Synthesis of Novel Bis-Indole Systems

SYNTHESIS OF NOVEL BIS-INDOLE SYSTEMS

This thesis is submitted in fulfilment of the degree of

DOCTOR OF PHILOSOPHY

HAKAN KANDEMIR

Supervisors

Prof. David StC. Black A/Prof. Naresh Kumar

School of Chemistry The University of New South Wales Kensington, Australia August, 2011

CERTIFICATE OF ORIGINALITY

I hereby declare that this submission is my own work and that, to the best of my knowledge and belief, it contains no material previously published or written by another person, nor material which to a substantial extent has been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis.

I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project’s design and conception or in style, presentation and linguistic expression is acknowledged.

Signed………………………………………

Date ...…………………………………….

ABSTRACT

The primary aim of this project was to synthesize novel 2,2- and 7,7-linked bis- indole systems from methoxy activated indoles, and investigate their ability to undergo electrophilic substitution reactions at C7 and C2 respectively. As an integral part of achieving this aim, the development of a new series of methoxy activated indole precursors was investigated.

The construction of hydrazine bridged 2,2- and 7,7-linked bis-indoles was achieved from 2- and 7-glyoxylchlorides and 2- and 7- trichloroacetylindoles respectively. An efficient method was developed for the preparation of 7,7-bis-indoles containing an oxadiazole derived spacer unit via the cyclodehydration of 7,7- hydrazide linked bis- indoles. The preparation of a series of monomeric 1,3,4-thiadiazoles was also successfully achieved via the cyclodehydration of 2- and 7-thiosemicarbazides. Some of these 7,7-hydrazine bridged bis-indoles showed promising antibacterial activity against both Gram positive and Gram negative bacteria. Based on these interesting biological results, some novel 7-carbohydrazides and 7-carboxamides were prepared in order to determine the effect of other substituents at the C7 position.

A 7-aminomethylindole was synthesised by the reduction of the corresponding 7- cyanoindole and used as a functional precursor to prepare a range of 7,7-bis-indoles Also, the reduction of 7-nitroethyl indoles led to the formation of 7-tryptamine analogues. These were used to generate amide and imine linked 7,7-bis-indoles and for the construction of imine linked macrocycles, which were subsequently reduced to the corresponding amine linked macrocycles.

7-Bromoindoles are key intermediates for the synthesis of biindolyl systems. However, all attempts to synthesize 7-bromoindoles failed, but interestingly led to the generation of unexpected compounds such as 4,6-dimethoxybenzotriazole. This led to the subsequent investigation of the C7 reactivity of this system by exploring reactions such as formylation, acylation and acid catalysed dimerization.

The synthesis of 7-oxotryptamines was accomplished via hydrogenation of the corresponding 7-acyl cyanides. 7-Oxotryptamines were subsequently reacted with 7- trichloroacetyindoles to form amide linked bis-indoles, which were converted to the oxazole linked bis-indoles. Some monomeric 7-methyloxazoles were also prepared ii from the 7-keto amides via cyclodehydration. However, the synthesis of 7-hydroxy tryptamine was unsuccessful and led to the formation of a dimer and an alcohol.

iii

ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to my supervisors, Prof. David Black and A/Prof. Naresh Kumar for giving me the opportunity to work on indole chemistry and I thank them for all the help, valuable advice and guidance, many helpful suggestions and ideas they have given me over the course of the project. I was impressed by their extensive knowledge in organic chemistry and their ability to overcome problems related to experiments. I was never surprised to leave David’s office with several ideas regarding my ongoing and future experiments.

My thanks also go to both past and present members of the Black and Kumar group. I feel fortunate to have worked with all these people. It was a pleasure for me to work with past members Alam, Daniel, Frank and Taj, and present members from lab 336: George, Rick, Samuel, Kitty, Ren, Chris, Nicholas and Mike, from lab 333: Abel, Ibrahim, Murat, Kasey, Santosh and Nidup, and from lab 266: Ruth, Ray, Venty, Adeline and Elenor.

Obviously, some of these people deserve my special thanks. Thanks to Dr. George Iskander for his suggestions related to my experiments, Rick for all his practical help, Ruth and especially Kasey for all their assistance in writing and proof reading this thesis.

I also wish to thank the faculty members in the School of Chemistry, especially the professional staff, namely, Jim Hook, Donald Thomas, Adelle Moore from the NMR facility and Mohan Bhadbhade from the X-ray crystallography unit.

I am thankful to my housemates in Sydney during the last three years for their friendship and support. Thanks to Ibrahim, Murat, Emrullah, Sefer, Sinan, Cemal and Gokhan.

I am extremely grateful to my family, who have been so dear to me. I owe my thanks to my parents, my sisters Yıldız and Filiz, my brother Mehmet, my brothers in law Mehmet and Hakan, my sister in law Filiz, my nephew and nieces Betül, Selin, Irem, Halit, Yigit, Emir, Zeynep and Ecrin and my fiance Hacer for their love, constant

iv support and moral encouragement. I also thank all my relatives and friends for their good wishes for my success.

Finally, I am grateful to thank the Ministry of Education of Turkey for my scholarship.

TABLE OF CONTENTS

Certificate of originality...... i

Abstract...... ii

Acknowledgements...... iv

Table of contents...... vi

CHAPTER I: INTRODUCTION

1.1. Background...... 1 1.2. Indole Chemistry...... 2 1.3. Bis-indoles...... 4 1.4. Synthetic strategies towards bis-indoles...... 6 1.5. Thesis aims...... 11

CHAPTER II: SYNTHESIS OF BIS-INDOLES WITH HYDRAZIDE BRIDGES

2.1. Introduction...... 13

2.2. Synthesis of hydrazide bridged bis-indoles...... 14

2.3. Synthesis of 7-carbohydrazides...... 20

2.4. Synthesis of indole-7-carbaldehydes...... 23

2.5. Biological screening of bis-indoles...... 28

2.6. Conclusions...... 30

CHAPTER III: SYNTHESIS OF 7,7′-BIS-INDOLYL-1,3,4-OXADIAZOLES AND INDOLYL-1,3,4-THIADIAZOLES

3.1. Introduction...... 31

3.2. Synthesis of 7,7-bis-indolyl-1,3,4-oxadiazoles...... 32

3.3. Synthesis of indolyl-1,3,4-oxothiadiazoles...... 37

3.4. Conclusions...... 40

CHAPTER IV: SYNTHESIS OF 7-AMINOMETHYLINDOLE AND RELATED BIS-INDOLE DERIVATIVES

4.1. Introduction...... 41

4.2. Synthesis of 7-aminomethylindole...... 42

4.3. Synthesis of bis-indoles...... 45

4.4. Conclusions...... 48

CHAPTER V: SYNTHESIS OF 7,7′-BIS-INDOLES VIA 7-TRYPTAMINE ANALOGUES

5.1. Introduction...... 49

5.2. Synthesis of 7-tryptamine analogues...... 50

5.3. Synthesis of bis-indoles...... 53

5.4. Synthesis of macrocyclic structures...... 58

5.5. Conclusions...... 66

vii

CHAPTER VI: STRATEGIES TOWARDS 7-BROMO-4,6- DIMETHOXYINDOLE AND REACTIVITY OF 4,6- DIMETHOXYBENZOTRIAZOLE

6.1. Introduction...... 67

6.2. Attempted synthesis of 7-bromoindole via direct bromination...... 69

6.3. Attempted synthesis of 7-aminoindole...... 72

6.4. Attempted synthesis of 2-bromoaniline via diazotization...... 76

6.5. Reactivity of 4,6-dimethoxy-1,2,3-benzotriazole...... 78

6.5.1. Synthesis of 4,6-dimethoxy-1,2,3-benzotriazole...... 78

6.5.2. Attempted formylation of 4,6-dimethoxybenzotriazole...... 79

6.5.3. Attempted acylation of 4,6-dimethoxybenzotriazole...... 79

6.5.4. Attempted synthesis of 7,7-bisbenzotriazolemethanes...... 81

6.5.5. Cyclization of benzotriazole...... 82

6.6. Conclusion...... 84

CHAPTER VII: SYNTHESIS OF 7,7ʹ-BIS-INDOLE ANALOGUES FROM 7- OXOTRYPTAMINE ANALOGUES

7.1. Introduction...... 85

7.2. Synthesis of oxotryptamine...... 86

7.3. Synthesis of 7-oxotryptamines...... 87

7.4. Synthesis of monomeric 7-indole oxazoles...... 90

7.5. Synthesis of bis-indoles...... 91

7.6. Attempt to synthesize 7-hydroxytryptamine...... 94

7.7. Conclusions...... 97

viii

CHAPTER VIII: EXPERIMENTAL

8.1. General Information...... 98

8.2. Experimental Details...... 99

CHAPTER IX: REFERENCES...... 166

APPENDIX: X-ray crystallography data...... 171

CHAPTER I

INTRODUCTION

1.1. Background

The indole or 2,3-benzopyrrole nucleus has been subjected to intense study over the last fourteen decades. The indoles are a class of heterocyclic compounds, widely found in nature, whose derivatives therefore have a strong link to natural products. These natural indolic compounds and their synthetic analogues show a wide range of biological activities. For example, the simple indole amino acid L-tryptophan 1 is necessary in the human diet1 and the complex indole antipsychotic reserpine 2 has been used for the treatment of hypertension and mental disorders2.

The potent biological properties of indole derivatives containing electron donating methoxy groups in the benzenoid ring has led to research into their use as medicinal drugs. Such clinically proven indole compounds include the anti-inflammatory agent indomethacine 3 for the gastrointestinal tract3 and the tranquilizer oxypertine 4 which is an anti-hypertensive drug.4

1.2. Indole Chemistry

The preferred site of electrophilic substitution for indole 5 is the C3 position. The blocking of this position, as in 3-substituted indoles 6, directs the electrophilic substitution to the C2 position. Indoles 7 which are activated by the presence of electron donating methoxy groups at C4 and C6 are capable of undergoing reactions at the C7 position. Consequently, 3-substituted 4,6-dimethoxyindoles 8 undergo electrophilic substitution at both the C2 and C7 positions (Figure 1-1). In addition to increasing the reactivity of C7, the methoxy groups have also been found to augment the general activity of indoles.5

Figure 1-1.

4,6-Dimethoxyindoles 9 therefore enable a range of reactions such as formylation6 and halogenation7 to be performed at C7, generating compounds such as 10 and 11 respectively (Scheme 1-1). These intermediates can then be readily converted into other functional groups such as the nitrile compound 128. This capacity enables ready entry to innovative bis-indoles such as structure 139 and macrocyclic indoles like 146, with links between C2 and C7. Macrocycles such as imine 15 can also be generated and further used for the formation of metal complexes 16.10-12 Moreover, new annulated indoles such as compound 1713 are formed by linking C7 and N1.

Scheme 1-1.

Synthetic routes to 2,3-disubstituted and 3-monosubstituted indoles bearing methoxy groups at the C4 and C6 positions have been established by our group via a modified Bischler indole synthesis. For example, 2,3-diphenylindole 21 was prepared by heating the commercially available 3,5-dimethoxyaniline 18 and benzoin 19 as a melt to form the intermediate aniline ketone 20 which was then cyclised using glacial acetic acid in the presence of an equivalent of aniline (Scheme 1-2).14

Scheme 1-2. Reagents and conditions: aniline, AcOH, reflux

Similarly, the preparation of 3-substituted indole derivatives 26 was achieved via condensation of 3,5-dimethoxyaniline 18 and halogenated ketones 22 in the presence of sodium bicarbonate in ethanol to give anilino ketones 23, which were subsequently protected with acetic anhydride to give N-acetyl derivatives 24. Cyclisation in trifluoroacetic acid gave the N-acetylindoles 25, which were then deprotected in methanolic potassium hydroxide to afford the target 3-substituted 4,6- dimethoxyindoles 26 (Scheme 1-3).15-17

Scheme 1-3. Reagents and conditions: a) NaHCO3, ethanol, reflux; b) Ac2O; c) TFA, reflux; d) KOH, methanol

1.3. Bis-indoles

More complex indoles, such as bis-indoles are very important biologically active scaffolds as they are found in many pharmacologically active alkaloids. For example, bis-indole alkaloids such as nortopsentin derivatives 27 containing an imidazole linker and topsentin derivates 28 which have a keto-imidazole moiety, are deep-sea sponge metabolites that possess antitumor, antiviral and anti-inflammatory activities.18,19

The simple bis-indole 29, isolated from cruciferous plants, is another example of a bioactive bis-indole compound having a strong effect on the proliferation and induction of apoptosis in human prostate and breast cancer cells.20

Bis-indoles may also be used as acyclic or macrocyclic chelating ligand precursors 10,11 and serve as highly active and efficient metal complex catalysts for organic reactions. Recently, Black et al. have developed the manganese complex 30 as an excellent catalyst for alkene epoxidation.12

A particular group of bis-indole systems is the biindolyls. This group of bis-indoles contains C-N or C-C bonds between two indole units. To date, twenty-eight structural isomers have been reported, seven of which contain a C-N linkage while the rest possess a C-C linkage.21 Biindolyls have a recurring prominence in nature, with the best known example being the dye indigo 31. Another example is 8.8- biskoenigii 32, isolated from Murraya Koenigii22, which has been identified as a pharmacophore in a drug discovery program.23 7,7-Biindolyls could also play an important role in asymmetric catalysis because of their structural similarity to BINAP.24

Given the various potential applications of bis-indoles, it is important to develop new classes of natural and unnatural bis-indole derivatives. This development can be greatly facilitated by the use of activated indoles which are capable of undergoing reaction at the otherwise unreactive C7 position.

1.4. Synthetic strategies towards bis-indoles

For the construction of bis-indoles two basic strategies have been used. The first strategy involves the formation of symmetrical bis-indoles by joining the indole scaffolds utilizing a bifunctional linker such as oxalyl chloride.

Figure 1-2.

Examples related to the first strategy can be found in the literature. In order to prepare large-ring bis-indolic dilactams from a precursor such as 34, the reaction of tryptamine 33 with bis-acid chlorides was carried out in tetrahydrofuran at room temperature (Scheme 1-4).25

Scheme 1-4. Reagents and conditions: sebacoyl chloride, THF, rt

In addition, preparation of bis-indoles via the first strategy was also achieved by our group. For example, the acid chloride 35 can be easily converted to the corresponding acid, ester or amide derivatives 36 by the treatment with water, or the desired alcohols or amines.

Scheme 1-5.

In this fashion, use of a disubstituted amine can afford amide linked bis-indoles. For example, the ethylene bridged bis-glyoxylamide 36 was prepared during a study into the self-assembly of indolylglyoxylamides,9 by treatment of acid chloride 35 with ethylene diamine in diethyl ether (Scheme 1-6).

Scheme 1-6. Reagents and conditions: ethylenediamine, (C2H5)2O, rt

The trichloromethyl group is an excellent leaving group and consequently 2- and 7- trichloroacetyl indoles can smoothly react with amines or alcohols under mild

8 conditions to give the corresponding 2- or 7- amide or ester derivatives such as 38 and 39.

This methodology can be extended for the preparation of bis-indoles. For example, the synthesis of bis-indoles 42 and 43 was achieved by the reaction of acid chlorides 40 and 41 with 1,2-diaminoethane and 1,2-diaminopropane respectively in anhydrous acetonitrile (Scheme 1-7).9

Scheme 1-7. Reagents and conditions: 1,2-diaminoethane or 1,2-diaminopropane,

CH3CN, rt

The second strategy was to gather two different indole units, which have different functionalisation, under suitable reaction conditions to form unsymmetrical bis- indoles. In this strategy, various linkers such as amide, imine, amine, hydrazide, and related cyclic systems e.g. oxadiazole or oxazole have been utilized and various bis- indoles have been synthesized.

Figure 1-3.

For example, heating oxotryptamine 44 with indole glyoxylamide 45 in the presence of methanesulfonic acid at 130 ºC for 3 days in chlorobenzene afforded 3,6-bis (indol-3-yl)-2(1H)-pyrazinone 46 in 30% yield (Scheme 1-8).26

Scheme 1-8. Reagents and conditions: CH3SO3H, chlorobenzene, 130 ºC, 3 d

Another example using the second strategy was formation of a 7,7-bis-indole 48 prepared by Black et al. Accordingly, diphenylindole 21 was heated with indole-7- glyoxylchloride 47 at reflux in the presence of graphite powder in ethylene chloride to give the symmetrical product 48 (Scheme 1-9).27

Scheme 1-9. Reagents and conditions: ethylene chloride, graphite powder, reflux

1.5. Thesis Aims

The central aim of the project described in this thesis was to develop novel bis-indole systems based on the methoxy activated indoles. In particular, the synthesis of 2,3- disubstituted and 3-substituted 7,7-linked bis-indoles using different linkages was examined. 3-Substituted 7,7-bis-indoles have a nucleophilic C2 position for further substitutions. This chemistry was also extended to the C2 position, with the corresponding 3-substituted 2,2-bis-indoles, which are nucleophilic at C7 (Figure 1- 4).

MeO R R N H MeO linkage OMe N N linkage Reactive H H C2 positon

H N Reactive C7 positon MeO

Figure 1-4.

As an integral part of achieving this aim, the development of a new series of indole precursors was explored. Finally, some of the new compounds generated throughout this project were screened for biological activity.

Accordingly, Chapter 2 of this thesis describes the construction of hydrazine bridged bis-indoles and the biological results of the screened compounds. Hydrazine bridged bis-indoles were subsequently used as precursors to develop new 1,3,4-oxadiazoles described in Chapter 3. Chapter 4 discusses the preparation of systems based upon 7- aminomethylindoles while Chapter 5 describes the development of 7-tryptamines and related bis-indoles. Chapter 6 discloses an exploratory investigation into the use of 7- bromoindole in the generation of new 7,7-biindolyl systems. In Chapter 7 the preparation of new activated 7-oxotryptamines and related bis-indoles is presented.

CHAPTER II

SYNTHESIS OF BIS-INDOLES WITH HYRAZIDE BRIDGES

2.1. Introduction

In general it has been shown that amides have a high propensity to form hydrogen bonds. When these hydrogen bonds are formed intramolecularly, they can confer greater stability and rigidity to the system.28-30 This has been noted in the case of the indol-2-glyoxylamide moiety 49, where it was found that the formation of six and five membered rings, through hydrogen-bonding, conferred rigidity without the necessity of synthesising a covalent ring system.31

Figure 2-1.

In order to take advantage of the tendency for amide bonds to provide novel structural rigidity, hydrazine hydrate was chosen as a linker. Not only are reactions with hydrazine hydrate simple, clean and in general high yielding, they offer the option to form bis-indoles in a single step. Alternatively, the initially formed 7- carbonylhydrazide can be further reacted with a variety of electrophiles to form a range of bis-indole systems.

2.2. Synthesis of hyrazide bridged bis-indoles

The reaction of 4,6-dimethoxyindoles 50 with oxalyl chloride yields a mixture of the 2- and 7- substituted indolylglyoxyloyl chlorides 51 and 52 (Scheme 2-1). The preference of solvent dramatically affected the ratio of these acid chlorides. The use of dichloromethane or tetrahydrofuran gives a 70:30 ratio of 7-isomer to 2-isomer while the use of diethyl ether produces a 30:70 mixture in which the 2- glyoxyloylchloride precipitates out and 7-glyoxyloyl chloride remains in solution.32

R1 R1 R1

OMe OMe OMe O R2 + R2 MeO N MeO N Cl MeO N H H H O O O 50R1 = H, Me, Cl, Br, OMe 51 Cl R2 = H, Ph, 4-OMeC6H4 52

Scheme 2-1. Reagents and conditions: oxalyl chloride, (C2H5)2O, rt

The reaction of 2- and 7-glyoxyloyl chlorides 51 and 52 with hydrazine hydrate was subsequently investigated. Indolylglyoxyl chlorides react readily with water, alcohols and amines to give glyoxylic acids, esters and amides respectively. They undergo a similar reaction with hydrazine hydrate to produce bis(indolylglyoxyloyl)hyrazide systems such as compound 56, which was formed during an investigation into the synthesis of double cone calix[3]indoles (Scheme 2-2). The compound 56 was prepared by reacting one equivalent of hydrazine hydrate with two equivalents of acid chloride 53 in tetrahydrofuran at room temperature overnight.33 With a slight modification of this method, the orange bis(indolylglyoxyloyl)hyrazides 57 and 58 were synthesized in excellent yield by reacting the acid chlorides 54 and 55 with half an equivalent of hydrazine hydrate in the presence of triethylamine in acetonitrile at room temperature. Triethylamine served as the catalyst and led to completion of the reaction in an hour.

Scheme 2-2. Reagent and conditions: NH2NH2.H2O, Et3N, CH3CN, rt

Similarly, the reaction of 7-acid chlorides 47, 59 and 60 with half an equivalent of hydrazine hydrate produced the 7,7-bis(indolylglyoxyloyl)hyrazides 61-63 in excellent yields of 76-100% (Scheme 2-3). In contrast to the orange colour of 2,2- bis-indoles 56-58, the 7,7-bis-indoles 61-63 were yellow in colour.

Scheme 2-3. Reagent and conditions: NH2NH2.H2O, Et3N, CH3CN, rt

The characteristic peak of all these symmetrical 2,2- and 7,7- bis(indolylglyoxyloyl)hyrazides in the 1H NMR spectrum was a broad singlet integrating for 2H at ~10 ppm indicating the presence of the hydrazine NH groups. The 1H NMR spectrum of the compound 61, as an example, displayed two singlets at 3.83 ppm and 4.02 ppm corresponding to the two methoxy groups. The H5 resonance appeared at 6.49 ppm and the aromatic protons of phenyl rings appeared as multiplets at 7.28-7.32 ppm. The NH protons were found significantly downfield due to hydrogen-bonding to carbonyl groups, with the NH of the hydrazide appearing at 10.64 ppm, and the indole NH appearing at 11.01 ppm. The 13C NMR spectrum also indicated carbonyl resonances at 166.81 ppm and 188.53 ppm. A high resolution mass spectrum provided further confirmation of the structure with a molecular ion peak at 821.2555 (M+Na)+.

The synthesis of 7-oxoacetohydrazides 64-66 was subsequently examined because they could serve as key intermediate building blocks in the preparation of unsymmetrical 7,7-bis(indolyloxoacetyl)hydrazines. When one equivalent of hydrazine hydrate was added to one equivalent of 7-glyoxyloyl chlorides 47, 59 and 60, mixtures of 7,7-bis(indolylglyoxyloyl)hyrazides 61-63 and 7- oxoacetohydrazides 64-66 were obtained. Unfortunately, 7-oxoacetohydrazides 64- 66 could not be isolated from the reaction mixture via column chromatography either because of very close Rf values to those of bis-indoles 61-63, or because they could not be removed from the silica gel (Scheme 2-4).

Scheme 2-4. Reagent and conditions: NH2NH2.H2O, Et3N, CH3CN, rt

In order to comprehensively evaluate the biological activity of bis(indolylglyoxyloyl)hyrazides 61-63 (discussed further in section 2.5), the synthesis of 2,3-diphenyl-3,4,5-trimethoxy-7,7-bis(indolylglyoxyloyl)hyrazide 71 and some mono indole 7-glyoxylamides were subsequently investigated.

The synthesis of the 2,3-diphenyl 3,4,5-trimethoxyindole 69 has been reported by Charrier.34 The preparation of intermediate benzyl arylamine 68 was accomplished by the condensation of 3,4,5-trimethoxyaniline 67 with benzil 19 in the presence of acetic acid in ethanol at reflux. Indole 69 was subsequently synthesized upon reaction of benzyl arylamine with phosphorus pentasulfide in toluene (Scheme 2-5).

Scheme 2-5. Reagent and conditions: a) AcOH, ethanol, reflux; b) P4S10, toluene, reflux

In this instance, however, indole 69 was synthesized via the more familiar Bischler synthesis discussed in Chapter 1 by the treatment of 3,4,5-trimethoxyaniline 67 with benzoin 19. Indole 7-glyoxyloyl chloride 70 was subsequently prepared by the treatment of indole 69 with oxalyl chloride in tetrahydrofuran (Scheme 2-6).

Scheme 2-6. Reagent and conditions: a) AcOH, reflux; b) oxalyl chloride, THF, rt

Addition of one equivalent of hydrazine hydrate to two equivalents of acid chloride 70 in acetonitrile readily afforded the target 7,7-bis(indolylglyoxyloyl)hyrazide 71 in 83% yield (Scheme 2-7).

Scheme 2-7. Reagent and conditions: NH2NH2.H2O, Et3N, CH3CN, rt

The preparation of esters and amides from 7-glyoxyloyl chlorides 52 has been previously reported by our group.9 This protocol was extended to the preparation of 7-glyoxylamides 72-75 and 7-hydrazides 76 and 77. Treatment of 7-glyoxylchlorides 35 and 59 with aniline or p-toluidine at room temperature in diethyl ether produced 7-glyoxylamides 72-75 in 27-41% yields (Scheme 2-8).

Scheme 2-8. Reagent and conditions: aniline or p-toluidine, Et3N, (C2H5)2O, rt

Similarly, the reaction of 7-glyoxylchlorides 35 and 59 with an excess of phenylhydrazine in diethyl ether in the presence of triethylamine resulted in the formation of 7-hydrazides 76 and 77 in 30% and 31% yield respectively (Scheme 2- 9).

Scheme 2-9. Reagent and conditions: phenylhydrazine, Et3N, (C2H5)2O, rt

Interestingly, the 1H NMR spectra of analogues 76 and 77 indicated that these compounds were present as a mixture of two rotamers as shown in Figure 2-2. It was postulated that two strong intermolecular hydrogen bonding structures were formed relating to the formation of a six or five membered ring about the hydrazine moiety as shown in Figure 2-2. Indole 7-hydrazide 77, as an example, showed two indole NH doublets at 11.55 ppm and 11.47 ppm which is suggestive of strong hydrogen bonding with carbonyl groups. Moreover, the chemical shift of the amide nitrogen at 10.64 ppm was also indicative of another hydrogen bond with a carbonyl group.

Figure 2-2.

The high resolution mass spectrum provided further structure confirmation with a molecular ion at 450.1212 being consistent with compound 76 and an m/z of 494.071 being consistent with indole 77.

2.3. Synthesis of 7-carbohydrazides

Indole 78 can also react with trichloroacetyl chloride in chloroform without a catalyst to give 2- and 7-trichloracetylindoles 40 and 41 in a ratio of 1:4. However, when the reaction was carried out in dichloroethane, the ratio of the 7-isomer compared to 2- isomer increased to 18:1.9,35

Scheme 2-10. Reagents and conditions: CCl3COCl, chloroform or dichloroethane, reflux

Recently, an extension of this study was performed by Wood,13 in which the use of dichloroethane as solvent was also found to produce a trace amount of a third product identified as the N-trichloroacetylindole analogue. Moreover, extension of the reaction time was found to produce a fourth product thought to be the 2,7- disubstituted compound. However, the 7-isomer and the 2-isomer respectively were the major products in both situations.

Following this, the readily available 2- and 7-trichloroacetylindoles 40 and 79, and 41, 82 and 83 were reacted with hydrazine hydrate to yield either 2,2- and 7,7-bis- indole carbohydrazides 80 and 81, and 84-86 or 7-carbohydrazides 87-89. The products of these reactions were found to be dependent upon the relative amount of hydrazine hydrate used.

2-Trichloroacetylindoles 40 and 79 were heated at reflux for 24 hours with half an equivalent of hydrazine hydrate in the presence of triethylamine in acetonitrile to afford the 2,2-bis-indoles 80 and 81 in 55% and 51% yield respectively.

Scheme 2-11. Reagent and conditions: NH2NH2.H2O, Et3N, CH3CN, reflux, 24 h

Similarly, the synthesis of 7,7-bis-indole carbohydrazides 84-86 was achieved in 49- 81% yield by the treatment of two equivalents of 7-trichloroacetylindoles 41, 82 and 83 with one equivalent of hydrazine hydrate in acetonitrile (Scheme 2-12).

Scheme 2-12. Reagent and conditions: NH2NH2.H2O, Et3N, CH3CN, reflux

High resolution mass spectra of the compounds 84-86 revealed molecular ions at 681.1273 (35Cl), 769.0265 (79Br) and 742.2782 respectively. The 1H NMR spectra of compounds 84 and 85 showed characteristic H5 peaks at 6.28 ppm and 6.56 ppm respectively. The characteristic amide NH peak appeared at ~10.5 ppm while the indole NH resonated at ~11.5 ppm. The appearance of NH protons at a significantly downfield chemical shift indicated a strong hydrogen bonding between the carbonyl groups and NH protons.

Treatment of 7-trichloroacetylindole 41 with a twofold or more excess of hydrazine hydrate afforded a mixture of 7,7-bis-indole 84 and 7-carbohydrazides 87. The successful preparation of 7-carbohydrazides 87-89 contrasts with the difficulties encountered in the synthesis of the corresponding 7-oxoacetohydrazide analogues 64-66. Presumably, hydrazine hydrate served as catalyst in this particular situation as it was a strong base as well as a reagent and enabled the generation of 7,7-bis-indole carbohydrazide 84 as a second product.

On the other hand, the reaction of indole 7-trichloroacetylindoles 41, 82 and 83 with one or one and an half equivalents of hydrazine hydrate in the presence of triethylamine in acetonitrile at room temperature afforded the monomeric 7- carbohydrazides 87-89 in high yields as the only products (Scheme 2-13).

Scheme 2-13. Reagent and conditions: NH2NH2.H2O, Et3N, CH3CN, rt

Clear evidence of the formation of 7-carbohydrazide 88 was found in the 1H NMR spectrum which demonstrated the appearance of an amide NH at 9.05 ppm. The indole NH shifted further downfield to 11.07 ppm, indicating a strong hydrogen bond between the carbonyl group and the indole NH. In addition, the structure was further confirmed by a high resolution mass spectrum which showed a molecular ion at 79 412.0267 corresponding to C17H16 BrN3O3Na.

2.4. Synthesis of indole-7-carbaldehydes

Vilsmeier formylation of 3-substituted 4,6-dimethoxyindoles 8 occurs at the C2 and C7 positions depending upon the nature of the C3 substituent. In general, the degree of C2 substitution increases in accordance with the electron donating capacity of the substituent. Indoles 50 typically generate the 7-carbaldehydes 90 in the presence of one equivalent of Vilsmeier reagent while using an excess amount results in the formation of 2,7-diformylated products 91 (Scheme 2-14).6

Scheme 2-14. Reagents and conditions: a) POCl3, DMF 0 ºC; b) POCl3 (excess), DMF, rt

Aldehydes are well known precursors to imines through condensation with amines. Furthermore, condensation of 7-indolecarbaldehydes with amines is an established method of producing 7,7-imine linked bis-indole compounds such as 92 which are generally utilized to build indole-based macrocycles and ligand systems. Previously, the general method for the preparation of the imines was the Dean-Stark method which involves the treatment of an aldehyde with an amine in refluxing toluene in the presence of molecular sieves. However, this method was found to be rather tiresome and chromatography was essential to isolate the product.10-12,31,36

Scheme 2-15. Reagents and conditions: a) ethylene diamine, toluene, reflux

Recently, it was discovered that the replacement of toluene with slightly acidic solvents such as alcohols removed the requirement of Dean-Stark apparatus. In particular, the use of ethanol or isopropanol as a solvent resulted in the product precipitating from the solution without the requirement of further purification.37

7-Carbohydrazides 87-89 served as key building blocks in the preparation of a range of novel bis-indoles. For instance, the acid catalysed reaction of 7-carbohydrazides 87-89 with the readily available 7-aldehydes 93-95 was performed in ethanol to generate imine linked 7,7-bis-indoles 96-98 upon filtration (Scheme 2-16).

Scheme 2-16. Reagent and conditions: absolute ethanol, reflux

The compounds 96-98 were fully characterized, for example, the high resolution mass spectroscopy of indole 96 showing a molecular ion at 665.1324 which was consistent with the structure 96 (M+Na)+. The acquisition of 13C NMR spectra proved to be problematic due to the insolubility of these compounds in common organic solvents.

Preparation of the related symmetrical 7,7-bis-glyoxylylhydrazides 99-101 which possess an extended linker was subsequently examined. The reaction was carried out by addition of oxalyl chloride to 7-carbohydrazide 87-89 in dichloromethane at room temperature. Heating the crude products in methanol or ethanol for 30 minutes gave analytically pure compounds. (Scheme 2-17).

Scheme 2-17. Reagent and conditions: oxalyl chloride, Et3N, DCM, rt

The melting points of the compounds 99-101 were found to be very high, exceeding 300 ºC. Also, the characteristic hydrazine NH signals were present in the 1H NMR spectrum at ~9.8 ppm and ~10.8 ppm while the 13C NMR spectra showed the carbonyl peaks of the compounds 99-101 at ~159 ppm and ~166 ppm. Moreover, the elemental analysis and the high resolution mass spectroscopy also confirmed the structures of these compounds.

Based upon the biological screening results of 7,7-bis-indole carbohydrazides 84-86 (discussed further in section 2.5) some novel N-phenyl-7-carbohydrazides and 7- carboxamides were subsequently targeted as second generation analogues.

Black et al. have successfully synthesized N-phenyl-7-carboxamide 102 via the treatment of 7-trichloroacetylindole 41 with aniline in the presence of triethylamine under reflux in acetonitrile. The reaction mixture was then acidified and the resulting precipitate filtered. However, this led to a low yield of ~24% of the 7-carboxamide 102.9 The preparation of the target 7-carboxamides 102-105 was achieved in a 26 similar manner (Scheme 2-18). Evaporation of the solvent and redissolution of the product in diethyl ether before filtration of the resulting solid was found to improve the yields to 51-60%. Interestingly, the bromophenyl compounds 104 and 105 were found to be less soluble in organic solvents with respect to chlorophenyl compounds 102 and 103. Moreover, while the 1H NMR spectrum showed the characteristic NH proton signals at 9.55 ppm for compounds 104 and 105, they appeared at 10.05 ppm for compounds 102 and 103. The high resolution mass spectra of compounds 103- 105 were consistent with their structures.

Scheme 2-18. Reagent and conditions: aniline or p-toluidine, Et3N, CH3CN, rt

The synthesis of the related indole 7-carbohydrazide 106 has also been previously described by Black et al.38 Compound 106 and the corresponding bromo analogue 107 were obtained in satisfactory yields upon treatment of indole 41 and 82 with phenylhydrazine in the presence of triethylamine in acetonitrile and workup as optimised above (Scheme 2-19).

R R

OMe OMe

MeO N MeO N H H

Cl3C O HN O NH

41 R = Cl 106 R = Cl 52% 82 R = Br 107 R = Br 61%

Scheme 2-19. Reagent and conditions: phenylhydrazine, Et3N, CH3CN, rt

2.5. Biological screening of bis-indoles

It is well known that the enzyme RNA polymerase (RNAP) transcribes DNA into RNA in a highly regulated process that is controlled through association with appropriate transcription factors. Transcription can be broadly divided into initiation, elongation and termination, and transcription factors possess assigned functional activity to the stage they control. Sigma factors are bacterial transcription initiation factors, unique to bacteria and hence represent an ideal target for the development of new chemical moieties that disrupt essential protein-protein interactions.

Bacterial and eukaryotic RNAPs both contain a remarkably well conserved structural motif called the CH region which is the major site for interaction with initiation factors (sigma factor in prokaryotes and TFIIB in eukaryotes). Although RNAP from all kingdoms has a similar structure, the initiation factor binding sites are completely different, thus suggesting specific targeting of the sigma factor interaction site will result in compounds with specific antibacterial action.

As part of an on-going project, our research group has constructed a preliminary structure-based pharmacophore which classifies the crucial interactions in the CH region. In silico screening of the Mini-Maybridge database identified the hit compounds GK02098 and HTS05234 which contain structural elements reminiscent of the bis-indoles generated in this work. As such, preliminary screening of the first

28 generation bis-indoles 2,2- and 7,7-glyoxyloylcarbohydrazides (57, 61-63, and 71), 2,2- and 7,7-carbohydrazides (80, 81 and 84, 86) was performed.

In vitro testing of the selected compounds was carried out using a standard native gel electrophoresis method to assess their ability to inhibit the formation of the key - RNAP complex in prokaryotes and the results are shown in Figure 2 -3. Notably, compounds 62 and 84 were found to inhibit the formation of -RNAP complexes evidenced by the bands at the bottom of the gel. Significantly, these compounds were not seen to have the same effect on the TF11B-CH interaction in eukaryotes.

σ HE 84 86 62 71 61 57 80 81 63

Figure 2-3. In vitro testing. A composite native gel of the tested compounds is shown

against the free and RNAP haloenzyme (HE) controls.

Based on these results compounds 62 and 84 were subsequently screened for their concentration dependent effect on the microbial growth against Gram negative bacteria (E.coli) and Gram positive bacteria (Staphylococcus aureus). The preliminary results (Figure 2-4) indicate that both compounds 62 and 84 had an effect against Gram positive bacteria at higher concentrations of 120-240 µg/ml. Compound 84 was similarly found to have an effect against Gram negative bacteria at higher concentrations, though the poor solubility of this compound hindered the calculation of accurate concentrations. Confirmation of these results and further analysis of the biological activity of compounds 62 and 84 is on-going.

29 A. C.

B. Figure 2-4. Concentration dependent effect on microbial growth of; A) compound 84 against Gram positive

bacteria; B) compound 62 against Gram positive bacteria; C) compound 84 against Gram negative bacteria.

Overall, it was interesting to note that the 7,7-glyoxylcarbohydrazides and 7,7- carbohydrazides displayed good antibacterial inhibition, whereas the corresponding 2,2-glyoxylcarbohydrazides and 2,2-carbohydrazides were found to be inactive. Moreover, the 7,7-hydrazide analogues which were 2,3-disubstituted were also found to be inactive. It is postulated that this trend relates to unfavourable steric factors and to confirm this hypothesis in silico screening of these compounds against the developed CH region pharmacophore is on-going. Furthermore, biological screening of the synthesised second generation 7-susbtituted monomeric analogues is currently underway.

2.6. Conclusions

Novel hydrazine linked 2,2- and 7,7-bis-indoles were successfully synthesized from 2- and 7-glyoxalylchlorides and 2- and 7-trichloroacetylindoles respectively. However, the preparation of 7-glyoxyloylcarbohydrazides failed to give pure 7,7- bis(indolylglyoxyloyl)hyrazides. In addition, the 7,7-glyoxyloylcarbohydrazides and 7,7-carbohydrazide bis-indoles showed promising antibacterial results in preliminary screens.

30 CHAPTER III

SYNTHESIS OF 7,7′-BIS-INDOLYL-1,3,4- OXADIAZOLES AND INDOLYL 1,3,4-THIADIAZOLES

3.1. Introduction

The 1,3,4-oxadiazoles 108 and 1,3,4-thiadiazoles 109 are unique heterocyclic systems with importance in synthetic, medicinal and material chemistry.39 These five-membered heterocycles play a vital role in medicinal chemistry and have a variety of biological activities such as antiviral, antibacterial, anti-fungal, anti- inflammatory and antihypertensive.40-43 They are also utilised in pharmacophores due to their favourable metabolic profile and propensity to form hydrogen bonds. In particular, these ring systems have been found in marketed antihypertensive agents such as tiodazosin and nesapidil, a carbonic anhydrase inhibitor acetazolamide and also antibiotics such as furamizole.44-46 Additionally, these molecules are used as HIV integrase inhibitors and antiangiogenesis inhibitors.46,47

N N N N R2 R2 O S R1 R1 109 108 Figure 3-1.

Recently, novel indolyl-1,3,4-oxodiazoles have been screened as potent anticancer agents. It was established that the cell viability of human cancer cell lines from prostate, breast and pancreas decreased significantly in the presence of these compounds.48

Several synthetic approaches have been reported for the synthesis of 1,3,4- oxadiazoles 108. Many of these protocols involve the cyclisation of acylhydrazines with a wide range of reagents such as thionyl chloride, triflic anhydride and phosphoryl chloride.49-51 Many of these reagents are toxic, however, and thus other cyclodehydration reagents such as Burgess reagent, amide coupling reagent HATU,

4-methylbenzenesulfonyl chloride (TsCl) and propylphosphonic anhydride (T3P®) have also been used for their synthesis.

Of all the aforementioned reagents, T3P was anticipated to be the most convenient to use due to its high reactivity and its ability to act as both the coupling and cyclodehydration agent in the synthesis of 1,3,4-oxadiazoles 108 and 1,3,4 thiadiazoles 109. Augustine et al., for example, described the one-pot dehydrative cyclisation of 1,3,4-oxadiazole 111 from benzohydrazide 110 in the presence of T3P.52

NH N HN O O N

Br Br

110 111

Scheme 3-1. Reagent and conditions: T3P, Et3N, ethyl acetate, reflux

3.2. Synthesis of 7,7′-bis-indolyl-1,3,4-oxadiazoles

Initial attempts to generate the 7,7-bis-indolyl-1,3,4-oxadiazoles 112-114 using this reagent were, however, unsuccessful. Heating bis-indoles 84-86 at reflux with 1.1 equivalents of T3P in the presence of triethylamine in ethyl acetate for 12 hours resulted in recovery of the starting materials. Increasing the amount of T3P or base gave the same result. Similarly, no reaction was observed when a stronger base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used. It was eventually concluded that the T3P was not a strong enough reagent for the dehydrative cyclisation of 7,7- bis-indoles.

The alternative stronger cyclodehydration reagent phosphoryl chloride was subsequently investigated. However, treatment of bis-indoles 84-86 with phosphoryl chloride either at room temperature or at 50 ºC resulted in formation of a black tar.

Dilution of the reaction mixture through use of a solvent was subsequently investigated. Accordingly, the treatment of bis-indoles 84-86 with excess phosphoryl chloride at reflux in ethyl acetate for 2 hours afforded the desired bis-indolyl-1,3,4- oxadiazoles 112-114 in good yields (Scheme 3-2).

R1 R1

OMe OMe

R2 R MeO N 2 H MeO N H HN O N O HN O N H H MeO N MeO N R2 R2

OMe OMe

R1 R1

84 R1 = Cl, R2 = H 112 R1 = Cl, R2 = H 61% 85 R1 = Br, R2 = H 113 R1 = Br, R2 = H 71% 86 114 R1 = H, R2 = Ph R1 = H, R2 = Ph 82%

Scheme 3-2. Reagent and conditions: POCl3, ethyl acetate, reflux

No formation of any by-products was observed; however, some baseline impurities were generated and were readily eliminated by subjecting the crude products to column chromatography. Both bis-indoles 84-86 and 112-114 were poorly soluble in organic solvents, had high melting points and good stability under normal laboratory conditions.

The 1H NMR spectrum of the compound 112 was characteristic for these oxadiazole linked bis-indoles, showing the disappearance of amide NH protons of the starting material 84 at 10.5 ppm. The indole NH was also observed to shift downfield appearing at 11.17 ppm (Figure 3-2).

112

1 Figure 3-2. H NMR spectrums of compounds 84 and 112 in DMSO-d6

Having these successful results in hand, the tandem ring closure of 7,7- bisoxalohydrazide 101 was investigated. 2,5-Bis-indolyl-bis-1,3,4-oxadiazole 115 was synthesized by reacting the readily available 7,7-bisoxaloylhydrazide 101 with phosphoryl chloride in ethyl acetate. In comparison to the reaction of bis-indoles 84- 86, the reaction time was dramatically increased from 2 hours to 24 hours.

OMe Ph OMe Ph Ph MeO N Ph H MeO N H HN O N HN O N O

HN O N O HN O N H H MeO MeO N N Ph Ph

OMe Ph OMe Ph

101 115

Scheme 3-3. Reagent and conditions: POCl3, ethyl acetate, reflux

34 A clear distinction between the two compounds 101 and 115 was indicated through comparison of their 1H NMR spectra which showed the disappearance of the amide NH proton at 10.87 ppm in compound 115. The high resolution mass spectrum further confirmed that tandem cyclisation had occurred by showing a molecular ion at 793 (M+1)+.

Cyclisation of the related 3-arylindoles proved to be problematic. Attempts to cyclise indoles 99 and 100 via the same methodology were unsuccessful. Reaction monitoring by thin layer chromatography was difficult because compounds 99 and 100 had very high polarities. Reaction monitoring by 1H NMR found a mixture of products was being formed and after 24 hours the characteristic peak for the amide nitrogen at 10.87 ppm had disappeared. Unfortunately, the complex mixture of products could not be separated by column chromatography.

Scheme 3-4. Reagent and conditions: POCl3, ethyl acetate, reflux

The corresponding cyclisation of the 2,2-linked systems 57 and 58 was also attempted in order to form the 2,2-bis-oxaloindolyl-1,3,4-oxadiazoles 118 and 119.

However, under the optimised conditions above only recovery of the starting material was observed. The use of different solvents such as chloroform, dichloromethane and tetrahydrofuran or even neat phosphoryl chloride at either room temperature or reflux had no effect. Moreover, the use of T3P was also attempted but similarly gave no reaction.

Scheme 3-5. Reagent and conditions: POCl3, ethyl acetate, reflux

With the unsuccessful result observed in the dehydration of 2,2- bisglyoxylcarbohydrazides 57 and 58, attention was turned to the preparation of 7,7- bis-oxaloindolyl-1,3,4-oxadiazole 120. Unfortunately, as with the previous example, only the starting material 61 was recovered when phosphoryl chloride and T3P were used in different solvents.

Scheme 3-6. Reagent and conditions: POCl3, ethyl acetate, reflux

Two possible reasons causing the inhibition of the dehydrative cyclisation in both the 2,2- and 7,7-linked systems 57, 58 and 61 are postulated. Firstly, there is potentially a greater steric restriction in the formation of indolyl-1,3,4-oxadiazoles due to the neighbouring glyoxyl carbonyl group. Alternatively, the strong hydrogen bonding between the carbonyl groups and NH protons results in the formation of stable five or six membered rings which cannot be broken even under vigorous conditions.

3.3. Synthesis of indolyl-1,3,4-oxothiadiazoles

There are only limited reports relating to the preparation of indolyl-1,3,4-thiadiazoles or 1,3,4-oxothiadiazoles in the literature. Recently, the synthesis of 5-(3- indolyl)thiadiazoles which possess anticancer activity has been reported.48

An initial exploration into the synthesis of 1,3,4-oxothiadiazoles was conducted through modification of the procedure for 1,3,4-oxadiazoles described above. The synthesis of 1,3,4-oxothiadiazoles was achieved following a convenient three step procedure starting from the readily available 7-glyoxylchlorides 47 and 70 as outlined in Scheme 3-7. The indoles 121 and 122 were prepared from the reaction of 7-glyoxylchlorides 47 and 70 with commercially available 4,4-dimethyl-3- thiosemicarbazide in the presence of triethylamine in acetonitrile. Subsequent

37 cyclisation of 121 and 122 with phosphoryl chloride in ethyl acetate led to the formation of indolyl-1,3,4-oxothiadiazoles 123 and 124 in 59% and 57% yield respectively.

Scheme 3-7. Reagent and conditions: a) 4,4-dimethyl-3-thiosemicarbazide, Et3N,

CH3CN; b) POCl3, ethyl acetate, reflux

The compounds 121 and 122 were crystallised for X-ray structure determination in order to assess the possible hydrogen bonding present in the molecule. The compound 122 gave a suitable single crystal and its X-ray crystal structure is displayed in Figure 3-3.

Figure 3-3. ORTEP diagram of compound 122

Further, 2-indolyl-1,3,4-oxothiadiazoles 127 and 128 were readily prepared in a similar fashion in 33% and 36% yield respectively (Scheme 3-8).

Scheme 3-8. Reagent and conditions: a) 4,4-dimethyl-3-thiosemicarbazide, Et3N,

CH3CN; b) POCl3, ethyl acetate, reflux

The mass spectra of the products 127 and 128 revealed a molecular ion at 443 (M+H)+ and 489 (81Br, 22%) respectively, while their infrared spectra showed that the NH absorption of the starting material at 3130 cm-1 had disappeared. The 1H NMR spectrum of the compound 128, as an example, displayed meta-coupled doublets (1H, J = 1.93 Hz) at 6.14 ppm and 6.84 ppm corresponding to H5 and H7 respectively. The disappearance of the NH signals at 9.35 ppm and 10.8 ppm also confirmed that cyclisation had occurred. The comparison of the 1H NMR spectra of the compounds 126 and 128 is shown in Figure 3-4.

128

126

1 Figure 3-4. H NMR spectrums of compounds 126 and 128 in DMSO-d6

3.4. Conclusions

In conclusion, an efficient methodology for the synthesis of 7,7-indolyl-1,3,4- oxadiazoles was developed. Although the tandem ring closure of 7,7- bisoxalohydrazide was achieved for the 2,3-diphenyl indole, the preparation of 3-aryl bisoxalohydrazides was found to be problematic. Moreover, a series of monomeric indole 1,3,4-thiadiazoles was successfully synthesized.

40 CHAPTER IV

SYNTHESIS OF 7-AMINOMETHYLINDOLE AND RELATED BIS-INDOLE DERIVATIVES

4.1. Introduction

The aminomethyl moiety is found in many indole alkaloids which possess biological activity. For example, brassinin 129 and cyclobrassinin 130, are representative members of the phytoalexin family that have been isolated from cabbage and exhibit antitumor activity.53 During the last two decades, approximately thirty phytoalexins have been isolated from cruciferous plants. The key intermediate for the synthesis of the phytoalexins is 3-aminomethylindole 131.54

3-Aminomethylindole 131 was first synthesized by Putochin in 1926 via the reduction of indole-3-aldoxime with sodium in boiling ethanol.55 Since then many efficient routes have been developed, and one of the most convenient is via hydrogenation of 3-cyanoindole 132 in ammoniacal ethanol in the presence of Raney nickel (Scheme 4-1).56

Scheme 4-1. Reagent and conditions: H2(38 p.s.i), Raney Ni, ammonia solution, ethanol, rt

Kutschy et al. described another possible route which involved the reduction of oxime 133 with nickel chloride and sodium borohydride in methanol to afford the amine 131 in 82% yield.57

Scheme 4-2. Reagent and conditions: NiCl2.6H2O, NaBH4, methanol, rt

4.2. Synthesis of 7-aminomethylindole

7-Aminomethylindoles have previously been of interest to our group as key intermediates in the synthesis of metal coordinating indole based macrocycles. For example, Nugent described the preparation of 7-aminomethylindole 136 via the lithium aluminium hydride reduction of 7-aldoxime 135 which in turn was obtained through treatment of the corresponding indole carbaldehyde 134 with hydroxylamine hydrochloride. However, 7-aminomethylindole 136 was found to be unstable.58

OMe OMe OMe

a b MeO N MeO N MeO N H H H

H O H N NH2 OH 135 134 136

Scheme 4-3. Reagent and conditions: a) NH2OH.HCl, NaOAc, methanol; b) LiAlH4, THF, rt

It was believed that the stability of the product could be increased through introduction of a 3-aryl group. The synthesis of 7-aldoxime 137 was achieved via the treatment of 7-carbaldehyde 93 with hydroxylamine hydrochloride and sodium hydroxide.59 In the next step, 7-aldoxime 137 was reduced to 7-aminomethylindole 138 with lithium aluminium hydride in tetrahydrofuran. However, the yield of the

42 reaction was very low because of the formation of unwanted by-products and baseline impurities. This was not entirely unexpected because the reduction reactions of oximes are known to be problematic and difficult to reproduce as well as low yielding.53

Scheme 4-4.a) NH2OH.HCl, NaOH, absolute ethanol, reflux; b) LiAlH4, THF, rt

Unlike the problematic reduction of 7-aldoxime 137, the reduction of nitriles to primary amines is well established. Therefore, our attention turned to the synthesis of 7-cyanoindole 140. 7-Aldoxime 137 was converted to the 7-oxime ether 139 intermediate through treatment with sodium ethoxide in absolute ethanol, followed by addition of fluoro-2,4-dinitrobenzene at room temperature. Subsequent heating of the 7-oxime ether 139 at reflux with triethylamine in tetrahydrofuran afforded the 7- nitrile 140 in 89% yield (Scheme 4-5).59

Scheme 4-5. Reagent and conditions: a) Na, absolute ethanol, fluoro-2,4-

dinitrobenzene, rt; b) Et3N, THF, reflux

Although 3-aminomethylindole 131 was obtained by Raney nickel catalysed hydrogenation of indole-3-nitrile 132 as mentioned earlier, we preferred a general method which did not use gaseous hydrogen. Therefore, the reduction of the 7-nitrile 140 was performed with lithium aluminium hydride in tetrahydrofuran. Pleasingly, the reaction was clean and gave exclusively the 7-aminomethylindole 138 in 73% yield (Scheme 4-6). This amine could be recrystallised from acetonitrile to give brown crystals which were stable in air.

Scheme 4-6. Reagent and conditions: LiAlH4, THF, rt

The infrared spectrum of the amine 138 showed the characteristic absorption of two primary amino groups at 3368 and 3360 cm-1. The formation of the amine was also

44 deduced from the alkyl protons being present in the 1H NMR spectrum at 4.15 ppm and a CH2 signal appearing in the DEPT135 experiment. An m/z of 316.0973 was also obtained via high resolution mass spectroscopy which was consistent for the target structure 138.

4.3. Synthesis of bis-indoles

The amide functionality is one of the most prevalent structural moieties present in polymers, natural products and pharmaceuticals.60 However, to the best of our knowledge, preparation of amide linked bis-indoles utilizing 3-aminomethylindole 131 as the precursor have not been reported yet. The central aim of this project though was the preparation of 7,7-amide linked bis-indole systems using the 7- aminomethylindole 138 as the starting material.

Accordingly, the first target 7,7-bis-indole carboxamide 141 was prepared in 83% yield by the reaction of equal equivalents of 7-trichloroacetylindole 41 and 7- aminomethyindole 138 in hot acetonitrile (Scheme 4-7).

OMe Cl Cl

N OMe OMe MeO H HN O + H N N MeO MeO H MeO H N

Cl3C O NH2 OMe

41 138 141 Cl

Scheme 4-7. Reagent and conditions: Et3N, CH3CN, reflux, overnight

The construction of amide linked bis-indoles 142 and 143 was achieved by the treatment of the indole 138 with oxalyl chloride and adipoyl chloride respectively in the presence of the triethylamine in dichloromethane. Both of the reactions were

45 completed in an hour and the bis-indoles 142 and 143 were afforded in 81% and 86% yield respectively (Scheme 4-8).

Scheme 4-8. Reagent and conditions: oxalyl chloride or adipoyl chloride, Et3N, DCM, rt, 1 h

In the 1H NMR spectrum of compound 143, as an example, the amide NH appeared as a triplet at 8.27 ppm, while the indole NH resonance was observed at 10.91 ppm. The high chemical shift is indicative that there is strong hydrogen bonding within the system. Compound 143 also showed good solubility in deuterated dimethyl sulfoxide, allowing observation of carbonyl resonance at 173 ppm in the 13C NMR 13 spectrum. Moreover, the CH2 group resonance was determined both with C NMR and DEPT135 experiments.

As discussed in the introduction chapter, 7,7-imine linked indole structures can be produced through the reaction of 7-formylindoles with amines. Following this, the condensation of the readily available 7-formylindole 93 with 7-aminomethylindole 138 was undertaken in ethanol to give a 75% yield of the bis-indole 144 (Scheme 4- 9).

Cl Cl OMe

OMe OMe N MeO H + N MeO N MeO N H H H MeO N H O NH2

OMe

93 138 144 Cl Scheme 4-9. Reagent and conditions: absolute ethanol, HCl, reflux

The imine 144 was fully characterized with the exception of 13C NMR spectrum due to its poor solubility. The 1H NMR spectrum showed the imine proton at 8.91 ppm and the indole NH resonances at 11.38 ppm and 11.49 ppm, indicating the presence of strong hydrogen bonding within the system. The four methoxy protons appeared at 3.82, 3.89, 3.90, 3.94 ppm and the H5 and H5 protons at 6.46 ppm and 6.49 ppm confirmed the unsymmetrical nature of the structure. A high resolution mass spectrum further confirmed the structure, showing a molecular ion at 614.1599 (M+Na)+.

In general, secondary amines have been prepared from the imines via catalytic hydrogenation and reduction with sodium and alcohol.61 Following this, the desired amine 145 was prepared by heating the imine 144 with sodium borohydride at reflux in a mixture of ethanol and tetrahydrofuran.

Scheme 4-10. Reagent and conditions: NaBH4, THF and absolute ethanol, reflux

The 1H NMR spectrum of the compound 145 indicated an indole amine, as expected, in combination with the disappearance of the imine bond resonance and the presence of CH2 resonance at 4.01 ppm clearly indicated the reaction occurred across the double bond as anticipated. Also, ESI mass spectral analysis showed a molecular ion at 616.1768 (M+H)+.

4.4. Conclusions

In summary, 7-aminomethylindole was synthesised by reduction of the corresponding 7-cyanoindole. The 7-aminomethylindole proved to be a useful precursor for a range of 7,7-bis-indoles, which have a nucleophilic unsubstituted C2 position. The amide linked bis-indoles were obtained upon reaction of 7- aminomethylindole with acyl chlorides while imine linked dimer was produced upon reaction with 7-formylindoles. The corresponding amine linked bis-indole was obtained through reduction of the imine linkage with sodium borohydride.

CHAPTER V

SYNTHESIS OF 7,7′-BIS-INDOLES VIA 7- TRYPTAMINE ANALOGUES

5.1. Introduction

Tryptamine 146 and its derivatives are a class of organic compounds built around an indole nucleus with an ethanamine substituent at the C3 position. Many members of this family display various biological properties. For example, the neurotransmitter serotonin (5-hydroxytryptamine) 147 is active in the central nervous system and regulates mood, appetite, sleep and self control1, and melatonin (N-acetyl-5- methoxytryptamine) 148 is responsible for the control of circadian rhythm and blood pressure regulation.62 It has recently been reported that tryptamine derivatives may also function as bacterial efflux pumps and inhibitors of CDK4, an anticancer drug.63,64

NH NH N 2 HO 2 MeO H O

N N N H H H 146 148 147

In addition to the biological importance of tryptamine and its derivatives, the ethanamine substituent offers a great number of possibilities for functionalisation and derivatisation, allowing a large number of analogues to be synthesised. Importantly, it is also possible to functionalise the benzenoid ring, allowing the addition of primary amines at the C7 position and subsequent formation of 7,7-bis-indole systems.

5.2. Synthesis of 7-tryptamine analogues

The first example of a 4,6-dimethoxyindole tryptamine compound was developed by Nugent in the synthesis of metal coordinating indole based macrocycles. The readily available 3-methyl-indole-2-aldehyde 149 was treated with nitromethane and ammonium nitrate to generate 2-(-nitrovinyl)indole 150 which was subsequently reduced to the corresponding primary amine 151 via lithium aluminium hydride reduction. However, the tryptamine derivative 151 was found to be unstable and completely decomposed over the course of twenty minutes.58

Scheme 5-1. Reagents and conditions: a) CH3NO2, ammonium acetate, reflux; b)

LiAlH4, THF, rt

It was anticipated that the corresponding 7-tryptamines could be generated in a similar fashion. Wood65 has previously reported the synthesis of the 7- nitroethylindoles 152-154 via the classical Henry reaction.66 7-Nitrovinylindoles 152-154 were prepared by refluxing indole-7-carbaldehydes 93-95 with excess ammonium acetate in nitromethane for 3 hours to give the target intermediates 152- 154 in 92-95% yields (Scheme 5-2).

Scheme 5-2. Reagents and conditions: CH3NO2, ammonium acetate, reflux, 3 h

The reduction of these nitrovinylindoles to the corresponding amines was then examined. Accordingly, 7-nitrovinylindole 152 was treated with lithium aluminium hydride in tetrahydrofuran, however, the reaction was found to produce many side products and the desired tryptamine could not be isolated.

As an alternative strategy, a two stage reduction of the 7-nitrovinylindole 152-154 was undertaken in an attempt to avoid the formation of a complex mixture. In the first step, indoles 152-154 were reduced with sodium borohydride in a mixture of tetrahydrofuran and ethanol (1:1) to produce the 7-nitroethylindoles 155-157 in yields of 66-88%. The reaction was found to similarly produce a number of unwanted side products, however, they were minimised upon cooling the reaction mixture in an ice bath. The 1H NMR spectrum of compound 152 exhibited doublets at 8.14 and 8.67 ppm indicating the presence of the vinyl group. In reduction, the doubles were found to be replaced by triplets at 3.44 ppm of 4.65 ppm in the 1H NMR specrum of 155, confirming the reaction outcome.

In order to reduce the nitro group to the primary amine, the 7-nitroethylindoles 155- 157 were heated with hydrazine hydrate and 10% Pd/C in ethanol for 4 hours to give in each case a single product in 79-93% yield (Scheme 5-3).

R1 R1 R1

OMe OMe OMe a b R2 R2 R2 MeO N MeO N MeO N H H H

NO2 NO2 NH2

158 152 R1 = Cl, R2 = H 155 R1 = Cl, R2 = H R1 = Cl, R2 = H 159 153 R1 = Br, R2 = H 156 R1 = Br, R2 = H R1 = Br, R2 = H 154 157 160 R1 = H, R2 = Ph R1 = H, R2 = Ph R1 = H, R2 = Ph

Scheme 5-3. Reagents and conditions: a) NaBH4, absolute ethanol and THF, rt; b)

NH2NH2.H2O, Pd/C, absolute ethanol, 4 h

The 1H NMR spectrum of the compound 160 showed the upfield shift of the methylene triplets to 3.04 ppm and 3.11 ppm respectively. The 13C NMR spectrum also indicated methylene carbon attached to C7 of the indole nucleus at 27.46 ppm and the methylene carbon adjacent to the amino group at 41.87 ppm. Interestingly, the 1H NMR spectra of the anticipated compounds 158 and 159 did not demonstrate the two characteristic aromatic doublets expected for the para-substituted rings. Instead, the aryl protons appeared as multiplets between 7.15-7.55 ppm and integrated for 5H, indicating the halogen atoms had been lost during the reduction to give amine 161 (Scheme 5-4). This dehalogenation was further confirmed by high resolution mass spectrometry, as well as through the presence of three aryl CH resonances at 125.82, 127.91 and 129.88 ppm in the 13C NMR spectrum, as opposed to the two aryl CH resonances expected. This result is not entirely surprising as the Pd/C-catalysed dehalogenation of aromatic halides is well known in the literature.67- 70 Moreover, the reducing reagent hydrazine hydrate is also known to cause dehalogenation.71

Scheme 5-4. Reagents and conditions: NH2NH2.H2O, Pd/C, absolute ethanol, 4 h

In contrast to the 2-tryptamine derivative 151, the 7-tryptamines 160 and 161 with a free amino group were found to be air stable, and it was not necessary to convert them to the hydrochloride or hydrobromide salt in order to increase their stability. Purification, however, was hindered by the high polarity of the 7-tryptamines, which remained on the baseline of thin layer chromatography plates even with the use of highly polar solvent systems such as methanol or ethanol. Due to this, purification was instead achieved by washing the crude product with diethyl ether.

5.3. Synthesis of Bis-indoles

Tryptamine based bis-indoles have been isolated from natural sources and demonstrate potential as biologically active compounds and useful synthetic targets. For example, bis-indole 162, isolated from the roots of Antirhea lucida, has been synthesized for the first time from tryptamine derivatives through acid catalysed

53 nucleophilic substitution of 1-hydroxytryptamine72, while chondriamide C 163 was isolated from red alga Chondria atropurpurea and posesses antihelminthic activity.73

Recently, other analogues of marine natural products containing a tryptamine nucleus have been synthesized and screened for biological activity. For instance, 8,9- dihydrocoscinamide 165, possessing a structure derived from tryptamine 146 and indole oxalyl chloride 164, was found to display inhibition against promastigote and amastigote protozoa74

Scheme 5-5. Reagents and conditions: THF, 0 °C, rt

Following the central aim of the thesis, the primary amine functionality of the developed 7-tryptamines was used as a functional handle in the synthesis of a range of unsymmetrical and symmetrical bis-indoles.

Unsymmetrical 7,7-amide linked bis-indoles were synthesised at room temperature via the reaction of 7-tryptamines 160 and 161 with 7-trichloroacetylindoles 41 and 83 in acetonitrile in the presence of triethylamine. The target amide linked bis- indoles 166 and 167 were isolated in 59% and 79% yield respectively (Scheme 5-6).

Scheme 5-6. Reagents and conditions: Et3N, CH3CN, rt

The new amide functionality was clearly evident in the 1H and 13C NMR spectra of compound 167, with the amide NH proton present as a triplet at 8.38 ppm and the carbonyl group appearing at 167.29 ppm. The 1H NMR spectrum also showed the indole NH protons as singlets at 11.13 ppm and 11.30 ppm and the ethylene protons as a quartet at 2.48 ppm (J = 5.41 Hz) and triplet at 3.18 ppm (J = 13.54 Hz).

Unsymmetrical 7,7-imine linked bis-indoles were then prepared from indoles 160 and 161 upon reflux with 7-formylindoles 93, 95 and 168 in ethanol. Bis-indoles 169-171 precipitated out of solution and were collected by filtration to give yields of 43-69% (Scheme 5-7).

Scheme 5-7. Reagents and conditions: absolute ethanol, reflux

The structure of bis-indole 170 was confirmed by high resolution mass spectrometry, which showed the molecular ion at 712.3159 (M+H)+. The 1H NMR spectrum showed the imine proton signal at 8.30 ppm and four methoxy protons at 3.72, 3.76, 3.88 and 3.91 ppm. However, compound 170 was found to be highly insoluble and this inhibited the collection of a satisfactory 13C NMR spectrum.

Symmetrically linked 7-bisoxaloamides 172 and 173 were prepared in moderate yields by reacting 7-tryptamines 160 and 161 with oxalyl chloride in dichloromethane at room temperature (Scheme 5-8).

Scheme 5-8. Reagents and conditions: oxalyl chloride, Et3N, DCM, rt

Evidence for the formation of compound 173 was provided by the 1H NMR spectra, which showed the appearance of a triplet at 8.53 ppm corresponding to the amide NH proton while the indole NH was a doublet at 11.02 ppm. The 13C NMR spectrum showed the presence of the carbonyl carbon at 160.21 ppm, and the IR spectrum further supported the structure by showing the distinctive carbonyl absorption at 1650 cm-1.

In all cases, the synthesised bis-indoles were found to be very stable under standard laboratory conditions and showed poor solubility in the majority of organic solvents.

5.4. Synthesis of macrocylic structures

The acid catalysed macrocyclisation of bis-indoles was first explored by Black et al. with the formation of the twenty-one membered diamine macrocycle 175 from bis- indole 174 and formaldehyde in the presence of concentrated hydrochloric acid in methanol.9

Scheme 5-9. Reagents and conditions: HCHO, HCl, methanol, reflux

This methodology was subsequently applied to bis-amide 166 and bis-imine 171, which were treated at reflux with formaldehyde and concentrated hydrochloric acid in either methanol or acetic acid overnight. However, these reactions failed to form the desired macrocyclic compounds 176 and 177, instead producing a complex mixture or returning only the starting materials. The failure to form the target compounds was possibly due to the low solubility of the bis-indoles and conformation restrictions in forming the macrocylic structures.

Scheme 5-10. Reagents and conditions: HCHO, HCl, methanol, reflux or AcOH, HCl, reflux

An alternative strategy was therefore devised in which the methylene bridge was introduced prior to attempted macrocyclisation via the formation of imine bonds. To this end, intermediate 7-nitroethylindoles 155 and 156 were condensed with an excess of formaldehyde in the presence of hydrochloric acid in glacial acetic acid. The disappearance of starting material was monitored by thin layer chromatography; however, the 1H NMR spectra of the resulting solids showed a complex mixture of products had been produced. The condensation of 7-nitroethylindoles 155 and 156 was subsequently achieved in moderate yields using concentrated hydrochloric acid in anhydrous methanol (Scheme 5-11). The reactions were slow, taking 20 hours to reach completion, and produced baseline impurities which were removed via chromatography to give 178 and 179 as the clean products.

Scheme 5-11. Reagents and conditions: HCHO, HCl, methanol, reflux

The 1H NMR spectrum of the compound 179 exhibited the methylene protons attached to C7 of the indole nucleus as triplets at 3.41 and 4.04 ppm, while the methylene group linking the two indole units was observed at 4.65 ppm. In the 13C NMR spectrum, the methylene carbon adjacent to the nitro group appeared at 74.51 ppm while the methylene carbon linking the two indole units and the methylene carbon attached to C7 of the indole nucleus appeared together at 23.05 ppm, as confirmed through HSQC and HMBC NMR experiments. This overlapping pattern of the methylene carbon linking the two indole units and the methylene carbon attached to C7 of the indole nucleus was similarly observed at 23.08 ppm in the 13C NMR spectrum of compound 178. Finally, the high resolution mass spectra for compounds 178 and 179 revealed the molecular ion peaks at 733.1825 (M+H)+ and 820.0738 (M+H)+ respectively.

Reduction of compounds 178 and 179 to the corresponding primary amino compounds 180 and 181 with hydrazine hydrate and 10% Pd/C was carried out in a mixture of ethanol and tetrahydrofuran. The mixed solvent system was employed in order to increase the solubility of the starting materials. The reaction reached completion after 8 hours of heating under reflux and the resulting products isolated. As with the previous reduction of the nitro group, 1H NMR spectroscopy indicated that the halogens on the aromatic rings had been eliminated to instead give bis-indole 182 (Scheme 5-12). This assignment was supported by other analytical data, with the

13C NMR spectra showing resonances at 125.46, 127.30 and 131.11 ppm corresponding to aryl carbons of the benzenoid ring and mass spectrometry showing an m/z of 605.3115 which is consistent for C37H40N4O4.

Scheme 5-12. Reagents and conditions: NH2NH2.H2O, Pd/C, absolute ethanol and THF, reflux

Synthesis of unsymmetrical macrocycles 186-188 was then achieved by the tandem condensation of diamine 182 with 2,7-dialdehydes 183-185 in absolute ethanol. Products 186-188 precipitated from the reaction mixture and were collected by filtration in 58-71% yields. These twenty-one membered macrocyclic compounds were found to be stable on silica and were purified by passing through a plug of silica.

Scheme 5-13. Reagents and conditions: absolute ethanol, reflux

In the 1H NMR spectrum of compound 186, the methylene protons appeared as a singlet at 2.87 ppm and a doublet at 3.15 ppm while the imine protons appeared at 7.34 ppm and 8.79 ppm and the methylene bridge proton appeared at 4.01 ppm. The six methoxy singlets appeared at 3.63, 3.70, 3.77, 3.84, 3.87, 3.92 ppm and the three indole NH proton resonances shared at 8.40, 9.55 and 12.03 ppm. The high resolution mass spectrum with a molecular ion peak at 912.3509 (M+H)+ further confirmed the structure.

The imine linked macrocyclic compounds 186-188 were reduced to the corresponding amine linked macrocyclic compounds 189-191 with sodium borohydride in a mixture of hot ethanol and tetrahydrofuran. The compounds 189- 191 were found to be very polar and thus remained at the baseline of the thin layer chromatography plate, but did not appear to have the same solubility issues in deuterated chloroform as the previous compounds, allowing for the acquisition of satisfactory analytical data.

Ph Ph Ph Ph MeO OMe MeO OMe

NH HN NH HN

MeO OMe MeO OMe

N N NH HN H H N N

MeO MeO

OMe OMe R R 186 R = Cl 189 R = Cl 187 R = Br 190 R = Br 188 R = H 191 R = H

Scheme 5-14. Reagents and conditions: NaBH4, absolute ethanol and THF, reflux

Evidence for the formation of compound 190 was provided by 1H NMR spectroscopy data which showed the absence of the imine protons and the appearance of the methylene peaks at 4.15 ppm and 4.24 ppm, and by 13C NMR and

DEPT135 experiment indicating the appearance of seven CH2 groups at 23.02, 25.03, 25.42, 43.56, 44.21, 48.31, 49.26 ppm. This was supported by the high resolution mass spectrum which revealed the molecular ion at 960.3338 (M+H)+.

The next synthetic target was a symmetrically linked macrocycle containing four indole units. Using similar methodology to that previously described, diaminoethylene bis-indole 182 was heated at reflux with indolylmethane dicarbaldehyde 192 in ethanol. In contrast to the successful synthesis of twenty-one membered macrocycle, the larger twenty-six membered macrocycle 193 was not produced (Scheme 5-15). The disappearance of amino compound 182 was monitored by thin layer chromatography and the filtration of resulting solid resulted in the isolation of the starting formyl compound 192. Another effort to generate the target macrocyclic indole was carried out in high boiling point solvents such as toluene, but either a mixture of products or polymeric materials were obtained.

Scheme 5-15. Reagents and conditions: absolute ethanol or toluene, reflux

The final cyclic target of interest was the 1,7-annulation of the 7-tryptamines to give a nitrogen containing medium sized ring. It was anticipated that the one-pot reductive-cyclisation in the presence of phosphoryl chloride described in Chapter 3 in the synthesis of the 2,3-annulated traditional medicine rutaecarpine75 could be exploited for this purpose. Therefore, the indole 7-tryptamine 160 was N-protected using acetic anhydride at 0 ºC to give the 7-ethyl acetamide 194. Subsequent annulation was carried out at reflux by treatment of indole 194 with phosphoryl chloride in acetonitrile. The product was obtained after extensive column chromatography in only 9.5% yield.

However, the 1H NMR spectrum of the resulting solid did not correspond with the structure 195 as shown in Figure 5-1. The H5 proton appeared as singlet at 6.79 ppm as expected but only one methoxy group was observed at 3.87 ppm. This suggested that substitution of the second methoxy group had occurred. The other protons were present as anticipated, with the methyl group appearing at 1.75 ppm, the methylene protons appearing as a broad singlet at 3.06 ppm and as triplet at 4.20 ppm and the two phenyl rings appearing as multiplets at 7.17-7.30 ppm.

Similarly, the high resolution mass spectrum also showed a molecular ion peak at 401.1465 which was not consistent with the expected m/z of 396.1838 for compound 195. The mass spectrum suggested that one methoxy group had been replaced by a chlorine atom due to the presence of the distinctive halogen isotope pattern. This was

64 confirmed through X-ray crystallography which showed that the C4-methoxy had been substituted (Figure 5-2).

Scheme 5-16. Reagents and conditions: POCl3, CH3CN, reflux

7.30 7.26 7.24 7.23 7.22 7.17 6.79 4.22 4.20 4.19 3.87 3.06 1.75

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm 1.00 2.31 3.47 2.12 3.33 10.90

1 Figure 5-1. H NMR spectrum of compound 196 in CDCl3

Figure 5-2. ORTEP diagram of annulated indole 196

5.5. Conclusions

In summary, the reduction of 7-nitroethylindoles via palladium catalysed reaction led to formation of dehalogenated 7-tryptamine which was used to form the amide and imine linked 7,7-bis-indoles. Similarly, condensation of 7-nitroethylindoles with formaldehyde gave indolylmethanes which were successfully used for the construction of more complex macrocyclic systems. Additionally, the 1,7-annulation of 7-tryptamines was investigated and found to give an interesting chlorinated product due to substitution of a methoxy group.

CHAPTER VI

STRATEGIES TOWARDS 7-BROMO-4,6- DIMETHOXYINDOLE AND REACTIVITY OF 4,6-DIMETHOXYBENZOTRIAZOLE

6.1. Introduction

As discussed in the introduction chapter, biindolyls are one of the powerful bis- indole structural fragments. Biindolyls are frequently found in a range of natural products and possess a variety of biological activity. Two examples are Arcyriaforum A 19776 isolated from marine sources and an antitumor antibiotic Rebeccamycin 19877 isolated from the fermentation products of the microbe Nocarda erocoligenes.

Our effort was to generate novel 7,7-biindolyls related to the aim of this thesis. Several methods have been developed for the synthesis of the 7,7-biindolyl systems.78-80 The diborane reduction of a 7,7-bis-isatin78 and the oxidation of 4,6,7- hydroxyindoles with sodium periodate80 are some examples. Also, Black et al. have reported the construction of 2,3-disubtituted-7,7-biindolyl systems via the quinone oxidation of indoles.81 Unfortunately, the preparation of 3-substituted-7,7-biindolyls has not been achieved yet. An attractive approach for the synthesis of 3-substituted-

7,7-biindolyls would be use of the Suzuki-Miyaura reaction, which is one of the most powerful methods of carbon-carbon bond formation.82 Recently, 7,7-biindolyl 200 was synthesized via a one pot Suzuki-Miyaura reaction using 7-bromoindole 199 and the palladium catalyst.83

Scheme 6-1.

In order to perform the Suzuki-Miyaura method, we attempted synthesis of the required 3-substituted-7-arylindole. Previous studies have shown that 7-iodo-2,3- disubstituted indoles were unstable and converted directly to 7,7-biindolyls in the absence of light. On the other hand, the readily available 7-bromo-4,6-dimethoxy- 2,3-diphenylindole was found to be stable and was successfully converted into the N- allyl derivates.7 Therefore, it is presumed that 7-bromoindoles 201 would be the key intermediates for the construction of 7,7-biindolyls 202.

R OMe

OMe MeO N H H MeO N MeO H N Br

OMe

202 R 201 Scheme 6-2.

6.2. Attempted synthesis of 7-bromoindole via direct bromination

Considerable interest has been shown in the development of methods for the bromination of 3-substituted-4,6-dimethoxyindoles. Although the synthesis of C2 or C2 and C5 brominated indoles was achieved, the desired C7 brominated indoles have not yet been prepared.

The bromination of indole 203 using trimethylammonium tribromide in tetrahydrofuran resulted in decomposition.84 Milder bromination conditions such as the use of N-bromosuccinimide were also used in the presence of silica. However, decomposition occurred with the isolation of a trace amount of the 2,7-dibromo product 204 (Scheme 6-3).85

Scheme 6-3. Reagents and conditions: NBS, CH2Cl2, silica

In addition, the above strategy was repeated in the presence of deactivating groups such as an N-formyl or N-acetyl group with the aim of avoiding decomposition (Scheme 6-4). No trace of the mono-brominated compound was seen, however, with the 2,7-dibromo products 207 and 208 instead being isolated from the reaction mixture along with the unconsumed starting material.85

Scheme 6-4. Reagents and conditions: NBS, CH2Cl2, silica

Some regioselectivity was obtained in the presence of the bulky deactivating phenylsulfonyl group. Heating of 3-phenyl-N-phenylsulfonylindole 209 with 1:1 equivalent of N-bromosuccinimide at reflux in carbon tetrachloride afforded 2- bromo-N-phenylsulfonylindole 210 while the use of 2:1 equivalents of N- bromosuccinimide gave 3-phenyl-2,5-dibromo-N-phenylsulfonylindole 211 (Scheme 6-5).This result indicates a bulky N-substituent hinders C7-substitution to the point that the less common C5-substitution is favoured.85

Scheme 6-5. Reagents and conditions: a) 1.1 eq.NBS, CCl4, reflux, 5 h; b) 2.1

eq.NBS, CCl4, reflux, 5 h

In accordance with the previous studies, the reactivity of other 3-substituted indoles towards direct bromination was found to result in decomposition. It was also found that the presence of deactivating groups on the indole nucleus did not favour of the formation of 7-bromoindoles 201. Hence, it was decided to investigate the synthesis of 7-bromoindoles 201 via modified Bischler indole synthesis starting from 2-bromo- 3,5-dimethoxyaniline 212.

Scheme 6-6. Modified Bischler indole synthesis

3,5-Dimethoxyaniline 18 was first protected with an excess of formic acid in order to avoid the formation of the hydrobromide salt product. Bromination of the formanilide 213 was then carried out using a variety of different conditions such as bromine in dichloromethane at -78 ºC in dry ice, trimethylammonium tribromide in tetrahydrofuran and bromine in acetic acid at room temperature in order to furnish the 2-bromo-phenylformanilide 214. However, the above conditions were found to generate two products, 2-bromo-phenylformanilide 214 and 4-bromo phenylformanilide 215 (Scheme 6-7). The desired 2-bromo-phenylformanilide 214 was isolated in only 20% yield and the undesired 4-bromoformanilide 215 was isolated in 17% yield after extensive column chromatography. The 1H NMR spectrum of the 4-bromo-phenylformamide 215 demonstrated the disappearance of the doublets at 6.77 ppm corresponding to aryl H4 and the appearance of a singlet showing 2H at 7.03 ppm corresponding to the aryl H2 and H6. 2-Bromo- phenylformamide 214 was similarly identified from the 1H NMR spectrum by the presence of two doublets at 6.47 ppm and 7.41 ppm each having a coupling constant of J = 2.7 Hz.

Scheme 6-7. Reagents and conditions: a) HCOOH, reflux; b) i) Br2, DCM, -78 °C;

ii) PhN(CH3)3Br3, THF, rt; iii) Br2, AcOH, rt

Since the yield of 2-bromoformanilide attained was clearly not satisfactory to pursue further synthesis, an alternative method was investigated. In particular, attention turned to the formation of 7-aminoindole 216 for its subsequent conversion into 7- bromoindole 201 via diazotization.

Scheme 6-8.

6.3. Attempted synthesis of 7-aminoindole

7-Aminoindoles 216 do not only play a potentially important role in the synthesis of 7-bromoindoles 201 but could also enable the synthesis of 7,7-linked bis-indole systems. A number of methods for the preparation of 7-aminoindoles 216 are discussed in this section. For all reactions related to synthesis of the 7-aminoindoles 216, 2,3-diphenyl-4,6-dimethoxyindole derivatives were chosen to be initial compounds because of their easy preparations compared to the 3-substituted 4,6- dimethoxyindole derivatives.

Curtius rearrangement is one of the convenient methods for the preparation of amines from carbonyl azides. Accordingly, the azides 217 give the isocyanates 218 which convert to ureas 219 and the hydrolysis of ureas forms the amines 220.86

Scheme 6-9.

In the light of this pathway, the preparation of the 2,3-diphenyl analogue of 216 from 7-carbonylazindole 221 was attempted. The readily available 7-trichloracetylindole 83 was reacted with sodium azide in N,N-dimethylformamide or acetone in order to give 7-azide compound 221, however, the reaction resulted in the formation of 7-

72 carboxylic acid 222, probably due to the preferable nucleophilic attack by water on the trichloroacetyl group versus the azide group.

Scheme 6-10. Reagents and conditions: NaN3, DMF or acetone, rt or reflux

An alternative strategy in the preparation of 7-azide compound 221 was the treatment of 7-carbohydrazide 89 with sodium nitrite in aqueous hydrochloric acid solution.86 Unfortunately, only the starting material was recovered after stirring the reaction mixture at room temperature or heating at reflux. Initially, this failure was attributed to the solubility problem. Chloroform was subsequently used in order to overcome the solubility problem but again no reaction was observed.

Scheme 6-11. Reagents and conditions: NaNO2, HCl, CHCl3, rt

With the difficulties found in preparing 7-azidoindole 221, attention was subsequently directed to the synthesis of 7-isopropyl urethane 223 without isolation of the intermediate azide via a modified Curtius rearrangement. However, heating indole 222 at reflux with diphenylphosphoryl azide (DDPA) in the presence of triethylamine in isopropanol gave the 7-isopropyl carboxylate 224 (Scheme 6-12). X- ray crystallographic analysis was used to confirm the structure of the compound (Figure 6-1).

OMe Ph

Ph MeO N H HN O

O OMe Ph 223 Ph MeO N H OMe HO O Ph

222 Ph MeO N H O O

224

Scheme 6-12. Reagents and conditions: DPPA, Et3N, isopropanol, reflux

Figure 6-1. ORTEP diagram of compound 224

This ester condensation was presumably initiated by the presence of the azide ion which served as a catalyst rather than as a nucleophile so as to afford the azido 74 carbonyl intermediate. This assumption was supported by additional reactions. Heating indole 222 at reflux in isopropanol for two days and monitoring by thin layer chromatography showed no reaction. Addition of triethylamine to the reaction and heating for an additional day again failed to yield the indole-7-carboxylate 224 or any other product.

Scheme 6-13 Reagents and conditions: Et3N, isopropanol, reflux

In order to recover the 7-carboxylic acid 222 to use in other reactions, the deprotection of 7-indole ester 224 was attempted with ethanolic sodium hydroxide. It was interesting to find that indole 224 was converted to the parent diphenylindole 21 (Scheme 6-14). This reaction was repeated in an acidic environment such as trifluoroacetic acid at reflux and gave the same result. This decarboxylation of the 7- carboxylic acid was found to be a facile process.

Scheme 6-14. Reagents and conditions: NaOH, ethanol, rt or TFA, reflux

6.4. Attempted synthesis of 2-bromoaniline via diazotization

The Sandmeyer reaction is a very important transformation in aromatic chemistry, because it can result in some substitution patterns that are not achievable by direct substitution. The substitution of an aromatic amino group is possible via the preparation of the corresponding diazonium salt followed by subsequent displacement with a suitable nucleophile.87

2-Amino-3,5-dimethoxyacetamide 226 was previously prepared via the convenient three step process as outlined in Scheme 6-15. The first step involved the protection of the 3,5-dimethoxyaniline 18 with acetic anhydride at 0 ºC, followed by nitration of acetamide 213 with nitric acid in acetic anhydride. Lastly, the 2-amino-3,5- dimethoxyacetamide 226 was obtained by the palladium-catalysed hydrazine reduction of the 2-acetamidoaniline 225.88

Scheme 6-15. Reagents and conditions: a) Ac2O, 0 ºC; b) HNO3, Ac2O, 0 ºC; c)

NH2NH2.H2O, Pd/C, absolute ethanol, reflux

The diazotization reaction was performed by dissolving 2-acetamido-aniline 226 in 5 M hydrochloric acid solution and cooling the reaction mixture to -5 ºC. Sodium nitrite was then added all at once in order to generate the diazonium salt 227. After 5 minutes, copper bromide (CuBr) was added as the bromine source before the reaction was finally quenched with water. Surprisingly, the reaction failed to form the target 2-bromoacetamide 214 with the unstable diazonium salt 227, instead undergoing a direct cyclisation reaction with the acetamide nitrogen to form a new benzotriazole compound 228 as illustrated in Scheme 6-16. The reaction was repeated without the addition of CuBr and again resulted in the formation of compound 228. The reaction was very fast and took place in under ten minutes. The product was purified via recrystallisation from acetonitrile to give a 72% yield. The structure of the isolated

76 compound was confirmed by a mass spectrum which found an m/z of 222 (M+1)+. Also, the 1H NMR spectrum showed the methyl group at 2.88 ppm and the methoxy groups at 3.82 ppm and 3.99 ppm. The aryl protons H5 and H7 were shown by resonances at 6.36 ppm and 7.13 ppm respectively. The structure of compound 228 was further confirmed by an X-ray crystallographic analysis (Figure 6-2).

Scheme 6-16. Reagents and conditions: NaNO2, aq. HCl, -5 ºC

Figure 6-2. Ortep diagram of compound 228

6.5. Reactivity of 4,6-dimethoxy-1,2,3-benzotriazole Benzotriazole derivatives are an important class of compounds due to their wide range of applications which include use as anti-rusting or anticorrosion agents for metals, anti-freezing agents for cars, anti-dust agents for photography, polymer stabilizers and synthetic detergents.89 1,2,3-Benzotriazole typically undergoes electrophilic substitution at the N1 position. For example, the formylation of benzotriazole with formic acid in the presence of diisopropylcarbodiimide in dichloromethane produces N-formyl benzotriazole.90 Also the acetylation of benzotriazole either with acetic anhydride or acetyl chloride under optimised conditions generates the N-acetyl benzotriazole.91,92 Direct bromination of benzotriazole has not yet been reported though 5-bromobenzotriazole has been synthesized from 1,2-diamino-4- bromobenzene.93,94 With the serendipitous formation of 1-acetyl-4,6-dimethoxy-1,2,3-benzotriazole 228, it was of interest to explore the chemistry of this system further. In particular, we wanted to investigate the reactivity at C7 to determine whether the presence of the electron rich substituents on the benzenoid ring would provide similar activation of the nucleus as evidenced with 4,6-dimethoxyindole. Reactivity at C7 would enrich the benzotriazole chemistry and hence lead to development of novel triazo scaffolds including bis-triazoles related to the general aim of this project.

6.5.1. Synthesis of 4,6-dimethoxy-1,2,3-benzotriazole The parent 4,6-dimethoxybenzotriazole 229 was prepared via deprotection of N- acetylbenzotriazole 228, whose synthesis is described above. Treatment of N- acetylbenzotriazole 228 with methanol in the presence of potassium hydroxide produced the benzotriazole in 86% yield. The product 229 was found to precipitate out of solution upon addition of 10% phosphoric acid (Scheme 6-17). The disappearance of methyl group in the 1H NMR spectrum and carbonyl group in the 13C NMR spectrum confirmed the formation of the parent compound 229. In addition, the high resolution mass spectrometry result of 180.0778 was consistent with C8H9N3O2 and further confirmed the formation of 4,6-dimethoxy benzotriazole.

Scheme 6-17. Reagents and conditions: KOH, methanol, 10% H3PO4, rt

6.5.2. Attempted formylation of 4,6-dimethoxybenzotriazole

Formylation of benzotriazole 229 was attempted using the general protocol applied in the preparation of formylated indoles. In contrast to methoxy substituted indoles, however, no reaction was observed upon treatment of benzotriazole 229 with phosphoryl chloride and N,N-dimethylformamide at room temperature. Likewise, no reaction was observed upon use of more vigorous conditions such as an excess of Vilsmeier reagent, longer reaction times and heating. Finally, no reaction was observed when the formylation reagent triethyl orthoformate in trifluoroacetic acid was used (Scheme 6-18).

Scheme 6-18. Reagents and conditions: i) POCl3, DMF, rt or reflux; ii) TFA, triethyl orthoformate, rt or reflux.

6.5.3. Attempted acylation of 4,6-dimethoxybenzotriazole

The general C7-acylation method employed for activated indoles is the modified Vilsmeier-Haack reaction using phosphoryl chloride and N,N-dimethylacetamide. However, this method was anticipated to be unsuitable owing to the reaction being in general less reactive than the corresponding Vilsmeier formylation95 and the inability of benzotriazole 229 to undergo formylation. Benzimidazole 231 was also found by

Black et al. to be insufficiently nucleophilic to undergo C7 Vilsmeier-Haack acylation. Conversely, under Friedel-Crafts acylation conditions, the corresponding 7-acetylbenzimidazoles 232 were prepared in moderate yields (Scheme 6-19).96

Scheme 6-19. Reagents and conditions: SbCl5, CH3COCl, DCM, rt

The acylation of benzotriazole 229 was therefore performed by the addition of acetyl chloride and antimony pentachloride as catalyst to a solution of the benzotriazole 229 in dichloromethane. The reaction was found to be slower, taking 3 hours to complete, in comparison to the indole and benzimidazole examples, where the reaction was completed in 80 minutes and 2 hours respectively.88,96 The 13C NMR spectrum indicated an acylation had occurred due to the presence of a carbonyl peak at 170 ppm. However, the remaining presence of meta coupling doublets at 6.36 ppm and 7.13 ppm in the 1H NMR spectrum indicated the acylation had occurred at N1 rather than at C7 to give N-acetyl-benzotriazole 228 instead of the target compound 233.

Scheme 6-20. Reagents and conditions: SbCl5, CH3COCl, DCM, rt, 3 h

6.5.4. Attempted synthesis of 7,7′-bisbenzotriazolylmethanes

With the difficulties arising in the formation of 7-acetyl or 7-formyl benzotriazole compounds, efforts were directed to the preparation of 7,7-bisbenzotriazolylmethanes. The preparation of related 7,7-diindolylmethane derivatives has been achieved by acid-catalysed addition of aldehydes to 2,3-diphenylindole. For example, the reaction of diphenylindole 21 with formaldehyde in a solution of tetrahydrofuran under the acidic conditions of hydrochloric acid gave 7,7- diindolylmethane 234 upon filtration.5

Scheme 6-21. Reagents and conditions: HCHO, HCl, THF

Similar treatment of benzotriazole 229 with formaldehyde in the presence of concentrated hydrochloric acid was carried out in tetrahydrofuran at room temperature, however, no reaction was observed and the starting material was recovered unchanged. Repeating the reaction by the addition of formaldehyde to a hot solution of benzotriazole in glacial acetic acid, followed by a few drops of concentrated hydrochloric acid and overnight heating also did not initiate a reaction. Similar methods were investigated with aromatic aldehydes possessing electron withdrawing substituent in the para-position such as 4-nitrobenzaldehyde or 4- chlorobenzaldehyde in place of formaldehyde. However, the reaction again failed to generate compound 235 (Scheme 6-22).

Scheme 6-22. Reagents and conditions: i) HCHO, HCl, THF, rt; ii) HCHO, HCl, AcOH, rt or reflux

6.5.5. Cyclisation of benzotriazole

The reactions studied thus far suggest the C7 of 1,2,3-benzotriazole is insufficiently reactive to undergo direct substitution so as an alternate strategy ring closure onto the C7 position was investigated. This phenomenon has been observed previously with 4,6-dimethoxyindoles with, for example, treatment of N-substituted indole 236 with polyphosphoric acid affording pyrroloindole 237.97

Scheme 6-23. Reagents and conditions: PPA, 100 ºC

As an extension of this reaction, we decided to examine the preparation of the corresponding pyrrolobenzotriazole system. Accordingly, benzotriazole 229 was first reacted with 4-bromoacetophenone in the presence of potassium carbonate in N,N- dimethylformamide at room temperature to afford N-phenylacyl benzotriazole 238 in 26% yield (Scheme 6-24). The reaction was found to be low yielding because of the formation of many side products which were eliminated via column chromatography. 82

The IR spectrum of the compound indicated the carbonyl absorption at 1701 cm-1 and the 1H NMR spectrum also indicated the appearance of a singlet at 6.08 ppm corresponding to CH2 and multiplets at 7.49-8.00 ppm corresponding to five aromatic protons of the phenyl ring.

Scheme 6-24. Reagents and conditions: 2-bromoacetophenone, K2CO3, DMF, rt

The second step involved the cyclisation of the compound 238 with polyphosphoric acid at 100 ºC, however, a mixture of products was formed in the reaction mixture. Trifluoroacetic acid was consequently substituted for polyphosphoric acid and the reaction carefully monitored by thin layer chromatography. After heating the reaction at reflux for 3 days, the formation of a single product was observed though some of the starting material remained unchanged. The product was isolated upon work up and intensive column chromatography. However, both the high resolution mass spectrum and the 1H NMR spectrum of the resulting solid were not consistent with the desired benzotriazole 239 as shown in Scheme 6-25. The 1H NMR spectrum showed only one methoxy group at 4.11 ppm and the appearance of a broad singlet at 13.72 ppm suggested the second methoxy group had undergone demethylation. The anticipated vinyl proton integrating for 1H was also not present, with a new singlet which integrated for 2H instead appearing at 6.12 ppm. In addition, the 13C NMR spectrum showed a CH2 resonance at 61.77 ppm, a carbonyl carbon at 189 ppm and a

CF3 resonance at 114 ppm. It was therefore concluded that the cyclisation had not occurred as expected by nucleophilic attack at the carbonyl group but, instead resulted in the formation of compound 240.

OMe N N MeO N

OMe N 239 N N MeO OMe O N N N HO O O CF 238 3

240 Scheme 6-25. Reagents and conditions: TFA, reflux, 3 d

6.6. Conclusions

In summary, all attempts to synthesize 7-bromoindole or 7-aminoindole failed due to the formation of unexpected compounds. Although there are still many methods which could be applied, no further strategies were examined because of the time limitation. The unexpected formation of 4,6-dimethoxybenzotriazole in this study led to the subsequent investigation of the C7 reactivity of this system towards a variety of reactions including formylation, acylation and acid catalysed dimerization. The presence of electron-withdrawing nitrogen atoms in the five membered rings was found to still deactivate the C7-position towards electrophilic substitution despite the presence of the activating methoxy groups however ring closure of N- phenylethanone benzotriazole 238 led to formation of an interesting 5-membered ring containing a trifluoroacetate group.

Chapter VII

SYNTHESIS OF 7,7′-BIS-INDOLE ANALOGUES FROM 7-OXOTRYPTAMINE ANALOGUES

7.1. Introduction

Marine sponges have been of interest to chemists over the past two decades as they are recognized as a very rich source of bioactive indole and bis-indole metabolites. For example, antifungal nortopsentins 27 and antitumor and antiviral active topsentins 28 have been isolated from Spongosorites ruetzleri and Topsentia genitrix respectively.98 In addition, cytotoxic dragmacidin B 241 and 2,5-bis (6-bromo-3- indolyl) piperazine 242 have been isolated from Dragmacidon sponge,99,100 and antifungal hamacanthins B 243 were isolated from a deep-water sponge of the genus Hamacantha.98,101

H N R Br H N O N Br Br N Br N R N N N H H H

241 = CH3 243 242 = H

The synthetic preparation of these bis-indole series has been facilitated by the use of 3-aminoacetylindole derivatives. For example, the oxidative dimerization of 3- aminoacetylindole 44 in ammonium hydroxide solution and air at 100 ºC produced topsentin A 244 (Scheme 7-1).102

Scheme 7-1. Reagent and conditions: NH4OH, 100 ºC

Also, heating 5-bromooxotryptamine 245 in a mixture of xylene and ethanol (4:1) at 130 ºC under an argon atmosphere for 3 days followed by exposure to air resulted in the formation of pyrazine 246. The reduction of pyrazine 246 was then performed with cyanoborohydride either in acetic acid or formic acid to afford the corresponding dragmacidin derivatives 241 and 242 (Scheme7-2).103

H H O N N R NH 2 Br N Br a N b

Br N H Br N Br N R N N H H

245 246 241 = CH3 242 = H

Scheme 7-2. Reagent and conditions: a) xylene, ethanol, 130 ºC, 3 d; b) NaBH3CN, AcOH or HCOOH

7.2. Synthesis of oxotryptamine

Oxotryptamine 44 is most typically synthesized from the corresponding 3- acylcyanide 247 via hydrogenation using Pd/C in acetic acid. In turn, the parent indolyl-3-carbonyl nitrile 247 can be prepared via treatment of the readily available indole oxalyl chloride 164 with cuprous cyanide (Scheme 7-3).104

Scheme 7-3. Reagent and conditions: a) CuCN, rt; b) H2, Pd/C, AcOH, rt

Recently, Janosik et al. reported another efficient synthesis of the acyl cyanide 247 via the cyanohydrin silylether 249 intermediate which is prepared through treatment of 3-formylindole 248 with trimethlysilyl cyanide (TMSCN) under reflux in acetonitrile. Oxidation of intermediate 249 with 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ) in dioxane at room temperature then affords the corresponding indole carbonyl nitrile 247 (Scheme 7-4).105

Scheme 7-4. Reagent and conditions: a) TMSCN, CH3CN, reflux; b) DDQ, dioxane, rt

7.3. Synthesis of 7-oxotryptamines

Our effort was aimed at the synthesis of 7-oxotryptamines followed by utilisation of their primary amine moiety to prepare 7,7-bis-indole metabolites. As described in Chapter 2, indoles react with oxalyl chloride to yield 7-glyoxalyl chlorides in around 13-15% yields. In contrast, 7-formyl indoles can be prepared in 70-100% yields via Vilsmeier formylation. Consequently, the strategy starting from the 7-formylindoles was found to be the more convenient and reliable.

The synthesis of 7-acylcyanides 254-256 was successfully accomplished over two consecutive steps as illustrated in Scheme 7-5. The first step involved the treatment

87 of 7-formylindoles 93, 95 and 250 with TMSCN in acetonitrile at reflux to afford the 7-cyanohydrin silylether intermediates 251-253 in good yields. The stability of these 7-indolyl silylethers at room temperature was found to be very high in comparison to the 3-indolyl silylethers.

The 1H NMR spectrum of the compound 251, as an example, displayed the trimethyl protons at 0.2 ppm, the CH proton at 6.19 ppm and the H5 proton appeared at 6.26 ppm. This assignment was confirmed by the both HSQC and the HSBC analysis. The 13C NMR spectrum indicated the presence of the trimethyl groups and the nitrile groups with carbon resonances at 0.58 ppm and 119 ppm respectively. Also, the nitrile (CN) band absorption was seen at 3428 cm-1in the infrared spectrum.

The compounds 251-253 were subsequently oxidized with DDQ in dioxane at room temperature to the corresponding 7-carbonyl nitriles 254-256. Although a single product was isolated from the reaction mixture, the residue was subjected to column chromatography in order to eliminate baseline impurities. The orange compounds were obtained in 80-90% yields.

Scheme 7-5. Reagent and conditions: a) TMSCN, CH3CN, reflux; b) DDQ, dioxane, rt

The infrared spectrum of the compound 256 showed the carbonyl frequency at 1583 cm-1 and the nitrile frequency at 3381 cm-1. The 1H NMR spectrum also showed the absence of trimethyl protons and CH proton and the 13C NMR spectrum showed the appearance of the carbonyl resonance at 164 ppm and still demonstrated the nitrile resonance at 119 ppm.

The ensuing step was hydrogenation of the 7-acylcyanides to the 7-oxotryptamines as shown in Scheme 7-6. Accordingly, 7-acylcyanides 254-256 was stirred under hydrogen in the presence of 10% Pd/C in a mixture of ethyl acetate and acetic acid (2:3) for 20 hours to afford 7-oxotryptamines 257-259 in 65-91% yields. Indole 258 was found to be oily and was therefore converted to the hydrochloride salt whilst indole 259 was obtained as the acetate salt.

Scheme 7-6. Reagent and conditions: H2, Pd/C, AcOH, rt

The 1H NMR spectrum of the compound 258 showed methylene protons at 4.30 ppm as a doublet, indicating the reduction was successful. The 13C NMR spectrum also indicated methylene carbon resonances at 48.6 ppm and the carbonyl resonance at 190.7 ppm. Interestingly, the 1H NMR spectra of the anticipated compound 257 demonstrated two H5 protons at 6.5 ppm and two indole NHs at 11.58 ppm and 11.63 ppm. Two carbonyl resonances at 190.02 ppm and 190.06 ppm were also in the 13C NMR spectrum, indicating a mixture of halogenated and dehalogenated 7- oxotryptamines 257 and 260 (Scheme 7-7). The formation of this mixture was further confirmed by high resolution mass spectrometry which showed two molecular ions at 345 (35Cl) and 311 (35Cl) correspond to oxotryptamines 257 and 260 respectively. An attempt to separate the mixture was hindered by the high polarity of the compounds which remained on the baseline of thin layer chromatography.

Cl Cl

OMe OMe OMe

+ MeO N MeO N MeO N H H H NC O O O

NH2 NH2 254 260 257

Scheme 7-7. Reagent and conditions: H2, Pd/C, AcOH, rt

7.4. Synthesis of monomeric 7-indole oxazoles

The oxotryptamine 44 moiety is found in a number of indole-related natural products and biologically active compounds such as prealmazole C 261 and antibiotic pimprinine 262 which is a streptomyces metabolite.106

It was of interest to use a monomeric model for the preparation of 7-oxazole substituted indoles before extending the chemistry to bis-indole systems. Therefore, the synthetic study began with the acylation of readily available 7-oxotryptamines 258 and 259 with acetic anhydride at 0-10 ºC for 4 hours to produce the corresponding ketoamides 263 and 264 in 72% and 71% yield respectively.

The next step involved the treatment of indoles 263 and 264 with excess phosphoryl chloride at reflux in ethyl acetate for 2 hours. This process afforded the 7- methyloxazoles 265 and 266 in 79% and 51% yield respectively (Scheme 7-8).

Scheme 7-8. Reagents and conditions: a) (CH3CO)2, 0-10 ºC for 4 h; b) POCl3, ethyl acetate, reflux, 2h

The disappearance of the amide NH proton at 6.88 ppm and methylene peak at 4.72 ppm, and the appearance of a new CH peak were noted in the 1H NMR spectrum of compound 266. Furthermore, the disappearance of two carbonyl resonances at 170 ppm and 193 ppm and appearance of a new CH resonance at 121 ppm were evident in the 13C NMR spectrum, indicating that cyclisation was successful. The structural determination was further confirmed by a high resolution mass spectrum which revealed the molecular ion peak at 348.1472 (M)+.

7.5. Synthesis of bis-indoles

With the successful execution of the monomeric model in hand, preparation of related bis-indole systems was examined. The first target was to generate the oxazole linked bis-indoles because oxazole containing heterocycles are found in nature, are used as cytotoxic agents and have metal binding properties.107,108

The successful preparation of 7,7-bis-oxazoles 270 and 271 was achieved with a convenient two step process as shown in Scheme 7-9. The first step involved heating 7-oxotryptamines 258 and 261 with 7-trichloroacetylindoles 83 and 267 at reflux overnight in the presence of triethylamine in acetonitrile to afford the unsymmetrical 7,7-amide linked bis-indoles 268 and 269 in 61% and 55% yield respectively.

The new amide functionality was clearly evident in the 1H NMR and 13C NMR spectra of compound 268, with the appearance of amide NH proton as a triplet at 9.33 ppm (J = 8.52 Hz) and the carbonyl groups at 167 ppm and 194 ppm. The 1H NMR spectrum also showed the indole NH protons as downfield singlets at 11.10 ppm and 11.29 ppm, indicating a strong hydrogen bond between the carbonyl groups and the indole nitrogens. The ethylene proton appeared as a doublet at 4.93 ppm with a coupling constant of J = 4.39 Hz. In addition, the infrared spectrum also showed two carbonyl resonances at 1588 and 1615 cm-1.

In the next step, cyclodehydration was carried out by the treatment of bis-indoles 268 and 269 with excess phosphoryl chloride at reflux in ethyl acetate for 2 hours. The process afforded the desired bis-indolyl-oxazoles 270 and 271 in 63% and 61% yield respectively (Scheme7-9). Purification by column chromatography removed baseline impurities.

The high resolution mass spectroscopy of indole 271 showing a molecular ion at 640.2414 which was consistent with the structure 271 (M+Na)+. The 1H NMR spectrum of the compound 271 indicated the disappearance of amide nitrogen protons of the starting material 269 at 9.37 ppm and the appearance of CH proton at 7.64 ppm. The indole nitrogens remained as downfield singlets at 10.56 ppm and 11.31 ppm. The compound 271 was not soluble enough to obtain a 13C NMR spectrum.

Scheme 7-9. Reagents and conditions: a) Et3N, CH3CN, reflux; b) POCl3, ethyl acetate, reflux, 2h

Subsequently, an attempt was made to prepare piperazine linked bis-indoles 272 by heating 7-oxotryptamine 258 in a xylene/ethanol solution under argon atmosphere at 130 ºC. After 4 days, however, no reaction was apparent and only the starting material was observed (Scheme 7-10).

Scheme 7-10. Reagents and conditions: xylene and ethanol, reflux, 4 d

Synthesis of imidazole linked bis-indoles was also attempted using 7-oxotryptamines 258 and 259 via oxidative dimerization. The substrates were heated in 40% ammonia solution at 100 ºC and it was observed that the reaction failed to take place with indole 258 but produced a complex mixture of products for compound 259. One possible reason for this difference is the solubility issues of indole 258 and it was found that the addition of ethanol to the reaction mixture containing 259 overcome the solubility problem and led to formation of a complex mixture of products which could be not isolated.

Scheme 7-11. Reagents and conditions: NH4OH, 100 ºC

7.6. Attempt to synthesize 7-hydroxytryptamine

The related hydroxytryptamine, in which the C=O of the indole 255 is reduced in addition to the cyano group, is a key synthetic precursor to a range of bioactive natural products such as bis-indoles Coscinamide A 275 and Coscinamide B 276 and the monomeric indole igzamide 277. The former were isolated from the marine sponge, Concinoderma sp. and possess partial cytoprotection against HIV in the NCI assay109 while the latter displays weak cytotoxicity against the L1210 murine leukemia cell lines and is produced from the marine sponge, Plocamissa igzo.109

The preparation of amino alcohol 278 from acylcyanide 247 was successfully achieved by Hornbaker et al. through treatment with lithium aluminium hydride in anhydrous diethyl ether.110

Scheme 7-12. Reagent and conditions: LiAlH4, (C2H5)2O

Accordingly, indole 255 was reduced with lithium aluminium hydride in an ice cold solution of tetrahydrofuran. Unlike the analogous reaction above, two products were isolated as white solids after chromatography. The product with higher Rf displayed a 1H NMR spectrum consistent with the well known diindolylmethane 234.

The product with lower Rf, giving a fluorescing colour under the UV light, and was found to be the 7-hydroxymethylindole 280 (Scheme 7-13). The 1H NMR spectrum 13 demonstrated the presence of the CH2 resonance at 5.07 ppm whilst the C NMR spectrum showed the absence of both the cyano and carbonyl signals of indole 255. The high resolution mass spectrum also revealed the molecular weight of compound 280 showing a molecular ion at 359.1514 (M)+.

Scheme 7-13. Reagent and conditions: LiAlH4, THF, rt

The postulated mechanism is shown in Figure 7-1. Reduction of the carbonyl group to an alcohol by lithium aluminium hydride forms intermediate 281 which undergo conversion to the aldehyde with loss of hydrogen cyanide to form indole 95. The aldehyde 95 could then be further reduced to the primary alcohol 280, which could undergo further reaction to produce the dimer 234 upon addition of water in the work-up process.

Figure 7-1. Mechanism for the formation of alcohol and dimer

7.7. Conclusions

In conclusion, the synthesis of 7-oxotryptamine was successfully achieved via hydrogenation of the corresponding indole 7-acylcyanides. The reduction, however, led to formation of halogenated and dehalogenated 7-oxotryptamines 257 and 260. Amide linked bis-indoles were obtained upon reaction of 7-oxotryptamines with 7- trichloroacetyl chlorides and underwent cyclisation with phosphoryl chloride to form oxadiazole linked bis-indoles. The preparation of monomeric 7-oxadiazoles from 7- ketoamides was also achieved in the same manner. An attempt to produce a 7- hydroxytryptamine from 7-acylcyanide via lithium aluminium reduction was unsuccessful, but was found to lead to the formation of a dimer and an alcohol.

CHAPTER VIII

Experimental

8.1. General Information

All reactions requiring anhydrous conditions were performed under an argon atmosphere, and anhydrous solvents were obtained using a PureSolv MD Solvent Purification System. Commercially available reagents were purchased from Fluka, Sigma-Aldrich, Alfa Aesar, Across Organics and Lancaster, and used without further purification.

1H NMR and 13C NMR spectra were recorded in the designated solvents on a Bruker Avance DPX 300 (300 MHz) and DMX 600 (600 MHz) as designated. Chemical shifts on the scale are in parts per million (ppm) and internally referenced to the solvent peaks. Multiplicities are reported as singlet (s), broad singlet (bs) doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublet (dd) where appropriate and the observed coupling constants (J=) are reported in Hertz (Hz).

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

High resolution mass spectra 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, University of Otago, New Zealand.

Gravity column chromatography was carried out using Grace Davison LC60A 40-63 micron silica gel and Grace Davison LC60A 6-35 micron silica gel was used for

98 flash column chromatography. Thin-layer chromatography, performed on Merck DC aluminium foil coated with silica gel GF254, was used to monitor the reactions. Compounds were detected by short and long wavelength ultraviolet light and permanganate solution.

8.2. Experimental Details

2-(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-2-yl)-Nʹ-(2-(3-(4-bromophenyl)- 4,6-dimethoxy-1H-indol-2-yl)-2-oxoacetyl)-2-oxoacetohydrazide (57)

To a solution of 2-glyoxyloyl Br Br chloride 54 (0.75 g, 1.77 mmol) in anhydrous OMe OMe acetonitrile (40 mL), O O hydrazine hydrate (0.044 mL, MeO N NH NH N OMe H H O O 0.907 mmol) was added followed by triethylamine (7 drops) and the mixture was stirred at room temperature for 30 min. The reaction was quenched with ice-water and the resulting precipitate was filtered, dried and recrystallised from methanol to yield the title compound 57 1 (0.66 g, 93%) as a red solid. Mp 296-298 ºC. H NMR (300 MHz, DMSO-d6): 3.61 (s, 6H, OMe), 3.83 (s, 6H, OMe), 6.18 (d, J = 1.80 Hz, 2H, H5), 6.69 (d, J = 1.80 Hz, 2H, H7), 7.32, 7.49 (2d, J = 8.45 Hz, 8H, aryl H), 10.86 (s, 2H, NH), 11.84 (bs, 2H, 13 NH). C NMR (75 MHz, DMSO-d6): 55.56, 55.76 (OMe), 87.07 (C5), 93.84 (C7), 130.03, 133.07 (aryl CH) 112.61, 126.92, 127.08, 133.73, 140.33, 156.40, 161.33

(aryl C), 162.31, 177.86 (C=O). IR (KBr): νmax 3348, 1616, 1519, 1416, 1381, 1316, -1 -1 -1 1250, 1160, 996, 816 cm . UV-vis (CH2Cl2): max 228 nm ( 64,162 cm M ), 263 79/81 + (46,196), 380 (39,138). HRMS (+ESI): C36H29 Br2N4O8 [M+H] requires 805.0352, found 805.0347.

2-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-2-yl)-Nʹ-(2-(4,6-dimethoxy-3-(p-tolyl)-1H- indol-2-yl)-2-oxoacetyl)-2-oxoacetohydrazide (58)

To a solution of 2-glyoxyloyl chloride 55 (1.5 g, 4.2 mmol) OMe OMe in anhydrous acetonitrile (50 O O mL), hydrazine hydrate (0.1 MeO N NH NH N OMe H H mL, 2.05 mmol) was added O O followed by triethylamine (10 drops) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with ice-water and the resulting precipitate was filtered, dried and recrystallised from methanol to afford the title compound 58 (1.34 g, 95%) as a red solid. Mp 275-277 ºC. 1H NMR (300 MHz,

DMSO-d6): 2.31 (s, 3H, Me), 3.57 (s, 6H, OMe), 3.80 (s, 6H, OMe), 6.14 (d, J = 1.78 Hz, 2H, H5), 6.64 (d, J = 1.78 Hz, 2H, H7), 7.08, 7.23 (2d, J = 7.93 Hz, 8H, 13 aryl H), 10.61 (s, 2H, NH), 11.70 (bs, 2H, NH). C NMR (75 MHz, DMSO-d6): 21.32 (Me), 55.47, 55.69 (OMe), 86.94 (C5), 93.58 (C7), 127.66, 130.96 (aryl CH), 112.71, 127.25, 128.58, 131.24, 136.29, 140.34, 156.61, 161.16 (aryl C), 162.19,

178.12 (C=O). IR (KBr): νmax 3356, 1608, 1520, 1448, 1415, 1382, 1250, 1129, 811 -1 -1 -1 cm . UV-vis (MeOH): max 211 nm ( 66,884 cm M ), 259 (32,205), 363 (24,272). + HRMS (+ESI): C38H34N4O8 [M+H] requires 675.2455, found 675.2449.

2-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-Nʹ-(2-(4,6-dimethoxy-2,3- diphenyl-1H-indol-7-yl)-2-oxoacetyl)-2-oxoacetohydrazide (61)

To a solution of 7-glyoxyloyl chloride 47 (0.504 g, 1.2 mmol) OMe Ph in anhydrous acetonitrile (30 mL), hydrazine hydrate (0.031 Ph MeO N mL, 0.64 mmol) was added followed by triethylamine (10 H O drops) and the solution was stirred at room temperature for O 1.5 h. The reaction was quenched with ice-water and the NH NH resulting precipitate was filtered, dried and recrystallised O O from ethanol to yield the title compound 61 (0.503 g, 100%) H MeO N as a yellow solid. Mp 284-286 ºC. 1H NMR (300 MHz, Ph

DMSO-d6): 3.83 (s, 6H, OMe), 4.02 (s, 6H, OMe), 6.49 (s, OMe Ph 2H, H5), 7.28-7.32 (m, 20H, aryl H), 10.64 (bs, 2H, NH), 11.01 (bs, 2H, NH). 13C

100

NMR (75 MHz, DMSO-d6): 56.24, 57.33 (OMe), 89.14 (C5), 126.80, 127.77, 127.90, 128.19, 128.33, 128.46, 128.69, 128.82, 131.40 (aryl CH), 101.33, 112.76, 114.87, 132.03, 133.18, 135.51, 137.10, 161.85, 162.45 (aryl C), 166.81, 188.53

(C=O). IR (KBr): νmax 3414, 1643, 1583, 1466, 1361, 1348, 1242, 1219, 1140, 756, -1 -1 -1 699 cm . UV-vis (CH2Cl2): max 230 nm ( 83,197 cm M ), 272 (73,085), 337 + (52,685). HRMS (+ESI): C48H38N4O8 [M+Na] requires 821.2587, found 821.2582.

2-(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-7-yl)-Nʹ-(2-(3-(4-bromophenyl)- 4,6-dimethoxy-1H-indol-7-yl)-2-oxoacetyl)-2-oxoacetohydrazide (62)

The 7-glyoxyloyl chloride 59 (0.215 g, 0.65 mmol) was Br dissolved in anhydrous acetonitrile (30 mL). Hydrazine hydrate OMe (0.016 mL, 0.33 mmol) was added followed by triethylamine (10 drops) and the solution was stirred at room temperature for MeO N 1.5 h. The reaction was quenched with ice-water and the H O O resulting precipitate was filtered, dried and recrystallised from NH methanol to yield the title compound 62 (0.198 g, 76%) as a NH 1 O yellow solid. Mp 277-279 ºC. H NMR (300 MHz, DMSO-d6): O H 3.97 (s, 6H, OMe), 3.99 (s, 6H, OMe), 6.51 (s, 2H, H5), 7.25 MeO N (d, J = 2.53 Hz, 2H, H2), 7.50, 7.55 (2d, J = 8.74 Hz, 8H, aryl H), 10.53 (s, 2H, NH), 11.56 (d, J = 2.35 Hz, 2H, NH). 13C OMe

NMR (75 MHz, DMSO-d6): 56.22, 57.33 (OMe), 88.86 (C5), 124.04 (C2), 130.88, 131.46 (aryl CH), 101.68, 110.16, 116.70, Br 119.21, 135.02, 137.48, 161.39, 162.31, 167.01 (aryl C), 179.47, 188.32 (C=O). IR -1 (KBr): max 3396, 1610, 1581, 1557, 1534, 1323, 1217 cm . UV-vis (THF): max 212 -1 -1 + nm ( 50,688 cm M ), 331 (18,767). HRMS (+ESI): C36H28Br2N4O8 [M+H] requires 803.0352, found 803.0347.

101

2-(4,6-Dimethoxy-2,3-bis(4-methoxyphenyl)-1H-indol-7-yl)-Nʹ-(2-(4,6- dimethoxy-2,3-bis(4-methoxyphenyl)-1H-indol-7-yl)-2-oxoacetyl)-2- oxoacetohydrazide (63) OMe To a solution of 7-glyoxyloyl chloride 60 (0.39 g, 0.81 mmol) in anhydrous acetonitrile (25 mL), OMe hydrazine hydrate (0.0198 mL, 0.41 mmol) was added followed by triethylamine (7 drops) and the OMe MeO N H solution was stirred at room temperature for 30 O O min. The reaction was quenched with ice-water NH and the resulting precipitate was filtered, dried and NH O recrystallised from ethanol to yield the title O H MeO compound 63 (0.36 g, 97%) as a yellow solid. Mp N OMe 1 197-199 ºC. H NMR (300 MHz, CDCl3): 3.63 (s, 6H, OMe), 3.68 (s, 6H, OMe), 3.76 (s, 6H, OMe OMe), 3.88 (s, 6H, OMe), 5.92 (s, 2H, H5), 6.69- OMe 6.75 (m, 8H, aryl H), 7.06-7.14 (m, 8H, aryl H), 13 10.25 (bs, 2H, NH), 10.52 (bs, 2H, NH). C NMR (75 MHz, DMSO-d6): 58.00, 58.20, 58.93, 60.00 (OMe), 91.71 (C5), 116.09, 117.06, 132.26, 135.16 (aryl CH), 104.03, 115.63, 116.20, 127.32, 130.44, 135.65, 139.64, 160.83, 161.60, 164.39,

164.82 (aryl C), 169.51, 191.31 (C=O). IR (KBr): νmax 3415, 3227, 2941, 2835, -1 1585, 1361, 1249, 1031, 990, 830, 796 cm . UV-vis (CH2Cl2): max 224 nm ( 67,342 -1 -1 + cm M ). HRMS (+ESI): C52H47N4O12 [M+H] requires 919.3190, found 919.3185.

4,5,6-Trimethoxy-2,3-diphenylindole (69) OMe A mixture of 3,4,5-trimethoxyaniline 67 (1 g, 5.46 mmol) and Ph MeO benzoin 19 (1.4 g, 6.6 mmol) was heated with stirring at 140 Ph MeO N ºC for 2 h. On cooing, aniline (0.8 mL, 8.78 mmol) was H added together with acetic acid (10 mL) and the mixture was heated under reflux for 5 h. On cooling, methanol (20 mL) was added to the mixture and the resulting precipitate was filtered, washed with methanol and n-hexane to yield the title compound 69 (0.98 g, 50%) as a grey solid. Mp 218-220 ºC (lit.34 219-220 ºC). 1H

NMR (300 MHz, DMSO-d6): 3.35 (s, 3H, OMe), 3.69 (s, 3H, OMe), 3.83 (s, 3H,

102

OMe), 6.75 (s, 1H, H5), 7.19-7.32 (m, 10H, aryl H), 11.35 (bs, 1H, NH). 13C NMR

(75 MHz, DMSO-d6): 56.24, 60.91, 61.18 (OMe), 90.72 (C7), 126.38, 127.15, 127.86, 128.0, 128.65, 131.31 (aryl CH), 90.73, 113.53, 115.77, 132.89, 132.96, 133.35, 136.56, 136.75, 146.67, 150.95 (aryl C).

2-Oxo-Nʹ-(2-oxo-2-(4,5,6-trimethoxy-2,3-diphenyl-1H-indol-7-yl)acetyl)-2-(4,5,6- trimethoxy-2,3-diphenyl-1H-indol-7-yl)acetohydrazide (71)

To a solution of 7-glyoxyloyl chloride 70 (0.52 g, 1.15 mmol) OMe Ph MeO in anhydrous acetonitrile (30 mL), hydrazine hydrate (0.028 Ph mL, 0.57 mmol) was added followed by triethylamine (7 MeO N H O drops) and the solution was stirred at room temperature for O 1.5 h. The reaction was quenched with ice-water and the NH NH resulting precipitate was filtered, dried and recrystallised O O from ethyl acetate to yield the title compound 71 (0.41 g, H MeO N 83%) as a yellow solid. Mp 256-257 ºC. 1H NMR (300 MHz, Ph MeO CDCl ): 3.60 (s, 6H, OMe), 3.76 (s, 6H, OMe), 4.01 (s, 6H, 3 OMe Ph OMe), 7.18-7.29 (m, 20H, aryl H), 8.49 (bs, 2H, NH), 10.17 (bs, 2H, NH). 13C NMR

(75 MHz, CDCl3): 61.61, 61.68, 62.99 (OMe), 127.02, 128.15, 128.35, 129, 131.54 (aryl CH), 106.64, 115.15, 119.18, 132.12, 133.74, 135.32, 135.43, 139.61, 155.66,

156.85 (aryl C), 164.38, 188.85 (C=O). IR (KBr): νmax 3420, 3192, 1683, 1572, -1 1480, 1449, 1377, 1325, 1283, 1155, 1053, 984 cm . UV-vis (MeOH): max 228 nm -1 -1 + ( 59,612 cm M ), 336 (35,111). HRMS (+ESI): C50H42N4O10 [M+Na] requires 881.2799, found 881.2793.

103

2-(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-oxo-N-phenylacetamide (72) Cl Indole 78 (0.66 g, 2.3 mmol) was partially dissolved in anhydrous diethyl ether (40 mL). Oxalyl chloride (1 mL) was OMe added in one portion. The mixture was stirred for 3 h at room temperature. The resulting red precipitate was filtered off. The MeO N H filtrate containing 2-indol-7-ylglyoxyloyl chloride 35 was O O evaporated under pressure. The residue was redissolved in NH diethyl ether (10 mL) and excess aniline was added. The mixture was allowed to stir for 1 h. The resulting precipitate was filtered and washed with water to yield the title compound 72 (0.28 g, 28%) as a 1 yellow solid. Mp 286-289 ºC. H NMR (300 MHz, DMSO-d6): 3.79 (s, 3H, OMe), 3.92 (s, 3H, OMe), 6.48 (s, 1H, H5), 7.06-7.39 (m, 6H, H2, aryl H), 7.53, 7.67 (2d, J = 8.70 Hz, 4H, aryl H), 10.49 (bs, 1H, NH), 11.60 (d, J = 2.01 Hz, 1H, NH). 13C

NMR (75 MHz, DMSO-d6): 56.21, 57.95 (OMe), 89.34 (C5), 123.91 (C2), 119.89, 124.23, 127.96, 129.24, 131.09 (aryl CH), 101.52, 110.51, 116.70, 130.73, 134.61,

137.48, 139.18, 161.35, 162.07 (aryl C), 166.73, 188.31 (C=O). IR (KBr): νmax 3323, -1 1655, 1585, 1535, 1326, 1216, 1119, 1091 cm . UV-vis (THF): max 234 nm ( -1 -1 + 54,021 cm M ), 252 (52,668), 337 (24,547). HRMS (+ESI): C24H19ClN2O4 [M+H] requires 435.1111, found 435.1107.

2-(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-oxo-N-(p-tolyl)acetamide (73)

Indole 78 (0.48 g, 1.67 mmol) was partially dissolved in Cl anhydrous diethyl ether (40 mL). Oxalyl chloride (1 mL) was added in one portion. The mixture was stirred for 3 h at room OMe temperature. The resulting red precipitate was filtered off. The MeO N filtrate containing 2-indol-7-ylglyoxyloyl chloride 35 was H O evaporated under pressure. The residue was redissolved in O NH diethyl ether (15 mL) and excess p-toluidine was added. The mixture was allowed to stir for 1 h. The resulting precipitate

104 was filtered and washed with water to yield the title compound 73 (0.2 g, 27%) as a yellow solid. Mp 275-277 ºC. (Found: C, 66.90; H, 4.67; N, 6.26; C25H21ClN2O4 1 requires C, 66.89; H, 4.72; N, 6.26%). H NMR (300 MHz, DMSO-d6): 2.28 (s, 3H, Me), 3.78 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.47 (s, 1H, H5), 7.13-7.55 (m, 9H, H2, aryl H), 10.39 (bs, 1H, NH), 11.57 (d, J = 2.19 Hz, 1H, NH). 13C NMR (75

MHz, DMSO-d6): 20.86 (Me), 56.21, 57.95 (OMe), 89.34 (C5), 123.08 (C2), 119.88, 124.21, 127.95, 129.61, 131.09 (aryl CH), 101.56, 110.48, 116.67, 130.07, 130.42, 130.71, 132.84, 134.61, 136.64, 137.47, 161.28, 162.03 (aryl C), 166.57, -1 188.45 (C=O). IR (KBr): max 3336, 1653, 1585, 1536, 1326, 1216, 1093 cm . UV- -1 -1 vis (THF): max 203 nm ( 63,495 cm M ), 253 (40,124), 336 (17,235). HRMS + (+ESI): C25H21ClN2O4 [M+H] requires 449.1268, found 449.1263

2-(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-oxo-N-phenylacetamide (74)

3-(4-Bromophenyl)-4,6-dimethoxyindole (0.56 g, 1.69 mmol) Br was partially dissolved in anhydrous diethyl ether (40 mL). Oxalyl chloride (1 mL) was added in one portion. The mixture OMe was stirred for 3 h at room temperature. The resulting red MeO N precipitate was filtered off. The filtrate containing 2-indol-7- H O ylglyoxyloyl chloride 59 was evaporated under pressure. The O NH residue was redissolved in diethyl ether (20 mL) and excess aniline was added. The mixture was allowed to stir for 1 h. The resulting precipitate was filtered and washed with water to yield the title compound 74 (0.31 g, 38%) as a yellow solid. Mp 286-288 ºC. 1H

NMR (300 MHz, DMSO-d6): 3.79 (s, 3H, OMe), 3.92 (s, 3H, OMe), 6.48 (s, 1H, H5), 7.09 (t, J = 14.89 Hz, 1H, aryl H), 7.23 (d, J = 7.23 Hz, 2H, H2), 7.34 (t, J = 16.06 Hz, 2H, aryl H), 7.46, 7.51 (2d, J = 8.76 Hz, 4H, aryl H), 7.67 (d, J = 7.59 Hz, 2H, aryl H), 10.47 (bs, 1H, NH), 11.60 (d, J = 2.09 Hz, 1H, NH). 13C NMR (75

MHz, DMSO-d6): 56.23, 57.96 (OMe), 89.35 (C5), 123.91 (C2), 119.22, 124.22, 129.24, 130.87, 131.47 (aryl CH), 101.51, 110.45, 116.71, 119.88, 134.98, 137.48,

139.17, 161.34, 162.06 (aryl C), 166.71, 188.30 (C=O). IR (KBr): max 3330, 1655, -1 -1 -1 1585, 1530, 1326, 1215, 1118 cm . UV-vis (THF): max 219 nm ( 27,919 cm M ),

105

+ 238 (47.710), 331 (20,269). HRMS (+ESI): C24H19BrN2O4 [M+H] requires 479.0606, found 479.0594.

2-(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-oxo-N-p-tolylacetamide (75)

3-(4-Bromophenyl)-4,6-dimethoxyindole (0.52 g, 1.57 mmol) Br was partially dissolved in anhydrous diethyl ether (40 mL). OMe Oxalyl chloride (1 mL) was added in one portion. The mixture was stirred for 3 h at room temperature. The resulting red MeO N precipitate was filtered off. The filtrate containing 2-indol-7- H O ylglyoxyloyl chloride 59 was evaporated under pressure. The O NH residue was redissolved in diethyl ether (15 mL) and excess p- toluidine was added. The mixture was allowed to stir 1 h. The resulting precipitate was filtered and washed with water to yield the title compound 75 (0.317 g, 41%) as a yellow solid. Mp 275-277 ºC.

(Found: C, 60.84; H, 4.29; N, 5.73; C25H21BrN2O4 requires C, 60.86; H, 4.29; N, 1 5.68%). H NMR (300 MHz, DMSO-d6): 2.26 (s, 3H, Me), 3.78 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.47 (s, 1H, H5), 7.13-7.56 (m, 9H, H2, aryl H), 10.38 (bs, 1H, NH), 13 11.58 (d, J = 2.21 Hz, 1H, NH). C NMR (75 MHz, DMSO-d6): 20.86 (Me), 56.21, 57.95 (OMe), 89.36 (C5), 122.69 (C2), 119.87, 124.20, 129.61, 130.44, 130.86, 131.46 (aryl CH), 101.57, 110.44, 116.69, 119.22, 132.83, 135.00, 136.65,

137.50, 161.28, 162.04 (aryl C), 166.56, 188.46 (C=O). IR (KBr): νmax 3332, 1652, -1 -1 -1 1588, 1536, 1325, 1215, 1094 cm . UV-vis (THF): max 203 nm ( 67,030 cm M ), + 253 (36,194), 336 (15,964). HRMS (+ESI): C25H21BrN2O4 [M+H] requires 493.0763, found 493.0756.

106

2-(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-oxo-Nʹ- phenylacetohydrazide (76)

Indole 78 (0.51 g, 1.77 mmol) was partially dissolved in Cl anhydrous diethyl ether (40 mL). Oxalyl chloride (1 mL) was added in one portion. The mixture was stirred for 3 h at room OMe temperature. The resulting red precipitate was filtered off. The MeO N filtrate containing 2-indol-7-ylglyoxyloyl chloride 35 was H O evaporated under pressure. The residue was redissolved in O NH diethyl ether (15 mL) and excess phenyl hydrazine was added. NH The mixture was allowed to stir for 1 h. The resulting precipitate was filtered and washed with water to yield the title compound 76 (0.24 g, 30%) as a yellow solid. Mp 247-249 ºC. (Found: C, 63.89; H, 1 4.41; N, 9.38; C24H20ClN3O4 requires C, 64.07; H, 4.48; N, 9.34%). H NMR (300

MHz, DMSO-d6): 3.87 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.45 (s, 1H, H5), 6.49 (s, 1H, H5), 7.40-7.90 (m, 20H, H2, aryl H), 9.53 (bs, 1H, NH), 10.11 (d, J = 2.39 Hz, 1H, NH), 11.48, 11.57 (2d, J = 1.91 Hz, 13 2H, NH). C NMR (75 MHz, DMSO-d6): 56.11, 56.20, 57.38, 57.55 (OMe), 88.71, 89.12 (C5), 123.93, 124.12 (C2), 112.71, 113.84, 118.99, 119.93, 127.93, 128.82, 129.05, 131.07 (aryl CH), 101.56, 101.70, 110.22, 110.34, 116.48, 116.67, 130.63, 130.71, 134.61, 134.67, 137.15, 137.44, 148.78, 149.61, 160.83, 161.30,

161.69, 162.11 (aryl C), 168.05, 172.38, 189.24, 189.36 (C=O). IR (KBr): νmax 3314, -1 3284, 1693, 1581, 1345, 1219, 1184, 1089 cm . UV-vis (THF): max 203 nm ( 63,197 cm-1M-1), 231 (37.084), 253 (28,037), 337 (15,398). HRMS (+ESI): + C24H20ClN3O4 [M+H] requires 450.1220, found 450.1212.

107

2-(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-oxo-Nʹ- phenylacetohydrazide (77)

3-(4-Bromophenyl)-4,6-dimethoxyindole (0.51 g, 1.77 mmol) Br was partially dissolved in anhydrous diethyl ether (40 mL). Oxalyl chloride (1 mL) was added in one portion. The mixture OMe was stirred for 3 h at room temperature. The resulting red MeO N precipitate was filtered off. The filtrate containing 2-indol-7- H O ylglyoxyloyl chloride 59 was evaporated under pressure. The O NH residue was redissolved in diethyl ether (15 mL) and excess NH phenyl hydrazine was added. The mixture was allowed to stir 1 h. The resulting precipitate was filtered and washed with water to yield the title compound 77 (0.247 g, 31%) as a yellow solid. Mp 248-250 ºC. 1H

NMR (300 MHz, DMSO-d6): 3.87 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.45 (s, 1H, H5), 6.49 (s, 1H, H5), 7.40-7.90 (m, 20H, H2, aryl H), 9.53 (bs, 1H, NH), 10.11 (d, J = 2.39 Hz, 1H, NH), 11.48, 11.57 (2d, J = 13 1.91 Hz, 2H, NH). C NMR (75 MHz, DMSO-d6): 56.12, 56.20, 57.38, 57.55 (OMe), 88.72, 89.16 (C5), 123.93, 124.11 (C2), 112.71, 113.84, 118.99, 119.22, 119.94, 128.82, 129.05, 130.84, 131.45 (aryl CH), 101.56, 101.71, 110.17, 110.29, 116.48, 116.69, 119.14, 134.99, 135.05, 137.17, 137.46, 148.79, 149.61, 160.83, 161.30, 161.70, 162.12, 168.04 (aryl C), 172.38, 189.24, 189.36 (C=O). IR (KBr): -1 νmax 3318, 3284, 1695, 1578, 1345, 1218, 1087 cm . UV-vis (THF): max 203 nm ( -1 -1 + 67,889 cm M ), 232 (41.854), 337 (17,467). HRMS (+ESI): C24H20BrN3O4 [M+H] requires 494.0715, found 494.0710.

3-(4-Chlorophenyl)-Nʹ-(3-(4-chlorophenyl)-4,6-dimethoxy-1H-indole-2- carbonyl)-4,6-dimethoxy-1H-indole-2-carbohydrazide (80) Cl Cl To a solution of 2- trichloroacetylindole 40 (0.5 g, 1.16 OMe OMe mmol) in acetonitrile (20 mL), O O hydrazine hydrate (0.028 mL, 0.57 MeO N HN NH N OMe mmol) followed by triethylamine (5 H H drops) was added and the mixture was heated under reflux for 24 h. The solvent was

108 then evaporated and the residue was quenched with water. The resulting precipitate was filtered, washed with water, dried and recrystallised from methanol to yield the title compound 80 (0.21 g, 55%) as a white solid. Mp 292-294 ºC. 1H NMR (300

MHz, CDCl3): 3.53 (s, 6H, OMe), 3.76 (s, 6H, OMe), 6.05 (d, J = 1.71 Hz, 2H, H5), 6.33 (d, J = 1.59 Hz, 2H, H7), 7.37 (s, 8H, aryl H), 7.70 (bs, 2H, NH). 9.05 (bs, 13 2H, NH). C NMR (75 MHz, CDCl3): 55.51, 56.02 (OMe), 86.26 (C5), 93.54 (C7), 129.08, 132.44 (aryl CH) 113.29, 119.22, 122.51, 133.17, 134.54, 137.82,

156.39, 159.40 (aryl C), 160.55 (C=O). IR (KBr): νmax 3354, 1626, 1536, 1259, -1 -1 -1 1210, 1132, 1089, 811 cm . UV-vis (THF): max 214 nm ( 64,497 cm M ), 254 + (49,623), 315 (26,062). HRMS (+ESI): C34H28Cl2N4O6 [M+Na] requires 681.1284, found 681.1292.

3-(4-Bromophenyl)-Nʹ-(3-(4-bromophenyl)-4,6-dimethoxy-1H-indole-2- carbonyl)-4,6-dimethoxy-1H-indole-2-carbohydrazide (81)

To a solution of 7- Br Br trichloroacetylindole 79 (0.23 g, 0.48 mmol) in acetonitrile (20 mL), OMe OMe O O hydrazine hydrate (0.012 mL, 0.25 MeO N HN NH N OMe mmol) followed by triethylamine (3 H H drops) was added and the mixture was heated under reflux for 24 h. The resulting precipitate was filtered, washed with water, dried and recrystallised from methanol to afford the title compound 81 (0.09 g, 51%) as a light brown solid. Mp >300 ºC. 1H

NMR (300 MHz, DMSO-d6): 3.58 (s, 6H, OMe), 3.76 (s, 6H, OMe), 6.15 (d, J = 1.94 Hz, 2H, H5), 6.49 (d, J = 1.47 Hz, 2H, H7), 7.32, 7.47 (2d, J = 8.46 Hz, 8H, 13 aryl H), 9.19 (s, 2H, NH), 11.63 (bs, 2H, NH). C NMR (75 MHz, DMSO-d6): 55.38, 55.63 (OMe), 86.95 (C5), 92.97 (C7), 130.19, 133.51 (aryl CH), 111.49, 118.59, 120.21, 124.02, 134.23, 137.91, 155.42, 158.97 (aryl C), 160.61 (C=O). IR -1 (KBr): max 3307, 1627, 1597, 1524, 1290, 1203, 1153, 1135 cm . IR (CH2Cl2): max 228 nm ( 62,802 cm-1M-1), 256 (66,872), 328 (39,879). HRMS (+ESI): + C34H28Br2N4O6 [M+H] requires 747.0454, found 747.0450.

109

3-(4-Chlorophenyl)-Nʹ-(3-(4-chlorophenyl)-4,6-dimethoxy-1H-indole-7- carbonyl)-4,6-dimethoxy-1H-indole-7-carbohydrazide (84)

To a solution of 7-trichloroacetylindole 41 (0.372 g, 0.86 Cl mmol) in acetonitrile (25 mL), hydrazine hydrate (0.021 mL, 0.43 mmol) followed by triethylamine (5 drops) was added and OMe the mixture was heated under reflux for 24 h. The resulting MeO N precipitate was filtered, washed with acetonitrile and water to H afford the title compound 84 (0.23 g, 81%) as a brown solid. HN O HN O Mp >300 ºC. 1H NMR (300 MHz, DMSO-d ): 3.95 (s, 6H, 6 H MeO OMe), 4.15 (s, 6H, OMe), 6.59 (s, 2H, H5), 7.28 (d, J = 2.14 N Hz, 2H, H2), 7.41, 7.56 (2d, J = 8.49 Hz, 8H, aryl H), 10.54 (s, OMe 2H, NH), 11.54 (bs, 2H, NH). IR (KBr): νmax 3388, 1592, 1448, -1 1340, 1213, 1151, 792 cm . UV-vis (THF): max 243 nm ( Cl 86,634 cm-1M-1), 279 (45,830), 348 (57,198), 364 (42,599). 35 + HRMS (+ESI): C34H28 Cl2N4O6 [M+Na] requires 681.1284, found 681.1273. The sample was not soluble enough for 13C NMR measurement.

3-(4-Bromophenyl)-Nʹ-(3-(4-bromophenyl)-4,6-dimethoxy-1H-indole-7- carbonyl)-4,6-dimethoxy-1H-indole-7-carbohydrazide (85) Br To a solution of 7-trichloroacetylindole 82 (0.6 g, 1.25 mmol) in acetonitrile (20 mL), hydrazine hydrate (0.03 mL, 0.43 OMe mmol) followed by triethylamine (5 drops) was added and the mixture was heated under reflux for 24 h. The resulting MeO N precipitate was filtered, washed with acetonitrile and water to H HN O afford the title compound 85 (0.23 g, 49%) as a pale brown HN O 1 solid. Mp >300 ºC. H NMR (300MHz, DMSO-d6): 3.92 (s, H MeO N 6H, OMe), 4.11 (s, 6H, OMe), 6.56 (s, 2H, H5), 7.24 (d, J = 2.51 Hz, 2H, H2), 7.46, 7.50 (2d, J = 8.86 Hz, 8H, aryl H), OMe 10.50 (s, 2H, NH), 11.51 (d, J = 2.27 Hz, 2H, NH). IR (KBr): ν -1 max 3389, 1589, 1448, 1340, 1212 cm . UV-vis (THF): max Br

110

242 nm ( 65,192 cm-1M-1), 281 (34,432), 348 (42,581), 365 (31,563). HRMS 79 + (+ESI): C34H28 Br2N4O6 [M+Na] requires 769.0273, found 769.0265. The sample was not soluble enough for 13C NMR measurement.

N-(4,6-dimethoxy-2,3-diphenyl-1H-indole-7-carbonyl)-4,6-dimethoxy-2,3- diphenyl-1H-indole-7-carbohydrazide (86) OMe To a solution of 7-trichloroacetylindole 83 (0.5 g, 1.05 mmol) Ph in acetonitrile (20 mL), hydrazine hydrate (0.028 mL, 0.57 Ph MeO N mmol) followed by triethylamine (5 drops) was added and the H mixture was heated under reflux for 24 h. The resulting HN O HN O precipitate was filtered, washed with acetonitrile and water to H MeO N afford the title compound 86 (0.22 g, 57%) as a brown solid. Ph 1 Mp >320 ºC. H NMR (300 MHz, CDCl3): 3.80 (s, 6H, OMe Ph OMe), 4.19 (s, 6H, OMe), 6.28 (s, 2H, H5), 7.20-7.42 (m,

20H, aryl H), 10.94 (s, 2H, NH), 11.12 (bs, 2H, NH). IR (KBr): νmax 3392, 2359, -1 1594, 1453, 1346, 1226, 1173, 1143, 991, 752, 699 cm . UV-vis (CH2Cl2): max 227 -1 -1 nm ( 102,839 cm M ), 250 (120,114), 323 (109,587). HRMS (+ESI): C48H38N4O6 [M]+ requires 742.2791, found 742.2782. The sample was not soluble enough for 13C NMR measurement.

3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indole-7-carbohydrazide (87) Cl To a solution of 7-trichloroacetylindole 41 (1.06 g, 2.46 mmol) in anhydrous acetonitrile (50 mL), hydrazine hydrate (0.167 OMe mL, 3.44 mmol) was added followed by triethylamine (5 drops) and the mixture was stirred at room temperature for 1 h. Water MeO N was added to quench the reaction, the resulting precipitate was H HN O filtered and recrystallised from methanol to yield the title NH2 compound 87 (0.72 g, 85%) as a light brown solid. Mp 203-205 ºC. 1H NMR (300

MHz, CDCl3): 3.91 (s, 3H, OMe), 4.06 (s, 3H, OMe), 6.28 (s, 1H, H5), 7.16 (d, J = 2.38 Hz, 1H, H2), 7.33, 7.53 (2d, J = 8.56 Hz, 4H, aryl H), 9.08 (s, 1H, NH), 11.11 13 (bs, 2H, NH). C NMR (75 MHz, CDCl3): 55.64, 57.16 (OMe), 87.65 (C5),

111

122.48 (C2), 128.13, 131.12 (aryl CH), 96.55, 111.31, 117.21, 131.99, 134.72,

139.69, 157.17, 157.85 (aryl C), 168.96 (C=O). IR (KBr): νmax 3372, 3347, 1621, -1 -1 - 1590, 1462, 1346, 1214, 1093 cm . UV-vis (MeOH): max 202 nm ( 38,856 cm M 1 + ), 238 (39,409), 309 (18,220). HRMS (+ESI): C17H16ClN3O3 [M+H] requires 346.0958, found 346.0953.

3-(4-Bromophenyl)-4,6-dimethoxy-1H-indole-7-carbohydrazide (88)

A solution of 7-trichloroacetylindole 82 (0.499 g, 1.05 mmol) Br in anhydrous acetonitrile (20 mL), hydrazine hydrate (0.064 mL, 1.31 mmol) was added followed by triethylamine (3 OMe drops) and the mixture was stirred at room temperature for 1 h. MeO N Water was added to quench the reaction, the resulting H precipitate was filtered and recrystallised from ethanol to HN O NH afford the title compound 88 (0.3 g, 74%) as a pale yellow 2 1 solid. Mp 215-217 ºC. H NMR (300 MHz, CDCl3): 3.87 (s, 3H, OMe), 4.02 (s, 3H, OMe), 6.25 (s, 1H, H5), 7.12 (d, J = 2.37 Hz, 1H, H2), 7.43, 7.47 (2d, J = 8.93 13 Hz, 4H, aryl H), 9.04 (s, 1H, NH). 11.07 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 55.13, 56.67 (OMe), 87.19 (C5), 121.95 (C2), 130.56, 130.98 (aryl CH), 96.07, 110.78, 116.72, 119.63, 134.69, 139.21, 156.68, 157.35 (aryl C), 168.44 (C=O). IR -1 (KBr): νmax 3363, 3344, 1621, 1588, 1463, 1344, 1214, 1093 cm . UV-vis (MeOH): -1 -1 max 203 nm ( 29,177 cm M ), 237 (30,105), 306 (14,214). HRMS (+ESI): 79 + C17H16 BrN3O3 [M+Na] requires 412.0273, found 412.0267.

4,6-Dimethoxy-2,3-diphenyl-1H-indole-7-carbohydrazide (89)

To a solution of 7-trichloroacetylindole 83 (1.06 g, 2.46 OMe Ph mmol) in anhydrous acetonitrile (50 mL), hydrazine hydrate Ph (0.167 mL, 3.44 mmol) was added followed by triethylamine MeO N H (5 drops) and the mixture was stirred at room temperature for HN O 1 h. Water was added to quench the reaction, the resulting NH2 precipitate was filtered and recrystallised from ethanol to afford the title compound 89 (0.72 g, 85%) as a light brown solid. Mp 224-226 ºC. 1H NMR (300 MHz,

112

CDCl3): 3.79 (s, 3H, OMe), 4.04 (s, 3H, OMe), 6.23 (s, 1H, H5), 7.24-7.45 (m, 13 10H, aryl H), 9.09 (s, 1H, NH), 11.21 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 55.71, 57.12 (OMe), 87.82 (C5), 126.48, 127.52, 127.83, 128.15, 128.34, 128.50, 128.83, 131.90 (aryl CH), 96.24, 114.17, 114.22, 133.00, 133.61, 136.26, 138.78,

157.07, 158.21 (aryl C), 169.10 (C=O). IR (KBr): νmax 3392, 1620, 1596, 1494, -1 -1 -1 1462, 1235, 1112, 991, 700 cm . UV-vis (MeOH): max 205 nm ( 57,239 cm M ), + 249 (36,035), 319 (23,289). HRMS (+ESI): C23H22N3O3 [M+H] requires 388.1661, found 388.1656.

(E)-3-(4-chlorophenyl)-Nʹ-((3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7- yl)methylene)-4,6-dimethoxy-1H-indole-7-carbohydrazide (96)

A mixture of 7-carbohydrazide 87 (0.256 g, 0.74 mmol) and 7- Cl carbaldehyde 93 (0.27 g, 0.74 mmol) was heated under reflux together in absolute ethanol (30 mL) containing concentrated OMe hydrochloric acid (2 drops) overnight. The precipitate was MeO N filtered, washed with water and dried. The crude product was H purified by flash chromatography using dichloromethane as HN O N eluent to afford the title compound 96 (0.293 g, 59%) as a H 1 MeO N yellow solid. Mp 276-278 ºC. H NMR (300 MHz, DMSO-d6): 3.89 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.97 (s, 3H, OMe), 4.09 (s, 3H, OMe), 6.52 (s, 1H, H5), 6.53 (s, 1H, H5), 7.21 (s, OMe 1H, H2), 7.22 (s, 1H, H2), 7.40 (m, J = 30.46 Hz, 4H, aryl H), Cl 7.55 (m, J = 24.99 Hz, 4H, aryl H), 8.96 (s, 1H, CH), 11.29 (d, J = 1.64 Hz, 1H, NH), 11.41 (s, 1H, NH), 11.55 (d, J = 2.05 Hz, 1H, NH). IR (KBr): -1 νmax 3387, 1590, 1347, 1211, 1150, 1086, 981, 793 cm . UV-vis (CH2Cl2): max 223 -1 -1 nm ( 58,916 cm M ), 281 (32,428), 375 (51,050). HRMS (+ESI): C34H28Cl2N4O5 [M+Na]+ requires 665.1334, found 665.1324. The sample was not soluble enough for 13C NMR measurement.

113

(E)-3-(4-chlorophenyl)-Nʹ-((3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7- yl)methylene)-4,6-dimethoxy-1H-indole-7-carbohydrazide (97)

A mixture of 7-carbohydrazide 88 (0.124 g, 0.32 mmol) and 7- Br carbaldehyde 94 (0.114 g, 0.32 mmol) was heated under reflux together in absolute ethanol (25 mL) containing concentrated OMe hydrochloric acid (2 drops) overnight. The precipitate was MeO N filtered, washed with water and dried. The crude product was H purified by flash chromatography using dichloromethane as HN O N eluent to afford the title compound 97 (0.11 g, 69%) as a H 1 MeO N yellow solid. Mp 278-280 ºC. H NMR (300 MHz, DMSO-d6): 3.90 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.99 (s, 3H, OMe), 4.17 (s, 3H, OMe), 6.29 (s, 1H, H5), 6.33 (s, 1H, H5), 7.17, OMe 7.23 (2d, J = 2.32 Hz, 2H, H2, H2), 7.47-7.49 (m, 8H, aryl H), Br 8.66 (s, 1H, CH), 11.07 (d, J = 4.33 Hz, 1H, NH), 11.25 (s, 1H, -1 NH). IR (KBr): νmax 3387, 2360, 1588, 1538, 1347, 1212 cm . UV-vis (CH2Cl2): -1 -1 max 233 nm ( 69,208 cm M ), 248 (38,984), 376 (57,527). HRMS (+ESI): + C34H28Br2N4O5 [M+H] requires 731.0504, found 731.0501. The sample was not soluble enough for 13C NMR measurement.

(E)-Nʹ-((4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)methylene)-4,6-dimethoxy- 2,3-diphenyl-1H-indole-7-carbohydrazide (98)

A mixture of 7-carbohydrazide 89 (0.206 g, 0.53 mmol) and OMe Ph 7-carbaldehyde 95 (0.19 g, 0.53 mmol) was heated under Ph MeO N reflux together in absolute ethanol (30 mL) containing H concentrated hydrochloric acid (2 drops) overnight. The HN O precipitate was filtered, washed with water and dried. The N H crude brown product was purified by flash chromatography MeO N Ph using dichloromethane as eluent to afford the title compound 98 (0.257 g, 67%) as a yellow solid. Mp 298-300 ºC. 1H OMe Ph

NMR (300 MHz, CDCl3): 3.72 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.97 (s, 3H, OMe), 4.11 (s, 3H, OMe), 6.45 (s, 1H, H5), 6.49 (s, 1H, H5), 7.25-7.49 (m, 20H, aryl H), 9.00 (s, 1H, CH), 11.39 (s, 1H, NH), 11.56 (s, 1H, NH), 11.99 (s, 1H, NH).

114

-1 IR (KBr): νmax 3377, 3302, 2839, 2359, 1596, 1501, 1358, 1240, 993, 697 cm . UV- -1 -1 vis (THF): max 212 nm ( 104,907 cm M ), 248 (77,631), 376 (56,811). HRMS + (+ESI): C46H38N4O5 [M+Na] requires 749.2740, found 749.2711. The sample was not soluble enough for 13C NMR measurement.

Nʹ1,Nʹ2-bis-(3-(4-chlorophenyl)-4,6-dimethoxy-1H-indole-7- carbonyl)oxalohydrazide (99)

Oxalyl chloride (0.04 mL, 0.46 mmol) in dry dichloromethane Cl (5 mL) was added dropwise to a solution of 7-carbohydrazide 87 (0.21 g, 0.61 mmol) in dry dichloromethane (10 mL) OMe containing triethylamine (0.084 mL, 0.61 mmol). The reaction MeO N mixture was stirred at room temperature for 1.5 h. The solvent H was then evaporated and the residue was quenched with water. HN O HN O The resulting precipitate was filtered, dried and recrystallised from methanol to yield the title compound 99 (0.208 g, 92%) as HN O HN O a pale yellow solid. Mp >300 ºC. (Found: C, 56.49; H, 4.13; N, H MeO N 10.92; C36H30Cl2N6O8 0.3 CH2Cl2 requires C, 56.55; H, 4.0; N, 1 10.9%). H NMR (300 MHz, DMSO-d6): 3.89 (s, 6H, OMe), 4.05 (s, 6H, OMe), 6.49 (s, 2H, H5), 7.23 (d, J = 2.54 Hz, 2H, OMe H2), 7.36 (d, J = 8.65 Hz, 4H, aryl H), 7.51 (d, J = 8.40 Hz, Cl 4H, aryl H ), 9.84 (bs, NH, 2H), 10.80 (bs, NH, 2H), 11.41 (d, 13 J = 1.21 Hz, 2H, NH) C NMR (75 MHz, DMSO-d6): 55.80, 57.19 (OMe), 88.37 (C5), 123.81 (C2), 127.88, 131.04 (aryl CH), 96.23, 110.41, 115.78, 130.43, 135.01,

138.59, 157.20, 157.67 (aryl C), 158.69, 165.39 (C=O). IR (KBr): νmax 3396, 1623, -1 -1 -1 1591, 1454, 1347, 1215 cm . UV-vis (THF): max 213 nm ( 58,639 cm M ), 241 + (67,568), 281 (34,826), 340 (35,719). HRMS (+ESI): C36H30Cl2N6O8 [M+H] requires 745.1580, found 745.1572.

115

Nʹ1,Nʹ2-bis-(3-(4-bromophenyl)-4,6-dimethoxy-1H-indole-7- carbonyl)oxalohydrazide (100)

Oxalyl chloride (0.04 mL, 0.46 mmol) in dry dichloromethane Br (5 mL) was added dropwise to a solution of 7-carbohydrazide 88 (0.202 g, 0.52 mmol) in dry dichloromethane (10 mL) OMe containing triethylamine (0.07 mL, 0.52 mmol). The reaction MeO N mixture was stirred at room temperature for 1.5 h. The solvent H was then evaporated and the residue was quenched with water. HN O HN O The resulting precipitate was filtered, dried and recrystallised from methanol to yield the title compound 100 (0.18 g, 83%) HN O HN O as a pale yellow solid. Mp >300 ºC. (Found: C, 50.66; H, 3.71; H MeO N N, 9.75; C36H30Br2N6O8 0.3 CH2Cl2 requires C, 50.70; H, 3.59; 1 N, 9.77%). H NMR (300 MHz, DMSO-d6): 3.89 (s, 6H, OMe), 4.05 (s, 6H, OMe), 6.49 (s, 2H, H5), 7.23 (d, J = 2.36 OMe Hz, 2H, H2), 7.45 (d, J = 8.77 Hz, 4H, aryl H ), 7.50 (d, J = Br 9.11 Hz, 4H, aryl H), 9.84 (s, NH, 2H), 10.78 (bs, NH, 2H), 13 11.41 (d, J = 1.65 Hz, 2H, NH). C NMR (75 MHz, DMSO-d6): 55.80, 57.19 (OMe), 88.39 (C5), 123.80 (C2), 130.79, 131.42 (aryl CH), 96.23, 110.35, 115.80, 118.92, 135.39, 138.60, 157.20, 157.67 (aryl C), 158.79, 165.38 (C=O). IR (KBr): -1 νmax 3395, 1621, 1589, 1457, 1347, 1215 cm . UV-vis (THF): max 212 nm ( 53,667 -1 -1 cm M ), 241 (60,878), 284 (31,756), 343 (33,143). HRMS (+ESI): C36H30Br2N6O8 [M+Na]+ requires 855.0390, found 855.0385.

116

Nʹ1,Nʹ2-bis-(4,6-dimethoxy-2,3-diphenyl-1H-indole-7-carbonyl)oxalohydrazide (101)

Oxalyl chloride (0.04 mL, 0.46 mmol) in dry OMe Ph dichloromethane (5 mL) was added dropwise to a solution of Ph MeO N 7-carbohydrazide 89 (0.34 g, 0.87 mmol) in dry H dichloromethane (10 mL) containing triethylamine (0.12 mL, HN O 0.87 mmol). The reaction mixture stirred at room temperature HN O for 1.5 h. The solvent was then evaporated and the residue HN O was quenched with water. The resulting precipitate was HN O H filtered, dried and recrystallised from methanol to yield the MeO N Ph title compound 101 (0.191 g, 53%) as a pale yellow solid. Mp Ph >300 ºC. (Found: C, 68.65; H, 4.93; N, 9.91; C48H40N6O8 0.2 OMe 1 CH2Cl2 requires C, 68.44; H, 4.81; N, 9.94%). H NMR (300 MHz, DMSO-d6): 3.74 (s, 6H, OMe), 4.05 (s, 6H, OMe), 6.45 (s, 2H, H5), 7.21-7.28 (m, 20H, aryl H), 13 9.94 (s, 2H, NH), 11.11 (s, 2H, NH). C NMR (75 MHz, DMSO-d6): 55.86, 57.15 (OMe), 88.76 (C5), 126.67, 127.59, 127.72, 127.85, 128.98, 131.45 (aryl CH), 95.84, 112.99, 114.00, 132.30, 132.34, 135.85, 137.93, 157.34, 158.08 (aryl C), 158.95, -1 165.90 (C=O). IR (KBr): νmax 3379, 1629, 1594, 1430, 1351, 1238, 1144, 696 cm . -1 -1 UV-vis (THF): max 212 nm ( 84,937 cm M ), 248 (67,769), 332 (60,239). HRMS + (+ESI): C48H40N6O8 [M+H] requires 829.2986, found 829.2978.

3-(4-Chlorophenyl)-4,6-dimethoxy-N-(p-tolyl)-1H-indole-7-carboxamide (103)

A solution of 7-trichloroacetylindole 41 (0.178 g, 0.41 mmol) Cl in anhydrous acetonitrile (20 mL) was treated with p-toluidine (1.5 g, 10.16 mmol) and triethylamine (7 drops). The solution OMe was heated under reflux overnight. The solvent was evaporated MeO N and the residue was treated with diethyl ether (10 mL) and the H solid obtained was filtered to yield the title compound 103 HN O (0.097 g, 56%) as a white solid. Mp 234-236 ºC. 1H NMR (300

MHz, DMSO-d6): 2.27 (s, 3H, Me), 3.89 (s, 3H, OMe), 4.10 (s, 3H, OMe), 6.53 (s, 1H, H5), 7.13-7.37 (m, 5H, H2, aryl H), 7.51, 7.65 (2d, J = 8.37 Hz, 4H, aryl H), 10.05 (s, 1H, NH), 11.47 (d, J = 1.55 Hz,

117

13 1H, NH). C NMR (75 MHz, DMSO-d6): 20.84 (Me), 55.82, 57.63 (OMe), 88.77 (C5), 123.95 (C2), 120.47, 127.87, 129.48, 131.02 (aryl CH), 98.57, 110.64, 115.70, 130.39, 132.72, 135.06, 136.65, 138.35, 156.43, 157.24 (aryl C), 164.59 (C=O). IR -1 (KBr): νmax 3336, 1636, 1592, 1529, 1311, 1242, 978 cm . UV-vis (THF): max 247 -1 -1 nm ( 35,710 cm M ), 282 (21,846), 330 (24,703). HRMS (+ESI): C24H21ClN2O3 [M+H]+ requires 421.1319, found 421.1312.

3-(4-Bromophenyl)-4,6-dimethoxy-N-phenyl-1H-indole-7-carboxamide (104) Br A solution of 7-trichloroacetylindole 82 (0.17 g, 0.35 mmol) in anhydrous acetonitrile (20 mL) was treated with aniline (3 mL, OMe 32.9 mmol) and triethylamine (8 drops). The solution was heated under reflux overnight. The solvent was evaporated and MeO N the residue was treated with diethyl ether (10 mL) and the solid H HN O obtained was filtered to yield the title compound 104 (0.097 g, 60%) as a white solid. Mp 226-228 ºC. 1H NMR (300 MHz,

CDCl3): 3.89 (s, 3H, OMe), 4.11 (s, 3H, OMe), 6.30 (s, 1H, H5), 7.13 (d, J = 2.40 Hz, 1H, H2), 7.11-7.66 (m, 9H, aryl H), 10.03 (bs, 1H, NH),

11.21 (bs, 1H, NH). IR (KBr): νmax 3384, 1644, 1591, 1542, 1442, 1313, 1249, 975, -1 -1 -1 756 cm .UV-vis (THF): max 246 nm ( 35,396 cm M ), 279 (22,503), 330 + (23,894). HRMS (+ESI): C23H19BrN2O3 [M+H] requires 451.0649, found 451.0657. The sample was not soluble enough for 13C NMR measurement.

3-(4-Bromophenyl)-4,6-dimethoxy-N-(p-tolyl)-1H-indole-7-carboxamide (105)

A solution of 7-trichloroacetylindole 82 (0.169 g, 0.35 mmol) Br in anhydrous acetonitrile (20 mL) was treated with p-toluidine (1.62 g, 15.11 mmol) and triethylamine (8 drops). The solution OMe was heated under reflux overnight. The solvent was evaporated MeO N and the residue was treated with diethyl ether (10 mL) and the H solid obtained was filtered to yield the title compound 105 HN O (0.084 g, 51%) as a white solid. Mp 239-241 ºC. 1H NMR (300

MHz, DMSO-d6): 2.23 (s, 3H, Me), 3.89 (s, 3H, OMe), 4.11

118

(s, 3H, OMe), 6.30 (s, 1H, H5), 7.12 (d, J = 2.36 Hz, 1H, H2), 7.43, 7.45 (2d, J = 2.91 Hz, 4H, aryl H), 7.16, 7.51 (2d, J = 8.49 Hz, 4H, aryl H), 9.55 (bs, 1H, NH), -1 11.22 (bs, 1H, NH). IR (KBr): νmax 3336, 1635, 1587, 1535, 1311, 1241, 978 cm . -1 -1 UV-vis (THF): max 247 nm ( 40,905 cm M ), 238 (25,723), 331 (29,303). HRMS + (+ESI): C24H21BrN2O3 [M+H] requires 465.0808, found 465.0814. The sample was not soluble enough for 13C NMR measurement.

3-(4-Bromophenyl)-4,6-dimethoxy-Nʹ-phenyl-1H-indole-7-carbohydrazide (107)

A solution of 7-trichloroacetylindole 82 (0.13 g, 0.27 mmol) in Br anhydrous acetonitrile (20 mL) was treated with phenyl hydrazine (0.08 mL, 0.81 mmol) and triethylamine (4 drops). OMe The solution was stirred at room temperature for 3 h. The MeO N solvent was evaporated and the residue was quenched with H water. The resulting solid was filtered, dried and recrystallised HN O NH from methanol to afford the title compound 107 (0.078 g, 61%) as a yellow solid. Mp 248-250 ºC. 1H NMR (300 MHz,

DMSO-d6): 3.89 (s, 3H, OMe), 4.07 (s, 3H, OMe), 6.51 (s, 1H, H5), 6.66-7.17 (m, 6H, H2, aryl H), 7.43, 7.49 (2d, J = 8.74 Hz, 4H, aryl H), 13 9.74 (s, 1H, NH), 11.36 (d, J = 2.12 Hz, 1H, NH). C NMR (75 MHz, DMSO-d6): 55.79, 57.24 (OMe), 88.49 (C5), 123.75 (C2), 112.77, 118.85, 129.05, 130.77, 131.38 (aryl CH), 96.83, 110.37, 115.67, 135.46, 138.52, 150.22, 157.01, 157.25

(aryl C), 166.86 (C=O). IR (KBr): νmax 3346, 3315, 1641, 1591, 1540, 1343, 1270, -1 -1 -1 1218, 976 cm . UV-vis (THF): max 202 nm ( 56,325 cm M ), 238 (42,373), 280 + (22,117). HRMS (+ESI): C23H20BrN3O3 [M+H] requires 466.0766, found 466.0759.

119

2,5-Bis-(3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-1,3,4-oxadiazole (112)

To a solution of bis-indole 84 (0.109 g, 0.16 mmol) in ethyl Cl acetate (30 mL), POCl3 (10 mL) was added and the solution was heated under reflux for 2 h. The solvent was evaporated OMe under reduced pressure and the remaining residue was MeO N quenched with water and made alkaline by the addition of 5N H N NaOH (30 mL). The resulting precipitate was collected by O N filtration, washed with water, dried and purified by flash H MeO N chromatography using dichloromethane/ethyl acetate (90:10) as eluent to afford the title compound 112 (0.079 g, 74%) as a OMe pale yellow solid. Mp 303-304 ºC. (Found: C, 62.32; H, 4.10;

N, 8.35; C34H26Cl2N4O5 0.2 CH2Cl2 requires C, 62.38; H, 4.04; Cl 1 N, 8.51%). H NMR (300 MHz, CDCl3): 3.93 (s. 6H, OMe), 4.06 (s, 6H, OMe), 6.63 (s, 2H, H5), 7.37 (d, J = 2.46 Hz, 1H, H2), 7.40, 7.57 (2d, J = 8.62 Hz, 8H, aryl

H), 11.17 (d, J = 2.46 Hz, 2H, NH). IR (KBr): νmax 3352, 1596, 1411, 1332, 1214, -1 -1 -1 1149, 1084, 985 cm . UV-vis (THF): max 247 nm ( 64,595 cm M ), 282 (35,032), + 358 (51,327), 375 (40,386). HRMS (+ESI): C34H26Cl2N4O5 [M+H] requires 641.1359, found 641.1348. The sample was not soluble enough for 13C NMR measurement.

120

2,5-Bis-(3-(4-bromophenyl)-4,6-dimethoxy-1H-indol-7-yl)-1,3,4-oxadiazole (113)

To a solution of bis-indole 85 (0.101 g, 0.13 mmol) in ethyl Br acetate (30 mL), POCl3 (10 mL) was added and the solution was heated under reflux for 2 h. The solvent was evaporated OMe under reduced pressure and the remaining residue was MeO N quenched with water and made alkaline by the addition of 5N H N NaOH (30 mL). The resulting precipitate was collected by O N filtration, washed with water, dried and purified by flash H MeO N chromatography using dichloromethane/ethyl acetate (90:10) as eluent to afford the title compound 113 (0.068 g, 71%) as a OMe 1 brown solid. Mp 299-301 ºC. H NMR (300 MHz, DMSO-d6):

3.93 (s. 6H, OMe), 4.07 (s, 6H, OMe), 6.63 (s, 2H, H5), 7.37 Br (d, J = 2.51 Hz, 1H, H2), 7.50, 7.53 (2d, J = 8.97 Hz, 8H, aryl H), 11.18 (d, J = 2.24

Hz, 2H, NH). IR (KBr): νmax 3353, 1596, 1537, 1484, 1411, 1332, 1214, 1084, 985 -1 -1 -1 cm . UV-vis (THF): max 239 nm ( 56,890 cm M ), 284 (30,889), 358 (43,786), 79/81 + 375 (34,530). HRMS (+ESI): C34H26 Br2N4O5 [M+H] requires 731.0328, found 731.0324. The sample was not soluble enough for 13C NMR measurement.

2,5-Bis-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-1,3,4-oxadiazole (114)

To a solution of bis-indole 86 (0.11 g, 0.14 mmol) in ethyl OMe Ph acetate (30 mL), POCl3 (15 mL) was added and the solution Ph was heated under reflux for 2 h. The solvent was evaporated MeO N H N under reduced pressure and the remaining residue was O N quenched with water and made alkaline by the addition of 5N H MeO N NaOH (30 mL). The resulting precipitate was collected by Ph filtration, washed with water, dried and recrystallised from OMe Ph methanol to afford the title compound 114 (0.09 g, 82%) as a 1 white solid. Mp >320 ºC. H NMR (300MHz, CDCl3): 3.82 (s. 6H, OMe), 4.04 (s, 6H, OMe), 6.38 (s, 2H, H5), 7.24-7.45 (m, 20H, aryl H), 10.79 (bs, 2H, NH). IR -1 (KBr): νmax 3380, 3353, 1598, 1489, 1351, 1328, 1220, 1147, 692 cm . UV-vis -1 -1 (CH2Cl2): max 247 nm ( 105,018 cm M ), 343 (90,292), 380 (65,425). HRMS

121

+ (+ESI): C46H36N4O5 [M+H] requires 725.2764, found 725.2761. The sample was not soluble enough for 13C NMR measurement.

5,5ʹ-Bis-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2,2ʹ-bi-(1,3,4-oxadiazole) (115)

OMe To a solution of bis-indole 101 (0.094 g, 0.11 mmol) in ethyl Ph acetate (30 mL), POCl3 (15 mL) was added and the solution Ph was heated under reflux for 24 h. The solution was poured MeO N H N slowly into ice-water and made alkaline by the addition of N O 5N NaOH (30 mL). The resulting precipitate was collected by filtration, washed with water, dried and recrystallised N O N H from methanol to afford the title compound 115 (0.058 g, MeO N 64%) as a yellow solid. Mp >300 ºC. 1H NMR (300 MHz, Ph

CDCl3): 3.82 (s. 6H, OMe), 4.13 (s, 6H, OMe), 6.32 (s, OMe Ph

2H, H5), 7.26-7.43 (m, 20H, aryl H), 10.79 (bs, 2H, NH). IR (KBr): νmax 1597, 1485, -1 -1 -1 1425, 1358, 1219, 1149, 698 cm . UV-vis (THF): max 229 nm ( 67,977 cm M ), + 248 (78,752), 334 (79,385). HRMS (+ESI): C48H36N6O6 [M+H] requires 793.2775, found 793.2771. The sample was not soluble enough for 13C NMR measurement.

2-(2-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-oxoacetyl)-N,N- dimethylhydrazinecarbothioamide (121)

To a solution of 7-glyoxyloyl chloride 47 (1.03 g, 2.46 mmol) OMe Ph in acetonitrile (30 mL), 4,4-dimethyl-3-thiosemicarbazide Ph (0.306 g, 2.56 mmol) was added followed by triethylamine (7 MeO N H O drops). The mixture was stirred at room temperature for 1.5 h O HN after which water was added to quench the reaction. The NH resulting precipitate was filtered, dried and recrystallised N S from dichloromethane/n-hexane to afford the title compound 121 (0.975 g, 79%) as a yellow solid. Mp 153-155 ºC. 1H NMR (300 MHz, DMSO- d6): 3.24 (s, 6H, Me), 3.77 (s, 3H, OMe), 3.92 (s, 3H, OMe), 6.41 (s, 1H, H5), 7.24-7.29 (m, 10H, aryl H), 9.33 (s, 1H, NH), 10.38 (s, 1H, NH), 10.91 (bs, 1H, NH).

122

13 C NMR (75 MHz, DMSO-d6): 41.25 (Me), 56.18, 57.51 (OMe), 89.14 (C5), 126.74, 127.68, 127.86, 128.33, 128.76, 131.40 (aryl CH), 101.47, 112.67, 114.80, 132.06, 133.07, 135.57, 137.14, 161.54, 162.29 (aryl C), 183.38 (C=S), 165.95,

188.79 (C=O). IR (KBr): νmax 3421, 1675, 1588, 1387, 1360, 1320, 1219, 1162, 696 -1 -1 -1 cm . UV-vis (MeOH): max 203 nm ( 41,405 cm M ), 247 (27,253), 331 (13,238). + HRMS (+ESI): C27H26N4O4S [M+H] requires 503.1753, found 503.1748.

N,N-dimethyl-2-(2-oxo-2-(4,5,6-trimethoxy-2,3-diphenyl-1H-indol-7-yl)-acetyl)- hydrazinecarbothioamide (122)

To a solution of 7-glyoxyloyl chloride 70 (0.185 g, 0.41 OMe Ph MeO mmol) in acetonitrile (10 mL), 4,4-dimethyl-3- Ph MeO N thiosemicarbazide (0.054 g, 0.45 mmol) was added followed H O by triethylamine (3 drops). The mixture was stirred at room O HN temperature for 1.5 h after which water was added to quench NH the reaction. The resulting precipitate was filtered, dried and N S recrystallised from dichloromethane/n-hexane to afford the title compound 122 (0.165 g, 75%) as a yellow solid. Mp 180-182 ºC. 1H NMR (300

MHz, CDCl3): 3.37 (s, 6H, Me), 3.66 (s, 3H, OMe), 3.82 (s, 3H, OMe), 4.02 (s, 3H, OMe), 7.26-7.36 (m, 10H, aryl H), 8.21 (d, J = 7.12 Hz, 1H, NH), 9.82 (d, J = 13 6.41 Hz, 1H, NH), 10.28 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 40.76 (Me), 61.28, 61.31, 62.59 (OMe), 126.60, 127.73, 127.98, 128.58, 131.14 (aryl CH), 106.39, 114.74, 118.78, 131.78, 133.37, 134.97, 135.07, 139.25, 155.21, 156.22 (aryl

C), 178.68 (C=S), 162.06, 188.02 (C=O). IR (KBr): νmax 3427, 3188, 2936, 1685, 1623, 1572, 1448, 1378, 1324, 1260, 1052, 828, 764, 698 cm-1. UV-vis (MeOH): -1 -1 max 206 nm ( 71,393 cm M ), 249 (51,334), 363 (21,532). HRMS (+ESI): + C28H28N4O5S [M+H] requires 533.1858, found 533.1852.

123

(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)(5-(dimethylamino)-1,3,4-thiadiazol- 2-yl)-methanone (123)

To a solution of indole 121 (0.121 g, 0.24 mmol) in ethyl OMe Ph acetate (15 mL), POCl (4 mL) was added and the solution 3 Ph was heated under reflux for 2 h. The solvent was evaporated MeO N H N under reduced pressure and the remaining residue was O N quenched with water and made alkaline by the addition of S N 5N NaOH (12 mL). The resulting precipitate was collected by filtration, washed with water, dried and purified by flash chromatography using dichloromethane/ethyl acetate (70:30) as eluent to afford the title compound 123 1 (0.067 g, 59%) as a yellow solid. Mp 180-182 ºC. H NMR (300 MHz, CDCl3): 3.26 (s. 6H, Me), 3.79 (s, 3H, OMe), 3.87 (s, 3H, OMe), 6.25 (s, 1H, H5), 7.21-7.39 13 (m, 10H, aryl H), 10.05 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 41.54 (Me), 55.32, 57.08 (OMe), 89.02 (C5), 126.07, 127.08, 127.34, 127.82, 128.34, 131.28 (aryl CH), 113.24, 114.86, 132.26, 132.82, 135.49, 137.67, 159.33, 160.48, 161.06,

173.66 (aryl C), 183.74 (C=O). IR (KBr): νmax 3390, 1566, 1452, 1287, 1237, 1219, -1 -1 -1 1147, 698 cm . UV-vis (MeOH): max 283 nm ( 29,879 cm M ), 329 (21,026). + HRMS (+ESI): C27H24N4O3S [M] requires 484.1569, found 484.1564.

(5-(Dimethylamino)-1,3,4-thiadiazol-2-yl)-(4,5,6-trimethoxy-2,3-diphenyl-1H- indol-7-yl)-methanone (124)

To a solution of indole 122 (0.109 g, 0.2 mmol) in ethyl OMe Ph MeO acetate (10 mL), POCl (3 mL) was added and the solution 3 Ph MeO N was heated under reflux for 2 h. The solvent was evaporated H N under reduced pressure and the remaining residue was N O quenched with water and made alkaline by the addition of S N 5N NaOH (10 mL). The resulting precipitate was collected by filtration, washed with water, dried and purified by flash chromatography using dichloromethane/ethyl acetate (70:30) as eluent to afford the title compound 124 1 (0.06 g, 57%) as a yellow solid. Mp 116-118 ºC. H NMR (300 MHz, CDCl3): 3.29 (s. 6H, Me), 3.60 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.97 (s, 3H, OMe), 7.23-7.41 (m, 13 10H, aryl H), 9.61 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 41.63 (Me), 61.04,

124

61.17, 62.48 (OMe), 126.31, 127.39, 127.57, 127.89, 128.40, 131.10 (aryl CH), 109.06, 114.55, 118.61, 132.02, 132.87, 134.41, 135.26, 140.05, 153.28, 153.33,

159.18, 174.10 (aryl C), 184.83 (C=O). IR (KBr): νmax 3497, 2359, 2341, 1558, -1 -1 -1 1465, 1281, 1102, 1049, 695 cm . UV-vis (MeOH): max 231 nm ( 45,168 cm M ), + 318 (29,426). HRMS (+ESI): C28H26N4O4S [M+H] requires 515.1753, found 515.1744.

2-(2-(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-2-yl)-2-oxoacetyl)-N,N- dimethylhydrazinecarbothioamide (125) Cl To a solution of 2-glyoxyloyl chloride 53 (0.535 g, 1.42 mmol) in acetonitrile (25 mL), 4,4- OMe dimethyl-3-thiosemicarbazide (0.186 g, 1.56 O mmol) was added followed by triethylamine (6 H H S MeO N N N drops). The mixture was stirred at room H O N temperature for 1.5 h after which water was added to quench the reaction. The resulting precipitate was filtered, dried and recrystallised from dichloromethane/n-hexane to afford the title compound 125 1 (0.552 g, 55%) as a yellow solid. Mp 219-221 ºC. H NMR (300 MHz, DMSO-d6): 3.21 (s, 6H, Me), 3.58 (s, 3H, OMe), 3.79 (s, 3H, OMe), 6.15 (d, J = 1.89 Hz, 1H, H5), 6.65 (d, J = 1.89 Hz, 1H, H7), 7.36 (s, 4H, aryl H), 9.35 (bs, 1H, NH), 10.80 13 (bs, 1H, NH), 11.91 (s, 1H, NH). C NMR (75 MHz, DMSO-d6): 41.25 (Me), 55.57, 55.76 (OMe), 86.89 (C5), 93.98 (C7), 127.06, 132.89 (aryl CH), 112.67, 126.37, 126.69, 131.90, 133.57, 139.99, 156.30, 161.29 (aryl C), 182.96 (C=S),

163.13, 178.05 (C=O). IR (KBr): νmax 3129, 1701, 1631, 1529, 1389, 1309, 1207, -1 -1 -1 809 cm . UV-vis (THF): max 226 nm ( 27,146 cm M ), 247 (25,510), 356 + (13,956). HRMS (+ESI): C21H21ClN4O4S [M+H] requires 461.1050, found 461.1047.

125

2-(2-(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-2-yl)-2-oxoacetyl)-N,N- dimethylhydrazinecarbothioamide (126) Br To a solution of 2-glyoxyloyl chloride 54 (0.606 g, 1.44 mmol) in acetonitrile (25 mL), 4,4- OMe dimethyl-3-thiosemicarbazide (0.189 g, 1.58 O mmol) was added followed by triethylamine (6 H H S MeO N N N H drops). The mixture was stirred at room O N temperature for 1.5 h after which water was added to quench the reaction. The resulting precipitate was filtered, dried and recrystallised from dichloromethane/n-hexane to afford the title compound 126 (0.45 1 g, 62%) as a yellow solid. Mp 217-219 ºC. H NMR (300 MHz, DMSO-d6): 3.21 (s, 6H, Me), 3.58 (s, 3H, OMe), 3.79 (s, 3H, OMe), 6.15 (d, J = 1.88 Hz, 1H, H5), 6.65 (d, J = 1.88 Hz, 1H, H7), 7.30, 7.49 (2d, J = 8.27 Hz, 4H, aryl H), 9.35 (bs, 1H, 13 NH), 10.80 (bs, 1H, NH), 11.92 (s, 1H, NH). C NMR (75 MHz, DMSO-d6): 41.22 (Me), 55.59, 55.76 (OMe), 86.89 (C5), 94.0 (C7), 129.97, 133.23 (aryl CH), 112.60, 126.37, 126.66, 133.97, 140.01, 156.30, 161.30 (aryl C), 182.94 (C=S), -1 163.12, 178.08 (C=O). IR (KBr): νmax 3134, 1701, 1638, 1389, 1207, 1156, 809 cm . -1 -1 UV-vis (THF): max 226 nm ( 35,871 cm M ), 252 (32,259), 356 (17,138). HRMS + (+ESI): C21H21BrN4O4S [M+H] requires 505.0545, found 505.0532.

(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-2-yl)-(5-(dimethylamino)-1,3,4- thiadiazol-2-yl)-methanone (127)

To a solution of indole 125 (0.186 g, 0.4 mmol) in Cl ethyl acetate (20 mL), POCl3 (3 mL) was added and OMe the solution was heated under reflux for 2 h. The O solution was poured slowly into ice-water (40 mL) MeO N S and made alkaline by the addition of 5N NaOH (10 H N mL). It was then extracted with ethyl acetate (2x20 N N mL) and dichloromethane (1x20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using dichloromethane/ethyl acetate (90:10) as eluent to afford the title compound 127 (0.057 g, 33%) as an orange-

126

1 brown solid. Mp 276-278 ºC. H NMR (300 MHz, CDCl3): 3.27 (s. 6H, Me), 3.64 (s, 3H, OMe), 3.87 (s, 3H, OMe), 6.10 (d, J = 1.89 Hz, 1H, H5), 6.43 (d, J = 1.96 Hz, 1H, H7), 7.34, 7.44 (2d, J = 8.71 Hz, 4H, aryl H), 11.50 (bs, 1H, NH). 13C NMR (75

MHz, CDCl3): 41.56 (Me), 55.04, 55.46 (OMe), 85.77 (C5), 93.35 (C7), 126.97, 131.98 (aryl CH), 113.07, 126.85, 127.68, 132.74, 133.13, 139.41, 156.64, 161.44

(aryl C), 162.72 (N-C=N), 170.54 (C=O-C=N), 174.03 (C=O). IR (KBr): νmax 3343, -1 1611, 1484, 1290, 1203, 1154, 1047, 921 cm . UV-vis (THF): max 226 nm ( 45,388 -1 -1 + cm M ), 337 (16,151). HRMS (+ESI): C21H19ClN4O3S [M+H] requires 443.0945, found 443.0936.

(3-(4-Bromophenyl)-4,6-dimethoxy-1H-indol-2-yl)-(5-(dimethylamino)-1,3,4- thiadiazol-2-yl)-methanone (128)

To a solution of indole 126 (0.45 g, 0.89 mmol) in Br ethyl acetate (20 mL), POCl3 (3 mL) was added and the solution was heated under reflux for 2 h. The OMe O solution was poured slowly into ice-water (40 mL) MeO N S and made alkaline by the addition of 5N NaOH (10 H N mL). It was then extracted with ethyl acetate (2x20 N N mL) and dichloromethane (1x 20 mL). The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using dichloromethane/ethyl acetate (90:10) as eluent to afford the title compound 128 (0.153 g, 36%) as an orange- brown solid. Mp 280-282 ºC. (Found: C, 51.28; H, 3.87; N, 11.23; C21H19BrN4O3S 1 0.1 CH2Cl2 requires C, 51.11; H, 3.90; N, 11.30%). H NMR (300 MHz, DMSO-d6): 3.20 (s. 6H, Me), 3.57 (s, 3H, OMe), 3.79 (s, 3H, OMe), 6.14 (d, J = 1.93 Hz, 1H, H5), 6.84 (d, J = 1.93 Hz, 1H, H7), 7.27, 7.45 (2d, J = 8.79 Hz, 4H, aryl H), 11.83 13 (bs, 1H, NH). C NMR (75 MHz, DMSO-d6): 41.66 (Me), 55.28, 55.54 (OMe), 87.62 (C5), 93.65 (C7), 129.88, 133.26 (aryl CH), 112.40, 120.18, 125.61, 127.06, 134.68, 139.84, 156.08 (aryl C), 160.69 (N-C=N), 172.39 (C=O-C=N), 173.95 -1 (C=O). IR (KBr): νmax 1610, 1540, 1456, 1291, 1242, 1203, 1154, 813 cm . UV-vis -1 -1 (THF): max 292 nm ( 31,349 cm M ), 329 (13,366). HRMS (+ESI): 81 + C21H19 BrN4O3S [M+H] requires 489.0374, found 489.0408.

127

(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-methanamine (138)

A suspension of lithium aluminium hydride (2.5 g, 65.8 mmol) Cl in anhydrous tetrahydrofuran (30 mL) was cooled in an ice bath and stirred under while 7-nitrile 140 (2.58 g, 8.26 mmol) OMe in anhydrous tetrahydrofuran (20 mL) was added via a MeO N dropping funnel over 30 min. Stirring was continued for 30 H min with cooling, followed by stirring at room temperature for NH2 4 h. The mixture was recooled in ice and cautiously treated sequentially with water (5 mL), 5M NaOH (10 mL) and water (10 mL). The resulting granular solid was filtered and washed with ethyl acetate. The combined organic filtrate was washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. Recrystallisation from acetonitrile afforded the title compound 138 (1.9 g, 73%) as 1 brown crystals. Mp 179-181ºC. H NMR (300 MHz, CDCl3): 3.74 (s, 3H, OMe),

3.81 (s, 3H, OMe), 4.15 (s, 2H, CH2), 6.24 (s, 1H, H5), 7.98 (s, 1H, H2), 7.24, 7.46 13 (2d, J = 8.77 Hz, 4H, aryl H), 9.92 (bs, 1H, NH). C NMR (75 MHz, DMSO-d6):

36.05 (CH2), 55.47, 57.28 (OMe), 89.76 (C5), 123.10 (C2), 127.75, 130.84 (aryl CH), 107.98, 110.22, 115.96, 129.29, 129.97, 135.75, 137.99, 152.88, 153.38 (aryl -1 C). IR (KBr): νmax.3368, 3360, 1623, 1592, 1464, 1322, 1168, 1085, 938, 795 cm . -1 -1 UV-vis (MeOH): max 202 nm ( 24,560 cm M ), 228 (26,014), 281 (12,201). + HRMS (+ESI): C17H17Cl2N2O2 [M] requires 316.0979, found 316.0973.

128

3-(4-Chlorophenyl)-N-((3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7- yl)methyl)-4,6-dimethoxy-1H-indole-7-carboxamide (141)

To a suspension of 7-trichloroacetylindole 41 (0.677 g, 1.57 Cl mmol) and 7-aminomethylindole 138 (0.498 g, 1.57 mmol) in acetonitrile (40 mL), triethylamine (15 drops) was added and OMe the mixture was heated under reflux overnight. After cooling, MeO N the reaction mixture was poured into ice-water and the H resulting precipitate was filtered, washed with water and HN O H recrystallised from ethanol to give the title compound 141 (0.82 MeO N g, 83%) as a white solid. Mp 234-236 ºC. 1H NMR (300 MHz,

CDCl3): 3.87 (s, 3H, OMe), 3.90 (s, 3H, OMe), 4.01 (s, 3H, OMe

OMe), 4.02 (s, 3H, OMe), 4.97 (d, J = 6.65 Hz, 2H, CH2), 6.26 (s, 1H, H5), 6.36 (s, 1H, H5), 7.14 (d, J = 2.31 Hz, 1H, H2), Cl 7.19 (d, J = 2.38 Hz, 1H, H2), 7.31-7.56 (m, 8H, aryl H), 8.69 (t, J = 13.39 Hz, 1H, 13 NH), 10.65 (bs, 1H, NH), 11.30 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 32.86

(CH2), 55.62, 55.76, 57.27, 57.95 (OMe), 87.76 (C5), 89.34 (C5), 122.36 (C2), 122.65 (C2), 128.04, 128.12, 131.03, 131.15, 132.58 (aryl CH), 97.78, 104.00, 110.96, 111.36, 117.23, 117.60, 131.62, 134.76, 135.30, 138.85, 139.86, 154.51,

154.61, 157.34, 157.88 (aryl C), 169.22 (C=O). IR (KBr): max 3401, 3207, 2942, -1 2841, 1596, 1542, 1452, 1325, 1218, 981, 836, 796, 600 cm . UV-vis (THF): max -1 -1 + 214 nm ( 80,153 cm M ), 284 (32,464). HRMS (+ESI): C34H29Cl2N3O5 [M+Na] requires 652.1382, found 652.1373.

129

Bis-((3-(4-chlorophenyl)-4,6-dimethoxyindol-7-yl)-methyl)-oxalamide (142) Cl Oxalyl chloride (0.05 mL, 0.6 mmol) in dry dichloromethane (10 mL) was added dropwise over 10 min to a solution of 7- OMe aminomethylindole 138 (0.309 g, 0.97 mmol) in dry dichloromethane (18 mL) containing triethylamine (0.134 MeO N mL, 0.97 mmol) and the mixture was stirred at room H NH temperature for 1 h. The solvent was then evaporated and the O O residue was quenched with water. The resulting precipitate HN was filtered, dried and washed with hot methanol and n- H MeO N hexane to yield the title compound 142 (0.27 g, 81%) as a pale yellow solid. Mp 278-280 ºC. (Found: C, 63.25; H, 4.95; OMe N, 7.85; C36H32Cl2N4O6 0.1 C6H14 requires C, 63.14; H, 4.84; 1 N, 8.05%). H NMR (300 MHz, CDCl3): 1.47 (s, 4H, CH2), Cl 2.10 (s, 4H, CH2), 3.81 (s, 6H, OMe), 3.86 (s, 6H, OMe),

4.64 (d, J = 6.89 Hz, 4H, CH2), 6.20 (s, 2H, H5), 6.93 (d, J = 2.38 Hz, 2H, H2), 7.21, 7.39 (2d, J = 8.56 Hz, 8H, aryl H), 7.95 (t, J = 14.02 Hz, 2H, NH), 9.56 (bs, 2H, 13 NH). C NMR (75 MHz, DMSO-d6): 33.75 (CH2), 55.49, 57.61 (OMe), 89.84 (C5), 123.23 (C2), 127.77, 130.92 (aryl CH), 101.63, 110.17, 116.23, 130.12,

135.47, 137.90, 153.88, 154.35 (aryl C), 160.15 (C=O). IR (KBr): νmax 3286, 2935, -1 1637, 1521, 1327, 1218, 1155, 1109, 798 cm . UV-vis (THF): max 215 nm ( -1 -1 + 101,553 cm M ), 284 (42,428). HRMS (+ESI): C36H32Cl2N4O6 [M] requires 686.1699, found 686.1693.

130

N1,N3-bis((3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-methyl)-propane- 1,3-diamine (143)

Adipoyl chloride (0.06 mL, 0.41 mmol) in dry Cl dichloromethane (5 mL) was added dropwise to a solution of 7- aminomethylindole 138 (0.208 g, 0.65 mmol) in dry OMe dichloromethane (10 mL) containing triethylamine (0.09 mL, MeO N 0.65 mmol) and the reaction mixture stirred at room H temperature for 1 h. The solvent was then evaporated and the NH residue was quenched with water. The resulting precipitate was O (CH2)4 filtered, dried and recrystallised from methanol to yield the title O compound 143 (0.193 g, 86%) as a white solid. Mp 258-260 NH H ºC. (Found: C, 64.03; H, 5.44; N, 7.39; C40H40Cl2N4O6 0.05 MeO N 1 CH2Cl2 requires C, 64.32; H, 5.40; N, 7.49%). H NMR (300

MHz, DMSO-d6): 1.47 (s, 4H, CH2), 2.10 (s, 4H, CH2), 3.81 OMe (s, 6H, OMe), 3.86 (s, 6H, OMe), 4.44 (d, J = 5.38 Hz, 4H,

CH2-NH), 6.43 (s, 2H, H5), 7.28 (d, J = 2.44 Hz, 2H, H2), Cl 7.37, 7.54 (2d, J = 13.39 Hz, 8H, aryl H), 8.27 (t, J = 10.86 Hz, 2H, NH), 10.91 (d, J 13 = 2.11 Hz, 2H, NH). C NMR (75 MHz, DMSO-d6): 25.42, 35.21 (CH2), 32.92

(CH2-NH), 55.55, 57.38 (OMe), 89.61 (C5), 123.19 (C2), 127.79, 130.85 (aryl CH), 102.79, 110.03, 116.23, 130.85, 135.51, 138.34, 153.79, 154.11 (aryl C), 173.69

(C=O). IR (KBr): νmax 3314, 2936, 2839, 1612, 1536, 1428, 1326, 1218, 1157, 788 -1 -1 -1 cm . UV-vis (THF): max 229 nm ( 83,294 cm M ), 284 (37,771). HRMS (+ESI): + C40H40Cl2N4O6 [M] requires 743.2403, found 743.2403.

131

(E)-1-(3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-N-((3-(4-chlorophenyl)- 4,6-dimethoxy-1H-indol-7-yl)-methylene)-methanamine (144) Cl A mixture of 7-carbaldehyde 93 (0.144 g, 0.45 mmol) and 7- aminoethylindole 138 (0.143 g, 0.45 mmol) was heated under OMe reflux in absolute ethanol (30 mL) for 24 h. The precipitate obtained was filtered, washed with water and dried. The crude MeO N product was purified by flash chromatography using H N dichloromethane/ethyl acetate (90:10) as eluent to yield the H MeO title compound 144 (0.207 g, 75%) as a white solid. Mp 221- N 1 223 ºC. H NMR (300 MHz, CDCl3): 3.82 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.90 (s, 3H, OMe), 3.94 (s, 3H, OMe), 5.02 OMe

(s, 1H, CH2), 6.46 (s, 1H, H5), 6.49 (s, 1H, H5), 7.30-7.59 (m, Cl 10H H2+H2, aryl H), 8.91 (s, 1H, CH), 11.38 (d, J = 2.34 Hz,

1H, NH), 11.49 (bs, 1H, NH). IR (KBr): νmax 3453, 1623, 1594, 1341, 1216, 1146, -1 -1 -1 1093, 788 cm . UV-vis (THF): max 225 nm ( 85,432 cm M ), 307 (35,426). 35/37 + HRMS (+ESI): C34H29 Cl2N3O4 [M+H] requires 614.1569, found 614.1599. The sample was not soluble enough for 13C NMR measurement.

Bis-((3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-methyl)-amine (145)

To a solution of bis-indole 144 (0.083 g, 0.13 mmol) in a Cl mixture of absolute ethanol/tetrahydrofuran (30 mL) (1:1), sodium borohydride (1 g, 26.3 mmol) was added and the OMe mixture was heated under reflux for 8 h. The solvent was MeO N removed under reduced pressure, and the residue was treated H with water and neutralized using dilute hydrochloric acid (2 NH H M). The resulting precipitate was filtered, dried and MeO N recrystallised from dichloromethane/n-hexane to afford the title compound 145 (0.054 g, 65%) as a white solid. Mp 134-136 OMe 1 ºC. H NMR (300 MHz, CDCl3): 3.74 (s, 6H, OMe), 3.78 (s, Cl 6H, OMe), 4.01 (s, 4H, CH2) 6.23 (s, 2H, H5), 6.83 (s, 2H, H2), 7.22, 7.41 (2d, J = 8.55 Hz, 8H, aryl H), 9.29 (bs, 2H, NH). 13C NMR (75 MHz,

CDCl3): 42.94 (CH2), 55.26, 57.01 (OMe), 88.87 (C5), 121.66 (C2), 127.66,

132

130.61 (aryl CH), 110.59, 117.39, 131.39, 134.60, 138.48, 154.09, 154.52 (aryl C).

IR (KBr): νmax 3307, 2933, 2836, 1622, 1597, 1540, 1518, 1463, 1329, 1201, 1123 -1 -1 -1 cm . UV-vis (THF): max 305 nm ( 29,765 cm M ). HRMS (+ESI): C34H31Cl2N3O4 [M+H]+ requires 616.1770, found 616.1768.

3-(4-Chlorophenyl)-4,6-dimethoxy-7-(2-nitrovinyl)-1H-indole (152) Cl A mixture of 7-carbaldehyde 93 (0.73 g, 2.31 mmol) and ammonium acetate (1.114 g, 14.45 mmol) in nitromethane (18 OMe mL) was heated at reflux for 3 h and evaporated to dryness in vacuo. The residue was quenched with water and the solid MeO N obtained was filtered, dried and washed with ethanol to give H the title compound 152 (0.77 g, 93%) as a red solid. Mp 228- NO2 230 ºC. (Found: C, 60.41; H, 4.26; N, 7.71; C18H15ClN2O4 requires C, 60.26; H, 1 4.21; N, 7.81%). H NMR (300 MHz, DMSO-d6): 3.93 (s, 3H, OMe), 4.06 (s, 3H, OMe), 6.54 (s, 1H, H5), 7.35 (s, 1H, H2), 7.40, 7.55 (2d, J = 8.40 Hz, 4H, aryl H), 8.14, 8.66 (2d, J = 13.18 Hz, 2H, CH), 11.89 (bs, 1H, NH). 13C NMR (75 MHz,

DMSO-d6): 56.02, 57.01 (OMe), 89.07 (C5), 123.80 (C2), 131.68, 134.55 (ethenyl CH), 127.87, 131.10 (aryl CH), 96.93, 110.24, 117.08, 130.65, 134.68, 138.36,

159.50, 160.31 (aryl C). IR (KBr): max 3439, 3293, 1614, 1578, 1292, 1274, 1254, -1 -1 -1 1181, 1103, 979 cm . UV-vis (MeOH): max 202 nm ( 33,365 cm M ), 228 + (30,656), 283 (14,387). HRMS (+ESI): C18H15ClN2O4 [M+H] requires 359.0799, found 359.0793.

3-(4-Bromophenyl)-4,6-dimethoxy-7-(2-nitroethenyl)-1H-indole (153)

A mixture of 7-carbaldehyde 94 (3.73 g, 10.38 mmol) and Br ammonium acetate (4.78 g, 62 mmol) in nitromethane (25 mL) was heated at reflux for 3 h and evaporated to dryness in OMe vacuo. The residue was quenched with water and the solid MeO N obtained was filtered, dried and washed with ethanol to give H the title compound 153 (3.84 g, 92%) as a red solid. Mp 226- NO2 228 ºC. (Found: C, 53.67; H, 3.67; N, 6.94; C18H15BrN2O4

133

1 requires C, 53.62; H, 3.75; N, 6.95%). H NMR (300 MHz, DMSO-d6): 3.94 (s, 3H, OMe), 4.07 (s, 3H, OMe), 6.55 (s, 1H, H5), 7.36 (d, J = 1.85 Hz, 2H, H2), 7.48, 7.54 (2d, J = 8.58 Hz, 4H, aryl H), 8.14, 8.67 (2d, J = 13.20 Hz, 2H, CH), 11.90 (bs, 13 1H, NH). C NMR (75 MHz, DMSO-d6): 56.04, 57.03 (OMe), 89.10 (C5), 123.80 (C2), 131.68, 134.58 (ethenyl CH), 130.80, 131.48 (aryl CH), 96.94, 110.20, 117.12,

119.16, 135.06, 138.39, 159.50, 160.32 (aryl C). IR (KBr): max 3279, 1618, 1577, -1 -1 -1 1461, 1209, 1111, 795 cm . UV-vis (MeOH): max 202 nm ( 40,891 cm M ), 228 + (40,144), 284 (19,182). HRMS (+ESI): C18H15BrN2O4 [M+H] requires 403.0293, found 403.0284.

4,6-Dimethoxy-2,3-diphenyl-7-(2-nitroethenyl)-1H-indole (154)

A mixture of 7-carbaldehyde 95 (1.98 g, 5.53 mmol) and OMe Ph ammonium acetate (3.8 g, 49.29 mmol) in nitromethane (25 Ph mL) was heated at reflux for 3 h and evaporated to dryness in MeO N H vacuo. The residue was quenched with water and the solid obtained was filtered, dried and washed with ethanol to give NO2 the title compound 154 (2.1 g, 95%) as a red solid. Mp 215-217 ºC. (Found: C, 1 71.89; H, 5.02; N, 7.03; C24H20N2O4 requires C, 71.99; H, 5.03; N, 7.00%). H NMR

(300 MHz, CDCl3): 3.74 (s, 3H, OMe), 4.03 (s, 3H, OMe), 6.46 (s, 1H, H5), 7.22- 7.28 (m, 10H, aryl H), 8.14, 8.86 (2d, J = 12.63 Hz, 2H, CH), 11.83 (bs, 1H, NH). 13 C NMR (75 MHz, CDCl3): 55.96, 56.91 (OMe), 89.18 (C5), 132.39, 135.05 (ethenyl CH) 126.46, 127.58, 127.69, 128.42, 129.21, 131.46 (aryl CH), 96.88, 112.73, 114.76, 132.29, 134.12, 135.77, 138.16, 159.48, 160.37 (aryl C). IR (KBr): -1 max 3342, 1601, 1460, 1280, 1247, 1140, 989, 696 cm . UV-vis (MeOH): max 204 -1 -1 nm ( 37,613 cm M ), 241 (26,809), 314 (15,285). HRMS (+ESI): C24H20N2O4 [M+H]+ requires 401.1501, found 401.1492.

134

3-(4-Chlorophenyl)-4,6-dimethoxy-7-(2-nitroethyl)-indole (155)

Sodium borohydride (1 g, 26.31 mmol) was added in portions Cl to a stirred suspension of 7-nitroethenylindole 152 (0.7 g, 1.95 mmol) in a mixture of ethanol/tetrahydrofuran (30 mL) (2:1) at OMe room temperature with cooling using an ice bath. Stirring was MeO N continued with cooling for 1 h. The mixture was poured into H ice water and acidified to low pH (pH-3) with dilute NO hydrochloric acid (2 M). The resulting precipitate was filtered, 2 dried and recrystallised from dichloromethane/n-hexane to yield the title compound 155 (0.62 g, 88%) as a yellow solid. Mp 176-178 ºC. (Found: C, 60.00; H, 4.72; N, 1 7.86; C18H17ClN2O4 requires C, 59.92; H, 4.75; N, 7.76%). H NMR (300 MHz,

DMSO-d6): 3.41 (t, J = 15.10 Hz, 2H, CH2), 3.77 (s, 3H, OMe), 3.83 (s, 3H, OMe),

4.64 (t, J = 14.44 Hz, 2H, CH2), 6.42 (s, 1H, H5), 7.28 (d, J = 2.65 Hz, 1H, H2), 7.34, 7.52 (2d, J = 8.38 Hz, 4H, aryl H), 11.25 (d, J = 1.55 Hz, 1H, NH). 13C NMR

(75 MHz, DMSO-d6): 22.95 (CH2), 55.47, 57.05 (OMe), 74.63 (CH2-NO2), 89.39 (C5), 123.30 (C2), 127.76, 130.88 (aryl CH), 98.98, 110.08, 116.23, 135.51, 138.16,

153.44, 154.16 (aryl C). IR (KBr): max 3386, 2938, 2840, 1622, 1597, 1541, 1328, -1 -1 -1 1121, 1099, 835 cm . UV-vis (MeOH): max 228 nm ( 32,931 cm M ), 282 + (15,451). HRMS (+ESI): C18H17ClN2O4 [M+H] requires 361.0955, found 361.0948.

3-(4-Bromophenyl)-4,6-dimethoxy-7-(2-nitroethyl)-indole (156)

Sodium borohydride (2 g, 52.62 mmol) was added in portions Br to a stirred suspension of 7-nitroethenylindole 153 (2.8 g, 6.96 mmol) in ethanol/tetrahydrofuran (75 mL) (2:1) at room OMe temperature with cooling using an ice bath. Stirring was MeO N continued with cooling for 1 h. The mixture was poured into H ice water and acidified to low pH (pH-3) with dilute NO hydrochloric acid (2 M). The resulting precipitate was filtered, 2 dried and recrystallised from dichloromethane/n-hexane to yield the title compound 1 156 (2.02 g, 72%) as a yellow solid. Mp 184-186ºC. H NMR (300 MHz, CDCl3):

3.44 (t, J = 13.56 Hz, 2H, CH2), 4.65 (t, J = 13.56 Hz, 2H, CH2), 3.81 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.32 (s, 1H, H5), 7.03 (d, J = 2.49 Hz, 1H, H2), 7.42-7.49 (m,

135

13 4H, aryl H), 8.37 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 23.18 (CH2), 55.21,

56.34 (OMe), 74.63 (CH2-NO2), 88.45 (C5), 121.51 (C2), 130.52, 130.98 (aryl CH), 98.27, 110.30, 117.96, 119.65, 134.77, 137.86, 153.92, 154.42 (aryl C). IR (KBr): -1 max.3392, 2937, 2839, 1621, 1593, 1541, 1328, 1120, 1007, 798 cm . UV-vis -1 -1 (MeOH): max 203 nm ( 50,389 cm M ), 221 (46,348), 283 (18,816). HRMS + (+ESI): C18H17N2O4 [M+Na] requires 427.0264, found 427.0263.

4,6-Dimethoxy-2,3-diphenyl-7-(2-nitroethyl)-indole (157)

Sodium borohydride (1 g, 26.31 mmol) was added in portions OMe Ph to a stirred suspension of 7-nitroethylindole 154 (1.85 g, 4.62 Ph mmol) in a mixture of ethanol/tetrahydrofuran (45 mL) (2:1) MeO N H at room temperature with cooling using an ice bath. Stirring was continued with cooling for 1 h. The mixture was poured NO2 into ice water and acidified to low pH (pH-3) with dilute hydrochloric acid (2 M). The resulting precipitate was filtered, dried and recrystallised from dichloromethane/n-hexane to yield the title compound 157 (1.23 g, 66%) as a yellow 1 solid. Mp 196-198 ºC. H NMR (300 MHz, CDCl3): 3.53 (t, J = 13.87 Hz, 2H,

CH2), 3.72 (s, 3H, OMe), 3.94 (s, 3H, OMe), 4.72 (t, J = 13.18 Hz, 2H, CH2), 6.32 (s, 1H, H5), 7.25-7.43 (m, 10H, aryl H), 8.40 (bs, 1H, NH). 13C NMR (75 MHz,

CDCl3): 23.27 (CH2), 55.57, 56.46 (OMe), 74.83 (CH2-NO2), 89.02 (C5), 126.01, 127.18, 127.34, 128.04, 128.52, 131.43 (aryl CH), 98.17, 113.45, 115.20, 132.78,

133.02, 135.84, 137.05, 154.46, 154.50 (aryl C). IR (KBr): νmax 3443, 2359, 2341, -1 -1 -1 1600, 1548, 1220, 1126, 697 cm . UV-vis (MeOH): max 206 nm ( 46,739 cm M ), + 246 (27,614), 323 (15,818). HRMS (+ESI): C24H22N2O4 [M+Na] requires 425.1472, found 425.1460.

136

2-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-ethanamine (160)

To a refluxing solution of 7-nitroethylindole 157 (1 g, 2.48 OMe Ph mmol) in absolute ethanol/tetrahydrofuran (60 mL) (3.1), Ph 10% Pd/C (0.32 g) was added under argon followed by the MeO N H dropwise addition of hydrazine monohydrate (5 mL) over 15 min. The reaction mixture was heated under reflux for NH2 another 4 h. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The residue was quenched with water and the resulting precipitate was filtered, dried and washed with diethyl ether to yield the title compound 160 (0.73 g, 79%) as a grey solid. Mp 170-172 ºC. 1H NMR (300

MHz, CDCl3): 3.04 (t, J = 9.86 Hz, 2H, CH2), 3.11 (t, J = 10.03 Hz, 2H, CH2), 3.69 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.31 (s, 1H, H5), 7.17-7.44 (m, 10H, aryl H), 10.98 13 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 27.46, 41.87 (CH2), 55.55, 57.57 (OMe), 90.17 (C5), 125.66, 126.55, 127.21, 127.87, 128.23 (aryl CH), 104.50, 113.58, 114.51, 132.88, 133.38, 136.42, 137.92, 153.29, 153.21 (aryl C). IR (KBr): -1 νmax 3341, 3193, 2936, 1601, 1454, 1292, 1104, 701 cm . UV-vis (MeOH): max 246 -1 -1 + nm ( 29,361 cm M ), 323 (16,541). HRMS (+ESI): C24H24N2O2 [M+H] requires 373.1916, found 373.1917.

2-(4,6-Dimethoxy-3-phenyl-1H-indol-7-yl)-ethanamine (161)

To a refluxing solution of 7-nitroethylindole 155 (1.587 g, 4.4 OMe Ph mmol) in absolute ethanol/tetrahydrofuran (60 mL) (3:1), 10%

Pd/C (0.4 g) was added under argon followed by the dropwise MeO N H addition of hydrazine monohydrate (6 mL) over 15 min. The reaction mixture was heated under reflux for another 4 h. The NH2 reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The residue was quenched with water and the resulting precipitate was filtered, dried and washed with diethyl ether to yield the title compound 161 (1.1 1 g, 93%) as a grey solid. Mp 135-137 ºC. H NMR (300 MHz, CDCl3): 2.90, 2.94

(2d, J = 4.50 Hz, 4H, CH2), 3.71 (s, 3H, OMe), 3.79 (s, 3H, OMe), 6.26 (s, 1H, H5), 6.98 (s, 1H, H2), 7.15-7.55 (m, 5H, aryl H), 10.23 (bs, 1H, NH). 13C NMR (75 MHz,

CDCl3): 28.12, 42.26 (CH2), 55.86, 55.97 (OMe), 90.47 (C5), 122.13 (C2), 125.82,

137

1287.91, 129.88 (aryl CH), 104.88, 111.36, 118.98, 136.90, 139.37, 153.56, 154.06 -1 (aryl C). IR (KBr): νmax 2933, 2359, 1600, 1519, 1462, 1331, 1215, 1127 cm . UV- -1 -1 vis (MeOH): max 229 nm ( 44,541 cm M ), 281 (16,821). HRMS (+ESI): + C18H20N2O2 [M+H] requires 297.1603, found 297.1596.

3-(4-Chlorophenyl)-N-(2-(4,6-dimethoxy-3-phenyl-1H-indol-7-yl)-ethyl)-4,6- dimethoxy-1H-indole-7-carboxamide (166) Cl To a suspension of 7-trichloroacetylindole 41 (0.26 g, 0.6 mmol) and 7-tryptamine 161 (0.2 g, 0.6 mmol) in acetonitrile OMe (20 mL), triethylamine (3 drops) was added and the mixture was stirred at room temperature for 4 h. The reaction mixture MeO N was poured into the ice-water and the resulting precipitate was H HN O filtered, washed with water and recrystallised from methanol to give the title compound 166 (0.218 g, 59%) as a cream solid. H MeO N Mp 196-198 ºC. (Found: C, 68.31; H, 5.30; N, 6.94;

C35H32ClN3O5 0.25 CH3OH requires C, 68.50; H, 5.38; N, OMe Ph 1 6.80%). H NMR (300 MHz, CDCl3): 3.21 (t, J = 15.34 Hz, 2H, CH2), 3.66 (q, J =

21.72 Hz, 2H, CH2), 3.84 (s, 3H, OMe), 3.88 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.95 (s, 3H, OMe), 6.25 (s, 1H, H5), 6.36 (s, 1H, H5), 7.19 (d, J = 2.02 Hz, 1H, H2), 7.24 (d, J = 2.36 Hz, 1H, H2), 7.25-7.68 (m, 9H, aryl H), 8.52 (t, J = 11.83 Hz, 1H, NH), 13 10.43 (bs, 1H, NH), 11.29 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 24.91, 39.56

(CH2), 55.14, 55.36, 56.70, 57.53 (OMe), 87.36 (C5), 89.49 (C5), 122.01 (C2), 122.20 (C2), 125.33, 127.50, 127.64, 129.37, 130.67 (aryl CH), 97.48, 102.72, 110.66, 110.92, 116.72, 118.32, 131.49, 134.33, 136.42, 138.89, 139.33, 153.22,

153.25, 156.83, 157.27 (aryl C), 168.62 (C=O). IR (KBr): νmax 3397, 2927, 2834, -1 1619, 1593, 1540, 1330, 1264, 1209, 1106 cm . UV-vis (THF): max 232 nm ( -1 -1 37 + 74,876 cm M ), 286 (31,789). HRMS (+ESI): C35H32 ClN3O5 [M+Na] requires 634.1899, found 634.1896.

138

N-(2-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-ethyl)-4,6-dimethoxy-2,3- diphenyl-1H-indole-7-carboxamide (167)

To a suspension of 7-trichloroacetylindole 83 (0.191 g, 0.4 OMe Ph mmol) and 7-tryptamine 160 (0.15 g, 0.4 mmol) in Ph MeO N acetonitrile (20 mL), triethylamine (3 drops) was added and H the mixture was stirred at room temperature for 2 h. The HN O reaction mixture was poured into the ice-water and the H resulting precipitate was filtered, washed with water, dried MeO N Ph and recrystallised from methanol to afford the title compound Ph 167 (0.255 g, 79%) as a pale green solid. Mp 283-285 ºC. OMe

(Found: C, 77.27; H, 5.72; N, 5.82; C47H41N3O5 requires C, 77.56; H, 5.68; N, 1 5.82%). H NMR (300 MHz, DMSO-d6): 2.48 (q, J = 5.41 Hz, 2H, CH2), 3.18 (t, J

= 13.54 Hz, 2H, CH2), 3.62 (s, 3H, OMe), 3.70 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.84 (s, 3H, OMe), 6.38 (s, 1H, H5), 6.40 (s, 1H, H5), 7.10-7.27 (m, 20H, aryl H), 8.38 (t, J = 10.33 Hz, 1H, NH), 11.13 (bs, 1H, NH), 11.30 (bs, 1H, NH). 13C NMR

(75 MHz, DMSO-d6): 24.20, 39.19 (CH2), 55.55, 55.76, 56.98, 57.26 (OMe), 88.80 (C5), 90.03 (C5), 126.11, 126.52, 127.14, 127.58, 127.77, 127.87, 128.40, 128.66, 128.96, 131.47, 131.53 (aryl CH), 97.08, 102.35, 112.91, 113.0, 113.71, 114.13, 132.37, 132.53, 133.07, 133.25, 135.91, 136.65, 137.71, 138.11, 153.26, 153.93,

156.92, 157.35 (aryl C), 167.29 (C=O). IR (KBr): νmax 3407, 2927, 1618, 1502, -1 -1 -1 1264, 1213, 1116, 697 cm . UV-vis (CH2Cl2): max 228 nm ( 74,978 cm M ), 250 + (86,747), 335 (54,085). HRMS (+ESI): C47H41N3O5 [M+H] requires 728.3124, found 728.3115.

139

(E)-N-((3-(4-chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-methylene)-2-(4,6- dimethoxy-3-phenyl-1H-indol-7-yl)-ethanamine (169)

A mixture of 7-carbaldehyde 93 (0.22 g, 0.71 mmol) and 7- Cl tryptamine 161 (0.234 g, 0.71 mmol) was refluxed in absolute ethanol (30 mL) for 24 h. The precipitate was filtered, washed OMe with water and dried. The crude product was purified by flash MeO N chromatography using dichloromethane/ethyl acetate (90:10) H as eluent to yield the title compound 169 (0.248 g, 65%) as a N 1 yellow solid. Mp 284-286 ºC. H NMR (300 MHz, DMSO-d6): H MeO N 3.18 (t, J = 13.74 Hz, 2H, CH2), 3.75 (s, 3H, OMe), 3.84 (s, 6H, OMe), 3.88 (s, 3H, OMe), 6.41 (s, 1H, H5), 6.42 (s, 1H, Ph H5), 7.16 (t, J = 6.80 Hz, 2H, H2, H2), 7.21-7.52 (m, 9H, aryl OMe

H), 8.72 (s, 1H, CH), 11.14 (bs, 1H, NH), 11.27 (bs, 1H, NH). IR (KBr): νmax 3336, -1 1593, 1463, 1344, 1210, 1173, 1148, 1089 cm . UV-vis (THF): max 228 nm ( -1 -1 + 69,603 cm M ), 286 (28,474). HRMS (+ESI): C35H32ClN3O4 [M+H] requires 594.2160, found 594.2153. The sample was not soluble enough for 13C NMR measurement.

(E)-2-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-N-((4,6-dimethoxy-2,3- diphenyl-1H-indol-7-yl)-methylene)-ethanamine (170)

A mixture of 7-carbaldehyde 95 (0.19 g, 0.53 mmol) and 7- OMe Ph tryptamine 160 (0.198 g, 0.53 mmol) was heated under reflux Ph MeO N in absolute ethanol (25 mL) for 24 h. The precipitate was H filtered, washed with water and dried. The crude product was N purified by flash chromatography using H dichloromethane/ethyl acetate (90:10) as eluent to yield the MeO N Ph title compound 170 (0.162 g, 43%) as a pale yellow solid. Mp 1 OMe Ph 131-133 ºC. H NMR (300 MHz, CDCl3): 3.22 (t, J = 12.33

Hz, 2H, CH2), 3.71 (s, 3H, OMe), 3.75 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.91 (s, 3H,

OMe), 4.00 (t, J = 11.72 Hz, 2H, CH2), 6.16 (s, 1H, H5), 6.35 (s, 1H, H5), 6.75-7.32

(m, 20H, aryl H), 8.30 (s, 1H, CH), 8.86 (bs, 1H, NH). IR (KBr): max 3427, 2931, -1 2835, 1624, 1597, 1462, 1361, 1244, 1123, 696 cm . UV-vis (CH2Cl2): max 229 nm

140

-1 -1 + ( 81,089 cm M ), 251 (78,447), 328 (46,743). HRMS (+ESI): C47H41N3O4 [M+H] requires 712.3175, found 712.3159. The sample was not soluble enough for 13C NMR measurement.

(E)-2-(4,6-dimethoxy-3-phenyl-1H-indol-7-yl)-N-((4,6-dimethoxy-3-phenyl-1H- indol-7-yl)-methylene)-ethanamine (171)

A mixture of 7-tryptamine 161 (0.225 g, 0.75 mmol) and 7- OMe Ph carbaldehyde 168 (0.212 g, 0.75 mmol) was heated under reflux in absolute ethanol (30 mL) for 8 h. The precipitate was filtered, MeO N H washed with water and dried. The crude product was purified by N flash chromatography using dichloromethane/ethyl acetate H (90:10) as eluent to yield the title compound 171 (0.29 g, 69%) as MeO N 1 a yellow solid. Mp 229-231 ºC. H NMR (300 MHz, CDCl3): OMe Ph 3.23 (t, J = 13.88 Hz, 2H, CH2), 3.77 (s, 3H, OMe), 3.85 (s, 6H, OMe), 3.87 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.42 (s, 1H, H5), 6.45 (s, 1H, H5), 7.17-7.56 (m, 12H, H2, H2, aryl H), 8.76 (s, 1H, CH), 11.17 (d, J = 2.21 Hz, 1H, 13 NH), 11.26 (bs, 1H, NH). C NMR (75 MHz, DMSO-d6): 26.86 (CH2), 55.51,

55.72, 57.05, 57.21 (OMe), 61.10 (CH2), 88.53 (C5), 89.75 (C5), 122.90 (C2), 125.37 (C2), 125.80, 127.90, 128.04, 129.37, 129.42 (aryl CH), 101.31, 103.70, 109.94, 110.26, 117.43, 117.54, 136.34, 136.93, 137.02, 138.79, 152.75, 153.65,

157.21, 157.72 (aryl C), 156.82 (C=N). IR (KBr): νmax 3425, 3314, 2927, 2834, 1625, 1596, 1517, 1462, 1358, 1328, 1209, 1148, 1085, 1025, 701 cm-1. UV-vis -1 -1 + (THF): max 311 nm ( 28,725 cm M ). HRMS (+ESI): C35H33N3O4 [M+H] requires 560.2549, found 560.2538.

141

N1,N2-bis-(2-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-ethyl)-oxalamide (172)

Oxalyl chloride (0.05 mL, 0.48 mmol) in dry OMe Ph dichloromethane (5 mL) was added dropwise to a solution of Ph 7-tryptamine 160 (0.304 g, 0.81 mmol) in dry MeO N H dichloromethane (10 mL) containing triethylamine (0.11 mL, 0.81 mmol). The reaction mixture was stirred at room O NH temperature for 1.5 h. The solvent was evaporated and the O NH residue was quenched with water. The resulting precipitate H was filtered, dried and recrystallised from ethanol to yield the MeO N Ph title compound 172 (0.146 g, 45%) as a pale yellow solid. Mp Ph 278-280 ºC. (Found: C, 73.93; H, 5.82; N, 7.18; C50H46N4O6 OMe 1 0.16 CH2Cl2 requires C, 74.15; H, 5.75; N, 6.90%). H NMR (300 MHz, DMSO-d6):

3.04 (s, 4H, CH2), 3.61 (s, 6H, OMe), 3.81 (s, 6H, OMe), 6.36 (s, 2H, H5), 7.22-7- 26 (m, 20H, aryl H), 8.50 (s, 2H, NH), 10.86 (bs, 2H, NH). 13C NMR (75 MHz,

DMSO-d6): 23.90, 39.55 (CH2), 55.51, 57.10 (OMe), 89.77 (C5), 126.05, 127.24, 127.53, 128.50, 128.95, 131.52 (aryl CH), 102.04, 112.79, 114.11, 133.10, 133.34,

136.55, 137.40, 153.23, 153.88 (aryl C), 160.09 (C=O). IR (KBr): νmax 3353, 1646, -1 - 1598, 1518, 1326, 1217, 1128, 698 cm . UV-vis (THF): max 214 nm ( 112,167 cm 1 -1 + M ), 248 (73,181), 329 (40,981). HRMS (+ESI): C50H46N4O6 [M+H] requires 799.3496, found 799.3487.

142

N1,N2-bis-(2-(4,6-dimethoxy-3-phenyl-1H-indol-7-yl)-ethyl)-oxalamide (173)

Oxalyl chloride (0.06 mL, 0.69 mmol) in dry dichloromethane (6 OMe Ph mL) was added dropwise to a solution of 7-tryptamine 161 (0.362 g, 1.22 mmol) in dry dichloromethane (10 mL) containing MeO N H triethylamine (0.15 mL, 1.09 mmol). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated O NH and the residue was quenched with water. The resulting O NH precipitate was filtered, dried and recrystallised from methanol to H yield the title compound 173 (0.2 g, 51%) as a pale yellow solid. MeO N

Mp 284-286 ºC. (Found: C, 70.07; H, 5.99; N, 8.72; C38H38N4O6 1 Ph 0.05 CH2Cl2 requires C, 70.20; H, 5.90; N, 8.61%). H NMR OMe

(300 MHz, DMSO-d6): 3.01 (t, J = 13.91 Hz, 4H, CH2), 3.78 (s, 6H, OMe), 3.85 (s, 6H, OMe), 6.42 (s, 2H, H5), 7.16-7.57 (m, 12H, H2, aryl H), 8.53 (t, J = 11.26 Hz, 13 1H, NH), 11.02 (d, J = 1.74 Hz, 2H, NH). C NMR (75 MHz, DMSO-d6): 24.14,

39.67 (CH2), 55.55, 57.24 (OMe), 89.65 (C5), 122.89 (C2), 125.48, 127.92, 129.41 (aryl CH), 102.31, 110.40, 117.69, 136.83, 138.50, 153.12, 153.73 (aryl C), 160.21 -1 (C=O). IR (KBr): νmax 3350, 1650, 1600, 1520, 1323, 1204, 1054 cm . UV-vis -1 -1 (CH2Cl2): max 230 nm ( 66,696 cm M ), 286 (28,178). HRMS (+ESI): + C38H38N4O6 [M+H] requires 647.2870, found 647.2855.

Bis-(3-(4-chlorophenyl)-4,6-dimethoxy-7-(2-nitroethyl)-1H-indol-2-yl)-methane (178)

To a mixture of 7-nitroethylindole 155 (2.27 g, 6.3 Cl Cl mmol) and formaldehyde solution (6 mL, 40%) in methanol (60 mL) was added concentrated MeO OMe hydrochloric acid (6 mL). The mixture was heated NH HN under reflux for 20 h. The solvent was evaporated, the residue was quenched with water and the solid MeO OMe obtained was filtered. The resulting green solid was NO2 NO2 purified by flash chromatography using dichloromethane as eluent to yield the title compound 178 (1.18 g, 51%) as a cream solid. Mp 238-240 ºC. 1H NMR (300 MHz,

DMSO-d6): 3.43, 4.67 (2t, J = 14.74 Hz, 8H, CH2), 3.60 (s, 6H, OMe), 3.79 (s, 6H,

143

OMe), 4.06 (s, 2H, CH2), 6.33 (s, 2H, H5), 7.04, 7.14 (2d, J = 8.35 Hz, 8H, aryl H), 13 10.87 (bs, 2H, NH). C NMR (75 MHz, DMSO-d6): 23.08, 74.53 (CH2), 55.46, 57.02 (OMe), 89.40 (C5), 127.14, 132.50 (aryl CH), 98.55, 111.32, 112.68, 130.51,

131.48, 134.53, 136.67, 153.14, 153.99 (aryl C). IR (KBr): νmax 3419, 1601, 1547, -1 -1 -1 1490, 1334, 1123, 994 cm . UV-vis (THF): max 232 nm ( 62,601 cm M ), 284 + (28,921). HRMS (+ESI): C37H34Cl2N4O8 [M+H] requires 733.1832, found 733.1825.

Bis-(3-(4-bromophenyl)-4,6-dimethoxy-7-(2-nitroethyl)-1H-indol-2-yl)methane (179)

To a mixture of 7-nitroethylindole 156 (2.13 g, Br Br 5.27 mmol) and formaldehyde solution (5 mL, 40%) in methanol (60 mL) was added concentrated MeO OMe hydrochloric acid (6 mL). The mixture was heated NH HN under reflux for 20 h. The solvent was evaporated, the residue was quenched with water and the solid MeO OMe obtained was filtered. The resulting green solid was NO2 NO2 purified by flash chromatography using dichloromethane as eluent to yield the title compound 179 (1.15 g, 53%) as a cream solid. Mp 239-241 ºC. (Found: C, 53.48; H, 1 4.12; N, 6.77; C37H34Br2N4O8 0.1 CH2Cl2 requires C, 53.62; H, 4.15; N, 6.74%). H

NMR (300 MHz, DMSO-d6): 3.41, 4.65 (2t, J = 14.73 Hz, 8H, CH2), 3.58 (s, 6H,

OMe), 3.77 (s, 6H, OMe), 4.04 (s, 2H, CH2), 6.31 (s, 2H, H5), 6.96, 7.26 (2d, J = 13 8.49 Hz, 8H, aryl H), 10.86 (bs, 2H, NH). C NMR (75 MHz, DMSO-d6): 23.05,

74.51 (CH2), 55.44, 56.99 (OMe), 89.37 (C5), 130.05, 132.87 (aryl CH), 98.51, 111.19, 112.69, 119.08, 131.39, 134.87, 136.67, 153.12, 153.98 (aryl C). IR (KBr): -1 max 3419, 1600, 1547, 1487, 1334, 1123, 993 cm . UV-vis (THF): max 232 nm ( -1 -1 + 70,051 cm M ), 284 (33,010). HRMS (+ESI): C37H34Br2N4O8 [M] requires 820.0743, found 820.0738.

144

2,2ʹ-(2,2ʹ-Methylenebis-(4,6-dimethoxy-3-phenyl-1H-indole-7,2-diyl))- diethanamine (182)

To a refluxing solution of bis-indole 179 (0.74 g, Ph Ph MeO OMe 0.9 mmol) in absolute ethanol/tetrahydrofuran (40 NH HN mL) (3:1), 10% Pd/C (0.3 g) was added under argon followed by the dropwise addition of MeO OMe hydrazine monohydrate (8 mL) over 15 min. The NH2 NH2 reaction mixture was heated under reflux for another 8 h. The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure. The residue was quenched with water, the resulting precipitate was filtered and dried to yield the title compound 182 (0.46 g, 84%) as a yellow-green solid. Mp 150-153 ºC. 1 H NMR (300 MHz, CDCl3): 2.92, 2.94 (2d, J = 4.17 Hz, 8H, CH2), 3.66 (s, 6H,

OMe), 3.83 (s, 6H, OMe), 4.21 (s, 2H, CH2), 6.26 (s, 2H, H5), 7.22-7.37 (m, 10H, 13 aryl H), 10.34 (bs, 2H, NH). C NMR (75 MHz, CDCl3): 23.05, 28.71, 41.89

(CH2), 55.43, 57.20 (OMe), 89.88 (C5), 125.46, 127.30, 131.11 (aryl CH), 103.18,

111.44, 113.64, 131.42, 135.83, 137.20, 152.33, 153.16 (aryl C). IR (KBr): max 3272, 2931, 2834, 1601, 1519, 1495, 1453, 1332, 1210, 1123, 989 cm-1. UV-vis -1 -1 (MeOH): max 288 nm ( 17,865 cm M ), 290 (17,600). HRMS (+ESI): C37H40N4O4 [M+H]+ requires 605.3128, found 605.3115.

Macrocyclic imine (186) Ph Ph A mixture of bis-indole 182 (0.33 g, 0.54 mmol) MeO OMe and 2,7-dicarbaldehyde 183 (0.18 g, 0.54 mmol) NH HN was heated under reflux in absolute ethanol (40 MeO OMe mL) overnight. The precipitate was filtered, dried N N and passed through a plug of silica to yield the title H N compound 186 (0.339 g, 69%) as a yellow solid. 1 MeO Mp 203 ºC (dec.). H NMR (300 MHz, CDCl3):

2.87 (s 2H, CH2), 3.15 (d, J = 4.48 Hz, 2H, CH2), OMe Cl 3.63 (s, 3H, OMe), 3.67 (t, J = 10.09 Hz, 2H, CH2), 3.71 (s, 3H, OMe), 3.76 (s, 3H,

OMe), 3.83 (s, 3H, OMe), 3.87 (s, 3H, OMe), 3.93 (s, 3H, OMe), 4.03 (s, 2H, CH2), 6.09 (s, 1H, H5), 6.32 (s, 1H, H5), 6.33 (s, 1H, H5), 6.66-7.09 (m, 14H, aryl H),

145

7.34 (s, 1H, CH), 8.40 (bs, 1H, NH), 8.79 (s, 1H, CH), 9.55 (bs, 1H, NH), 12.03 (bs, 13 1H, NH). C NMR (75 MHz, CDCl3): 22.80, 25.16, 26.69, 61.91, 62.31 (CH2), 55.13, 55.45, 56.03, 57.24, 57.96, 60.29 (OMe), 87.67 (C5), 89.74 (C5), 90.58 (C5), 125.01, 125.09, 126.79, 126.88, 127.04, 130.40, 131.08, 132.23 (aryl CH), 151.97, 158.16 (CH), 100.66, 103.17, 105.94, 111.93, 112.02, 112.12, 112.52, 115.09, 120.87, 130.93, 131.17, 131.68, 135.0, 135.59, 137.07, 137.28, 138.48,

152.69, 153.04, 153.40, 158.48, 159.51 (aryl C). IR (KBr): νmax 3361, 2930, 2837, -1 1614, 1592, 1516, 1463, 1246, 1122, 989, 699 cm . UV-vis (THF): max 232 nm ( -1 -1 + 84,077 cm M ), 271 (45,477), 348 (23,721). HRMS (+ESI): C55H50ClN5O6 [M+H] requires 912.3528, found 912.3509.

Macrocyclic imine (187)

A mixture of bis-indole 182 (0.164 g, 0.27 mmol) Ph Ph MeO OMe and 2,7-dicarbaldehyde 184 (0.104 g, 0.27 mmol) NH HN was heated under reflux in absolute ethanol (30 mL) overnight. The precipitate was filtered, dried MeO OMe and passed through a plug of silica to yield the title N N H compound 187 (0.148 g, 71%) as a yellow solid. N 1 Mp 198 ºC (dec.). H NMR (300 MHz, CDCl3): MeO

2.96 (s, 2H, CH2), 3.15 (d, J = 4.66 Hz, 2H, CH2), OMe Br 3.63 (s, 3H, OMe), 3.70 (s, 3H, OMe), 3.76 (s, 3H,

OMe), 3.83 (s, 3H, OMe), 3.86 (s, 3H, OMe), 3.92 (s, 3H, OMe), 4.01 (s, 2H, CH2), 6.10 (s, 1H, H5), 6.31 (s, 1H, H5), 6.32 (s, 1H, H5), 6.67-7.23 (m, 14H, aryl H), 7.39 (s, 1H, CH), 8.54 (bs, 1H, NH), 8.80 (s, 1H, CH), 9.63 (bs, 1H, NH), 12.04 (bs, 13 1H, NH). C NMR (75 MHz, CDCl3): 22.80, 25.22, 26.77, 61.85, 62.08 (CH2), 55.14, 55.46, 56.06, 57.23, 57.92 (OMe), 87.65 (C5), 89.72 (C5), 90.53 (C5), 125.02, 125.09, 126.82, 126.88, 130.02, 130.43, 131.07, 132.58 (aryl CH), 151.88, 158.03 (CH), 100.67, 103.12, 105.71, 111.92, 112.28, 112.47, 115.08, 120.60, 120.96, 130.90, 131.01, 131.62, 132.18, 135.01, 135.56, 137.16, 137.26, 138.40,

152.70, 153.04, 153.41, 158.47, 159.53 (aryl C). IR (KBr): νmax 3364, 2981, 2829, -1 1829, 1614, 1592, 1518, 1462, 1243, 1150, 1122, 991, 699 cm . UV-vis (THF): max

146

232 nm ( 128,488 cm-1M-1), 272 (71,169), 348 (37,575). HRMS (+ESI): 81 + C55H50 BrN5O6 [M+H] requires 958.3002, found 958.3022.

Macrocyclic imine (188)

A mixture of bis-indole 182 (0.258 g, 0.42 mmol) Ph Ph MeO OMe and 2,7-dicarbaldehyde 185 (0.132 g, 0.42 mmol) NH HN was heated under reflux in absolute ethanol (30 mL) overnight. The precipitate was filtered, dried MeO OMe and passed through a plug of silica to yield the title N N H compound 188 (0.22 g, 58%) as a yellow solid. Mp N 1 MeO 185 ºC (dec.). H NMR (300 MHz, CDCl3): 3.08 Ph

(s, 2H, CH2), 3.17 (t, J = 10.78 Hz, 2H, CH2), 3.63 OMe (s, 3H, OMe), 3.68 (s, 6H, OMe), 3.76 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.86 (s, 6H,

OMe), 3.93 (s, 3H, OMe), 4.02 (d, J = 4.29 Hz, 2H, CH2), 6.12 (s, 1H, H5), 6.31 (s, 1H, H5), 6.33 (s, 1H, H5), 6.87-7.18 (m, 15H, aryl H), 7.52 (s, 1H, CH), 8.71 (bs, 13 1H, NH), 8.82 (s, 1H, CH), 9.69 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 22.87,

25.48, 27.01, 61.97, 62.02 (CH2), 55.28, 55.62, 55.70, 56.22, 57.43, 58.01 (OMe), 87.84 (C5), 90.17 (C5), 90.72 (C5), 125.08, 125.22, 126.47, 126.91, 130.68, 131.14, 131.24 (aryl CH), 152.43, 158.01 (CH), 100.86, 103.56, 105.71, 112.31, 112.37, 112.71, 115.12, 122.70, 127.01, 127.04, 131.03, 131.66, 133.30, 135.27, 135.76, 137.44, 138.46, 152.83, 152.87, 153.14, 153.56, 158.77, 159.63 (aryl C). IR

(KBr): νmax 3319, 2932, 2834, 1623, 1592, 1518, 1462, 1351, 1242, 1201, 1149, -1 -1 -1 1122, 990, 699 cm . UV-vis (THF): max 293 nm ( 36,889 cm M ), 348 (29,347). + HRMS (+ESI): C55H51N5O6 [M+H] requires 878.3918, found 878.3912.

147

Macrocyclic amine (189) Ph Ph To a solution of cyclic indole 186 (0.102 g, 0.11 MeO OMe mmol) in a mixture of absolute NH HN ethanol/tetrahydrofuran (32 mL) (1:3), Sodium MeO OMe borohydride (1 g, 26.3 mmol) was added and the NH HN mixture was heated under reflux for 12 h. The H N solvent was removed under reduced pressure, and MeO the residue was treated with water and neutralized using dilute hydrochloric acid (2 M). The resulting OMe Cl precipitate was filtered, dried and recrystallised from methanol to yield the title compound 189 (0.071 g, 69%) as a yellow-green solid. Mp 183 ºC (dec). 1H NMR

(300 MHz, CDCl3): 2.78, 2.97 (2t, J = 11.63 Hz, 4H, CH2), 3.14 (s, 4H, CH2), 3.54

(s, 2H, CH2), 3.64 (s, 3H, OMe), 3.65 (s, 3H, OMe), 3.76 (s, 3H, OMe), 3.82 (s, 3H,

OMe), 3.86 (s, 3H, OMe), 3.92 (s, 3H, OMe), 4.14 (s, 2H, CH2), 4.24 (s, 2H, CH2), 6.24 (s, 1H, H5), 6.28 (s, 1H, H5), 6.30 (s, 1H, H5), 7.12-7.35 (m, 14H, aryl H), 9.55 (bs, 1H, NH), 10.17 (bs, 1H, NH), 10.73 (bs, 1H, NH). 13C NMR (75 MHz,

CDCl3): 23.02, 25.04, 25.33, 43.46, 44.18, 48.29, 49.21 (CH2), 55.26, 55.47, 55.55, 56.75, 57.16, 57.37 (OMe), 88.85 (C5), 89.27 (C5), 89.69 (C5), 125.27, 125.33, 127.06, 127.14, 127.38, 130.95, 131.03, 132.15 (aryl CH), 111.35, 111.78, 111.99, 114.34, 114.80, 115.16, 130.60, 130.72, 131.72, 133.63, 135.32, 135.35, 137.15,

137.49, 137.75, 152.99, 153.03, 153.16, 153.52, 153.94 (aryl C). IR (KBr): νmax -1 3314, 2931, 2835, 1600, 1493, 1334, 1203, 1147, 990 cm . UV-vis (THF): max 230 -1 -1 + nm ( 105,518 cm M ), 285 (49,930). HRMS (+ESI): C55H54ClN5O6 [M+H] requires 916.3841, found 916.3844.

148

Macrocyclic amine (190)

To a solution of cyclic indole 187 (0.129 g, 0.13 Ph Ph MeO OMe mmol) in a mixture of absolute NH HN ethanol/tetrahydrofuran (32 mL) (1:3), Sodium borohydride (1 g, 26.3 mmol) was added and the MeO OMe mixture was heated under reflux for 12 h. The NH HN H solvent was removed under reduced pressure, and N the residue was treated with water and neutralized MeO using dilute hydrochloric acid (2 M). The resulting OMe Br precipitate was filtered, dried and recrystallised from methanol to yield the title compound 190 (0.078 g, 60%) as a yellow-green 1 solid. Mp 243 ºC (dec). H NMR (300 MHz, CDCl3): 2.80, 2.97 (2t, J = 5.56 Hz,

4H, CH2), 3.14 (s, 4H, CH2), 3.54 (s, 2H, CH2), 3.64 (s, 3H, OMe), 3.65 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.82 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.93 (s, 3H, OMe),

4.15 (s, 2H, CH2), 4.24 (s, 2H, CH2), 6.25 (s, 1H, H5), 6.28 (s, 1H, H5), 6.30 (s, 1H, H5), 7.10-7.53 (m, 14H, aryl H), 9.62 (bs, 1H, NH), 10.18 (bs, 1H, NH), 10.71 (bs, 13 1H, NH). C NMR (75 MHz, CDCl3): 23.02, 25.03, 25.42, 43.56, 44.21, 48.31,

49.26 (CH2), 50.60, 55.25, 55.51, 56.77, 57.18, 57.37 (OMe), 88.90 (C5), 89.27 (C5), 89.70 (C5), 125.27, 125.33, 127.06, 127.14, 130.32, 130.96, 131.02, 132.53 (aryl CH), 101.44, 102.16, 111.29, 111.78, 111.98, 114.36, 114.81, 115.12, 119.92, 130.59, 130.71, 134.12, 135.34, 137.22, 137.48, 137.73, 153.02, 153.18, 153.52, - 153.91 (aryl C). IR (KBr): νmax 3353, 2933, 2837, 1600, 1463, 1335, 1214, 1122 cm 1 -1 -1 . UV-vis (THF): max 291 nm ( 60,885 cm M ). HRMS (+ESI): C55H54BrN5O6 [M+H]+ requires 960.3336, found 960.3338.

149

Macrocyclic amine (191)

To a solution of cyclic indole 188 (0.097 g, 0.11 Ph Ph MeO OMe mmol) in a mixture of absolute NH HN ethanol/tetrahydrofuran (32 mL) (1:3), Sodium borohydride (1 g, 26.3 mmol) was added and the MeO OMe mixture was heated under reflux for 12 h. The NH HN H solvent was removed under reduced pressure, and N the residue was treated with water. The resulting MeO Ph precipitate was filtered, dried and recrystallised OMe from methanol to yield the cyclic amine 191 (0.061 g, 62%) as a yellow-green solid. 1 Mp 159 ºC (dec.). H NMR (300 MHz, CDCl3): 2.71 (s, 2H, CH2), 2.91 (s, 2H,

CH2), 3.07 (s, 4H, CH2), 3.55 (s, 3H, OMe), 3.56 (s, 3H, OMe), 3.67 (s, 3H, OMe),

3.72 (s, 3H, OMe), 3.81 (s, 3H, OMe), 3.84 (s, 3H, OMe), 4.06 (s, 2H, CH2), 4.17 (s,

2H, CH2), 6.15 (s, 1H, H5), 6.19 (s, 1H, H5), 6.22 (s, 1H, H5), 7.03-7.34 (m, 15H, aryl H), 9.31 (bs, 1H, NH), 10.09 (bs, 1H, NH), 10.75 (bs, 1H, NH). 13C NMR (75

MHz, CDCl3): 23.05, 25.09, 25.39, 43.42, 44.30, 48.29, 49.34 (CH2), 55.47, 55.59, 55.67, 56.87, 57.31, 57.54 (OMe), 89.07 (C5), 89.45 (C5), 89.86 (C5), 125.34, 125.41, 125.96, 127.15, 127.23, 127.31, 131.07, 131.16 (aryl CH), 101.60, 102.30, 111.66, 111.90, 112.11, 114.41, 114.86, 116.72, 130.73, 130.85, 130.94, 135.16, 135.46, 137.19, 137.61, 137.91, 153.10, 153.14, 153.20, 153.65, 154.02, 154.25 (aryl

C). IR (KBr): νmax 3305, 2931, 2834, 1601, 1518, 1495, 1451, 1333, 1203, 1147, -1 -1 -1 1124, 990, 699 cm . UV-vis (THF): max 293 nm ( 66,546 cm M ). HRMS (+ESI): + C55H55N5O6 [M+H] requires 882.4231, found 882.4251.

N-(2-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)ethyl)acetamide (194)

7-Tryptamine 160 (0.977 g, 2.62 mmol) was dissolved in OMe Ph acetic anhydride (20 mL) and the mixture was stirred for 2 h Ph in an ice bath. Ice-water was added, and the resulting solid MeO N H was filtered, washed with water and dried. The crude product was purified by flash chromatography using NHCOCH3 dichloromethane/ethyl acetate (90:10) as eluent to give the title compound 194 (0.62 1 g, 57%) as a yellow solid. Mp 223-225 ºC. H NMR (300 MHz, DMSO-d6): 2.96

150

(t, J = 14.45 Hz, 2H, CH2), 3.17-3.24 (m, 2H, CH2), 3.60 (s, 3H, OMe), 3.82 (s, 3H, OMe), 6.35 (s, 1H, H5), 7.19-7.30 (m, 10H, aryl H),7.96 (t, J = 10.44 Hz, 1H, NH), 13 11.00 (bs, 1H, NH). C NMR (75 MHz, DMSO-d6): 23.04 (Me), 24.38, 39.16

(CH2), 55.53, 57.24 (OMe), 90.01 (C5), 126.09, 127.14, 127.57, 128.48, 128.70, 131.53 (aryl CH), 102.68, 112.93, 114.16, 133.07, 133.15, 136.71, 137.48, 153.12,

153.81 (aryl C), 170.06 (C=O). IR (KBr): νmax 3436, 3187, 1655, 1600, 1454, 1271, -1 -1 -1 1214, 1163, 1125, 765, 700 cm . UV-vis (MeOH): max 205 nm ( 71,241 cm M ), + 247 (42,385), 325 (24,437). HRMS (+ESI): C26H26N2O3 [M+H] requires 415.2021, found 415.2009.

8-Chloro-10-methoxy-4-methyl-6,7-diphenyl-1,2-dihydro-[1,3]diazepino-[6,7,1- hi]-indole (196)

To a solution of indole 194 (0.169 g, 0.4 mmol) in Cl Ph acetonitrile (20 mL), POCl (1 mL) was added and the 3 Ph solution was heated under reflux for 4 h. The solvent was MeO N evaporated under reduced pressure and the residue was N quenched with water and made alkaline by the addition of 5N NaOH (10 mL). The resulting precipitate was collected by filtration, washed with water, dried and purified by flash chromatography using dichloromethane as eluent to afford the title compound 196 (0.015 g, 9.5%) as a grey solid. Mp 237-239 ºC. 1H NMR (300 MHz,

CDCl3): 1.75 (s, 3H, Me), 3.06 (s, 2H, CH2), 3.87 (s, 3H, OMe), 4.20 (t, J = 10.13 13 Hz, 2H, CH2), 6.79 (s, 1H, H5), 7.17-7.30 (m, 10H, aryl H). C NMR (75 MHz,

CDCl3): 25.00 (CH2), 26.20 (Me), 48.56 (CH2), 56.42 (OMe), 108.05, 126.93, 127.35, 127.59, 128.37, 129.28 (aryl CH), 113.38, 120.68, 120.76, 124.05, 131.67,

132.65, 134.14, 137.47, 137.56, 153.88, 155.37 (aryl C). IR (KBr): max 3450, 2953, -1 2927, 1664, 1334, 1236, 1115, 717 cm . UV-vis (MeOH): max 227 nm ( 45,755 -1 -1 + cm M ), 315 (20,464). HRMS (+ESI): C25H21ClN2O [M+H] requires 401.1421, found 401.1421.

151

N-(2-bromo-3,5-dimethoxyphenyl)-formamide (214) and N-(4-bromo-3,5- dimethoxyphenyl)-formamide (215)

To a solution of 3,5-dimethoxy acetamide 213 (1 g, 5.52 mmol) in glacial acetic acid (10 mL), bromine (0.311 mL, 6.07 mmol) in glacial acetic acid (5 mL) was added dropwise and the yellow solution was stirred at room temperature for 1.5 h. The reaction mixture was poured into ice-water and treated with saturated sodium metabisulfite (50 mL). The white precipitate obtained was filtered and purified by column chromatography using dichloromethane/ethyl acetate (70:30) as eluent to give 2-bromo-3,5dimethoxyacetamide 214 (0.286 g, 20%) and 4-bromo-3,5- dimethoxyacetamide 215 (0.25 g, 17%) as white powders.

N-(2-bromo-3,5-dimethoxyphenyl)-formamide (214) OMe Mp 107-108 ºC. 1H NMR (300 MHz, DMSO-d ): 3.74 (s, 6 Br 3H, OMe), 3.81 (s, 3H, OMe), 6.47 (d, J = 2.74 Hz, 1H, H4), 7.41 (d, J = 2.74 Hz, 1H, H6), 8.33 (s, 1H, CHO), 9.58 (bs, MeO NHCHO 13 1H, NH). C NMR (75 MHz, DMSO-d6): 55.83, 56.78 (OMe), 96.08, 100.77 (aryl

CH), 94.39, 137.28, 156.80, 159.84 (aryl C), 161.01 (C=O). IR (KBr): νmax 3256, -1 1637, 1592, 1529, 1342, 1152, 1071, 848 cm . UV-vis (MeOH): max 218 nm ( -1 -1 + 34,962 cm M ), 289 (2,676). HRMS (+ESI): C9H10BrNO3 [M+Na] requires 281.9736, found 281.9738.

N-(4-bromo-3,5-dimethoxyphenyl)-formamide (215) OMe Mp 183-184 ºC. 1H NMR (300 MHz, DMSO-d ): 3.77 (s, 6 Br 3H, OMe), 3.79 (s, 3H, OMe), 7.03 (s, 2H, CH), 8.28 (s, 1H, 13 MeO NHCHO CHO), 10.29 (bs, 1H, NH). C NMR (75 MHz, DMSO-d6): 56.48, 56.72 (OMe), 95.00, 96.55 (aryl CH), 139.44, 156.82, 157.32 (aryl C), 160.31 -1 (C=O). IR (KBr): νmax 3119, 1682, 1589, 1484, 1273, 822 cm . UV-vis (MeOH): -1 -1 max 215 nm ( 32,910 cm M ), 261 (15,817). HRMS (+ESI): C9H10BrNO3 [M+Na]+ requires 281.9736, found 281.9732.

152

Isopropyl 4,6-dimethoxy-2,3-diphenyl-1H-indole-7-carboxylate (224)

A mixture of 7-carboxylate 222 (0.91 g, 2.43 mmol), OMe Ph diphenylphosphoryl azide (1.05 mL, 4.87 mmol) and Ph triethylamine (0.67 mL) was heated under reflux in MeO N H isopropanol (25 mL) for 24 h. The resulting precipitate was O O filtered, dried and recrystallised from dichloromethane/n- hexane to give the title compound 224 (0.71 g, 70%) as a yellow solid. Mp 155-157 1 ºC. H NMR (300 MHz, CDCl3): 3.80 (s, 3H, OMe), 4.01(s, 3H, OMe), 5.34-5.43 (m, 1H, CH), 6.28 (s, 1H, H5), 7.24-7.44 (m, 10H, aryl H), 10.31 (bs, 1H, NH). 13C

NMR (75 MHz, CDCl3): 22.69 (Me), 55.68, 58.17 (OMe), 68.21 (CH), 90.26 (C5), 126.52, 127.50, 127.83, 128.14, 128.91, 131.84 (aryl CH), 96.59, 113.79, 114.87,

133.03, 136.16, 138.74, 159.34, 160.78 (aryl C), 166.90 (C=O). IR (KBr): max.3403, -1 1637, 1598, 1382, 1271, 1181, 1104, 991, 751, 697 cm . UV-vis (MeOH): max 204 -1 -1 nm ( 62,774 cm M ), 248 (39,275), 337 (25,491). HRMS (+ESI): C26H25NO4 [M+Na]+ requires 438.1676, found 438.1695.

N-acetyl-4,6-dimethoxybenzo[1,2,3]triazole (228) OMe Aminoacetamide 226 (4.2 g, 20 mmol) was dissolved in 5 M N hydrochloric acid (40 mL) with heating. The mixture was N MeO N allowed to cool until 0-5 ºC before dropwise addition of O previously cooled NaNO2 (1.82 g, 26.4 mmol) in water (15 mL). After stirring for 10 min at 0 ºC, water was added and the white product was filtered, washed with water and recrystallised from acetonitrile to afford the title compound 228 (3.18 g, 72%) as white crystals. Mp 195-196 ºC. (Found: C, 54.22; H, 1 5.07; N, 18.83; C10H11N3O3 requires C, 54.29; H, 5.01; N, 19.0%). H NMR (300

MHz, CDCl3): 2.88 (Me), 3.82 (s, 3H, OMe), 3.99 (s, 3H, OMe), 6.36 (d, J = 1.96 13 Hz, 1H, H5), 7.13 (d, J = 1.96 Hz, 1H, H7). C NMR (75 MHz, CDCl3): 23.79 (Me), 56.53, 56.82 (OMe), 88.21 (C5), 98.64 (C7), 133.86, 134.33, 152.15, 164.22

(aryl C), 170.46 (C=O). IR (KBr): νmax 1740, 1613, 1508, 1421, 1365, 1290, 1207, -1 -1 -1 1157, 1037, 944, 671 cm . UV-vis (MeOH): max 217 nm ( 35,613 cm M ), 272 + (8,923). HRMS (+ESI): C10H11N3O3 [M+H] requires 222.0879, found 222.0870.

153

4,6-Dimethoxy-benzo[1,2,3]triazole (229) OMe A solution of N-acetyl triazole 228 (1 g, 4.52 mmol) in methanol N (20 mL) was stirred with potassium hydroxide (0.5 g, 8.9 mmol) N MeO N at room temperature for 30 min. The mixture was then diluted H with ice water and pH was adjusted to pH-5 with 10% H3PO4. The resulting precipitate was filtered, washed with water and dried to yield the title compound 229 1 (0.697 g, 86%) as a white solid. Mp 209-211 ºC. H NMR (300 MHz, DMSO-d6): 3.84 (s, 3H, OMe), 3.98 (s, 3H, OMe), 6.36 (d, J = 1.63 Hz, 1H, H5), 6.73 (s, 1H, H7). 13C NMR (75 MHz, DMSO-d6): 56.05, 56.28 (OMe), 83.67 (C5), 96.67 (C7),

132.57, 135.72, 151.13, 160.65 (aryl C). IR (KBr): max 3319, 1627, 1524, 1469, -1 -1 -1 1432, 1154, 933, 828 cm . UV-vis (MeOH): max 217 nm ( 29,532 cm M ), 273 + (7,493). HRMS (+ESI): C8H9N3O2 [M+Na] requires 202.0587, found 202.0600

2-(4,6-Dimethoxy-1H-benzo[d][1,2,3]triazol-1-yl)-1-phenylethanone (238)

Benzotriazole 229 (0.8 g, 4.47 mmol) was introduced into a OMe N stirring mixture of DMF (5 mL) and K2CO3 (0.57 g, 4.12 N mmol). After stirring 10 min, the reaction mixture was cooled, MeO N followed by the addition of 4-bromoacetophenone (0.88 g, 4.47 O mmol). After stirring for 1 h at room temperature, the reaction mixture was quenched with water. The resulting precipitate was filtered, dried and purified by flash chromatography using dichloromethane as eluent to afford the title compound 238 (0.35 g, 26%) as a white solid. Mp 129-130 ºC. 1H

NMR (300 MHz, CDCl3): 3.85 (s, 3H, OMe), 3.97 (s, 3H, OMe), 6.08 (s, 2H,

CH2), 6.34 (d, J = 1.89 Hz, 1H, H5), 6.67 (d, J = 1.89 Hz, 1H, H7), 7.46-7.98 (m, 13 5H, aryl H). C NMR (75 MHz, CDCl3): 55.58, 55.81 (OMe), 61.42 (CH2), 87.24 (C5), 99.03 (C7), 128.03, 128.94, 134.13 (aryl CH), 134.21, 134.89, 146.74, 150. 59,

160.06 (aryl C), 190.35 (C=O). IR (KBr): νmax 2986, 2959, 1701, 1626, 1580, 1477, -1 -1 -1 1289, 1203, 1162, 882 cm . UV-vis (THF): max 224 nm ( 37,004 cm M ), 282 + (12,803). HRMS (+ESI): C16H15N3O3 [M+H] requires 298.1192, found 298.1187.

154

2,2,2-trifluoro-1-(6-hydroxy-4-methoxy-1-(2-oxo-2-phenylethyl)-1H- benzo[d][1,2,3]triazol-7-yl)ethanone (240)

Benzotriazole 238 (0.098 g, 0.33 mmol) was dissolved in OMe TFA (8 mL) and heated under reflux for 3 days. Water was N N added to the mixture and the resulting brown solid was N HO O filtered and purified by column chromatography using O CF3 dichloromethane/n-hexane (50:50) as eluent to afford the title compound 240 (0.018 g, 14%) as a white solid. Mp 1 177-179 ºC. H NMR (300 MHz, CDCl3): 4.11 (s, 3H, OMe), 6.12 (s, 2H, CH2), 6.42 (s, 1H, H5), 7.52-8.00 (m, 5H, aryl H), 13.72 (s, 1H, OH). 13C NMR (75 MHz,

CDCl3): 56.91 (OMe), 61.77 (CH2), 98.72 (C5), 114.89 (CF3), 128.06, 129.00, 134.36 (aryl CH), 97.08, 118.69, 133.94, 142.46, 159.82, 174.03, (aryl C), 180.07, -1 189.66 (C=O). IR (KBr): νmax 3400, 1697, 1619, 1579, 1469, 1440, 1205, 829 cm . -1 -1 UV-vis (THF): max 217 nm ( 25,956 cm M ), 242 (28,186), 346 (18,597). HRMS + (+ESI): C17H12F3N3O4 [M+H] requires 380.0858, found 380.0841.

2-(3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indol-7-yl)-2-(trimethylsilyloxy)- acetonitrile (251)

Indole-7-carbaldehyde 93 (1.7 g, 5.39 mmol) was heated Cl under reflux with TMSCN (3 mL, 22.5 mmol) in acetonitrile (40 mL) overnight. The solution was cooled and the solvent OMe was reduced under pressure. The residue was purified by flash MeO N chromatography using dichloromethane as eluent to afford the H title compound 251 (1.6 g, 71%) as a white solid. Mp 155-157 NC OSi(CH3)3 1 ºC. H NMR (300 MHz, CDCl3): 0.20 (s, 9H, Me), 3.83 (s, 3H, OMe), 3.93 (s, 3H, OMe), 6.19 (s, 1H, CH), 6.26 (s, 1H, H5), 7.08 (d, J = 2.40 Hz, 1H, H2), 7.33, 7.51 13 (2d, J = 8.57 Hz, 4H, aryl H), 8.93 (s, 1H, NH). C NMR (75 MHz, CDCl3): 0.58 (Me), 55.16, 56.70 (OMe), 56.90 (CH), 87.79 (C5), 119.21 (CN), 121.65 (C2), 127.60, 130.66 (aryl CH), 99.34, 111.18, 117.44, 131.55, 134.17, 136.39, 152.78,

155.70 (aryl C). IR (KBr): νmax 3428, 2962, 1594, 1518, 1462, 1343, 1255, 1212, -1 -1 -1 1052, cm . UV-vis (THF): max 234 nm ( 34,540 cm M ), 285 (17,485). HRMS + (+ESI): C21H24ClN2O3Si [M+H] requires 415.1245, found 415.1237.

155

2-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-(trimethylsilyloxy)-acetonitrile (252)

Indole-7-carbaldehyde 95 (1.7 g, 4.76 mmol) was heated OMe Ph under reflux with TMSCN (3 mL, 22.5 mmol) in acetonitrile Ph (30 mL) overnight. The solution was cooled and the solvent MeO N H reduced under pressure. The residue was purified by flash NC OSi(CH3)3 chromatography using dichloromethane as eluent to afford the title compound 252 1 (1.7 g, 78%) as a white solid. Mp 171-173 ºC. H NMR (300 MHz, CDCl3): 0.26 (s, 9H, Me), 3.73 (s, 3H, OMe), 3.95 (s, 3H, OMe), 6.22 (s, 1H, CH), 6.24 (s, 1H, 13 H5), 7.25-7.42 (m, 10H, aryl H), 8.97 (s, 1H, NH). C NMR (75 MHz, CDCl3): 0.51 (Me), 55.32, 56.66 (OMe), 57.22 (CH), 88.04 (C5), 119.29 (CN), 125.97, 127.09, 127.28, 127.78, 128.47, 131.37 (aryl CH), 98.89, 114.07, 114.47, 132.62,

132.86, 135.43, 135.63, 152.73, 156.06 (aryl C). IR (KBr): νmax 3474, 3054, 3003, -1 2957, 2842, 1599, 1518, 1448, 1354, 1254, 1076, cm . UV-vis (THF): max 245 nm -1 -1 + ( 37,864 cm M ), 324 (21,245). HRMS (+ESI): C27H28N2O3Si [M+H] requires 457.1947, found 457.1941.

2-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-((trimethylsilyl)oxy)-acetonitrile (253)

Indole-7-carbaldehyde 250 (3.69 g, 12.5 mmol) was heated under reflux with TMSCN (7 mL, 52.5 mmol) in acetonitrile OMe (60 mL) overnight. The solution was cooled and the solvent reduced under pressure. The residue was purified by flash MeO N chromatography using dichloromethane as eluent to afford the H NC OSi(CH ) title compound 253 (3.16 g, 64%) as a white solid. Mp 119- 3 3

121 ºC. (Found: C, 67.08; H, 6.92; N, 7.14; C22H26N2O3Si requires C, 66.97; H, 6.64; 1 N, 7.10%). H NMR (300 MHz, CDCl3): 0.01 (s, 9H, Me), 2.19 (s, 3H, Me), 3.62 (s, 3H, OMe), 3.72 (s, 3H, OMe), 6.0 (s, 1H, CH), 6.05 (s, 1H, H5), 6.87 (d, J = 2.36 Hz, 1H, H2), 7.0, 7.29 (2d, J = 8.28 Hz, 4H, aryl H), 8.68 (s, 1H, NH). 13C NMR (75

MHz, CDCl3): 0.47 (Me), 21.2 (Me), 55.31, 56.84 (OMe), 57.04 (CH), 87.86 (C5), 119.39 (CN), 121.52 (C2), 128.39, 129.45 (aryl CH), 99.39, 111.62, 118.62, 132.84,

135.35, 136.49, 152.77, 156.0 (aryl C). IR (KBr): νmax 3348, 1620, 1589, 1466, 1343,

156

-1 -1 -1 1254, 1215, 1072, 849 cm . UV-vis (MeOH): max 295 nm ( 13,545 cm M ). + HRMS (+ESI): C22H26N2O3Si [M+H] requires 395.1791, found 395.1785.

3-(4-Chlorophenyl)-4,6-dimethoxy-1H-indole-7-carbonyl cyanide (254)

A solution of DDQ (1.64 g, 7.22 mmol) in dioxane (35 mL) Cl was added dropwise to the indole 251 (1.5 g, 3.62 mmol) dissolved in dioxane (30 mL) at room temperature. The OMe mixture was stirred for 3 h and the solid formed was thereafter MeO N filtered off. The filtrate was evaporated, the resulting residue H was quenched with water, the solid obtained was filtered and NC O washed with water until a colourless solution was observed. The red solid was passed through a plug of silica to yield the title compound 254 (1.05 g, 85%) as an orange 1 solid. Mp 230-232 ºC. H NMR (300 MHz, DMSO-d6): 3.96 (s, 3H, OMe), 4.04 (s, 3H, OMe), 6.46 (s, 1H, H5), 7.18 (d, J = 2.38 Hz, 1H, H2), 7.36, 7.48 (2d, J = 8.79 13 Hz, 4H, aryl H), 11.63 (d, J = 1.44 Hz, 1H, NH). C NMR (75 MHz, DMSO-d6): 56.69, 57.37 (OMe), 88.94 (C5), 124.34 (C2), 117.60 (CN), 127.98, 131.05 (aryl CH), 103.33, 110.18, 116.13, 131.13, 134.03, 136.82, 160.32, 163.52 (aryl C), -1 164.06 (C=O). IR (KBr): νmax 3411, 1590, 1471, 1352, 1248, 1219, 1094, 796 cm . -1 -1 UV-vis (THF): max 218 nm ( 27,704 cm M ), 266 (21,855), 364 (12,106). HRMS + (+ESI): C18H13ClN2O3 [M+Na] requires 363.0512, found 363.0502.

4,6-Dimethoxy-2,3-diphenyl-1H-indole-7-carbonyl cyanide (255)

A solution of DDQ (0.76 g, 3.35 mmol) in dioxane (15 mL) OMe Ph was added dropwise to the indole 252 (1.02 g, 2.23 mmol) Ph dissolved in dioxane (30 mL) at room temperature. The MeO N H mixture was stirred for 3 h and the solid formed was NC O thereafter filtered off. The filtrate was evaporated, the resulting residue was quenched with water, the solid obtained was filtered and washed with water until a colourless solution was observed. The red solid was passed through a plug of silica to yield the title compound 255 (0.77 g, 90%) as an orange solid. Mp 208-210 ºC.

(Found: C, 75.32; H, 4.81; N, 7.34; C24H18N2O3 requires C, 75.38; H, 4.74; N,

157

1 7.33%). H NMR (300 MHz, CDCl3): 3.86 (s, 3H, OMe), 4.09 (s, 3H, OMe), 6.13 (s, 1H, H5), 7.24-7.34 (m, 10H, aryl H), 10.53 (s, 1H, NH), 11.21 (bs, 1H, NH). 13C

NMR (75 MHz, CDCl3): 55.75, 56.43 (OMe), 87.26 (C5), 115.53 (CN). 126.56, 127.55, 127.63, 127.76, 128.53, 131.07 (aryl CH), 103.32, 131.39, 133.57, 134.51,

137.16, 161.25, 163.22 (aryl C), 164.17 (C=O). IR (KBr): νmax 3403, 1675, 1574, -1 -1 -1 1501, 1467, 1352, 987 cm . UV-vis (THF): max 231 nm ( 33,266 cm M ), 293 + (23,893), 363 (16,251). HRMS (+ESI): C24H18N2O3 [M] requires 382.1317, found 382.1306.

4,6-Dimethoxy-3-(p-tolyl)-1H-indole-7-carbonyl cyanide (256)

A solution of DDQ (2.4 g, 10.6 mmol) in dioxane (50 mL) was added dropwise to the indole 253 (2.61 g, 6.62 mmol) OMe dissolved in dioxane (30 mL) at room temperature. The mixture was stirred for 3 h and the solid formed was thereafter filtered MeO N off. The filtrate was evaporated, the resulting residue was H NC O quenched with water, the solid obtained was filtered and washed with water until a colourless solution was observed. The red solid was passed through a plug of silica to yield the title compound 256 (1.69 g, 80%) as an orange solid. Mp 220-222 ºC. (Found: C, 71.18; H, 4.99; N, 8.75; C19H16N2O3 requires C, 1 71.24; H, 5.03; N, 8.74%). H NMR (300 MHz, DMSO-d6): 2.32 (s, 3H, Me), 3.96 (s, 3H, OMe), 4.06 (s, 3H, OMe), 6.47 (s, 1H, H5), 7.12 (d, J = 2.4 Hz, 1H, H2), 7.15, 7.37 (2d, J = 8.05 Hz, 4H, aryl H), 11.57 (bs, 1H, NH). 13C NMR (75 MHz,

DMSO-d6): 21.18 (Me), 56.70, 57.43 (OMe), 88.87 (C5), 123.77 (C2), 119.04 (CN), 128.76, 129.46 (aryl CH), 103.44, 110.51, 116.29, 132.30, 135.48, 136.87,

160.33, 163.56 (aryl C), 164.37 (C=O). IR (KBr): νmax 3381, 1583, 1502, 1466, -1 1350, 1313, 1284, 1213, 1091, 976 cm . UV-vis (MeOH): max 305 nm ( 14,273 -1 -1 + cm M ), 364 (10,469). HRMS (+ESI): C19H16N2O3 [M+H] requires 321.1239, found 321.1239.

158

2-Amino-1-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-ethanone (258)

A mixture of 7-carbonyl cyanide 255 (1.08 g, 2.82 mmol) and OMe Ph 10% Pd/C (0.4 g) in a mixture of ethyl acetate/acetic acid Ph MeO N solution (20:40) was stirred under a balloon of hydrogen gas. H After 20 h, the reaction mixture was filtered over Celite and O the filtrate was concentrated under reduced pressure. The NH2 resulting residue was dissolved in ethanol containing concentrated hydrochloric acid (5% by volume). Concentration under vacuo yielded the title compound 258 (1.09 g, 1 91%) as a yellow solid. Mp 262 ºC (dec.). H NMR (300 MHz, DMSO-d6): 3.80 (s,

3H, OMe), 4.06 (s, 3H, OMe), 4.30 (d, J = 4.01 Hz, 2H, CH2), 6.48 (s, 1H, H5), 13 7.23-7.32 (m, 8H, aryl H), 8.45 (bs, 3H, NH2+HCl), 11.08 (bs, 1H, NH). C NMR

(75 MHz, DMSO-d6): 48.60 (CH2), 56.34, 57.40 (OMe), 89.03 (C5), 126.92, 127.87, 127.99, 128.06, 129.05 (aryl CH), 101.72, 112.77, 114.75, 132.13, 132.86,

135.52, 137.36, 161.30, 162.21 (aryl C), 190.77 (C=O). IR (KBr): νmax 3423, 2848, 2578, 1624, 1590, 1544, 1462, 1393, 1360, 1252, 1168, 1146, 989 cm-1. UV-vis -1 -1 + (MeOH): max 328 nm ( 22,139 cm M ). HRMS (+ESI): C24H22N2O3 [M+H] requires 387.1709, found 387.1702.

2-Amino-1-(4,6-dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-ethanone (259)

A mixture of 7-carbonyl cyanide 256 (1 g, 3.12 mmol) and 10% Pd/C (0.4 g) in a mixture of ethyl acetate/acetic acid OMe solution (30:60) was stirred under a balloon of hydrogen. After 20 h, the reaction mixture was filtered over Celite and the MeO N filtrate concentrated under reduced pressure to yield the title H O compound 259 (0.886 g, 77%) as a white solid. M.p. 181-183 NH2 1 ºC. H NMR (300 MHz, DMSO-d6): 1.84 (s, 3H, Me), 2.32

(s, 3H, Me), 3.90 (s, 3H, OMe), 4.02 (s, 3H, OMe), 4.93 (d, J = 4.01 Hz, 2H, CH2),

6.48 (s, 1H, H5), 7.23-7.32 (m, 8H, aryl H), 8.45 (bs, 3H, NH2+HCl), 11.08 (bs, 1H, 13 NH). C NMR (75 MHz, DMSO-d6): 21.17, 22.53 (Me), 52.16 (CH2), 55.96, 57.08 (OMe), 88.46 (C5), 123.27 (C2), 128.67, 129.43 (aryl CH), 102.92, 110.47, 117.53, 133.13, 134.94, 137.89, 159.85, 161.23 (aryl C), 173.11, 197.21 (C=O). IR -1 (KBr): νmax 3289, 2941, 1563, 1465, 1397, 1344, 1248, 1217, 1184, 1104, 791 cm .

159

-1 -1 UV-vis (MeOH): max 330 nm ( 28, 038 cm M ). HRMS (+ESI): C21H23N2O4 [M+H]+ requires 325.1552, found 325.1546.

N-(2-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-oxoethyl)-acetamide (263)

7-Oxotryptamine 258 (0.34 g, 0.8 mmol) was dissolved in OMe Ph acetic anhydride (15 mL) and the mixture was stirred for 4 h Ph in an ice-water bath. Ice-water was added and the resulting MeO N H solid was filtered, washed with water and dried. The crude O product was recrystallised from dichloromethane/n-hexane to NHCOCH3 give the title compound 263 (0.25 g, 72%) as a yellow solid. M.p. 220-222 ºC.

(Found: C, 72.76; H, 5.60; N, 6.56; C26H24N2O4 requires C, 72.88; H, 5.65; N, 1 6.54%). H NMR (300 MHz, CDCl3): 2.13 (s, 3H, Me), 3.80 (s, 3H, OMe), 4.04 (s,

3H, OMe), 4.74 (d, J = 4.21 Hz, 2H, CH2), 6.16 (s, 1H, H5), 6.89 (bs, 1H, NH), 7.23- 13 7.40 (m, 10H, aryl H), 11.06 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 23.33

(Me), 50.85 (CH2), 55.36, 56.22 (OMe), 86.99 (C5), 126.27, 127.33, 127.50, 127.78, 128.50, 131.36 (aryl CH), 102.17, 113.07, 114.51, 132.34, 132.89, 135.52, 138.10,

160.77, 161.58 (aryl C), 170.12, 193.50 (C=O). IR (KBr): νmax 3405, 1614, 1587, -1 -1 -1 1390, 1223, 1165, 990 cm . UV-vis (THF): max 324 nm ( 33,740 cm M ). HRMS + (+ESI): C26H24N2O4 [M+Na] requires 451.1634, found 451.1623.

N-(2-(4,6-dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-oxoethyl)-acetamide (264)

7-Oxotryptamine 259 (0.325 g, 0.88 mmol) was dissolved in acetic anhydride (15 mL) and the mixture was stirred for 4 h in OMe an ice-water bath. Ice-water was added and the resulting solid was filtered, washed with water and dried. The crude product MeO N was recrystallised from dichloromethane/n-hexane to give the H title compound 264 (0.23 g, 71%) as a yellow solid. M.p. 208- O NHCOCH3 210 ºC. (Found: C, 68.78; H, 6.27; N, 7.53; C21H22N2O4 1 requires C, 68.84; H, 6.05; N, 7.65%). H NMR (300 MHz, CDCl3): 2.13 (s, 3H, Me), 2.41 (s, 3H, Me), 3.93 (s, 3H, OMe), 4.06 (s, 3H, OMe), 4.72 (d, J = 3.69 Hz,

2H, CH2), 6.22 (s, 1H, H5), 6.88 (bs, 1H, NH), 7.10 (d, J = 2.37 Hz, 1H, H2), 7.21,

160

13 7.48 (2d, J = 8.14, 4H, aryl H), 10.93 (bs, 1H, NH). C NMR (75 MHz, CDCl3):

21.17, 23.34 (Me), 50.88 (CH2), 55.35, 56.23 (OMe), 86.79 (C5), 121.42 (C2), 128.45, 129.38 (aryl CH), 102.38, 110.53, 118.73, 132.50, 135.60, 138.97, 160.66,

161.67 (aryl C), 170.09, 193.44 (C=O). IR (KBr): νmax 3408, 1615, 1583, 1345, -1 -1 -1 1222, 1085 cm . UV-vis (THF): max 328 nm ( 13,291 cm M ). HRMS (+ESI): + C21H22N2O4 [M+H] requires 367.1658, found 367.1653.

5-(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-methyloxazole (265)

To a solution of the indole 263 (0.121 g, 0.28 mmol) in ethyl OMe Ph acetate (20 mL), POCl (5 mL) was added and the solution 3 Ph was heated under reflux for 2 h. The solvent was evaporated MeO N H under reduced pressure and the residue was quenched with O water (20 mL) and made strongly alkaline by the addition of N 5N NaOH (20 mL). The resulting precipitate was collected by filtration, washed with water, dried and purified by flash chromatography using dichloromethane as eluent to afford the title compound 265 (0.092 g, 79%) as a brown solid. Mp 229-231 ºC.

(Found: C, 74.75; H, 5.31; N, 6.61; C26H22N2O3 0.1 CH2Cl2 requires C, 74.82; H, 1 5.34; N, 6.69%). H NMR (300 MHz, CDCl3): 2.64 (s, 3H, Me), 3.77 (s, 3H, OMe), 4.03 (s, 3H, OMe), 6.37 (s, 1H, H5), 7.28-7.45 (m, 11H, CH, aryl H), 9.33 13 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 14.27 (Me), 55.42, 56.49 (OMe), 88.92 (C5), 124.03 (CH), 126.08, 127.19, 127.36, 127.92, 128.64, 131.49 (aryl CH), 94.32, 113.70, 114.73, 132.62, 132.94, 133.61, 135.73, 148.01, 153.66, 155.03, 158.03 (aryl

C). IR (KBr): νmax 3364, 2931, 2838, 1603, 1451, 1433, 1347, 1298, 1266, 1209, -1 -1 -1 1071, 990, 699 cm . UV-vis (THF): max 334 nm ( 32,051 cm M ). HRMS (+ESI): + C26H22N2O3 [M+H] requires 411.1709, found 411.1706.

161

5-(4,6-Dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-methyloxazole (266)

To a solution of the indole 264 (0.105 g, 0.28 mmol) in ethyl acetate (30 mL), POCl3 (5 mL) was added and the solution was OMe heated under reflux for 2 h. The solvent was evaporated under reduced pressure and the residue was quenched with water (20 MeO N mL) and made strongly alkaline by the addition of 5N NaOH H (20mL). The resulting precipitate was collected by filtration, O N washed with water, dried and purified by flash chromatography using dichloromethane as eluent to afford the title compound 266 (0.051 g, 51%) as a 1 white solid. Mp 202-204 ºC. H NMR (300 MHz, CDCl3): 2.31 (s, 3H, Me), 2.51 (s, 3H, Me), 3.76 (s, 3H, OMe), 3.91 (s, 3H, OMe), 6.28 (s, 1H, H5), 7.01 (d, J = 2.43 Hz, 1H, H2), 7.10-7.42 (2d, J = 8.07 Hz, 4H, aryl H), 7.33 (s, 1H, CH), 9.23 13 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 14.24, 21.19 (Me), 55.29, 56.47 (OMe), 88.55 (C5), 121.13 (CH), 123.95 (C2), 128.38, 129.48 (aryl CH), 94.56, 111.15,

118.64, 132.91, 134.45, 135.38, 153.57, 154.80 (aryl C). IR (KBr): νmax 3253, 2956, 2923, 1596, 1541, 1459, 1339, 1299, 1208, 1121, 1098, 814 cm-1. UV-vis (THF): -1 -1 + max 322 nm ( 23,999 cm M ). HRMS (+ESI): C21H20N2O3 [M] requires 348.1474, found 348.1472.

N-(2-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-2-oxoethyl)-4,6-dimethoxy-2,3- diphenyl-1H-indole-7-carboxamide (268)

To a suspension of 7-trichloroacetylindole 83 (0.241 g, 0.51 OMe Ph mmol) and 7-oxotryptamine 258 (0.215 g, 0.51 mmol) in Ph acetonitrile (40 mL), triethylamine (10 drops) was added and MeO N H the mixture was heated under reflux overnight. The solvent O was removed under pressure and the resulting solid was HN O H quenched with water, filtered, dried and washed with MeO N Ph methanol to give the title compound 268 (0.23 g, 61%) as a 1 OMe Ph white solid. Mp 291-293 ºC. H NMR (300 MHz, CDCl3): 3.67 (s, 3H, OMe), 3.71 (s, 3H, OMe), 3.98 (s, 3H, OMe), 4.09 (s, 3H, OMe), 4.93

(d, J = 4.35 Hz, 2H, CH2), 6.09 (s, 1H, H5), 6.16 (s, 1H, H5), 7.09-7.35 (m, 20H, aryl H), 9.33 (t, J = 8.52 Hz, 1H, NH), 11.10 (bs, 1H, NH), 11.29 (bs, 1H, NH). 13C

162

NMR (75 MHz, CDCl3): 51.44 (CH2), 55.27, 55.33, 56.27, 57.21 (OMe), 87.03 (C5), 87.83 (C5), 125.93, 126.18, 126.93, 127.17, 127.36, 127.45, 128.02, 128.05, 128.28, 128.47, 131.42, 131.56 (aryl CH), 97.66, 102.49, 113.02, 113.67, 113.69, 114.44, 132.57, 132.74, 132.97, 133.12, 135.63, 136.11, 138.24, 138.69, 157.13,

157.52, 160.45, 161.42 (aryl C), 167.49, 194.05 (C=O). IR (KBr): νmax 1615, 1588, -1 1493, 1461, 1388, 1340, 1221, 1165, 994, 697 cm . UV-vis (THF): max 325 nm ( -1 -1 + 52,779 cm M ). HRMS (+ESI): C47H39N3O6 [M+H] requires 742.2917, found 742.2916.

N-(2-(4,6-dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-2-oxoethyl)-4,6-dimethoxy-3-(p- tolyl)-1H-indole-7-carboxamide (269)

To a suspension of 7-oxotryptamine 259 (0.241 g, 0.65 mmol) and 7-trichloroacetylindole 267 (0.27 g, 0.65 mmol) in OMe acetonitrile (40 mL), triethylamine (10 drops) was added and the mixture was heated under reflux overnight. The solvent was MeO N removed under pressure and the resulting solid was quenched H with water, filtered, dried and washed with methanol to give O HN O the title compound 269 (0.22 g, 55%) as a brown solid. Mp H MeO 1 N 284-286 ºC. H NMR (300 MHz, CDCl3): 2.32 (s, 3H, Me), 2.33 (s, 3H, Me), 3.84 (s, 3H, OMe), 3.87 (s, 3H, OMe), 4.05 OMe (s, 3H, OMe), 4.13 (s, 3H, OMe), 4.92 (d, J = 4.25 Hz, 2H,

CH2), 6.19 (s, 1H, H5), 6.26 (s, 1H, H5), 7.04 (t, J = 4.86 Hz, 2H, H2, H2), 7.10, 7.13 (2d, J = 3.52 Hz, 4H, aryl H), 7.41, 7.43 (2d, J = 5.71 Hz, 4H, aryl H), 9.37 (t, J = 8.26 Hz, 1H, NH), 11.0 (bs, 1H, NH), 11.12 (bs, 1H, NH). -1 IR (KBr): νmax 1618, 1585, 1492, 1462, 1332, 1212, 1150, 1105, 794 cm . UV-vis -1 -1 + (THF): max 323 nm ( 45,951 cm M ). HRMS (+ESI): C37H35N3O6 [M+Na] requires 640.2424, found 640.2414. The sample was not soluble enough for 13C NMR measurement.

163

2,5-Bis-(4,6-dimethoxy-2,3-diphenyl-1H-indol-7-yl)-oxazole (270)

To a solution of the bis-indole 268 (0.131 g, 0.17 mmol) in OMe Ph ethyl acetate (30 mL), POCl (10 mL) was added and the 3 Ph MeO N solution was heated under reflux for 2 h. The solvent was H evaporated under reduced pressure and the residue was O N quenched with water (30 mL) and made strongly alkaline by H MeO N the addition of 5N NaOH (30 mL). The resulting precipitate Ph was collected by filtration, washed with water, dried and OMe Ph recrystallised from methanol to afford the title compound 270 1 (0.081 g, 63%) as a yellow solid. Mp 278-280 ºC. H NMR (300 MHz, CDCl3): 3.44 (s, 3H, OMe), 3.77 (s, 3H, OMe), 3.78 (s, 3H, OMe), 4.08 (s, 3H, OMe), 6.28 (s, 1H, H5), 6.41 (s, 1H, H5), 7.27-7.45 (m, 20H, aryl H), 7.74 (s, 1H, CH), 10.35 13 (bs, 1H, NH), 11.32 (bs, 1H, NH). C NMR (75 MHz, CDCl3): 55.39, 55.49, 56.56, 57.83 (OMe), 88.93 (C5), 89.30 (C5), 123.46 (CH), 125.83, 126.04, 127.05, 127.24, 127.28, 127.42, 128.06, 128.43, 128.46, 129.01, 131.52, 131.56 (aryl CH), 93.31, 113.37, 113.66, 114.57, 132.91, 133.22, 133.84, 135.55, 135.84, 135.95,

145.98, 153.54, 155.02, 155.78, 156.65 (aryl C). IR (KBr): νmax 3384, 1599, 1449, -1 - 1427, 1299, 1165, 1143, 991, 697 cm . UV-vis (THF): max 326 nm ( 39,279 cm 1 -1 M ), 358 (38,612), 377 (48,459), 398 (38,667). HRMS (+ESI): C47H37N3O5 [M+H]+ requires 724.2804, found 724.2811. The sample was not soluble enough for 13C NMR measurement.

164

2,5-Bis-(4,6-dimethoxy-3-(p-tolyl)-1H-indol-7-yl)-oxazole (271)

To a solution of the bis-indole 269 (0.112 g, 0.18 mmol) in ethyl acetate (25 mL), POCl3 (10 mL) was added and the OMe solution was heated under reflux for 2 h. The solvent was evaporated under reduced pressure and the residue was MeO N quenched with water (30 mL) and made strongly alkaline by H O the addition of 5N NaOH (30 mL). The resulting precipitate N H was collected by filtration, washed with water, dried and MeO N recrystallised from methanol to afford the title compound 271 1 (0.067 g, 61%) as a white solid. Mp 294 ºC (dec.). H NMR OMe

(600 MHz, DMSO-d6): 2.35 (s, 3H, Me), 2.36 ( s, 3H, Me), 3.89 (s, 3H, OMe), 3.94 (s, 3H, OMe), 4.09 (s, 3H, OMe), 4.25 (s, 3H, OMe), 6.63 (s, 1H, H5), 6.69 (s, 1H, H5), 7.19 (t, J = 13.9 Hz, 4H, aryl H), 7.31 (d, J = 2.12 Hz, 1H, H2), 7.46, 7.50 (2d, J = 7.77 Hz, 4H, aryl H), 7.57 (d, J = 2.17 Hz, 1H, H2), 7.64 (s, 1H, CH), 10.56 (bs, 1H, NH), 11.31 (bs, 1H, NH). IR -1 (KBr): νmax 3406, 3377, 2934, 2838, 1596, 1463, 1340, 1305, 1208, 1153, 791 cm . -1 -1 UV-vis (THF): max 375 nm ( 49,046 cm M ), 396 (39,919). HRMS (+ESI): + C37H33N3O5 [M+H] requires 600.2498, found 600.2490. The sample was not soluble enough for 13C NMR measurement.

Di-(4,6-trimethoxy-2,3-diphenylindol-7-yl)-methane (234) and (4,6-dimethoxy- 2,3-diphenyl-1H-indol-7-yl)-methanol (280)

A suspension of lithium aluminium hydride (0.68 g, 18 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled in an ice bath and stirred under nitrogen while indole 255 (0.703 g, 1.84 mmol) in tetrahydrofuran (40 mL) was added via a dropping funnel over 30 min. Stirring was continued for 30 min with cooling, followed by stirring at room temperature for 2 h. The mixture was then recooled in ice and cautiously treated sequentially with water (5 mL), 5M NaOH (10 mL) and water (10 mL). The resulting granular solid was filtered and washed with ethyl acetate. The combined organic filtrate was washed with brine, dried over anhydrous sodium sulfate and the solvent evaporated in vacuo. The solid was dried and purified

165 by flash chromatography using dichloromethane as eluent to give di-indolylmethane 234 (0.105 g, 17%) and 7-alcohol 280 (0.065 g, 10%) as white powders.

Di-(4,6-trimethoxy-2,3-diphenylindol-7-yl)methane (234)

5 1 Mp 290-292 ºC, (lit. Mp 293-295). H NMR (300 MHz, OMe Ph CDCl ): 3.66 (s, 6H, OMe), 4.13 (s, 6H, OMe), 4.41 (s, 2H, 3 Ph CH ), 6.33 (s, 1H, H5), 7.22-7.38 (m, 20H, aryl H), 10.16 (bs, MeO N 2 H 2H, NH). H MeO N Ph

Ph OMe

(4,6-Dimethoxy-2,3-diphenyl-1H-indol-7-yl)methanol (280)

1 Mp 281-283ºC. H NMR (300 MHz, CDCl3): 3.70 (s, 3H, OMe Ph OMe), 3.89 (s, 3H, OMe), 5.07 (s, 2H, CH ), 6.27 (s, 1H, 2 Ph 13 MeO N H5), 7.20-7.41 (m, 10H, aryl H), 8.92 (bs, 1H, NH). C H

NMR (75 MHz, CDCl3): 55.42, 57.03 (OMe), 57.38 (CH2), OH 89.17 (C5), 125.81, 126.92, 127.23, 127.94, 128.32, 131.36 (aryl CH), 103.53, 113.56, 114.52, 132.81, 132.86, 135.87, 136.90, 153.38, 154.61 (aryl C). IR (KBr): -1 νmax 3320, 2933, 2835, 1598, 1451, 1432, 1350, 1161, 1117, 997, 696 cm . UV-vis -1 -1 (THF): max 221 nm ( 45,968 cm M ), 263 (42,766), 322 (24,699). HRMS (+ESI): + C23H21NO3 [M] requires 359.1521, found 359.1514.

166

CHAPTER IX

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171

APPENDIX

X-ray crystallography data

A1. Introduction

Don Craig and Mohan Bhadbhade at the University of New South Wales, Sydney, obtained the X-ray crystallography data shown in the appendix.

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 2 were refined using full matrix least squares. Reflection weights used were 1/σ (Fo), 2 2 1/2 with σ(Fo) being derived from σ (Io) = [σ (Io) + (0.04Io) ] . The weighted residual 2 2 1/2 is defined as Rw = (Σw∆ /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). International tables for X-ray Crystallography Vol. 4, Kynoch Press, Birmingham, 1974. 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.

172

A2. N-acetyl-4,6-dimethoxy-benzo[1,2,3]triazole (228)

EXPERIMENTAL DETAILS Crystal data

Chemical formula C10H11N3O3

Mr 221.22

Crystal system, Orthorhombic, Pnma space group

Temperature (K) 293 a, b, c (Å) 9.9817 (12), 6.6498 (8), 15.4052 (18)

V (Å3) 1022.5 (2)

Z 4

Radiation type Mo K

 (mm-1) 0.11

Crystal size (mm) 0.31 × 0.13 × 0.08

Data collection

Diffractometer Bruker kappa APEXII CCD Diffractometer

Absorption Multi-scan correction SADABS (Bruker, 2001)

Tmin, Tmax 0.967, 0.992

No. of measured, 2940, 964, 843 independent and observed [I > 2(I)] reflections

Rint 0.045

Refinement

R[F2 > 2(F2)], 0.039, 0.110, 1.11 wR(F2), S

173

No. of reflections 964

No. of parameters 118

No. of restraints 0

H-atom treatment H atoms treated by a mixture of independent and constrained refinement

max, min (e 0.20, -0.28 Å-3)

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS

O1 O 0.55200(15) 0.2500 0.69755(10) 0.0395(4)

O2 O 0.54828(15) 0.2500 0.27663(9) 0.0369(4)

O3 O 0.17294(14) 0.2500 0.46493(10) 0.0370(4)

N1 N 0.64124(16) 0.2500 0.56310(11) 0.0264(4)

N2 N 0.75456(16) 0.2500 0.51128(12) 0.0327(5)

N3 N 0.71686(17) 0.2500 0.43122(11) 0.0310(5)

C1 C 0.3919(2) 0.2500 0.53174(13) 0.0254(5)

H1 H 0.3599 0.2500 0.5884 0.030

C2 C 0.3086(2) 0.2500 0.46012(13) 0.0275(5)

C3 C 0.3568(2) 0.2500 0.37389(14) 0.0295(5)

H3 H 0.2960 0.2500 0.3281 0.035

C4 C 0.4920(2) 0.2500 0.35635(13) 0.0278(5)

C5 C 0.5789(2) 0.2500 0.42822(13) 0.0259(5)

C6 C 0.52811(19) 0.2500 0.51184(13) 0.0238(5)

C7 C 0.6523(2) 0.2500 0.65447(14) 0.0321(5)

C8 C 0.7903(3) 0.2500 0.6902(2) 0.0510(7)

C9 C 0.4571(3) 0.2500 0.20486(15) 0.0434(6)

174

C10 C 0.1129(2) 0.2500 0.54925(16) 0.0420(6)

H101 H 0.017(3) 0.2500 0.5372(16) 0.045(7)

H102 H 0.1416(17) 0.128(2) 0.5800(12) 0.051(5)

H91 H 0.513(3) 0.2500 0.154(2) 0.064(8)

H92 H 0.4023(19) 0.126(3) 0.2047(12) 0.056(5)

H81 H 0.789(5) 0.2500 0.746(4) 0.134(18)

H82 H 0.839(3) 0.142(3) 0.6696(16) 0.079(7)

O1 0.0321(9) 0.0560(9) 0.0302(8) 0.000 0.0043(7) 0.000

O2 0.0343(9) 0.0525(8) 0.0239(8) 0.000 0.0032(7) 0.000

O3 0.0196(8) 0.0584(9) 0.0330(9) 0.000 0.0012(7) 0.000

N1 0.0196(9) 0.0325(8) 0.0272(9) 0.000 0.0012(7) 0.000

N2 0.0232(9) 0.0421(9) 0.0327(10) 0.000 0.0063(8) 0.000

N3 0.0242(9) 0.0371(8) 0.0316(10) 0.000 0.0056(7) 0.000

C1 0.0231(10) 0.0270(9) 0.0261(10) 0.000 0.0028(8) 0.000

C2 0.0224(11) 0.0293(9) 0.0307(11) 0.000 0.0012(9) 0.000

C3 0.0282(12) 0.0342(9) 0.0261(10) 0.000 -0.0030(8) 0.000

C4 0.0307(11) 0.0294(8) 0.0233(10) 0.000 0.0022(9) 0.000

C5 0.0242(10) 0.0251(8) 0.0283(10) 0.000 0.0043(8) 0.000

C6 0.0227(10) 0.0220(9) 0.0266(10) 0.000 -0.0006(8) 0.000

C7 0.0314(12) 0.0371(10) 0.0277(11) 0.000 -0.0006(9) 0.000

C8 0.0318(14) 0.084(2) 0.0368(15) 0.000 -0.0067(12) 0.000

C9 0.0440(15) 0.0633(15) 0.0228(11) 0.000 0.0002(10) 0.000

C10 0.0233(12) 0.0656(15) 0.0371(13) 0.000 0.0062(11) 0.000

175

SELECTED GEOMETRIC PARAMETERS BOND LENGTHS

O1—C7 1.202 (2) C2—C3 1.413 (3)

O2—C4 1.351 (2) C3—C4 1.376 (3)

O2—C9 1.432 (3) C3—H3 0.9300

O3—C2 1.356 (2) C4—C5 1.407 (3)

O3—C10 1.431 (3) C5—C6 1.384 (3)

N1—C6 1.378 (2) C7—C8 1.483 (3)

N1—N2 1.385 (2) C8—H81 0.86 (6)

N1—C7 1.412 (3) C8—H82 0.92 (2)

N2—N3 1.289 (3) C9—H91 0.96 (3)

N3—C5 1.378 (3) C9—H92 0.987 (18)

C1—C2 1.382 (3) C10—H101 0.97 (3)

C1—C6 1.393 (3) C10—H102 0.983 (18)

C1—H1 0.9300

BOND ANGLES C4—O2—C9 115.96 (17) N3—C5—C6 109.57 (17)

C2—O3—C10 117.91 (18) N3—C5—C4 130.02 (18)

C6—N1—N2 109.82 (16) C6—C5—C4 120.42 (19)

C6—N1—C7 129.47 (17) N1—C6—C5 103.48 (17)

N2—N1—C7 120.71 (17) N1—C6—C1 132.33 (18)

N3—N2—N1 108.25 (16) C5—C6—C1 124.19 (18)

N2—N3—C5 108.89 (16) O1—C7—N1 119.03 (19)

C2—C1—C6 114.31 (18) O1—C7—C8 124.7 (2)

C2—C1—H1 122.8 N1—C7—C8 116.3 (2)

176

C6—C1—H1 122.8 C7—C8—H81 111 (4)

O3—C2—C1 123.88 (19) C7—C8—H82 111.1 (15)

O3—C2—C3 113.03 (18) H81—C8—H82 110 (2)

C1—C2—C3 123.08 (19) O2—C9—H91 104.6 (19)

C4—C3—C2 121.2 (2) O2—C9—H92 110.8 (11)

C4—C3—H3 119.4 H91—C9—H92 108.8 (14)

C2—C3—H3 119.4 O3—C10—H101 103.7 (15)

O2—C4—C3 125.91 (19) O3—C10—H102 108.4 (10)

O2—C4—C5 117.32 (19) H101—C10— 112.2 (12) H102

C3—C4—C5 116.77 (19)

A3. Isopropyl 4,6-dimethoxy-2,3-diphenyl-1H-indole-7-carboxylate (224)

EXPERIMENTAL DETAILS

Crystal data

Chemical formula C26H25NO4

Mr 415.47

Crystal system, Monoclinic, P21/n space group

Temperature (K) 150 a, b, c (Å) 17.2745 (6), 7.3695 (4), 17.8125 (7) b (°) 110.301 (2)

V (Å3) 2126.75 (16)

Z 4

Radiation type Mo Ka

177 m (mm-1) 0.09

Crystal size (mm) 0.39 × 0.14 × 0.09

Data collection

Diffractometer Bruker kappa APEXII CCD Diffractometer

Absorption Multi-scan correction SADABS (Bruker, 2001)

Tmin, Tmax 0.967, 0.992

No. of measured, 13292, 3732, 2778 independent and observed [I > 2s(I)] reflections

Rint 0.032

Refinement

R[F2 > 2s(F2)], 0.036, 0.130, 0.82 wR(F2), S

No. of reflections 3732

No. of parameters 284

No. of restraints 0

H-atom treatment H-atom parameters constrained

- Dmax, Dmin (e Å 0.22, -0.23 3)

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS

C1 C -0.02137(10) 0.8029(2) 0.90851(10) 0.0206(4)

C2 C -0.06860(10) 0.7742(2) 0.95644(10) 0.0216(4)

H2 H -0.1269 0.7866 0.9339 0.026 Uiso 1 1 calc R . .

C3 C -0.03239(10) 0.7273(2) 1.03729(10) 0.0205(4)

178

C4 C 0.05342(10) 0.7078(2) 1.07383(10) 0.0201(4)

C5 C 0.09894(10) 0.7390(2) 1.02263(10) 0.0192(4)

C6 C 0.20324(10) 0.7677(2) 0.97507(10) 0.0204(4)

C7 C 0.13244(10) 0.8027(2) 0.91143(10) 0.0201(4)

C8 C 0.06493(10) 0.7866(2) 0.94135(10) 0.0196(4)

C9 C -0.14156(10) 0.8635(3) 0.79464(10) 0.0286(4)

H9A H -0.1677 0.7499 0.8018 0.043

H9B H -0.1568 0.8895 0.7374 0.043

H9C H -0.1604 0.9628 0.8207 0.043

C10 C -0.16656(10) 0.7122(3) 1.04834(11) 0.0278(4)

H10A H -0.1808 0.8361 1.0283 0.042

H10B H -0.1919 0.6856 1.0886 0.042

H10C H -0.1871 0.6262 1.0039 0.042

C11 C 0.09952(10) 0.6542(2) 1.15662(10) 0.0224(4)

C12 C 0.09678(11) 0.5724(3) 1.28574(10) 0.0264(4)

H12 H 0.1412 0.4837 1.2875 0.032

C13 C 0.03176(12) 0.4796(3) 1.31010(11) 0.0346(5)

H13A H -0.0144 0.5631 1.3031 0.052

H13B H 0.0553 0.4432 1.3664 0.052

H13C H 0.0119 0.3718 1.2767 0.052

C14 C 0.13423(13) 0.7344(3) 1.33679(12) 0.0380(5)

H14A H 0.1771 0.7870 1.3190 0.057

H14B H 0.1588 0.6966 1.3928 0.057

H14C H 0.0913 0.8252 1.3318 0.057

C15 C 0.29042(10) 0.7654(2) 0.98150(9) 0.0211(4)

C16 C 0.34484(10) 0.6391(3) 1.02993(10) 0.0251(4)

179

H16 H 0.3257 0.5548 1.0599 0.030

C17 C 0.42685(11) 0.6345(3) 1.03507(11) 0.0306(5)

H17 H 0.4633 0.5474 1.0684 0.037

C18 C 0.45547(11) 0.7559(3) 0.99196(11) 0.0321(5)

H18 H 0.5115 0.7518 0.9950 0.038

C19 C 0.40221(11) 0.8839(3) 0.94411(11) 0.0298(4)

H19 H 0.4218 0.9679 0.9144 0.036

C20 C 0.32065(11) 0.8900(3) 0.93932(10) 0.0257(4)

H20 H 0.2848 0.9796 0.9071 0.031

C21 C 0.13066(10) 0.8386(2) 0.82859(9) 0.0214(4)

C22 C 0.17223(11) 0.7205(3) 0.79443(10) 0.0270(4)

H22 H 0.1964 0.6129 0.8221 0.032

C23 C 0.17876(11) 0.7583(3) 0.72058(11) 0.0327(5)

H23 H 0.2077 0.6773 0.6982 0.039

C24 C 0.14340(11) 0.9133(3) 0.67943(10) 0.0335(5)

H24 H 0.1482 0.9401 0.6291 0.040

C25 C 0.10082(11) 1.0294(3) 0.71232(10) 0.0307(5)

H25 H 0.0760 1.1358 0.6840 0.037

C26 C 0.09394(10) 0.9924(3) 0.78600(10) 0.0237(4)

H26 H 0.0639 1.0727 0.8075 0.028

N1 N 0.18243(8) 0.7288(2) 1.04160(8) 0.0211(3).

H1 H 0.2179 0.7015 1.0892 0.025

O1 O -0.05379(7) 0.84646(18) 0.82981(7) 0.0260(3)

O2 O -0.07929(7) 0.69600(19) 1.08364(7) 0.0262(3)

O3 O 0.17460(7) 0.63161(19) 1.18200(7) 0.0301(3)

O4 O 0.05418(7) 0.63072(17) 1.20319(7) 0.0257(3)

180

C1 0.0224(8) 0.0188(9) 0.0199(8) -0.0016(7) 0.0065(7) 0.0005(8)

C2 0.0183(8) 0.0216(9) 0.0248(9) -0.0020(8) 0.0074(7) 0.0005(7)

C3 0.0229(9) 0.0169(9) 0.0257(9) -0.0023(7) 0.0135(7) -0.0011(7)

C4 0.0215(8) 0.0182(9) 0.0218(8) -0.0013(7) 0.0091(7) -0.0007(7)

C5 0.0198(8) 0.0164(9) 0.0231(8) -0.0007(7) 0.0095(7) 0.0008(7)

C6 0.0216(8) 0.0196(9) 0.0225(8) 0.0017(7) 0.0107(7) 0.0007(7)

C7 0.0198(8) 0.0179(9) 0.0241(8) 0.0004(7) 0.0094(7) 0.0002(7)

C8 0.0202(8) 0.0164(9) 0.0231(8) -0.0014(7) 0.0086(7) 0.0000(7)

C9 0.0202(9) 0.0335(11) 0.0274(9) 0.0041(8) 0.0022(7) 0.0030(8)

C10 0.0197(9) 0.0327(11) 0.0338(10) -0.0007(9) 0.0125(8) -0.0008(8)

C11 0.0261(9) 0.0203(9) 0.0237(8) -0.0010(8) 0.0122(7) -0.0018(8)

C12 0.0297(9) 0.0304(11) 0.0197(8) 0.0050(8) 0.0096(7) 0.0024(8)

C13 0.0418(11) 0.0365(12) 0.0301(10) 0.0062(9) 0.0183(8) -0.0021(10)

C14 0.0450(12) 0.0404(13) 0.0292(10) -0.0019(9) 0.0133(9) -0.0076(10)

C15 0.0209(8) 0.0234(10) 0.0201(8) -0.0036(7) 0.0084(7) -0.0005(8)

C16 0.0223(8) 0.0273(10) 0.0251(8) -0.0001(8) 0.0073(7) -0.0008(8)

C17 0.0217(9) 0.0327(11) 0.0336(10) -0.0078(9) 0.0047(7) 0.0049(8)

C18 0.0197(9) 0.0411(13) 0.0375(11) -0.0172(10) 0.0126(8) -0.0044(9)

C19 0.0281(9) 0.0353(12) 0.0315(9) -0.0090(9) 0.0172(8) -0.0101(9)

C20 0.0263(9) 0.0279(10) 0.0250(9) -0.0013(8) 0.0115(7) -0.0023(8)

C21 0.0173(8) 0.0257(10) 0.0209(8) -0.0021(8) 0.0061(6) -0.0040(8)

C22 0.0256(9) 0.0296(11) 0.0257(9) -0.0019(8) 0.0090(7) 0.0021(8)

C23 0.0273(9) 0.0463(13) 0.0271(9) -0.0073(9) 0.0127(8) 0.0008(9)

C24 0.0289(9) 0.0535(14) 0.0197(8) 0.0013(9) 0.0106(7) -0.0051(10)

C25 0.0285(9) 0.0366(12) 0.0253(9) 0.0089(9) 0.0070(7) 0.0004(9)

C26 0.0221(8) 0.0254(10) 0.0236(8) 0.0007(8) 0.0079(7) -0.0004(8)

181

N1 0.0172(7) 0.0252(8) 0.0205(7) 0.0022(6) 0.0062(6) 0.0011(6)

O1 0.0191(6) 0.0355(8) 0.0222(6) 0.0041(6) 0.0056(5) 0.0016(6)

O2 0.0192(6) 0.0357(8) 0.0273(6) 0.0025(6) 0.0126(5) 0.0014(6)

O3 0.0206(6) 0.0439(9) 0.0257(6) 0.0072(6) 0.0080(5) 0.0023(6)

O4 0.0248(6) 0.0334(8) 0.0210(6) 0.0045(6) 0.0109(5) 0.0008(6)

SELECTED GEOMETRIC PARAMETERS

BOND LENGTHS

C1—O1 1.355 (2) C13—H13A 0.9800

C1—C2 1.387 (2) C13—H13B 0.9800

C1—C8 1.405 (2) C13—H13C 0.9800

C2—C3 1.400 (2) C14—H14A 0.9800

C2—H2 0.9500 C14—H14B 0.9800

C3—O2 1.3622 (19) C14—H14C 0.9800

C3—C4 1.404 (2) C15—C16 1.390 (2)

C4—C5 1.414 (2) C15—C20 1.397 (2)

C4—C11 1.466 (2) C16—C17 1.388 (2)

C5—N1 1.365 (2) C16—H16 0.9500

C5—C8 1.405 (2) C17—C18 1.377 (3)

C6—C7 1.373 (2) C17—H17 0.9500

C6—N1 1.382 (2) C18—C19 1.385 (3)

C6—C15 1.470 (2) C18—H18 0.9500

C7—C8 1.445 (2) C19—C20 1.382 (2)

C7—C21 1.489 (2) C19—H19 0.9500

C9—O1 1.4310 (19) C20—H20 0.9500

182

C9—H9A 0.9800 C21—C26 1.389 (3)

C9—H9B 0.9800 C21—C22 1.395 (2)

C9—H9C 0.9800 C22—C23 1.387 (3)

C10—O2 1.423 (2) C22—H22 0.9500

C10—H10A 0.9800 C23—C24 1.380 (3)

C10—H10B 0.9800 C23—H23 0.9500

C10—H10C 0.9800 C24—C25 1.384 (3)

C11—O3 1.228 (2) C24—H24 0.9500

C11—O4 1.3349 (19) C25—C26 1.385 (2)

C12—O4 1.462 (2) C25—H25 0.9500

C12—C13 1.502 (2) C26—H26 0.9500

C12—C14 1.504 (3) N1—H1 0.8800

C12—H12 1.0000

BOND ANGLES O1—C1—C2 123.56 (15) H13B—C13— 109.5 H13C

O1—C1—C8 116.67 (14) C12—C14—H14A 109.5

C2—C1—C8 119.77 (15) C12—C14—H14B 109.5

C1—C2—C3 121.52 (15) H14A—C14— 109.5 H14B

C1—C2—H2 119.2 C12—C14—H14C 109.5

C3—C2—H2 119.2 H14A—C14— 109.5 H14C

O2—C3—C2 121.18 (15) H14B—C14— 109.5 H14C

O2—C3—C4 117.13 (15) C16—C15—C20 118.38 (16)

183

C2—C3—C4 121.68 (15) C16—C15—C6 120.66 (15)

C3—C4—C5 114.71 (15) C20—C15—C6 120.96 (15)

C3—C4—C11 127.68 (15) C17—C16—C15 120.82 (17)

C5—C4—C11 117.58 (14) C17—C16—H16 119.6

N1—C5—C8 107.28 (13) C15—C16—H16 119.6

N1—C5—C4 127.41 (15) C18—C17—C16 120.21 (18)

C8—C5—C4 125.30 (15) C18—C17—H17 119.9

C7—C6—N1 108.94 (14) C16—C17—H17 119.9

C7—C6—C15 131.40 (15) C17—C18—C19 119.67 (16)

N1—C6—C15 119.66 (14) C17—C18—H18 120.2

C6—C7—C8 106.37 (14) C19—C18—H18 120.2

C6—C7—C21 123.90 (15) C20—C19—C18 120.35 (17)

C8—C7—C21 129.64 (15) C20—C19—H19 119.8

C1—C8—C5 117.02 (15) C18—C19—H19 119.8

C1—C8—C7 135.63 (15) C19—C20—C15 120.56 (17)

C5—C8—C7 107.33 (14) C19—C20—H20 119.7

O1—C9—H9A 109.5 C15—C20—H20 119.7

O1—C9—H9B 109.5 C26—C21—C22 118.54 (15)

H9A—C9—H9B 109.5 C26—C21—C7 122.34 (15)

O1—C9—H9C 109.5 C22—C21—C7 118.96 (16)

H9A—C9—H9C 109.5 C23—C22—C21 120.77 (18)

H9B—C9—H9C 109.5 C23—C22—H22 119.6

O2—C10—H10A 109.5 C21—C22—H22 119.6

O2—C10—H10B 109.5 C24—C23—C22 120.22 (18)

H10A—C10— 109.5 C24—C23—H23 119.9 H10B

184

O2—C10—H10C 109.5 C22—C23—H23 119.9

H10A—C10— 109.5 C23—C24—C25 119.29 (16) H10C

H10B—C10— 109.5 C23—C24—H24 120.4 H10C

O3—C11—O4 121.75 (15) C25—C24—H24 120.4

O3—C11—C4 122.85 (15) C24—C25—C26 120.82 (18)

O4—C11—C4 115.39 (14) C24—C25—H25 119.6

O4—C12—C13 104.98 (14) C26—C25—H25 119.6

O4—C12—C14 109.61 (16) C25—C26—C21 120.32 (17)

C13—C12—C14 113.26 (15) C25—C26—H26 119.8

O4—C12—H12 109.6 C21—C26—H26 119.8

C13—C12—H12 109.6 C5—N1—C6 110.07 (13)

C14—C12—H12 109.6 C5—N1—H1 125.0

C12—C13—H13A 109.5 C6—N1—H1 125.0

C12—C13—H13B 109.5 C1—O1—C9 117.93 (13)

H13A—C13— 109.5 C3—O2—C10 118.67 (13) H13B

C12—C13—H13C 109.5 C11—O4—C12 117.64 (13)

H13A—C13— 109.5 H13C

A4. N,N-dimethyl-2-(2-oxo-2-(4,5,6-trimethoxy-2,3-diphenyl-1H-indol-7-yl)- acetyl)-hydrazinecarbothioamide (122)

EXPERIMENTAL DETAILS

Crystal data

Chemical formula C28.50H29ClN4O5S

185

Mr 575.07

Crystal system, Triclinic, P¯ 1 space group

Temperature (K) 150 a, b, c (Å) 12.834 (5), 13.534 (6), 16.858 (7)

, ,  (°) 101.868 (14), 97.982 (13), 95.312 (15)

V (Å3) 2815 (2)

Z 4

Radiation type Mo K

 (mm-1) 0.26

Crystal size (mm) 0.13 × 0.07 × 0.04

Data collection

Diffractometer Bruker kappa APEXII CCD Diffractometer

Absorption Multi-scan correction SADABS (Bruker, 2001)

Tmin, Tmax 0.967, 0.990

No. of measured, 27088, 9638, 2328 independent and observed [I > 2(I)] reflections

Rint 0.327

Refinement

R[F2 > 2(F2)], 0.092, 0.218, 0.92 wR(F2), S

No. of reflections 9638

No. of parameters 662

No. of restraints 0

186

H-atom treatment H-atom parameters constrained

max, min (e 0.40, -0.40 Å-3)

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS

S1A S 0.7146(2) 0.4693(2) 0.99866(16) 0.0368(9)

O1A O 0.4755(5) 0.8276(5) 1.0760(4) 0.0250(19)

O2A O 0.3254(5) 0.9602(5) 1.0636(4) 0.032(2)

O3A O 0.1782(6) 0.9294(5) 0.9185(4) 0.033(2)

O4A O 0.4824(5) 0.5822(5) 0.8877(4) 0.029(2)

O5A O 0.6574(5) 0.7320(5) 1.0070(4) 0.031(2)

N1A N 0.3186(6) 0.6445(6) 0.8005(5) 0.029(3)

H1A H 0.3591 0.5959 0.7905 0.035 Uiso 1 1 calc R . .

N2A N 0.5764(7) 0.6159(6) 1.0667(5) 0.026(2)

H2A H 0.5162 0.5806 1.0689 0.031 Uiso 1 1 calc R . .

N3A N 0.6673(7) 0.6114(6) 1.1205(5) 0.029(2)

H3A H 0.6782 0.6472 1.1714 0.034 Uiso 1 1 calc R . .

N4A N 0.8278(7) 0.5578(6) 1.1451(5) 0.032(3)

C1A C 0.4029(8) 0.8132(8) 1.0050(6) 0.021(3)

C2A C 0.3253(9) 0.8767(8) 0.9987(7) 0.028(3)

C3A C 0.2515(9) 0.8657(9) 0.9288(7) 0.032(3)

C4A C 0.2527(8) 0.7798(8) 0.8637(6) 0.027(3)

C5A C 0.1863(8) 0.7440(8) 0.7833(6) 0.025(3)

C6A C 0.2304(8) 0.6579(8) 0.7478(6) 0.025(3)

C7A C 0.3320(8) 0.7192(8) 0.8707(6) 0.020(3)

C8A C 0.4077(8) 0.7304(7) 0.9406(6) 0.022(3)

187

C9A C 0.4324(9) 0.8205(8) 1.1493(5) 0.048(4)

H9A1 H 0.3980 0.8811 1.1671 0.073

H9A2 H 0.4897 0.8158 1.1929 0.073

H9A3 H 0.3801 0.7597 1.1380 0.073

C10A C 0.3958(9) 1.0487(8) 1.0619(6) 0.051(4)

H10A H 0.4694 1.0356 1.0743 0.076

H10B H 0.3827 1.1069 1.1030 0.076

H10C H 0.3831 1.0639 1.0072 0.076

C11A C 0.1209(9) 0.9652(8) 0.9830(6) 0.057(4)

H11A H 0.1092 0.9120 1.0136 0.086

H11B H 0.0523 0.9822 0.9596 0.086

H11C H 0.1617 1.0260 1.0201 0.086

C12A C 0.0948(5) 0.7830(5) 0.7447(5) 0.033(3)

C13A C 0.0110(7) 0.8041(6) 0.7870(4) 0.043(4)

H13A H 0.0134 0.7929 0.8410 0.052

C14A C -0.0762(5) 0.8415(5) 0.7504(6) 0.052(4)

H14A H -0.1334 0.8559 0.7794 0.062

C15A C -0.0796(6) 0.8579(5) 0.6714(6) 0.053(4)

H15A H -0.1392 0.8835 0.6464 0.063

C16A C 0.0041(8) 0.8368(6) 0.6290(4) 0.051(4)

H16A H 0.0017 0.8480 0.5750 0.061

C17A C 0.0913(6) 0.7994(6) 0.6656(5) 0.046(4)

H17A H 0.1485 0.7850 0.6367 0.056

C18A C 0.1966(4) 0.5786(3) 0.6702(2) 0.038(3)

C19A C 0.0901(4) 0.5430(5) 0.6417(3) 0.039(3)

H19A H 0.0370 0.5747 0.6679 0.047

188

C20A C 0.0613(4) 0.4610(4) 0.5749(3) 0.040(3)

H20A H -0.0115 0.4366 0.5554 0.047

C21A C 0.1389(5) 0.4146(4) 0.5366(3) 0.045(4)

H21A H 0.1192 0.3586 0.4909 0.054

C22A C 0.2454(4) 0.4502(5) 0.5651(2) 0.051(4)

H22A H 0.2985 0.4185 0.5389 0.061

C23A C 0.2743(4) 0.5322(4) 0.6319(2) 0.040(3)

H23A H 0.3471 0.5566 0.6514 0.048

C24A C 0.4837(4) 0.6584(3) 0.9430(2) 0.026(3)

C25A C 0.5801(4) 0.6744(3) 1.0109(2) 0.028(3)

C26A C 0.7403(4) 0.5494(4) 1.0925(3) 0.022(3)

C27A C 0.8447(4) 0.6248(5) 1.2280(3) 0.040(3)

H27A H 0.8595 0.6958 1.2239 0.059

H27B H 0.9050 0.6065 1.2621 0.059

H27C H 0.7809 0.6166 1.2531 0.059

C28A C 0.9111(8) 0.4945(8) 1.1262(6) 0.046(4)

H28A H 0.8840 0.4228 1.1202 0.070

H28B H 0.9718 0.5138 1.1709 0.070

H28C H 0.9336 0.5044 1.0748 0.070

S1B S 1.0340(2) -0.1238(2) 0.20256(18) 0.0498(11)

O1B O 0.8297(5) -0.0747(6) 0.3723(4) 0.031(2)

O2B O 0.8197(5) -0.0103(5) 0.5381(4) 0.029(2)

O3B O 0.6716(5) 0.1203(5) 0.5864(4) 0.0247(19)

O4B O 0.6442(6) 0.0281(6) 0.1981(4) 0.034(2)

O5B O 0.6999(5) -0.1934(5) 0.2201(4) 0.0235(19)

N1B N 0.5557(7) 0.1362(6) 0.3194(5) 0.025(2)

189

H1B H 0.5475 0.1272 0.2656 0.030

N2B N 0.8096(6) -0.0927(6) 0.1643(5) 0.036(3)

H2B H 0.8358 -0.0297 0.1661 0.043

N3B N 0.8420(7) -0.1733(6) 0.1126(4) 0.025(2)

H3B H 0.7959 -0.2161 0.0747 0.030

N4B N 0.9753(7) -0.2488(6) 0.0560(5) 0.026(2)

C1B C 0.7506(9) -0.0172(8) 0.3957(7) 0.028(3)

C2B C 0.7470(8) 0.0182(8) 0.4799(6) 0.025(3)

C3B C 0.6749(9) 0.0838(8) 0.5043(6) 0.024(3)

C4B C 0.6128(9) 0.1244(8) 0.4467(6) 0.020(3)

C5B C 0.5397(8) 0.1974(8) 0.4521(6) 0.023(3)

C6B C 0.5014(8) 0.2043(7) 0.3723(6) 0.023(3)

C7B C 0.6204(9) 0.0889(8) 0.3641(6) 0.028(3)

C8B C 0.6871(8) 0.0178(8) 0.3360(6) 0.022(3)

C9B C 0.8268(8) -0.1739(8) 0.3949(5) 0.032(3)

H9B1 H 0.8234 -0.1647 0.4537 0.047

H9B2 H 0.8909 -0.2043 0.3831 0.047

H9B3 H 0.7641 -0.2188 0.3631 0.047

C10B C 0.9064(8) 0.0673(8) 0.5711(6) 0.047(4)

H10D H 0.9506 0.0731 0.5289 0.070

H10E H 0.9489 0.0499 0.6181 0.070

H10F H 0.8795 0.1323 0.5891 0.070

C11B C 0.6614(8) 0.0446(8) 0.6361(6) 0.039(3)

H11D H 0.6434 -0.0233 0.6001 0.058

H11E H 0.6053 0.0589 0.6692 0.058

H11F H 0.7288 0.0475 0.6725 0.058

190

C12B C 0.5155(5) 0.2642(5) 0.5275(3) 0.024(3)

C13B C 0.4720(5) 0.2227(4) 0.5861(4) 0.028(3)

H13B H 0.4519 0.1513 0.5763 0.034

C14B C 0.4578(5) 0.2855(6) 0.6592(3) 0.035(3)

H14B H 0.4281 0.2571 0.6993 0.042

C15B C 0.4873(5) 0.3899(6) 0.6736(3) 0.034(3)

H15B H 0.4776 0.4328 0.7235 0.040

C16B C 0.5309(5) 0.4314(4) 0.6149(4) 0.039(3)

H16B H 0.5510 0.5028 0.6247 0.047

C17B C 0.5450(5) 0.3686(5) 0.5418(4) 0.032(3)

H17B H 0.5748 0.3970 0.5017 0.038

C18B C 0.4251(5) 0.2620(5) 0.3366(4) 0.024(3)

C19B C 0.3429(5) 0.2907(5) 0.3785(3) 0.027(3)

H19B H 0.3392 0.2748 0.4304 0.032

C20B C 0.2661(4) 0.3425(5) 0.3444(4) 0.033(3)

H20B H 0.2099 0.3621 0.3730 0.040

C21B C 0.2715(5) 0.3657(5) 0.2683(4) 0.029(3)

H21B H 0.2190 0.4012 0.2450 0.035

C22B C 0.3537(6) 0.3371(5) 0.2264(3) 0.039(3)

H22B H 0.3573 0.3529 0.1745 0.047

C23B C 0.4305(5) 0.2852(5) 0.2605(4) 0.030(3)

H23B H 0.4866 0.2656 0.2319 0.036

C24B C 0.6879(8) -0.0134(9) 0.2479(7) 0.028(3)

C25B C 0.7365(9) -0.1121(9) 0.2123(6) 0.029(3)

C26B C 0.9467(9) -0.1848(8) 0.1218(6) 0.030(3)

C27B C 0.8975(8) -0.2957(8) -0.0188(5) 0.035(3)

191

H27D H 0.8411 -0.2523 -0.0246 0.052

H27E H 0.8667 -0.3629 -0.0143 0.052

H27F H 0.9332 -0.3028 -0.0671 0.052

C28B C 1.0811(8) -0.2819(8) 0.0590(7) 0.050(4)

H28D H 1.1150 -0.2616 0.0152 0.074

H28E H 1.0747 -0.3561 0.0513 0.074

H28F H 1.1243 -0.2502 0.1124 0.074

C1S C 0.7618(9) 0.3183(9) 0.7134(6) 0.065(5)

H1S1 H 0.6905 0.3021 0.6793 0.078

H1S2 H 0.7844 0.2540 0.7251 0.078

Cl1S Cl 0.7547(3) 0.4014(2) 0.80513(17) 0.0606(11)

Cl2S Cl 0.8512(3) 0.3701(3) 0.6585(2) 0.0863(14)

S1A 0.051(2) 0.024(2) 0.0334(18) -0.0032(15) 0.0110(16) 0.0086(16)

O1A 0.042(5) 0.016(5) 0.023(4) 0.009(3) 0.010(4) 0.013(4)

O2A 0.043(5) 0.016(5) 0.036(4) 0.000(4) 0.013(4) 0.006(4)

O3A 0.042(5) 0.025(5) 0.044(5) 0.018(4) 0.019(4) 0.021(4)

O4A 0.032(5) 0.016(5) 0.036(4) -0.002(4) 0.003(4) 0.012(4)

O5A 0.040(5) 0.021(5) 0.036(4) 0.013(4) 0.010(4) 0.006(4)

N1A 0.022(6) 0.033(6) 0.025(5) -0.009(5) 0.004(5) 0.003(5)

N2A 0.030(6) 0.026(6) 0.021(5) 0.002(5) 0.004(5) 0.006(5)

N3A 0.047(7) 0.028(6) 0.012(5) 0.003(4) 0.004(5) 0.017(5)

N4A 0.049(7) 0.026(6) 0.018(5) -0.004(4) -0.004(5) 0.021(5)

C1A 0.012(7) 0.023(8) 0.031(7) 0.013(6) -0.001(6) 0.002(6)

C2A 0.039(8) 0.018(8) 0.034(7) 0.009(6) 0.020(7) 0.011(6)

C3A 0.026(8) 0.034(9) 0.041(8) 0.021(7) 0.002(7) 0.001(6)

C4A 0.026(8) 0.021(8) 0.032(7) 0.004(6) 0.007(6) -0.005(6)

192

C5A 0.022(7) 0.026(8) 0.026(7) 0.003(6) 0.011(6) 0.005(6)

C6A 0.027(7) 0.021(8) 0.028(7) 0.016(6) -0.004(6) 0.000(6)

C7A 0.012(7) 0.023(8) 0.031(7) 0.012(6) 0.008(6) 0.007(6)

C8A 0.032(7) 0.006(7) 0.028(7) -0.001(5) 0.008(6) 0.010(5)

C9A 0.062(9) 0.067(10) 0.018(7) 0.017(6) 0.001(6) 0.011(7)

C10A 0.072(10) 0.015(8) 0.063(8) -0.003(6) 0.026(8) -0.002(7)

C11A 0.063(9) 0.071(11) 0.062(8) 0.026(8) 0.050(8) 0.045(8)

C12A 0.024(8) 0.028(8) 0.046(8) 0.013(6) -0.006(7) 0.009(6)

C13A 0.043(9) 0.039(9) 0.055(8) 0.020(7) 0.018(8) 0.010(7)

C14A 0.040(10) 0.033(9) 0.085(11) 0.023(8) 0.000(8) 0.001(7)

C15A 0.040(10) 0.031(9) 0.090(11) 0.035(8) -0.018(8) 0.008(7)

C16A 0.053(10) 0.038(9) 0.062(9) 0.027(7) -0.007(9) -0.008(8)

C17A 0.054(10) 0.044(9) 0.037(8) 0.012(7) 0.000(7) -0.007(7)

C18A 0.042(9) 0.039(9) 0.030(7) 0.003(6) 0.001(6) 0.009(7)

C19A 0.044(9) 0.037(9) 0.042(8) 0.017(6) 0.012(7) 0.015(7)

C20A 0.036(8) 0.040(9) 0.036(7) 0.009(6) -0.012(6) -0.005(7)

C21A 0.071(10) 0.044(9) 0.025(7) 0.015(6) 0.014(7) 0.013(8)

C22A 0.045(9) 0.066(10) 0.036(8) -0.002(7) 0.000(7) 0.018(8)

C23A 0.040(8) 0.035(9) 0.041(7) 0.007(6) -0.005(6) 0.010(6)

C24A 0.037(8) 0.016(8) 0.034(7) 0.021(6) 0.017(6) 0.003(6)

C25A 0.041(9) 0.024(9) 0.016(7) -0.004(6) 0.004(6) 0.020(7)

C26A 0.039(8) 0.018(7) 0.016(6) 0.013(5) 0.010(6) 0.008(6)

C27A 0.054(9) 0.032(8) 0.029(7) -0.001(6) 0.009(6) 0.001(6)

C28A 0.053(9) 0.034(9) 0.047(8) 0.005(7) -0.003(7) 0.011(7)

S1B 0.041(2) 0.054(3) 0.044(2) -0.0079(18) -0.0026(17) 0.0097(18)

O1B 0.027(5) 0.029(5) 0.034(4) -0.004(4) 0.006(4) 0.012(4)

193

O2B 0.029(5) 0.019(5) 0.033(5) 0.003(4) -0.012(4) 0.005(4)

O3B 0.036(5) 0.019(5) 0.020(4) 0.003(4) 0.006(4) 0.008(4)

O4B 0.042(6) 0.037(6) 0.030(5) 0.014(4) 0.014(4) 0.020(4)

O5B 0.036(5) 0.005(5) 0.030(4) 0.002(4) 0.009(4) 0.008(4)

N1B 0.036(6) 0.025(6) 0.012(5) 0.000(5) 0.007(5) 0.001(5)

N2B 0.038(6) 0.027(6) 0.039(6) -0.011(5) 0.024(5) -0.003(5)

N3B 0.030(6) 0.023(6) 0.023(5) 0.003(4) 0.003(5) 0.013(5)

N4B 0.027(6) 0.014(6) 0.036(6) 0.003(5) -0.001(5) 0.003(5)

C1B 0.030(8) 0.008(7) 0.041(8) -0.005(6) 0.006(6) -0.005(6)

C2B 0.027(8) 0.017(7) 0.027(7) -0.005(6) 0.003(6) 0.002(6)

C3B 0.044(8) 0.024(8) 0.006(6) 0.002(5) 0.014(6) 0.005(6)

C4B 0.039(8) 0.014(7) 0.006(6) 0.004(5) 0.009(6) -0.011(6)

C5B 0.029(7) 0.025(8) 0.021(7) 0.015(6) 0.012(6) 0.005(6)

C6B 0.037(8) 0.009(7) 0.025(7) 0.008(5) 0.012(6) 0.000(6)

C7B 0.026(8) 0.026(8) 0.029(7) 0.010(6) -0.007(6) 0.005(6)

C8B 0.027(7) 0.028(8) 0.015(6) 0.014(6) -0.001(6) 0.006(6)

C9B 0.037(8) 0.031(9) 0.025(6) -0.002(6) 0.004(6) 0.014(6)

C10B 0.039(8) 0.048(9) 0.046(8) -0.003(7) 0.001(7) 0.007(7)

C11B 0.048(9) 0.047(9) 0.022(6) 0.011(6) 0.007(6) 0.001(7)

C12B 0.035(7) 0.021(8) 0.019(6) 0.004(6) 0.008(6) 0.006(6)

C13B 0.028(7) 0.035(8) 0.023(6) 0.008(6) 0.003(5) 0.010(6)

C14B 0.019(7) 0.068(10) 0.020(7) 0.011(6) 0.004(5) 0.011(7)

C15B 0.044(8) 0.037(9) 0.011(6) -0.009(6) -0.006(6) 0.010(6)

C16B 0.043(8) 0.032(8) 0.038(7) -0.003(7) 0.005(6) 0.003(6)

C17B 0.043(8) 0.027(8) 0.025(7) 0.006(6) 0.001(6) 0.012(6)

C18B 0.029(8) 0.019(8) 0.025(7) 0.005(6) 0.006(6) 0.009(6)

194

C19B 0.023(7) 0.039(8) 0.017(6) 0.006(6) 0.001(6) 0.007(6)

C20B 0.043(9) 0.026(8) 0.034(7) 0.004(6) 0.010(6) 0.021(6)

C21B 0.038(8) 0.025(8) 0.028(7) 0.010(6) 0.005(6) 0.014(6)

C22B 0.061(9) 0.032(8) 0.028(7) 0.004(6) 0.019(7) 0.015(7)

C23B 0.038(8) 0.027(8) 0.022(7) -0.004(6) 0.009(6) 0.010(6)

C24B 0.025(8) 0.020(8) 0.038(8) 0.006(6) 0.010(6) -0.010(6)

C25B 0.040(8) 0.008(8) 0.033(7) 0.001(6) -0.008(6) 0.008(6)

C26B 0.047(9) 0.023(8) 0.032(7) 0.016(6) 0.022(7) 0.014(6)

C27B 0.042(8) 0.027(8) 0.036(7) -0.005(6) 0.021(6) 0.008(6)

C28B 0.046(9) 0.036(9) 0.071(9) 0.011(7) 0.016(7) 0.015(7)

C1S 0.079(10) 0.061(10) 0.046(8) -0.013(7) 0.029(8) -0.009(8)

Cl1S 0.085(3) 0.045(2) 0.046(2) -0.0003(18) 0.0080(19) 0.008(2)

Cl2S 0.081(3) 0.092(3) 0.092(3) 0.018(2) 0.045(2) 0.003(2)

SELECTED GEOMETRIC PARAMETERS BOND LENGTHS

S1A—C26A 1.694 (5) O1B—C9B 1.467 (11)

O1A—C1A 1.378 (11) O2B—C2B 1.396 (12)

O1A—C9A 1.440 (9) O2B—C10B 1.421 (10)

O2A—C2A 1.402 (10) O3B—C3B 1.378 (9)

O2A—C10A 1.439 (11) O3B—C11B 1.458 (11)

O3A—C3A 1.350 (12) O4B—C24B 1.207 (12)

O3A—C11A 1.425 (9) O5B—C25B 1.194 (11)

O4A—C24A 1.236 (6) N1B—C7B 1.338 (12)

O5A—C25A 1.222 (7) N1B—C6B 1.443 (10)

195

N1A—C7A 1.367 (10) N1B—H1B 0.8800

N1A—C6A 1.389 (12) N2B—C25B 1.363 (12)

N1A—H1A 0.8800 N2B—N3B 1.385 (9)

N2A—C25A 1.350 (9) N2B—H2B 0.8800

N2A—N3A 1.390 (10) N3B—C26B 1.358 (12)

N2A—H2A 0.8800 N3B—H3B 0.8800

N3A—C26A 1.381 (9) N4B—C26B 1.377 (10)

N3A—H3A 0.8800 N4B—C28B 1.466 (11)

N4A—C26A 1.311 (9) N4B—C27B 1.481 (10)

N4A—C28A 1.460 (11) C1B—C8B 1.394 (13)

N4A—C27A 1.478 (8) C1B—C2B 1.409 (12)

C1A—C2A 1.381 (13) C2B—C3B 1.387 (13)

C1A—C8A 1.404 (12) C3B—C4B 1.403 (14)

C2A—C3A 1.377 (14) C4B—C7B 1.396 (12)

C3A—C4A 1.429 (13) C4B—C5B 1.422 (14)

C4A—C7A 1.372 (13) C5B—C6B 1.392 (13)

C4A—C5A 1.459 (13) C5B—C12B 1.488 (9)

C5A—C6A 1.402 (13) C6B—C18B 1.451 (11)

C5A—C12A 1.458 (12) C7B—C8B 1.400 (13)

C6A—C18A 1.493 (10) C8B—C24B 1.461 (12)

C7A—C8A 1.392 (13) C9B—H9B1 0.9800

C8A—C24A 1.444 (11) C9B—H9B2 0.9800

C9A—H9A1 0.9800 C9B—H9B3 0.9800

C9A—H9A2 0.9800 C10B—H10D 0.9800

C9A—H9A3 0.9800 C10B—H10E 0.9800

196

C10A—H10A 0.9800 C10B—H10F 0.9800

C10A—H10B 0.9800 C11B—H11D 0.9800

C10A—H10C 0.9800 C11B—H11E 0.9800

C11A—H11A 0.9800 C11B—H11F 0.9800

C11A—H11B 0.9800 C12B—C13B 1.3900

C11A—H11C 0.9800 C12B—C17B 1.3900

C12A—C13A 1.3900 C13B—C14B 1.3900

C12A—C17A 1.3900 C13B—H13B 0.9500

C13A—C14A 1.3900 C14B—C15B 1.3900

C13A—H13A 0.9500 C14B—H14B 0.9500

C14A—C15A 1.3900 C15B—C16B 1.3900

C14A—H14A 0.9500 C15B—H15B 0.9500

C15A—C16A 1.3900 C16B—C17B 1.3900

C15A—H15A 0.9500 C16B—H16B 0.9500

C16A—C17A 1.3900 C17B—H17B 0.9500

C16A—H16A 0.9500 C18B—C19B 1.3900

C17A—H17A 0.9500 C18B—C23B 1.3900

C18A—C19A 1.3900 C19B—C20B 1.3900

C18A—C23A 1.3900 C19B—H19B 0.9500

C19A—C20A 1.3900 C20B—C21B 1.3900

C19A—H19A 0.9500 C20B—H20B 0.9500

C20A—C21A 1.3900 C21B—C22B 1.3900

C20A—H20A 0.9500 C21B—H21B 0.9500

C21A—C22A 1.3900 C22B—C23B 1.3900

C21A—H21A 0.9500 C22B—H22B 0.9500

197

C22A—C23A 1.3900 C23B—H23B 0.9500

C22A—H22A 0.9500 C24B—C25B 1.568 (14)

C23A—H23A 0.9500 C27B—H27D 0.9800

C24A—C25A 1.5305 C27B—H27E 0.9800

C27A—H27A 0.9800 C27B—H27F 0.9800

C27A—H27B 0.9800 C28B—H28D 0.9800

C27A—H27C 0.9800 C28B—H28E 0.9800

C28A—H28A 0.9800 C28B—H28F 0.9800

C28A—H28B 0.9800 C1S—Cl1S 1.734 (9)

C28A—H28C 0.9800 C1S—Cl2S 1.754 (10)

S1B—C26B 1.653 (11) C1S—H1S1 0.9900

O1B—C1B 1.386 (11) C1S—H1S2 0.9900

BOND ANGLES C1A—O1A—C9A 116.0 (7) C7B—N1B—C6B 110.1 (8)

C2A—O2A— 114.3 (7) C7B—N1B—H1B 125.0 C10A

C3A—O3A— 120.3 (8) C6B—N1B—H1B 125.0 C11A

C7A—N1A—C6A 108.8 (9) C25B—N2B— 119.2 (8) N3B

C7A—N1A—H1A 125.6 C25B—N2B— 120.4 H2B

C6A—N1A—H1A 125.6 N3B—N2B—H2B 120.4

C25A—N2A— 120.3 (7) C26B—N3B— 118.4 (8) N3A N2B

C25A—N2A— 119.9 C26B—N3B— 120.8 H2A H3B

198

N3A—N2A—H2A 119.9 N2B—N3B—H3B 120.8

C26A—N3A— 118.7 (6) C26B—N4B— 122.0 (9) N2A C28B

C26A—N3A— 120.7 C26B—N4B— 121.5 (8) H3A C27B

N2A—N3A—H3A 120.7 C28B—N4B— 116.3 (7) C27B

C26A—N4A— 120.9 (7) O1B—C1B—C8B 118.7 (9) C28A

C26A—N4A— 122.7 (7) O1B—C1B—C2B 119.6 (11) C27A

C28A—N4A— 116.2 (8) C8B—C1B—C2B 120.9 (10) C27A

O1A—C1A—C2A 120.8 (9) C3B—C2B—O2B 120.6 (9)

O1A—C1A—C8A 118.1 (10) C3B—C2B—C1B 120.2 (11)

C2A—C1A—C8A 121.0 (10) O2B—C2B—C1B 119.1 (10)

C3A—C2A—C1A 122.8 (10) O3B—C3B—C2B 120.8 (11)

C3A—C2A—O2A 118.0 (10) O3B—C3B—C4B 118.2 (9)

C1A—C2A—O2A 119.0 (10) C2B—C3B—C4B 120.6 (9)

O3A—C3A—C2A 124.7 (10) C7B—C4B—C3B 117.1 (10)

O3A—C3A—C4A 118.4 (10) C7B—C4B—C5B 108.7 (10)

C2A—C3A—C4A 116.9 (11) C3B—C4B—C5B 134.3 (9)

C7A—C4A—C3A 118.9 (10) C6B—C5B—C4B 107.2 (8)

C7A—C4A—C5A 109.2 (9) C6B—C5B— 124.5 (10) C12B

C3A—C4A—C5A 131.7 (11) C4B—C5B— 128.0 (9) C12B

199

C6A—C5A— 125.3 (9) C5B—C6B—N1B 106.1 (9) C12A

C6A—C5A—C4A 103.5 (10) C5B—C6B— 134.4 (9) C18B

C12A—C5A— 131.2 (9) N1B—C6B— 119.6 (8) C4A C18B

N1A—C6A—C5A 110.0 (9) N1B—C7B—C4B 108.0 (10)

N1A—C6A— 117.2 (8) N1B—C7B—C8B 127.7 (10) C18A

C5A—C6A— 132.7 (10) C4B—C7B—C8B 124.3 (11) C18A

N1A—C7A—C4A 108.4 (10) C1B—C8B—C7B 116.6 (9)

N1A—C7A—C8A 127.2 (10) C1B—C8B— 124.2 (10) C24B

C4A—C7A—C8A 124.3 (9) C7B—C8B— 119.1 (11) C24B

C7A—C8A—C1A 115.7 (10) O1B—C9B— 109.5 H9B1

C7A—C8A— 119.6 (8) O1B—C9B— 109.5 C24A H9B2

C1A—C8A— 124.8 (9) H9B1—C9B— 109.5 C24A H9B2

O1A—C9A— 109.5 O1B—C9B— 109.5 H9A1 H9B3

O1A—C9A— 109.5 H9B1—C9B— 109.5 H9A2 H9B3

H9A1—C9A— 109.5 H9B2—C9B— 109.5 H9A2 H9B3

200

O1A—C9A— 109.5 O2B—C10B— 109.5 H9A3 H10D

H9A1—C9A— 109.5 O2B—C10B— 109.5 H9A3 H10E

H9A2—C9A— 109.5 H10D—C10B— 109.5 H9A3 H10E

O2A—C10A— 109.5 O2B—C10B— 109.5 H10A H10F

O2A—C10A— 109.5 H10D—C10B— 109.5 H10B H10F

H10A—C10A— 109.5 H10E—C10B— 109.5 H10B H10F

O2A—C10A— 109.5 O3B—C11B— 109.5 H10C H11D

H10A—C10A— 109.5 O3B—C11B— 109.5 H10C H11E

H10B—C10A— 109.5 H11D—C11B— 109.5 H10C H11E

O3A—C11A— 109.5 O3B—C11B— 109.5 H11A H11F

O3A—C11A— 109.5 H11D—C11B— 109.5 H11B H11F

H11A—C11A— 109.5 H11E—C11B— 109.5 H11B H11F

O3A—C11A— 109.5 C13B—C12B— 120.0 H11C C17B

H11A—C11A— 109.5 C13B—C12B— 120.7 (6) H11C C5B

201

H11B—C11A— 109.5 C17B—C12B— 119.1 (6) H11C C5B

C13A—C12A— 120.0 C14B—C13B— 120.0 C17A C12B

C13A—C12A— 119.9 (7) C14B—C13B— 120.0 C5A H13B

C17A—C12A— 120.1 (7) C12B—C13B— 120.0 C5A H13B

C14A—C13A— 120.0 C13B—C14B— 120.0 C12A C15B

C14A—C13A— 120.0 C13B—C14B— 120.0 H13A H14B

C12A—C13A— 120.0 C15B—C14B— 120.0 H13A H14B

C13A—C14A— 120.0 C14B—C15B— 120.0 C15A C16B

C13A—C14A— 120.0 C14B—C15B— 120.0 H14A H15B

C15A—C14A— 120.0 C16B—C15B— 120.0 H14A H15B

C16A—C15A— 120.0 C17B—C16B— 120.0 C14A C15B

C16A—C15A— 120.0 C17B—C16B— 120.0 H15A H16B

C14A—C15A— 120.0 C15B—C16B— 120.0 H15A H16B

C17A—C16A— 120.0 C16B—C17B— 120.0 C15A C12B

202

C17A—C16A— 120.0 C16B—C17B— 120.0 H16A H17B

C15A—C16A— 120.0 C12B—C17B— 120.0 H16A H17B

C16A—C17A— 120.0 C19B—C18B— 120.0 C12A C23B

C16A—C17A— 120.0 C19B—C18B— 118.6 (6) H17A C6B

C12A—C17A— 120.0 C23B—C18B— 121.4 (6) H17A C6B

C19A—C18A— 120.0 C20B—C19B— 120.0 C23A C18B

C19A—C18A— 121.1 (5) C20B—C19B— 120.0 C6A H19B

C23A—C18A— 118.5 (5) C18B—C19B— 120.0 C6A H19B

C20A—C19A— 120.0 C19B—C20B— 120.0 C18A C21B

C20A—C19A— 120.0 C19B—C20B— 120.0 H19A H20B

C18A—C19A— 120.0 C21B—C20B— 120.0 H19A H20B

C19A—C20A— 120.0 C22B—C21B— 120.0 C21A C20B

C19A—C20A— 120.0 C22B—C21B— 120.0 H20A H21B

C21A—C20A— 120.0 C20B—C21B— 120.0 H20A H21B

203

C22A—C21A— 120.0 C23B—C22B— 120.0 C20A C21B

C22A—C21A— 120.0 C23B—C22B— 120.0 H21A H22B

C20A—C21A— 120.0 C21B—C22B— 120.0 H21A H22B

C21A—C22A— 120.0 C22B—C23B— 120.0 C23A C18B

C21A—C22A— 120.0 C22B—C23B— 120.0 H22A H23B

C23A—C22A— 120.0 C18B—C23B— 120.0 H22A H23B

C22A—C23A— 120.0 O4B—C24B— 123.2 (11) C18A C8B

C22A—C23A— 120.0 O4B—C24B— 116.2 (9) H23A C25B

C18A—C23A— 120.0 C8B—C24B— 120.3 (11) H23A C25B

O4A—C24A— 123.7 (6) O5B—C25B— 127.3 (10) C8A N2B

O4A—C24A— 113.2 (4) O5B—C25B— 120.6 (10) C25A C24B

C8A—C24A— 122.8 (4) N2B—C25B— 111.4 (10) C25A C24B

O5A—C25A— 124.8 (6) N3B—C26B— 114.0 (9) N2A N4B

O5A—C25A— 118.2 (4) N3B—C26B— 123.6 (7) C24A S1B

204

N2A—C25A— 116.7 (4) N4B—C26B— 122.4 (8) C24A S1B

N4A—C26A— 114.0 (6) N4B—C27B— 109.5 N3A H27D

N4A—C26A— 124.5 (5) N4B—C27B— 109.5 S1A H27E

N3A—C26A— 121.5 (4) H27D—C27B— 109.5 S1A H27E

N4A—C27A— 109.5 N4B—C27B— 109.5 H27A H27F

N4A—C27A— 109.5 H27D—C27B— 109.5 H27B H27F

H27A—C27A— 109.5 H27E—C27B— 109.5 H27B H27F

N4A—C27A— 109.5 N4B—C28B— 109.5 H27C H28D

H27A—C27A— 109.5 N4B—C28B— 109.5 H27C H28E

H27B—C27A— 109.5 H28D—C28B— 109.5 H27C H28E

N4A—C28A— 109.5 N4B—C28B— 109.5 H28A H28F

N4A—C28A— 109.5 H28D—C28B— 109.5 H28B H28F

H28A—C28A— 109.5 H28E—C28B— 109.5 H28B H28F

N4A—C28A— 109.5 Cl1S—C1S—Cl2S 111.8 (6) H28C

205

H28A—C28A— 109.5 Cl1S—C1S— 109.3 H28C H1S1

H28B—C28A— 109.5 Cl2S—C1S— 109.3 H28C H1S1

C1B—O1B—C9B 115.5 (8) Cl1S—C1S— 109.3 H1S2

C2B—O2B— 111.9 (8) Cl2S—C1S— 109.3 C10B H1S2

C3B—O3B— 116.5 (7) H1S1—C1S— 107.9 C11B H1S2

A4. 8-Chloro-10-methoxy-4-methyl-6,7-diphenyl-1,2-dihydro-[1,3]diazepino- [6,7,1-hi]-indole (196)

EXPERIMENTAL DETAILS

Crystal data

Chemical formula C25H21ClN2O

Mr 400.89

Crystal system, Triclinic, P¯ 1 space group

Temperature (K) 150 a, b, c (Å) 10.2277 (10), 10.5380 (9), 10.8016 (9)

, ,  (°) 66.525 (5), 66.409 (4), 80.984 (4)

V (Å3) 978.59 (15)

Z 2

Radiation type Mo K

 (mm-1) 0.22

206

Crystal size (mm) 0.15 × 0.08 × 0.07

Data collection

Diffractometer Bruker kappa APEXII CCD Diffractometer

Absorption Multi-scan correction SADABS (Bruker, 2001)

Tmin, Tmax 0.968, 0.984

No. of measured, 12931, 3434, 2274 independent and observed [I > 2(I)] reflections

Rint 0.075

Refinement

R[F2 > 2(F2)], 0.047, 0.112, 1.02 wR(F2), S

No. of reflections 3434

No. of parameters 264

No. of restraints 0

H-atom treatment H-atom parameters constrained

max, min (e 0.26, -0.28 Å-3)

ATOMIC COORDINATES AND DISPLACEMENT PARAMETERS

Cl1 Cl 1.29372(7) 0.70703(7) 0.42620(8) 0.0278(2)

O1 O 0.92732(19) 0.88589(19) 0.80745(19) 0.0287(5)

N1 N 0.7840(2) 0.7864(2) 0.4793(2) 0.0194(5)

N2 N 0.5551(2) 0.8359(2) 0.6320(2) 0.0246(5)

C1 C 0.8646(3) 0.7381(3) 0.3650(3) 0.0193(6)

207

C2 C 1.0043(3) 0.7243(3) 0.3510(3) 0.0190(6)

C3 C 1.0140(3) 0.7612(2) 0.4625(3) 0.0183(6)

C4 C 1.1221(3) 0.7590(3) 0.5114(3) 0.0196(6)

C5 C 1.0958(3) 0.7944(3) 0.6279(3) 0.0216(6)

H5 H 1.1692 0.7873 0.6632 0.026

C6 C 0.9595(3) 0.8413(3) 0.6951(3) 0.0217(6)

C7 C 0.8468(3) 0.8490(3) 0.6509(3) 0.0196(6)

C8 C 0.8766(3) 0.8031(2) 0.5375(3) 0.0186(6)

C9 C 0.7982(3) 0.7254(3) 0.2725(3) 0.0212(6)

C10 C 0.7075(3) 0.8270(3) 0.2229(3) 0.0259(7)

H10 H 0.6933 0.9088 0.2437 0.031

C11 C 0.6374(3) 0.8112(3) 0.1436(3) 0.0313(7)

H11 H 0.5749 0.8816 0.1116 0.038

C12 C 0.6577(3) 0.6940(3) 0.1110(3) 0.0341(7)

H12 H 0.6073 0.6816 0.0595 0.041

C13 C 0.7531(3) 0.5944(3) 0.1546(3) 0.0326(7)

H13 H 0.7717 0.5157 0.1280 0.039

C14 C 0.8212(3) 0.6080(3) 0.2359(3) 0.0273(7)

H14 H 0.8840 0.5376 0.2673 0.033

C15 C 1.1249(3) 0.6931(3) 0.2325(3) 0.0186(6)

C16 C 1.1586(3) 0.5577(3) 0.2404(3) 0.0254(7)

H16 H 1.1054 0.4835 0.3242 0.031

C17 C 1.2679(3) 0.5294(3) 0.1286(3) 0.0299(7)

H17 H 1.2894 0.4363 0.1357 0.036

C18 C 1.3467(3) 0.6372(3) 0.0052(3) 0.0285(7)

H18 H 1.4212 0.6182 -0.0727 0.034

208

C19 C 1.3159(3) 0.7712(3) -0.0029(3) 0.0281(7)

H19 H 1.3696 0.8452 -0.0865 0.034

C20 C 1.2056(3) 0.7991(3) 0.1115(3) 0.0254(7)

H20 H 1.1861 0.8920 0.1057 0.031

C21 C 1.0342(3) 0.8717(3) 0.8652(3) 0.0359(8)

H21A H 1.0640 0.7747 0.8964 0.054

H21B H 0.9956 0.9007 0.9487 0.054

H21C H 1.1165 0.9297 0.7902 0.054

C22 C 0.7066(3) 0.9140(3) 0.7157(3) 0.0245(6)

H22A H 0.7257 0.9964 0.7284 0.029

H22B H 0.6511 0.8472 0.8130 0.029

C23 C 0.6190(3) 0.9564(3) 0.6203(3) 0.0255(7)

H23A H 0.5429 1.0209 0.6502 0.031

H23B H 0.6811 1.0053 0.5178 0.031

C24 C 0.6329(3) 0.7604(3) 0.5638(3) 0.0219(6)

C25 C 0.5724(3) 0.6320(3) 0.5813(3) 0.0284(7)

H25A H 0.4751 0.6176 0.6544 0.043

H25B H 0.6317 0.5527 0.6127 0.043

H25C H 0.5705 0.6410 0.4881 0.043

Cl1 0.0191(4) 0.0333(4) 0.0335(4) -0.0173(3) -0.0099(3) 0.0072(3)

O1 0.0308(11) 0.0373(12) 0.0232(11) -0.0182(10) -0.0095(9) 0.0038(9)

N1 0.0157(11) 0.0250(12) 0.0176(12) -0.0101(10) -0.0047(9) 0.0016(9)

N2 0.0169(12) 0.0296(13) 0.0238(13) -0.0100(11) -0.0055(10) 0.0045(10)

C1 0.0197(14) 0.0181(14) 0.0165(14) -0.0064(12) -0.0036(11) 0.0010(11)

C2 0.0192(14) 0.0153(14) 0.0171(14) -0.0039(12) -0.0039(11) 0.0008(11)

C3 0.0174(14) 0.0154(14) 0.0164(14) -0.0039(12) -0.0031(11) 0.0013(11)

209

C4 0.0145(13) 0.0172(14) 0.0226(15) -0.0069(12) -0.0037(11) 0.0018(11)

C5 0.0190(14) 0.0232(15) 0.0223(15) -0.0059(13) -0.0096(12) -0.0007(11)

C6 0.0266(15) 0.0206(15) 0.0152(14) -0.0057(12) -0.0051(12) -0.0027(12)

C7 0.0205(14) 0.0171(14) 0.0167(14) -0.0044(12) -0.0050(12) 0.0015(11)

C8 0.0183(14) 0.0152(14) 0.0173(14) -0.0039(12) -0.0042(11) 0.0012(11)

C9 0.0149(14) 0.0300(16) 0.0159(14) -0.0103(13) -0.0003(11) -0.0021(11)

C10 0.0255(15) 0.0286(16) 0.0221(16) -0.0104(13) -0.0063(13) -0.0001(12)

C11 0.0236(16) 0.0408(19) 0.0247(16) -0.0065(15) -0.0109(13) 0.0024(13)

C12 0.0382(18) 0.045(2) 0.0225(16) -0.0093(15) -0.0147(14) -0.0080(15)

C13 0.0353(18) 0.0383(18) 0.0271(17) -0.0161(15) -0.0071(14) -0.0089(14)

C14 0.0230(15) 0.0297(16) 0.0272(16) -0.0096(14) -0.0082(13) -0.0006(12)

C15 0.0167(14) 0.0242(15) 0.0147(14) -0.0081(12) -0.0055(11) 0.0023(11)

C16 0.0211(15) 0.0215(15) 0.0239(16) -0.0037(13) -0.0023(12) -0.0032(12)

C17 0.0301(16) 0.0263(16) 0.0348(18) -0.0173(15) -0.0100(14) 0.0071(13)

C18 0.0184(15) 0.0442(19) 0.0272(17) -0.0223(15) -0.0053(13) 0.0049(13)

C19 0.0224(16) 0.0302(17) 0.0200(16) -0.0008(13) -0.0044(13) -0.0009(13)

C20 0.0198(15) 0.0221(15) 0.0290(17) -0.0081(13) -0.0062(13) 0.0025(12)

C21 0.0386(18) 0.050(2) 0.0328(18) -0.0249(16) -0.0179(15) 0.0031(15)

C22 0.0233(15) 0.0236(15) 0.0237(15) -0.0125(13) -0.0028(12) 0.0014(12)

C23 0.0207(15) 0.0249(15) 0.0262(16) -0.0118(13) -0.0050(12) 0.0081(12)

C24 0.0148(14) 0.0310(16) 0.0152(14) -0.0061(13) -0.0039(11) 0.0015(12)

C25 0.0233(16) 0.0336(17) 0.0279(16) -0.0113(14) -0.0067(13) -0.0070(13)

210

SELECTED GEOMETRIC PARAMETERS BOND LENGTHS Cl1—C4 1.742 (2) C12—H12 0.9500

O1—C6 1.374 (3) C13—C14 1.378 (4)

O1—C21 1.423 (3) C13—H13 0.9500

N1—C8 1.394 (3) C14—H14 0.9500

N1—C1 1.420 (3) C15—C20 1.379 (4)

N1—C24 1.449 (3) C15—C16 1.391 (4)

N2—C24 1.267 (3) C16—C17 1.378 (4)

N2—C23 1.457 (3) C16—H16 0.9500

C1—C2 1.366 (3) C17—C18 1.391 (4)

C1—C9 1.469 (4) C17—H17 0.9500

C2—C3 1.445 (4) C18—C19 1.373 (4)

C2—C15 1.487 (3) C18—H18 0.9500

C3—C4 1.397 (4) C19—C20 1.398 (4)

C3—C8 1.416 (3) C19—H19 0.9500

C4—C5 1.366 (4) C20—H20 0.9500

C5—C6 1.406 (3) C21—H21A 0.9800

C5—H5 0.9500 C21—H21B 0.9800

C6—C7 1.394 (4) C21—H21C 0.9800

C7—C8 1.398 (3) C22—C23 1.521 (4)

C7—C22 1.512 (3) C22—H22A 0.9900

C9—C10 1.387 (4) C22—H22B 0.9900

C9—C14 1.402 (4) C23—H23A 0.9900

C10—C11 1.385 (4) C23—H23B 0.9900

211

C10—H10 0.9500 C24—C25 1.490 (4)

C11—C12 1.379 (4) C25—H25A 0.9800

C11—H11 0.9500 C25—H25B 0.9800

C12—C13 1.389 (4) C25—H25C 0.9800

BOND ANGLES C6—O1—C21 117.7 (2) C9—C14—H14 119.9

C8—N1—C1 108.0 (2) C20—C15—C16 118.5 (2)

C8—N1—C24 121.9 (2) C20—C15—C2 120.2 (2)

C1—N1—C24 124.3 (2) C16—C15—C2 121.3 (2)

C24—N2—C23 118.6 (2) C17—C16—C15 121.1 (2)

C2—C1—N1 109.6 (2) C17—C16—H16 119.5

C2—C1—C9 129.6 (2) C15—C16—H16 119.5

N1—C1—C9 120.4 (2) C16—C17—C18 120.0 (3)

C1—C2—C3 107.0 (2) C16—C17—H17 120.0

C1—C2—C15 125.8 (2) C18—C17—H17 120.0

C3—C2—C15 126.9 (2) C19—C18—C17 119.4 (2)

C4—C3—C8 117.3 (2) C19—C18—H18 120.3

C4—C3—C2 135.0 (2) C17—C18—H18 120.3

C8—C3—C2 107.7 (2) C18—C19—C20 120.3 (3)

C5—C4—C3 121.3 (2) C18—C19—H19 119.9

C5—C4—Cl1 118.5 (2) C20—C19—H19 119.9

C3—C4—Cl1 120.18 (19) C15—C20—C19 120.6 (3)

C4—C5—C6 119.5 (2) C15—C20—H20 119.7

C4—C5—H5 120.3 C19—C20—H20 119.7

C6—C5—H5 120.3 O1—C21—H21A 109.5

212

O1—C6—C7 114.6 (2) O1—C21—H21B 109.5

O1—C6—C5 122.8 (2) H21A—C21— 109.5 H21B

C7—C6—C5 122.6 (2) O1—C21—H21C 109.5

C6—C7—C8 115.7 (2) H21A—C21— 109.5 H21C

C6—C7—C22 120.7 (2) H21B—C21— 109.5 H21C

C8—C7—C22 123.5 (2) C7—C22—C23 111.9 (2)

N1—C8—C7 128.9 (2) C7—C22—H22A 109.2

N1—C8—C3 107.6 (2) C23—C22—H22A 109.2

C7—C8—C3 123.5 (2) C7—C22—H22B 109.2

C10—C9—C14 118.3 (3) C23—C22—H22B 109.2

C10—C9—C1 120.8 (2) H22A—C22— 107.9 H22B

C14—C9—C1 120.8 (2) N2—C23—C22 110.8 (2)

C11—C10—C9 121.1 (3) N2—C23—H23A 109.5

C11—C10—H10 119.5 C22—C23—H23A 109.5

C9—C10—H10 119.5 N2—C23—H23B 109.5

C12—C11—C10 120.4 (3) C22—C23—H23B 109.5

C12—C11—H11 119.8 H23A—C23— 108.1 H23B

C10—C11—H11 119.8 N2—C24—N1 122.6 (2)

C11—C12—C13 119.0 (3) N2—C24—C25 119.6 (2)

C11—C12—H12 120.5 N1—C24—C25 117.5 (2)

C13—C12—H12 120.5 C24—C25—H25A 109.5

213

C14—C13—C12 120.9 (3) C24—C25—H25B 109.5

C14—C13—H13 119.5 H25A—C25— 109.5 H25B

C12—C13—H13 119.5 C24—C25—H25C 109.5

C13—C14—C9 120.2 (3) H25A—C25— 109.5 H25C

C13—C14—H14 119.9 H25B—C25— 109.5 H25C

214