 was obtained as a yellow solid (1.35 g, 90%). M.p. 160-162 oC lit63 158 oC; 1H NMR (300

MHz, DMSO-d6): į 2.71 (s, 6H, 2xMe), 7.67 (d, 2H, J=8.3 Hz, benzofuran H), 8.08 (dd,

2H, J=1.2, 1.2 Hz, benzofuran H), 8.48 (bs, 2H, benzofuran H).

1,1'-(9H-Carbazole-3,6-diyl)diethanone (64)

This compound was prepared as described in general O O Me Me procedure 1 using carbazole 40 (1.20 g, 7.40 mmol) and

N aluminium chloride (1.97 g, 14.80 mmol) in carbon disulfide H (30 ml) in the presence of acetyl chloride (1.16 ml, 14.80 mmol). The title compound 64 was obtained as a yellow solid (1.59 g, 85%). M.p. 236-238 oC lit119 233 oC; 1H NMR (300

MHz, DMSO-d6): į 2.64 (s, 6H, 2xMe), 7.53 (d, 2H, J=8.2 Hz, carbazole H), 8.00 (dd, 2H,

J=1.5, 1.5 Hz, carbazole H), 8.98 (bs, 2H, carbazole H), 12.03 (s, H, carbazole NH).

1,1'-(9-Methyl-9H-carbazole-3,6-diyl)diethanone (65)

This compound was prepared as described in general O O Me Me procedure 1 using N-methyl carbazole 61 (0.92 g, 5.08 mmol) and aluminium chloride (1.35 g, 10.16 mmol) in carbon N Me disulfide (30 ml) in the presence of acetyl chloride (0.80 ml,

ϭϭϳ 10.16 mmol). The title compound 65 was obtained as a yellow solid (1.45 g, 83%). M.p.

o 120 o 1 196-198 C lit 192 C; H NMR (300 MHz, DMSO-d6): į 2.77 (s, 6H, 2xMe), 4.03 (s,

3H, NMe), 7.81 (d, 2H, J=8.6 Hz, carbazole H), 8.21 (dd, 2H, J=1.5, 1.5 Hz, carbazole H),

9.11 (bs, 2H, carbazole H).

1,1'-(9-Ethyl-9H-carbazole-3,6-diyl)diethanone (66)

This compound was prepared as described in general O O procedure 1 using N-ethyl carbazole 62 (1.30 g, 6.66 mmol) Me Me and aluminium chloride (1.77 g, 13.33 mmol) in carbon N Et disulfide (30 ml) in the presence of acetyl chloride (1.00 ml,

13.33 mmol). The title compound 66 was obtained as a yellow solid (1.59 g, 86%). M.p.

o 121 o 1 186-188 C lit 182 C; H NMR (300 MHz, DMSO-d6): į 1.31 (t, 3H, J=7.0 Hz, CH2Me)

2.68 (s, 6H, 2xMe), 4.51 (q, 2H, J=8.7 Hz, CH2Me), 7.71 (d, 2H, J=8.2 Hz, carbazole H),

8.11 (dd, 2H, J=1.8, 1.8 Hz, carbazole H), 9.01 (bs, 2H, carbazole H).

2,8-Bis((E)-1-(2-phenylhydrazono)ethyl) dibenzo[b,d]furan (67)

The title compound was synthesized following general procedure 2 using 3,6-diacetyl Me Me NH N dibenzofuran 63 (1.00 g, 3.96 mmol) and HN N phenyl hydrazine 51 (0.85 g, 7. 93 mmol) in O ethanol (30 ml). The hydrazone 67 was obtained as yellow crystals (1.37 g, 80%). M.p 190-

o ,C; IR (KBr): ݝmax 3408, 3058, 2926, 1677, 1633, 1598, 1497, 1424, 1359, 1251, 1198 192

-1 -1 -1 1 1022, 818, 752, 693 cm ; UV (MeCN): λmax 331 nm (ܭ 69,546 cm M ), 235 (71,403); H

ϭϭϴ NMR (300 MHz, CDCl3): į 2.39 (s, 6H , 2xMe), 6.88 (t, 2H, J=6.7 Hz, aryl H), 7.22 and

7.36 (m, 10H, aryl H and NH), 7.57 (d, 2H, J=9.0 Hz, linker H), 7.97 (dd, 2H, J=5.2, 6.7

13 Hz, linker H), 8.33(d, 2H, J=1.8 Hz, linker H); C NMR (CDCl3): į 12.7 (CMe), 111.5,

113.2, 117.9, 120.2, 125.4, 129.2 (aryl CH), 118.8, 124.2, 131.7, 156.7 (aryl C), 145,1

+ (CMe); HRMS (ESI): Found m/z 433.1991 [M+H] ; C28H25N4O required 433.2023.

3,6-Bis((E)-1-(2-phenylhydrazono)ethyl)-9H-carbazole (68)

The title compound was synthesized following general procedure 2 using 3,6-diacetyl carbazole Me Me NH N 64 (1.00 g, 3.96 mmol) and phenyl hydrazine 51 HN N

(0.89 g, 7.93 mmol) in ethanol (30 ml). The N H hydrazone 68 was obtained as yellow crystals (1.19 g, 70%). M.p. 230-232 oC; (Found C,

76.2; H, 5.9; N, 14.9. C28H25N5.0.6C2H5OH required C, 76.3; H, 6.2; N, 15.2); IR (KBr):

ݝmax 3380, 3048, 1598, 1493, 1423, 1368, 1329, 1297, 1245, 1131, 1070, 1021, 877, 746

-1 -1 -1 1 cm ; UV (MeCN): λmax 340 nm (ܭ 46,107 cm M ), 248 (33,767); H NMR (300 MHz,

DMSO-d6): į 2.42 (s, 6H , 2xMe), 6.79 (t, 2H, J=6.7 Hz, aryl H), 7.20 and 7.30 (m, 10H, aryl H and NH), 7.45 (d, 2H, J=8.6 Hz, linker H), 8.02 (dd, 2H, J=1.8, 1.8 Hz, linker H)

13 8.54 (d, 2H, J=1.8 Hz, linker H), 11.39 (bs, 1H, carbazole NH); C NMR (DMSO-d6): į

13,7 (CMe) 111.3, 113.1, 117.8, 118.7, 123.7, 129.2 (aryl CH), 122.9, 130.8, 140.1, 146.8

+ (aryl C) 142.5 (CMe); HRMS (ESI): Found m/z 432.2167 [M+H] ; C28H26N5 required

432.2183.

ϭϭϵ 9-Methyl-3,6-bis((E)-1-(2-phenylhydrazono)ethyl)-9H-carbazole (69) and

(E)-1-(9-methyl-6-(1-(2-phenylhydrazono)ethyl)-9H-carbazol-3- yl)ethanone (71)

Thetitle compound was synthesized following general procedure 2 using 9-methyl-3,6- Me Me NH N diacetylcarbazole 65 (2.00 g, 7.50 mmol) and HN N phenyl hydrazine 51 (1.60 g, 15 mmol) in N Me ethanol (30 ml). The hydrazone 69 was obtained as yellow crystals (2.62 g, 78%). M.p.

o ,C; IR (KBr): ݝmax 3417, 3336, 3047, 2925, 1600, 1492, 1373, 1331, 1297, 1246 210-212

-1 -1 -1 1 1134, 806, 751, 690 cm ; UV (MeCN): λmax 344 nm (ܭ 69,268 cm M ), 251 (59,108); H

NMR (300 MHz, DMSO-d6): į 2.40 (s, 6H, 2xMe), 3.89 (s, 3H, linker NMe), 6.79 (t, 2H,

J=6.6 Hz, aryl H), 7.12 and 7.22 (m, 10H, aryl H and NH), 7.52 (d, 2H, J=8.6 Hz, linker

H), 8.03 (dd, 2H, J=1.8, 1.8 Hz, linker H), 8.50 (d, 2H, J=1.5 Hz, linker H); 13C NMR

(DMSO-D6): į 13.7 (CMe), 29.5 (NMe), 109.5, 113.1, 117.8, 118.8, 123.8, 129.2 (aryl

CH), 114.7, 122.4, 131.0, 141.0, 146.8 (aryl C), 142.4 (CMe); HRMS (ESI): Found m/z

+ 446.2296 [M+H] ; C29H28N5 required 446.2339.

The second band eluted from the column yielding the O mono substituted compound 65 as a yellow solid (0.34 Me Me HN N g, 13%). M.p. 216-218 0C (from N dichloromethane/hexane; (Found: C, 72.3; H, 5.7; N, Me

,C23H21N3O.0.4CH2Cl2 required C, 72.1; H, 5.6; N, 10.1%); IR (KBr): ݝmax 3329 .10.0 ϭϮϬ 3049, 2938, 1662, 1624, 1592, 1492, 1462, 1365, 1353, 1330, 1298, 1277, 1257, 1246,

-1 -1 -1 1214, 1160, 1144, 869, 810, 748 cm ; UV (MeOH): λmax 334 nm (ܭ 22,242 cm M ), 290

1 (37,663), 260 (30,130); H NMR (300 MHz, DMSO-d6): į 2.40 (s, 3H, COMe), 2.68 (s,

3H, Me), 3.90 (s, 3H, linker NMe), 6.75 (t, 1H, J=5.8 Hz, aryl H), 7.22 and 7.30 (m, 4H, aryl H), 7.63 (m, 2H, linker H), 8.04 and 8.13 (m, 2H, linker H), 8.63 (d, 1H. J=1.5 Hz,

13 linker H), 8.95 (d, 1H, J=1.5 Hz, linker H), 9.02 (s, 1H, NH); C NMR (DMSO-d6): į 13.6,

27.1, 29.7 (Me), 109.4, 109.9, 113.1, 118.1, 118.9, 122.6, 124.4, 126.2, 129.2, (aryl CH),

122.3, 128.8, 131.9, 141.3, 142.0, 143.9, 146.7 (aryl C) 197.4 (C=O); HRMS (ESI): Found

+ m/z 356.1755 [M+H] ; C23H22N3O required 356.1763.

9-Ethyl-3,6-bis((E)-1-(2-phenylhydrazono)ethyl)-9H-carbazole (70)

The title compound was synthesized following general procedure 2 using 9-ethyl-3,6-diacetyl Me Me NH N carbazole 66 (2.00 g, 7.20 mmol) and phenyl HN N hydrazine 51 (1.93 g, 14.4 mmol) in ethanol (30 N Et ml). The hydrazone 70 was obtained as yellow

o ,crystals (2.53 g, 77%). M.p. 188-190 C; IR (KBr): ݝmax 3444, 3047, 2979, 1666, 1626

-1 1599, 1492, 1370, 1352, 1301, 1252, 1236, 1136, 1072, 1021, 871, 806, 749, 693 cm ; UV

-1 -1 1 (MeOH): λmax 250 nm (ܭ 17,995 cm M ), 216 (21,127) ; H NMR (300 MHz, DMSO-d6):

į 1.06 (t, 3H, J=6.9 Hz, CH2Me), 2.40 (s, 6H, 2xMe), 4.46 (q, 2H, J=7.3 Hz, CH2Me), 6.73

(t, 2H, J=6.7 Hz, aryl H), 7.19 and 7.29 (m, 8H, aryl H and NH), 7.59 (d, 2H, J=8.7 Hz, aryl H), 8.07 (dd, 2H, J=1.7, 1.7 Hz, linker H), 8.56 (d, 2H, J=1.5 Hz, linker H), 9.15 (s,

13 2H, linker H); C NMR (DMSO-d6): į 13.7, 14.2 (Me), 37.5 (CH2), 109.5, 113.1, 118.0,

ϭϮϭ 118.8, 123.9, 129.2 (aryl CH) 113.1, 122.6, 131.0, 139.9, 142.4, 146.8 (aryl); HRMS (ESI):

+ Found m/z 460.2488 [M+H] ; C30H30N5 required 460.2501.

2,8-Di(1H-indol-2-yl)dibenzo[b,d]furan (72) and 1-(8-(1H-indol-2- yl)dibenzo[b,d]furan-2-yl)ethanone (76)

This compound was prepared as described in general procedure 3 from phenyl hydrazone 67 (2.00 g, 5.02 NH mmol) and methanesulfonic acid (10 ml). After HN purification, the title compound 72 was obtained as a O

o ,yellow powder (1.38 g, 75%). M.p. 214-216 C; IR (KBr): ݝmax 3407, 3047, 1600, 1477

-1 1448, 1425, 1347, 1298, 1275, 1199, 1022, 875, 791, 751, 738 cm ; UV (MeCN): λmax 318

-1 -1 1 nm (ܭ 105,507 cm M ), 244 (112,474), 205 (111,474); H NMR (300 MHz, DMSO-d6): į

6.96 (d, 2H, J=1.5 Hz, indole H), 7.01 and 7.13 (m, 4H, indole H), 7.42 (d, 2H, J=7.1 Hz, indole H), 7.55 (d, 2H, J=7.8 Hz, linker H), 7.83 (d, 2H, J=8.6 Hz, indole H), 8.05 (dd, 2H,

J=1.8, 1.8 Hz linker H), 8.65 (d, 2H, J=1.5 Hz, linker H), 11.66 (bs, 2H, indole NH); 13C

NMR (DMSO-d6): į 98.9, 111.6, 112.6, 118.0, 119.8, 120.3, 121.8, 125.6 (aryl CH), 124.5,

128.3, 129.1, 137.5, 138.1, 157.7 (aryl C); HRMS (ESI): Found m/z 399.1462 [M+H]+;

C28H19N2O required 399.1492.

ϭϮϮ The second band eluted from the column yielded the title O compound 76 as a yellow solid (0.18 g, 12%). M.p. 158- N Me H o ,C; IR (KBr): ݝmax 3408, 3326, 2921, 1672, 1635 160 O 1595, 1451, 1427, 1350, 1286, 1255, 1198, 1127, 1021, 811, 782, 746 cm-1; UV (MeCN):

-1 -1 1 λmax 309 nm (ܭ 45,630 cm M ), 247 (40, 365), 216 (3,575); H NMR (300 MHz, DMSO- d6): į 2.71 (s, 3H, COMe) 6.96 and 7.13 (m, 3H, indole H), 7.41 (dd, 1H, J=1.2, 1.2 Hz, indole H), 7.54 (d, 1H, J=7.8 Hz, indole H), 7.81 (dd, 2H, J=1.8,1.8 Hz, linker H), 8.04 (dd,

1H, J=1.5, 1.5 Hz, linker H), 8.17 (dd, 1H, J=1.5, 1.5 Hz, Hz, linker H), 8.78 (dd, 1H,

J=1.5, 1.5 Hz, linker H), 8.84 (dd, 1H, J=1.2, 1.2 Hz, linker H), 11.62 (s, 1H, indole NH);

13 C NMR (DMSO-d6): į 27.1 (COMe), 99.14, 111.6, 112.3, 112.7, 118.4, 119.8, 120.3,

121.9, 122.6, 125.9, 128.7 (aryl CH), 124.2, 125.9, 129.1, 132.9, 137.5, 137.9, 155.9 (aryl

+ C) 197.3 (C=O); HRMS (ESI): Found m/z 326.1168 [M+H] ; C22H16NO2 required

326.1181.

3,6-Di(1H-indol-2-yl)-9H-carbazole (73) and 3-(1H-indol-2-yl)-9H- carbazole (77)

The compound was prepared as described in general procedure 3 from phenyl hyrazone 68 (1.40 g, 3.52 HN NH mmol) and methanesulfonic acid (10 ml). After purification, the title compound 73 was obtained as a N H yellow powder (0.83 g, 67%). M.p. >300 0C; (Found C, 79.7; H, 4.8; N, 9.7.

,C28H19N3.1.5H2O required C, 79.9; H, 5.1; N, 9.9%); IR (KBr): ݝmax 3403, 3049, 1604

-1 1481, 1450, 1441, 1404, 1346, 1281, 1236, 1134, 787, 749, 590 cm ; UV (MeOH): λmax

ϭϮϯ -1 -1 1 330 nm (ܭ 72,743 cm M ), 250 (59,353), 205 (71,296); H NMR (300 MHz, DMSO-d6): į

6.88 (d, 2H, J=1.5 Hz, indole H), 6.99 and 7.11 (m, 4H, indole H), 7.44 (d, 2H, J=7.17 Hz, indole H), 7.55 (d, 2H, J=7.53 Hz, linker H), 7.61 (d, 2H, J=8.67 Hz, indole H), 7.92 and

7.95 (dd, 2H, J=1.8, 1.8 Hz, linker H), 8.68 (d, 2H, J=1.5 Hz, linker H), 11.48 (bs, 1H,

13 linker NH), 11.55 (bs, 2H, indole NH); C NMR (DMSO-d6): į 97.5, 111.4, 111.9, 117.2,

119.5, 119.9, 121.5, 124.1 (aryl CH), 123.2, 123.8, 129.4, 137.4, 139.6, 140.1 (aryl C);

+ HRMS (ESI): Found m/z 398.1616 [M+H] ; C28H20N3 required 398.1652.

The second band yielded the title compound 77 as a yellow

0 ,solid (0.02 g, 14%). M.p. 178-180 C; IR (KBr): ݝmax 3421 N H 3373, 3050, 2960, 2918, 1624, 1661, 1601, 1492, 1450, 1437, N 1259, 1246, 1098, 1025, 792, 748, 731, 603 cm-1; UV (MeOH): H

-1 -1 1 λmax 307 nm (ܭ 36,885 cm M ), 246 (11,731), 215 (7,444); H NMR (300 MHz, DMSO- d6): į 6.86 (s, 1H, indole H), 6.96 and 7.21 (m, 4H, indole H), 7.38 and 7.48 (m, 4H, linker

H), 7.88 (d, 1H, J=6.9 Hz, linker H), 8.15 (d, 1H, J=7.8 Hz, linker H), 8.60 (s, 1H, linker

13 H), 11.35 (s, 1H, linker NH), 11.49 (s, 1H, indole NH); C NMR (DMSO-d6): į 97.5,

111.3, 111.5, 111.6, 117.0, 119.1, 119.5, 119.8, 120.5, 121.1, 123.8, 126.1 (aryl CH),

123.1, 123.5, 123.8, 129.4, 137.3, 139.5, 139.6, 140.0 ( aryl C); HRMS (ESI): Found m/z

+ 283.1225 [M+H] ; C20H15N2 required 283.1235.

ϭϮϰ 3,6-Di(1H-indol-2-yl)-9-methyl-9H-carbazole (74)

This compound was prepared as described in general procedure 3 from phenyl hyrazone 69 (2.20 g, 5.35 HN NH mmol) and methanesulfonic acid (10 ml). After purification, the title compound 74 was obtained as a N Me 0 ,yellow powder (1.48 g, 73%). M.p. >300 C; IR (KBr): ݝmax 3406, 3048, 1626, 1598, 1486

-1 1453, 1426, 1350, 1295, 1255, 1155, 787, 751 cm ; UV (MeCN): λmax 331 nm (ܭ 38,385

-1 -1 1 cm M ), 311 (39,503), 252 (40,210), 203 (49,453); H NMR (300 MHz, DMSO-d6): į

3.96 (s, 3H, linker NMe), 6.92 (d, 2H, J=1.5 Hz, indole H), 7.00 and 7.11 (m, 4H, indole

H), 7.44 (d, 2H, J= 7.8 Hz, indole H), 7.56 (d, 2H, J=7.9 Hz, linker H), 7.73 (d, 2H, J=8.6

Hz, indole H), 8.02 (dd, 2H, J=1.8, 1.8 Hz, linker H), 8.71 (d, 2H, J=1.5 Hz, linker H),

13 11.58 (bs, 2H, indole NH); C NMR (DMSO-d6): į 29.6 (NMe), 97.7, 110.2, 111.4, 117.3,

119.6, 119.9, 121.3, 124.1 (aryl CH), 122.8, 124.1, 129.4, 137.4, 139.4, 140.9 (aryl C),

+ HRMS (ESI): Found m/z 412.1777 [M+H] ; C29H22N3 required 412.1808.

9-Ethyl-3,6-di(1H-indol-2-yl)-9H-carbazole (75) and 9-Ethyl-3-(1H-indol-

2-yl)-9H-carbazole (78)

The title compound was prepared as described in general procedure 3 from phenyl hydrazone 70 (2.00 HN NH g, 5.02 mmol) and methanesulfonic acid (10 ml).

After purification, the title compound 75 was obtained N Et as a yellow powder (1.38 g, 75%). M.p. 280-282 oC

(from dichloromethane/hexane); (Found: C, 81.8; H, 6.0; N, 8.7 C30H23N3.0.9CH2Cl2 ϭϮϱ ,required C, 81.7; H, 6.1; N, 9.0%); IR (KBr): ݝmax 3407, 3046, 2966, 2924, 1607, 1480

-1 1453, 1347, 1287, 1230, 1150, 1007, 783, 752 cm ; UV (MeOH): λmax 332 nm (ܭ 66,300

-1 -1 1 cm M ), 312 (67,291) 251 (40,445), 212 (14,379); H NMR (300 MHz, DMSO-d6): į

1.34 (t, 3H, J=6.9 Hz, CH2Me), 4.43 (q, 2H, J=7.2 CH2Me), 6.88 (d, 2H, J=1.2 Hz, indole

H), 6.98 and 7.09 (m, 4H, indole H), 7.28 (s, 1H, linker H), 7.43 (d, 2H, J=7.4 Hz, indole

H), 7.53 (d, 2H, J=7.5 Hz, linker H), 7.71 (d, 2H, J=8.6 Hz, indole H), 7.97 (dd, 2H, J=1.6,

13 1.6 Hz, linker H), 8.72 (d, 1H, J=1.3 Hz, linker H), 11.57 (bs, 2H, indole H); C NMR

(DMSO-d6): į 14.2 (Me), 37.6 (CH2), 97.6, 110.1, 111.4, 117.4, 119.5, 119.9, 121.2, 124.1

(aryl CH), 123.0, 124.0, 129.4, 137.4, 139.4, 139.9 (aryl C); HRMS (ESI): Found m/z

+ 426.1959 [M+H] ; C30H24N3 required 426.1970.

The second band eluted from the column yielding the title

o compound 78 as a yellow solid (0.05 g, 18%). M.p. 194-196 C; N H (Found: C, 82.0; H, 6.1; N, 8.3 C22H18N2.0.7H2O required C, N

H, 6.0; N, 8.6%); IR (KBr): ݝmax 3426, 3045, 2964, 2927, Et ;81.8

1598, 1490, 1473, 1454, 1349, 1298, 1232, 1148, 1085, 1042, 789, 737, 719 cm-1; UV

-1 -1 1 (MeCN): λmax 310 nm (ܭ 44,993 cm M ), 242 (47,041); H NMR (300 MHz, DMSO-d6): į

1.34 (t, 3H, J=7.2 Hz, CH2Me), 4.40 (q, 2H, J=7.2 Hz, CH2Me), 6.85 (d, 1H, J=1.2 Hz, indole H), 7.13 and 7.30 (m, 3H, indole H), 7.42 and 7.51 (m, 4H, linker H), 7.64 (d, 1H,

J=5.8 Hz, indole H), 7.80 (dd, 1H, J=1.7, 1.7 Hz, linker H), 8.17 (d, 1H, J=7.1 Hz, indole

13 H), 8.36 (d, 1H, J=1.6 Hz, linker H), 8.42 (s, 1H, indole NH); C NMR (DMSO-d6): į 13.7

(Me), 37.6 (CH2), 98.6, 108.6, 108.9, 110.6, 116.9, 119.0, 120.0, 120.1, 120.4, 121.6,

ϭϮϲ 123.5, 126.0 (aryl CH), 122.7, 123.3, 123.4, 129.5, 136.6, 139.2, 139.5, 140.3 (aryl C);

+ HRMS (ESI); Found m/z 311.1058 [M+H] ; C22H19N2 required 311.1548 .

1,4-Bis((9H-carbazol-9-yl)methyl)benzene (82)

This was prepared as described in general procedure 4 from carbazole

40 (0.50 g, 2.99 mmol), potassium hydroxide (0.67 g, 12.00 mmol) N and Į,Į'-dibromo-p-xylene 79 (0.39 g, 1.50 mmol) in DMSO (15 ml).

After purification, the title compound 82 was obtained as a colorless solid (0.48 g, 74%). M.p. 256-258 oC lit66 248 oC; 1H NMR (300 N

MHz, CDCl3): į 5.46 (s, 4H, NCH2), 7.03 (s, 4H, xylene H), 7.22 and

7.33 (m, 8H, aryl H), 7.44 (ddd, 4H, J=1.5, 1.1, 1.1 Hz, aryl H), 8.13 (d, 4H, J=7.5 Hz, aryl

H).

1,3-Bis((9H-carbazol-9-yl)methyl)benzene (83)

This was prepared as described in general procedure 4 from carbazole 40

(0.50 g, 3.00 mmol), potassium hydroxide (0.67 g, 12.00 mmol) and Į,Į'- N dibromo-m-xylene 80 (0.39 g, 1.50 mmol) in DMSO (15 ml). After purification, the title compound 83 was obtained as a colorless solid N (0.44 g, 68%). M.p. 200-202 oC lit66 208 oC; 1H NMR (300 MHz,

CDCl3): į 5.45 (s, 4H, NCH2), 6.95 and 7.14 (m, 4H, xylene H), 7.24 and

7.34 (m, 4H, aryl H), 7.44 (ddd, 4H, J=1.2, 1.5, 1.1 Hz, aryl H), 8.15 (dd, 4H, J=1.1, 1.1

Hz, aryl H).

ϭϮϳ 1,2-Bis((9H-carbazol-9-yl)methyl)benzene (84)

This was prepared as described in general procedure 4 from carbazole

40 (1.67 g, 10.00 mmol), potassium hydroxide (2.24 g, 40.00 mmol) and N

Į,Į'-dibromo-o-xylene 81 (1.32 g, 5.00 mmol) in DMSO (15 ml). After purification, the title compound 84 was obtained as a colorless solid N (1.55 g, 71%). M.p. 224-226 oC lit66 227 oC; 1H NMR (300 MHz,

CDCl3): į 5.44 (s, 4H, NCH2), 6.66 (q, 2H, J=3.6 Hz, xylene H), 6.97 (q, 2H, J=3.4 Hz, xylene H), 7.10 (d, 4H, J=8.2 Hz, aryl H), 7.16 and 7.24 (m, 4H, aryl H), 7.30 (ddd, 4H,

J=1.1, 1.1, 1.1 Hz, aryl H), 8.00 (d, 4H, J=7.5 Hz, aryl H).

1,1',1'',1'''-(9,9'-(1,4-Phenylenebis(methylene))bis(9H-carbazole-9,6,3- triyl))tetraethanone (85)

O The title compound was synthesized following general O Me procedure 1 using acetyl chloride (0.35 ml, 5.20 mmol), p- Me linker di-carbazole 82 (1.00 g, 2.60 mmol) and aluminium N chloride (0.36 g, 5.20 mmol) in carbon disulfide (45 ml) and was obtained 85 as a yellow solid (0.69 g, 48%). M.p. 258-

0 N 260 C; (Found: C,77.0; H,5.5; N,4.3 C40H32N2O4.H2O Me ,required C, 77.1; H, 5.5; N, 4.5%); IR (KBr): ݝmax 3424 Me O 2921, 1671, 1624, 1591, 1488, 1356, 1303, 1269, 1142, 955, O

-1 -1 -1 807, 618 cm ; UV (MeCN): λmax 326 nm (ܭ 43,512 cm M ), 289 (85,848), 259 (105,840);

1 H NMR (300 MHz, CDCl3): į 2.67 (s, 12H, 4xMe), 5.44 (s, 4H, 2xCH2), 6.94 (s, 4H, xylene H), 7.30 (d, 4H, J=8.6 Hz, carbazole H), 8.05 (dd, 4H, J=1.5, 1.9 Hz, carbazole H), ϭϮϴ 13 8.72 (d, 4H, J=1.1 Hz, carbazole H); C NMR (CDCl3): į 27.0 (Me), 50.5 (CH2), 109.5,

122.4, 127.4, 127.6, (aryl CH), 127.1, 131.0, 131.3, 134.2, 139.7, 147.9 (aryl C), 201.4

+ (C=O); HRMS (ESI) Found: m/z 627.2209 [M+Na] ; C40H32N2O4Na required 627.2254.

1,1',1'',1'''-(9,9'-(1,3-Phenylenebis(methylene))bis(9H-carbazole-9,6,3- triyl))tetraethanone (86)

The title compound was synthesized following general O O Me procedure 1 using acetyl chloride (0.26 ml, 3.90 mmol) m- Me linker di-carbazole 83 (0.75 g, 1.95 mmol) and aluminium N chloride (0.27 g, 3.90 mmol) in carbon disulfide (45 ml) and was obtained as a yellow compound 86 (0.51 g, 50%). M.p. N 242-244 0C (from dichloromethane/hexane); (Found: C, 68.7; Me Me H, 4.6; N, 3.4. C40H32N2O4.1.4CH2Cl2 required C, 68.7; H, O O

,N, 3.8%); IR (KBr): ݝmax 2933, 2919, 1661, 1591, 1571, 1487, 1371, 1306, 1271, 1250 ;4.8

-1 -1 -1 1207, 1146, 1131, 952, 880, 811, 706 cm ; UV (MeOH): λmax 331 nm (ܭ 27,280 cm M ),

1 292 (58,588), 259 (50,736); H NMR (300 MHz, CDCl3): į 2.67 (s, 12H, 4xMe), 5.49 (d,

4H, J=3.3 Hz, 2xCH2), 7.12 and 7.22 (m, 4H, xylene H), 7.33 (d, 4H, J=8.6 Hz, carbazole

H), 8.10 (dd, 4H, J=1.8, 1.8 Hz, carbazole H), 8.77 (d, 4H, J=1,5 Hz, carbazole H).

The compound was not sufficiently soluble for a 13C NMR spectrum to be obtained.

+ HRMS (ESI): Found m/z 627.2229 [M+Na] ; C40H32N2O4Na required 627.2254.

ϭϮϵ 1,1',1'',1'''-(9,9'-(1,2-Phenylenebis(methylene))bis(9H-carbazole-9,6,3- triyl))tetraethanone (87)

The title compound was synthesized following general O O Me procedure 1 using acetyl chloride (0.74 ml, 10.41 mmol), o- Me linker di-carbazole 84 (2.00 g, 5.20 mmol) and aluminium N chloride (0.73 g, 10.41 mmol) in carbon disulfide (45 ml) and was obtained as a yellow solid compound 87 (1.52 g, N

53%). M.p. 240-242 0C (from dichloromethane/hexane); Me Me O (Found: C, 59.0; H, 4.2; N, 2.9. C40H32N2O4.3.2CH2Cl2 O

,requires C, 59.2; H, 4.4; N, 3.2%); IR (KBr): ݝmax 3419, 2993, 1661, 1627, 1591, 1571

-1 -1 - 1487, 1271, 1250, 1306, 953, 811, 706 cm ; UV (CH3CN): λmax 328 nm (ܭ 29,008 cm M

1 1 ), 290 (51,900), 258 (72,128), 197 (85,142); H NMR (300 MHz, CDCl3); į 2.67 (s, 12H,

4xMe), 5.51 (s, 4H, 2xCH2), 7.12 and 7.26 (m, 4H, xylene H), 7.36 (d, 4H, J=8.6 Hz, carbazole H), 8.09 (dd, 4H, J=1.5, 1.5 Hz, carbazole H), 8.77 (d, 4H, J=1.5 Hz, carbazole

13 H); C NMR (CDCl3): į 27.1 (Me), 47.2 (CH2), 109.6, 122.4, 126.6, 127.2, 127.7, 129.1,

130.0 (aryl CH), 123.5, 128.7, 130.6, 136.8, 139.2, 144.4 (aryl C), 197.8 (C=O); HRMS

+ (ESI): Found m/z 627.2207 [M+Na] ; C40H32N2O4Na required 627.2254.

ϭϯϬ 2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3-carbaldehyde) (94)

The compound was prepared as described in general procedure 5 using phosphoryl chloride (1.10 ml, 11.00 CHO OHC mmol) and 2-indolyl dibenzofuran 72 (1.00 g, 2.22 HN NH mmol) in dimethylformamide (5 ml). The title O compound 94 was obtained as a yellow solid (1.02 g, 90%). M.p. 258-260 0C; IR (KBr):

-1 ݝmax 3415, 1633, 1583, 1452, 1374, 1203, 1101, 743, 699, 548 cm ; UV (MeCN): λmax 308

-1 -1 1 nm (ܭ 22,552 cm M ), 255 (43,423), 228 (27,381); H NMR (300 MHz, DMSO-d6): į

7.24 and 7.34 (m, 4H, indole H), 7.54 (d, 2H, J=4.5 Hz, linker H), 8.02 (d, 4H, J=2.2 Hz, indole H), 8.22 (d, 2H, J=6.6 Hz, linker H), 8.82 (bs, 2H, linker H), 10.08 (s, 2H, 2xCHO),

13 12.55 (bs, 2H, indole NH); C NMR (DMSO-d6): į 112.3, 112.8, 121.4, 122.8, 124.0,

124.1, 130.1 (aryl CH), 113.8, 124.2, 126.2, 136.3, 149.3, 157.0 (aryl C), 186.1 (CHO);

+ HRMS (ESI): Found m/z 453.1234 [M+H] ; C30H19N2O3 required 453.1245.

2,2'-(9H-Carbazole-3,6-diyl)bis(1H-indole-3-carbaldehyde) (95)

The compound was prepared as described in general procedure 5 using phosphoryl chloride (1.10 mL, 11.00 CHO OHC mmol) and 2-indolyl carbazole 73 (1.00 g, 2.20 mmol) HN NH in dimethylformamide (5 ml). The title compound 95 N H was obtained as a yellow solid (0.96 g, 85%). M.p. 254-

0 256 C; (Found: C, 74.9; H, 4.7; N, 8.8.C30H19N3O2.1.5H2O required C, 74.9; H, 4.6; N,

-1 IR (KBr): ݝmax 3237, 1628, 1581, 1453, 1372, 1245, 1135, 747, 629 cm ; UV ;(8.7%

-1 -1 1 (MeCN): λmax 310 nm (ܭ 49,916 cm M ), 255 (71,109), 200 (69,436); H NMR (300 ϭϯϭ MHz, DMSO-d6): į 7.22 and 7.27 (m, 4H, indole H), 7.52 (d, 2H, J=5.5 Hz, linker H), 7.78

(d, 2H, J=8.3 Hz, linker H), 7.87 (dd, 2H, J=1.6, 1.6 Hz, linker H), 8.23 (d, 2H, J=5.0 Hz, indole H), 8.78 (d, 2H, J=1.2 Hz, linker H), 10.07 (s, 2H, 2xCHO), 11.53 (bs, 1H, linker

13 NH), 11.68 (bs, 2H, indole NH); C NMR (DMSO-d6): į 112.2, 121.3, 122.6, 123.2,

123.7, 128.2 (aryl CH), 113.4, 121.1, 123.1, 126.4, 136.3, 141.3, 151.1 (aryl C), 186.3

+ (CHO); HRMS (ESI): Found m/z 454.1517 [M+H] ; C30H20N3O2 required 454.1556.

2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1H-indole-3-carbaldehyde) (96)

The compound was prepared as described in general procedure 5 using phosphoryl chloride (1.00 mL, 10.71 CHO OHC HN NH mmol) and 2-indolyl-N-methyl carbazole 74 (1.00 g,

2.14 mmol) in dimethylformamide (5 ml). The title N Me compound 96 was obtained as a yellow solid (1.05 g,

0 ,M.p. 240-242 C; IR (KBr): ݝmax 3410, 2930, 1662, 1488, 1452, 1370, 1283, 1248 .(90%

-1 -1 -1 1147, 1153, 811, 748 cm ; UV (MeCN): λmax 307 nm (ܭ 33,438 cm M ), 255 (48,414);

1 H NMR (300 MHz, DMSO-d6): į 4.05 (s, 3H, linker NMe), 7.24 and 7.30 (m, 4H, indol

H), 7.55 (d, 2H, J=7.1 Hz, linker H), 7.94 (d, 4H, J=9.4 Hz, indole H), 8.25 (d, 2H, J=7.1

Hz, linker H), 8.83 (bs, 2H, linker H), 10.08 (s, 2H, 2xCHO), 12.55 (bs, 2H, indole NH);

13 C NMR (DMSO-d6): į 29.8 (NMe), 110.5, 112.2, 121.3, 122.6, 123.2, 123.8, 128.3 9

(aryl CH) , 124.2, 126.3, 136.3, 142.2, 150.9, 162.7 (aryl C) 186.3 (CHO); HRMS (ESI):

+ Found m/z 490.1492 [M+H] ; C31H22N3O2 required 490.1526.

ϭϯϮ 2,2'-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H-indole-3-carbaldehyde) (97)

The compound was prepared as described in general procedure 5 using phosphoryl chloride (0.54 ml, 5.88 CHO OHC mmol) and 2-indolyl-N-ehtyl carbazole 75 (0.50 g, 1.17 HN NH mmol) in dimethylformamide (5 ml). The title N compound 97 was obtained as a yellow solid (0.45 g, Et

0 ,M.p. >300 C; IR (KBr): ݝmax 3384, 1626, 1451, 1377, 1286, 1233, 1152, 1129 .(80%

-1 -1 -1 1091, 810, 748, 664 cm ; UV (MeOH): λmax 368 nm (ܭ 20,330 cm M ), 299 (30,270),

1 255 (17,251); H NMR (300 MHz, DMSO-d6): į 1.40 (t, 3H, J=6.9 Hz, CH2Me), 4.60 (d,

2H, J=7.1 Hz, CH2Me), 7.19 and 7.24 (m, 4H, indole H), 7.50 (d, 2H, J=5.3 Hz, linker H),

7.89 and 7.91 (m, 4H, indole H), 8.22 (d, 2H, J=6.3 Hz, linker H), 8.51 (s, 1H, linker H),

8.80 (s, 1H, linker H), 10.05 (s, 2H, 2xCHO), 11.32 (s, 2H, indole NH); 13C NMR (DMSO- d6): į 14.6 (Me), 36.5 (CH2), 110.7, 113.0, 121.6, 122.8, 123.7, 123.9, 128.7 (aryl CH),

113.8, 122.3, 123.2, 127.1, 137.6, 141.4, 163.1 (aryl C), 186.4 (C=O); HRMS (ESI); Found

+ m/z 482.1859 [M+H] ; C32H24N3O2 required 482.1869.

2,8-Bis(1-methyl-1H-indol-2-yl)dibenzo[b,d]furan (98)

Potassium hydroxide (0.76 g, 12.5 mmol) was added to dimethylsulfoxide (40 ml) and the mixture was N stirred at r.t. for 5 min. 2-Indolyl dibenzofuran 72 N Me Me (1.20 g, 3.14 mmol) was added and stirring was O continued for 1 h at r.t. Dimethyl sulfate (0.79 g, 6.28 mmol) was then added, and the mixture was stirred for further 1 h at r.t. Water (50 ml) was poured on the dark brown

ϭϯϯ solution and the mixture was extracted, with diethyl ether. After washing each ether extract with water (3x30 ml), the combined ethereal phases were combined, dried over sodium

0 sulfate and evaporated, giving compound 98 (0.82 g 64%). M.p. 238-240 C; IR (KBr): ݝmax

3415, 3051, 2934, 2104, 1605, 1462, 1427, 1338, 1195, 1122, 1024, 780, 749 cm-1; UV

-1 -1 1 (MeCN): λmax 302 nm (ܭ 61,142 cm M ), 198 (113,293); H NMR (300 MHz, DMSO-d6):

į 3.82 (s, 6H, indole NMe), 6.66 (s, 2H, indole H), 7.09 and 7.21 (m, 4H, J=7.9 Hz, indole

H), 7.52 (d, 2H, J=8.2 Hz, indole H), 7.61 (d, 2H, J=7.5 H, indole H), 7.77 (dd, 2H, J=1.8,

1.8 Hz, indole H), 7.91 (d, 2H, J=8.6 Hz, linker H), 8.51 (d, 2H, J=1.5 Hz, indole H); 13C

NMR (DMSO-d6): į 31.5 (NMe), 101,7, 110.5, 112.3, 119.9, 120.3, 121.7, 122.5, 129.4

(aryl CH), 124.2, 127.7, 127.9, 138.4, 141.1, 155.9 (aryl C); HRMS (ESI): Found m/z

+ 427.1784 [M+H] ; C30H23N2O required 427.1805.

9-Methyl-3,6-bis(1-methyl-1H-indol-2-yl)-9H-carbazole (99)

Potassium hydroxide (0.56 g, 10.00 mmol) was added to dimethylsulfoxide (30 ml) and the mixture was N N stirred at room temperature for 5 min. 2-Indolyl Me Me carbazole 73 (1.00 g, 2.50 mmol) was added and N Me stirring was continued for 45 min at room temperature. Dimethly sulfate (0.63 g, 5.00 mmol) was then added, and the mixture was stirred for further 45 min at room temperature.

Water (20 ml) was added to the dark brown solution and the mixture was extracted with diethyl ether (3 x 100 ml). After washing each ether extract with water (3x 30 ml), the combined ethereal phases were combined, dried over sodium sulphate and evaporated,

o ,giving compound 99 (0.79 g, 72%). M.p. 128-130 C; IR (KBr): ݝmax 3422, 3049, 1603

ϭϯϰ -1 1486, 1467, 1422, 1359, 1336, 1313, 1283, 1251, 1126, 952, 750 cm ; UV (MeCN): λmax

-1 -1 1 304 nm (ܭ 16,261 cm M ), 246 (19,955); H NMR (300 MHz, CDCl3): į 3.73 (s, 6H, indole NMe), 3.90 (s, 3H, linker NMe), 6.55 (s, 2H, indole H), 7.05 and 7.18 (m, 4H, indole H), 7.33 (d, 2H, J=7.8 Hz, indole H), 7.48 (d, 2H, J=8.2 Hz, indole H), 7.61 (dd, 4H,

13 J=1.8, 1.8 Hz, linker H), 8.17 (d, 2H, J=1.1 Hz, linker H); C NMR (CDCl3): į 29.8, 31.5

(NCH3), 101.7, 109.1, 109.9, 120.1, 120.6, 121.7, 121.7, 128.1 (aryl CH), 123.1, 124.2,

+ 128.5, 138.6, 141.4, 142.8 (arly C); HRMS (ESI): Found m/z 440.2105 [M+H] ; C31H26N3 required 440.2127.

2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1-methyl-1H-indole-3-carbaldehyde)

(100)

The compound was prepared as described in general

OHC procedure 5 using phosphoryl chloride (0.58 ml, 6.28 CHO N N mmol), and compound 98 (0.50 g, 1.25 mmol) in Me Me dimethylformamide (5.00 ml). The title compound 100 O was obtained as a yellow solid (0.52 g, 86%). M.p. 108-1120C (from dichloromethane/hexane); (Found: C, 62.4; H, 4.1; N, 4.3 C32H22N2O3.2.CH2Cl2 required

,C, 62.5; H, 4.0; N, 4.2%); IR (KBr): ݝmax 3416, 2916, 2813, 1647, 1611, 1464, 1435, 1408

-1 1381, 1325, 1199, 1126, 1061, 1024, 951, 826, 748 cm ; UV (MeCN): λmax 302 nm (ܭ

-1 -1 1 24,819 cm M ), 255 (41,551), 200 (36,669); H NMR (300 MHz, DMSO-d6): į 3.76 (s,

6H, indole NMe) 7.31 and 7.43 (m, 4H, indole H), 7.72 (d, 2H, J=7.9 Hz, indole H), 7.88,

(dd, 2H, J=1.8, 1.8 Hz, linker H), 8.06 (d, 2H, J=8.2 Hz, linker H), 8.26 (d, 2H, J=7.1 Hz,

13 linker H), 8.61 (d, 2H, J=1.5, indole H), 9.69 (s, 2H, 2xCHO); C NMR (DMSO-d6): į

ϭϯϱ 31.4 (Me), 111.3, 112.5, 121.2, 123.3, 124.2, 125.2, 131.3 (aryl CH), 115.0, 123.7, 123.9,

124.8, 137.4, 151.3, 156.9 (aryl C), 185.9 (C=O) HRMS (ESI): Found m/z 483.1686

+ [M+H] ; C32H23N2O3 required 483.1703.

2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1-methyl-1H-indole-3- carbaldehyde) (101)

The compound was prepared as described in general CHO OHC procedure 5 using phosphoryl chloride (0.63 ml, 6.80 N N Me mmol), and compound 98 (0.60 g, 1.36 mmol) in Me dimethylformamide (5 ml). The title compound 101 N Me 0 ,was obtained as a yellow solid (0.52 g, 77%). M.p. 136-138 C; IR (KBr): ݝmax 3424, 3050

-1 2934, 1642, 1601, 1579, 1464, 1408, 1379, 1289, 1252, 1126, 748 cm ; UV (MeCN): λmax

-1 -1 1 253 nm (ܭ 95,664 cm M ), 197 (115,992) ; H NMR (300 MHz, DMSO-d6): į 3.67 (s,

6H, indole NMe), 4.00 (s, 3H, linker NMe), 7.21 and 7.32 (m, 4H, indole H), 7.61 (d, 2H,

J=8.2, linker H), 7.75 (dd, 2H, J=1.8, 1.8 Hz, linker H), 7.85 (d, 2H, J=8.2 Hz, indole H),

8.17 (d, 2H, J=7.1 Hz, linker H), 8.57 (d, 2H, J=1.1 Hz, indole H), 9.60 (s, 2H, 2xCHO);

13 C NMR (DMSO-d6): į 29.8, 31.5 (NMe), 110.2, 111.2, 121.1, 123.2, 123.9, 124.4, 129.2

(aryl CH), 114.8, 119.1, 122.2, 125.0, 137.5, 141.9, 152.8 (aryl C), 186.0 (CHO) HRMS

+ (ESI): Found m/z 518.1808 [M+Na] ; C33H25N3O3Na required 518.1839.

ϭϯϲ (2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))dimethanol (102)

This compound was prepared as described in general HO OH procedure 6 from formyl indole 94 (0.80 g, 1.70 mmol)

NH and excess sodium borohydride in absolute ethanol (20 HN ml). The title compound 102 was obtained as a yellow O 0 ,solid (0.62 g, 78%), M.p. >300 C; IR (KBr): ݝmax 3386, 1643, 1557, 1451, 1342, 1260

-1 -1 -1 1198, 1127, 1024, 1000, 819, 743 cm ; UV (MeCN): λmax 304 nm (ܭ 48,290 cm M ), 238

1 (62,723), 205 (59,716); H NMR (300 MHz, DMSO-d6): į 4.67 (s, 4H, 2xCH2), 4.99 (s,

2H, 2xOH), 6.94 and 7.07 (m, 4H, indole H), 7.34 (d, 2H, J=7.9 Hz, indole H), 7.62 (d, 2H,

J=7.5 Hz, indole H), 7.84 (d, 2H, J=8.6 Hz, linker H), 7.93 (dd, 2H, J=1.8, 1.8 Hz, linker

13 H), 8.46 (d, 2H, J=1.5 Hz, linker H), 11.45 (bs, 2H, indole NH); C NMR (DMSO-d6): į

54.3 (CH2), 79.5, 111.2, 112.4, 119.2, 119.3, 120.8, 121.9, 128.6 (aryl CH), 112.6, 124.3,

128.3, 129.7, 136.3, 155.7 (aryl C); HRMS (ESI): Found m/z 481.1483 [M+Na]+;

C30H22N2O3Na required 481.1523.

(2,2'-(9H-Carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))dimethanol (103)

This compound was prepared as described in general HO OH procedure 6 from formyl indole 95 (0.60 g, 1.30 mmol) NH and excess sodium borohydride in absolute ethanol (20 HN ml). The title compound 103 was obtained as a yellow N H 0 ,solid, (0.37 g, 63%). M.p. >300 C; IR (KBr): ݝmax 3412, 2924, 1608, 1485, 1453, 1342

-1 -1 -1 1284, 1135, 965, 744 cm ); UV (MeCN): λmax 317 nm (ܭ 35,290 cm M ), 246 (35,610),

1 200 (38,891); H NMR (300 MHz, DMSO-d6): į 4.80 (d, 4H, J=4.5 Hz, 2xCH2), 5.02 (bs, ϭϯϳ 2H, 2xOH), 7.03 and 7.15 (m, 4H, indole H), 7.44 (d, 2H, J=7.5 Hz, indole H), 7.68 (d, 4H,

J=6.7 Hz, indole and linker H), 7.93 (dd, 2H, J=1.8, 1.8 Hz, linker H), 8.58 (d, 2H, J=1.11

13 Hz, linker H), 11.43 (s, 2H, indole NH), 11.67 (bs,1H, linker NH); C NMR (DMSO-d6): į

54.3 (CH2), 111.3, 111.7, 119.0, 119.1, 120.1, 121.3, 126.8 (aryl CH), 111.5, 123.1, 123.7,

129.4, 136.1, 137.7, 140.1 (aryl C); HRMS (ESI): Found m/z 480.1669 [M+Na]+;

C30H23N3O2Na required 480.1682.

2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))dimethanol (104)

This compound was prepared as described in general HO OH procedure 6 from the formyl indole 96 (0.23 g, 0.49 mmol) and excess sodium borohydride in absolute ethanol HN NH

(20 ml).The title compound 104 was obtained as a yellow N 0 Me ,solid, (0.13 g, 57 %). M.p. >300 C; IR (KBr): ݝmax 3396

3051, 2926, 1604, 1487, 1452, 1362, 1285, 1248, 1153, 1127, 967, 745 cm-1; UV (MeCN):

-1 -1 1 λmax 308 nm (ܭ 55,306 cm M ), 249 (59,459), 205 (50,197); H NMR (300 MHz, DMSO- d6): į 4.02 (s, 3H, linker NMe), 4.78 (d, 4H, J=4.8 Hz, 2xCH2), 5.00 (bs, 2H, 2xOH), 7.04 and 7.16 (m, 4H, indole H), 7.44 (d, 2H, J=7.8 Hz, linker H), 7.71 (d, 2H, J=7.5 Hz, indole

H), 7.83 (d, 2H, J=8.6 Hz, indole H), 8.01 (dd, 2H, J=1.8, 1.5 Hz, linker H), 8.60 (d, 2H,

13 J=1.5 Hz, linker H), 11.42 (bs, 2H, indole NH); C NMR (DMSO-d6): į 29.7 (NMe), 54.5

(CH2), 110.0, 111.3, 119.0, 119.1, 120.0, 121.4, 126.9 (aryl CH), 111.7, 122.7, 124.0,

129.4, 136.2, 137.5, 140.9 (aryl C); HRMS (ESI): Found m/z 472.2072 [M+H]+;

C31H26N3O2 required 472.2025.

ϭϯϴ (2,2'-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))dimethanol

(105)

This compound was prepared as described in general HO OH procedure 6 from formyl indole 97 (0.29 g, 0.60 mmol) HN NH and excess sodium borohydride in absolute ethanol (20 ml).The title compound 105 was obtained as a yellow N Et 0 ,solid (0.21 g, 73%). M.p. >300 C; IR (KBr): ݝmax 3399, 30533, 1603, 1483, 1453, 1377

-1 1345, 1315, 1287, 1232, 1153, 1130, 968, 745 cm ; UV (MeOH): λmax 313 nm (ܭ 73,891

-1 -1 1 cm M ), 249 (83,305), 207 (68,185); H NMR (300 MHz, DMSO-d6): į 1.23 (t, 3H, J=6.9

Hz, CH2Me), 4.39 (q, 2H, J=7.1 Hz, CH2Me), 4.60 (d, 4H, J=4.5 Hz, 2xCH2), 4.80 (bs, 2H,

2xOH), 6.86 and 6.93 (m, 4H, indole H), 7.22 (d, 2H, J=7.5 Hz, indole H), 7.49 (d, 2H,

J=7.5 Hz, indole H), 7.64 (d, 2H, J=8.7 Hz, linker H), 7.77 (dd, 2H, J=1.5, 1.5 Hz, linker

13 H), 8.40 (d, 2H, J=1.2 Hz, linker H); C NMR (DMSO-d6): į 14.3 (Me), 37.7, 54.6 (CH2),

110.2, 111.6, 119.0, 119.2, 120.4, 121.7, 127.9 (aryl CH), 111.1, 121.4, 124.0, 129.6,

+ 136.2, 137.6, 142.9 (aryl C); HRMS (ESI): Found m/z 486.2127 [M+H] ; C32H28N3O2 required 486.2182.

ϭϯϵ (2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1-methyl-1H-indole-3,2- diyl))dimethanol (106)

This compound was prepared as described in general HO OH procedure 6 from the formyl indole 100 (0.40 g, 0.86 N N Me mmol) and excess sodium borohydride in absolute Me ethanol (20 ml). The title compound 107 was obtained O

0 ,as a yellow solid, (0.30 g, 72%). M.p. >300 C; IR (KBr): ݝmax 3451, 2291, 2225, 1642

-1 - 1563, 1426, 1355, 1274, 1197, 999, 827, 743 cm ; UV (MeCN): λmax 296 nm (ܭ 16,933 cm

1 -1 1 M ), 233 (31,509); H NMR (300 MHz, DMSO-d6): į 3.83 (s, 6H, indole NMe), 4.74 (d,

4H, J=4.9 Hz, 2xCH2), 4.99 (bs, 2H, 2xOH), 7.26 and 7.42 (m, 4H, indole H), 7.70 (d, 2H,

J=8.2 Hz, linker H), 7.89 and 7.94 (m, 4H, indole H), 8.13 (d, 2H, J=8.6, linker H), 8.29 (s,

13 2H, linker H); C NMR (DMSO-d6): į 31.2 (NMe), 54.6 (CH2), 110.1, 112.1, 119.5,

122.0, 123.8, 130.8 (aryl CH), 113.9, 124.0, 126.5, 127.6, 137.2, 138.6, 156.0 (aryl C);

+ HRMS (ESI): Found m/z 487.1468 [M+H] ; C32H27N2O3 required 487.2022.

(2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1-methyl-1H-indole-3,2- diyl))dimethanol (107)

This compound was prepared as described in general HO OH procedure 6 from formyl indole 101 (0.18 g, 0.10 N N Me mmol) and sodium borohydride in absolute ethanol Me

(20 ml). The title compound 107 was obtained as a N Me 0 ,yellow solid, (0.08 g, 48%) M.p. 198-200 C; IR (KBr); ݝmax 3381, 3048, 2931, 1630, 1604

1488, 1467, 1427, 1399, 1355, 1286, 1249, 1126, 1026, 970, 821, 744 cm-1; UV (MeOH): ϭϰϬ -1 -1 1 λmax 298 nm (ܭ 72,795 cm M ), 249 (35,517); H NMR (300 MHz, DMSO-d6): į 3.69 (s,

6H, indole NMe), 4.05 (s, 3H, linker NMe), 4.49 (s, 4H, 2xCH2), 4.51 (s, 2H, 2xOH), 7.13 and 7.26 (m, 4H, indole H), 7.54 (d, 2H, J=7.9 Hz, linker H), 7.65 and 7.72 (m, 4H, indole

H), 7.83 (d, 2H, J=8.4 Hz, linker H), 8.39 (d, 2H, J=0.9 Hz, linker H); 13C NMR (DMSO- d6): į 29.7, 31.1 (NMe), 65.5 (CH2), 109.8, 110.2, 118.9, 119.8, 121.8, 122.8, 128.8 (aryl

CH), 109.6, 122.3, 122.9, 127.9, 137.0, 141.2, 141.3 (aryl C) HRMS (ESI): Found m/z

+ 522.2152 [M+Na] ; C33H29N3O2Na required 522.2157.

1,1'-(Dibenzo[b,d]furan-2,8-diyl)bis(2-bromoethanone) (123) and 1,1'-

(Dibenzo[b,d]furan-2,8-diyl)bis(2,2-dibromoethanone) (124)

Bromine (0.62 g, 3.90 mmol) in acetic acid (10 ml) was O O Br Br added dropwise to a warm solution (40 0C) of 3,6- diacetyldibenzofuran 63 (2.00 g, 7.90 mmol) in acetic acid O

(30 ml). After 4 h at room temperature, the crude product purified via flash chromatography

(from dichloromethane/hexane) to yield compound 123 (1.08 g, 54%) as a yellow solid.

0 M.p. 192-194 C; (Found C, 47.1; H, 2.6. C16H10Br2O3 requires C, 46.8; H, 2.6%); IR

,KBr): ݝmax 3070, 2933, 1674, 1630, 1591, 1430, 1413, 1270, 1204, 1168, 1126, 1004, 936)

-1 -1 -1 827, 763, 588 cm ; UV (MeCN): λmax 280 nm (ܭ 20,770 cm M ), 254 (50,665), 212

1 (29,207); H NMR (300 MHz, CDCl3): į 4.57 (s, 4H, CH2Br), 7.71 (d, 2H, J=8.6 Hz, benzofuran H), 8.22 (d, 2H, J=8.6 Hz, benzofuran H), 8.69 (d, 2H, J=1.5, benzofuran H);

13 C NMR (CDCl3): į 30.4 (CH2), 112.4, 122.6, 129.4 (aryl CH), 124.1, 129.8, 159.7 (aryl

+ C), 190.3 (C=O); HRMS (ESI): Found m/z 410.9045 [M+H] , C16H11Br2O3 required

410.9054.

ϭϰϭ The second band eluted from the column yielded the O O Br compound 124 (0.71 g, 16%) as a yellow solid. M.p. 170- Br Br Br 0 ,C; IR (KBr): ݝmax 3090, 3009, 1689, 1593, 1579 172 O 1481, 1468, 1350, 1311, 1255, 1203, 1169, 1122, 1024, 877, 845, 703, 576 cm-1; UV

-1 -1 1 (MeCN): λmax 289 nm (ܭ 27,400 cm M ), 259 (60,141), 203 (39,911); H NMR (300

MHz, CDCl3): į 6.79 (s, 2H, CHBr ), 7.71 (d, 2H, J=9.3 Hz, benzofuran H), 8.34 (dd, 2H,

13 J=1.8, 1.8 Hz, benzofuran H), 8.82 (d, 2H, J=1.5 Hz, benzofuran H); C NMR (CDCl3): į

39.4 (CHBr), 112.5, 123.6, 130.3 (aryl CH), 124.0, 126.6, 159.9 (aryl C), 185.0 (C=O);

+ HRMS (ESI): Found m/z 568.7066 [M+H] ; C16H9Br4O3 required 568.7244.

1,1'-(Dibenzo[b,d]furan-2,8-diyl)bis(2-(3,5- dimethoxyphenylamino)ethanone) (125)

A mixture of 3,5 dimethoxyaniline (0.73 g, MeO OMe MeO OMe 4.80 mmol), dibenzofuran bromo-ketones O O 123 (1.00 g, 2.40 mmol), sodium HN NH bicarbonate (0.61 g, 7.22 mmol) and O absolute ethanol (20 ml) was refluxed for 5 h. The reaction mixture was cooled to r.t. and stirred for 1 h. The product was filtered, washed with water (100 ml) and cold ethanol and dried to afford the title compound 125 as a yellow powder (1.22 g, 90%). M.p. 146-148 0C

(from dichloromethane/hexane); (Found C, 60.9; H, 4.7; N, 3.9. C32H30N2O7.1.2CH2Cl2

,required C, 60.6; H, 4.9; N, 4.2%); IR (KBr): ݝmax 3389, 2933, 2838, 1686, 1615, 1595

-1 -1 -1 1482, 1460, 1203, 1152, 810 cm ; UV (MeCN): λmax 251 nm (ܭ 92,877 cm M ), 216

1 (96,763); H NMR (300 MHz, CDCl3): į 3.80 (s, 12H, 4xOMe), 4.73 (s, 4H, 2xCH2), 5.02

ϭϰϮ (bs, 2H, NH), 5.95 (bs, 6H, aryl H), 7.73 (d, 2H, J=8.6 Hz, linker H), 8.23 (d, 2H, J=6.7

13 Hz, linker H), 8.73 (d, 2H, J=1.5 Hz, linker H); C NMR (CDCl3): į 50.3 (CH2), 55.1

(OMe), 90.0, 91.9, 112.4, 121.3, 128.1 (aryl CH), 124.1, 130.7, 148.8, 159.7, 161.7 (aryl

+ C), 193.6 (C=O); HRMS (ESI): Found m/z 555.2089 [M+H] ; C32H31N2O7 required

555.2126.

N,N'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(2-oxoethane-2,1-diyl))bis(N-

(3,5-dimethoxyphenyl)acetamide) (126)

MeO OMe A mixture of the aniline ketone 125 (2.00 MeO OMe g, 3.12 mmol) and acetic anhydride (3.80 O O N o N g, 37.44 mmol) was heated at 50 C for 1 Me Me O O h. Water (50 ml) wad added and the O mixture was stirred overnight at r.t. The precipitated product was filtered washed with water and dried to yield the compound 126 (1.90 g, 83%) as a yellow solid. M.p. 140-142

0 C (from dichloromethane/hexane); (Found C, 66.9; H, 5.2; N, 3.9. C36H30N2O9.0.2CH2Cl2

,required C, 66.9; H, 5.4; N, 4.3%); IR (KBr): ݝmax 3452, 3086, 2934, 2839, 1696, 1600

-1 1595, 1461, 1414, 1338, 1203, 1154, 1063, 1025, 828, 692 cm ; UV (MeCN): λmax 250 nm

-1 -1 1 (ܭ 89,488 cm M ), 204 ( 121,448); H NMR (300 MHz, CDCl3): į 2. 06 (s, 6H, 2x

COMe), 3.80 (s, 12H, 4xOMe), 5.18 (s, 4H, 2xCH2), 6.43 (s, 2H, aryl H), 6.59 (s, 4H, aryl

H), 7.64 (d, 2H, J=8.6 Hz, linker H), 8.14 (d, 2H, J=6.7 Hz, linker H), 8.60 (s, 2H, linker

13 H); C NMR (CDCl3): į 21.9 (COMe), 55.4 (CH2), 56.0 (OMe), 100.1, 106.1, 112.1,

121.5, 128.3 (aryl CH), 123.9, 131.0, 145.0, 159.4, 161.3 (aryl C), 170.8, 192.4 (C=O);

+ HRMS (ESI): Found m/z 639.2322 [M+H] , C36H35N2O9 required 639.2437.

ϭϰϯ 1-(3-(8-(1-Acetyl-4,6-dimethoxy-1H-indol-3-yl)dibenzo[b,d]furan-2-yl)-

5,7-dimethoxy-1H-indol-1-yl)ethanone (127)

A mixture of ketone 126 (2.00 g, 3.30 Me Me O O mmol) and trifluoroacetic acid (5 ml) was MeO N N OMe refluxed under argon atmosphere for 3 h.

OMe MeO The reaction mixture was cooled to r.t. and O poured into ice-cold water (30 ml). The precipitated product was filtered, washed with cold water and dried to yield compound 127

0 ,g, 92%) as a yellow solid. M.p. 238-240 C; IR (KBr): ݝmax 3403, 2935, 2837, 1698 1.70)

-1 1594, 1495, 1464, 1420, 1335, 1266, 1207, 1024, 965, 813 cm ; UV (MeCN): λmax 220 nm

-1 -1 1 (ܭ 42,526 cm M ), 197 (48,256); H NMR (300 MHz, DMSO-d6): į 2.68 (s, 6H,

2xCOMe), 3.74 (s, 6H, 2xOMe), 3.82 (s, 6H, 2xOMe), 6.53 (d, 2H, J=2.2 Hz, indole H),

7.70 (d, 2H, J=2.2 Hz, indole H), 7.73 (s, 6H, linker and indole H), 8.31 (s, 2H, linker H);

13 C NMR (DMSO-d6): į 24.6 (COMe), 55.8 (OMe), 93.1, 95.6, 111.0, 121.8, 123.1, 129.5

(aryl CH), 112.0, 123.5, 129.7, 137.7, 154.2, 155.3, 159.3 ( aryl C), 170.2 (C=O); HRMS

+ (ESI): Found m/z 603.2109 [M+H] ; C36H31N2O7 required 603.2126.

2,8-Bis(4,6-dimethoxy-1H-indol-3-yl)dibenzo[b,d]furan (128)

To a suspension of protected indole 127 H7 H H H7 OMe (1.00 g, 1.90 mmol) in methanol (15 ml), MeO N N H2 H2 H5 H5 was added potassium hydroxide (0.78 g, OMe OMe

14.10 mmol). The mixture was stirred at r.t. O for 2 h and then poured into ice water (50 ml). The precipitated product was filtered, ϭϰϰ washed with water and dried to yield the title compound 128 (0.60 g, 69%). M.p. 238-240

0 ,C; IR (KBr): ݝmax 3409, 2932, 2836, 2105, 1687, 1622, 1590, 1546, 1463, 1330, 1197

-1 -1 -1 1 1158, 1118, 810 cm ; UV (MeCN): λmax 232 nm (ܭ 97,251 cm M ), 197 (91,135); H

NMR (300 MHz, DMSO-d6): į 3.73 (s, 6H, 2xOMe), 3.76 (s, 6H, 2xOMe), 6.21 (d, 2H,

J=1.9 Hz, H5), 6.54 (d, 2H, J= 1.9 Hz, H7), 7.25 (d, 2H, J=2.3 Hz, H2), 7.63 and 7.71 (m,

4H, linker H), 8.23 (d, 2H, J=1.2 Hz, linker H), 11.11 (bs, 2H, indole NH); 13C NMR

(DMSO-d6): į 55.3, 55.5 (OMe), 87.6, 92.0, 110.7, 121.0, 121.9, 129.0 (aryl CH), 110.1,

117.0, 123.8, 131.8, 138.8, 1545.5, 156.9 (aryl C) HRMS (ESI); Found m/z 519.1900

+ [M+H] ; C32H27N2O5 required 519.1914.

3,3'-(Dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-indole-7- carbaldehyde) (134)

The title compound 134 was prepared as OHC CHO H H MeO N N OMe described in general procedure 5 using phosphoryl chloride (0.07 ml, 0.80 mmol), OMe OMe and 3-indolyl dibenzofuran 128 (0.20 g, O

0.40 mmol) in dimethylformamide (5 ml). The formyl indole 47 was obtained as a yellow

0 ,solid (0.17 g, 77%). M.p. 286-288 C; IR (KBr): ݝmax 3420, 1648, 1586, 1509, 1462, 1435

-1 -1 -1 1387, 1357, 1251, 1209, 1110 cm ; UV (MeCN): λmax 321 nm (ܭ 24,099 cm M ), 251

1 (57,632), (65,914); H NMR (300 MHz, DMSO-d6): į 3.92 (s, 6H, 2xOMe), 3.99 (s, 6H,

2xOMe), 6.47 (s, 2H, H5), 7.23 (d, 2H, J=1.1 Hz, linker H), 7.64 (d, 4H, J=1.1 Hz, linker

H), 8.32 (s, 2H, H2), 10.36 (s, 2H, 2xCHO), 11.46 (bs, 2H, indole NH); 13C NMR (DMSO- d6): į 56.1, 57.0 (Me), 88.1, 110.9, 121.4, 123.8, 129.2 (aryl CH), 104.3, 110.9, 117.3,

ϭϰϱ 130.8, 136.2, 154.8, 161.3, 163.8 (aryl C), 186.8 (C=O) HRMS (ESI): Found m/z 575.1757

+ [M+H] ; C34H27N2O7 required 575.1813.

3,3'-(Dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-indole-2,7- dicarbaldehyde) (135)

The title compound 135 was prepared as CHO CHO H H MeO OMe described in general procedure 5 using N N CHOOHC excess phosphoryl chloride and 3-indolyl OMe OMe dibenzofuran 128 (0.15 g, 0.28 mmol) in O dimethylformamide (5 ml). The formyl indole 135 was obtained as a yellow solid (0.12 g,

0 ,M.p. >300 C; IR (KBr): ݝmax 3420, 2936, 2853, 1646, 1589, 1463, 1384, 1236 .(68%

-1 -1 -1 1117, 983, 843, 802 cm ; UV (MeCN): λmax 345 nm (ܭ 15,278 cm M ), 306 (17,945), 248

1 (32,592); H NMR (300 MHz, DMSO-d6): į 3.90 (s, 6H, 2xOMe), 4.00 (s, 6H, 2xOMe),

6.56 (s, 2H, H5), 7.77 and 7.80 (m, 4H, linker H), 8.43 (d, 2H, J=1.1 Hz, linker H), 9.60 (s,

2H, 2xCHO), 10.30 (s, 2H, 2xCHO), 11.13 (bs, 2H, indole NH).

The compound was not sufficiently soluble for a 13C NMR spectrum to be obtained.

+ HRMS (ESI): Found m/z 653.1475 [M+Na] C36H26N2O9Na required 653.1531.

ϭϰϲ (3,3'-(Dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-indole-7,3- diyl))dimethanol (139)

The title compound 139 was prepared as OH HO described in general procedure 6 using the H H MeO N N OMe formyl indole 134 (0.20 g, 0.30 mmol) and excess sodium borohydride in absolute OMe OMe ethanol (20 ml). The alcohol 139 was O

0 ,obtained as a white solid, (0.13 g, 77%). M.p. >300 C; IR (KBr): ݝmax 3411, 2934, 2836

-1 1621, 1596, 1517, 1462, 1330, 1199, 1148, 1117, 1023, 999, 821 cm ; UV (MeCN): λmax

-1 -1 1 277 nm (ܭ 34,601 cm M ), 230 (73,410), 198 (72,208); H NMR (300 MHz, DMSO-d6): į

3.86 (s, 6H, 2xOMe), 3.91 (s, 6H, 2xMe), 4.80 (s, 4H, 2xCH2), 6.43 (s, 2H, 2xOH), 6.64 (s,

2H, H5), 7.33 (d, 2H, J=2.64 Hz, linker H), 7.70 and 7.75 (m, 4H, linker H), 8.27 (s, 2H,

13 H2), 10.97 (bs, 2H, indole NH); C NMR (DMSO-d6): į 53.9 (CH2), 55.5, 57.5 (OMe),

89.6, 110.7, 121.0, 129.0 (aryl CH), 79.6, 106.2, 116.8, 122.8, 138.3, 153.4, 153.7, 154.5

+ (aryl C) HRMS (ESI): Found m/z 601.1887 [M+Na] ; C34H30N2O7Na required 601.1945.

3,3'-(Dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-indole-2,7- dimethanol) (140)

The title compound 140 was prepared as OH HO H H described in general procedure 6 using MeO N OHHO N OMe formyl indole 135 (0.12 g, 0.19 mmol) and OMe OMe excess sodium borohydride in absolute O ethanol (20 ml).The alcohol 50 was obtained as a white solid (0.07 g, 65%). M.p. >300 0C; ϭϰϳ IR (KBr): ݝmax 3441, 2934, 1622, 1519, 1462, 1412, 1336, 1202, 1150, 1118, 1023, 559

-1 -1 -1 1 cm ; UV (MeCN): λmax 235 nm (ܭ 5,360 cm M ); H NMR (300 MHz, DMSO-d6): į 3.70

(s, 6H, 2xOCH3), 3.85 (s, 6H, 2xCH3O), 4.53 (s, 4H, 2xCH2), 4.78 (s, 4H, 2xCH2), 6.37 (s,

2H, indole H5), 7.56 (d, 2H, J=7.8 Hz, linker H), 7.69 (d, 2H, J= 8.6 Hz, linker H), 8.07 (s,

2H, linker H), 11.34 (bs, 2H, indole NH); HRMS (ESI): Found m/z 661.2149 [M+Na]+;

C36H34N2O7Na required 661.2162.

2,8-Di(1H,1'H-2,3'-biindol-2'-yl)dibenzo[b,d]furan (159)

The bis-biindolyl 159 was prepared from 2- indolyl dibenzofuran 72 (0.80 g, 2.00 mmol) and H3 H3' NH HN indolin-2-one 150 (0.53 g, 4.00 mmol) in phosphoryl chloride (5 ml) according to general N N H H procedure 7 to yield the title compound 159 as a O

0 ,yellow powder (0.76 g, 56%). M.p. 196-198 C; IR (KBr): ݝmax 3626, 3396, 3051, 1595

-1 1475, 1453, 1398, 1340, 1305, 1241, 1123, 1023, 822, 785, 745 cm ; UV (MeCN): λmax

-1 -1 1 293 nm (ܭ 67,367 cm M ), 246 (106,189); H NMR (300 MHz, DMSO-d6): į 6.44 (s, 2H, indole H3, H3'), 6.96 and 7.07 (m, 4H, indole H), 7.11 and 7.15 (m, 4H, indole H), 7.36 (d,

2H, J=7.9 Hz, indole H), 7.53 (d, 4H, J=7.8 Hz, linker H) 7.57 and 7.73 (m, 6H, indole H),

8.39 (s, 2H, linker H), 10.94 (s, 2H, indole NH), 11.94 (s, 2H, indole NH); 13C NMR

(DMSO-d6): į 100.9, 111.5, 112.4, 119.2, 119.4 119.7, 119.8, 120.2, 120.7, 121.1, 122.5,

128.8 (aryl CH), 105.8, 124.0, 128.5, 129.0, 133.0, 135.6, 136.4, 136.9 (aryl C); HRMS

+ (ESI): Found m/z 629.2307 [M+H] ; C44H29N4O required 629.2336.

ϭϰϴ 3,6-Di(1H,1'H-2,3'-biindol-2'-yl)-9H-carbazole (160)

The bis-biindolyl 160 was prepared from 2- indolyl carbazole 73 (1.10 g, 2.70 mmol) and NH HN indolin-2-one 160 (0.73 g, 5.40 mmol) in phosphoryl chloride (5 ml) according to general N N H H procedure 7 to yield the title compound 160 as a N H 0 ,yellow powder (1.00 g, 57%). M.p. 240-242 C; IR (KBr): ݝmax 3396, 3053, 2961, 2924

-1 2852, 1606, 1455, 1399, 1260, 1096, 1025, 799, 746 cm ; UV (MeOH): λmax 300 nm (ܭ

-1 -1 1 38,808 cm M ), 245 (51,810), 206 (59,730); H NMR (300 MHz, DMSO-d6): į 6.37 (s,

2H, H3, H3'), 6.92 and 6.99 (m, 4H, indole H), 7.07 and 7.16 (m, 4H, indole), 7.30 (d, 2H,

J=7.8 Hz, linker H), 7.42 (m,8H, indole H), 7.64 (d, 2H, J=7.7 Hz, linker H), 8.35 (s, 2H, linker H), 10.93 (s, 2H, indole NH), 11.52 (s, 1H, linker NH), 11.64 (s, 2H, indole NH); 13C

NMR (DMSO-d6): į 100.8, 111.5, 111.7, 119.1, 119.5, 119.7, 119.9, 120.6, 122.1, 127.0

(aryl CH), 104.9, 123.0, 123.7, 128.9, 129.1, 133.6, 136.4, 136.9, 137.2, 140.2 (aryl C);

+ HRMS (ESI): Found m/z 628.2480 [M+H] ; C44H30N5 required 628.2496.

3,6-Di(1H,1'H-2,3'-biindol-2'-yl)-9-methyl-9H-carbazole (161)

The bis-biindolyl 161 was prepared from 2- indolyl N-metyhl carbazole 74 (1.00 g, 2.43 NH HN mmol) and indolin-2-one 150 (0.64 g, 4.86

N mmol) in phosphoryl chloride (5 ml) according N H H to general procedure 7 to yield the title N Me compound 161 as a yellow powder (0.82 g, 53%). M.p. 220-222 0C (from ethanol); (Found:

ϭϰϵ C, 81.0; H, 5.4; N, 9.8. C45H32N5.1.5C2H5OH required C, 81.1; H, 5.6; N, 9.8%); IR (KBr):

,ݝmax 3397, 3051, 2922, 2850, 1599, 1485, 1454, 1423, 1304, 1281, 1241, 1021, 790, 745

-1 -1 -1 1 702 cm ; UV (MeCN): λmax 298 nm (ܭ 61,800 cm M ), 247 (80,854); H NMR (300

MHz, DMSO-d6): į 3.87 (s, 3H, linker NMe), 6.38 (bs, 2H, H3, H3'), 6.93 and 7.02 (m,

4H, indole H), 7.05, 7.19 (m, 4H, indole H), 7.32 (d, 2H, J=7.8 Hz, indole H), 7.48 (d, 4H,

J= 7.6 Hz, indole H), 7.57 (s, 4H, linker H), 7.65 (d, 2H, J= 7.8 Hz, indole H), 8.39 (s, 2H,

13 indole H), 10.96 (s, 2H, indole NH), 11.67 (s, 2H, indole NH); C NMR (DMSO-d6): į

29.6, (NMe), 100.8, 110.0, 111.5, 111.7, 119.2, 119.5, 119.7, 119.9, 120.1, 120.7, 122.2,

+ 127.0 (aryl CH); HRMS (ESI): Found m/z 642.2630 [M+H] ; C45H33N5 required 642.2652.

3,6-Di(1H,1'H-2,3'-biindol-2'-yl)-9-ethyl-9H-carbazole (162)

The bis-biindolyl 162 was prepared from 2- indolyl N-ethyl carbazole 75 (1.25 g, 1.90 mmol) NH HN and indolin-2-one 150 (0.41 g, 3.80 mmol) in phosphoryl chloride (5 ml) according to general N N H H procedure 7 to yield the title compound 162 as a N Et 0 ,yellow powder (1.23 g, 64%). M.p. 208-210 C; IR (KBr): ݝmax 3395, 3053, 2954, 2925

2868, 1618, 1599, 1573, 1479, 1454, 1370, 1305, 1280, 1233, 1129, 10022, 784, 745 cm-1;

-1 -1 1 UV (MeOH): λmax 300 nm (ܭ 96,023 cm M ), 247 (126,677); H NMR (300 MHz,

DMSO-d6): į 1.38 (t, 3H, J=6.9 Hz, CH2Me), 4.41 (q, 2H, J=6.9 Hz, CH2Me), 6.40 (bs,

2H, H3, H3'), 6.94 and 7.00 (m, 4H, indole H), 7.08 and 7.17 (m, 4H, indole), 7.30 (d, 2H,

J=7.8 Hz, linker H), 7.46 (m, 8H, indole H), 7.64 (d, 2H, J=7.7 Hz, linker H), 8.40 (s, 2H,

13 linker H), 10.98 (s, 2H, indole NH), 11.67 (s, 2H, indole NH); C NMR (DMSO-d6): į

ϭϱϬ 14.3 (CH2), 31.3 (Me), 100.8, 109.8, 111.4, 111.6, 119.0, 119.4, 119.6, 119.8, 120.0, 120.5,

122.1, 126.(aryl CH), 104.9, 122.6, 123.8, 128.9, 129.1, 133.4, 136.3, 136.8, 136.9, 139.9

+ (aryl C); HRMS (ESI): Found m/z 656.2785 [M+H] ; C46H34N5 required 656.2736.

2,8-Bis(4,6-dimethoxy-1H,1'H-2,3'-biindol-2'-yl)dibenzo[b,d]furan (163)

The bis-biindolyl 163 was prepared from 2-indolyl OMe MeO H5 H5 dibenzofuran 72 (1.00 g, 2.51 mmol) and 4,6 OMe MeO H7 H7 dimethoxyindolin-2-one 155 (0.96 g, 5.02 mmol) in HN H3 NH H3 phosphoryl chloride (5 ml) according to general N N H procedure 7 to yield the title compound 163 as a H O yellow powder (1.12 g, 60%). M.p. 200-202 0C; IR

,KBr): ݝmax 3394, 2958, 2917, 2848, 1624, 1599, 1582, 1509, 1452, 1368, 1309, 1247)

-1 -1 -1 1197, 1146, 1123, 1023, 804, 744 cm ; UV (MeOH): λmax 298 nm (ܭ 43,851 cm M ), 244

1 (80,410); H NMR (300 MHz, DMSO-d6): į 3.71 (s, 6H, 2xOMe), 3.79 (s, 6H, 2xOMe),

6.13 (d, 2H, J=1.8 Hz, H5), 6.27 (d, 2H, J=2.0 Hz, H7), 6.44 (d, 2H, J=1.1 Hz, H3), 7.08 and 7.18 (m, 4H, indole H), 7.47 (d, 2H, J=7.9 Hz, indole H), 7.57 and 7.62 (m, 4H, linker

H), 7.74 (d, 2H, J=8.7 Hz, linker H), 8.32 (d, 2H, J=1.4 Hz, indole H), 10.80 (s, 2H, indole

13 NH), 11.71 (s, 2H, indole NH); C NMR (DMSO-d6): į 55.2, 55.5 (OMe), 87.5, 91.2, 98.1,

111.7, 112.4, 119.6, 120.1, 120.5, 122.4, 128.7 (aryl CH), 106.0, 113.9, 124.0, 128.4,

129.7, 135.2, 136.3, 138.0, 152.8, 155.7, 156.5 (aryl C); HRMS (ESI): Found m/z 749.2714

+ [M+H] ; C48H37N4O5 required 749.2764.

ϭϱϭ 4,6-Dimethoxy-1-(phenylsulfonyl)-3-(p-tolyl)-1H-indole (172)

Potassium hydroxide was added to dimethylsulfoxide (20 ml) Me and the mixture was stirred at room temperature for 5 min. 4,6- OMe Dimethoxy-3-(p-tolyl)-1H-indole 171 (0.42 g, 1.53 mmol) was H5 H2 added and stirring was continued for 1 h at room temperature. n- MeO N H7 O S O Butyllithium (0.16 ml, 1.73 mmol) was added slowly over 5 min and the solution stirred for 1 h at room temperature. The reaction mixture was then poured into ice water and extracted with diethyl ether (3x50ml).

The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure. The residue was purified via column chromatography (eluent dichloromethane/n-hexane) to give the N-phenylsulfonylindole 172 as a white powder (0.48

0 ,g, 75%). M.p. 154-156 C; IR (KBr) ݝmax: 3439, 2989, 2929, 2832, 1602, 1589, 1568, 1490

-1 1467, 1417, 1367, 1333, 1206, 1114, 1100, 819, 754 cm ; UV (MeOH): λmax 204 nm (ܭ

-1 -1 1 30,309 cm M ); H NMR (300 MHz, DMSO-d6): į 2.32 (s, 3H, CH3), 3.67 (s, 3H, OMe),

3.58 (s, 3H, OMe), 6.35 (d, 1H, J=1.8 Hz, H5), 7.11 (d, 1H, J=2.1 Hz, H7), 7.15 (d, 2H,

J=7.8 Hz aryl H), 7.42 (d, 2H, J=8.1 Hz, aryl H), 7.53 (s, 1H, H2), 7.60 and 7.63 (m, 2H,

13 aryl H), 8.06 (d, 2H, J=7.2 Hz, aryl H); C NMR (DMSO-d6): į 21.2 (Me), 55.7, 56.1

(OMe), 90.1, 95.6, 121.7, 127.3, 128.6, 129.7, 130.3, 135.1 (aryl CH), 112.5, 124.4, 134.0,

136.2, 137.1, 154.8, 159.4 (aryl C); HRMS (ESI): Found m/z 408.1255 [M+H]+;

C23H22N3O2 required 408.1270.

ϭϱϮ 2-Bromo-4,6-dimethoxy-1-(phenylsulfonyl)-3-(p-tolyl)-1H-indole (173)

N-phenylsulfonyindole 172 (0.23 g, 0.56 mmol) was suspended Me in carbon tetrachloride (30 ml) and dissolved with warming. N- OMe Bromosuccinimide (0.10 g, 0.61 mmol) was added to the H5 Br warmed solution and brought to a gentle reflux for 5 h. After MeO N H7 O S O cooling, the reaction mixture was filtered and the filtrate concentrated under reduced pressure. The resulting residue was passed through a plug of silica, using dichloromethane as the eluent, and recrystallised from dichloromethane and n-hexane to give the 2-bromo product 173 (0.18 g, 67%) as a yellow

0 ,powder. M.p. 235-237 C; IR (KBr) ݝmax : 3396, 3420, 2921, 2849, 1631, 1554, 1539, 1451

-1 1361, 1281, 1258, 1200, 1094 1026, 822, 738 cm ; UV (MeOH): λmax 248 nm (ܭ 119,639

-1 -1 1 cm M ), 203 (93,991); H NMR (300 MHz DMSO-D6) 2.32 (s, 3H, Me), 3.67 (s, 3H,

OMe), 3.85 (s, 3H, OMe) 6.35 (d, 1H, J= 1.8 Hz, H5), 7.11 and 7.21 (m, 6H, aryl and H7),

13 7.47 (d, 2H, J=7.5 Hz aryl H), 7.95 (m, 2H, aryl H); C NMR (DMSO-D6) 21.2 (Me),

55.7, 56.1 (OMe), 91.9, 95.8, 127.0, 127.7, 128.6, 129.1, 130.6, 134.0 (aryl CH), 113.4,

126.4, 133.3, 138.2, 139.3 (aryl C); HRMS (ESI): Found m/z 486.0358 [M+H]+;

C23H21BrNO4 required 486.0375.

2-Bromo-4,6-dimethoxy-3-(p-tolyl)-1H-indole (174)

Me 2-Bromo-N-phenylsulfonylindole 173 (0.15 g, 0.30 mmol) and excess potassium hydroxide were suspended in dry methanol (20 OMe H5 ml) and heated under reflux for 1 h. After cooling, the reaction Br MeO N H7 H

ϭϱϯ mixture was poured into ice water (100 ml) and the resulting precipitate was filtered and washed with cold methanol to give 2-bromoindole 174 (0.07 g, 66%). M.p. >300 0C; IR

,KBr) ݝmax: 334, 3004, 2957, 2936, 2837, 1623, 1583, 1545, 1508, 1465, 1448, 1428, 1394)

-1 1333, 205, 1196, 1147, 1123, 1046, 932, 808 cm ; UV (MeOH): λmax 265 nm (ܭ 22,149

-1 -1 1 cm M ), 225 (61,065); H NMR (300 MHz, DMSO-d6): į 2.31 (s, 3H, Me), 3.69 (s, 3H,

OMe), 3.81(s, 3H, OMe), 6.21 (d, 1H, J=1.9 Hz, H5), 6.40 (d, 1H, J=1.9 Hz, H7), 7.19 (d,

2H, J=7.8 Hz aryl H), 7.43 (dd, 2H, J=1.6, 1.5 Hz, aryl 2H), 8.05 (s, 1H, indole NH); 13C

NMR (DMSO-d6): į 21.3 (Me), 55.4, 55.7 (OMe), 87.2, 92.4, 128.1, 131.0 (aryl CH)

105.3,115.3, 129.2, 129.9, 131.8, 132.0, 132.1, 138.3 (aryl C); HRMS (ESI): Found m/z

+ 346.0434 [M+H] ; C17H17BrNO2 required 346.0443.

2,8-Bis(4,6-dimethoxy-3-(p-tolyl)-1H,1'H-[2,3'-biindol]-2'- yl)dibenzo[b,d]furan (175)

One drop of trifluoroacetic acid OMe MeO H5 H5 OMe MeO was added to a stirred solution of 2- H7 H7 Me indolyl dibenzofuran 72 (0.43 g, NH HN Me 1.00 mmol) and 2-bromoindole 174 N N H (0.72 g, 2.00 mmol) in H O dichloromethane at room temperature. After stirring for 30 min, the reaction mixture was washed thoroughly with sodium hydroxide (10%). The resulting dichloromethane layer was then separated, dried and concentrated under vacuum. It was then purified by column chromatography with dichloromethane as eluent and recrystallized from dichloromethane and petroleum ether to yield the product 175 as a fluffy white solid (0.71 g, 72%). M.p.

ϭϱϰ 0 ,C: IR (KBr): ݝmax 3426, 3406, 2919, 1620, 1590, 1508, 1448, 1426, 1329, 1299 248-250

-1 -1 -1 1215, 1170, 792, 750, 739 cm ; UV (MeOH): λmax 319 nm (ܭ 146,370 cm M ), 243

1 (179,694); H NMR (300 MHz, DMSO-d6); į 2.26 (s, 6H, aryl 2xMe), 3.66 (s, 6H,

2xOMe), 3.80 (s, 6H, 2xOMe), 6.19 (d, 2H, J=2.1 Hz, H5), 6.48 (d, 2H, J=2.1 Hz, H7),

6.99 and 7.18 (m, 12H, indole and aryl H), 7.49 (dd, 2H, J=0.9, 0.6 Hz, aryl H), 7.65 (d,

2H, J=7.8 Hz, aryl H), 7.87 (d, 2H, J=8.7 Hz, linker H), 8.12 (dd, 2H, J=1.8, 1.8 Hz, linker

H), 8.72 (d, 2H, J=1.2 Hz, linker H), 11.21 (bs, 2H, indole NH), 11.74 (bs, 2H, indole NH);

13 C NMR (DMSO-d6): į 21.1 (Me), 55.2, 55.6 (OMe), 87.1, 91.8, 99.0, 111.7, 112.7, 118.1,

119.9, 120.4, 121.9, 125.8, 127.6, 130.5 (aryl CH), 111.8, 117.1, 124.6, 128.4, 129.2,

133.1, 134.1, 137.6, 137.8, 138.2, 154.6, 155.8, 157.1 (aryl C); HRMS (ESI) Found m/z

+ 929.3719 [M+H] ; C64H49N4O5 required 929.3703.

3,6-Bis(4,6-dimethoxy-3-p-tolyl-1H,1'H-2,3'-biindol-2'-yl)-9-ethyl-9H- carbazole (176)

One drop of trifluoroacetic acid H5 OMe MeO H5 OMe MeO was added to a stirred solution of 2- H7 H7 Me NH HN indolyl N-ethyl carbazole 75 (0.43 Me g, 1.00 mmol) and 2-bromoindole N N H 174 (0.72 g, 2.00 mmol) in H N dichloromethane at room Et temperature. After stirring for 30 min, the reaction mixture was washed thoroughly with sodium hydroxide (10%). The resulting dichloromethane layer was then separated and dried concentrated under vacuum. It was then purified by column chromatography with

ϭϱϱ dichloromethane as eluent and recrystallized from dichloromethane and petroleum ether to

0 yield the product 176 as a fluffy white solid (0.71 g, 72%). M.p. 260-262 C; IR (KBr): ݝmax

3406, 3346, 2930, 2837, 1608, 1583, 1545, 1508, 1452, 1429, 1331, 1233, 1205, 1147,

-1 -1 -1 1124, 1045, 784, 808 cm ; UV (MeOH): λmax 310 nm (ܭ 80,051 cm M ), 228 (159,541);

1 H NMR (300 MHz, DMSO-d6): į 1.35 (t, 3H, J=7.0 Hz, CH2Me), 2.31 (s, 6H, 2xMe),

3.60 (s, 6H, 2xOMe), 3.74 (s, 6H, 2xOMe), 4.48 (q, 2H, J=6.9 Hz, CH2Me), 6.17 (d, 2H,

J=1.9 Hz, H5), 6.43 (d, 2H, J=1.9 Hz, H7), 6.89 (d, 2H, J=1.3 Hz, indole H), 6.99 and 7.08

(m, 4H, indole H), 7.15 (d, 4H, J=7.8 Hz, aryl H), 7.26 (d, 4H, J=6.24 Hz, aryl H), 7.41 (d,

2H, J=7.1 Hz, linker H), 7.54 (d, 2H, J=7.7 Hz, linker H), 7.71 (d, 2H, J=8.6 Hz, linker H),

8.00 (dd, 2H, J=1.7, 1.7 Hz, linker H), 8.71 (d, 2H, J=1.4 Hz, indole H), 11.58 (s, 2H, NH),

13 11.75 (bs, 2H, NH); C NMR (DMSO-d6): į 21.1, 22.4 (Me), 31.3 (CH2), 55.3, 55.5

(OMe), 86.9, 92.3, 97.7, 110.1, 111.4, 117.4, 119.6, 1119.9, 121.3, 124.1, 128.1, 130.9

(aryl CH), 104.8, 110.9, 115.4, 123.0, 124.0, 129.4, 131.6, 135.3, 137.4, 138.0, 139.4,

+ 139.9, 153.6, 157.1 (aryl C); HRMS (ESI) Found m/z 957.1595 [M+H] ; C64H54N5O4 required 957.1476.

2',2''-(Dibenzo[b,d]furan-2,8-diyl)bis(1H,1'H-2,3'-bibenzo[b]pyrrole-3- carbaldehyde) (177)

The title compound was synthesized following general procedure 5 using excess phosphoryl CHO OHC NH HN chloride and bis-indolyl 158 (0.20 g, 0.30 mmol)

N in dimethylformamide (5.00 ml). The bis- N H H biindolyl-3-carbaldehyde 177 was obtained as a O

ϭϱϲ 0 ,yellow solid (0.19 g, 90%). M.p. 296-298 C; IR (KBr): ݝmax 3375, 1633, 1451, 1405, 1375

-1 -1 - 1326, 1245, 1199, 1120, 1024, 828, 745 cm ; UV (MeCN): λmax 298 nm (ܭ 46,243 cm M

1 1 ), 244 (63,519); H NMR (300 MHz, DMSO-d6): į 7.13 and 7.29 (m, 8H, indole H), 7.45

(d, 4H, 7.53 Hz, indole H), 7.49 and 7.58 (m, 4H, linker H), 7.71 (d, 2H, J=6.1 Hz, indole

H), 8.09 (d, 2H, J=6.9 Hz, linker H), 8.38 (s, 2H, indole H), 9.57(s, 2H, 2xCHO), 12.20 (s,

13 2H, indole NH), 12.28 (s, 2H, indole NH); C NMR (DMSO-d6): į 112.3, 112.8, 119.2,

121.0, 121.1, 122.4, 123.1, 123.4, 129.1 (aryl CH), 101.8, 113.5, 124.1, 125.9, 127.5,

128.9, 136.5, 137.1, 138.7, 144.9, 155.9 (aryl C), 185.7 (CHO) HRMS (ESI): Found m/z

+ 707.2019 [M+H] ; C46H29N4O3Na required 707.2054

2',2''-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H,1'H-2,3'-bibenzo[b]pyrrole-3- carbaldehyde) (178)

The title compound was synthesized following general procedure 5 using excess phosphoryl CHO OHC NH HN chloride and bis-indolyl 161 (0.30 g, 0.48 mmol) in dimethylformamide (5.00 ml). The bis- N N H H biindolyl-3-carbaldehyde 178 was obtained as a N Et yellow solid (0.32 g, 85%). M.p. 284-286 0C; IR

,KBr): ݝmax 3374, 3236, 3060, 2975, 1632, 1581, 1453, 1375, 1322, 1288, 1234, 1152)

-1 -1 -1 1095, 829, 745 cm ; UV (MeOH): λmax 305 nm (ܭ 78,281 cm M ), 249 (91,719), 209

1 (97,264); H NMR (300 MHz, DMSO-d6): į 1.26 (t, 3H, J=7.2 Hz, CH2Me), 4.38 (q, 2H,

J=7.2 Hz, CH2Me), 7.11 and 7.26 (m, 8H, indole H), 7.36 (dd, 2H, J=1.2, 1.0 Hz, linker H),

7.51 and 7.59 (m, 6H, indole H), 8.01 (dd, 2H, J=1.8, 2.4 Hz, indole H), 8.43 (s, 2H, linker

ϭϱϳ 13 H), 9.58 (s, 2H, 2xCHO), 12.15 (s, 2H, indole NH), 12.23 (s, 2H, indole NH); C NMR

(DMSO-d6): į 14.1 (Me), 36.1 (CH2), 110.3, 112.1, 112.2, 118.9, 120.2, 120.9, 122.4,

122.7, 123.4, 127.0 (aryl CH), 100.9, 113.5, 121.0, 123.0, 125.9, 129.3, 136.4, 137.1,

139.8, 140.0, 145.5, 162.7 (aryl C), 185.8 (CHO); HRMS (ESI): Found m/z 712.2695

+ [M+H] ; C48H34N5O2 required 712.2713.

2',2'''-(9-Ethyl-9H-carbazole-3,6-diyl)bis(4,6-dimethoxy-3-(p-tolyl)-

1H,1'H-[2,3'-biindole]-7-carbaldehyde) (179)

The title compound was synthesized OMe MeO OMe MeO following general procedure 5 using Me O O HN excess posphoryl chloride and bis- Me NH indolyl 176 (0.30 g, 0.31 mmol) in N N H dimethylformamide (5.00 ml). The H N bis-biindolyl 179 was obtained as a Et

0 ,yellow powder (0.32 g, 80%). M.p. >300 C; IR (KBr): ݝmax 3397, 3249, 2934, 2870, 1641

1584, 1545, 1512, 1451, 1378, 1345, 1312, 1240, 1261, 1158, 1112, 982, 791, 748 cm-1;

-1 -1 1 UV (MeOH): λmax 315 nm (ܭ 78,158 cm M ), 253 (138,818); H NMR (300 MHz,

DMSO-d6): į 1.43 (t, 3H, J=6.9 Hz, CH2Me), 2.34 (s, 6H, 2xMe), 3.81 (s, 6H, 2xOMe),

3.90 (s, 6H, 2xOMe), 4.64 (q, 2H, J=6.7 Hz, CH2Me), 6.45 (bs, 2H, H5), 7.19 and 7.30 (m,

12 H, indole and linker H), 7.53 (d, 4H, J=1.3 Hz, aryl H), 8.26 (d, 4H, J=6.8 Hz, aryl H),

8.84 (s, 2H, linker H), 10.30 (s, 2H, 2xCHO), 11.67 (bs, 2H, indole NH), 12.44 (bs, 2H,

13 indole NH); C NMR (DMSO-d6): į 14.1, 21.3 (Me), 36.2 (CH2), 56.2, 57.1 (OMe), 88.7,

110.6, 112.3, 121.4, 122.7, 123.5, 123.9, 128.3, 131.0 (aryl CH), 104.8, 110.9, 122.9,

ϭϱϴ 126.5, 131.0, 135.3, 135.6, 136.4, 141.2, 150.9, 160.1, 162.9 (aryl C), 186.4 (CHO); HRMS

+ (ESI): Found m/z 1034.3894 [M+Na] ; C66H53N5O6Na required 1034.7292.

(2',2'''-(Dibenzo[b,d]furan-2,8-diyl)bis(1H,1'H-[2,3'-biindole]-3,2'- diyl))dimethanol (180)

The title compound was synthesized following

CH2OH general procedure 6 using the formyl bis-indolyl HOH2C NH HN 177 (0.23 g, 0.32 mmol) and sodium borohydride N N H in absolute ethanol for 6 h. The desired alcohol H O 180 was obtained as a yellow solid, (0.12 g,

0 ,M.p. >300 C; IR (KBr): ݝmax 3594, 3396, 3053, 2927, 2871, 1616, 1453, 1372 .(54%

-1 1324, 1285, 1242, 1198, 1157 1126, 1007, 978, 823, 745 cm ; UV (MeOH): λmax 296 nm

-1 -1 1 (ܭ 118,680 cm M ), 242 (185,760), 223 (190,920); H NMR (300 MHz, DMSO-d6): į

4.40 (bs, 4H, 2xCH2), 4.52 (s, 2H, 2xOH), 7.01 and 7.13 (m, 6H, indole H), 7.23 (m, 2H, indole H), 7.30 (d, 2H, J=7.8 Hz, indole H), 7.46 and 7.56 (m, 6H, indole and linker H),

7.63 (d, 2H, J=8.7 Hz, indole H), 7.73 (d, 2H, J=7.5 Hz, linker H), 8.36 (bs, 2H, linker H),

13 10.96 (s, 2H, indole NH), 11.88 (s, 2H, indole H); C NMR (DMSO-d6): į 31.6 (CH2)

111.3, 111.9, 112.5, 118.8, 119.8, 120.0, 120.1, 120.2, 121.2, 122.6, 128.4 (aryl CH) 104.8,

113.6, 124.1, 128.5, 128.8, 129.5, 130.0, 136.4, 136.5, 136.9, 155.7 (aryl C); HRMS (ESI):

+ Found m/z 711.2358 [M+Na] ; C46H32N4O3Na required 711.2372.

ϭϱϵ (2',2''-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H,1'H-2,3'-bibenzo[b]pyrrole-

3,2'-diyl))dimethanol (181)

The title compound was synthesized following

CH2OH general procedure 6 using formyl bis-indolyl 178 HOH2C NH HN (0.32 g, 0.45 mmol) and sodium borohydride in N N H absolute ethanol for 6h. The desired alcohol 181 H N was obtained as a yellow solid, (0.18 g, 59%). Et 0 ,M.p. >300 C: IR (KBr): ݝmax 3565, 3411, 3057, 2929, 1602, 1455, 1379, 1347, 1320, 1287

-1 -1 - 1230, 1154, 1130, 1007, 809, 746, 710 cm ; UV (MeOH): λmax 298 nm (ܭ 87,140 cm M

1 1 ), 223 (121,996); H NMR (300 MHz, DMSO-d6): į 1.23 (t, 3H, J=6.9 Hz, CH2Me), 4.37

(q, 2H, J=7.2 Hz, CH2Me), 4.42 (bs, 4H, 2xCH2) 4.54 (s, 2H, 2xOH), 6.97 and 7.07 (m,

6H, indole H), 7.15 (t, 2H, J=7.4 Hz, indole H), 7.27 (d, 2H, J=7.1 Hz, indole H), 7.36 (dd,

2H, J=1.5, 1.3 Hz, linker H), 7.48 (t, 6H, J=8.2 Hz, indole H), 7.69 (d, 2H, J=7.5 Hz, linker

H), 8.42 (s, 2H, linker H), 10.91 (s, 2H, indole NH), 11.7 (s, 2H, indole H); 13C NMR

(DMSO-d6): į 14.1 (Me), 39.8, 55.4 (CH2) 109.9, 111.2, 111.5, 118.5, 119.2, 119.5, 119.6,

119.9, 120.9, 122.0, 126.4 (aryl CH) 103.7, 113.4, 122.6, 123.9, 128.7, 129.7, 130.4, 136.3,

+ 136.8, 137.6, 139.6 (aryl C); HRMS (ESI): Found m/z 738.2825 [M+Na] ; C48H37N5O2Na required 738.2845.

ϭϲϬ Bis-indole imine macrocycle (198)

The imine macrocycle 198 was prepared from 3,3'- diformyl-3,6-bis-(2-indolyl)-dibenzofuran 94 (0.4 g, 0.88 N N mmol) and 1,4-diaminobutane (0.07 g, 0.88 mmol) in NH HN ethanol (30 ml) according to general procedure 8 to yield O the desired compound 198 as a yellow solid (0.32 g, 73%).

0 ,M.p. >300 C: IR (KBr): ݝmax 3625, 3172, 2923, 2858, 1632, 1577, 1483, 1449, 1379, 1245

-1 -1 -1 1190, 1123, 1024, 822, 747 748 cm ; UV (MeCN): λmax 307 nm (ܭ 44,399 cm M ), 256

1 (78,342); H NMR (300 MHz, DMSO-d6): į 1.87 (s, 4H, 2xCH2), 3.67 (s, 4H, CH2N), 7.13 and 7.26 (m, 4H, indole H), 7.51 (d, 2H, J=7.9 Hz, linker H), 7.98 (s, 4H, indole H), 8.21

(d, 2H, J=7.6 Hz, linker H), 8.62 (s, 2H, CH=N), 8.67 (s, 2H, linker H) 11.57 (bs, 2H,

13 indole NH); C NMR (DMSO-d6): į 28.0 (CH2), 61.8 (CH2N), 111.9, 112.6, 120.8, 121.4,

123.0, 124.1, 127.6 (aryl CH), 110.7, 122.2, 123.8, 126.8, 141.3, (aryl C), 156.3 (CH=N);

+ HRMS (ESI): Found m/z 507.2176 [M+H] ; C34H27N4O required 507.2185.

Bis-indole imine macrocycle (199)

The imine macrocycle 199 was prepared from 3,3'-

N N diformyl-3,6-bis-(2-indolyl)-carbazole 95 (0.20 g, 0.44

NH mmol) and 1,4-diaminobutane (0.03 g, 0.44 mmol) in HN ethanol (30 ml) according to general procedure 8 to yield N H the desired compound 199 as a yellow solid (0.14 g,

67%). M.p. >300 oC (from dichloromethane/hexane); (Found C, 65.3; H, 4.9; N, 10.4.

,C34H27N5.1.8CH2Cl2 required C, 65.3; H, 4,6; N, 10.3%); IR (KBr): ݝmax 3395, 3230, 2925

ϭϲϭ -1 2849, 1625, 1578, 1452, 1377, 1339, 1283, 1242, 745 cm ; UV (MeCN): λmax 308 nm (ܭ

-1 -1 1 41,262 cm M ), 256 (52,302); H NMR (300 MHz, DMSO-d6): į 1.87 (s, 4H, 2xCH2),

3.68 (s, 4H, CH2N), 7.11 and 7. 24 (m, 4H, indole H), 7.49 (d, 2H, J=7.8 Hz, linker H),

7.77 (d, 2H, J=8.4 Hz, indole H), 7.85 (s, 2H, indole H), 7.88 (dd, 2H, J=1.5, 1.5 Hz, linker

H), 8.26 (d, 2H, J=7.4 Hz indole H), 8.47 (s, 2H, CH=N), 8.63 (s, 2H, linker H), 11.87 (bs,

13 2H, indole NH) 11.94 (bs, 1H, linker NH); C NMR (DMSO-d6): į 27.9 (CH2), 61.9

(CH2N), 111.6, 112.1, 120.7, 121.4, 122.6, 123.4, 125.9 (aryl CH), 109.9, 122.1, 122.7,

127.4, 136.5, 140.5, 143.1 (aryl C), 156.7 (CH=N); HRMS (ESI): Found m/z 506.2231

+ [M+H] ; C34H28N5 required 506.2345.

Bis-indole imine macrocycle (200)

The imine macrocycle 200 was prepared from 3,3'-

N N diformyl-3,6-bis-(2-indolyl)-N-methylcarbazole 96 (0.2

NH g, 0.42 mmol) and 1,4-diaminobutane (0.04 g, 0.42 HN mmol) in ethanol (30 ml) according to general procedure N 8 to yield the desired compound 200 as a yellow solid Me

0 ,g, 75%). M.p >300 C; IR (KBr): ݝmax 3170, 2922, 2856, 1616, 1577, 1488, 1453 0.16)

-1 1380, 1284, 1244, 1155, 1125, 1052, 880, 805, 747 cm ; UV (MeCN): λmax 308 nm (ܭ

-1 -1 1 14,917 cm M ), 256 (17,290); H NMR (300 MHz, DMSO-d6): į 1.86 (s, 4H, 2xCH2),

3.49 (s, 4H, CH2N), 3.66 (s, 3H, linker NMe), 7.09 and 7. 21 (m, 4H, indole H), 7.48 (d,

2H, J=7.9 Hz, linker H), 7.86 (d, 2H, J=8.2 Hz, indole H), 7.93 (d, 2H J=1.8 Hz, indole H),

7.97 (dd, 2H, J=1.5, 1.5 Hz, linker H), 8.24 (d, 2H, J=7.1 Hz indole H), 8.50 (s, 2H,

13 CH=N), 8.61 (s, 2H, linker H), 11.77 (bs, 2H, indole NH); C NMR (DMSO-d6): į 27.9

ϭϲϮ (CH2), 29.8 (NMe), 61.9 (CH2N), 110.3, 111.9, 120.4, 121.3, 122.3, 126.0 9 (aryl CH),

109.8, 122.2, 122.9, 127.7, 141.3 (aryl C), 156.8 (CH=N); HRMS (ESI): Found m/z

+ 520.2488 [M+H] ; C35H30N5 required 520.2501.

Bis-indole imine macrocycle (201)

The imine macrocycle 201 was prepared from3,3'- diformyl-3,6-bis-(2-indolyl)-dibenzofuran 94 (0.30 g, N N 0.56 mmol) and 1,6-diaminohexane (0.06 g, 0.56 NH N mmol) in ethanol (30 ml) according to general H procedure 8 to yield the desired compound 201 as a O yellow solid (0.24 g, 68%). M.p. >300 0C (from dichloromethane/hexane); (Found: C, 71.7;

; H, 6.1; N, 9.3. C36H32N4O.1.2CH2Cl2 required C, 71.6; H, 6.2; N, 9.2%): IR (KBr): ݝmax

3145, 2972, 2925, 2846, 1627, 1579, 1481, 1449, 1380, 1344, 1198, 1121, 1048, 892, 823,

-1 -1 -1 1 749, 646 cm ; UV (MeCN): λmax 306 nm (ܭ 22,782 cm M ), 258 (42,175); H NMR (300

MHz DMSO-d6): į 1.54 (s, 4H, 2xCH2), 1.80 (s, 4H, 2xCH2), 3.63 (s, 4H, CH2N), 7.16 and

7. 30 (m, 4H, indole H), 7.52 (d, 2H, J=7.8 Hz, linker H), 7.94 (d, 2H, J=1.5 Hz, indole H),

7.96 (d, 2H, J=1.5 Hz, indole H), 8.05 (d, 2H, J=8.2 Hz, indole H), 8.37 (s, 2H, indole

CH=N), 8.43 (d, 2H, J=7.5 Hz, linker H), 8.56 (s, 2H, linker H), 11.97 (bs, 2H, indole NH)

13 ); C NMR (DMSO-d6): į 24.1, 28.5 (CH2), 61.4 (CH2N), 111.7, 112.8, 120.9, 122.5,

123.1, 123.7, 128.9 (aryl CH), 110.6, 124.0, 126.7, 127.0, 136.6, 142.5, 156.3 (aryl C),

+ 156.5 (CH=N); HRMS (ESI): Found m/z 535.2475 [M+H] ; C36H31N4O required 535.2498.

ϭϲϯ Bis-indole imine macrocycle (202)

The imine macrocycle 202 was prepared from 3,3'- diformyl-3,6-bis-(2-indolyl)-carbazole 95 (0.3 g, 0.66 N N mmol), and 1,6-diaminohexane (0.07 g, 0.66 mmol)

NH in ethanol (30 ml) according to general procedure 8 N H to yield the desired compound 202 as a yellow solid N H 0 ,g, 55%). M.p. >300 C; IR (KBr): ݝmax 3339, 2934, 2853, 1632, 1556, 1452, 1393 0.19)

-1 -1 -1 1318, 1282, 1245, 821, 748, 609 cm ; UV (MeCN): λmax 308 nm (ܭ 10,680 cm M ), 256

1 (14,294); H NMR (300 MHz, DMSO-d6): į 1.50 (s, 4H, 2xCH2), 1.76 (s, 4H, 2xCH2), 3.57

(s, 4H, CH2 N), 7.11 and 7. 23 (m, 4H, indole H), 7.46 (d, 2H, J=7.5 Hz, linker H), 7.77 (s,

4H, indole H), 8.28 (s, 2H, CH=N), 8.37 (d, 2H, J=7.5 Hz, linker H), 8.55 (s, 2H, linker H),

13 11.87 (bs, 2H, indole NH) 11.94 (bs, 1H, linker NH); C NMR (DMSO-d6): į 23.9, 28.5

(CH2), 61.4 (CH2N), 111.5, 112.2, 122.1, 122.5, 122.7, 122.9, 127.1 (aryl CH), 109.8,

122.2, 126.9, 127.4, 136.7, 140.6, 144.3 (aryl C), 156.8 (CH=N); HRMS (ESI): Found m/z

+ 534.2622 [M+H] ; C36H32N5 required 534.2658.

Bis-indole imine macrocycle (203)

The imine macrocycle 203 was prepared from 3,3’- diformyl-3,6-bis-(2-indolyl)-N-methylcarbazole 96 N N (0.15 g, 0.32 mmol) and 1,6-diaminohexane (0.03 g, NH N 0.32 mmol) in ethanol (30 ml) according to general H procedure 8 to yield the desired compound 203 as a N Me o ,yellow solid (0.11 g, 63%). M.p. >300 C: IR (KBr): ݝmax 3365, 3052, 2922, 2847, 1626

ϭϲϰ -1 1485, 1452, 1368, 1339, 1282, 1244, 1156, 1124, 813, 760, 740 cm ; UV (MeCN): λmax

-1 -1 1 308 nm (ܭ 46,032 cm M ), 258 (62,472); H NMR (300 MHz, DMSO-d6): į 1.49 (s, 4H,

2xCH2), 1.76 (s, 4H, 2xCH2) 3.56 (s, 4H, CH2 N), 4.06 (s, 3H, linker NMe), 7.14 and 7. 22

(m, 4H, indole H), 7.47 (d, 2H, J=7.8 Hz, linker H), 7.87 and 7.90 (m, 4H, indole H), 8.33

(s, 2H, CH=N), 8.40 (d, 2H, J=7.6 Hz, linker H), 8.54 (s, 2H, linker H), 11.77 (bs, 2H,

13 indole NH); C NMR (DMSO-d6): į 23.9, 28.4 (CH2), 29.8 (NMe), 61.5 (CH2N), 110.5,

111.5, 120.8, 122.4, 122.8, 127.2, (aryl CH), 109.9, 122.6, 122.7, 126.9, 136.6, 141.5,

+ 144.0 (aryl C), 156.7 (CH=N); HRMS (ESI): Found m/z 548.2786 [M+H] ; C37H34N5 required 548.2814.

N1,N1'-((3,3'-(dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-indole-

7,3-diyl))bis(methanylylidene))bis(ethane-1,2-diamine) (207)

The 7,7'-bis-indole dicarbaldehyde 134 NH2 NH2

(0.23 g , 0.40 mmol) and 1,2- (CH2)2 (CH2)2 N N diaminoethane (0.03 g, 0.60 mmol) were CH CH H H MeO OMe heated under reflux in dry isopropanol N N

(20 ml) and in the presence of OMe OMe dichloromethane (10 ml) for 12 h. The O reaction mixture was brought to room temperature and the precipitate was filtered off. The filtrate was removed under reduced pressure and the residue was recrystallised from dichloromethane to yield the title compound 207 (0.13 g, 53%) as a yellow solid. M.p. 150-

o ,C: IR (KBr): ݝmax 3305, 2942, 1663, 1628, 1579, 1481, 1438, 1358, 1324, 1207, 1183 152

-1 -1 -1 1 1162, 821, 793 cm ; UV (MeCN): λmax 332 nm (ܭ 6,401 cm M ), 249 (12,632); H NMR

ϭϲϱ (300 MHz, DMSO-d6): į 2.92 (s, 4H, 2xCH2), 3.65 (s, 4H, CH2N), 3.90 (s, 6H, 2xOMe),

3.97 (s, 6H, 2xOMe), 6.50 (s, 2H, 2xH5), 7.34 (s, 2H, linker H), 7.68 (s, 4H, linker ), 8.26

13 (s, 2H, 2xH2), 8.83 (s, 2H, CH=N), 11.39 (bs, 2H, indole NH); C NMR (DMSO-d6): į

44.2, (CH2NH2), 61.5 (CH2N), 88.6, 110.9, 121.3, 123.6, 124.7, (aryl CH), 101.4, 110.3,

117.3, 136.7, 154.8 (aryl C), 157.9 (CH=N); HRMS (ESI): Found m/z 659.2982 [M+H]+;

C38H40N6O5 required 659.2970.

N1,N1'-((3,3'-(dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-indole-

7,3-diyl))bis(methanylylidene))bis(butane-1,4-diamine) (208)

The 7,7'-bis-indole dicarbaldehyde 134 NH2 NH2 (CH ) (0.16 g , 0.28 mmol) and 1,4- 2 4 (CH2)4 N N diaminobutane (0.05 g, 0.70 mmol) were CH CH H H MeO N N OMe heated under reflux in dry isopropanol

o ,C: IR (KBr): ݝmax 3324, 2932, 1631, 1561, 1474, 1474, 1428, 1396, 1380, 1328, 1261 170

-1 -1 -1 1208, 1155, 1048, 822, 689 cm ; UV (MeCN): λmax 332 nm (ܭ 12,679 cm M ), 249

1 (18,685); H NMR (300 MHz, DMSO-d6): į 1.25 and 1.37 (m, 8H, 4xCH2), 2.41 (s, 4H,

2xCH2), 3.60 (t, 4H, CH2N) 3.90 (s, 6H, 2xOMe), 3.96 (s, 6H, 2xOMe), 6.49 (s, 2H,

2xH5), 7.36 (s, 2H, linker H), 7.68 (s, 4H, linker ), 8.25 (s, 2H, 2xH2), 8.81 (s, 2H, CH=N),

ϭϲϲ 13 11.36 (bs, 2H, indole NH); C NMR (DMSO-d6): į 29.5, 31.7 (CH2), 42.1 (CH2NH2), 61.8

(CH2N), 88.6, 111.1, 121.5, 122.8, 129.2, (aryl CH), 101.3, 110.0, 121.3, 123.2, 123.9,

131.4, 136.9, 154.7 (aryl C), 156.7 (CH=N); HRMS (ESI): Found m/z 715.3598 [M+H]+;

C42H48N6O5 required 715.3608.

N1,N1'-((3,3'-(dibenzo[b,d]furan-2,8-diyl)bis(4,6-dimethoxy-1H-indole-

7,3-diyl))bis(methanylylidene))bis(dodecane-1,12-diamine) (209)

The 7,7'-bis-indole dicarbaldehyde 134 NH2 NH2

(CH2)12 (CH2)12 (0.19 g , 0.33 mmol) and 1,12- N N CH CH diaminododecane (0.16 g, 0.80 mmol) were H H MeO N N OMe heated under reflux in dry isopropanol (20 ml) and in the presence of dichloromethane OMe OMe O (10 ml) for 12 h. The reaction mixture was brought to room temperature and the precipitate was filtered off. The filtrate was removed under reduced pressure and the residue was recrystallised from dichloromethane to yield

o ,the title compound 209 (0.17 g, 55%) as a yellow solid. M.p. >300 C: IR (KBr): ݝmax 3323

2925, 1628, 1594, 1542, 1514, 1464, 1376, 1357, 1325, 1251, 1208, 1147, 1109, 1079, 787

-1 -1 -1 1 cm ; UV (MeCN): λmax 332 nm (ܭ 14,116 cm M ), 249 (27,858); H NMR (300 MHz,

DMSO-d6): į 1.42 and 1.44 (m, 20H, 10xCH2), 2.66 (s, 4H, 2xCH2), 3.62 (s, 4H, CH2N)

3.90 (s, 6H, 2xOMe), 3.97 (s, 6H, 2xOMe), 6.50 (s, 2H, 2xH5), 7.36 (s, 2H, linker H), 7.69

(s, 4H, linker ), 8.23 (s, 2H, 2xH2), 8.81 (s, 2H, CH=N), 11.35 (bs, 2H, indole NH);

The compound was not sufficiently soluble for a 13C NMR spectrum to be obtained.

ϭϲϳ + HRMS (ESI): Found m/z 939.6152 [M+H] ; C58H79N6O5 required 7939.6112.

Bis-biindolyl imine macrocycle (211)

The imine macrocycle 211 was MeO OMe N N H5 prepared form bis-biindolyl H5 OMe dicarbaldehyde 179 (0.12 g, 0.11 MeO NH HN Me Me mmol) and 1,4-diaminobutane

(0.01g, 0.11 mmol) in ethahol N NH H (20ml) according to general N Et procedure 8 to yield the desired compound 211 as a yellow solid (0.03 g, 24%) M.p. 244-

o ,C: IR (KBr): ݝmax 3315, 2940, 1631, 1576, 1475, 1429, 1396, 1380, 1330, 1241, 1155 246

-1 -1 -1 1111, 1049, 1000, 913, 821, 752, 688 cm ; UV (MeOH): λmax 261 nm (ܭ 26,854 cm M );

1 H NMR (300 MHz, DMSO-d6): 1.34 (s, 4H, 2xCH2) į 1.43 (t, 3H, J=6.9 Hz, CH2Me),

2.35 (s, 6H, 2xMe), 3.65 (s, 4H, CH2N), 3.77 (s, 6H, 2xOMe), 3.93 (s, 6H, 2xOMe), 4.56

(q, 2H, J=6.7 Hz, CH2Me), 6.43 (s, 2H, H5), 7.10 and 7. 31 (m, 14H, indole H and phenyl

H), 7.45 (d, 2H, J=7.8 Hz, linker H), 7.90 (s, 2H, CH=N), 8.24 (d, 2H, J=7.8 Hz, linker H),

8.49 (s, 1H, indole H), 8.62 (s, 1H, linker H), 8.75 (s, 1H, linker H) 11.87 (bs, 2H, indole

NH).

The compound was not sufficiently soluble for a 13C NMR spectrum to be obtained.

+ HRMS (ESI): Found m/z 1087.7313 [M+Na] ; C70H61N7O4Na required 1087.4716.

ϭϲϴ Bis-indole imine macrocycle (212)

The diamino macrocycle was prepared from NH compound 198 (0.10 g, 0.19 mmol) and excess sodium HN

NH borohydride in ethanol (20 ml) according to general HN procedure 6 to afford the desired macrocycle 212 (0.05 O 0 ,g, 58%). M.p. >300 C: IR (KBr): ݝmax 3389, 3053, 2926, 2826, 1633, 1557, 1451, 1343

-1 -1 -1 1196, 1126, 1008, 817, 750 cm ; UV (MeCN): λmax 305 nm (ܭ 9,300 cm M ), 242

1 (11,923); H NMR (300 MHz, DMSO-d6): į 1.69 (s, 4H, CH2), 2.96 (s, 4H, 2xCH2), 3.94

(s, 4H, CH2 N), 7.14 and 7.28 (m, 4H, indole H), 7.49 (d, 2H, J=7.8 Hz, linker H), 7.70 (d,

2H, J=7.6 Hz, linker H), 7.91 and 7.98 (m, 4H, indole H), 8.89 (s, 2H, linker H), 11.57 (bs,

13 2H, indole NH); C NMR (DMSO-d6): į 26.3, 44.2, 49.0 (CH2), 111.5, 112.4, 118.6,

119.2, 121.4, 121.7, 127.9 (aryl CH), 110.9, 124.4, 128.0, 128.5, 129.1, 136.0, 136.2, 155.7

+ (aryl C); HRMS (ESI): Found m/z 511.2492 [M+H] ; C34H31N4O required 511.2498.

Bis-indole amine macrocycle (213)

The diamino macrocycle was prepared from compound 199

(0.15 g, 0.29 mmol) and excess sodium borohydride in ethanol HN NH (20 ml) according to general procedure 6 to afford the desired NH HN 0 macrocycle 213 (0.09 g, 61%). M.p. >300 C; IR (KBr): ݝmax

N 3443, 2930, 1630, 1487, 1455, 1364, 1286, 1248, 1155, 1125, H

-1 -1 -1 1 810, 746 cm ; UV (MeCN): λmax 323 nm (ܭ 21,596 cm M ), 251 (22,759); H NMR (300

MHz, DMSO-d6): į 1.79 (s, 4H, CH2), 2.91 (s, 4H, 2xCH2 ), 3.84 (s, 4H, CH2 N), 6.98 and

7.09 (m, 4H, indole H), 7.35 (d, 2H, J=7.7 Hz, linker H ), 7.63 (d, 2H, J=7.5 Hz, linker H), ϭϲϵ 7.67 and 7.71 (m, 4H, indole H), 8.67 (s, 2H, linker H), 11.29 (bs, 2H, indole NH), 11.71

13 (bs, 1H, linker NH); C NMR (DMSO-d6): į 26.1, 48.8 (CH2), 110.0, 111.2, 118.5, 119.0,

120.8, 121.3, 126.4 (aryl CH), 110.9, 124.4, 128.0, 128.5, 129.1, 136.0, 136.2, 155.7 (aryl

+ C); HRMS (ESI): Found m/z 510.2650 [M+H] ; C34H32N5 required 510.2658.

Bis-indole amine macrocycle (214)

The diamino macrocycle was prepared from NH compound 200 (0.12 g, 0.23 mmol) and excess HN sodium borohydride in ethanol (20 ml) according to NH HN general procedure 6 to afford the desired macrocycle N 0 g, 65%). M.p. >300 C: IR (KBr): ݝmax Me 0.07) 214

3405, 2927, 1601, 1487, 1456, 1346, 1282, 1245, 1158, 1129, 1005, 945, 811, 747 cm-1;

-1 -1 1 UV (MeCN): λmax 323 nm (ܭ 20,855 cm M ), 306 (20,051), 251 (23,125); H NMR (300

MHz, DMSO-d6): į 1.70 (s, 4H, 2xCH2), 2.81 (s, 4H, 2xCH2), 3.81 (d, 4H, J=4.95, CH2N),

3.93 (s, 3H, linker NMe), 6.93 and 7.01 (m, 4H, indole H), 7.32 (d, 2H, J=7.6 Hz, linker

H), 7.53 (d, 2H, J=7.5 Hz, linker H), 7.72 (s, 4H, indole H ), 8.66 (s, 2H, linker H), 11.22

13 (bs, 2H, indole NH); C NMR (DMSO-d6): į 26.1, 44.5, 48.8 (CH2), 29.6 (NMe), 110.1,

111.4, 118.5, 119.1, 120.8, 121.4, 126.6 (aryl CH), 122.8, 124.1, 126.5, 129.3, 136.1,

+ 137.2, 140.9 (aryl C); HRMS (ESI): Found m/z 524.2798 [M+H] ; C35H34N5 required

524.2809.

ϭϳϬ Bis-indole amine macrocycle (215)

The diamino macrocyle was prepared from the compound 201 (0.14 g, 0.26 mmol) and excess NH HN sodium borohydride in ethanol (20 ml) according to NH N general procedure 6 to afford the desired macrocycle H

0 O g, 58 %). M.p. >300 C; IR (KBr): ݝmax 0.08) 215

3422, 2925, 2850, 1633, 1483, 1450, 1341, 1273, 1200, 1124, 821, 743, 610 cm-1; UV

-1 -1 1 (MeCN): λmax 305 nm (ܭ 43,973 cm M ), 240 (61,221); H NMR (300 MHz, DMSO-d6):

į 1.39 (s, 4H, 2xCH2), 2.10 (s, 4H, 2xCH2), 2.72 (s, 4H, 2xCH2), 3.90 (s, 4H, 2xCH2), 7.05 and 7.17 (m, 4H, indole H), 7.43 (d, 2H, J=7.9 Hz, linker H), 7.72 (d, 2H, J=7.8 Hz, linker

H), 7.78 (d, 2H, J=1.6 Hz indole H), 7.94 (d, 2H, J=8.5 Hz, indole H), 8.66 (s, 2H, indole

13 H), 11.33 (bs, 2H, indole NH); C NMR (DMSO-d6): į 26.3, 29.0, 44.2, 49.1 (CH2), 111.4,

112.4, 119.2, 121.7, 128.6 (aryl CH), 124.1, 128.6, 129.4, 136.1, 155.7 (aryl C); HRMS

+ (ESI): Found m/z 539.2787 [M+H] ; C36H35N4O required 539.2805.

Bis-indole amine macrocycle (216)

The diamino macrocycle was prepared from the

NH compound 202 (0.17 g, 0.31 mmol) and excess HN sodium borohydride in ethanol (20 ml) according to NH N general procedure 6 to afford the desired macrocycle H

0 N g, 56 %). M.p. >300 C; IR (KBr): ݝmax H 0.09) 216 3420, 2926, 2852, 1631, 1487, 1455, 1363, 1284, 11246, 1153, 1125, 809 cm-1; UV

-1 -1 1 (MeCN): λmax 318 nm (ܭ 30,573 cm M ), 250 (33,759); H NMR (300 MHz, DMSO-d6): ϭϳϭ į 1.20 (s, 4H, 2xCH2), 2.27 (s, 4H, 2xCH2), 3.67 (s, 4H, 2xCH2), 3.77(s, 4H, 2xCH2) 6.77 and 6.90 (m, 4H, indole H), 7.18 (d, 2H, J=7.8 Hz, linker H), 7.43 (d, 2H, J=7.6 Hz, linker

H), 7.51 (d, 2H, J=1.2 Hz, indole H), 7.58 (d, 2H, J=8.5 Hz, indole H), 8.44 (s, 2H, linker

13 H), 11.04 (bs, 2H, indole NH) 11.10 (bs, 1H, linker NH); C NMR (DMSO-d6): į 26.3,

29.1, 44.3, 49.0 (CH2) 109.9, 111.2, 121.1, 121.2, 126.9 (aryl CH), 110.6, 120.0, 124.3,

+ 129.5, 136.1, 137.4, 140.9 (aryl C); HRMS (ESI): Found m/z 538.2930 [M+H] ; C36H36N5 required 538.2971.

Bis-indole amine macrocycle (217)

The diamino macrocycle was prepared from compound 203 (0.17 g, 0.31 mmol) and excess NH HN sodium borohydride in ethanol (20 ml) according to NH N general procedure 6 to afford the desired H macrocycle 217 (0.10 g, 62%). M.p. 290-292 0C: IR N Me KBr): ݝmax 3410, 3051, 2929, 1604, 1488, 1456, 1360, 1285, 1246, 1152, 1022, 810, 746)

-1 -1 -1 1 cm ; UV (MeCN): λmax 312 nm (ܭ 13,649 cm M ), 250 (14,653); H NMR (300 MHz,

DMSO-d6): į 1.27 (s, 4H, 2xCH2), 1.54 (s, 4H, 2xCH2), 2.77 (s, 4H, 2xCH2), 4.00 (s, 3H, linker NMe), 4.10 (s, 4H, 2xCH2), 7.04 and 7.17 (m, 4H, indole H), 7.45 (d, 2H, J=7.8 Hz, linker H), 7.72 (dd, 2H, J=1.3, 1.2 Hz, linker H), 7.80 (t, 4H, J=5.3 Hz, indole H), 8.84 (s,

13 2H, linker H), 11.52 (bs, 2H, indole NH); C NMR (DMSO-d6): į 29.7 (NMe), 26.4, 44.3,

49.2 (CH2) 110.0, 111.4, 119.2, 121.5, 127.2 (aryl CH), 121.0, 122.5, 127.0, 136.1, 141.0

+ (aryl C); HRMS (ESI): Found m/z 552.3117 [M+H] ; C37H38N5 required 552.3127.

ϭϳϮ 2,8-Bis(3-(hydrazonomethyl)-1H-indol-2-yl)dibenzo[b,d]furan (218)

This compound was prepared as described for the

NH2 general procedure 9 from 3,3'-diformyl-3,6-bis-(2- NH2 N N indolyl)-dibenzofuran 94 (0.80 g, 1.76 mmol) and NH excess hydrazine hydrate in ethanol (20 ml). After HN purification, the title compound 218 was obtained as a O 0 ,yellow solid (0.71g, 84%). M.p. >300 C; IR (KBr): ݝmax 3496, 3210, 2975, 1616, 1575

-1 1451, 1381, 1137, 12774, 1198, 1125, 1024, 819, 746 cm ; UV (MeOH): λmax 306 nm (ܭ

-1 -1 1 26,108 cm M ), 248 (39,363); H NMR (300 MHz, DMSO-d6): į 6.26 (bs, 4H, 2xNH2),

7.03 and 7.18 (m, 4H, indole H), 7.41 (d, 2H, J=7.9 Hz, linker H), 7.77 (dd, 2H, J=1.8, 1.8

Hz, linker H), 7.90 (d, 2H, J=8.5 Hz, indole H), 8.15 (s, 2H, CH=N), 8.22 (d, 2H, J=7.3 Hz,

13 indole H), 8.44 (bs, 2H, linker H), 11.60 (s, 2H, indole NH); C NMR (DMSO-d6): į

111.5, 112.5, 120.2, 122.3, 122.5, 122.7, 129.3 (aryl CH), 137.4 (CH=N) 109.7, 124.2,

126.3, 127.8, 136.7, 155.9 (aryl C), HRMS (ESI): Found m/z 483.1916 [M+H]+;

C30H23N6O4 required 483.1933.

3,6-Bis(3-(hydrazonomethyl)-1H-indol-2-yl)-9H-carbazole (219)

This compound was prepared as described in general NH2 NH2 N procedure 9 from 3,3'-diformyl-3,6-bis-(2-indolyl)- N carbazole 95 (1.00 g, 2.20 mmol) and excess NH HN hydrazine hydrate in ethanol (20 ml). After N purification, the title compound 219 was obtained as a H

0 ,yellow solid (0.82 g, 78%). M.p. >300 C; IR (KBr): ݝmax 3367, 3331, 2921, 2849, 1606

ϭϳϯ -1 148614451, 1378, 1336, 1282, 1241, 1161, 1135, 817, 746 cm ; UV (MeOH): λmax 305 nm

-1 -1 1 (ܭ 39,816 cm M ), 251 (49,168); H NMR (300 MHz, DMSO-d6): į 7.04 and 7.13 (m, 4H, indole H), 7.41 (d, 2H, J=7.9 Hz, linker H), 7.69 (bs, 4H, indole and linker H), 8.18 (s, 2H,

CH=N), 8.21 (d, 2H, J=7.3 Hz, indole H), 8.45 (bs, 2H, linker H), 11.51 (s, 2H, indole

13 NH); C NMR (DMSO-d6): į 111.3, 111.9, 120.1, 121.3, 122.3, 122.3, 127.5 (aryl CH),

138.4 (CH=N), 108.8, 123.0, 123.2, 126.5, 136.7 , 139.2, 140.3 (aryl C); HRMS (ESI):

+ Found m/z 482.2084 [M+H] ; C30H24N7 required 482.2093.

3,6-Bis(3-(hydrazonomethyl)-1H-indol-2-yl)-9-methyl-9H-carbazole (220)

This compound was prepared as described in general NH2 NH2 N procedure 9 from 3,3'-diformyl-3,6-bis-(2-indolyl)-N- N

NH methylcarbazole 96 (0.65 g, 1.39 mmol) and excess HN hydrazine hydrate in ethanol (20 ml). After N purification, the title compound 220 was obtained as a Me

0 ,yellow solid (0.53 g, 78%). M.p. >300 C; IR (KBr): ݝmax 3525, 3327, 2922, 1602, 1575

1457, 1384, 1313, 1282, 1247, 1153, 1126, 1153, 1077, 1010, 811, 756, 642 cm-1; UV

-1 -1 1 (MeOH): λmax 257 nm (ܭ 45,311 cm M ); H NMR (300 MHz, DMSO-d6): į 4.01 (s, 3H, linker NMe), 6.23 (bs, 4H, 2xNH2), 7.04 and 7.19 (m, 4H, indole H), 7.43 (d, 2H, J=7.9

Hz, linker H), 7.79 (d, 4H, J=7.8 Hz, indole and linker H), 7.90 (d, 2H, J=8.5 Hz, indole

H), 8.19 (s, 2H, CH=N), 8.24 (d, 2H, J=7.7 Hz, indole H), 8.51 (bs, 2H, linker H), 11.52 (s,

13 2H, indole NH); C NMR (DMSO-d6): į 29.7 (Me), 110.1, 111.3, 120.1, 121.3, 122.4,

127.6 (aryl CH), 138.1 (CH=N) 109.0, 122.6, 123.4, 126.5, 136.7, 138.9, 141.1 (aryl C);

+ HRMS (ESI): Found m/z 496.2238 [M+H] ; C31H26N7 required 496.2250.

ϭϳϰ 9-Ethyl-3,6-bis(3-(hydrazonomethyl)-1H-indol-2-yl)-9H-carbazole (221)

This compound was prepared as described in general NH2 NH2 N procedure 9 from 3,3'-diformyl-3,6-bis-(2-indolyl)-N- N ethylcarbazole 97 (0.50 g, 1.01 mmol) and excess NH HN hydrazine hydrate in ethanol (20 ml). After purification, N the title compound 221 was obtained as a yellow solid Et

0 ,g, 82%). M.p. >300 C; IR (KBr): ݝmax 3411, 3277, 2966, 1602, 1575, 1482, 1453 0.53)

-1 1383, 1345, 1285, 1232, 1153, 1129, 1046, 877, 812, 747 cm ; UV (MeOH): λmax 253 nm

-1 -1 1 (ܭ 70,896 cm M ); H NMR (300 MHz, DMSO-d6): į 1.39 (t, 3H, J=7.0 Hz, CH2Me),

4.56 (q, 2H, J=6.7 Hz, CH2Me), 6.21 (bs, 4H, 2xNH2), 7.06 and 7.16 (m, 4H, indole H),

7.40 (d, 2H, J=7.9 Hz, linker H), 7.73 (dd, 2H, J=1.8, 1.8 Hz, linker H), 7.85 (d, 2H, J=8.7

Hz, indole H), 8.20 (s, 2H, CH=N), 8.23 (d, 2H, J=7.7 Hz, indole H), 8.50 (bs, 2H, linker

13 H), 11.51 (s, 2H, indole NH); C NMR (DMSO-d6): į 14.2 (Me), 56.4 (CH2), 110.1,

111.3,120.1, 121.5, 122.3, 127.6 (aryl CH), 138.1 (CH=N) 109.0, 122.8, 123.4, 126.5,

+ 136.7, 138.9, 140.0 (aryl C); HRMS (ESI): Found m/z 510.2401 [M+H] ; C32H29N7 required 510.2406.

ϭϳϱ 2,8-Bis(7-((E)-hydrazonomethyl)-4,6-dimethoxy-1H-indol-3- yl)dibenzo[b,d]furan (222)

This compound was prepared as described NH2 NH2 N N in general procedure 9 from 7,7'-diformyl- HC CH H H MeO OMe 3,6-bis-(3-indolyl)-dibenzofuran 134 (0.1 N N g, 0.17 mmol) and hydrazine hydrate OMe OMe

(0.02 ml, 0.40 mmol) in ethanol (20 ml). O

After purification, the title compound 222 was obtained as a yellow solid (0.07 g, 74%).

0 ,M.p. >300 C; IR (KBr): ݝmax 3375, 2934, 2837, 1620, 1605, 1591, 1477, 1463, 1329, 1205

-1 -1 -1 1173, 1146, 802, 765, 659 cm ; UV (MeOH): λmax 330 nm (ܭ 101,211 cm M ), 249

1 (157,272); H NMR (300 MHz, DMSO-d6): į 3.82 (s, 6H, 2xOMe), 3.88 (s, 6H, 2xOMe),

6.47 (d, 6H, J=9.00 Hz, indole H and NH2), 7.29 (d, 2H, J=2.37 Hz, linker H), 7.64 (d, 4H,

J=2.85 Hz, linker H), 8.22 (d, 2H, J=1.41 Hz, indole H), 8.27 (s, 2H, CH=N), 10.85 (bs,

13 2H, indole NH); C NMR (DMSO-d6): į 55.6, 57.2 (OMe), 89.2, 110.8, 121.2, 123.0,

129.1, 137.2 (aryl CH), 101.3, 110.8, 117.1, 123.8, 131.5, 135.1, 154.4, 154.6, 154.7 (aryl

+ C); HRMS (ESI): Found m/z 603.2341 [M+H] ; C34H31N6O5 required 603.2356

ϭϳϲ Bis-indole hydrazone macrocycle (223)

A mixture of compound 221 (0.38 g, 0.74 Et N mmol) and 3,3'-diformyl-3,6-bis-(2-indolyl)-N- H H N N ethylcarbazole 97 (0.35 g, 0.74 mmol), was HC HC refluxed in absolute ethanol (30 ml) for 12 h. N N N N The precipitate was filtered, washed with water CH CH and air dried. The crude product was purified N N by flash column chromatography to yield the H H N title compound 223 (0.34 g, 48%) as yellow Et

0 ,crystals. M.p. >300 C; ݝmax : 3344, 3262, 2973, 1576, 1448, 1378, 1318, 1233, 1150, 1129

-1 -1 -1 1 1047, 808 746, cm ; UV (MeOH): λmax 252 nm (ܭ 15,055 cm M ), 207 (14,999); H

NMR (300 MHz DMSO-d6); 1.44 (bs, 6H, 2xCH2Me), 4.61 (s, 4H, 2xCH2Me); 7.12 (bs,

8H, indole H), 7.42(bs, 4H, indole H), 7.93, (d, 8H, J=22.4 Hz, indole and linker H), 8.41

(d, 4H, J=6.4 Hz, linker H), 8.68 (s, 4H, 4xCH), 9.03 (s, 4H, linker H), 12.02 (bs, 4H, indole NH).

This compound was not sufficiently soluble for a 13C NMR spectrum to be obtained.

+ HRMS (ESI): Found m/z 955.3970 [M+H] ; C64H47N10 required 955.3985.

ϭϳϳ 2,2'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(2- oxoacetyl chloride) (238)

The title compound 238 was prepared as described in Cl Cl general procedure 10 from 2-indolyl dibenzofuran 72 O O O O (1.00 g, 2.50 mmol) and excess oxalyl chloride in N N H H anhydrous diethyl ether (20 ml). After filtration, the O desired compound 238 was obtained as a brown solid

o ,g, 80%). M.p. 174-176 C; IR (KBr): ݝmax 3385, 3059, 1602, 1573, 1467, 1448, 1348 1.16)

-1 -1 -1 1198, 1127, 885, 750 cm ; UV (CH3CN): λmax 307 nm (ܭ 61,268 cm M ), 243 (83,397),

1 208 (77,782); H NMR (300 MHz, DMSO-d6): į 7.31 and 7.35 (m, 4H, indole H), 7.56 (d,

2H, J=6.2 Hz, indole H), 7.82 (d, 2H, J=6.6 Hz, linker H), 7.95 (d, 2H, J=8.1 Hz, indole

H), 8.15 (d, 2H, J=7.0 Hz, linker H), 8.49 (d, 2H, J=1.38 Hz, linker H), 12.80 (s, 2H, indole

13 NH); C NMR (DMSO-d6) 112.1, 112.6, 121.3, 123.0, 123.6, 124.0, 130.4 (aryl

CH),109.2, 126.6, 127.3, 136.2, 148.2, 157.0 (aryl CH), 167.2, 184.8 (C=O); HRMS (ESI):

+ Found m/z 580.1490 [M+H] ; C32H17Cl2N2O5 required 580.3938.

ϭϳϴ 2,2'-(2,2'-(9H-Carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(2-oxoacetyl chloride) (239)

The title compound 239 was prepared as described for Cl Cl O O the general procedure 10 from 2-indolyl carbazole 73 O O (0.60 g, 1.50 mmol) and excess oxalyl chloride in N N H H anhydrous diethyl ether (20 ml). After filtration, the N H desired compound 239 was obtained as a brown solid

0 ,g, 67%). M.p. 210-212 C; IR (KBr): ݝmax 3417, 1627, 1601, 1561, 1463, 1421, 1349 0.47)

-1 -1 -1 1254, 1254, 1200, 1142, 751 cm ; UV (MeOH): λmax 317 nm (ܭ 55,392 cm M ), 251

1 (109,341), 203 (122,035); H NMR (300 MHz, DMSO-d6): į 7.29 and 7.32 (m, 4H, indole

H), 7.55 (d, 2H, J=6.5 Hz, linker H), 7.71 (s, 4H, indole H), 8.17 (d, 2H, J=6.8 Hz, linker

H), 8.45 (s. 2H, linker H), 11.97 (s, 1H, linker NH), 12.60 (s, 2H, indole H); 13C NMR

(DMSO-d6): į 111.5, 112.4, 121.0, 122.8, 123.7, 128.2 (aryl CH), 108.7, 121.9, 122.6,

127.7, 136.3, 141.4, 149.9 (aryl C), 167.3, 185.0 (C=O); HRMS (ESI): Found m/z

+ 579.5334[M+H] ; C32H18Cl2N3O4 required 579.4090.

ϭϳϵ 2,2'-(2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(2- oxoacetyl chloride) (240)

The title compound 240 was prepared as described in Cl Cl O O general procedure 10 from 2-indolyl-N- O O

N N methylcarbazole 74 (0.80 g, 1.90 mmol) and excess H H oxalyl chloride in anhydrous diethyl ether (20 ml). N Me After filtration, the desired compound 240 was

0 ,obtained as a brown solid (0.84 g, 75%). M.p. 224-226 C; IR (KBr): ݝmax 3420, 3217

1790, 1596, 1452, 1423, 1372, 1316, 1243, 1194, 1022, 930, 797, 755, 629, 600 cm-1; UV

-1 -1 1 (MeCN): λmax 203 nm (ܭ 12,753 cm M ); H NMR (300 MHz, DMSO-d6): į 4.06 (s, 3H, linker NMe), 7.28 and 7.33 (m, 4H, indole H), 7.55 (d, 2H, J=4.8 Hz, linker H), 7.81 (d,

4H, J=3.2 Hz, indole H), 8.17 (d, 2H, J=6.7 Hz, linker H), 8.49 (s, 2H, linker H), 12.57, (s,

13 2H, indole NH); C NMR (DMSO-d6): į 29.8 (Me), 109.7, 112.4, 121.0, 122.8, 123.7,

128.4 (aryl CH), 108.8, 122.1, 122.2, 127.7, 136.3, 142.2, 149.6 (aryl C), 167.2, 185.0

+ (C=O); HRMS (ESI): Found m/z 615.4299 [M+Na] ; C33H19Cl2N3O4Na required 615.4174.

ϭϴϬ 2,2'-(2,2'-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(2- oxoacetyl chloride) (241)

The title compound 241 was prepared as described Cl Cl O O in general procedure 10 from 2-indolyl-N- O O ethylcarbazole 75 (0.70 g, 1.65 mmol) and excess N N H H oxalyl chloride in anhydrous diethyl ether (20 ml). N After filtration, the desired compound 241 was Et

0 ,obtained as a brown solid (0.76 g, 77%). M.p. 252-254 C; IR (KBr): ݝmax 3196, 2978

1783, 1596, 1489, 1450, 1350, 1238, 1195, 1129, 836, 796, 754, 690, 628 cm-1; UV

-1 -1 1 (MeCN): λmax 248 nm (ܭ 28,360 cm M ); H NMR (300 MHz, DMSO-d6): į 1.42 (t, 3H,

J=6.9 Hz, CH2Me), 4.57 (q, 2H, J=7.0 Hz, CH2Me), 7.25 and 7.29 (m, 4H, indole H), 7.52

(dd, 2H, J=2.0, 1.8 Hz, indole H), 7.75 and 7.85 (m, 4H, linker H), 8.12 (dd, 2H, J=2.0, 2.0

Hz, linker H), 8.45 (d, 2H, J=1.3 Hz, indole H), 12.65 (s, 2H, indole NH); 13C NMR

(DMSO-d6): į 14.3 (Me), 37.8 (CH2), 109.8, 112.4, 121.0, 122.8, 123.0, 123.8, 128.2 (aryl

CH), 108.6, 122.1, 122.2, 127.7, 136.3, 141.1, 149.6 (aryl C), 167.3, 185.0 (C=0): HRMS

+ (ESI): Found m/z 607.3909 [M+H] ; C34H22Cl2N3O4 required 607.4632.

ϭϴϭ 2,2'-(2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1-methyl-1H-indole-3,2- diyl))bis(2-oxoacetyl chloride) (242)

The title compound 242 was prepared as described Cl Cl O O for the general procedure 10 from bis-indole 99 O O

(0.74 g, 1.68 mmol) and excess oxalyl chloride in N N Me Me anhydrous ether (20 ml). After filtration, the desired N compound 242 was obtained as a brown solid (0.48 Me

0 ,g, 46%): M.p. 232-234 C; IR (KBr): ݝmax 3379, 3046, 2936, 1696, 1600, 1466, 1434, 1360

-1 1289, 1249, 1155, 1126, 1078, 814, 747, 706, cm ; UV (MeOH): λmax 299 nm (ܭ 53,644

-1 -1 1 cm M ), 245 (76,343), 211 (61,212); H NMR (300 MHz, DMSO-d6): į 3.65 (s, 6H, indole NMe), 4.05 (s, 3H, linker NMe), 7.30 and 7.38 (m, 4H, indole H), 7.60 and 7.69 (m,

4H, indole H), 7.82 (d, 2H, J=8.55 Hz, linker H), 8.23 (dd, 2H, J=1.77, 1.14 Hz, linker H),

13 8.34 (s, 2H, linker H); C NMR (DMSO-d6): į 29.7, 31.5 (Me), 109.6, 111.5, 121.2, 123.4,

124.0, 129.3 (aryl CH), 110.1, 122.0, 126.4, 137.8, 142.0, 150.8, 167.0 (aryl C), 167.2,

+ 185.0 (C=O); HRMS (ESI): Found m/z 644.2762 [M+Na] ; C35H23Cl2N3O4Na required

644.1934.

ϭϴϮ Diethyl-2,2'-(2,2'-(dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2- diyl))bis(2-oxoacetate) (243)

Indol-3-ylglyoxyloyl chloride 238 (0.30 g, 0.50 mmol) OEt EtO O O was heated in boiling ethanol to produce the ester 243 as O O a brown solid (0.19 g, 64%). M.p. >300 0C; IR (KBr): N N H H ,ݝmax 3417, 3179, 2981, 1735, 1595, 1579, 1469, 1449 O -1 -1 - 1376, 1251, 1201, 1093, 1023, 831, 756 cm ; UV (MeCN): λmax 304 nm (ܭ 35,731 cm M

1 1 ), 254 (62,991), 220 (56,636), 210 (56,360); H NMR (300 MHz, DMSO-d6): į 1.10 (t, 6H,

J=6.9 Hz, 2xMe), 3.57 (m, 4H, 2xCH2), 7.33 and 7.38 (m, 4H, indole H), 7.58 (d, 2H,

J=6.2 Hz, indole H), 7.79 (dd, 2H, J=1.8, 1.8 Hz, linker H), 8.02 (d, 2H, J=8.5 Hz, linker

H), 8.11 (d, 2H, J=8.0 Hz, linker H), 8.52 (d, 2H, J=1.4 Hz, indole H), 12.80 (bs, 2H,

13 indole NH); C NMR (DMSO-d6): į 13.6 (Me), 56.3 (CH2), 11.2, 112.6, 121.3, 123.3,

123.6, 124.4, 130.4 (aryl CH), 109.8, 123.5, 126.5, 127.2, 136.2, 148.8, 157.0 (aryl C),

+ 165.0, 182.8 (C=O); HRMS (ESI): Found m/z 621.1590 [M+Na] ; C36H26N2O7Na required

621.1632.

2,2'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(2- oxoacetamide) (244)

The amide 244 was prepared from concentrated NH2 H2N O O ammonia (10 ml) and indol-3-ylglyoxyloyl chloride O O

238 (0.23 g, 0.39 mmol) according to general N N H H procedure 11a to yield the title compound 244 as a O 0 ,yellow powder (0.15 g, 74%). M.p. 260-262 C; IR (KBr): ݝmax 3353, 3175, 1696, 1679 ϭϴϯ -1 1622, 1595, 1577, 1450, 1387, 1366, 1197, 1118, 748 cm ; UV (MeOH): λmax 316 nm (ܭ

-1 -1 1 81,000 cm M ), 251 (152,064), 224 (139,104); H NMR (300 MHz DMSO-d6) 7.23 and

7.28 (m, 6H, indole H), 7.51 (dd, 2H, J=2.4, 1.6 Hz, linker H), 7.80 (dd, 2H, J=1.8, 1.8 Hz, indole H), 7.83 (s, 2H, NH2), 7.93 (s, 2H, NH2), 8.08 (dd, 2H, J=1.8, 0.87 Hz, linker), 8.39

13 (d, 2H, J=1.3 Hz, linker H), 11.30 (bs, 2H, indole NH); C NMR (DMSO-d6): į 111.9,

112.3, 121.1, 122.5, 123,6, 123.8, 129.7 (aryl CH), 109.6, 123.5, 127.2, 127.8, 136.2,

147.4, 156.7 (aryl C), 168.9, 188.3 (C=O) HRMS (ESI): Found m/z 541.1500 [M+H]+;

C32H21N4O5 required 541.1512.

2,2'-(2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2- diyl))bis(2-oxoacetamide) (245)

The amide 245 was prepared from concentrated NH2 H2N O O ammonia (10 ml) and indol-3-ylglyoxyloyl chloride O O

240 (0.18 g, 0.30 mmol) according to general N N H H procedure 11a to yield the title compound 245 as a N yellow powder (0.11 g, 68%). M.p. 218-220 0C: IR Me

,KBr): ݝmax 3384, 3282, 1674,1601, 1452, 1390, 1319, 1286, 1247, 1183, 1153, 1096, 1022)

-1 -1 -1 787, 750 cm ; UV (MeOH): λmax 294 nm (ܭ 67,635 cm M ), 250 (82,417), 207 (85,455);

1 H NMR (300 MHz, DMSO-d6): į 4.00 (s, 3H, linker NMe), 7.19 and 7.26 (m, 6H, indole

H), 7.51 (d, 2H, J=6.69 Hz, linker H), 7.78 (d, 4H, J=4.29 Hz, 2xNH2), 7.95 (s, 2H, indole

H), 8.09 (d, 2H, J=6.72 Hz, linker H), 8.44 (s, 2H, linker H), 11.42 (s, 2H, indole NH); 13C

NMR (DMSO-d6): į 29.7 (Me), 109.5, 112.2, 121.3, 123.1, 123.3, 127.8 (aryl CH), 109.0,

ϭϴϰ 122.0, 122.8, 128.1, 136.3, 141.9, 148.9 (aryl C), 169.5, 188.5 (C=O) HRMS (ESI): Found

+ m/z 554.1820 [M+H] ; C33H24N5O4 required 554.1828.

2,2'-(2,2'-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(2- oxoacetamide) (246)

The amide 246 was prepared from concentrated NH2 H2N O O ammonia (10 ml) and indol-3-ylglyoxyloyl chloride O O

241 (0.18 g, 0.29 mmol) according to general N N H H procedure 11a to yield the title compound 246 as a N 0 yellow powder (0.11 g, 65%). M.p. 236-238 C: IR Et

,KBr): ݝmax 3422, 3289, 1675, 1599, 1448, 1382, 1289, 1233, 1185, 1130, 1097, 961, 809)

-1 -1 -1 783, 750, cm ; UV (MeOH): λmax 297 nm (ܭ 70,375 cm M ), 253 (81,635), 207 (81,123);

1 H NMR(300 MHz DMSO-d6): 1.38 (t, 3H, J=6.9 Hz, CH2Me), 4.56 (q, 2H, J=6.7 Hz,

CH2Me), 7.22 and 7.26 (m, 6H, indole H), 7.50 (dd, 2H, J=2.2,1.8 Hz, indole H), 7.79 (d,

4H, J=0.9 Hz, 2xNH2), 7.96 (s, 2H, linker H), 8.10 (dd, 2H, J=3.4, 2.0 Hz, linker H), 8.44

13 (s, 2H, linker H); C NMR (DMSO-d6): į 14.3 (Me), 37.7 (CH2), 101.5, 112.1, 121.0,

122.3, 123,3, 123.8, 127.7 (aryl CH), 109.0, 122.2, 122.8, 128.1, 136.3, 140.8 148.8 (aryl

+ C), 168.9, 188.3 (C=O) HRMS (ESI): Found m/z 568.1982 [M+H] ; C34H26N5O4 required

568.1985.

ϭϴϱ 2,2'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(N- methyl-2-oxoacetamide) (247)

The amide 247 was prepared from indol-3- NHMe MeHN O O ylglyoxyloyl chloride 238 (0.20 g, 0.30 mmol) in O O an excess of 40% aqueous methylamine solution N N H H according to general procedure 11b to yield the O title compound 247 as a yellow solid (0.14 g, 73%). M.p. 254-256 0C (from methanol);

(Found: C, 69.7; H, 4.3; N, 8.9.C32H24N4O5.1.1CH3OH requires C, 69.8; H, 4.7; N, 9.2%);

-1 ; IR (KBr):ݝmax 3187, 1601, 1489, 1441, 1373, 1272, 1241, 1201, 1119, 1024, 824, 750 cm

-1 -1 1 UV (MeOH): λmax 306 nm (ܭ 41,580 cm M ), 254 (75,060), 226 (69,360); H NMR (300

MHz, DMSO-d6): į 2.16 (d, 6H, J=4.7 Hz, NHMe), 7.24 and 7.29 (m, 4H, indole H), 7.50

(dd, 2H, J=2.2, 1.6 Hz, indole H), 7.76 (dd, 2H, J=1.8, 1.8 Hz, linker H), 7.90 (d, 2H, J=8.4

Hz, indole H), 8.12 (dd, 2H, J=1.9, 2.5 Hz, linker H), 8.40 (d, 2H, J=1.4 Hz, NHCH3), 8.47

13 (d, 2H, J=4.8 Hz, linker H), 12.53 (s, 2H, indole NH); C NMR (DMSO-d6): į 25.2

(NHMe), 111.8, 112.3, 121.3, 122.7, 123.3, 123.7, 129.8 (aryl CH), 110.0, 123.7, 127.0,

127.6, 136.1, 147.7, 156.7 (aryl C), 167.5, 188.2 (C=O); HRMS (ESI); Found m/z 569.1815

+ [M+H] ; C34H25N4O5 required 569.1825.

ϭϴϲ 2,2'-(2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(N- methyl-2-oxoacetamide) (248)

The amide 248 was prepared from indol-3- NHMe MeHN O O ylglyoxyloyl chloride 240 (0.33 g, 0.57 mmol) in an O O excess of 40% aqueous methylamine solution N N H H according to general procedure 11b to yield the title N Me compound 248 as a yellow solid (0.21 g, 64%).

0 ,M.p. 258-260 C: IR (KBr): ݝmax 3395, 1601, 1488, 1448, 1370, 1320, 1286, 1247, 1185

-1 -1 -1 1153, 750 cm ; UV (MeCN): λmax 293 nm (ܭ 48,970 cm M ), 253 (51,180), 207 (49,784);

1 H NMR (300 MHz, DMSO-d6): į 2.14 (d, 6H, J=4.02 Hz, NHMe), 4.03 (s, 3H, linker

NMe), 7.28 (s, 3H, indole H), 7.54 (d, 3H, J=7.2 Hz, indole and linker H), 7.78 (s, 4H, linker H), 8.14 (d, 2H, J=6.7 Hz, NHMe), 8.49 (s, 4H, J=7.8 Hz, indole H); 13C NMR

(DMSO-d6) 25.3 (NHMe), 29.8 (NMe), 109.5, 112.2, 121.1, 122.5, 123.5, 127.8 (aryl CH),

121.9, 122.6, 128.0, 136.2, 141.8, 149.2 (aryl C), 165.7, 188.4 (C=O) HRMS (ESI): Found

+ m/z 582.2137 [M+H] ; C35H28N5O4 required 582.2141.

2,2'-(2,2'-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(N- methyl-2-oxoacetamide) (249)

The amide 249 was prepared from indol-3- NHMe MeHN O O ylglyoxyloyl chloride 241 (0.40 g, 0.66 mmol) in an O O excess of 40% aqueous methylamine solution N N H H according to general procedure 11b to yield the title N Et ϭϴϳ 0 ,compound 249 as a yellow solid (0.27 g, 70%). M.p. 240-242 C; IR (KBr): ݝmax 3442

3289, 2977, 1675, 1599, 1448, 1382, 1289, 1233, 1185, 1153, 1130, 1097, 961, 750 cm-1;

-1 -1 1 UV (MeOH): λmax 251 nm (ܭ 88,230 cm M ), 204 (106,080); H NMR (300 MHz,

DMSO-d6): į 1.38 (t, 3H, J=6.9 Hz, CH2Me), 2.13 (d, 6H, J=4.7 Hz, NHMe), 4.56 (q, 2H,

J=7.2 Hz, CH2Me), 7.23 and 7.27 (m, 4H, indole H), 7.49 (dd, 3H, J=1.7, 1.8 Hz, linker H and indole H), 7.73, (d, 4H, J=6.5 Hz, indole H), 8.10 (d, 2H, J=2.6 Hz, NHMe), 8.46 (d,

13 3H, J=1.44 Hz, linker H); C NMR (DMSO-d6): į 14.1 (Me), 25.2 (NHMe), 37.1 (CH2)

109.4, 112.2, 121.1, 122.5, 122.6, 123.5, 127.9 (aryl CH), 109.5, 122.2, 122.6, 128.0,

136.2, 140.8, 149.2 (aryl C), 167.7, 188.24(C=O) HRMS (ESI): Found m/z 596.2296

+ [M+H] ; C36H30N5O4 required 596.2298.

2,2'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(N-(3,5- dimethoxyphenyl)-2-oxoacetamide) (250)

The amide 250 was prepared from indol-3- MeO OMeMeO OMe ylglyoxyloyl chloride 238 (0.40 g, 0.60 mmol) and HN HN 3,5-dimethoxyaniline (0.21 g, 1.38 mmol) in O O O O anhydrous diethyl ether (20 ml) according to

N N general procedure 11c to yield to the title H H compound 250 as a yellowish solid (0.43 g, 78%). O

0 ,M.p. 182-184 C; IR (KBr): ݝmax 3255, 3061, 2940, 2601, 1667, 1605, 1439, 1267, 1205

-1 -1 -1 1 1157, 1097, 1053, 836, 751, 678 cm ; UV (MeCN): λmax 214 nm (ܭ 144,977 cm M ); H

NMR (300 MHz, DMSO-d6): į 3.76 (s, 12H, 4xOMe), 5.96 (t, 2H, J=4.4 Hz, aniline H),

6.38 and 6.41 (m, 8H, aniline and indole H), 7.31 and 7.36 (m, 4H, linker H), 7.60 (dd, 2H,

ϭϴϴ J=1.6, 1.3 Hz, linker H), 7.67 and 7.76 (m, 3H, indole H), 8.17 and 8.21 (m, 3H, indole H),

13 10.53 (s, 2H, aniline NH), 12.56 (s, 2H, indole NH); C NMR (DMSO-d6): į 54.8, 55.7

(OMe), 96.2, 97.7, 100.4, 111.7, 112.5, 121.3, 122.8, 123.4, 123.9, 128.9 (aryl CH), 109.5,

123.5, 126.4, 127.8, 136.4, 139.6, 148.2, 160.2, 161.4, 165.3 (aryl C), 156.5, 186.8 (C=O);

+ HRMS (ESI): Found m/z 813.2502 [M+H] ; C48H37N4O9 required 813.2555.

2,2'-(2,2'-(9-Methyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(N-

(3,5-dimethoxyphenyl)-2-oxoacetamide) (251)

The amide 251 was prepared from indol-3- MeO OMe MeO OMe ylglyoxyloyl chloride 240 (0.25 g, 0.40 mmol) and HN HN 3,5-dimethoxyaniline (0.12 g, 0.80 mmol) in O O O O anhydrous diethyl ether (20 ml) according to

N N general procedure 11c to yield the title compound H H

251 as a yellowish solid (0.26 g, 75%). M.p. 196- N Me 0 ,C; IR (KBr): ݝmax 3418, 2937, 2957, 1604, 1452, 1417, 1354, 1208, 1159, 1051, 824 198

-1 -1 -1 840, 752, 676 cm ; UV (MeCN): λmax 293 nm (ܭ 71,714 cm M ), 250 (87,360), 214

1 (166,029); H NMR (300 MHz, DMSO-d6): į 3.76 (s, 12H, 4xOMe), 4.03 (s, 3H, NMe),

5.92 (d, 2H, J=1.9 Hz, aniline H), 6.32 (d, 4H, J=2.0 Hz, aniline and indole H), 6.44 and

6.47 (m, 4H, indole H), 7.10 and 7.15 (m, 2H, indole H), 7.33 and 7.38 (m, 2H, linker H),

7.74 (d, 2H, J=1.3 Hz, indole H), 8.18 (d, 2H, J=7.0 Hz, linker H), 8.30 (s, 2H, linker H),

13 10.24 (s, 2H, aniline NH), 12.23 (s, 2H, indole NH); C NMR (DMSO-d6): į 29.3 (NMe),

54.8, 55.8 (OMe), 96.1, 97.9, 98.4, 100.9, 111.6, 112.3, 121.1, 122.6, 122.7, 123.6, 127.1

(aryl CH), 109.3, 122.1, 128.1, 135.8, 136.4, 139.7, 141.7, 149.7, 160.1, 161.4 (aryl C),

ϭϴϵ + 165.4, 187.0 (C=O); HRMS (ESI): Found m/z 848.2792 [M+Na] C49H39N5O8Na required

848.2696.

2,2'-(2,2'-(9-Ethyl-9H-carbazole-3,6-diyl)bis(1H-indole-3,2-diyl))bis(N-

(3,5-dimethoxyphenyl)-2-oxoacetamide) (252)

The amide 252 was prepared from indol-3- MeO OMe MeO OMe ylglyoxyloyl chloride 241 (0.30 g, 0.49 mmol) and 3,5-dimethoxyaniline (0.16 g, 0.98 mmol) in HN HN O O O O anhydrous diethyl ether (20 ml) according to general procedure 11c to yield the title compound N N H H

252 as a yellowish solid (0.26 g, 63%). M.p. 202- N Et 0 ,C; IR (KBr): ݝmax 3233, 2935, 2599, 1601 204

-1 1447, 1350, 1234, 1206, 1157, 1053, 1089, 837, 751 cm ; UV (MeOH): λmax 298 nm (ܭ

-1 -1 1 45,404 cm M ), 211 (145,097); H NMR (300 MHz, DMSO-d6): į 1.34 (t, 3H, J=7.2 Hz,

CH2Me), 3.74 (s, 12H, 4xOMe), 4.43 (q, 2H, J=7.2 Hz, CH2Me), 5.92 (d, 2H, J=1.9 Hz, aniline H), 6.34 (d, 4H, J=2.2 Hz, aniline and indole H), 6.51 (s, 4H, indole H), 7.25 and

7.30 (m, 2H, indole H), 7.50 and 7.56 (m, 2H, linker H), 7.68 (d, 2H, J=1.6 Hz, indole H),

8.13 (d, 2H, J=7.0 Hz, linker H), 8.32 (s, 2H, linker H), 10.48 (s, 2H, aniline NH), 12.43 (s,

13 2H, indole NH); C NMR (DMSO-d6): į 13.6 (Me), 37.5 (CH2), 54.9, 55.9 (OMe), 96.1,

98.3, 99.3, 101.8, 109.2, 112.3, 121.1, 122.6, 122.8, 123.5, 127.3 (aryl CH), 109.1, 122.2,

128.1, 134.2, 136.4, 139.8, 140.7, 149.7, 160.2, 161.3 (aryl C), 165.4, 186.9 (C=O); HRMS

+ (ESI): Found m/z 840.3023 [M+H] ; C50H42N5O8 required 840.3033.

ϭϵϬ 2,2'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(2-oxo-N- p-tolylacetamide) (253)

Indol-3-ylglyoxyloyl chloride 238 (0.45 g, 0.77 Me Me mmol) in anhydrous diethyl ether (20 ml) was treated with p-toluidine (0.16 g, 1.44 mmol) in NH HN O O anhydrous diethyl ether (20 ml) at r.t. After stirring O O for 2 h, the resulting precipitate was filtered off, N N H H washed with water and air dried to afford the O 0 ,ketoamide 253 as a yellowish solid (0.43 g, 77%). M.p. 184-186 C; IR (KBr): ݝmax 3188

-1 2860, 2618, 1600, 1512, 1440, 1403, 1316, 1200, 1124, 809, 750 cm ; UV (MeOH): λmax

-1 -1 1 229 nm (ܭ 94,500 cm M ), 202 (109,125); H NMR (300 MHz, DMSO-d6): į 2.34 (s, 6H,

2xMe), 6.60 (d, 3H, J=8.3 Hz, indole H), 7.09 (d, 3H, J=8.4 Hz, indole H), 7.21 and 7.26

(m, 8H, p-toluidine H), 7.38 and 7.44 (m, 3H, linker H), 7.76 (dd, 2H, J=1.8, 1.8 Hz, linker

H), 8.13 (d, 2H, J=5.6 Hz, indole H), 8.32 (s, 1H, linker H), 10.51 (s, 2H, p-toluidine NH),

13 12.63 (s, 2H, indole NH); C NMR (DMSO-d6): į 20.8 (Me) 111.6, 112.5, 119.7, 121.2,

122.8, 123.3, 123.8, 128.9, 129.3, 130.4 (aryl CH), 109.7, 123.4, 126.5, 127.8, 132.9,

136.3, 137.9, 148.0, 156.5 (aryl C), 165.2, 187.1 (C=O); HRMS (ESI): Found m/z 721.2440

+ [M+H] ; C46H33N4O5 required 721.2451.

ϭϵϭ 2,2'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(N-(2-(4- bromophenyl)-2-oxoethyl)-N-(3,5-dimethoxyphenyl)-2-oxoacetamide)

(255)

Br Indol-3-ylglyoxyloyl chloride 238 Br

OMe OMe (0.45 g, 0.77 mmol) in anhydrous O O diethyl ether (20 ml) was treated with MeO N N OMe O 4-bromophenacyl bromide 254 (0.45 O O O g, 1.54 mmol) in anhydrous diethyl N N H H ether (20 ml) at r.t. After stirring for O 3 h, the resulting precipitate was filtered off, washed with water and air dried to afford the

0 ,ketoamide 255 as a yellowish solid (0.77 g, 83%). M.p. 268-270 C; IR (KBr): ݝmax 3281

2932, 1698, 1588, 1442, 1397, 1352, 1204, 1155, 1069, 982, 932, 820, 746, 691 cm-1; UV

-1 -1 1 (MeCN): λmax 257 nm (ܭ 111,293 cm M ), 205 (137,575); H NMR (300 MHz, DMSO- d6): į 3.38 (s, 12H, 4xOMe), 5.32 (s, 4H, 2xCH2), 6.30 (t, 2H, J=2.1 Hz, aromatic H), 6.39

(d, 4H, J=2.1 Hz, aromatic H), 7.33 and 7.36 (m, 4H, aromatic H), 7.54 and 7.57 (m, 2H, aromatic H), 7.73 (dd, 2H, J=1.83, 1.68 Hz, linker H), 7.80 (d, 4H, J=8.58 Hz, linker H),

7.92 (d, 6H, J=7.23 Hz, aromatic H), 8.09 and 8.12 (m, 2H, aromatic H), 8.22 (d, 2H, J=1.5

13 Hz, aromatic H), 12.68 (bs, 2H, indole NH); C NMR (DMSO-d6): į 55.1 (CH2), 55.3

(OMe), 99.7, 105.3, 111.9, 112.6, 120.6, 122.8, 123.7, 130.1, 130.4, 132.3 (aryl CH),

109.8, 123.3, 126.7, 128.3, 134.0, 136.1, 142.4, 146.4, 156.8, 160.5 (aryl C), 168.8, 184.7,

+ 193.4 (C=O) HRMS (ESI): Found m/z 1227.1365 [M+Na] ; C64H46N4O11Na required

1227.1422.

ϭϵϮ 1,1'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(2,2,2- trichloroethanone) (257)

Trichloroacetyl chloride (2.80 ml, 25 mmol) was CCl Cl3C 3 O O added dropwise to a solution of the 2-indolyl N N H dibenzofuran 72 (1.00 g, 2.5 mmol) in 1,2- H dichloroethane (20 ml). After completion of the O addition, the solution was refluxed under N2 atmosphere overnight. The mixture was cooled to room temperature and water (20 ml) was added. The organic layer was extracted in dichloromethane (2x20 ml). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. Column chromatography of the residue on silica gel

(dichloromethane: light petroleum (1:1) eluent) gave the title compound 257 as a yellow

0 ,solid (0.43 g, 68%). M.p. 208-210 C; IR (KBr): ݝmax 3363, 1656, 1467, 1488, 1451, 1426

-1 - 1332, 1275, 1199, 1118, 851, 819, 745, 669 cm ; UV (MeOH): λmax 225 nm (ܭ 100,752 cm

1 -1 1 M ), 211 (103,035); H NMR (300 MHz DMSO-d6) 7.29 and 7.32 (m, 4H, indole H),

7.53 and 7.55 (m, 2H, indole H),7.76 (dd, 2H, J=1.8, 1.8 Hz, linker H), 7.93(d, 2H, J=8.1

Hz, linker H), 8.00 (m, 2H, indole H), 8.45 (bs, 2H, linker NH),12.86 (bs, 2H, indole NH);

13 C NMR (DMSO-d6): į 112.2, 112.8, 122.4, 122.8, 123.0, 123.5, 129.9 (aryl CH) 97.3,

105.9, 123.6, 125.3, 127.9, 136.2, 149.3, 156.6 (aryl C) 180.1 (C=O); HRMS (ESI): Found

+ m/z 686.9371 [M+H] ; required C32H17Cl6N2O3 686.9370.

ϭϵϯ 1,1'-(2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3,2-diyl))bis(2,2,2- trichloroethanone) (258)

CCl Trichloroacetyl chloride (2.01 ml, 18 mmol) was Cl3C 3 O O added dropwise to a solution of the indole 75 (0.80 g, N N H 1.8 mmol) in 1,2-dichloroethane (20 ml). After H

N completion of the addition, the solution was heated Et under refluxed under N2 atmosphere overnight. The mixture was cooled to room temperature and water (20 ml) was added. The organic layer was extracted in dichloromethane (2x20 ml). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. Column chromatography of the residue over silica gel

(dichloromethane: light petroleum (1:1) eluent gave the title compound 258 as an orange

0 ,solid (0.75 g, 57%). M.p. 224-226 C; IR (KBr): ݝmax ; 3314, 3081, 1739, 1654, 1597, 1579

-1 1561, 1459, 1444, 1335, 1316, 1214, 1236, 1107, 829, 673 cm ; UV (MeCN): λmax 234 nm

-1 -1 1 (ܭ 14,600 cm M ); H NMR (300 MHz DMSO-d6): 1.43 (t, 3H, J= 7.2 Hz, CH2Me), 4.53

(q, 2H, J= 6.9 Hz CH2Me), 7.23 and 7.26 (m, 4H, indole H), 7.52 and 7.55 (m, 2H, indole

H), 7.67 (dd, 2H, J=1.8, 1.8 Hz, linker H), 7.76 (d, 2H, J=8.1 Hz, linker H), 8.01 (bs, 2H,

13 indole H), 8.32 (bs, 2H, linker NH), 12.65 (bs, 2H, indole NH); C NMR (DMSO-d6) 14.2

(Me), 55.0 (CH2) 79.2, 110.0, 112.7, 121.9, 122.3, 123.4, 127.8 (aryl CH) 97.3, 105.6,

122.3, 123.2, 125.8, 136.2, 140.8, 149.8 (aryl C) 181.6 (C=O); HRMS (ESI): Found m/z

+ 731.4144 [M+H] ; required C35H24Cl6N3O2 731.3020.

ϭϵϰ 2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(1H-indole-3-carboxamide) (259)

The compound 257 (0.20 g, 0.29 mmol) was NH H2N 2 partially dissolved in acetonitrile (10 ml) followed O O

N N by the addition of concentrated ammonia until the H H mixture was basic. The mixture was stirred at room O temperature for 1 h. The resulting precipitate was filtered, washed with acetonitrile and

0 ,dried to yield the title compound 259 (0.08 g, 60%). M.p. >300 C; IR (KBr): ݝmax 3448

3188, 2921, 2850, 1620, 1583, 1570, 1483, 1451, 1332, 1199, 1126, 1124, 740 cm-1; UV

-1 -1 1 (MeOH): λmax 305 nm (ܭ 52,243 cm M ), 243 (100,216); H NMR (300 MHz, DMSO-d6):

į 7.11 and 7.22 (m, 8H, linker and indole H), 7.44 (d, 2H, J= 6.4 Hz, linker H), 7.88 (d, 2H,

J= 3.6 Hz, linker H), 7.94 (bs, 4H, 2xNH2), 8.52 (s, 2H, indole H), 11.88 (bs, 2H, indole

13 NH); C NMR (DMSO-d6): į 111.8, 112.3, 120.7, 120.8, 121.9, 122.5, 129.5 (aryl CH),

109.6, 123.9, 127.9, 135.9, 138.8, 156.3 (aryl C), 167.7 (C=0); HRMS (ESI): Found m/z

+ 485.1600 [M+H] ; required C30H21N4O3 485.1614.

2,2'-(Dibenzo[b,d]furan-2,8-diyl)bis(N-methyl-1H-indole-3-carboxamide) (260)

A solution of the compound 257 (0.32 g, 0.46 mmol) in MeHN NHMe anhydrous acetonitrile (10 ml) was treated with methyl O O amine (25%, 2 ml). The mixture was stirred at room N N H H temperature for 1 h. After completion of reaction, the O resulting precipitate was filtered, washed with acetonitrile and dried to yield the title

0 ,compound 260 (0.17 g, 73%). M.p. 242-244 C; IR (KBr): ݝmax 3607, 3305, 2930, 1621

1577, 1530, 1480, 1446, 1404, 1277, 1223, 1182, 1152, 1126, 827, 743 cm-1; UV (MeOH):

ϭϵϱ -1 -1 1 λmax 309 nm (ܭ 67,360 cm M ), 243 (112,880); H NMR (300 MHz, DMSO-d6): į 2.84 (d,

6H, J= 4.6 Hz, NHMe) 7.17 and 7.26 (m, 4H, indole H), 7.50 (d, 2H, J= 7.8 Hz, linker H),

7.75 (d, 2H, J= 4.6 Hz, linker H), 7.81 (d, 2H, J=7.5 Hz, NHMe), 7.94 (bs, 4H, indole H),

13 8.54 (s, 2H, linker H); C NMR (DMSO-d6) 27.5 (NHMe), 111.9, 112.3, 120.4, 120.5,

121.4, 122.6, 129.1 (aryl CH), 110.1, 121.5, 124.0, 127.9, 136.0, 137.9, 156.3 (aryl C),

+ 166.3 (C=0); HRMS (ESI): Found m/z 513.1918 [M+H] ; required C30H21N4O3 513.1927.

ϭϵϲ CHAPTER 9

APPENDIX: X-Ray Crystallography Data

A1. Introduction

Mohan Bhadbhade at the University of New South Wales, Sydney, obtained the X-ray crystallography data shown in the appendix͘

Structure determination:

Reflection data were measured with an Enraf-Nonius CAD-4 diffractometer in 2/θ scan mode using nickel filtered copper radiation (λ 1.5418 Å). Reflections with I>3σ(I) were considered observed. The structures were determined by direct phasing and Fourier methods. Hydrogen atoms were included in calculated positions and were assigned thermal parameters equal to those of the atom to which they were bonded. Positional and anisotropic thermal parameters for the non-hydrogen atoms were refined using full matrix

2 least squares. Reflection weights used were 1/σ (Fo), with σ(Fo) being derived from σ (Io) =

2 2 1/2 2 2 1/2 [σ (Io) +(0.04Io) ] . The weighted residual is defined as Rw = (ΣwΔ /ΣwFo ) . Atomic scattering factors and anomalous dispersion parameters were from International Tables for

X-ray crystallography. 1 Structure solutions were performed by SIR922 and refinements used RAELS. 3 ORTEP II4 running on Macintosh was used for the structural diagrams.

1. Ibres, J. A. and Hamilton, W. C. (Eds). Intern atioanal tables for X-ray

Crystallography Vol. 4, Kynoch Press, Birmingham, 1974.

ϭϵϳ 2. Altomare, A. Burla, M. C., Camalli, M., Cascar ano, G., Giacovazzo, C.,

Guagliardi, A., Polidori, G., J. Appl. Cryst., 1994, 27, 435.

3. Rae, A. D. Comprehensive constrained least sq uares refinement program,

University of New South Wales, 1989.

4. Johnson, C. K., ‘ORTEP-II’, Oak Ridge National Laboratory, Tennessee, U. S. A.,

1976.

A2. h1

EXPERIMENTAL DETAILS

Crystal data

Chemical formula C32H26N2O5

Mr 518.55 Crystal system, Monoclinic, C2/c space group Temperature (K) 150 a, b, c (Å) 37.882 (2), 7.0430 (4), 9.4116 (5) (°) 93.315 (3) V (Å3) 2506.9 (2) Z 4 Radiation type Mo K (mm-1) 0.09 Crystal size (mm) 0.31 × 0.23 × 0.05 Data collection Diffractometer Bruker kappa APEXII CCD Diffractometer Absorption Multi-scan correction SADABS (Bruker, 2001)

Tmin, Tmax 0.972, 0.995

ϭϵϴ No. of measured, 6951, 2156, 1552 independent and observed [I > 2 (I)] reflections

Rint 0.030 Refinement R[F2 > 2 (F2)], 0.040, 0.129, 1.09 wR(F2), S No. of reflections 2156 No. of parameters 179 No. of restraints 0 H-atom treatment H-atom parameters constrained - ȡmax, ȡmin (e Å 0.20, -0.33 3)

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS

O1 O 0.13847(4) 0.9199(2) 0.40065(15) 0.0422(5)

O2 O 0.22889(4) 0.5284(2) 0.61571(16) 0.0395(4)

O3 O 0.0000 1.2230(3) 0.2500 0.0297(5)

N1 N 0.10250(4) 0.4424(2) 0.68760(17) 0.0309(5)

H1N H 0.1014 0.3431 0.7439 0.037

C1 C 0.07398(6) 0.5458(3) 0.6338(2) 0.0286(5)

H1 H 0.0500 0.5206 0.6524 0.034

C2 C 0.08488(5) 0.6888(3) 0.5502(2) 0.0255(5)

C3 C 0.12272(5) 0.6746(3) 0.55267(19) 0.0252(5)

C4 C 0.14995(6) 0.7773(3) 0.4904(2) 0.0283(5)

C5 C 0.18468(6) 0.7268(3) 0.5184(2) 0.0303(5)

ϭϵϵ H5 H 0.2029 0.7996 0.4799 0.036

C6 C 0.19333(6) 0.5679(3) 0.6038(2) 0.0305(5)

C7 C 0.16790(6) 0.4624(3) 0.6656(2) 0.0310(5)

H7 H 0.1739 0.3554 0.7236 0.037

C8 C 0.13292(6) 0.5193(3) 0.6393(2) 0.0260(5)

C9 C 0.16378(7) 1.0551(3) 0.3601(3) 0.0491(7)

H9A H 0.1771 1.1023 0.4451 0.074

H9B H 0.1517 1.1612 0.3109 0.074

H9C H 0.1800 0.9950 0.2964 0.074

C10 C 0.23938(6) 0.3652(4) 0.6978(3) 0.0517(7)

H10A H 0.2327 0.3823 0.7961 0.078

H10B H 0.2650 0.3489 0.6967 0.078

H10C H 0.2275 0.2524 0.6570 0.078

C11 C 0.06208(5) 0.8305(3) 0.47343(19) 0.0258(5)

C12 C 0.06875(6) 1.0255(3) 0.4953(2) 0.0309(5)

H12 H 0.0874 1.0628 0.5610 0.037

C13 C 0.04898(6) 1.1637(3) 0.4243(2) 0.0315(5)

H13 H 0.0536 1.2949 0.4399 0.038

C14 C 0.02232(5) 1.1037(3) 0.3299(2) 0.0258(5)

C15 C 0.01461(5) 0.9131(3) 0.30387(19) 0.0231(5)

C16 C 0.03454(5) 0.7757(3) 0.37774(19) 0.0251(5)

H16 H 0.0294 0.6449 0.3631 0.030

O1 0.0345(10) 0.0506(10) 0.0417(9) 0.0247(8) 0.0043(8) 0.0000(8) ϮϬϬ O2 0.0260(10) 0.0477(10) 0.0445(9) 0.0114(8) -0.0020(7) 0.0012(8)

O3 0.0308(13) 0.0276(11) 0.0302(11) 0.000 -0.0028(9) 0.000

N1 0.0295(11) 0.0338(10) 0.0291(10) 0.0076(8) 0.0002(8) -0.0026(8)

C1 0.0244(13) 0.0366(12) 0.0244(11) -0.0018(9) -0.0008(9) -0.0017(10)

C2 0.0261(13) 0.0319(11) 0.0184(10) -0.0047(9) -0.0004(9) -0.0001(9)

C3 0.0281(13) 0.0295(11) 0.0178(10) -0.0012(8) 0.0007(9) -0.0016(9)

C4 0.0331(14) 0.0334(11) 0.0182(10) 0.0028(9) -0.0001(9) 0.0000(10)

C5 0.0277(14) 0.0381(12) 0.0254(11) 0.0028(9) 0.0034(10) -0.0059(10)

C6 0.0233(13) 0.0402(13) 0.0275(11) -0.0011(10) -0.0036(10) 0.0013(10)

C7 0.0324(14) 0.0309(11) 0.0292(11) 0.0060(10) -0.0034(10) 0.0002(10)

C8 0.0261(13) 0.0302(11) 0.0214(10) -0.0019(9) -0.0015(9) -0.0033(10)

C9 0.0519(17) 0.0456(15) 0.0501(15) 0.0186(12) 0.0042(13) -0.0085(13)

C10 0.0318(15) 0.0539(16) 0.0684(18) 0.0216(14) -0.0049(13) 0.0047(13)

C11 0.0257(13) 0.0319(12) 0.0198(10) -0.0010(9) 0.0024(9) 0.0004(10)

C12 0.0291(14) 0.0347(12) 0.0283(11) -0.0045(9) -0.0034(10) -0.0027(10)

C13 0.0330(14) 0.0298(12) 0.0312(11) -0.0041(10) -0.0016(10) -0.0002(10)

C14 0.0252(13) 0.0300(11) 0.0221(10) 0.0012(9) 0.0016(9) 0.0029(9)

C15 0.0217(12) 0.0284(11) 0.0196(10) -0.0004(8) 0.0040(8) 0.0001(9)

C16 0.0245(12) 0.0279(11) 0.0232(10) -0.0014(9) 0.0051(9) -0.0010(9)

SELECTED GEOMETRIC PARAMETERS

BOND LENGTHS

ϮϬϭ O1—C4 1.367 (2) C7—C8 1.393 (3) O1—C9 1.419 (3) C7—H7 0.9500 O2—C6 1.374 (3) C9—H9A 0.9800 O2—C10 1.429 (3) C9—H9B 0.9800 O3—C14i 1.383 (2) C9—H9C 0.9800 O3—C14 1.383 (2) C10—H10A 0.9800 N1—C8 1.374 (2) C10—H10B 0.9800 N1—C1 1.375 (3) C10—H10C 0.9800 N1—H1N 0.8800 C11—C16 1.393 (3) C1—C2 1.357 (3) C11—C12 1.409 (3) C1—H1 0.9500 C12—C13 1.377 (3) C2—C3 1.436 (3) C12—H12 0.9500 C2—C11 1.481 (3) C13—C14 1.373 (3) C3—C8 1.405 (3) C13—H13 0.9500 C3—C4 1.414 (3) C14—C15 1.392 (3) C4—C5 1.374 (3) C15—C16 1.389 (3) C5—C6 1.405 (3) C15—C15i 1.457 (4) C5—H5 0.9500 C16—H16 0.9500 C6—C7 1.373 (3) BOND ANGLES C4—O1—C9 117.59 (18) O1—C9—H9A 109.5 C6—O2—C10 116.60 (17) O1—C9—H9B 109.5 C14i—O3—C14 105.2 (2) H9A—C9—H9B 109.5 C8—N1—C1 109.00 (17) O1—C9—H9C 109.5 C8—N1—H1N 125.5 H9A—C9—H9C 109.5 C1—N1—H1N 125.5 H9B—C9—H9C 109.5 C2—C1—N1 110.35 (19) O2—C10—H10A 109.5 C2—C1—H1 124.8 O2—C10—H10B 109.5 N1—C1—H1 124.8 H10A—C10— 109.5 H10B

ϮϬϮ C1—C2—C3 106.02 (18) O2—C10—H10C 109.5 C1—C2—C11 126.51 (19) H10A—C10— 109.5 H10C C3—C2—C11 127.47 (17) H10B—C10— 109.5 H10C C8—C3—C4 117.12 (19) C16—C11—C12 119.08 (19) C8—C3—C2 107.72 (17) C16—C11—C2 121.50 (18) C4—C3—C2 135.16 (19) C12—C11—C2 119.41 (19) O1—C4—C5 125.16 (18) C13—C12—C11 122.0 (2) O1—C4—C3 114.72 (19) C13—C12—H12 119.0 C5—C4—C3 120.08 (19) C11—C12—H12 119.0 C4—C5—C6 120.35 (19) C14—C13—C12 117.1 (2) C4—C5—H5 119.8 C14—C13—H13 121.5 C6—C5—H5 119.8 C12—C13—H13 121.5 C7—C6—O2 124.39 (19) C13—C14—O3 124.63 (18) C7—C6—C5 121.8 (2) C13—C14—C15 123.35 (19) O2—C6—C5 113.78 (18) O3—C14—C15 112.02 (18) C6—C7—C8 116.92 (19) C16—C15—C14 118.78 (19) C6—C7—H7 121.5 C16—C15—C15i 135.83 (12) C8—C7—H7 121.5 C14—C15—C15i 105.39 (12) N1—C8—C7 129.43 (19) C15—C16—C11 119.69 (18) N1—C8—C3 106.91 (18) C15—C16—H16 120.2 C7—C8—C3 123.66 (18) C11—C16—H16 120.2

ϮϬϯ CHAPTER 10

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