The Synthesis of 2- and 3-Substituted Indoles Tlabo Caiphus Leboho A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirement for the degree of Master of Science. January 2008 Declaration i Declaration I declare that the work presented in this dissertation was carried out exclusively by myself under the supervision of Professors C. B. de Koning and J. P. Michael. It is being submitted for the degree of Master of Science in the University of the Witwatersrand, Johannesburg. It has not been submitted before for any degree or examination in any other University. Tlabo Caiphus Leboho January 2008 Abstract ii Abstract One of the main groups of organic compounds containing nitrogen in both cyclic systems and straight chains is the alkaloids. Indole is perhaps the single most common heterocycle in all of chemistry and it is embodied in a myriad of natural products, pharmaceutical agents and a growing list of polymers. This dissertation presents method for the synthesis of substituted indoles bearing aryl substituents onto the 2- and 3- position as well as 2,3-fused indoles. The route for the synthesis of the aryl substituted indoles starts from the indole nucleus which was protected using the phenylsulfonyl group because it was found that the group is easy to remove and does not require harsh conditions. After successful protection of the indole nucleus NH as N- phenylsulfonyl, bromine was introduced at the 3-position of the indole nucleus while iodine was introduced at the 2-position of the indole nucleus. The bromination of the indole nucleus was not easily achieved because the reaction of molecular bromine with indole resulted in the formation of 2,3-dibromoindole while activated 5-methoxyindole gave an insoluble 2,3,4-tribromoindole. However, this problem was solved by refluxing indole with molecular bromine in the presence of sodium methoxide while activated 5-methoxyindole was refluxed with N-bromosuccinimide in the presence of catalytic benzoyl peroxide. 2-Iodoindoles were synthesized using directed ortho metallation, where isopropyl magnesium chloride was used in the presence of catalytic amount of diisopropylamine. Using standard aqueous Suzuki-Miyaura cross-coupling in the presence of sodium carbonate as a base, 2-aryl, 3-aryl as well as 2,3-diaryl substituted indoles were synthesized in good to excellent yields. The synthesis of 2,3-fused indoles was achieved in poor yields starting from 1-(phenylsulfonyl)indole which was alkylated using allyl bromide at the 2- position and formylated at the 3-position of the indole nucleus to the cyclization of the alcohols using mercury acetate. Acknowledgements iii Acknowledgements I would like to sincerely thank my supervisor and mentor Professor Charles de Koning. This project would have not been a success without his support, guidance, inputs, and most of all, for giving me the opportunity to work with him. Thank you Charles for the wonderful work you have done. To my co-supervisor, Professor J. P. Michael, for all the support you gave me, for his encouragement, for his invaluable advice and inputs, thank you. Dr. Willem van Otterlo, thank you for all the advice and the interest you have shown into my work and for taking some of the samples to biological testing. I would like to thank Professor Laurence Carlton, Richard Mampa for running NMR spectra for me, Sameshnee Govender and Garreth Morgans for running NMR spectra for me when Richard was not around, Tommie van der Merwe, Martin Brits and Dr. Andy Dinsmore for mass spectra that you run for me. To the organic group thank you for the enjoyable working environment you created and the advice. Winston, Thato, Siyanda, Susan, Garreth, Stefania, Jeremy, Warren, Jenny-Lee, Darren and Lee, thank you guys for the inputs and advice you shared with me. Dr. Simon Moleele and Dr. Stephen Pelly, thank you very much for the guidance and advice as well as your patience during the early days of my project, your help is appreciated. A big thank you to the reliable men in the store of the School of Chemistry, Elias Valoyi and David Moloto, Amanda Morgan thank you for ordering the chemicals required for my research, and the entire Administration of the School of Chemistry, thank you. A special thank you to NRF for their financial support. A warm appreciation to my entire family: My brother Matee Lebogo, my dear mother Mosibudi Lebogo, my father Ngoako Lebogo and all brothers and sisters, thank you for understanding and the support you have shown. Montshepet?a bo?ego, ke mo leboga bosele. Moya mahlong a tau, o ya a swere serumula. You taught me these. List of Abbreviations iv List of Abbreviations AcOH acetic acid Ar aromatic Bi(OTf)3 bismuth(III) triflate Boc2O di-tert-butyl dicarbonate (Boc anhydride) BuLi n-butyllithium DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxide DNA deoxyribonucleic acid DOM directed ortho metallation E+ electrophile EtOAc ethyl acetate EtOH ethanol GI50 growth inhibition h hour hv light IC50 inhibition concentration KOtBu potassium tert-butoxide LD50 lethal dose LDA lithium diisopropylamine M molar Me methyl MeOH methanol List of Abbreviations v Me3SnCl trimethyltin chloride min minutes NaOMe sodium methoxide NMR nuclear magnetic resonance OMe methoxy OTf trifluoromethanesulfonate (triflate) Ph phenyl PhSO2Cl phenylsulfonyl chloride psi pounds per square inch rt room temperature TBAB tetrabutylammonium bromide TBAF tetrabutylammonium fluoride THF tetrahydrofuran TsCl p-toluenesulfonyl chloride (tosyl chloride) Table of Contents vi Table of Contents Declaration...................................................................................................................................... i Abstract.......................................................................................................................................... ii Acknowledgements ...................................................................................................................... iii List of Abbreviations ................................................................................................................... iv Table of Contents ......................................................................................................................... vi Chapter 1: Introduction ............................................................................................................... 1 1.1 Alkaloids ............................................................................................................................... 1 1.2 Indole: Discovery, Synthesis and Reactivity......................................................................... 4 1.3 2-Substituted Indoles: Synthesis and Biological Importance................................................ 8 1.3.1 Synthesis......................................................................................................................... 8 1.3.2 Biological importance................................................................................................... 12 1.4 3-Substituted Indoles: Synthesis and Their Biological Importance .................................... 14 1.4.1 Synthesis....................................................................................................................... 14 1.4.2 Biological Importance .................................................................................................. 21 1.5 2- and 3-Disubstituted Indoles: Synthesis and Biological Importance ............................... 23 1.5.1 Synthesis....................................................................................................................... 23 1.5.2 Biological Importance .................................................................................................. 26 1.6 Fused indoles: Synthesis and Biological Importance of Carbazoles................................... 28 1.6.1 Synthesis....................................................................................................................... 28 1.6.2 Biological Importance .................................................................................................. 32 1.7 Aims of the Project.............................................................................................................. 34 Chapter 2: Results and Discussion ............................................................................................ 36 2.1 Protection and halogenations of indole nucleus.................................................................. 36 Table of Contents vii 2.1.1 Synthesis of 1-(phenylsulfonyl)-1H-indole (23) and 5-methoxy-1-(phenylsulfonyl)- 1H-indole (104) ..................................................................................................................... 36 2.1.2 Synthesis of 2-iodo-1-(phenylsulfonyl)-1H-indole (105) and 2-iodo-5-methoxy-1- (phenylsulfonyl)-1H-indole (106) ......................................................................................... 38 2.1.3 Synthesis of 3-bromo-1-(phenylsulfonyl)-1H-indole (107) ......................................... 39 2.1.4 Synthesis of 2,3-dibromo-1-(phenylsulfonyl)-1H-indole (108) ................................... 40 2.1.5 Synthesis of 3-bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole (109)....................... 42 2.2 Synthesis of 2-arylindoles and 3-arylindoles ...................................................................... 43 2.2.1 Synthesis of boronic acids ............................................................................................ 43 2.2.2 Suzuki-Miyaura cross-coupling of iodoindoles (105) and (106) followed by deprotection ........................................................................................................................... 45 2.2.3 Suzuki-Miyaura cross-coupling of bromoindoles (107) and (109) followed by deprotection ........................................................................................................................... 50 2.2.4 Suzuki-Miyaura cross-coupling of dibromoindole (108) followed by deprotection.... 58 2.3 Synthesis of 2-arylindoles via one-pot synthesis ................................................................ 60 2.3.1 Synthesis of 2-(4-bromo-2,5-dimethoxyphenyl)-1-(phenylsulfonyl)-1H-indole (164) and 2-(4-bromo-2,5-dimethoxyphenyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole (165) followed by deprotection ....................................................................................................... 60 2.4 Synthesis of indolopyrans ................................................................................................... 63 2.4.1 Synthesis of 2-allyl-1-(phenylsulfonyl)-1H-indole (169) and 2-Allyl-1- (phenylsulfonyl)-1H-indole-3-carbaldehyde (171) ............................................................... 64 2.4.2 Synthesis of (2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl) methanol (172) .................... 66 2.4.3 Synthesis of 1-(2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl)ethanol (173)..................... 67 2.4.4 Synthesis of 3-methyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (174) and 1,3-dimethyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (175)............. 68 Chapter 3: Conclusion and Future Work................................................................................. 72 Chapter 4: Experimental Procedures ....................................................................................... 79 4.0 General Experimental Procedures ....................................................................................... 79 Table of Contents viii 4.0.1 Purification of Solvents and Reagents.......................................................................... 79 4.0.2 Chromatographic Separations....................................................................................... 79 4.0.3 Spectroscopic and Physical Data.................................................................................. 79 4.1 Protection of the indole nucleus .......................................................................................... 81 4.1.1 1-(Phenylsulfonyl)-1H-indole (36)............................................................................... 81 4.1.2 1-(Phenylsulfonyl)-5-methoxy-1H-indole (104) .......................................................... 81 4.2 Iodination of indoles (36) and (104) ................................................................................... 82 4.2.1 2-Iodo-1-(phenylsulfonyl)-1H-indole (105) ................................................................. 82 4.2.2 2-Iodo-5-methoxy-1-(phenylsulfonyl)-1H-indole (106) .............................................. 83 4.3 Bromination of indoles (36) and (104)................................................................................ 84 4.3.1 3-Bromo-1-(phenylsulfonyl)-1H-indole (107) ............................................................. 84 4.3.2 2,3-Dibromo-1-(phenylsulfonyl)-1H-indole (108) ....................................................... 85 4.3.3 3-Bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole (109)........................................... 85 4.4 Typical procedure for the synthesis of 2-aryl-1-(phenylsulfonyl)-1H-indole and 2-aryl-5- methoxy-1-(phenylsulfonyl)-1H-indole .................................................................................... 86 (a) 2-Phenyl-1-(phenylsulfonyl)-1H-indole (119)................................................................. 87 (b) 5-Methoxy-2-phenyl-1-(phenylsulfonyl)-1H-indole (120).............................................. 87 (c) 1-(Phenylsulfonyl)-2-o-tolyl-1H-indole (121) ................................................................. 88 (d) 5-Methoxy-1-(phenylsulfonyl)-2-o-tolyl-1H-indole (122) .............................................. 88 (e) 1-(Phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-indole (123) ................................... 89 (f) 5-Methoxy-1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-indole (124)................. 90 (g) 2-(4-Methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (125) ............................................ 90 (h) 5-Methoxy-2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (126).......................... 91 (i) 2-(Naphthalen-1-yl)-1-(phenylsulfonyl)-1H-indole (127)................................................ 92 4.5 Typical procedure for removing of phenylsulfonyl protecting group on 2-aryl-1- (phenylsulfonyl)-1H-indoles and 2-aryl-5-methoxy-1-(phenylsulfonyl)-1H-indoles............... 92 Table of Contents ix (a) 2-Phenyl-1-H-indole (128)............................................................................................... 93 (b) 5-Methoxy-2-phenyl-1H-indole (129) ............................................................................. 93 (c) 2-o-Tolyl-1H-indole (130) ............................................................................................... 94 (d) 5-methoxy-2-o-tolyl-1H-indole (131).............................................................................. 94 (e) 2-(3,4,5-Trimethoxyphenyl)-1H-indole (132) ................................................................. 95 (f) 5-Methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indole (133) ................................................ 95 (g) 2-(4-Methoxyphenyl)-1H-indole (134)............................................................................ 96 (h) 5-Methoxy-2-(4-methoxyphenyl)-1H-indole (135) ......................................................... 96 (i) 2-(Naphthalen-1-yl)-1H-indole (136) ............................................................................... 97 (j) 2-(4-Bromo-2,5-dimethoxyphenyl)-1H-indole (166) ....................................................... 98 (k) 2-(4-Bromo-2,5-dimethoxyphenyl)-5-methoxy-1H-indole (167).................................... 98 4.6 General procedure for the synthesis of 3-aryl-1-(phenylsulfonyl)indole and 3-aryl-5- methoxy-1-(phenylsulfonyl)indole............................................................................................ 99 (a) 3-Phenyl-1-(phenylsulfonyl)-1H-indole (137)................................................................. 99 (c) 3-ortho-Tolyl-1-(phenylsulfonyl)-1H-indole (139) ....................................................... 101 (d) 5-Methoxy-1-(phenylsulfonyl)-3-o-tolyl-1H-indole (140) ............................................ 101 (e) 1-(Phenylsulfonyl)-3-(3,4,5-trimethoxyphenyl)-1H-indole (141) ................................. 102 (f) 5-Methoxy-1-(phenylsulfonyl)-3-(3,4,5-trimethoxyphenyl)-1H-indole (142)............... 103 (g) 3-(4-Methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (143) .......................................... 103 (h) 5-Methoxy-3-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (144)........................ 104 (i) 3-(2-Formylphenyl)-1-(phenylsulfonyl)-1H-indole (145) .............................................. 105 (j) 2-(5-Methoxy-1-(phenylsulfonyl)-1H-indol-3-yl)benzaldehyde (146) .......................... 105 (k) 1-(2-(1-(Phenylsulfonyl)-1H-indol-3-yl) acetophenone (147) ...................................... 106 (l) 1-(2-(5-Methoxy-1-(phenylsulfonyl)-1H-indol-3-yl) acetophenone (148) .................... 107 4.7 Typical procedure for removing of phenylsulfonyl protecting group on 3-aryl-1- (phenylsulfonyl)-1H-indoles and 3-aryl-5-methoxy-1-(phenylsulfonyl)-1H-indoles............. 107 Table of Contents x (a) 3-Phenyl-1H indole (149) .............................................................................................. 108 (b) 5-Methoxy-3-phenyl-1H-indole (150) ........................................................................... 108 (c) 3-ortho-Tolyl-1H-indole (151)....................................................................................... 109 (d) 5-Methoxy-3-o-tolyl-1H-indole (152) ........................................................................... 109 (e) 3-(3,4,5-Trimethoxyphenyl)-1H-indole (153) ............................................................... 110 (f) 5-Methoxy-3-(3,4,5-trimethoxyphenyl)-1H-indole (154) .............................................. 110 (g) 3-(4-Methoxyphenyl)-1H-indole (155).......................................................................... 111 (h) 5-Methoxy-3-(4-methoxyphenyl)-1H-indole (156) ....................................................... 111 (i) 3-(2-Formylphenyl)-1H-indole (157) ............................................................................. 112 (j) 2-(5-Methoxy-1H-indol-3-yl)benzaldehyde (158) ......................................................... 113 (k) 1-(2-(1H-indol-3-yl) acetophenone (159) ...................................................................... 113 (l) 1-(2-(5-Methoxy-1H-indol-3-yl) acetophenone (160).................................................... 114 4.8 Synthesis of 2,3-Diphenyl-1-(phenylsulfonyl)-1H-indole (161) ...................................... 114 4.9 Synthesis of 2,3-Diphenyl-1H indole (162) ...................................................................... 115 4.10 Synthesis of a novel class compounds ............................................................................ 116 4.10.1 Synthesis of 2-arylindoles via one-pot synthesis...................................................... 116 4.10.1.1 2-(4-Bromo-2,5-dimethoxyphenyl)-1-(phenylsulfonyl)-1-H-indole (164)........ 116 4.10.1.2 2-(4-Bromo-2,5-dimethoxyphenyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole (165) ................................................................................................................................. 117 4.10.2 Synthesis of indolo-fused pyrans.............................................................................. 118 4.10.2.1 2-Allyl-1-(phenylsulfonyl)-1H-indole (169) ..................................................... 118 4.10.2.2 2-Allyl-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (171) ........................... 119 4.10.2.3 (2-Allyl-1-(phenylsulfonyl)-1H-indol-3-yl) methanol (172) ............................. 119 4.10.2.4 1-(2-Allyl-1-(phenylsulfonyl)-1H-indol-3-yl)ethanol (173).............................. 120 4.10.2.5 3-Methyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (174) ..... 121 Table of Contents xi 4.10.2.6 1,3-Dimethyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (175)122 References .................................................................................................................................. 124 Appendix.................................................................................................................................... 129 Appendix 1: Selected 1H and 13C NMR spectra...................................................................... 129 Chapter 1 Introduction 1 Chapter 1: Introduction 1.1 Alkaloids One of the main groups of organic compounds containing nitrogen in both cyclic systems and straight chains is the alkaloids. Alkaloids are nitrogenous bases which occur naturally in plants and other living organisms. They nearly always contain their nitrogen as part of a heterocyclic system with few exceptions and are often complex in structure; however there is no very sharp distinction between alkaloids and many other naturally occurring nitrogenous compounds. In addition, the alkaloids usually show specific pharmacological activity1. As in the case of other classes of natural products, no uniform system of nomenclature has so far been devised for alkaloids. The name of the alkaloid in most cases is derived from the plant or organism name, usually the systematic name. Alkaloids, with few exceptions, are weak bases that usually occur in plants as salts of the inorganic or organic acids. The crude alkaloid salt is often separated from the powdered plant material by extraction with water, dilute acid or alcohol. Some material may be neutralized with alkali and the organic bases extracted with organic solvent. The crude mixture is often purified by fractional distillation of sparingly soluble salts such as hydrohalide, sulfate, oxalate, perchlorate, nitrate and others2. In ?working up? the plant material for the isolation of alkaloids, various extraction and concentration steps have to be carried out during which solvents, acids, and bases are brought into contact with the crude plant material3. It is believed that plants, animals and microorganisms produce alkaloids for specific purposes. Many alkaloids show biological activity. For example, some alkaloids show antifungal activity such as aporphine alkaloid, liriodenine (1), which displays a broad activity spectrum against fungi such as the yeast Candila albicans, Trichophyton mentagrophytes, and has high activity against phytopathogenic fungi, this provides a plausible reason for the synthesis of the compound Chapter 1 Introduction 2 in terms of the plant?s survival strategy. (?)-Senecionine (2) (Figure 1), a pyrrolizidine alkaloid can be regarded as a feeding deterrent where it is taken in by herbivores from plants and safely stored in the body as N-oxides which are nontoxic and rapidly transformed into toxic form when required4. N O O O N O O H O O HO 1 Liriodenine 2 (?)-Senecionine Figure 1 Some alkaloids have remarkable structural similarities to neurotransmitters in the central nervous system of humans. Examples include dopamine (3), serotonin (4) and acetylcholine (5) (Figure 2). The amazing effect of these alkaloids on humans has led to the development of powerful medications and ?spiritual? drugs5. NH2HO HO 3 dopamine NH2 N H HO 4 serotonin O N+ O 5 acetylcholine Figure 2 Chapter 1 Introduction 3 Alkaloids also form the basis of many drugs which are useful in treating diseases and pain, while other drugs such as cocaine, heroin and morphine can be harmful if abused but are believed to be helpful medicines6. Among the alkaloids in Figure 2, only (4) is an indole derivative. There are over 1200 naturally occurring indole alkaloids and many of them have biological applications7. Some of the known naturally occurring indoles include, as mentioned above, serotonin (4) a monoamine neurotransmitter synthesized in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract8, tryptophan (6) which is an essential amino acid7, and reserpine (7), a more complicated derivative which is used for the treatment of high blood pressure, as well as being a tranquilliser9 (Figure 3). N H N H H H H3CO2C OCH3 O O 7 reserpine OMe OMeMeO NH2 N H O OH 6 tryptophan Figure 3 Many reviews have been written on indole and its derivatives10, 11. Indole is perhaps the single most common heterocyclic system in all of chemistry. It is embodied in a myriad of natural products, pharmaceutical agents and a growing list of polymers. In addition to the hundreds of well-known indole plant alkaloids, the indole ring is present in an array of other structures. The central importance of the indole derivatives in living organisms has inspired chemists to design and synthesize indole-containing compounds12, 13, 14. The following sections cover some of these aspects. Chapter 1 Introduction 4 1.2 Indole: Discovery, Synthesis and Reactivity Indole is a benzopyrrole in which the benzene and pyrrole rings are fused through the 2-and 3- positions of the pyrrole nucleus. The indole ring is also found in many natural products such as the indole alkaloids, fungal metabolites and marine natural products15. The first preparation of indole dates from 1866 but the Fisher indole synthesis, which remains one of the most versatile methods for preparing indoles, was first reported in 188316. The principal commercial source of indole is extraction from coal tar, although the feasibility of industrial synthesis from starting materials such as aniline, ethylene glycol and others has also been demonstrated16. Indole (9) itself was first obtained by Adolf Baeyer by pyrolysis of oxindole (8) with zinc dust in 1886. Oxindole (8) was obtained from the reduction of isatin (10) which was obtained from oxidizing the natural insoluble dark blue dye called indigo (11) (Scheme 1)17. N H H N O O N H O O N H O N H Oxidation R eduction Pyrolysis 1110 8 9 1 2 345 6 7 Scheme 1 Chapter 1 Introduction 5 Although the main source of indole is extraction from coal tar, many researchers have reported synthetic methods for the preparation of various substituted indoles from readily available starting materials owing to their importance in natural products synthesis and pharmaceutical chemistry. One of the most widely used methods as mentioned previously is the Fischer indole synthesis. This method involves heating phenylhydrazine (12) with aldehyde or ketone (13) in acetic acid, forming phenylhydrazone (14) which subsequently rearranges with the loss of ammonia to give indole or 2- and 3-substituted indoles (9 and 15) as outlined in Scheme 2. N H NH2 12 13 14 9 R = R1 = H 15 R = R1 = alkyl, aryl ZnCl2 170 oC O R R1 HN N R R1 N H R1 R Scheme 2 Other methods include the Grandberg synthesis, Reissert synthesis, Leimgruber-Batcho synthesis, Madelung synthesis and Bischler synthesis to name a few. Both the Reissert and Leimgruber-Batcho syntheses depend on the acidity of methyl group ortho to an aromatic nitro group while Madelung synthesis proceeds via a Wittig-type reaction18. The Reissert synthesis is suitable for the preparation of 2-substituted indoles. For example, when 1-methyl-2-nitrobenzene (16) is treated with dimethyl oxalate (17) in the presence of sodium methoxide as a base it gave methyl 3-(2-nitrophenyl)-2-oxopropanoate (18), which upon catalytic hydrogenation (H2, Pd-C) reduced the nitro group to an amino group followed by a spontaneous cyclodehydration to give indole-2-carboxylic acid methyl ester (19) (Scheme 3)19. Chapter 1 Introduction 6 NO2 O COOMe NO2 NH COOMeNaOMe OMeO O OMe 16 17 18 19 H2, Pd-C -3H2O Scheme 3 On the other hand, the Leimgruber-Batcho synthesis is particularly suitable for the synthesis of indoles with substituents on the benzene ring but is unsubstituted on the pyrrole moiety. In this method, substituted 1-methyl-2-nitrobenzene (20) is treated with N,N-dimethylformamide dimethyl acetal (21) to give substituted 1-dimethylamino-2-(o-nitrophenyl)ethene (22), which on reductive cyclization yielded substituted indole (23) (Scheme 4). Madelung synthesis (not illustrated) is essentially confined to the preparation of 2-alkylindoles due to the vigorous reaction conditions, while Bischler synthesis (not illustrated) is particularly suitable for 2-and 3- disubstituted indoles19. R NO2 N OMe MeO R NO2 N N H RH2, Pd-C 20 21 22 23 Scheme 4 Up until now the methods discussed in the synthesis of indole have nitrogen atom bonded directly to an arene. Only a few indole syntheses make use of building blocks in which the nitrogen atom is not directly bonded an arene. The Nenitzescu synthesis is an example of this Chapter 1 Introduction 7 type. In this synthesis, 1,4-quinone (24) is condensed with (E)-methyl 3-aminobut-2-enoate (25) by a Michael addition to give (E)-methyl 3-amino-2-(2,5-dihydroxyphenyl)but-2-enoate (26). When (26) was subjected to oxidation, it gave (E)-methyl 3-amino-2-(3,6-dioxocyclohexa-1,4- dienyl)but-2-enoate (27) which was followed by a cyclodehydration to give methyl 2-methyl-5- oxo-5H-indole-3-carboxylate (28) and the reduction of (28) furnished 2,3-disubstituted indole, methyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate (29) (Scheme 5)19. This method provides a rapid means of preparing functionalized 5-hydroxyindoles from simple, readily accessible starting materials10, and the hydroxyl group can also be introduced onto the indole nucleus20. H2N COOMe H O O + OH HO COOMe NH2 O O COOMe NH2 N O COOMe N H HO COOMe oxidation -2H -H2O reduction +2H 24 25 26 27 2829 Scheme 5 Indole undergoes electrophilic substitution mainly on position 3 of the nucleus when the hydrogen on the indole nitrogen atom is substituted or when a strong magnesium base is used. This is because indole nitrogen is the most reactive towards reactions with electrophiles followed by position 3 of the indole nucleus. When both positions 1 and 3 of the indole nucleus are occupied by substituents other than hydrogen, position 2 is the most reactive one and when position 2 is occupied the electrophile occupies a position on the benzene ring21. Chapter 1 Introduction 8 N R E+ N R E+ N R N R E E 3-substituted indoles 2-sustituted indoles Reactivity of indole 1.3 2-Substituted Indoles: Synthesis and Biological Importance 1.3.1 Synthesis The synthesis of indoles is currently the object of wide investigations owing to their central role as useful building blocks in the synthesis of alkaloids and in the design of therapeutic agents and this would include the topic of this section, 2-substituted indoles. Some general methods for preparing 2-substituted indoles were discussed in the preceding section, but several more specific methods are described below. As the 2-alkynylphenylamine derivatives (30) are easily available by established synthetic procedures, the syntheses of 2-substituted indoles with these compounds as starting materials are some of the most useful procedures. Both base-promoted and electrophilic cyclization reactions of (30) to furnish 2-substituted indoles have been developed. For example, when (30) was treated with gold salts such as sodium chloroaurate (NaAuCl4) as a catalyst, it yielded 2-substituted indoles (31) in reasonable yields. This procedure is compatible with a variety of functional Chapter 1 Introduction 9 groups on the benzene ring of (30) as illustrated in Scheme 6, where the R group can be hydrogen, alkyl, aryl or a variety of substituted aryls22. Cl Cl N H R NaAuCl4.2H2O EtOH, rt, 65-83%30 31 Cl Cl R NH2 Scheme 6 2-Substituted indoles can also be synthesized by the previously discussed methods for indole synthesis. Fischer indole synthesis methodology can be generally employed. For example, treating acetophenone (32) with phenylhydrazine (12) in the presence of acetic acid in ethanol at 80 ?C as illustrated in Scheme 7 gave 2-phenylindole (33) in good yield23. O + HN NH2 N H AcOH EtOH, 80 oC. 80-90% 32 12 33 Scheme 7 Indole can also be halogenated at the 2-position but this has proved to be a difficult reaction if 3- position is not substituted. Powers reported the synthesis of 2-haloindoles (34 and 35) with phosphorus oxyhalides through a Vilsmeyer salt. This was performed using oxindole (8) as a source of the indole moiety but these compounds have limited stability as they cannot be stored for long without decomposing24, 90. Chapter 1 Introduction 10 N H O POCl3 POBr3N H Cl N H Br 834 35 Scheme 8 There is other methodology for introducing substituents at the 2-position of indole. This methodology employs the ortho-metallation of N-protected indoles. The most commonly used N- protecting groups are phenylsufonyl (PhSO2), p-toluenesulfonyl (4-MeC6H4SO2 or Ts) and tert- butoxycarbonyl (Boc). The N-protecting groups like these are required to effect metal stabilization at the 2-postion of the indole nucleus by lone pair donating properties of the ?protecting? group to allow for what is called directed ortho metallation (DOM). For instance, when 1-phenylsulfonylindole (36) is treated with a strong base like lithium diisopropylamide (LDA) at low temperatures, it gives a regioselective 2-lithiation product (37) which can be quenched with various electrophiles including halogen sources to afford 2-substituted indoles (38)25 (Scheme 9). N H N S O O N S O O N S O O NaOH TBAF PhSO2Cl 9 36 37 38 LDA Li EE + Scheme 9 Chapter 1 Introduction 11 When the electrophile is a halogen as in (35), this can also allow C-C bond formation through the now well-developed catalytic cross-coupling reactions. Most frequently, palladium cross- coupling reactions are used for the formation of C-C bonds. One of the most commonly used methods is the Suzuki-Miyaura cross-coupling reaction which employs palladium(0) under basic conditions, usually with aryl or heteroaryl boronic acids or esters to effect C-C bond formation26. Apart from the regioselective lithiation of N-protected indoles at the 2-position with strong bases such as LDA, the hydrogen at the 2-position of (36) can also be replaced by magnesium metal. Kondo et al. devised a methodology of replacing the hydrogen at the 2-position of (36) with magnesium using magnesium amide bases. When hydrogen is replaced by magnesium in (36), it acts much like lithiated (37) but this reaction can be achieved at room temperature while lithiation is achieved at lower temperatures due to the instability of lithiating reagents27. This methodology was modified by using Grignard reagents in the presence of a catalytic amount of amines instead of using magnesium amide bases and this showed improved yields28. The direct C-arylation of free (NH) indole holds a significant synthetic potential as it eliminates the need for introducing the protecting groups and reactive functionalities prior to C-C formation, thereby enabling direct access to valuable heteroaromatic compounds29. 2-Arylindoles in particular are important structures that serve as key components of variety of biologically active molecules. Many traditional approaches to these compounds have involved cross-coupling between 2-functionalized indole and functionalized arene derivative, a strategy that often requires more than one step. Recently, methodology has been developed to affect C-2 arylation of indoles without protecting the NH group or the requirement of the introduction of a halogen or boronic acid. For instance, treating (9) with phenyliodonium tetrafluoroborate (Ph2I+BF4-) in the presence of 1,3-bis(2,4,6-trimethylphenyl)imidazo-2-ylidene palladium acetate (IMesPd(OAc)2) as a catalyst afforded (33) in good yield at room temperature and this methodology is compatible with a diverse selection of electron-donating and electron-withdrawing substituents on indoles without competing N-arylation or other undesirable side reactions30. Chapter 1 Introduction 12 N H [Ph-I-Ph]BF4 IMesPd(OAc)2 AcOH, rt, 81% N H9 33 Scheme 10 1.3.2 Biological importance 2-Substituted indoles can have complex structures and interesting biological activities, but not all compounds having the indole skeleton have biological importance. For example, compound (39) and compound (40) both possessing a substituents at the 2-position of the indole nucleus were both tested for in vitro cytotoxic effects as well as in vivo cytotoxic effects. They were used on human melanoma cell line A2058 using an MTS cell proliferation assay. Compound (39) showed a mean GI50 value of 0.38 ?M while compound (40) showed a mean GI50 value of 0.182 ?M, indicating that these compounds have the potential for use as highly potent broad-spectrum anticancer compounds to inhibit the growth of a variety cancer cell lines31. When compounds (39) and (40) were tested for in vivo cytotoxic effects, they both showed intraperitoneal (ip) plus subcutaneous (sc) scores of larger than 20. If ip plus sc scores are larger than 20, the compounds are considered to be active and have potential as an antitumour or anticancer drug candidates. The in vivo test results showed that compounds (39) and (40) had total scores of 22 and 30 respectively. Another example is compound (41), again a 2-substituted indole, and this was tested for the inhibition of the cleavage activity of restriction endonuclease BamHI. The experimental results showed that compound (41) inhibits BamHI digestion and this is because it can bind to the DNA more efficiently31. Chapter 1 Introduction 13 N H O O OMe N N O H N H O MeO N N O H 39 40 41 N H MeO N N O O Figure 4 In another example, evaluation of the growth-inhibitory properties of the novel quinol (42) shown in Figure 5 was undertaken in two human colon cancer cell lines (HCT 116 and HT 29). The valuation results show that 4-(1-phenylsulfonyl-1H-6-fluoroindol-2-yl)-4- hydroxycyclohexa-2,5-dienone (42) was the most potent against the cell lines with the mean GI50 value of 16 nM and mean LC50 value of 2.2 ?M32. Finally in this section, compound (43) was examined for in vitro inhibitory effects towards the lipid peroxidation induced by free radicals in a rat brain homogenate and their scavenging activity towards DPPH (1,1-diphenyl-2- picrylhydrazyl) radicals and it showed antioxidative activity33 while bis(1H-2- indolyl)methanone (44) caused a strong inhibition of PDGF receptor activity with IC50 value of 1 ?M34. Chapter 1 Introduction 14 N S O O OH O N H OHHO 42 43 N H NH O 44 Figure 5 1.4 3-Substituted Indoles: Synthesis and Their Biological Importance 1.4.1 Synthesis As stated earlier in this dissertation, indole undergoes electrophilic substitution mainly on position 3 when the indole nitrogen is protected. The widespread natural occurrence and importance of indoles has stimulated the continuing development of new methods for their preparation. There are attractive reactions but only few directly produce indoles by annulation of commercially available N-aromatic precursors, as in the Fischer-indole synthesis. However, despite recently developed methodologies, the classical Fischer indole synthesis remains one of the most important approaches to 3-substituted indoles. In the traditional Fischer indole synthesis, the required hydrazone is generated via the condensation of the corresponding carbonyl compound with a hydrazine derivative. Chapter 1 Introduction 15 The desire for broad substrate scope, more accessible starting materials, improved regioselectivity, milder reaction conditions, and functional group tolerance has also spawned several transition metal-promoted route to indoles, most of which are intramolecular reactions that require a substituted N-aromatic precursor. When ntirosobenzene (45) and phenylacetylene (46) were heated together in the presence of [CpRu(CO)2]2 as a catalyst with carbon monoxide in benzene, at 170 oC and 750 psi, it produced regioselectively the 3-substituted indole, 3- phenylindole (47), in good yields and some small traces of aniline and azoxybenzene (48) but no trace of 2-phenylindole was detected35. NO + [CpRu(CO)2]2 170 oC, 750 psi benzene, 62% CO N H 45 46 47 N+ O- N + 48 Ph Scheme 11 Recently, Odom and co-workers reported an elegant atom-economical methodology of indole synthesis based on intermolecular titanium amide-catalyzed hydroamination reaction of alkynes with hydrazine derivatives followed by a cyclization employing Zinc chloride (ZnCl2). This methodology uses Fischer indole synthesis strategy, with the formation of a hydrazone intermediate. The method employs the inexpensive Lewis-acid titanium tetrachloride (TiCl4) as a precatalyst and amine like tert-butylamine (tBuNH2) to transform hydrazines and unsymmetrical alkynes into indoles. For example, 1,1-disubstituted hydrazine (49) is treated with unsymmetrical alkyne (50) in the presence of TiCl4 and tBuNH2 to afford 1,3-diubstituted indole (51) as depicted in Scheme 1236. Chapter 1 Introduction 16 N NH2 + N CF3 TiCl4, tBuNH2 Toulene, N2, 105 oC, 55-73% 49 50 51 CF3 Scheme 12 Recently, methodology which employs the inexpensive bismuth(III) trifluoromethanesulfonate (triflate) (Bi(OTf)3 which can be easily prepared on multi-gram scale in the laboratory from bismuth(III) oxide and triflic acid has been used to synthesize 3-substituted indoles. It was found that treating indole (9) with quinone (52) in the presence of Bi(OTf)3 as a catalyst in acetonitrile at room temperature gave exclusively 3-indolyhydroquinones (53 and 54) (Scheme 13).This method is clean and free from chlorinated side products that are usually observed under protic acid conditions and is applicable to both electron-rich and electron-deficient indoles37. N H O O O O 2 eq 2.5 eq N H OH HO N H OH HO H N 9 52 53 54 52 CH3CN, rt CH3CN, rt 2 mol % Bi(OTf)3, 80% 2 mol % Bi(OTf)3, 82% Scheme 13 Chapter 1 Introduction 17 C-Glycosides, wherein a carbon atom replaces the glycosidic oxygen have attracted considerable attention in carbohydrate and biological chemistry owing to their stability towards enzymatic and acidic hydrolysis. Indole C-glycosides are model compounds for the synthesis of nucleosides of 9-deazapurines and are believed to exist in biological systems. Indole C-glycosides are usually synthesized in the presence of Lewis acids such as zinc chloride (ZnCl2), mixture of boron trifluoride and diethyl ether (BF3-Et2O) or trimethylsilyl trifluoromethanesulfonate (TMSOTf) but these usually give unsatisfactory results with low stereoselectivity. Recently, the use of InCl3 to perform such reactions has been evaluated due to its water stability. When indole (9) is treated with acetobromoglucose (55) in the presence of indium trichloride (InCl3) as a catalyst in dichloromethane at room temperature, afforded exclusively 3-substituted-C-glycoside indole (56) in poor yields and high stereoselectivity as outlined in Scheme 1438. N H N H O OAc OAcAcO AcO InCl3 (10 mol%) CH2Cl2, rt, 10% O OH HO OH OH HO Br O acetobromoglucose 9 56 55 Scheme 14 C-Alkylation of indoles is one of the most common methods used to introduce substituents onto the 3-position but this methodology usually gives mixtures of products. The methodology employs metals like zinc and magnesium. Recently organometallic reactions have found a wide application in organic synthesis including C-alkylation of indoles and pyrroles. Organozinc Chapter 1 Introduction 18 reagents are especially owing to their compatibility with other functional groups, stability, reactivity and selectivity; and they also exhibit low nucleophilicity, thus permitting chemoselective transformations of groups with similar reactivity. Here preparation of 3-allylindole (58) through the zinc-mediated Barbier-type reaction is illustrated. Indole (9) was treated with allyl bromide (57) in the presence of zinc in tetrahydrofuran (THF) at room temperature to give 3-allylindole (58) in good yield and high regioselectivity. The methodology can also be used with crotyl, prenyl bromides and substituted indoles39. N H N H Br Zn, THF, rt, 85% 57 9 58 Scheme 15 The development of effective asymmetric entries to indole architecture constitutes an important research field. Some catalytic enantioselective additions of indoles to unsaturated carbonyl compounds, in particular Friedel-Crafts (F-C) alkylations, have been of particular recent interest. A number of highly selective metal-catalyzed F-C reactions of bidentate chelating carbonyls have been developed. Here efficient asymmetric organocatalytic addition of indoles to simple enones is demonstrated, a general and trivial protocol that allows rapid access to a broad range of highly enantioenriched 3 -indolyl derivatives. The method uses iminium ion activation strategy with enone substrates, based on catalytic use of an amine salt in which both the cation and the anion are chiral. Indole (9) was reacted with (E)-4-phenylbut-3-en-2-one (59) in the presence of Chapter 1 Introduction 19 chiral amine catalyst salt (60) to give 4-(1H-indol-3-yl)-4-phenylbutan-2-one (61) in good yield and with >90% ee. This method shows a significant tolerance towards steric and electronic demands of the ? -olefin substituents40 (Scheme 16). Ph O N H Ph O N H + catalytic salt Toluene, 88% + NH +NH3 N OMe N H Boc COO- Ph 2 Catalytic salt 9 59 61 60 Ph N+ Boc CO2- Ph iminium ion Scheme 16 Electrophilic aromatic bromination is one of the older reactions known to organic chemists. Aryl halides are important synthetic intermediates for a variety of transformations that range from formation of functionalized aromatic compounds to aryl organometallic reagents that are used in other reactions. Despite the many halogenation methods available, regioselective reaction of activated aromatic compounds such as 5-methoxyindole still remains a problem. Although bromination of indole gives mostly 3-bromoindole, sometimes it gives mixture of products where bromination can take place on the electron-rich benzene ring. However, there are a handful of selective bromination procedures. For example, the procedure outlined below proved to be selective with high yields. Treatment of indole (9) with n-butyllithium and trimethyltin chloride followed by the addition of bromine at ?78 ?C gave 3-bromoindole (62) with no sign of Chapter 1 Introduction 20 other brominated indole product and this method worked well with activated 5-methoxyindole41 (Scheme 17). N H SnMe3 N H N H Br 1. n-BuLi, THF, -78 oC 2. Me3SnCl, THF, -78 oC 3. Br2, THF, -78 oC 4. aq KF 80% rt 9 62 Scheme 17 The 3-arylindole structure represented is some of the biologically active indole containing compounds. Among the arylated indole compounds, 3-phenylindole is an antimicrobial compound active towards many fungi and Gram-positive bacteria42. 3-Arylated indoles have been prepared by ring closure synthesis or by introducing protecting groups on heterocyclic nitrogen atom and introducing functionalities prior to C-C formation. For example, N-protected 3-bromoindoles allow C-C bond formation through the developed catalytic cross-coupling reactions. One of the most commonly used methods is the Suzuki-Miyaura cross- coupling reaction26. C-3 Arylation of indoles containing an unprotected heterocyclic nitrogen atom is also possible with a highly specific palladium catalyst as illustrated here. When indole (9) was treated with 1-bromo-4-nitrobenzene (63) in the presence of the exotic catalyst (64) abbreviated a POPd, it gave 3-(4-nitrobenzene)indole (65) in good yield and selectivity. Palladium-phosphinous acid complex abbreviated (POPd) (64) has been found to be a superior catalyst in this type of cross-coupling reactions due to its air-stability42 (Scheme 18). Chapter 1 Introduction 21 N H N H NO2 Dioxane, 48% 9 65 Br NO2 Pd ClP P Cl Pd P P O OH O O H 63 64 Scheme 18 1.4.2 Biological Importance Many indoles substituted at C-3 have also been found to be biologically active. Most of the active 3-C substituted indoles were found to be anticancer agents and kinase inhibitors. Many have been synthesized but some are also found in Nature. For example, compound (66) was found to have strong potency against vessel growth in vivo chick embryo assay with 82% inhibition of vessel area after 24 hours incubation by application of 10 ?g per pellet and it was also found to be active against the kinase involved in the angiogenic process resulting in in vivo activity43. Angiogenesis, the formation of new capillaries from preexisting blood vessels, is essential in several physiological situations, including embryo development, female reproductive cycle, and wound healing during which angiogenesis is under strict control. The angiogenic process is regulated by a variety of endogenous molecules including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factors (TGF) and cytokines interleukin IL-2 and Il-845. Chapter 1 Introduction 22 N H H N OO OMe OMe MeO 66 Figure 6 Uptake into the presynaptic neuron is the principal mechanism for the rapid inactivation of released biogenic amines in the neural synapse. The tricyclic antidepressant agents inhibit to a varying extent the uptake of noradrenaline (NA) and 5-hydroxytryptamine (5-HT). Clomipramine was the most selective inhibitor of 5-HT uptake in vitro, but the selectivity was greatly reduced in vivo due to the biotransformation into chlordesipramine, an NA uptake inhibitor. In more detailed in vivo studies, indalpine (67) was shown to be the most potent and the most selective inhibitor of 5-HT and it was found to be the most active 5-hydroxytryptophan (5-HTP) potentiator44. It was found that indole-3-carbinol (68) inhibits the proliferation and tube formation, an in vitro maker of angiogenesis of phorbol myristate acetate (PMA) activated EA hy926 endothelial cells, a potential angiogenesis stimulator and such suppression is associated with decrease in secretion of VEGF and matrix metalloproteinase (MMP-2 and MMP-9)45. Indole-3-carbinol (68) is a naturally occurring anticancer agent and has entered clinical trials for cancer prevention. It (68) is a dietary component found in exclusively in cruciferous vegetables and it is known to suppress proliferation and induce apoptosis of various cancer cells, including breast, ovarian, lung, cervical, colon, prostate and liver. Chapter 1 Introduction 23 Compound (68) was able to selectively inhibit activation of Akt in the tumor-derived MDA-MB- 468 breast and PC-3 prostate cancer cell lines, but not in nontumorigenic human HBL100 breast and CRL2221 prostate epithelial cells46. Adrenaline or noradrenaline are prominent in the cardiovascular system, acting through ?- and ?-adrenergic receptors, which exist as a number of subtypes. The interaction of effects from these receptors is quite complex. Many common drugs are simple carbocyclic analogues of adrenaline but few of the important compounds are heterocyclic. One of them is indoramin (69) which is used for the treatment of hypertension and benign prostatic hypertrophy47. N H H N 67 N H OH 68 69 N H N NHCOPh Figure 1.5 2- and 3-Disubstituted Indoles: Synthesis and Biological Importance 1.5.1 Synthesis 2-and 3-Disubstituted indoles can be synthesized from either 3-substituted indoles by introducing substituents onto the 2-position, from 2-substituted indole by introducing substituents onto the 3- position or by cyclization reactions using starting materials that already bear the substituents that will occupy 2-and 3-positions of the indole nucleus. They can be formed from ?-halogenated or Chapter 1 Introduction 24 ?-hydroxy ketones with arylamines in the presence of halogen acid. For example, treating 2- bromo-1,2-diphenylethanone (70) with aniline gave 1,2-diphenyl-3-(phenylamino)propan-1-one (71). Heating (71) with aniline in the presence of hydrochloric acid for several hours under a nitrogen atmosphere gave 2,3-diphenylindole (72) in excellent yield48. 70 71 72 NH2 HCl, 84% N H Ph PhBr O O H N Scheme 19 The simplest way of building the indole skeleton with substituents at the 2-and 3-postions would be through intermolecular reaction between aminoarene and C2 fragments. The problem is that these types of reaction are usually carried out over a heterogeneous catalyst under very severe reaction conditions and at high temperatures. The ruthenium-catalyzed reactions between aminoarenes and glycols have paved a way for homogeneous transition metal catalysis at reduced reaction temperatures. It has been shown that aniline reacted smoothly with 1- phenylbutane-1,2-diol (73) in the presence of catalytic amount of ruthenium complex with the spontaneous hydrogen evolution to give 2-ethyl-3-phenylindole (74) in good yield49. Chapter 1 Introduction 25 + NH2 N H 73 74 RuCl2(PPh3)3 diglyme, 180 oC, 50% HO HO Scheme 20 Bischler indole synthesis is one the classical indole synthesis methods and it involves the reaction of aniline with ?-haloketones. Its use has been limited by the low accessibility of ?- haloketones. A Bischler-type indole synthesis that would avoid the use of haloketones, thereby making it a halogen-free reaction, has been used for the preparation of 2,3-disubstituted indoles. The reaction is based on the intermolecular addition of anilines to terminal alkynes and is efficiently catalyzed by a commercially available ruthenium carbonyl/additive mixture. As described in the literature, aniline was reacted with pent-1-yn-3-ol (75) in the presence of ruthenium carbonyl as a catalyst and ammonium hexafluorophosphate (NH4PF6) as an additive to give 3-ethyl-2-methylindole (76) in good yield50. NH2 + HO N H 0.36 mol% [Ru3(CO)12] + NH4PF6 140 oC, 7-9h, open air, solventless, 75% 75 76 Scheme 21 Chapter 1 Introduction 26 1.5.2 Biological Importance Indoles substituted at both the 2-and 3-positions are also of biological importance. The biological activities depend on the type of groups in these positions and the substituents can be aromatic, straight chains and non-aromatic rings. Indomethacin (77), a 5-methoxy indole ring which contains an acetic acid moiety at position 3 and a methyl substituent at position 2 has shown biological activities. Position 1 is occupied by 4-chlorobenzoyl group which also contributes to the observed properties. Indomethacin is a potent non-steroidal anti-inflammatory agent used primarily in the treatment of rheumatoid arthritis and has potential for use in uveitis, a common disease responsible for blindness. Indomethacin may also be used in the management of cystoid macular edema (CME), a disease characterized by a build-up of serous fluid in the extracellular space in the retina caused by a disruption of the blood-retinal barrier51. Nonsteroidal anti- inflammatory drugs (NSAIDs) remain among the most widely prescribed drugs worldwide for the treatment of inflammation including pain-releasing, antipyretic and rheumatoid arthritis. The mechanism of action is through their inhibition of prostaglandin biosynthesis via the enzyme cyclooxygenase-2 (COX-2). An example of a synthetic NSAID is 2-phenyl-3- phenylsulfonamide-1H indole (78), which was found to be more potent and selective against COX-2 than COX-152. N OO O Cl 78 N H Ph SO2NH2 77 OH Figure 8 Chapter 1 Introduction 27 Current drugs effective against the HIV-1 reverse transcriptase (RT) are classified according to their structure as nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). NRTIs interfere with the enzyme activity following metabolic activation to the triphosphate forms and incorporation into the growing DNA strand, which causes chain termination. On the other hand, NNRTIs do not require preliminary phosphorylation and are less toxic than NRTIs because they do not affect the activity of cellular polymerases and they give rise to the rapid emergence of drug-resistance strains which are cross-resistance of other inhibitors within the class. 5-Bromo-3-(3,5-dimethylphenylsulfonyl)indole-2-carboxamide (79) was tested against HIV-1 in acutely infected MT-4 cells. It showed to be very potent and selective anti-HIV-1 activity not only on wild type strains, but also against mutants carrying NNRTI-resistance mutations53. Compounds that interfere with the microtubule-tubulin equilibria in cells are useful in the treatment of human disease. [2-(3-Hydroxy-4-methoxyphenyl)-6-methoxy-indol-3-yl](3,4,5- trimethoxyphenyl)methanone (80) was showed good activity as tubulin polymerase inhibitors and was further evaluated for inhibitory effect on the binding of [3H]colchicine to tubulin and cytotoxicity against MCF-7 human breast carcinoma cells. However, (80) was found to be less potent than combretastatin A-4 (CA-4) as an inhibitor of [3H]colchicine binding to tubulin and as cytotoxins against MCF-7 human breast carcinoma cells and its cytotoxicity was less compared to CA-454. Chapter 1 Introduction 28 N H S O O O NH2 Br 79 N H O OMe MeO MeO OMe OH MeO 80 Figure 9 1.6 Fused indoles: Synthesis and Biological Importance of Carbazoles 1.6.1 Synthesis Carbazoles (benzo[b]indole) are natural products of medicinal and biochemical importance55. They display a range of biological activities that make them attractive compounds to synthetic and medicinal chemists. Many methods exist for their preparation in our laboratories. Synthetic methodology has been developed for the synthesis of indolocarbazoles employing a light-and base-assisted cyclization reaction. Starting from N-methyl-2-bromoindole-3-carbaldehyde (81) and treating it with 1,4-dimethoxy-3-methylnaphthalen-2-ylboronic acid (82) under aqueous Suzuki-Miyaura cross-coupling reaction conditions afforded the desired compound (83) in good yield. Compound (83) was then exposed to potassium tert-butoxide and light in 1,2- dimethylformamide (DMF) at 80 ?C to give the naphtho-fused carbazole (84) in fair yield and (84) was further oxidized with ceric(IV) ammonium nitrate (CAN) to afford (85) (Scheme 22)56. Chapter 1 Introduction 29 N Br CHO 81 10 mol% Pd(PPh3)4, DME, /EtOH, 2M aq. Na2CO3, reflux 48h, 60% 82 N CHO OMe MeO N OMe MeO KOtBu, DMF hv, 80 oC, 10 min., 86% N O O CAN, THF, rt, 77% OMe OMe (HO)2B 83 8485 Scheme 22 Many natural occurring compounds such as granulatimide (86) and isogranulatimide (87) isolated from the ascidian Didemnum granulatum (Figure 10) contain a maleimide unit attached to the carbazole. Their biological activity is linked to their capacity to interfere with the G2 checkpoint in cell growth, which represents a promising target for the development of new chemotherapeutic anticancer agents. Chapter 1 Introduction 30 N H N NH H N N H N N H NOO OO 86 87 Figure10 Other related compounds have also been assembled. For example, there is a new family of isogranulatimide analogues in which the imidazole moiety is replaced by a pyrrole heterocycle. In the synthesis of these examples, indole (9) was selectively brominated to give 3-bromoindole (62) which was then reacted with pyrrole (88) at room temperature in the presence of trifluoroacetic acid in dichloromethane which led to 2-(pyrrol-2-yl)indole (89). Reaction of (89) with pyrrole-2,5-dione (90) in the presence of stannous chloride gave the Michael adduct (91) in good yield. When (91) was treated with palladium black in nitrobenzene as a solvent at 200 ?C followed by elimination of the solvent by filtration over silica afforded the isogranulatimide analogue (92) in good yield57. Chapter 1 Introduction 31 N H N H N H Br N H H NO O SnCl2 toulene reflux, 90% N H H N N H O O N H N H N OO 9 62 89 90 9192 Br2, DMF, 83% TFA CH2Cl2, 83% H N 88 Pd black nitrobenzene 200 oC, 89% Scheme 23 A very large number of indole alkaloids belong to a class in which an unrearranged secologanin unit (93) can be recognized in combination with either tryptamine (94) or tryptophan (6). For example, tryptamine (94) was condensed with secologanin (93), catalyzed by the enzyme strictosidine synthetase which controls C-ring closure mechanism, resulting in the formation of strictosidine (95) (Scheme 24)58. Chapter 1 Introduction 32 N H NH2 N H NH O MeO2C OGluc.H H strictosidine synthetase O MeO2C OGluc. HH O 94 93 95 Scheme 24 1.6.2 Biological Importance The indolo[2,3-a]carbazole (96) framework contains an embedded indole unit and is found in many natural products which have a broad range of potent biological activities, such as antifungal, antimicrobial, antitumor, and antihypertensive activity. These carbazoles can be potent inhibitors of protein kinase C59. For example, staurosporine (97) and G? 6976 (98) both contain the indolo[2,3-a]carbazole nucleus. Staurosporine (97) has interesting biological activities including cytotoxic, antimicrobial, inhibition of protein kinase C, and platelet aggregation inhibition. Staurosporine (83) was also found to be one of the best ATP competitive kinase inhibitors with IC50 values in the nanomolar range for the serine kinases, protein kinase C, CDK2, CDK4, and CDK660. G? 6976 (98), a non-glycosidic indolo[2,3-a]carbazole, exhibits selective inhibition of protein kinase C and also acts as an antagonist of human immunodeficiency virus 1 (HIV-1) (Figure 11)59. Chapter 1 Introduction 33 N H N H indolo[2,3-a]carbazole N H N O N O HH MeO staurosporine OMe N H N O N C N G? 6976 96 97 98 Figure 11 Rebeccamycin (99) is an antitumor secondary metabolite isolated from cultures of Saccharothrix aerocolonigenes. Rebeccamycin (99) was found to have significant activity against P388 leukemia, L1210 leukemia and B-16 melanoma implanted in mice and inhibited the growth of human lung adenocarcinoma cells. It was found that (99) produces single-strand breaks in DNA and in a modified form, it is currently being considered for clinical evaluations as a potential treatment for cancer in humans61. On the other hand, fascaplysin (100), a red pigment isolated from the Fijian sponge Fascaplysinopsis Bergquist sp. was reported to inhibit the growth of several microbes including Staphylococcus aureus, Escherichia coli, Candida albicans, Saccharomyces cerevisiae and was also found to suppress proliferation of mouse leukemia cells L-1210 while its analogue, cryptolepine (101) has been demonstrated to efficiently intercalate into DNA and to act as a potent topoisomerase II inhibitor62. Chapter 1 Introduction 34 N H N O O N H Cl Cl OH OH OH NH N+ Rebeccamycin 99 O NH N+ Cl- Cl- Fascaplysin 100 Cryptolepine 101 Figure 12 1.7 Aims of the Project In this MSc project we wished to develop methodology to synthesize 2- and 3-substituted indoles, specifically with aryl substituents at those positions. The first part of the MSc project was to synthesize 2-arylsubstituted indoles using, as a key step, Suzuki reactions and conditions. Alternative methodology to the Suzuki-Miyaura coupling for introducing aryl substituents at C-2 was developed. For the second part of the project we focused on synthesizing 3-aryl substituted indoles with general formula 3-arylindole. In order to place aryl substituents in the 3-position, the method we wished to use was the Suzuki-Miyaura coupling reaction, which requires an aromatic halide as one component and an aromatic boronic acid as the other. Once these 2- arylindoles and 3-arylindoles were synthesized, they would be subjected to a range of biological screens. After we finished synthesizing 2- and 3-arylindoles, we turned our attention to fused indoles. We wished to explore the methodology to synthesize indolo fused pyrans and this was achieved by using mercury acetate as a key reagent for ring closure. Chapter 1 Introduction 35 N H Ar R N H R Ar 2-arylindoles 3-arylindoles N S O O OR1 R indolo fused pyrans Figure 13 Chapter 2 Results and Discussion 36 Chapter 2: Results and Discussion 2.1 Protection and halogenations of the indole nucleus In this section we will outline the synthesis of halogenated 2- and 3-substituted indole precursors. We required these precursors for the introduction of aryl substituents at both of these positions using a variety of different procedures that will be discussed later. However, initially we needed to protect the indole nitrogen such that it can also act as a directed ortho metallation (DOM) group, but this group needed to be readily removed once the required 2- and 3- arylindoles were synthesized. 2.1.1 Synthesis of 1-(phenylsulfonyl)-1H-indole (23) and 5-methoxy-1-(phenylsulfonyl)-1H- indole (104) N S OO RNaOH, TBABCH2Cl2, 100% S O O Cl (9) R = H (102) R = OMe 103 (36) R = H (104) R = OMe N H R Scheme 25 Gribble et al. have described procedures for introducing the phenylsulfonyl group at low temperatures. The method employs air and water sensitive chemicals namely, n-butyllithium at ? Chapter 2 Results and Discussion 37 78 ?C 63. Some of recently developed methodologies involve sodium hydroxide as base which is not sensitive to either air or water and the reaction takes place at 0 ?C to room temperature as compared to ?78 ?C. In this project, commercially available indole (9) or 5-methoxyindole (102) was treated with sodium hydroxide and phenylsulfonyl chloride (103) in the presence of a catalytic amount of tetrabutylammonium bromide to afford 1-(phenylsulfonyl)indole (36) and 5- methoxy-1-(phenylsufonyl)indole (104) in excellent yields of 100%60. Compound (36) was obtained as a cream white solid, with the melting point 75-78 ?C and the literature reported (36) isolated as colourless needles with melting point 76.5-77 ?C 64. The 1H NMR spectra of both compounds showed the disappearance of the NH signal. The 1H NMR spectrum of (36) was also characterized by the appearance of a doublet (J = 7.50) at 7.87 ppm integrating for two hydrogens which belonged to two equivalent hydrogens on the phenylsulfonyl group and other three hydrogens are embedded in the multiplet. This was also evident from the increased number of hydrogens in the aromatic region due to the introduction of the phenylsulfonyl group. The 13C NMR spectrum of (36) showed two peaks at 129.66 and 127.14 ppm each accounting for two equivalent carbons bearing a hydrogen of the phenyl ring of (36). N S OO N S OO MeO 36 104 Figure 14 Compound (104) was isolated as white solid with melting point 96-99 ?C. The literature reported that (104) was isolated as colourless crystals34, 63 with melting point 97-98 ?C34.On the other hand, the 1H NMR of compound (104) also showed two doublets at 7.83 (J = 7.51) and 7.40 (J = Chapter 2 Results and Discussion 38 7.89) ppm each integrating for two hydrogens which belonged to the four hydrogens on the phenylsulfonyl group. The 13C NMR spectrum showed two distinct peaks at 129.61 and 127.06 ppm belonging to the four carbons on the phenylsulfonyl group. 2.1.2 Synthesis of 2-iodo-1-(phenylsulfonyl)-1H-indole (105) and 2-iodo-5-methoxy-1- (phenylsulfonyl)-1H-indole (106) As a next step we needed to use methodology to introduce halogens at the 2-position of the indole nucleus for the proposed Suzuki coupling reaction. (105) R = H (79%) (106) R = OMe (85%)(36) R = H(104) R = OMe MgCl iPr2NH I2, THFN S OO R N S OO R I Scheme 26 Encouraged by the good yields obtained for compounds (36) and (104), we decided to attempt the next step, i.e. iodination at the 2-position of the indole nucleus. The iodination of these compounds proved not to be straight forward. The first method attempted was using lithium diisopropylamine as a base at ?78 ?C as described in the literature65 but this method failed. We attempted numerous methods without success until we tried a method developed in our Chapter 2 Results and Discussion 39 laboratories. The method was mainly used on pyrroles to introduce substituents onto the 2- position28, and is an extension of a procedure by Kondo et al. for introducing substituents at the 2?position of indole using magnesium amide bases27. Both compounds (36) and (104) were dissolved in THF and treated with isopropylmagnesium chloride and a catalytic amount of diisopropylamine, after which the reaction was left to stir at room temperature for 16 hours. After this time, the reaction mixture was treated with iodine and left to stir for 1 hour before being quenched by the aqueous solution of ammonium chloride as a part of the work up. Products (105) and (106) were obtained in yields of 79% and 85% respectively. Compound (105) was isolated as a cream white solid with melting point 95-98 ?C. The literature reported the isolation of (105) as colourless solid27 and tan crystalline solid65 with melting point 96-98 ?C66. The 1H NMR spectrum of (105) showed a distinctive singlet at 6.99 ppm integrating for one hydrogen. This signal belongs to the 3-position, showing that the 2-position is occupied by a substituent. The 13C NMR spectrum showed a distinctive quaternary carbon at 121.85 ppm that did not appear in the 13C NMR spectrum of (36). Compound (106) was isolated as a cream white solid with the melting point 127-130 ?C. The 1H NMR spectrum of (106) also showed the similar distinctive singlet at 6.89 ppm integrating for one hydrogen for the 3-position of indole nucleus (106). 2.1.3 Synthesis of 3-bromo-1-(phenylsulfonyl)-1H-indole (107) N S OO 36 Br2, NaOAc, AcOH, reflux, 80% 107 N S OO Br Scheme 27 Chapter 2 Results and Discussion 40 The next step for this project was to introduce a halogen at the 3-position of the indole nucleus. There are many different methods for preparing (107) described in the literature. One of the methodologies involves using reagents such as n-butyllithium and trimethyltin chloride followed by addition of bromine in order to convert (9) to 3-bromoindole (62)41 (Scheme 17). Compound (62) was then treated with phenysulfonyl chloride in the presence of potassium hydroxide to afford (107) but the problem with this method was the instability of compound (62) 68. Compound (36) can also be brominated using molecular bromine at room temperature using the correct number of equivalents of bromine67. In our case, a mixture of (36) and sodium acetate in acetic acid was treated with bromine. The overall mixture was the refluxed for 18 hours over which time it turned from brown to light yellow. After being allowed to cool to room temperature, the reaction mixture was filtered to remove sodium acetate and the acetic acid removed under reduced pressure. This was followed by water work up to give (107) as a white solid with a melting point of 120-124 ?C, literature reported (107) as a white solid with a melting point 122-124 ?C68. The 1H NMR spectrum of (107) showed a distinctive singlet at 7.62 ppm integrating for one hydrogen belonging to the hydrogen at the 2-position of (107) and disappearance of a doublet at about 6.50 ppm due to the hydrogen at the 3-position when compared to the 1H NMR spectrum of (36). 2.1.4 Synthesis of 2,3-dibromo-1-(phenylsulfonyl)-1H-indole (108) Br2, CCl4 47%N S OO N S OO Br Br 36 108 Scheme 28 Chapter 2 Results and Discussion 41 We also wished to assemble indoles containing aryl substituents at the 2- and 3-positions. If we wished to use Suzuki coupling methodology we required a substituted indole such as (108) with halogens in both the 2- and 3-position. There are also many different routes for the synthesis of (108). One can first synthesize (107) and subsequent bromination of (107) will yield (108)69. In our laboratories, (36) was dissolved in carbon tetrachloride and treated with 1.1 eq of bromine at room temperature and the reaction left to stir overnight. After this time, the reaction mixture was poured into a saturated solution of aqueous sodium hydrogen carbonate and washed successively with water, aqueous solution of sodium metabisulfate and brine to remove excess bromine. This resulted in a cream white solid in 47% yield with melting point 140-145 ?C while the literature reported (108) was isolated as white crystals with melting point 141-143 ?C70. When the 1H NMR spectrum of (108) was examined, there was no indication of the doublet at about 6.50 ppm for one hydrogen due to presence of both 2-and 3-position hydrogens. Neither was there the singlet at about 6.99 ppm that result when 2-position is occupied nor the singlet at about 7.62 ppm indicating that the 3-position is occupied was observed. Examination of 13C NMR spectrum revealed two distinctive quaternary carbons at 120.52 and 107.13 ppm showing that positions 2- and 3- are occupied by substituents other than hydrogen. The chemical shifts indicated that most likely a halogen occupied both of these positions. Chapter 2 Results and Discussion 42 2.1.5 Synthesis of 3-bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole (109) NBS,benzoyl peroxide, CCl4, reflux, 80% 109 104 Br2 CCl4 110 111 Br2 CCl4 N S OO MeO N S OO MeO Br N S OO MeO Br Br N S OO MeO BrBr Br Scheme 29 Once the synthesis of indole (108) was complete we turned our attention to the same set of reactions starting from 5-methoxyindole (104) also protected as the N-phenylsulfonyl derivative. However, the bromination of (104) proved not to be straightforward as compared to bromination of a (36). When (104) was brominated under the same conditions as for (36) (Br2, CCl4), the less soluble tribromide (110) was identified instead of the monobromo product (109). This was confirmed by mass spectroscopy with the M+ at 523.85 for 79Br isotope and 525.81 for 81Br isotope. It has been shown that bromination of (104) with molecular bromine as shown in Chapter 2 Results and Discussion 43 Scheme 29 does not afford (109) as required but usually affords (111) although not detected in this case and for one to obtain (109) under these conditions, one must be very careful in conducting this reaction56. Bromination of the benzene ring of the indole is occurring due to the activation of the benzene ring by the methoxy group. To resolve this problem, indole (104) was dissolved in dry carbon tetrachloride and mixed with N-bromosuccinimide and a catalytic amount of benzoyl peroxide at room temperature. The reaction mixture was then refluxed overnight after which excess succinimide was filtered off. Trace amounts succinimide were removed by washing with 5% solution of aqueous sodium hydroxide and water. This resulted in a cream white solid (109) being obtained with the melting point 129-132 ?C while the literature reported a white solid 131-133 ?C56. When 1H NMR spectrum of (109) was examined, a singlet integrating for one hydrogen at 7.58 ppm was observed. This singlet belonged to the proton at the 2-position and this showed that 3-position of the indole nucleus was occupied. Examination of 13C NMR spectrum of (109) showed the presence of a quaternary carbon at 98.69 ppm belonging to the carbon at the 3-postion. 2.2 Synthesis of 2-arylindoles and 3-arylindoles As the desired halogenated substrates (105)-(109) had now been synthesized, this section will deal with the synthesis of 2-arylindoles and 3-arylindoles from these precursors. The key step used in this section is the aqueous Suzuki-Miyaura cross-coupling of haloindoles and arylboronic acids, mediated by palladium catalyst. 2.2.1 Synthesis of boronic acids The other precursors required for the coupling reactions, the boronic acids, were prepared from the requisite halogenated aryl compounds using traditional methodology, i.e treatment with n- Chapter 2 Results and Discussion 44 butyllithium, followed by trimethyl borate and then converting the boronic ester into the required boronic acid by treating each intermediate with 10% aqueous hydrochloric acid. The boronic acids obtained in this way are difficult to purify and hence they were used in the subsequent reactions as crude materials. The boronic acids synthesized and used in this project were phenylboronic acid (112), o-tolylboronic acid (113), 1-naphthylboronic acid (114), p- methoxyphenylboronic acid (115) and 3,4,5-trimethoxyphenylboronic acid (116) (Scheme 30). Although some of these are also commercially available. Table 1 below lists the approximate yields of the crude boronic acids. Ar-Br BuLi, B(OMe)3, THF, -78 oC, 1 h, 10% HCl Ar-B(OH)2 112, 113, 114, 115 and 116 Scheme 30 Table 1: % Yields of boronic acids Ar Boronic acid % yield Phenyl 112 88 o-Tolyl 113 92 1-Naphthyl 114 70 p-Methoxyphenyl 115 81 3,4,5-Trimethoxyphenyl 116 80 Chapter 2 Results and Discussion 45 The other boronic acids used in this project were 2-formylphenylboronic acid (117) and 2- acetylphenyboronic acid (118), which are commercially available (Figure 15) and were bought for this project. O B(OH)2 117 118 B(OH)2O H Figure 15 2.2.2 Suzuki-Miyaura cross-coupling of iodoindoles (105) and (106) followed by deprotection N S O R N S O R I Ar O O R = H (105) R = OMe (106) [Pd(PPh3)4], ArB(OH)2, DME, EtOH, aq. Na2CO3 R = H (119, 121, 123, 125 and 127) R = OMe (120, 122, 124 and 126) Scheme 31 The next step in this synthesis was to perform the Suzuki-Miyaura cross-coupling of either indole (105) or methoxyindole (106) with the boronic acids (112)-(116). The two iodoindoles Chapter 2 Results and Discussion 46 (105) and (106) were exposed to the boronic acids (112)-(116) in the presence of catalytic amounts of [Pd(PPh3)4] and aqueous sodium carbonate and dimethoxyethane/ethanol under reflux to afford the desired cross-coupling products (119), (121), (123), (125) and (127) for R = H while for R = OMe, the products obtained were (120), (122), (124) and (126) in fair to excellent yields (Table 2). Table 2: The % yields of cross-coupling of iodoindoles (105) and (106) with the boronic acids (112)-(116) R = Ar Boronic acid Product % yield ?3-H ppm Melting point ?C H Phenyl 112 119 82 6.52 100-104 lit. 104- 10564 OMe Phenyl 112 120 60 6.48 Oil H o-Tolyl 113 121 44 6.46 Oil OMe o-Tolyl 113 122 78 6.32 Oil H 3,4,5-Trimethoxyphenyl 114 123 56 6.40 Oil OMe 3,4,5-Trimethoxyphenyl 114 124 77 6.48 Oil H p-Methoxyphenyl 115 125 60 6.53 209-212 OMe p-Methoxyphenyl 115 126 61 6.33 Oil H 1-Naphthyl 116 127 60 6.52 Oil The formation of all products was confirmed by 1H and 13C NMR spectroscopy. The 1H NMR spectra of (119)-(127) showed distinct singlet at ~6.00-6.55 ppm (Table 2) integrating for one Chapter 2 Results and Discussion 47 hydrogen, suggesting that the 2-position of each compound is occupied by a substituent other than hydrogen. The 1H NMR spectra of (121) and (122) showed further two singlets at 2.19 and 2.13 ppm respectively each accounting for three hydrogens, thereby suggesting the presence of methyl groups. The 1H NMR spectra of (123) and (124) were further characterized by two singlets. Compound (123) showed a singlet at 3.85 ppm accounting for nine hydrogens while compound (124) showed two singlets at 3.94 ppm accounting for three hydrogens and 3.87 ppm accounting for six hydrogens, hence indicating the presence of methoxy substituents in the compounds. The examination of 1H NMR spectra of (125) and (126) also revealed some useful information. Their spectra showed one singlets each at 3.80 and 3.79 ppm respectively each integrating for three hydrogens, suggesting the presence of methoxy substituents in the compounds. The examination of 1H NMR spectrum of (127) showed an increase in number of hydrogens in the aromatic region suggesting the presence of an aromatic system, and in our case, the presence of naphthalene moiety. N S OO R N S OO R N S OO R OMe OMe OMe N S OO R OMe N S OO 119 R = H 120 R = OMe 121 R = H 122 R = OMe 123 R = H 124 R = OMe 125 R = H 126 R = OMe 127 Figure 16 Chapter 2 Results and Discussion 48 The 13C NMR spectra of these compounds further confirmed the results obtained. The 13C NMR spectra of (119) and (120) showed two quaternary carbons at 115.79 and 131.72 ppm respectively, indicating that the 2-position of the two compounds is occupied and further showed two carbon signals at 114.19 and 103.22 ppm respectively suggesting that the 3-position of the two compounds is bonded to a hydrogen atom. On the other hand, the 13C NMR spectra of (121) and (122) showed one carbon signal each at 20.89 and 20.87 ppm respectively, suggesting the presence of methyl substituents of these compounds. The 13C NMR spectra of (123) and (124) showed two carbon signals each, 62.38 and 57.63 ppm for (123), 60.39 and 55.58 ppm for (124), all indicating the presence of methoxy groups in these compounds while the 13C NMR spectra of (125) and (126) showed one carbon signals each at 55.75 and 55.26 ppm respectively indicating the presence of methoxy groups of these compounds and overall the 13C NMR spectra of all compounds showed an increase in the number of aromatic carbons compared to those observed for starting materials (105) and (106). The next step was the removal of the phenylsulfonyl protecting group of the compounds (119)- (127) discussed above. This was done by treating the solution of the compounds (119)-(127) in methanol with potassium carbonate under reflux followed by treatment with 10% hydrochloric acid solution and subjection to column chromatography to afford the unprotected compounds (128)-(136) (Scheme 32). The envisaged unprotected compounds (128)-(136) were produced in good to excellent yields (Table 3), and their structures were confirmed by spectroscopy. N S O R Ar O R = H (119, 121, 123, 125 and 127) R = OMe (120, 122, 124 and 126) N H R Ar R = H (128, 130, 132, 134 and 136) R = OMe (129, 131, 133 and 135) K2CO3, MeOH, reflux, 10% HCl Scheme 32 Chapter 2 Results and Discussion 49 Table 3: The % yields of unprotected indoles (139)-(147) R = Ar Product % yield ?NH ppm Melting point ?C H Phenyl 128 78 8.36 182-186 lit. 182- 18479 OMe Phenyl 129 61 8.21 162-165 H o-Tolyl 130 82 8.04 81-85, lit. 92- 9380 OMe o-Tolyl 131 67 8.03 Oil H 3,4,5-Trimethoxyphenyl 132 51 8.42 206-209, lit. 205-206.581 OMe 3,4,5-Trimethoxyphenyl 133 86 8.38 152-155 H p-Methoxyphenyl 134 52 11.40 228-230, lit. 227-23182 OMe p-Methoxyphenyl 135 51 10.22 116-120 H 1-Naphthyl 136 52 8.19 96-100, lit. 99- 10283 Chapter 2 Results and Discussion 50 N H R N H R N H R OMe OMe OMe N H R OMe N H 128 R = H 129 R = OMe 130 R = H131 R = OMe 132 R = H 133 R = OMe 134 R = H 135 R = OMe 136 Figure 17 The 1H NMR spectra of all compounds (128)-(136) showed a decrease in number of protons in the aromatic region, suggesting that the phenylsulfonyl group was no longer present. The spectra further confirmed the results by showing the appearance of a new peak integrating for one hydrogen between 8.00 and 11.50 ppm (Table 3), suggesting the presence of NH groups of the indole. The examination of 13C NMR spectra of compounds (128)-(136) showed a decrease in number of carbon signals in the aromatic region, also suggesting that the phenylsulfonyl group was no longer present. A further confirmation of these results was also made through infrared spectroscopy. The infrared spectroscopy of compounds (128)-(136) showed medium to strong broad peak at a range of 3300-3450 wavenumbers, suggesting the presence of NH group in these compounds. 2.2.3 Suzuki-Miyaura cross-coupling of bromoindoles (107) and (109) followed by deprotection After the successful synthesis of 2-arylindoles, the next step was to synthesize 3-arylindoles. This was achieved because compounds (107) and (108) were successfully synthesized and Chapter 2 Results and Discussion 51 characterized as discussed previously. To achieve the synthesis of 3-aryindoles, the two compounds (107) and (109) were exposed to the boronic acids (112)-(116) and the other two boronic acids (117) and (118) as shown in Figure 15 in the presence of catalytic amounts of [Pd(PPh3)4] and aqueous sodium carbonate and dimethoxyethane/ethanol under reflux to afford the desired cross-coupling products (150)-(161). The products obtained for R = H were (137), (139), (141), (143), (145) and (147) while the ones obtained for R = OMe were (138), (140), (142), (144), (146) and (148) and they were obtained in good to excellent yields (Table 4). The structures are shown in Figure 18. N S O R N S O R O O R = H (107) R = OMe (109) [Pd(PPh3)4], ArB(OH)2, DME, EtOH, aq. Na2CO3 R = H (137, 139, 141, 143, 145, and 147) R = OMe (138, 140, 142, 144, 146 and 148) Br Ar Scheme 33 Table 4: The % yields of cross-coupling of (107) and (109) with boronic acids (112)-(118) R = Ar Boronic acid Product % yield ?2-H ppm Melting point ?C H Phenyl 112 137 81 7.70 139-142, lit. 141-14364 OMe Phenyl 112 138 85 7.65 Oil Chapter 2 Results and Discussion 52 H o-Tolyl 113 139 64 7.87 Oil, lit. Oil56 OMe o-Tolyl 113 140 86 7.41 111-114, lit. 127-12856 H 3,4,5-Trimethoxyphenyl 114 141 65 7.67 Oil OMe 3,4,5-Trimethoxyphenyl 114 142 72 7.47 132-136 H p-Methoxyphenyl 115 143 79 7.63 132-137, lit Oil84 OMe p-Methoxyphenyl 115 144 72 7.58 Oil H 2-Formylphenyl 117 145 72 7.68 Oil OMe 2-Formylphenyl 117 146 94 7.59 129-132 H 2-Acetylphenyl 118 147 92 7.46 Oil OMe 2-Acetylphenyl 118 148 82 7.42 105-109 Compounds (137)-(148) were characterized and the identity confirmed by spectroscopic techniques. Examination of the 1H NMR spectra of compounds (137)-(148) showed a distinctive singlet for the hydrogens at C-2 between 7.00 and 7.80 ppm, suggesting that the 3-position in the compounds was a substituent other than hydrogen. The spectra further showed an increase in number of hydrogens in the aromatic region, suggesting the presence of extra aromatic signals in comparison with the starting materials (107) and (109). The 1NMR spectrum of (137) showed a singlet at 7.69 ppm and a distinct doublet at 7.60 ppm due to the presence of phenyl ring at the 3- position of (137) while that of (138) showed a singlet at 7.65 ppm and a distinct doublet at 7.57 ppm also due to the presence of the phenyl at the 3-position of (138). The 1H NMR spectra of (139) and (140) showed one distinct singlet each at 2.21 ppm for (139) and 2.19 ppm for (140), each accounting for three hydrogens, suggesting the presence of a methyl substituent in the compounds (139) and (140). Further examination of the 1H NMR spectra of (141) and (142) Chapter 2 Results and Discussion 53 revealed a singlet at 6.80 ppm for (141) integrating for two hydrogens and a singlet at 3.91 ppm accounting for nine hydrogens indicating the presence of three methoxy substituents of (141) while that of (142) revealed a singlet at 6.77 ppm accounting for two hydrogens and further showed an additional two singlets at 3.91 ppm, accounting for six hydrogens and 3.90ppm accounting for three hydrogens, both indicating the presence of the extra three methoxy substituents of (142). N S OO R N S OO R N S OO R OMe OMe MeO N S OO R N S OO R OMe O 137 R = H 138 R = OMe 139 R = H 140 R = OMe 141 R = H 142 R = OMe 143 R = H 144 R = OMe 145 R = H 146 R = OMe 147 R = H 148 R = OMe N S OO R H O Figure 18 Chapter 2 Results and Discussion 54 The 1H NMR spectra of (143) and (144) showed two singlets each, accounting for one hydrogen at 7.63 ppm for (143) and 7.58 ppm for (144) suggesting that the 3-position of the compounds was occupied and they further showed two singlets at 3.85 ppm for (143) and 3.86 ppm for (144) each integrating for three hydrogens, suggesting the presence of methoxy substituents in the compounds. The 1H NMR spectra of (145) and (146) showed two singlets at 9.90 and 9.87 ppm respectively, each accounting for one hydrogen, suggesting the presence of aldehydes of the compounds and the 1H NMR spectra of (147) and (148) revealed two singlets at 1.90 and 1.87 ppm respectively, each integrating for three hydrogens, indicating the presence of the acetyl group in the compounds. The examination of the 13C NMR spectra of compounds (137)-(148) showed an increase in the number of carbon signals in the aromatic region in comparison with those of the starting materials (107) and (109). The 13C NMR spectra of (139) and (140) showed two distinct carbon signals at 20.80 and 20.78 ppm respectively, supporting the 1H NMR, suggesting the presence of methyl groups on (139) and (140). Two carbon signals at 59.26 and 54.53 ppm suggesting the presence of methoxy groups were observed on the 13C NMR spectrum of (141) and the examination of the 13C NMR spectrum of (142) also revealed two distinct carbon signals at 60.41 and 55.73 ppm, indicating the presence of methoxy groups on (142). Further examination of the 13C NMR spectra of (143) and (144) showed two carbon signals at 55.41 and 55.79 ppm suggesting the presence of methoxy groups on (143) and (144) while the 13C NMR spectra of (145), (146), (147) and (148) showed distinct carbon signals at 192.00, 192.11, 203.89 and 204.21 ppm respectively, which are characteristic of a carbonyl groups. The 13C NMR spectra of (147) and (148) also showed two distinct carbon signals at 30.14 and 30.11 ppm which is indicative of the presence of methyl groups on (147) and (148). The results of the formation of (145), (146), (147) and (148) were further supported by the information from infrared spectroscopy. The infrared spectra of (145), (146), (147) and (148) showed strong absorption peaks at 1693, 1681, 1685 and 1690 wavenumbers respectively, confirming the presence of carbonyl groups of the products. Chapter 2 Results and Discussion 55 After the successful synthesis of compounds (137)-(148), the next step was to remove the phenylsulfonyl protecting group of these compounds. This would be achieved as before by treating the solutions of compounds (137)-(148) in methanol with potassium carbonate under reflux followed by treatment with 10% hydrochloric acid and subjection to column chromatography afforded unprotected indoles (149)-(160) (Scheme 34). The envisaged unprotected indoles (149)-(160) were produced in good to excellent yields (Table 5) and their structures were confirmed by spectroscopic techniques. N H Ar R K2CO3, MeOH, reflux, 10% HCl R = H (149, 151, 153, 155, 157 and 159) R = OMe (150, 152, 154, 156, 158 and 160) R = H (137, 139, 141, 143, 145, and 147) R = OMe (138, 140, 142, 144, 146 and 148) N S O R O Ar Scheme 34 Table 5: The % yields of unprotected indoles (149)-(160) R = Ar Product % yield ?H ppm Melting point ?C H Phenyl 149 81 8.17 86-89, lit. 8985 OMe Phenyl 150 85 8.01 Oil, lit. 66-6786 H o-Tolyl 151 64 8.17 Oil, li. Oil56 Chapter 2 Results and Discussion 56 OMe o-Tolyl 152 86 8.11 Oil, lit. Oil56 H 3,4,5-Trimethoxyphenyl 153 65 8.35 Oil OMe 3,4,5-Trimethoxyphenyl 154 72 8.46 Oil H p-Methoxyphenyl 155 79 8.13 130-134, lit. 131-13387 OMe p-Methoxyphenyl 156 72 8.10 Oil, lit. 151.2- 15288 H 2-Formylphenyl 157 72 8.61 Oil OMe 2-Formylphenyl 158 95 8.51 Oil H 2-Acetylphenyl 159 92 8.61 Oil OMe 2-Acetylphenyl 160 82 8.56 116-120 Chapter 2 Results and Discussion 57 N H R N H R N H R OMe OMe MeO N H R N H R OMe O 149 R = H 150 R = OMe 151 R = H 152 R = OMe 153 R = H 154 R = OMe 155 R = H 156 R = OMe 157 R = H 158 R = OMe 159 R = H 160 R = OMe N H R H O Figure 19 The formation of compounds (149)-(160) was confirmed by the 1H NMR spectra in which the singlet between 8.00 and 8.65 ppm (Table 5) accounting for one hydrogen indicating the presence of the indole NH group. The results were further confirmed by 1H NMR spectra of the compounds when they showed a decrease in number of hydrogens in the aromatic region suggesting the removal of the phenylsulfonyl protecting group. When the 13C NMR spectra of (149)-(160) were examined, a decrease in the number of carbon signals in the aromatic region was noted further suggesting the removal of the phenylsulfonyl protecting group. The infrared spectra of these compounds further supported the results by showing medium to strong Chapter 2 Results and Discussion 58 absorption in the range of 3200-3480 wavenumbers suggesting the presence of NH group in these compounds. 2.2.4 Suzuki-Miyaura cross-coupling of dibromindole (108) followed by deprotection The next step was to attempt the synthesis of 2,3-disubstituted indoles by using the 2,3- dibromoindole (108) as the starting material with the hope of producing 2,3-diaryl substituted indoles. N S OO Br Br N S OO B(OH)2 112 108 161 [Pd(PPh3)4], DME, EtOH, aq. Na2CO3, reflux, 56% Scheme 35 Compound (108) was successfully synthesized and characterized as described in section 2.1.4 of this project. After the synthesis of (108), the next step required was to perform the Suzuki- Miyaura cross-coupling reaction with the boronic acids (112)-(116) (Table 1), however only phenylboronic acid (112) shown in Scheme 35 was successfully utilized in the cross-coupling reaction. Presumably the other boronic acids were not successful as a result of steric factors, Heck trapping or electron withdrawing groups for (114) and (115) in placing two substituted aryl substituents in adjacent positions on the indole nucleus. Compound (108) was treated with boronic acid (112) in the presence of catalytic amounts of [Pd(PPh3)4] and aqueous sodium Chapter 2 Results and Discussion 59 carbonate and dimethoxyethane/ethanol under reflux to afford the desired cross-coupling product (161) in 56% yield (Scheme 35) as a cream white solid with melting point 173-175 ?C with literature melting point of 174-176 ?C69. The formation of (161) was confirmed by spectroscopy. The 1H NMR spectrum showed that the number of hydrogens in the aromatic region has increased, suggesting the presence of extra aromatic systems in comparison with the starting material (108). This was further supported by the 13C NMR spectrum which also showed that the number of carbon signals in the aromatic region has increased. N H 162 K2CO3, MeOH, reflux, 10% HCl, 60%N S OO 161 Scheme 36 The next step was to remove the protecting group of (161). This was be achieved by treating the solution of compound (161) in methanol with potassium carbonate under reflux followed by treatment with 10% hydrochloric acid and subsequent column chromatography to afford (162) in 60% yield as a yellow solid with melting point 224-227 ?C (Scheme 36). The formation of (162) was verified by spectroscopic techniques. The examination of the 1H NMR spectrum of (162) showed a decrease in number of hydrogens in the aromatic region which is indicative of the removal of the phenylsulfonyl protecting group and a singlet at 8.21 ppm integrating for one hydrogen, indicating the presence of the indole NH group. This was further supported by the 13C NMR spectrum which showed that the number of carbon signals in the aromatic region has Chapter 2 Results and Discussion 60 decreased in comparison with that of the starting material (161). The infrared spectrum of (162) showed a medium-intensity absorption peak at 3461 wavenumbers, indicating the presence of the indole NH group of (162). 2.3 Synthesis of 2-arylindoles via one-pot synthesis The next step in the preparation of 2-arylsubstituted indoles was to attempt their construction without first preparing the 2-halogenated indoles. This would remove the need to form halogenated precursors. Fewer steps would then be needed in the synthesis and the use of reagents used for the introduction of a halogen would no longer be necessary. This can be important as often these reagents are toxic and especially from an industrial point of view their elimination is highly desirable. 2.3.1 Synthesis of 2-(4-bromo-2,5-dimethoxyphenyl)-1-(phenylsulfonyl)-1H- indole (164) and 2-(4-bromo-2,5-dimethoxyphenyl)-5-methoxy-1- (phenylsulfonyl)-1H-indole (165) followed by deprotection N S R O O N S R O O Br MeO OMe R = H (36) R = OMe (104) R = H (164) 21% R = OMe (165) 35% iPrMgCl, iPr2NH, Pd(PPh3)4, THF Br Br OMe MeO 163 Scheme 37 Chapter 2 Results and Discussion 61 As shown in Scheme 37, 2-substituted indoles were successfully synthesized via organomagnesium intermediate, made by treating the indole with magnesium amide base. Either previously prepared (36) or (104) was treated with isopropylmagnesium chloride and a catalytic amount of diisopropylamine in tetrahydrofuran at room temperature. The reaction mixture was stirred for 16 hours before being treated with 1,4-dibromo-2,5-dimethoxybenzene (163) in the presence of palladium(0) catalyst (Pd(PPh3)4) and the reaction mixture was left to stir for another 48 hours. After this time, the reaction mixture was quenched by the addition of saturated solution of aqueous ammonium chloride and then worked up. Following the work up, the excess solvent was removed, resulting in a black oil that was subjected to column chromatography and recrystallized from the mixture of dichloromethane and diethyl ether which gave white solids for both (164) and (165) in low yields with melting points of 181-183 ?C and 159-162 ?C respectively. The 1H NMR spectrum of (164) was characterized by two singlets at 7.13 and 6.77 ppm each integrating for one hydrogen belonging to hydrogens on the newly introduced benzene ring of (164). The spectrum also showed a singlet at 6.58 ppm integrating for one hydrogen, which belongs to the 3-position of the indole nucleus (164). The identity of the product was further proved by the presence of two singlets at 3.82 and 3.68 ppm, each accounting for three hydrogens, indicating the presence of methoxy group of (164). The 13C NMR spectrum of (164) also proved the results by showing two distinctive carbons signals at 57.36 and 56.54 ppm indicating the presence of methoxy groups supported by their respective quaternary carbons at 153.08 and 149.63 ppm. Chapter 2 Results and Discussion 62 N S MeO O O Br MeO OMe 165 N S OO Br MeO OMe 164 Figure 20 The formation of (165) was confirmed by the 1H NMR spectrum where two singlets each integrating for one hydrogen at 7.13 and 6.78 ppm were observed. The presence of a singlet at 6.52 ppm accounting for one hydrogen belongs to the hydrogen on the 3-position of indole (165). One singlet at 3.82 ppm accounting for six hydrogens and another singlet at 3.69 ppm accounting for three hydrogens indicating the presence of three methoxy groups on (165). The 13C NMR spectrum further confirmed the results by showing three carbon signals at 57.36, 56.56 and 56.05 ppm supported by their respective quaternary carbons at 157.24, 152.97 and 149.62 ppm indicating the presence of the three methoxy groups on (165). After the synthesis of (164) and (165) (Scheme 37), we then attempted to remove the phenylsufonyl protecting group. This was done by treating the solutions of the compounds (164) and (165) in methanol with potassium carbonate under reflux followed by treatment with 10% hydrochloric acid solution and subjection to column chromatography to afford the unprotected compounds (166) and (167) (Scheme 38). The envisaged unprotected compounds were produced in moderate yields. Chapter 2 Results and Discussion 63 R = H (164) 21% R = OMe (165) 35% R = H (166) 52% R = OMe (167) 40% K2CO3, MeOH, reflux, 10% HCl N S OO Br MeO OMe R N H Br MeO OMe R Scheme 38 The formation of (166) and (167) was also confirmed by spectroscopy. The 1H NMR spectra of (166) and (167) showed a decrease in the number of hydrogens in the aromatic region, suggesting that the phenylsulfonyl group was removed. The spectra further supported the formation of (166) and (167) by showing one singlet for each at ~9.00 ppm. The peak positions were 9.63 ppm for (166) and 9.54 ppm for (167), indicating the presence of NH groups of the indole. The 13C NMR spectra of (166) and (167) further agreed with the results from 1H NMR spectra by showing that the number of carbons in the aromatic region has decreased, suggesting that the phenylsulfonyl group was no longer present. The infrared spectroscopy of (166) showed a medium-sized signal at 3450 wavenumbers and that of (167) showed a signal at 3397 wavenumbers, both suggesting the presence of the NH group. 2.4 Synthesis of indolopyrans Substituted pyrans are ubiquitous structural elements in natural products, and some have important biological activity71. Their derivatives are often important intermediates in the synthesis of many natural products72. Apart from their biological activity, pyrans such as diaryl- Chapter 2 Results and Discussion 64 benzopyrans and naphthopyrans display highly desirable photochromic properties73. We wished to construct the pyran ring onto the 2- and 3-position of the indole nucleus using the methodology developed in our laboratories. This would represent a novel pyran fused to an indole nucleus. 2.4.1 Synthesis of 2-allyl-1-(phenylsulfonyl)-1H-indole (169) and 2-Allyl-1-(phenylsulfonyl)- 1H-indole-3-carbaldehyde (171) In order to construct the desired indolopyrans, substituents needed to be introduced at both the 2- and 3- position. Metallation at the 2-position of indole, for example using lithiation as a synthetic route to 2-substituted indoles, has been studied extensively. Owing to the low temperatures required for lithiating reagents and their instability including that of their intermediates, methods have been developed that use reagents that are more stable. Recently metallation of indoles using magnesium amide bases and their extension has been reported27, 28. In our laboratories, when (36) was treated with isopropylmagnesium chloride and allyl bromide (168) in the presence of catalytic amount of diisopropylamine, followed by quenching with saturated solution of aqueous ammonium chloride it gave a brown oil (Scheme 39). The oil was then subjected to column chromatography and the resultant solid recrystallized from a mixture of dichloromethane and diethyl ether to give (169) as a white solid in poor yield of 31% with melting point 88-91 ?C. The formation of (169) was confirmed by the 1H NMR spectrum which showed a distinct singlet at 6.40 ppm accounting for one hydrogen which belongs to the 3-position of (169). This was further confirmed by a multiplet at 6.08-5.96 ppm accounting for one hydrogen, another multiplet at 5.22-5.16 ppm accounting for two hydrogens and a triplet at 3.78-3.76 ppm integrating for two hydrogens, indicating the presence of an allyl group. The 13C NMR spectrum further confirmed the results by showing two distinct carbon signals in the aromatic region at 134.06 and 118.22 ppm and one at 33.78 ppm which also indicate the presence of allyl group of (169). Chapter 2 Results and Discussion 65 iPrMgCl, iPr2NH, THF, 31% Br 36 168 169 Cl H O Cl 170 171 TiCl4, -78 oC, CH2Cl2, 81%N S OO N S OO N S OO O H Scheme 39 As we wished to synthesise 2,3-disubstituted indoles and, in this particular case assemble a fused pyran ring onto the indole after the synthesis of the above mentioned 2-allyl indole (169), the next step was its formylation at the 3-postion of the indole nucleus using titanium(IV) chloride and dichloro(methoxy)methane (170). Compound (169) was added to mixture of titanium(IV) chloride and (170) in dichloromethane at ?78 ?C and the reaction mixture stirred for 2 hours. After the reaction mixture was allowed to warm up to room temperature, it was neutralized by water and worked up according to literature74 and gave (171) as a brown oil. The literature reported (171) isolated as solid with melting point 157-158.5 ?C75. The formation of (171) was supported by a singlet accounting for one hydrogen at 10.31 ppm in the 1H NMR spectrum of (171) and carbon signal at 186.18 ppm suggesting the presence of a carbonyl from the 13C NMR spectrum. This indicated the presence of the aldehyde (171). The infrared spectrum of (171) showed strong absorption at 1666 wavenumbers which clearly suggests the presence of a carbonyl group on (171). Chapter 2 Results and Discussion 66 2.4.2 Synthesis of (2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl) methanol (172) After the successful synthesis of (171), the next step was to reduce the aldehyde to alcohol. Due to the reactivity of aldehydes, sodium borohydride is usually employed in this regard. The reduction with sodium borohydride should be carried out at lower temperatures due the heat released during the reaction and requires that sodium borohydride be added in portions76. Compound (171) was treated with sodium borohydride at 0 ?C in ethanol and the reaction mixture was stirred for 6h. After this time, the solvent was removed under reduced pressure and the resulting white solid shaken up with 5% aqueous solution of sodium hydroxide and extracted with dichloromethane to give (172) as a yellow oil in 71% yield. N S OO O 171 NaBH4, 0 oC to rt, EtOH, 71% 172 N HO S OO H Scheme 40 The literature reported that (172) was isolated as solid with melting point 82-83 ?C76. The 1H NMR spectrum of (172) showed that the aldehyde peak had disappeared and the appearance of new broad singlet at 1.96 ppm suggesting the presence of the OH group on the desired product. This was further confirmed by the presence of another new singlet at 4.62 ppm, suggesting the presence of the methylene of the desired product. An investigation of the 13C NMR spectrum Chapter 2 Results and Discussion 67 showed that the carbonyl peak had disappeared, and there was a new carbon signal at 53.82 ppm again indicating the presence of the methylene substituent bearing oxygen. The infrared spectrum showed a broad absorption at 3406 wavenumbers which clearly suggests the presence of OH group on the desired product (172). 2.4.3 Synthesis of 1-(2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl) ethanol (173) After the successful synthesis of (172), we wanted to attempt the synthesis of similar alcohols. When (172) was synthesized, NaBH4 was used as a source of hydrogen for the reduction of the aldehyde. We attempted the synthesis of alcohol (173) using a Grignard reagent to added to the aldehyde (171) and in this case, methylmagnesium iodide in THF was used. 171 173 MeMgI, ether, 76% N S OO HO N S OO O H Scheme 41 Methylmagnesium iodide was prepared in situ from dry magnesium turnings and methyl iodide in ether. The resulting solution was then treated with the solution of (171) in ether. The reaction Chapter 2 Results and Discussion 68 mixture was left to stir overnight before being quenched with saturated aqueous ammonium chloride solution followed by work up to give alcohol (173) as a yellow oil in 76% yield. The 1H NMR spectrum of (173) showed that the aldehyde peak that was at 10.31 ppm for (171) had disappeared. The 1H NMR also showed a multiplet at 5.04-4.92 ppm accounting for one hydrogen, a doublet at 1.56-1.54 ppm suggesting the presence of a methyl substituent on (173) and a broad singlet at 1.91 ppm accounting for one hydrogen suggesting the presence of OH group on (173). This was further confirmed by infrared spectrum which showed a broad peak at 3567 wavenumbers suggesting the presence of OH group. An examination of the 13C NMR spectrum showed two distinctive carbon signals, one at 64.56 ppm which suggests the presence of methylene related substituent and another at 30.44 ppm which suggests the presence of a methyl substituent. 2.4.4 Synthesis of 3-methyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (174) and 1,3-dimethyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (175) After the successful synthesis of alcohols (172) and (173), the next step was to perform the ring closure reaction to afford a novel compound, a pyran-fused indole. The two alcohols were treated with mercury acetate in tetrahydrofuran at room temperature. The reaction mixture was left to stir for 38 hours after which it was quenched with mixture of aqueous sodium hydroxide and sodium borohydride whilst stirring and the reaction mixture was stirred for further 1h before the addition of aqueous solution of sodium carbonate (Scheme 42). The reaction mixture was allowed to stand and worked up according to literature procedures77. This gave (174) as clear solid with melting point 145-148 ?C and (175) as a clear oil. Chapter 2 Results and Discussion 69 R = H (172) R = Me (173) Hg(OAc)2, THF, rt R = H (174) 31% R = Me (175) 25% N S OO N S OO HO R O R Scheme 42 The formation of (174) was confirmed by 1H NMR spectroscopy which showed that the broad singlet has disappeared. It also showed a multiplet at 5.19-5.04 ppm integrating for two hydrogens, a multiplet at 4.17-4.10 ppm accounting for one hydrogen, a multiplet at 3.56-3.50 accounting for one hydrogen, another multiplet at 3.16-3.07 ppm accounting for one hydrogen and finally a doublet at 1.78-1.74 ppm accounting for three hydrogens. The identity of the product was further confirmed by 13C NMR spectrum which showed the alkene carbons that previously were in the aromatic region had disappeared. It also showed two carbon signals at 69.81 and 62.15 ppm which suggests the presence of carbons that are bonded to oxygen, another two carbon signals at 31.78 and 20.38 ppm which probably suggests the presence of methyl and methylene groups on (174). The 1H NMR of (175) also showed the disappearance of the broad singlet peak. It also showed multiplets at 5.10-5.04 ppm, 4.14-4.08 ppm, 3.26-3.16 and 2.85-2.69 ppm, each accounting for one hydrogen and finally two doublets at 1.56-1.54 and 1.40-1.38 ppm which clearly suggest the presence of two methyl substituents on the desired product (175). The 1H NMR also suggested the presence of the two isomers, with one isomer more than the other but this has to be correctly determined. Further confirmation of the results was obtained from the 13C NMR spectrum of Chapter 2 Results and Discussion 70 (175) which showed that alkene carbons that were observed in the aromatic region disappeared. It also showed two carbon signals at 67.55 and 64.04 ppm which suggests the presence of carbons that are bonded to oxygen, one carbon signal at 32.54 ppm which suggests the presence of a methylene substituent and two carbon signals at 21.19 and 19.98 ppm which suggest the presence of two methyl substituents on (175). The two compounds (174) and (175) were obtained in low yields. I was later found that the compounds stick to the silica during the filtration of mercury and purification stage. One should take care and make sure more solvent is used to get the product especially during the filtration process. N S OO O N S OO O 174 175 Figure 21 In summary, we managed to synthesis 2-allylindoles using isopropylmagnesium chloride and isopropylamine. The synthesis of 2-allyindole was followed by the formylation to afford 2-allyl- 3-formylindoles which were later reduced to afford the respective alcohols was a success. In addition to the alcohols, we managed to cyclize the alcohols to construct indolo-fused pyrans, a novel class of compounds. Chapter 3 Conclusion and Future Work 72 Chapter 3: Conclusion and Future Work During the course of this MSc we managed to synthesis 2-arylindoles (128)-(136) in fair to excellent yields. The 2-arylindoles (128)-(136) were synthesized in three steps starting from 2- iodo-1-(phenylsulfonyl)-1H-indole (105) or 2-iodo-5-methoxy-1-(phenylsulfonyl)-1H-indole (106) while (166) and (167) were synthesized in two steps starting from (36) and (104) respectively in a one-pot synthesis to the removal of the phenylsulfonyl protecting group. The future work on this will include improving the yields of the protected compounds (120), (121), (123), (125)-(127) and unprotected compounds (129), (131), (132), and (134)-(136). We will be submitting the compounds (128)-(136) for testing against cancer cells and malarial cell lines. N H R N H R N H R OMe OMe OMe N H R OMe N H 128 R = H 129 R = OMe 130 R = H131 R = OMe 132 R = H 133 R = OMe 134 R = H 135 R = OMe 136 N H Br MeO OMe MeO N H Br MeO OMe 166 167 Chapter 3 Conclusion and Future Work 73 N S OO R N S OO R N S OO R OMe OMe OMe N S OO R OMe N S OO 119 R = H 120 R = OMe 121 R = H 122 R = OMe 123 R = H 124 R = OMe 125 R = H 126 R = OMe 127 Also, we managed to synthesize the 3-arylindoles (149)-(160) in fair to excellent yields. The 3- arylindoles (149)-(160) were synthesized in three steps starting from 3-bromo-1- (phenylsulfonyl)-1H-indole (107) and 3-bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole (109). The future work in this section will involve submitting the compounds (149)-(160) for testing against cancer and malarial cell lines. Infact, (149) has been tested and showed promising results against bacterial and fungal cell lines. Also in the future work of this section will be to improve the yields in the reactions leading to the desired products (139), (141), (151) and (153). Chapter 3 Conclusion and Future Work 74 N H R N H R N H R OMe OMe MeO N H R N H R OMe O 149 R = H 150 R = OMe 151 R = H 152 R = OMe 153 R = H 154 R = OMe 155 R = H 156 R = OMe 157 R = H 158 R = OMe 159 R = H 160 R = OMe N H O H R We also successfully synthesized 2,3-dibromo-1-(phenylsulfonyl)-1H-indole (108) by treating (36) with bromine in carbon tetrachloride in acceptable yield of 47%. After synthesizing (108), we managed to synthesise 2,3-diphenyl-1-(phenylsulfonyl)-1H-indole (161) in a fair yield of 56% which was successfully deprotected using potassium carbonate in methanol to give 2,3- diphenyl-1H-indole (162) in a fair yield of 60%. The future work in this section will include submitting (162) for testing against cancer and malarial cell lines and as well improving the yields of (108), (161) and (162). Other future work will involve reacting (108) with other boronic acids such as (114), (115) and others to give a range of 2,3-diarylindoles (176) (Scheme 43) because boronic acid such as (113), (117) and (118) have been generated. However, there was no success in synthesizing these 2,3-diarylindoles with these boronic acids. Instead, 3-arylindoles were obtained and we attributed this to steric effects. Chapter 3 Conclusion and Future Work 75 N S OO Br Br 108 N S OO 161 N H 162 N S OO Br Br N H Ar Ar 108 176 Scheme 43 Using methodology developed in our laboratories, we also managed to synthesize compounds (174) and (175) in four steps starting from the allylation of (36), formylation of (169) to cyclization of (172) and (173) using mercury acetate in tetrahydrofuran at room temperature. Compounds (174) and (175) were synthesized successfully in poor yields of 31% and 25% respectively. The future work in this section will include improving the yield of (169) which was obtained at the highest yield of 31% and the yields of (174) and (175) will also need to be improved. Further future work will involve taking (174) and (175) and treating them with potassium carbonate in methanol in an attempt to remove the phenylsulfonyl protecting group to Chapter 3 Conclusion and Future Work 76 give unprotected compounds (177) and (178) (Scheme 44). If compounds (176) and (177) can be successfully obtained, they will be submitted for biological testing. Other future work will include treating (171) with different arylmagnesium halides followed by cyclization reaction using mercury acetate to give cyclized compound (180) which can be deprotected to give compound (181) (Scheme 45). 169 171 174 175 N SO O N SO O O N SO O O N S OO O H N S OO O R N H O R R = H (174) R = Me (175) R = H (177) R = H (178) K2CO3, MeOH, reflux, 10% HCl Scheme 44 Chapter 3 Conclusion and Future Work 77 N S OO O N S OO OH ArylMgBr N S OO O Ar N H O Ar Ar 171 179 180 181 Hg(OAc)2, THF Scheme 45 Chapter 4 Experimental Procedures 79 Chapter 4: Experimental Procedures 4.0 General Experimental Procedures 4.0.1 Purification of Solvents and Reagents All solvents used for reactions and preparative chromatography were distilled prior to use. Where necessary, they were also dried by standard methods as recommended by Perrin et al78. Tetrahydrofuran was distilled from the sodium benzophenone ketyl radical, dichloromethane, triethylamine from calcium hydride and toluene from sodium. Where necessary, solvents were stored over activated molecular sieves (4 ?) under nitrogen atmosphere. Unless otherwise noted, other reagents were obtained from commercial sources and used without further purification. 4.0.2 Chromatographic Separations Thin layer chromatography (TLC) was carried out on aluminum-backed Macherey-Nagel Alugram Sil G/UV254 plates pre-coated 0.25 mm silica gel 60. Detection was done by under ultra violet light at 254 nm. Preparative column chromatography was carried out on dry-packed columns using Macherey-Nagel Kieselgel 60 silica gel 60 (particle size 0.063-0.200 mm) as the adsorbent. Mixtures of EtOAc and hexane were used as the mobile phase. 4.0.3 Spectroscopic and Physical Data All melting points were obtained on a Reichert hot-stage microscope and are uncorrected. The 1H NMR (nuclear magnetic resonance) spectra were recorded on a Bruker AVANCE 300 (300.13 MHz) or a Bruker AVANCE 400 (400.13 MHz) spectrophotometer. Spectra were Chapter 4 Experimental Procedures 80 recorded in deuterated chloroform (CDCl3) or deuterated acetone (acetone-d6) and chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), the internal standard; coupling constants are given in Hertz (Hz). Splitting patterns are designated as ?s?, ?d?, ?t?, ?q?, and ?m?; and these symbols indicate ?singlet?, ?doublet?, ?triplet?, ?quartet? and ?multiplet? respectively. The 13C NMR (1H decoupled) spectra were recorded on a Bruker AVANCE 300 (75.47 MHz) or Bruker DRX 400 (100.63 MHz) spectrometer. Spectra were recorded in deuterated chloroform (CDCl3) or deuterated acetone (acetone-d6) and chemical shifts are reported in parts per million (ppm) relative to the central signal of deuterated chloroform, taken as ? 77.00 IR (infrared) spectra were recorded on a Bruker IFS-25 Fourier Transform spectrometer or on a Bruker Vector-22 Fourier Transform spectrometer. Liquid samples were recorded as thin films between sodium chloride plates while solid samples were recorded as solutions in dichloromethane in sodium chloride cells. The signals were reported on the wavenumber scale (v/cm-1). Signals were designated as ?s?, ?m?, ?w? and ?b?; these symbols indicate ?strong?, ?medium?, ?weak? and ?broad? respectively. Mass spectra were recorded on Thermo Fisher LXQ, Thermo Fisher DFS or VG 70 SEQ mass spectrometer. Chapter 4 Experimental Procedures 81 4.1 Protection of the indole nucleus 4.1.1 1-(Phenylsulfonyl)-1H-indole (36) To an ice-cold mixture of aqueous NaOH (4.10 g, 102 mmol, 3 eq) and tetra-n-butylammonium bromide (0.29 g, 0.89 mmol, 0.026 eq) in dichloromethane (20.0 ml) under N2, was added solid indole (9) (4.00 g, 34 mmol) in one portion followed by slow addition of phenylsulfonyl chloride (5.3 ml, 43 mmol, 1.25 eq).The light pink mixture was stirred at rt under N2 for 18 h over which time it turned milky white. Water was added and the reaction mixture was then extracted with CH2Cl2 (3 ? 20 ml). The organic extracts were combined, dried over MgSO4, filtered with the celite plug and the solvent removed on a rotary evaporator. The resulting brown oil was dried further on a high vacuum line. When it was left to stand, it became a cream white solid (36) (8.74g, 100%) Melting point: 75-78 ?C, lit. value 76.5-77 ?C64; vmax (Solid)/cm-1 3065 (w, CH), 1481 (m), 1448 (m), 1362 (m), 1264 (m), 1177 (s), 1092 (m), 726 (m); ?H (300 MHz; CDCl3; Me4Si) 7.99 (1H, d, J = 8.20, ArH), 7.87 (2H, d, J = 7.50, 2 ? ArH), 7.56 (1H, d, J = 3.70, ArH), 7.53-7.19 (6H, m, 6 ? ArH), 6.65 (1H, d, J = 3.7, ArH); ?C (75 MHz; CDCl3) 138.70 (C), 135.30 (C), 134.20 (CH), 131.20 (C), 129.70 (2 ? CH), 127.10 (2 ? CH), 126.70 (CH), 125.10 (CH), 123.80 (CH), 121.80 (CH), 113.90 (CH), 109.70 (CH); m/z 257 (M+, 100%), 141 (19%), 116 (85%), 89 (21%), 77 (43%) (Found: M+, 257.0521. C14H11SO2N requires 257.0511). 4.1.2 1-(Phenylsulfonyl)-5-methoxy-1H-indole (104) To an ice-cold mixture of sodium hydroxide (0.57 g, 14.30 mmol, 3 eq) and tetra-n-butylammonium bromide (0.04 g, 0.12 mmol, 0.026 eq) in dichloromethane (20.0 ml) under N2, was added solid 5-methoxyindole (102) (0.70 g, 4.77 mmol) in one N S OO N S O O MeO Chapter 4 Experimental Procedures 82 portion followed by slow addition of phenylsulfonyl chloride (0.77 ml, 6.00 mmol, 1.25 eq).The light pink mixture was stirred at rt under N2 for 18 h over which time it turned milky white. Water was added and the reaction mixture was then extracted with CH2Cl2 (3 ? 20 ml). The organic extracts were combined, dried over magnesium sulphate, filtered with the celite plug and the solvent removed on a rotary evaporator. The resulting light brown oil was dried further on a high vacuum line. When it was left to stand, it became a cream white solid (104) 1.37 g, (100%). Melting point: 96-99 ?C, lit. value 97-98 ?C34; vmax (Solid)/cm-1 3002 (w, C-H), 1613 (m), 15384 (m), 1471 (s), 1372 (s), 1226 (m, C-O), 1150 (m), 1092 (m), 940 (w), 844 (w), and 755 (m); ?H (300 MHz; CDCl3; Me4Si) 7.90-7.82 (3H, m, 3 ? ArH), 7.52-7.37 (4H, m, 4 ? ArH), 6.96-6.91 (2H, m, 2 ? ArH), 6.58 (1H, d, J = 3.60, ArH), 3.79 (3H, s, CH3O); ?C (300 MHz; CDCl3) 156.50 (C), 138.20 (C), 133.70 (CH), 129.60 (C), 129.40 (C), 129.20 (2 ? CH), 126.90 (CH), 126.70 (2 ? CH), 114.40 (CH), 113.80 (CH), 109.40 (CH), 103.70 (CH), 55.60 (CH3O); m/z 287 (M+, 61%), 218 (3%), 147 (11%), 146 (100%), 125 (8%), 103 (10%), 77 (16%), 51 (9%), 49 (3%). 4.2 Iodination of indoles (36) and (104) 4.2.1 2-Iodo-1-(phenylsulfonyl)-1H-indole (105) To 1-(phenylsulfonyl)-1H indole (36) (1.00 g, 3.89 mmol) in a dry flask was added isopropyl magnesium chloride solution in THF (~0.8 M in excess) and isopropyl amine (1.0 ml). The reaction mixture was maintained at rt under N2 atmosphere for 16 h. Iodine (2.50 g, 9.73 mmol, 2.5 eq) was added and the mixture was stirred at rt for 1 h. The reaction mixture was quenched by the addition of saturated aqueous solution of ammonium chloride. The mixture was extracted with CH2CH2 (3 ? 30 ml), the organic layers combined and dried over MgSO4, then filtered though celite plug and excess solvent removed on a rotary evaporator. This resulted in a brown oil that was subjected to column chromatography to give cream white solid (105) 1.18 g, (79%). Melting point: 96-99 ?C, N I S OO Chapter 4 Experimental Procedures 83 lit. value 96-98 ?C66; vmax (Solid)/cm-1 2924 (w, CH), 1449(w), 1430 (s), 1372 (s), 1215 (s), 1182 (s), 1123 (s), 1090 (s), 1013 (s), 812 (s), 761 (m), 725 (s), 684 (s), 646 (s); ?H (300 MHz; CDCl3; Me4Si) 8.27 (1H, d, J = 8.32 ArH), 7.90-7.87 (2H, m, 2 ? ArH), 7.56-7.51 (1H, m, ArH), 7.44- 7.38 (3H, m, 2 ? ArH), 7.29-7.20 (2H, m, 2 ? ArH), 6.99 (1H, s, ArH); ?C (75MHz; CDCl3) 141.80 (C), 137.22 (C), 136.94 (C), 132.74 (CH), 130.43 (C), 127.84 (CH), 125.85 (CH), 123.65 (CH), 123.36 (CH), 122.52 (CH), 118.44 (CH), 114.14 (CH); m/z 383 (M+, 5%), 263 (31%), 219 (100%), 150 (5%), 131 (55%), 69 (95%), (Found: 382.9471. C21H17NSO3I requires 382.9477). 4.2.2 2-Iodo-5-methoxy-1-(phenylsulfonyl)-1H-indole (106) To 5-methoxy-1-(phenylsulfonyl)-1H-indole (104) (0.50 g, 1.74 mmol) in a dry flask was added isopropyl magnesium chloride solution in THF (~0.8M in excess) and isopropyl amine (1.0 ml). The reaction mixture was maintained at rt under N2 atmosphere for 16 h. Iodine (0.88 g, 3.48 mmol, 2.5 eq) was added and the mixture was stirred at rt for 1 h. The reaction mixture was quenched by the addition of saturated aqueous solution of ammonium chloride. The mixture was extracted with CH2CH2 (3 ? 30 ml), organic layers combined and dried over MgSO4, then filtered though celite plug and excess solvent removed on a rotary evaporator. The resulting brown oil was subjected to column chromatography to give cream white solid (106) 0.61 g, (85%). Melting point: 127-130 ?C; vmax (Solid)/cm-1 2936 (w, CH), 1611 (m), 1446 (s), 1374 (s), 1226 (m), 1179 (s), 1146 (s), 1082 (s), 1023 (m), 840 (m), 800 (s), 756 (m), 724 (s), 687 (s), 621 (s); ?H (300 MHz; CDCl3; Me4Si) 8.18 (1H, d, J = 9.14, ArH), 7.87 (2H, d, J = 7.49, 2 ? ArH), 7.58-7.53 (1H, m, ArH), 7.46-7.41 (2H, m, 2 ? ArH), 6.93 (1H, s, ArH), 6.89 (1H, d, J = 2.59, ArH), 6.85 (1H, d, J = 2.47, ArH), 3.83 (3H, s, CH3O); ?C (75MHz; CDCl3) 156.94 (C), 138.47 (C), 134.56 (CH), 133.66 (C), 133.05 (C), 129.49 (2 ? CH), 127.48 (2 ? CH), 124.81 (CH), 116.79 (CH), 114.20 (CH), 102.39 (CH), 76.39 (C), 56.02 (CH3O); m/z 412 (M+, 88%), 397 (100%), 330 (18%), 272 (12%), 257 (20%), 191 (3%), 117 (3%), (Found: 412.1070. C15H12INO3 requires 412.9583). N I S OO MeO Chapter 4 Experimental Procedures 84 4.3 Bromination of indoles (36) and (104) 4.3.1 3-Bromo-1-(phenylsulfonyl)-1H-indole (107) To a mixture of 1-phenylsulfonylindole (36) (1.00 g, 3.9 mmol) and sodium acetate (0.32 g, 3.9 mmol, 1eq) in acetic acid (20.0 ml) at 0 ?C, bromine (0.50 ml, and 3.9 mmol, 1 eq) was added dropwise. The reaction mixture was then allowed to warm up to rt before being refluxed under N2 for 14 h over which time it turned from brown to light yellow. After being allowed to cool to rt, the mixture was filtered and the acetic acid from the reaction mixture was removed on the rotary evaporator. The resultant oil was partitioned between water (20 ml) and CH2Cl2 and extracted with CH2Cl2 (3 ? 20 ml). The organic extracts were combined, dried over MgSO4, then filtered with celite plug and excess solvent removed on rotary evaporator. The resulting oil was purified by column chromatography using 10% EtOAc/Hexane as an eluent and this gave the product in 80% yield as a white solid (107). Melting point: 120-124 ?C, lit. value 122-124 ?C68; vmax (Solid)/ cm-1 3139 (w, CH), 1446 (m), 1376 (m), 1176 (s), 1091 (m), 1032 (w), 932 (w), 728 (s); ?H (300 MHz; CDCl3; Me4Si) 8.00 (1H, d, J = 8.21, ArH), 7.88 (2H, d, J = 7.62, 2 ? ArH), 7.62 (1H, s, ArH), 7.57-7.21 (6H, m, 6 ? ArH); ) ?C (75 MHz; CDCl3) 138.21 (C), 134.72 (C), 134.5 (CH), 130.23 (C), 129.80 (2 ? CH), 127.30 (2 ? CH), 126.34 (CH), 125.25 (CH), 124.40 (CH), 120.56 (CH), 113.93 (CH), 99.80 (C); m/z 336 (79Br-M+, 63%), 334 (57%), 257 (11%), 196 (98%), 194 (10%), 193 (100%), 141 (18%), 116 (14%), 115 (27%), 88 (12%), 77 (53%), 51 (17%) (Found: 79Br-M+, 336.9650. C14H10SO2N79Br requires 334.9616). N Br S O O Chapter 4 Experimental Procedures 85 4.3.2 2,3-Dibromo-1-(phenylsulfonyl)-1H-indole (108) 1-(Phenylsulfonyl)-1H-indole (36) (3.00 g, 11.7 mmol) was dissolved in dry DMF (10.0 ml) and bromine (1.6 ml, 12.9 mmol, 1.1 eq) was added dropwise at rt. The red solution was then stirred at rt for 18 h. The resulting reaction mixture was poured into a saturated solution of aqueous NaHCO3 (20 ml). The layers were separated, and extracted with CH2Cl2 (3 ? 20 ml), washed successively with aqueous Na2S2O3 (20.0 ml) and then finally washed with brine (20.0 ml). The organic extracts were dried over MgSO4, filtered with the celite plug and solvent removed on a rotary evaporator. This gave a crude brown solid which was purified by column chromatography using 10% EtOAc/Hexane as an eluent. After the chromatography, the product was recrystallized from ethyl acetate and gave 47% yield of the product as a cream white solid (108). Melting point: 141- 144 ?C, lit. value 141-143 ?C70; vmax (Solid)/cm-1 3071 (w, CH), 1443 (m), 1383 (s),1194 (s), 1092 (m), 1038 (m), 909 (s), 739 (s), 570 (m); ?H (300 MHz; CDCl3; Me4Si) 8.30 (1H, d, J = 8.31 ArH), 7.88 (2H, d, J = 7.52, 2 ? ArH), 7.62-7.31 (6H, m, 6 ? ArH); ?C (75 MHz; CDCl3) 138.21 (C), 137.0 (C), 134.82 (CH), 129.43 (2 ? CH), 127.74 (2 ? CH), 127.55 (C), 127.26 (CH), 125.17 (CH), 120.08 (CH), 115.79 (CH), 111.60 (C), 107.11 (C); m/z 416 ( 81Br-M+, 30%), 415 (79Br-M+, 10%), 414 (58%), 412 (27%), 336 (17%), 275 (49%), 273 (100%), 271 (47%), 195 (24%), 193 (27%), 141 (41%), 114 (40%), 77 (58%), 51 (18%) (Found: 79Br-M+, 415.8816. C14H9SO2NBr2 requires 412.8721 79Br). 4.3.3 3-Bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole (109) A mixture of N-bromosuccinimide (0.060 g, 0.35 mmol, 1.01 eq), 5-methoxy-1 (phenylsulfonyl)-1H-indole (104) (0.10 g, 0.35 mmol) and benzoyl peroxide (0.01g) in dry CCl4 (5 ml), was gently refluxed for 18 h. The reaction mixture was allowed to cool to rt, cooled in ice bath before the succinimide was N Br Br S O O N S OO Br MeO Chapter 4 Experimental Procedures 86 separated by filtration. The last traces of succinimide were removed by shaking the filtrate in a separating funnel with an ice cooled aqueous sodium hydroxide (5%) solution followed by shaking with water. The organic layer was dried over MgSO4 before being evaporated on a rotary evaporator to afford a white solid (109) 0.11 g (85%). Melting point: 129-132 ?C, lit. value 131-133 ?C56; vmax (Solid)/cm-1 3146 (m, CH), 1612 (m), 1474 (s), 1445 (s), 1361 (s), 1313 (m), 1275 (s), 1211 (s), 1159 (s), 1136 (s), 1089 (s), 1034 (s), 963 (s), 835 (m), 819 (m), 800 (m), 765 (s), 749 (s), 722 (s), 683 (s), 650 (s); ?H (300 MHz; CDCl3; Me4Si) 7.90-7.85 (3H, m, 3 ? ArH), 7.58-7.53 (2H, m, 2 ? ArH), 7.47-7.42 (2H, m, 2 ? ArH), 6.98 (1H, d, J = 9.03, ArH), 6.89 (1H, d, J = 1.79, ArH), 3.84 (3H, s, CH3O); ?C (75MHz; CDCl3) 155.92 (C), 136.60 (C), 132.93 (CH), 129.65 (C), 128.24 (2 ? CH), 126.70 (C), 125.65 (2 ? CH), 124.22 (CH), 114.33 (CH), 113.56 (CH), 100.69 (CH), 98.69 (C), 54.59 (CH3O); 4.4 Typical procedure for the synthesis of 2-aryl-1-(phenylsulfonyl)-1H-indole and 2-aryl-5-methoxy-1-(phenylsulfonyl)-1H-indole To Pd(PPh3)4 (10 mol%) under N2 was added a deoxygenated mixture of 2-iodo-1- (phenylsulfonyl)-1H-indole or 2-iodo-5-methoxy-1-(phenylsulfonyl)-1H-indole in DME (5 ml) and arylboronic acid in ethanol (3 ml). The reaction mixture was stirred for about 10 min followed by the addition of a deoxygenated 2 M solution of Na2CO3 in water. The resulting reaction mixture was stirred for further 10 min at rt before being heated to reflux for 8 h. The reaction mixture was allowed to cool to room temperature, quenched with water (10.0 ml) and the organic extracts extracted with CH2Cl2 (3 ? 30 ml). The organic fractions were combined, dried over MgSO4, filtered through a celite plug and then the excess solvent was removed using a rotary evaporator. The resulting black oils were purified by column chromatography using 10% EtOAc/Hexane as an eluent. Chapter 4 Experimental Procedures 87 (a) 2-Phenyl-1-(phenylsulfonyl)-1H-indole (119) Pd(PPh3)4 (0.35 g, 10%), 2-iodo-1-(phenylsulfonyl)-1H-indole (105) (1.00 g, 3.04 mmol) phenyl boronic acid (0.56 g, 4.56 mmol, 1.5 eq), Na2CO3 (2.73 g, 25.8 mmol, 8.5 eq) in water (12.9 ml). This gave white solid (119) (0.89 g, 82%). Melting point: 100-104 ?C, lit value 104-105 ?C64; vmax (Solid)/cm-1 3055 (w, CH), 1585 (w), 1479 (m), 1434 (s), 1372 (s), 1248 (m), 1171 (s), 1115 (m), 1089 (s), 1049 (s), 1026 (s), 976 (s), 837 (m), 754 (s), 732 (s), 682 (s), 635 (s); ?H (300 MHz; CDCl3; Me4Si) 8.31 (1H, d, J = 8.28, ArH), 7.48-7.35 (9H, m, 9 ? ArH), 7.27-7.18 (4H, m, 4 ? ArH), 6.52 (1H, s, ArH); ?C (75MHz; CDCl3) 142.54 (C), 138.73 (C), 137.94 (C), 133.99 (CH), 132.73 (C), 130.79 (CH), 129.15 (CH), 129.02 (CH), 127.99 (CH), 127.17 (CH), 125.32 (CH), 124.88 (CH), 121.22 (CH), 117.07 (CH), 115.79 (C), 114.19 (CH); m/z 333 (M+, 80%), 277 (35%), 219 (96%), 192 (100%), 164 (53%), 131 (37%), 69 (80%), (Found: 333.0826. C21H17NSO3 requires 333.0824). (b) 5-Methoxy-2-phenyl-1-(phenylsulfonyl)-1H-indole (120) Pd(PPh3)4 (0.11 g, 10%), 2-iodo-5-methoxy-1- (phenylsulfonyl)-1H-indole (106) (0.40 g, 0.97 mmol), phenylboronic acid (0.18 g, 1.46 mmol, 1.5 eq), Na2CO3 (0.87 g, 8.23 mmol, 8.5 eq) in water (4.1 ml). This gave a brown oil (120), 0.21 g (60%); vmax (Liquid)/cm-1 3061 (w, CH), 1609 (m), 1468 (s), 1446 (s), 1386 (s), 1207 (m), 1175 (s), 1145 (s), 1089 (m), 1028 (m), 909 (m), 849 (m), 809 (s), 759 (m), 725 (s), 685 (s), 635 (m); ?H (300 MHz; CDCl3; Me4Si) 8.19 (1H, d, J = 9.08, ArH), 7.51-7.45 (2H, m, 2 ? ArH), 7.43-7.39 (4H, m, 4 ? ArH), 7.36-7.33 (2H, m, 2 ? ArH), 7.26-7.21 (2H, m, 2 ? ArH), 6.96 (1H, dd, J = 2.57 and 2.50, ArH), 6.87 (1H, d, J = 2.53, ArH), 6.48 (1H, s, ArH), 3.18 (3H, s, CH3O); ?C (75MHz; CDCl3) 157.14 (C), 143.06 (C), 137.22 (C), N S OO N S OO MeO Chapter 4 Experimental Procedures 88 133.43 (CH), 132.82 (C), 132.29 (C), 131.72 (C), 130.20 (2 ? CH), 128.68 (CH), 128.49 (2 ? CH), 127.53 (2 ? CH), 126.74 (2 ? CH), 117.70 (CH), 113.96 (CH), 113.50 (CH), 103.22 (CH), 55.57 (CH3O); m/z 364 (M+, 48%), 279 (6%), 223 (100%), 208 (2%), 149 (2%), (Found: 363.1920. C21H17NO3S requires 363.0929). (c) 1-(Phenylsulfonyl)-2-o-tolyl-1H-indole (121) Pd(PPh3)4 (0.24 g, 10%), 2-iodo-1-(phenylsulfonyl)-1H-indole (105) (0.50 g, 1.31 mmol), o-tolyl boronic acid (0.41 g, 3.10 mmol, 1.5 eq), Na2CO3 (1.84 g, 17.30 mmol, 8.5 eq) in water (8.7 ml). This gave a brown oil (121), 0.20 g (44%); vmax (Liquid)/cm-1 3063 (w, CH), 1585 (w), 1485 (s), 1369 (s), 1247 (m), 1220 (m), 1174 (s), 1121 (s), 1090 (s), 1064 (s), 995 (m), 822 (m), 747 (s), 724 (s), 684 (s), 641 (s); ?H (300 MHz; CDCl3; Me4Si) 8.37 (1H, d, J = 8.33, ArH), 7.50-7.42 (4H, m, 4 ? ArH), 7.39-7.33 (2H, m, 2 ? ArH), 7.30-7.24 (3H, m, 3 ? ArH), 7.21-7.16 (1H, m, ArH), 7.11-7.03 (2H, m, 2 ? ArH), 6.46 (1H, s, ArH), 2.19 (3H, s, CH3); ?C (75MHz; CDCl3) 140.67 (C), 139.79 (C), 138.97 (C), 137.81 (C), 134.09 (CH), 132.35 (C), 131.42 (CH), 130.52 (C), 130.10 (CH), 129.61 (CH), 129.22 (2 ? CH), 127.30 (2 ? CH), 125.15 (CH), 124.40 (CH), 121.21 (CH), 116.14 (CH), 115.35 (C), 112.90 (CH), 20.89 (CH3); m/z 348 (M+, 100%), 297 (3%), 222 (3%), 207 (80%), 141 (2%), (Found: 347.246. C21H17NO2S requires 347.098). (d) 5-Methoxy-1-(phenylsulfonyl)-2-o-tolyl-1H-indole (122) Pd(PPh3)4 (0.10 g, 0.078 mmol, 10%), 2-iodo-5-methoxy- 1-(phenylsulfonyl)-1H-indole (106) (0.33 g, 0.78 mmol), o-tolylboronic acid (0.16 g, 1.18 mmol, 1.5e q), Na2CO3 (0.71 g, 6.66 mmol, 8.5 eq) in water (3.3 ml). This gave a N S OO N SO O MeO Chapter 4 Experimental Procedures 89 yellow oil (122), 0.23 g (78%); vmax (Liquid)/cm-1 2930 (w, CH), 1611 (m), 1464 (s), 1446 (s), 1367 (s), 1201 (s), 1175 (s), 1144 (s), 1089 (m), 1038 (s), 995 (m), 854 (m), 807 (m), 753 (s), 722 (s), 684 (s); ?H (300 MHz; CDCl3; Me4Si) 8.14 (1H, d, J = 8.97, ArH), 7.36 (3H, d, J = 7.71, 3 ? ArH), 7.28-7.17 (5H, m, 5 ? ArH), 7.11 (1H, t, J = 14.82, ArH), 6.98 (1H, d, J = 7.50, ArH), 6.92-6.87 (2H, m, 2 ? ArH), 6.32 (1H, s, ArH), 3.76 (3H, s, CH3O), 2.13 (3H, s, CH3); ?C (75MHz; CDCl3) 157.24 (C), 141.55 (C), 139.67 (C), 138.78 (C), 133.95 (CH), 132.39 (C), 132.34 (C), 131.57 (C), 131.27 (CH), 130.08 (CH), 129.53 (CH), 129.12 (2 ? CH), 127.23 (2 ? CH), 125.11 (CH), 117.13 (CH), 113.87 (CH), 113.12 (CH), 103.57 (CH), 56.05 (CH3O), 20.87 (CH3). (e) 1-(Phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-indole (123) Pd(PPh3)4 (0.24 g, 10%), 2-iodo-1-(phenylsulfonyl)-1H- indole (105) (0.50 g, 1.31 mmol), 3,4,5-trimethoxy- phenyl boronic acid (0.66 g, 3.10 mmol, 1.5 eq), Na2CO3 (1.84 g, 17.30 mmol, 8.5 eq) in water (8.7 ml). This gave a cream white oil (123), 0.20 g (56%); vmax (Liquid)/cm-1 3066 (w, CH), 1584 (m), 1481 (m), 1447 (s), 1359 (s), 1263 (s), 1203 (s), 1175 (s), 1113 (s), 1091 (s), 1022 (m), 991 (s), 878 (s), 764 (s), 754 (s), 741 (s), 724 (s), 709 (s), 983 (s), 654 (s); ?H (300 MHz; CDCl3; Me4Si) 7.80 (1H, d, J = 8.24, ArH), 7.87 (1H, d, J = 7.58, ArH), 7.56 (1H, d, J = 3.64, ArH), 7.53-7.47 (2H, m, 2 ? ArH). 7.42-7.37 (2H, m, 2 ? ArH), 7.33-7.28 (1H, m, ArH), 7.24-7.19 (1H, m, ArH), 6.65 (1H, d, J = 3.61, ArH), 6.57 (1H, d, J = 8.40, ArH), 3.85 (9H, s, 3 ? CH3O); ?C (75MHz; CDCl3) 155.10 (C), 139.83 (C), 136.41 (C), 135.35 (CH), 132.31 (C), 130.80 (2 ? CH), 128.28 (2 ? CH), 127.86 (CH), 126.20 (CH), 125.20 (2 ? C), 124.93 (CH), 122.97 (CH), 115.07 (CH), 110.79 (CH), 106.84 (CH), 62.38 (CH3O), 57.63 (2 ? CH3O). N SO O OMe OMe OMe Chapter 4 Experimental Procedures 90 (f) 5-Methoxy-1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-indole (124) Pd(PPh3)4 (0.10 g, 0.078 mmol, 10%), 2-iodo-5- methoxy-1-(phenylsulfonyl)-1H-indole (106) (0.33 g, 0.78 mmol), 3,4,5- trimethoxyphenylboronic acid (0.20 g, 1.00 mmol, 1.5 eq), Na2CO3 (0.71 g, 6.66 mmol, 8.5 eq) in water (3.3 ml). This gave a brown oil (124), 0.20 g (77%); vmax (Liquid)/cm-1 2936 (w, CH), 1608 (w), 1581 (m), 1501 (w), 1470 (m), 1447 (m), 1411 (m), 1367 (m), 1336 (m), 1232 (m), 1173 (m), 1144 (m), 1121 (m), 1087 (m), 1029 (m), 998 (m), 909 (m), 840 (m), 803 (m), 754 (m), 721 (m), 685 (m); ?H (300 MHz; CDCl3; Me4Si) 8.21 (1H, d, J = 9.08, ArH), 7.44 (1H, t, J = 14.49, ArH), 7.36 (2H, d, J = 7.91, 2 ? ArH), 7.28-7.23 (2H, m, 2 ? ArH), 6.97 (1H, d, J = 9.11, ArH), 6.89 (1H, s, ArH), 6.66 (2H, s, 2 ? ArH), 6.48 (1H, s, ArH), 3.94 (3H, s, CH3O), 3.87 (6H, s, 2 ? CH3O), 3.83 (3H, s, CH3O); ?C (75MHz; CDCl3) 156.48 (C), 151.65 (2 ? C), 142.21 (C), 137.93 (C), 136.73 (C), 132.84 (CH), 132.26 (C), 130.85 (C), 127.82 (2 ? CH), 126.71 (C), 126.16 (2 ? CH), 117.12 (CH), 112.85 (2 ? CH), 107.21 (2 ? CH), 102.49 (CH), 60.39 (CH3O), 55.58 (2 ? CH3O), 54.93 (CH3O). (g) 2-(4-Methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (125) Pd(PPh3)4 (0.24 g, 10%), 2-iodo-1-(phenylsulfonyl)-1H- indole (105) (0.79 g, 2.06 mmol), 4?methoxy-phenyl boronic acid (0.47 g, 3.09 mmol, 1.5 eq), Na2CO3 (1.86 g, 17.51 mmol, 8.5 eq) in water (8.9 ml). This gave a cream white solid (125), 0.40 g (60%). Melting point 209-212 ?C; vmax (Solid)/cm-1 3066 (w, CH), 1614 (m), 1566 (m), 1503 (s), 1442 (s), 1353 (s), 1300 (m), 1249 (s), 1224 (m), 1172 (s), 1151 (m), 1121 (m), 1069 (m), 1027 (m), 998 (m), 833 (s), 809 (s), 772 (m), 732 (s), 698 (m), 660 (s); ?H (300 N SO O OMe OMe OMe MeO N S OO OMe Chapter 4 Experimental Procedures 91 MHz; CDCl3; Me4Si) 8.25 (1H, d, J = 8.27, ArH), 7.90 (1H, d, J = 7.42, ArH), 7.56 (1H, d, J = 7.51, ArH), 7.38-7.26 (4H, m, 4 ? ArH), 7.11-7.01 (4H, m, 4 ? ArH), 6.67 (2H, d, J = 8.53, 2 ? ArH), 6.53 (1H, s, ArH), 3.80 (3H, s, CH3O); ?C (75MHz; CDCl3) 160.30 (C), 142.95 (C), 142.71 (CH), 140.39 (C), 139.76 (C), 133.91 (CH), 132.46 (2 ? CH), 131.89 (CH), 129.22 (C), 127.94 (CH), 124.74 (CH), 123.82 (CH), 121.09 (CH), 116.96 (CH), 113.33 (2 ? CH), 111.49 (CH), 92.39 (C), 55.75 (CH3O); m/z 364 (M+, 82%), 347 (28%), 328 (4%), 267 (2%), 127 (2%), (Found: 362.2600. C21H17NO3S requires 363.0929). (h) 5-Methoxy-2-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (126) Pd(PPh3)4 (0.10 g, 0.078 mmol, 10%), 2-iodo-5- methoxy-1-(phenylsulfonyl)-1H-indole (106) (0.33 g, 0.78 mmol), 4-methoxy-phenylboronic acid (0.18 g, 1.18 mmol, 1.5 eq), Na2CO3 (0.71 g, 6.66 mmol, 8.5 eq) in water (3.3 ml). This gave a yellow oil (126), 0.19 g (61%); vmax (Liquid)/cm-1 2933 (w, CH), 1609 (m), 1505 (m), 1467 (s), 1446 (m), 1366 (m), 1248 (m), 12074 (m), 1172 (m), 1144 (m), 1088 (m), 1061 (m), 990 (m), 946 (m), 832 (m), 805 (m), 789 (m), 753 (m), 724 (m), 684 (m), 629 (m), 611 (m); ?H (300 MHz; CDCl3; Me4Si) 8.11 (1H, d, J = 9.04, ArH), 7.32 (3H, d, J = 8.58, 3 ? ArH), 7.26 (2H, d, J = 8.00, 2 ? ArH), 7.18-7.13 (2H, m, 2 ? ArH), 6.88-6.84 (3H, m, 3 ? ArH), 6.78 (1H, d, J = 2.31, ArH), 6.69 (2H, s, ? ArH), 6.33 (1H, s, ArH), 3.79 (3H, s, CH3O), 3.73 (3H, s, CH3O); ?C (75MHz; CDCl3) 159.75 (C), 156.79 (C), 142.67 (C)136.95 (C), 133.08 (CH), 132.40 (C), 131.53 (C), 131.22 (2 ? CH), 128.16 (2 ? CH), 126.42 (2 ? CH), 124.31 (C), 117.41 (CH), 115.71 (CH), 114.51 (CH), 112.87 (CH), 112.72 (2 ? CH), 102.80 (CH), 55.26 (CH3O), 55.00 (CH3O). N SO O MeO OMe Chapter 4 Experimental Procedures 92 (i) 2-(Naphthalen-1-yl)-1-(phenylsulfonyl)-1H-indole (127) Pd(PPh3)4 (0.24 g, 10%), 2-iodo-1-(phenylsulfonyl)-1H-indole (105) (0.50 g, 1.31 mmol), naphthalen-1-ylboronic acid (0.34 g, 1.97 mmol, 1.5 eq), Na2CO3 (1.84 g, 17.30 mmol, 8.5 eq) in water (8.7 ml). This gave a brown oil (127), 0.30 g (60%); vmax (Liquid)/cm-1 3061 (w, CH), 1575 (w), 1480 (m), 1423 (s), 1349 (s), 1263 (m), 1184 (s), 1119 (m), 1081 (s), 1043 (s), 1021 (s), 979 (s), 833 (m), 756 (s), 739 (s), 687 (s), 639 (s); ?H (300 MHz; CDCl3; Me4Si) 8.00 (1H, d, J = 8.26, ArH), 7.93 (1H, d, J = 8.06, ArH), 7.85 (2H, d, J = 7.75, 2 ? ArH), 7.63 (1H, d, J = 8.46, ArH), 7.55 (1H, d, J = 3.64, ArH), 7.51-7.12 (10H, m, 10 ? ArH), 6.65-6.62 (1H, m, ArH); ?C (75MHz; CDCl3) 140.22 (C), 139.64 (C), 139.01 (C), 136.25 (C), 135.18 (CH), 134.92 (CH), 134.46 (C), 132.14 (C), 130.98 (CH), 130.74 (CH), 130.62 (2 ? CH), 130.02 (CH), 129.45 (CH), 128.21 (CH), 128.09 (2 ? CH), 127.69 (CH), 127.45 (CH), 127.25 (CH), 126.29 (CH), 126.03 (CH), 125.84 (CH), 125.46 (CH), 124.77 (CH), 122.27 (CH), 117.17 (CH), 115.28 (C), 114.91 (CH), 110.64 (CH); m/z 382 (M-, 60%), 257 (20%), 242 (100%), 213 (10%), 141 (10%), 116 (21%), 88 (8%), 77 (25%) (Found: 383.9120. C24H17NSO2 requires 383.4623). 4.5 Typical procedure for removing of phenylsulfonyl protecting group on 2- aryl-1-(phenylsulfonyl)-1H-indoles and 2-aryl-5-methoxy-1-(phenylsulfonyl)- 1H-indoles The substrate was dissolved in methanol (20 ml) at rt under N2 atmosphere, K2CO3 was added to the solution and the reaction mixture was heated to reflux under N2 for 18 h. The reaction mixture was then allowed to cool to rt and filtered through a celite plug and then the filtrate concentrated under reduced pressure. Water was added to the crude material and slowly acidified to pH 2-4 with aqueous 10% HCl. The aqueous portion was saturated with solid NaCl and the organic material extracted with CH2Cl2 (3 ? 30 ml). The combined organic extracts were washed N S O O Chapter 4 Experimental Procedures 93 two times with water (20 ml), brine (20 ml), dried over MgSO4 and concentrated under reduced pressure. This resulted in brown oils that were subjected to column chromatography using 10% EtOAc/Hexane as an eluent. (a) 2-Phenyl-1-H-indole (128) 2-Phenyl-1-phenylsulfonylindole (119) (0.79 g, 2.37 mmol), K2CO3 (62.30 g, 450 mmol, 190 eq). Column chromatography gave a cream white solid (128) 0.36 g (78%). Melting point 182- 186 ?C, lit. value 182-184 ?C79; vmax (Solid)/cm-1 3441 (s, NH), 3050 (w, CH), 1601 (w), 1542 (m), 1480 (s), 1446 (s), 1403 (m), 1352 9s), 1298 (s), 1230 (m), 1184 (s), 1075 (m), 907 (s), 797 (m), 763 (s), 738 (s), 687 (s); ?H (300 MHz; CDCl3; Me4Si) 8.36 (1H, s, NH), 7.70 (3H, d, J = 7.31, 3 ? ArH), 7.51-7.35 (4H, m, 4 ? ArH), 7.28-7.16 (2H, m, 2 ? ArH), 6.88 (1H, s, ArH); ?C (75MHz; CDCl3) 138.33 (C), 137.27 (C), 132.81 (C), 129.71 (C), 129.45 (2 ? CH), 128.14 (CH), 125.56 (2 ? CH), 122.79 (CH), 120.71 (CH), 111.36 (CH), 100.43 (CH); m/z 194 (M+, 100%), 167 (4%), 116 (4%), (Found: 193.2140. C14H10N requires 193.0892). (b) 5-Methoxy-2-phenyl-1H-indole (129) 5-Methoxy-2-phenyl-1-(phenylsulfonyl)-1H-indole (120) (0.15 g, 0.41 mmol), K2CO3 (10.83 g, 79 mmol, 190 eq). Column chromatography gave a cream white solid (129) 0.055 g (61%). Melting point 162-165 ?C; vmax (Solid)/cm-1 3427 (m, NH), 2999 (w, CH), 1621 (m), 1476 (s), 1448 (s), 1301 (m), 1215 (s), 1150 (s), 1116 (m), 1026 (s), 945 (w), 840 (s), 801 (s), 763 (s), 736 (s), 692 (s); ?H (300 MHz; CDCl3; Me4Si) 8.21 (1H, s, NH), 7.64 (2H, d, J = 8.31, 2 ? ArH), 7.45-7.40 (2H, m, 2 ? ArH), 7.33-7.25 (2H, m, 2 ? ArH), 7.09 (1H, s, ArH), 6.85 (1H, dd, J = 2.37 and 2.34, ArH), 6.76 (1H, s, ArH), N H N H MeO Chapter 4 Experimental Procedures 94 3.86 (3H, s, CH3O); ?C (75MHz; CDCl3) 154.93 (C), 139.01 (C1), 132.85 (C1), 132.43 (C), 130.15 (C), 129.40 (2 ? CH), 128.03 (CH), 125.45 (2 ? CH), 113.04 (CH), 112.01 (CH), 102.71 (CH), 100.26 (CH), 56.26 (CH3O); m/z 224 (M+, 100%), 209 (6%), 143 (2%), (Found: 223.2430. C15H13NO requires 223.0997). (c) 2-o-Tolyl-1H-indole (130) 1-(phenylsulfonyl)-2-o-tolyl-1H-indole (121) (0.19 g, 0.55 mmol), K2CO3 (14.37 g, 104 mmol, 190 eq). Column chromatography gave a cream white solid (130) 0.09 g (82%). Melting point 81-85 ?C, lit. value 92-93 ?C80; vmax (Solid)/cm-1 3396 (s, NH), 3050 (w, CH), 1485 (m), 1452 (s), 1400 (m), 1345 (s), 1301 (s), 1230 (m), 1118 (m), 797 (s), 742 (s), 719 (s), 677 (m); ?H (300 MHz; CDCl3; Me4Si) 8.04 (1H, s, NH), 7.63 (1H, d, J = 7.65, ArH), 7.44-7.41 (1H, m, ArH), 7.35 (1H, d, J = 7.87, ArH), 7.27-7.24 (3H, m, 3 ? ArH), 7.19-7.10 (2H, m, 2 ? ArH), 6.59 (1H, s, ArH), 2.47 (3H, s, CH3); ?C (75MHz; CDCl3) 137.89 (C), 136.61 (C), 136.55 (C), 133.09 (C), 131.51 (CH), 129.44 (CH), 129.31 (C), 128.41 (CH), 126.53 (CH), 122.50 (CH), 120.98 (CH), 120.50 (CH), 111.23 (CH), 103.42 (CH), 21.55 (CH3); m/z 208 (M+, 100%), 193 (4%), 130 (2%), (Found: 207.2320. C15H13N requires 207.1048). (d) 5-methoxy-2-o-tolyl-1H-indole (131) 5-Methoxy-2-o-tolyl-1-(phenylsulfonyl)-1H-indole (122) (0.19 g, 0.50 mmol), K2CO3 (13.21 g, 96 mmol, 190 eq). Column chromatography gave a yellow oil (131) 0.080 g (67%); vmax (Liquid)/cm-1 3408 (m, NH), 2918 (m, CH), 1621 (w), 1585 (w), 1479 (s), 1436 (s), 1275 (w), 1215 (s), 1150 (m), 1117 (m), 1032 (m), 844 (m), 798 (m), 752 (s), 722 (m); ?H (300 MHz; CDCl3; Me4Si) 8.03 (1H, s, NH), 7.46 (1H, t, J = N H N H MeO Chapter 4 Experimental Procedures 95 8.31, ArH), 7.28-7.25 (4H, m, 4 ? ArH), 7.11 (1H, s, ArH), 6.87 (1H, dd, J = 10.56, ArH), 6.55 (1H, s, ArH), 3.87 (3H, s, CH3O), 2.50 (3H, s, CH3); ?C (75MHz; CDCl3) 154.43 (C), 138.24 (C), 136.07 (C), 132.71 (C), 131.32 (C), 131.08 (CH). 129.30 (C), 128.90 (CH), 127.93 (CH), 126.10 (CH), 112.36 (CH), 111.48 (CH), 102.86 (CH), 102.25 (CH), 55.94 (CH3O), 21.13 (CH3). (e) 2-(3,4,5-Trimethoxyphenyl)-1H-indole (132) 1-(phenylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-1H-indole (123) (0.15 g, 0.35 mmol), K2CO3 (9.18 g, 67 mmol, 190 eq). Column chromatography gave a white solid (132) 0.05 g (51%). Melting point 206-209 ?C, lit. value 205- 206.5 ?C81; vmax (Solid)/cm-1 3321 (m, NH), 3000 (w, CH), 1593 (s), 1501 (m), 1445 (m), 1427 (m), 1364 (m), 1286 (m), 1234 (s), 1126 (s), 996 (s), 836 (m), 784 (s), 728 (s), 693 (m), 633 (s); ?H (300 MHz; CDCl3; Me4Si) 8.42 (1H, s, NH), 7.62 (1H, d, J = 7.68, ArH), 7.40 (1H, d, J = 7.95, ArH), 7.25-7.10 (2H, m, 2 ? ArH), 6.86 (2H, s, 2 ? ArH), 6.75 (1H, s, ArH), 3.93 (6H, s, 2 ? CH3O), 3.90 (3H, s, CH3O); ?C (75MHz; CDCl3) 154.13 ( 2 ? C), 138.54 (C), 137.22 (C), 129.65 (C), 128.82 (C), 122.71 (CH), 120.95 (CH), 120.71 (CH), 111.30 (CH), 103.20 (2 ? CH), 100.31 (CH), 93.33 (C), 61.43 (CH3O), 56.66 (2 ? CH3O); m/z 284 (M+, 100%), 253 (4%), 155 (2%), 118 (2%), (Found: 283.2900. C17H17NO3 requires 283.1208). (f) 5-Methoxy-2-(3,4,5-trimethoxyphenyl)-1H-indole (133) 5-Methoxy-1-(phenylsulfonyl)-2-(3,4,5- trimethoxyphenyl)-1H-indole (124) (0.22 g, 0.49 mmol), K2CO3 (12.70 g, 92 mmol, 190 eq). Column chromatography gave a white solid (133) N H OMe OMe OMe N H MeO OMe OMe OMe Chapter 4 Experimental Procedures 96 0.12 g (86%). Melting point 152-155 ?C; vmax (Solid)/cm-1 3366 (m, NH), 2917 (m, CH), 1610 (w), 1583 (s), 1461 (s), 1354 (m), 1297 (s), 1227 (m), 1124 (s), 1001 (s), 804 (s), 765 (s), 727 (s); ?H (300 MHz; CDCl3; Me4Si) 8.38 (1H, s, NH), 7.30-7.26 (1H, m, ArH), 7.08 (1H, s, ArH), 6.85 (2H, s, 2 ? ArH), 7.72-6.66 (2H, m, 2 ? ArH), 3.93 (6H, s, 2 ? CH3O), 3.90 (3H, s, CH3O), 3.86 (3H, s, CH3O); ?C (75MHz; CDCl3) 154.88 (C), 154.09 (2 ? C), 153.78 (C), 139.29 (C), 132.40 (C), 130.11 (C), 128.87 (C), 112.86 (CH), 112.04 (CH), 103.03 (2 ? CH), 102.59 (CH), 100.12 (H), 66.43 (CH3O), 56.63 (2 ? CH3O), 56.25 (CH3O). (g) 2-(4-Methoxyphenyl)-1H-indole (134) 2-(4-Methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (125) (0.40 g, 1.10 mmol), K2CO3 (28.40 g, 209 mmol, 190 eq). Column chromatography gave a cream white solid (134) 0.13 g (52%). Melting point 228-230 ?C, lit. value 227-231 ?C82; vmax (Solid)/cm-1 3428 (m, NH), 2837 (w, CH), 1543 (m), 1431 (s), 1350 (m), 1287 (m), 1242 (m), 1114 (m), 1026 (s), 933 (w), 834 (s), 782 (s), 738 (s), 659 (m); ?H (300 MHz; DMSO; Me4Si) 11.40 (1H, s, NH), 7.79 (2H, d, J = 8.65, 2 ? ArH), 7.49 (1H, d, J = 7.71, ArH), 7.37 (1H, d, J = 7.96, ArH), 7.08- 6.95 (4H, m, 4 ? ArH), 6.76 (1H, s, ArH), 3.81 (3H, s, CH3O); ?C (75MHz; DMSO) 160.96 (C), 139.93 (C), 139.09 (C), 130.99 (C), 128.53 (2 ? CH), 127.08 (C), 123.19 (CH), 121.81 (CH), 121.38 (CH), 116.52 (2 ? CH), 113.22 (CH), 99.50 (CH), 57.38 (CH3O); m/z 224 (M+, 100%), 209 (4%), 141 (2%), (Found: 223.2450. C15H13NO requires 223.0997). (h) 5-Methoxy-2-(4-methoxyphenyl)-1H-indole (135) 5-Methoxy-2-(4methoxyphenyl)-1- (phenylsulfonyl)-1H-indole (126) (0.16 g, 0.41 mmol), K2CO3 (10.67 g, 77 mmol, 190 eq). Column chromatography gave a white solid (135) N H OMe N H MeO OMe Chapter 4 Experimental Procedures 97 0.051 g (51%). Melting point 116-120 ?C; vmax (Solid)/cm-1 3444 (w, NH), 2931 (w, CH), 1609 (m), 1504 (m), 1467 (s), 1352 (m), 1249 (m), 1210 (m), 1171 (s), 1143 (m), 1089 (m), 1067 (s), 946 (w), 829 (m), 800 (m), 790 (s), 764 (m), 678 (s), 624 (s); ?H (300 MHz; acetone-d6; Me4Si) 10.22 (1H, s, NH), 7.64-7.61 (2H, m, 2 ? ArH), 7.13 (1H, d, J = 8.71, ArH), 6.91-6.89 (2H, m, 2 ? ArH), 6.89 (1H, s, ArH), 6.60 (1H, d, J = 2.46, ArH), 6.58 (1H, d, J = 2.41, ArH), 6.55 (1H, s, ArH), 3.71 (3H, s, CH3O), 3.66 (3H, s, CH3O); ?C (75 MHz; acetone-d6) 160.26 (C), 155.29 (C), 139.60 (C), 133.40 (C), 130.92 (C), 127.18 (2 ? CH), 126.47 (C), 115.20 (2 ? CH), 112.45 (CH), 112.36 (CH), 102.55 (CH), 98.67 (CH), 55.82 (CH3O), 55.66 (CH3O); (i) 2-(Naphthalen-1-yl)-1H-indole (136) 2-(naphthalen-1-yl)-1-(phenylsulfonyl)-1H-indole (127) (0.30 g, 0.78 mmol), K2CO3 (20.57 g, 147 mmol, 190 eq). Column chromatography gave a cream white solid (136) 0.10 g (52%). Melting point 96-100 ?C, lit. value 99-102 ?C83; vmax (Solid)/cm-1 3344 (m, NH), 3048 (w, CH), 1595 (w), 1508 (w), 1453 (m), 1394 (m), 1344 (m), 1299 (m), 1107 (w), 783 (s), 773 (s), 737 (s), 693 (s), 656 (m); ?H (300 MHz; CDCl3; Me4Si) 8.30-8.27 (1H, m, ArH), 8.19 (1H, s, NH), 7.90-7.84 (2H, m, 2 ? ArH), 7.69 (1H, d, J = 7.60, ArH), 7.57 (1H, d, J = 6.23, ArH), 7.58-7.45 (3H, m, 3 ? ArH), 7.37 (1H, d, J = 7.85, ArH), 7.24-7.14 (2H, m, 2 ? ArH), 6.77 (1H, s, ArH); ?C (75MHz; CDCl3) 137.67 (C), 137.34 (C1), 134.89 (C), 132.51 (C), 132.07 (C1), 129.84 (C), 129.53 (CH), 129.43 (CH), 128.15 (CH), 127.63 (CH), 127.12 (CH), 126.66 (CH), 126.29 (CH), 123.15 (CH), 121.58 (CH), 1231.14 (CH), 111.84 (CH), 104.66 (CH); m/z 244 (M+, 100%), 217 92%), 155 (2%), 105 (2%), (Found: 243.2380. C18H13N requires 243.1048). N H Chapter 4 Experimental Procedures 98 (j) 2-(4-Bromo-2,5-dimethoxyphenyl)-1H-indole (166) 2-(4-Bromo-2,5-dimethoxyphenyl)-1-phenylsulfonylindole (164) (0.38 g, 0.806 mmol), K2CO3 (20.73 g, 150 mmol, 190 eq). Column chromatography gave a cream white solid (166) 0.14 g (52%). Melting point 158-161 ?C; vmax (Solid)/cm-1 3450 (m, NH), 2938 (w, CH), 1531 (m), 1482 (s), 1415 (m), 1325 (m), 1211 (s), 1178 (m), 1028 (m), 930 (w), 853 (w), 785 (s), 753 (s), 672 (m); ?H (300 MHz; CDCl3; Me4Si) 9.63 (1H, s, NH), 7.63 (1H, d, J = 7.79, ArH), 7.41 (1H, d, J = 8.03, ArH), 7.32 (1H, s, ArH), 7.24-7.17 (2H, m, 2 ? ArH), 7.14-7.08 (1H, m, ArH), 6.88 (1H, s, ArH), 3.94 (3H, s, CH3O), (3H, s, CH3O); ?C (75MHz; CDCl3) 151.12 (C), 150.51 (C), 136.65 (C1), 135.51 (C), 128.27 (C), 122.68 (CH), 120.96 (CH), 120.75 (C), 120.45 (CH), 118.04 (CH), 111.81 (C), 111.46 CH), 111.12 (CH), 100.56 (CH) 57.31 (CH3O), 57.19 (CH3O); m/z 331 (M+, 78%), 316 (22%), 264 (26%), 219 (100%), 131 (44%), 69 (90%), (Found: 331.0234. C21H17NSO3 requires 331.0208). (k) 2-(4-Bromo-2,5-dimethoxyphenyl)-5-methoxy-1H-indole (167) 2-(4-Bromo-2,5-dimethoxyphenyl)-5-methoxy-1- (phenylsulfonyl)-1H-indole (165) (0.070 g, 0.14 mmol), K2CO3 (3.67 g, 27 mmol, 190 eq). Column chromatography gave a yellow solid (167) 0.020 g (40%). Melting point 166-170 ?C; vmax (Solid)/cm-1 3397 (m, NH), 2919 (m, CH), 1623 (w), 1531 (w), 1497 (m), 1464 (m), 1438 (m), 1413 (m), 1275 (m), 1204 (s), 1181 (w), 1149 (m), 1023 (s), 948 (w), 843 (m), 825 (m), 750 (s), 618 (w); ?H (300 MHz; CDCl3; Me4Si) 9.54 (1H, s, NH), 7.33-7.26 (2H, m, 2 ? ArH), 7.21 (1H, s, ArH), 7.08 (1H, s, ArH), 6.88-6.82 (2H, m, 2 ? ArH), 3.97 (3H, s, CH3O), 3.94 (3H, s, CH3O), 3.86 (3H, s, CH3O); ?C (75MHz; CDCl3) 154.41 (C), 150.77 (C), 150.10 (C), 135.69 (C), 131.57 (C), N H Br MeO OMe N H MeO Br OMe MeO Chapter 4 Experimental Procedures 99 128.32 (C), 120.66 (C), 117.67 (CH), 112.82 (CH), 111.80 (CH), 111.41 (CH), 110.63 (C), 101.73 (CH), 99.89 (CH), 56.95 (CH3O), 56.81 (CH3O), 55.85 (CH3O); 4.6 General procedure for the synthesis of 3-aryl-1-(phenylsulfonyl)indole and 3-aryl-5-methoxy-1-(phenylsulfonyl)indole To Pd(PPh3)4 (10 mol%) under N2 was added a deoxygenated mixture of 3-bromo-1- (phenylsulfonyl)-1H-indole or 3-bromo-5-methoxy-1-(phenylsulfonyl)-1H-indole in DME (5 ml) and arylboronic acid in ethanol (3 ml). The reaction mixture was stirred for about 10 min followed by the addition of deoxygenated solution of Na2CO3 in water. The resulting reaction mixture was stirred for further 10 mins at rt before being heated to reflux for 8 h. The reaction mixture was allowed to cool to rt, quenched with water (10.0 ml) and the organic extracts extracted with CH2CH2 (3 ? 30 ml). The organic fractions were combined, dried over MgSO4, filtered through a celite plug and then the excess solvent was removed on a rotary evaporator. The resulting black oil was purified by column chromatography using 10% EtOAc/Hexane as an eluent. (a) 3-Phenyl-1-(phenylsulfonyl)-1H-indole (137) Pd(PPh3)4 (0.16 g, 10%), 3-bromo-1-(phenylsulfonyl)-1H-indole (107) (0.45 g, 1.34 mmol), phenylboronic acid (0.25 g, 2.01 mmol, 1.5 eq), Na2CO3 (1.21 g, 11.4 mmol, 8.5 eq). This gave a yellow oil (137) that solidified on standing in 89% yield. Melting point: 139-142 ?C, lit. value 141-143 ?C64; vmax (Solid)/cm-1 3067 (m, CH), 1607 (w), 1447 (s), 1373 (s), 177 (s), 1132 (s), 1015 (m), 909 (s), 733 (s); ?H (300 MHz; CDCl3; Me4Si) 8.07 (1H, d, J = 8.21, ArH), 7.92 (2H, d, J = 7.52, 2 ? N S O O Chapter 4 Experimental Procedures 100 ArH), 7.77 (1H, d, J = 7.83, ArH) 7.70 (1H, s, ArH), 7.61-7.24 (10H, m, 10 ? ArH); ?C (75 MHz; CDCl3) 138.61 (C), 135.92 (C), 134.30 (CH), 133.43 (C),129.74 (2 ? CH), 129.62 (C), 129.48 (2 ? CH), 128.39 (2 ? CH), 128.06 (CH), 127.27 (2 ? CH), 125.40 (CH), 124.55 (C), 124.11 (CH), 123.38 (CH), 120.94 (CH), 114.30 (CH); m/z 333 (M+, 42%), 193 (18%), 192 (100%), 165 (13%) and 77 (7%) (Found: 333.0830. C20H15SO2N requires 333.0824). (b) 5-Methoxy-3-phenyl-1-(phenylsulfonyl)-1H-indole (138) Pd(PPh3)4 (0.10 g, 0.055 mmol, 10%), 3-bromo-5-methoxy-1- (phenylsulfonyl)-1H-indole (109) (0.20 g, 0.55 mmol), phenylboronic acid (0.10 g, 0.82 mmol, 1.5 eq), Na2CO3 (0.49 g, 4.70 mmol, 8.5 eq) in water (2.3 ml). This gave a yellow oil (138), 0.17 g (86%); vmax (Liquid)/cm-1 3004 (w, CH), 1607 (m), 1470 (s), 1448 (s), 1364 (s), 1262 (s), 1211 (s), 1171 (s), 1143 (s), 1129 (s), 1086 (s), 1029 (s), 997 (w), 958 (m), 850 (m), 836 (m), 801 (s), 750 (s), 723 (s), 682 (s), 650 (m); ?H (300 MHz; CDCl3; Me4Si) 7.96 (1H, d, J = 8.64, ArH), 7.89 (2H, d, J = 7.69, 2 ? ArH), 7.65 (1H, s, ArH), 7.57 (2H, d, J = 7.68, 2 ? ArH), 7.51-7.37 (6H, m, 6 ? ArH), 7.19 (1H, s, ArH), 6.98 (1H, d, J = 9.13, ArH), 3.80 (3H, s, CH3O); ?C (75MHz; CDCl3) 156.23 (C), 137.49 (C), 133.26 (CH), 132.46 (C), 129.77 (C), 128.72 (2 ? CH), 128.41 (2 ? CH), 127.24 (2 ? CH), 127.03 (CH), 126.35 (C), 126.19 (2 ? CH), 123.72 (C), 123.20 (CH), 114.18 (CH), 113.37 (CH), 102.39 (CH), 55.17 (CH3O). N S OO MeO Chapter 4 Experimental Procedures 101 (c) 3-ortho-Tolyl-1-(phenylsulfonyl)-1H-indole (139) Pd(PPh3)4 (0.17g, 10%), 3-bromo-1-(phenylsulfonyl)-1H-indole (107) (0.50 g, 1.49 mmol), o-tolylboronic acid (0.30 g, 2.23 mmol, 1.5 eq), Na2CO3 (1.34 g, 12.7 mmol, 8.5 eq) in water (6.3 ml). This gave a brown oil (139) that did not solidify on standing (0.35g, 68%) literature reported (139) as a light orange oil56; vmax (Liquid)/cm-1 3069 (w, CH), 1600 (m), 1448 (m), 1376 (m), 1186 (m), 1014 (w), 909 (s), and 731 (s); ?H (300 MHz; CDCl3; Me4Si) 8.07 (1H, d, J = 8.21, ArH), 7.98-7.87 (2H, m, 2 ? ArH), 7.52-7.22 (11H, m, 11 ? ArH), 2.21 (3H, s, CH3); ?C (75 MHz; CDCl3) 138.60 (C), 137.91 (C), 137.33 (C), 135.42 (C), 134.23 (CH), 130.94 (CH), 129.96 (C), 129.78 (2 ? CH), 128.45 (CH), 127.20 (2 ? CH), 126.25 (CH), 125.36 (CH), 124.57 (CH), 123.90 (CH), 121.23 (CH), 114.29 (CH), 120.50 (CH), 100.38 (C), 20.85 (CH3); m/z 347 (M+, 9%), 336 (37%), 334 (36%), 258 (16%), 257 (100%), 206 (13%), 195 (52%), 193 (55%), 141 (31%), 117 (13%), 116 (88%), 89 (29%), 88 (10%), 77 (84%), 63 (11%), 51 (28%) (Found: 347.0979. C21H17SO2N requires 347.0980). (d) 5-Methoxy-1-(phenylsulfonyl)-3-o-tolyl-1H-indole (140) Pd(PPh3)4 (0.10 g, 0.055 mmol, 10%), 3-bromo-5-methoxy-1- (phenylsulfonyl)-1H-indole (109) (0.20 g, 0.55 mmol), o- tolylboronic acid (0.11 g, 0.82 mmol, 1.5 eq), Na2CO3 (0.49 g, 4.70 mmol, 8.5 eq) in water (2.3 ml). This gave a cream white solid (140), 0.20 g (95%). Melting point 111-114 ?C, lit. value 127-128 ?C56; vmax (Solid)/cm-1 3198 (w, CH), 1606 (m), 1470 (s), 1445 (s), 1362 (s), 1257 (s), 1213 (m), 1172 (s), 1134 (s), 1085 (s), 1030 (s), 985 (m), 855 (s), 804 (m), 755 (s), 720 (s), 682 (s), 652 (s), 630 (s); ?H (300 MHz; CDCl3; Me4Si) 7.96 (1H, d, J = 9.02, ArH), 7.87 (2H, d, J = 8.47, 2 ? ArH), 7.56-7.41 (4H, m, 4 ? ArH), 7.32-7.24 (4H, N S O O N S OO MeO Chapter 4 Experimental Procedures 102 m, 4 ? ArH), 6.96 (1H, dd, J = 2.12 and 2.16, ArH), 6.73 (1H, d, J = 2.04, ArH), 3.73 (3H, s, CH3O), 2.19 (3H, s, CH3); ?C (75MHz; CDCl3) 157.17 (C), 138.44 (C), 137.28 (C), 134.18 (CH), 132.31 (C), 132.22 (C), 130.95 (CH), 130.78 (CH), 130.07 (C), 129.63 (2 ? CH), 128.04 (CH), 127.13 (2 ? CH), 126.28 (CH), 125.30 (CH), 124.38 (C), 115.20 (CH), 114.48 (CH), 103.29 (CH), 56.10 (CH3O), 20.78 (CH3). (e) 1-(Phenylsulfonyl)-3-(3,4,5-trimethoxyphenyl)-1H-indole (141) Pd(PPh3)4 (0.10 g, 0.060 mmol, 10%), 3-bromo-1- (phenylsulfonyl)-1H-indole (107) (0.20 g, 0.60 mmol), 3,4,5- trimethoxyphenylboronic acid (0.10 g, 0.89 mmol, 1.5 eq), Na2CO3 (0.53 g, 5.06 mmol, 8.5 eq) in water (2.5 ml). This gave a yellow oil (141), 0.19 g (83%); vmax (Liquid)/cm-1 2935 (w, CH), 1587 (m), 1502 (m), 1446 (m), 1415 (m), 1359 (s), 1268 (m), 1238 (s), 1173 (s), 1123 (s), 1090 (s), 999 (m), 969 (m), 908 (m), 837 (m), 724 (s), 684 (s), 657 (m); ?H (300 MHz; CDCl3; Me4Si) 8.07 (1H, d, J = 8.16, ArH), 7.93 (2H, d, J = 7.62, 2 ? ArH), 7.77 (1H, d, J = 7.75, ArH), 7.67 (1H, s, ArH), 7.38-7.31 (2H, m, 2 ? ArH), 7.11-7.06 (3H, m, 3 ? ArH), 6.80 (2H, s, ? x ArH), 3.91 (9H, s, 3 ? CH3O); ?C (75MHz; CDCl3) 151.91 (3 ? C), 136.33 (C), 133.71 (C), 132.77 (CH), 132.23 (CH), 128.97 (C), 128.26 (CH), 127.63 (2 ? CH), 125.94 (CH), 125.11 (2 ? CH), 124.86 (C), 123.36 (CH), 122.45 (C), 121.99 (CH), 120.98 (CH), 118.66 (CH), 112.15 (CH), 103.31 (2 ? CH), 59.26 (CH3O), 54.53 (2 ? CH3O); m/z 424 (M+, 10%), 371 (4%), 295 (2%), 273 (26%), 231 (51%), 213 (89%), 173 (100%), 133 (10%), 119 (2%) (Found: 423.3420. C23H21NO5S requires 423.1140). N S OO MeO OMe OMe Chapter 4 Experimental Procedures 103 (f) 5-Methoxy-1-(phenylsulfonyl)-3-(3,4,5-trimethoxyphenyl)-1H-indole (142) Pd(PPh3)4 (0.10 g, 0.055 mmol, 10%), 3-bromo-5- methoxy-1-(phenylsulfonyl)-1H-indole (109) (0.20 g, 0.55 mmol), 3,4,5-trimethoxyphenylboronic acid (0.17 g, 0.82 mmol, 1.5 eq), Na2CO3 (0.49 g, 4.70 mmol, 8.5 eq) in water (2.3 ml). This gave a cream white solid (142), 0.15 g (60%). Melting point 132-136 ?C; vmax (Solid)/cm-1 2934 (w, CH), 1576 (m), 1503 (m), 1445 (m), 1364 (m0, 1276 (m), 1240 (m), 1221 (m), 1170 (s), 1122 (s), 1031 (m), 997 (m), 976 (m), 903 (m), 833 (m), 815 (m), 751 (s), 725 (m), 691 (m), 643 (m); ?H (300 MHz; CDCl3; Me4Si) 7.96 (1H, d, J = 905, ArH), 7.90 (2H, d, J = 7.62, 2 ? ArH), 7.64 (1H, s, ArH), 7.57-7.52 (1H, m, ArH), 7.47-7.42 (2H, m, 2 ? ArH), 7.20 (1H, d, J = 2.12, ArH), 6.99 (1H, dd, J = 2.14 and 2.22, ArH), 6.77 (2H, s, 2 ? ArH), 3.94 (3H, s, CH3O), 3.91 (6H, s, 2 ? CH3O), 3.90 (3H, s, CH3O); ?C (75MHz; CDCl3) 156.20 (C), 153.10 (C), 152.82 (2 ? C), 137.47 (C), 137.09 (C), 137.02 (C), 133.31 (CH), 129.75 (C), 129.55 (C), 128.76 (2 ? CH), 128.02 (C), 126.22 (2 ? CH), 123.68 (C), 122.97 (CH), 114.23 (CH), 113.33 (CH), 104.39 ( 2 ? CH), 104.03 (2 ? CH), 102.41 (CH), 60.41 (CH3O), 55.73 (2 ? CH3O), 55.69 (CH3O). (g) 3-(4-Methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (143) Pd(PPh3)4 (0.34 g, 10%), 3-bromo-1-(phenylsulfonyl)-1H-indole (107) (1.00 g, 2.98 mmol), 4-methoxyphenylboronic acid (0.68 g, 5.84 mmol, 1.5 eq), Na2CO3 (2.68 g, 33.10 mmol, 8.5 eq) in water (2.5 ml). This gave a white solid (143) (0.89 g, 82%). Melting point: 132-137 ?C, literature reported (143) as an oil84; vmax (Solid)/cm-1 2964 (w, CH), 1610 (m), 1501 (m), 1446 (m), 1361 (m), 1242 (m), 1131 (s), 1018 (m), 998 (m), 832 (m), 774 (s), 684(m); ?H (300 MHz; CDCl3; Me4Si) N S OO MeO MeO OMe OMe N S OO OMe Chapter 4 Experimental Procedures 104 8.06 (1H, d, J = 8.20, ArH), 7.91 (2H, d, J = 7.58, 2 ? ArH), 7.74 (1H, d, J = 7.65, ArH), 7.63 (1H, s, ArH), 7.53-7.51 (3H, m, 3 ? ArH), 7.30-7.25 (2H, m, 2 ? ArH), 7.14 (1H, d, J = 8.72, ArH)7.03-6.98 (2H, m, 2 ? ArH), 6.82-6.76 (1H, m, ArH), 3.85 (3H, s, CH3O); ?C (75MHz; CDCl3) 159.67 (C), 138.19 (C), 133.87 (CH), 133.41 (CH), 130.92 (CH). 129.59 (C), 129.33 (2 ? CH), 129.08 (2 ? CH), 126.84 (2 ? CH), 125.38 (C), 125.05 (CH), 123.61 (CH), 120.49 (CH), 119.93 (C), 116.33 (C), 114.41 (2 ? CH), 55.41 (CH3O); m/z 363 (M+, 16%), 263 (24%), 219 (100%), 131 (35%), 100 (15%), 69 (35%), (Found: 363.0931. C21H17NSO3 requires 363.0929). (h) 5-Methoxy-3-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (144) Pd(PPh3)4 (0.10 g, 0.055 mmol, 10%), 3-bromo-5-methoxy-1- (phenylsulfonyl)-1H-indole (109) (0.20 g, 0.55 mmol), 4- methoxyphenylboronic acid (0.12 g, 0.82 mmol, 1.5 eq), Na2CO3 (0.49 g, 4.70 mmol, 8.5 eq) in water (2.3 ml). This gave a yellow oil (144), 0.18 g (83%); vmax (Liquid)/cm-1 2933 (w, CH), 1610 (m), 1589 (m), 1571 (m), 1507 (s), 1469 (s), 1445 (s), 1366 (s), 1303 (s), 1244 (s), 1211 (s), 1172 (s), 1129 (s), 1103 (s), 1087 (s), 1031 (s), 958 (m), 835 (s), 788 (s), 769 (s), 751 (s), 722 (s), 684 (s), 665 (s); ?H (300 MHz; CDCl3; Me4Si) 7.95 (1H, d, J = 9.02, ArH), 7.88 (2H, d, J = 8.23, 2 ? ArH), 7.58-7.40 (5H, m, 5 ? ArH), 7.15 (1H, s, ArH), 7.02-6.95 (3H, m, 2 ? ArH), 6.77 (1H, s, ArH), 3.86 (3H, s, CH3O), 3.81 (3H, s, CH3O); ?C (75MHz; CDCl3) 159.60 (C), 157.14 (C), 138.49 (C), 134.17 (CH), 131.01 (C), 130.61 (C), 129.66 (2 ? CH), 129.37 (2 ? CH), 127.16 (2 ? CH), 125.79 (C), 124.44 (C), 123.54 (CH), 116.42 (C), 115.15 (CH), 114.83 (2 ? CH), 114.22 (CH), 103.36 (CH), 56.15 (CH3O), 55.79 (CH3O). N S OO MeO OMe Chapter 4 Experimental Procedures 105 (i) 3-(2-Formylphenyl)-1-(phenylsulfonyl)-1H-indole (145) Pd(PPh3)4 (10%, 0.34 g), starting material (107) (1.00 g, 2.98 mmol), 2-formylphenylboronic acid (0.67g, 4.46 mmol, 1.5 eq), Na2CO3 (2.68 g, 25.3 mmol, 8.5 eq) in water (12.6 ml). This gave a brown oil (145) that did not solidify on standing in 67% yield; vmax (Liquid)/cm-1 3065 (w, CH), 1693 (s, C=O), 1599 (m), 1447 (s), 1374 (s), 1184 (s), 1131 (s), 1014 (m), 911 (m), 784 (s); ?H (300 MHz; CDCl3; Me4Si) 9.90 (1H, s, CHO), 8.08 (2H, t, J = 8.10, 2 ? ArH), 7.95 (2H, d, J = 7.80, 2 ? ArH) and 7.68-7.26 (10H, m, 10 ? ArH); ?C (75 MHz; CDCl3) 192.00 (CHO), 141.61 (C), 138.43 (C), 136.35 (C), 135.39 (C), 134.61 (CH), 134.43 (CH), 131.80 (CH), 129.97 (2 ? CH), 129.22 (C),128.93 (CH), 128.46 (CH), 127.35 (2 ? CH), 126.00 (CH), 125.92 (CH), 124.68 (CH), 120.55 (CH), 120.39 (C), 114.34 (CH); m/z 361 (M+, 4%), 220 (11%), 210 (11%), 182 (15%), 181 (100%), 165 (10%), 153 (13%), 152 (24%), 151 (7%), 83 (11%), 77 (7%), 76 (9%) (Found: 361.0789. C21H15SO3N requires 361.0773). (j) 2-(5-Methoxy-1-(phenylsulfonyl)-1H-indol-3-yl)benzaldehyde (146) Pd(PPh3)4 (0.10 g, 0.085 mmol, 10%), 3-bromo-5-methoxy- 1-(phenylsulfonyl)-1H-indole (109) (0.31 g, 0.85 mmol), 2- formylphenylboronic acid (0.20 g, 1.27 mmol, 1.5 eq), Na2CO3 (0.76 g, 7.22 mmol, 8.5 eq) in water (3.6 ml). This gave a white solid (146), 0.25 g (76%); Melting point 129- 132 ?C; vmax (Solid)/cm-1 2920 (w, CH), 1681 (s, C=O), 1601 (m), 1468 (m), 1446 (m), 1364 (s), 1256 (m), 1214 (m), 1173 (s), 1134 (s), 1086 (m), 1029 (m), 996 (m), 960 (m), 838 (w), 810 (m), 750 (s), 723 (s), 683 (s), 628 (s); ?H (300 MHz; CDCl3; Me4Si) 9.87 (1H, s, CHO), 8.07 (1H, d, J = 7.75, ArH), 7.98 (1H, d, J = 9.06, N S O O H O N S OO MeO H O Chapter 4 Experimental Procedures 106 ArH), 7.92 (2H, d, J = 7.77, 2 ? ArH), 7.69 (1H, t, J = 14.83, ArH), 7.59-7.46 (6H, m, 6 ? ArH), 7.26 (1H, s, ArH), 7.01 (1H, d, J = 9.05, ArH), 6.76 (1H, s, ArH), 3.73 (3H, s, CH3O); ?C (75MHz; CDCl3) 192.11 (C=O), 157.61 (C), 138.26 (C), 136.41 (C), 134.87 (C), 134.55 (CH), 134.52 (CH), 132.24 (C), 131.64 (CH), 129.83 (2 ? CH), 128.89 (CH), 128.37 (CH), 127.18 (2 ? CH), 126.57 (CH), 120.40 (C), 115.25 (CH), 102.44 (CH), 56.10 (CH3O). (k) 1-(2-(1-(Phenylsulfonyl)-1H-indol-3-yl) acetophenone (147) Pd(PPh3)4 (0.14 g, 10%), 3-bromo-1-(phenylsulfonyl)-1H-indole (107) (0.40 g, 1.19 mmol), 2-acetylphenylboronic acid (0.29 g, 1.79 mmol, 1.5 eq), Na2CO3 (1.61 g, 15.2 mmol, 8.5 eq) in water (7.6 ml). This gave a brown oil (147), 0.38 g (84%); vmax (Liquid)/cm-1 3063 (w, CH), 1685 (s, C=O), 1446 (s), 1370 (s), 1273 (m), 1242 (m), 1175 (s), 1127 (s), 1089 (s), 1012 (s), 931 (m), 745 (s), 724 (s), 684 (s), 636 (s); ?H (300 MHz; CDCl3; Me4Si) 8.09 (1H, d, J = 8.11, ArH), 7.92 (2H, d, J = 7.49, 2 ? ArH), 7.61 (1H, d, J = 7.30, ArH), 7.55 (1H, s, ArH), 7.52 (2H, d, J = 7.34, 2 ? ArH), 7.46-7.35 (6H, m, 6 ? ArH), 7.27-7.22 (1H, m, ArH), 1.90 (3H, s, CH3); ?C (75MHz; CDCl3) 203.89 (C=O), 141.77 (C), 138.61 (C), 135.52 (C), 134.42 (CH), 131.40 (CH), 131.37 (CH), 130.76 (C), 130.53 (C), 129.78 (2 ? CH), 128.56 (CH), 127.18 (2 ? CH), 125.83 (CH), 124.91 (CH), 124.40 (CH), 123.45 (C), 120.57 (CH), 114.37 (CH), 30.14 (CH3); m/z 376 (M+, 80%), 358 (2%), 248 (3%), 235 (32%), 218 (2%), 163 (1%), 135 (4%), (Found: 375.1530. C22H17NO3S requires 375.0929). N S OO O Chapter 4 Experimental Procedures 107 (l) 1-(2-(5-Methoxy-1-(phenylsulfonyl)-1H-indol-3-yl) acetophenone (148) Pd(PPh3)4 (0.10 g, 0.055 mmol, 10%), 3-bromo-5methoxy- 1-(phenylsulfonyl)-1H-indole (109) (0.20 g, 0.55 mmol), 2- acetylphenylboronic acid (0.14 g, 0.82 mmol, 1.5 eq), Na2CO3 (0.49 g, 4.70 mmol, 8.5 eq) in water (2.3 ml). This gave a cream white solid (148), 0.17 g (77%). Melting point 105-109 ?C; vmax (Solid)/cm-1 2895 (w, CH), 1690 (s, C=O), 1610 (w), 1478 (s), 1447 (m), 1363 (s), 1271 (m), 1246 (s), 1212 (s), 1174 (s), 1134 (s), 1089 (s), 1030 (m), 961 (s), 851 (m), 834 (m), 757 (m), 724 (s), 687 (m), 632 (m); ?H (300 MHz; CDCl3; Me4Si) 7.98 (1H, d, J = 9.05, ArH), 7.89 (2H, d, J = 7.73, 2 ? ArH), 7.62- 7.42 (8H, m, 8 ? ArH), 6.99 (1H, dd, J = 1.95 and 1.96, ArH), 6.77 (1H, s, ArH), 3.74 (3H, s, CH3O), 1.87 (3H, s, CH3); ?C (75MHz; CDCl3) 204.21 (C=O), 157.44 (C), 141.77 (C), 138.50 (C), 134.35 (CH), 131.51 (CH), 131.21 (CH), 130.78 (C), 130.09 (C), 129.73 (2 ? CH), 128.60 (CH), 128.57 (CH), 127.11 (2 ? CH), 125.50 (CH), 123.71 (C), 115.39 (CH), 115.21 (C), 102.50 (CH), 56.05 (CH3O), 30.11 (CH3). 4.7 Typical procedure for removing of phenylsulfonyl protecting group on 3- aryl-1-(phenylsulfonyl)-1H-indoles and 3-aryl-5-methoxy-1-(phenylsulfonyl)- 1H-indoles The substrate was dissolved in methanol (20 ml) at rt under N2 atmosphere, K2CO3 was added to the solution and the reaction mixture was heated to reflux under N2 for 18 h. The reaction mixture was then allowed to cool down to rt and filtered through a celite plug and then the filtrate concentrated under reduced pressure. Water was added to the crude material and slowly acidified to pH 2-4 with aqueous 10% HCl. The aqueous portion was saturated with solid NaCl and the organic material extracted with CH2Cl2 (3 ? 30 ml). The combined organic extracts were washed two times with water (20 ml), brine (20 ml), dried over MgSO4 and concentrated under N S OO MeO O Chapter 4 Experimental Procedures 108 reduced pressure. This resulted in brown oils that were subjected to column chromatography using 10% EtOAc/Hexane as an eluent. (a) 3-Phenyl-1H indole (149) 3-Phenyl-1-phenylsulfonylindole (137) (0.36 g, 1.08 mmol), K2CO3 (28.35 g, 205.4 mmol, 190 eq). Column chromatography gave a yellow oil that solidified on standing to yellow solid (149) in 81% yield. Melting point: 86-89 ?C, li. value 89 ?C85; vmax (Solid)/cm-1 3412 (s, NH), 3055 (m, CH), 1602 (m), 1545 (m), 1457 (m), 1416 (m), 1337 (m), 1264 (s), 1100 (m), 1014 (w), 960 (w), 823 (w), 741 (s); ?H (300 MHz; CDCl3; Me4Si) 8.17 (1H, s, NH), 7.94 (1H, d, J = 7.70, ArH), 7.66 (2H, d, J = 7.10, 2 ? ArH), 7.46-7.18 (7H, m, 7 ? ArH); ?C (75 MHz; CDCl3) 137.15 (C), 136.00 (C), 129.23 (2 ? CH), 127.98 (2 ? CH), 126.43 (CH), 126.27 (C), 122.86 (CH), 122.34 (CH), 120.7 (CH), 120.20 (CH), 118.71 (C), 111.90 (CH); m/z 193 (M+, 100%), 192 (9%), 191 (4%), 165 (21%), 164 (4%), 163 (4%), 96 (6%), 95 (6%), 90 (3%) (Found: 193.0897. C14H10N requires 193.0892). (b) 5-Methoxy-3-phenyl-1H-indole (150) 5-Methoxy-3-phenyl-1-(phenylsulfonyl)-1H-indole (138) (0.17 g, 0.47 mmol), K2CO3 (12.30 g, 89 mmol, 190 eq). Column chromatography gave a brown oil (150) 0.085 g (85%), literature reported (150) as a solid with melting point 66-67 ?C86; vmax (Liquid)/cm-1 3409 (s, NH), 2935 (w, CH), 1620 (m), 1601 (m), 1581 (m), 1542 (s), 1477 (m), 1437 (m), 1310 (m0, 1293 (m), 1268 (s), 1238 (s), 1207 (m), 1175 (m), 1154 (m), 1109 (s), 1071 (m), 1026 (m), 966 (m), 913 (m), 834 (s), 797 (s), 762 (s), 697 (s), 679 (s); ?H (300 MHz; CDCl3; Me4Si) 8.01 (1H, s, NH), 7.56 (2H, d, J = 7.83, 2 ? ArH), 7.39-7.34 (2H, m, 2 ? ArH), 7.31 (1H, s, ArH), 7.23-7.16 (3H, N H N H MeO Chapter 4 Experimental Procedures 109 m, 3 ? ArH), 6.83 (1H, d, J = 8.46, ArH), 3.77 (3H, s, CH3O); ?C (75MHz; CDCl3) 154.14 (C), 135.18 (C), 130.21 (C), 128.51 (C), 128.31 (2 ? CH), 126.83 (2 ? CH), 126.46 (C), 125.38 (CH), 122.15 (CH), 112.12 (CH), 111.64 (CH), 55.46 (CH3O). (c) 3-ortho-Tolyl-1H-indole (151) 3-ortho-olyl-1-phenylsulfonylindole (139) (0.21 g, 0.61 mmol), K2CO3 (15.87 g, 115.0 mmol, 190 eq). Column chromatography a gave brown oil (151) that did not solidify on standing in 64% yield, literature reported (151) as an oil56; vmax (Liquid)/cm-1 3476 (s, NH), 3061 (w, CH), 1620 (w), 1551 (w), 1456 (m), 1344 (w), 1253 (w), 1094 (m), 909 (s), 731 (s), 650 (m); ?H (300 MHz; CDCl3; Me4Si) 8.17 (1H, s, NH), 7.52 (1H, d, J = 7.91, ArH), 7.43-7.39 (2H, m, 2 ? ArH), 7.32-7.23 (4H, m, 4 ? ArH), 7.14- 7.10 (2H, m, 2 ? ArH), 2.31 (3H, s, CH3); ?C (75 MHz; CDCl3) 137.30 (C), 136.35 (C), 134.93 (C), 131.39 (CH), 130.85 (CH), 127.67 (C), 127.26 (CH), 126.12 (CH), 123.24 (CH), 122.68 (CH), 120.60 (CH), 120.41 (CH), 117.97 (C), 111.63 (CH), 21.16 (CH3); m/z 207 (M+, 100%), 206 (73%), 205 (7%), 204 (16%), 180 (7%), 179 (10%), 178 (15%), 103 (7%), 102 (8%), 89 (6%) (Found: 207.1051. C15H13N requires 207.1048). (d) 5-Methoxy-3-o-tolyl-1H-indole (152) 5-Methoxy-1-(phenylsulfonyl)-3-o-tolyl-1H-indole (140) (0.25 g, 0.74 mmol), K2CO3 (19.5 g, 140 mmol, 190 eq). Column chromatography gave a yellow oil (152) 0.16 g (86%), literature reported (151) as an oil56; vmax (Liquid)/cm-1 3411 (m, NH), 1622 (m), 1580 (m), 1478 (s), 1437 (s), 1261 (s), 1208 (s), 1175 (s), 1122 (m), 1093 (s), 1026 (s), 916 (m), 790 (s), 763 (s), 745 (s), 724 (m), 668 (m); ?H (300 MHz; CDCl3; Me4Si) 8.11 (1H, s, NH), 7.43-7.40 (1H, m, ArH), N H N H MeO Chapter 4 Experimental Procedures 110 7.35-7.22 (3H, m, 3 ? ArH), 7.12 (1H, d, J = 1.95, ArH), 6.94 (1H, s, ArH), 6.89 (1H, dd, J = 1.81 and 1.92, ArH), 3.78 (3H, s, CH3O), 2.32 (3H, s, CH3); ?C (75MHz; CDCl3) 154.63 (C), 137.13 (C), 134.80 (C), 131.20 (C), 130.99 (CH), 130.60 (CH), 127.71 (C), 126.96 (CH), 125.90 (CH), 123.81 (CH), 117.50 (C), 112.83 (CH), 112.18 (CH), 101.75 (CH), 56.12 (CH3O), 20.93 (CH3). (e) 3-(3,4,5-Trimethoxyphenyl)-1H-indole (153) 1-(Phenylsulfonyl)-3-(3,4,5-trimethoxyphenyl)-1H-indole (141) (0.19 g, 0.45 mmol), K2CO3 (11.80 g, 85 mmol, 190 eq). Column chromatography gave a brown oil (153) 0.085 g (65%); vmax (Liquid)/cm-1 3350 (m, NH), 2931 (m), CH), 1583 (s), 1498 (m), 1456 (s), 1408 (m), 1361 (m), 1334 (m), 1120 (s), 999 (s), 836 (m), 739 (s), 659 (m), 623 (m); ?H (300 MHz; CDCl3; Me4Si) 8.35 (1H, s, NH), 7.92 (1H, d, J = 7.74, ArH), 7.44 (1H, d, J = 7.96, ArH), 7.35 (1H, d, J = 2.34, ArH), 7.24-7.21 (2H, m, 2 ? ArH), 6.88 (2H, s, 2 ? ArH), 3.93 (6H, s, 2 ? CH3O), 3.91 (3H, s, CH3O); ?C (75MHz; CDCl3) 152.06 (2 ? C), 151.94 (C), 135.17 (C), 129.87 (C), 124.28 (C), 121.05 (CH), 120.19 (CH), 118.90 (CH), 118.17 (CH), 117.01 (C), 110.06 (CH), 103.27 (2 ? CH), 54.85 (CH3O), 54.74 (2 ? CH3O); (f) 5-Methoxy-3-(3,4,5-trimethoxyphenyl)-1H-indole (154) 5-Methoxy-1-(phenylsulfonyl)-3-(3,4,5- trimethoxyphenyl)-1H-indole (142) (0.11 g, 0.24 mmol), K2CO3 (6.40 g, 46 mmol, 190 eq). Column chromatography gave a brown oil (154) 0.055 g (72%); vmax (Liquid)/cm-1 3348 (m, NH), 2937 (w, CH), 1586 (s), 1481 (s), 1334 (m), 1212 (m), 1172 (s), 1118 (s), 994 (s), N H MeO MeO OMe OMe N H MeO OMe OMe Chapter 4 Experimental Procedures 111 798 (m), 725 (m); ?H (300 MHz; CDCl3; Me4Si) 8.46 (1H, s, NH), 7.37-7.32 (3H, m, 3 ? ArH), 6.93 (1H, d, J = 8.82, ArH), 6.85 (2H, s, 2 ? ArH), 6.10 (2H, s, 2 ? ArH), 3.87 (3H, s, CH3O), 3.78 (3H, s, CH3O), 3.77 (6H, s, 2 ? CH3O); ?C (75MHz; CDCl3) 154.20 (C), 153.33 (C), 153.13 (2 ? C), 131.47 (C), 131.27 (C), 125.74 (C), 122.26 (CH), 117.66 (C), 112.19 (CH), 111.96 (CH), 101.14 (CH), 92.52 (2 ? CH), 60.68 (CH3O), 55.81 (2 ? CH3O), 55.60 (CH3O). (g) 3-(4-Methoxyphenyl)-1H-indole (155) 3-(4-Methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (143) (0.83 g, 2.39 mmol), K2CO3 (62.40 g, 452 mmol, 190 eq). Column chromatography gave a cream white solid (155) (0.53 g, 79%). Melting point: 130-134 ?C, lit. value 131-133 ?C87; vmax (Solid)/cm-1 3427 (s, NH), 2955 (w, CH), 1611 (m), 1542 (m), 1440 (m), 1322 (m), 1241 (s), 1181 (m), 1030 (s), 957 (w), 809 (m), 794 (m), 648 (s); ?H (300 MHz; CDCl3; Me4Si) 8.13 (1H, NH), 7.89 (1H, d, J = 7.77, ArH), 7.58 (2H, d, J = 8.68, 2 ? ArH), 7.38 (1H, d, J = 7.90, ArH), 7.25-7.17 (3H, m, 3 ? ArH), 6.99 (2H, d, J = 8.67, 2 ? ArH), 3.85 (3H, s, CH3); ?C (75MHz; CDCl3) 158.49 (C), 136.98 (C), 131.30 (C), 129.01 (2 ? CH), 128.52 (C), 122.69 (CH), 121.56 (CH), 120.53 (CH), 120.12 (CH), 114.66 (2 ? CH), 113.25 (C), 111.75 (CH), 55.76 (CH3); m/z 223 (M+, 32%), 219 (100%), 208 (21%), 131 (41%), 100 (16%), 69 (80%), (Found: 223.0995. C21H17NO requires 223.0997). (h) 5-Methoxy-3-(4-methoxyphenyl)-1H-indole (156) 5-Methoxy-3-(4-methoxyphenyl)-1-(phenylsulfonyl)-1H-indole (144) (0.15 g, 0.38 mmol), K2CO3 (10.00 g, 73 mmol, 190 eq). Column chromatography gave a yellow oil (156) 0.070 g (72%), literature reported (156) as a solid with melting point 151.2-152 ?C88; vmax (Liquids)/cm-1 3405 (m), NH), 2916 (w), N H OMe N H MeO OMe Chapter 4 Experimental Procedures 112 CH), 1612 (m), 1547 (m), 1503 (s), 1479 (s), 1438 (m), 1296 (m), 1276 (s), 1240 (s), 1207 (s), 1173 (s), 1104 (s), 1027 (s), 968 (m), 916 (m), 833 (m), 790 (s), 750 (m), 638 (m); ?H (300 MHz; CDCl3; Me4Si) 8.10 (1H, s, NH), 7.56 (2H, d, J = 8.49, 2 ? ArH), 7.33-7.25 (3H, m, 3 ? ArH), 7.01 (2H, d, J = 8.50, 2 ? ArH), 6.91 (1H, dd, J = 2.03 and 2.08, ArH), 3.86 (6H, s, 2 ? CH3O); ?C (75MHz; CDCl3) 158.43 (C), 154.99 (C), 132.12 (C), 128.93 (2 ? CH), 126.68 (C), 122.45 (CH), 118.21 (C), 116.43 (C), 115.22 (C), 114.71 (2 ? CH), 112.99 (CH), 112.46 (CH), 101.86 (CH), 56.40 (CH3O), 55.79 (CH3O) (i) 3-(2-Formylphenyl)-1H-indole (157) 3-(2-formylphenyl)-1-phenylsulfonylindole (145) (0.36 g, 0.99 mmol), K2CO3 (25.96 g, 188.1 mmol, 190 eq), Column chromatography gave a brown oil (157) that did not solidify on standing in 72% yield; vmax (Liquid)/cm-1 3461 (m, NH), 3055 (m, CH), 1687 (m, C=O), 1600 (w), 1545 (w), 1420 (m), 1265 (s), 1196 (w), 1099 (w), 896 (m), 735 (s); ?H (300 MHz; CDCl3; Me4Si) 10.10 (1H, s, CHO), 8.61 (1H, s, NH), 8.06 (1H, d, J = 1.10, ArH), 7.67-7.60 (3H, m, 3 ? ArH), 7.47 (2H, d, J = 8.08, 2 ? ArH), 7.26-7.19 (3H, m, 3 ? ArH); ?C (75 MHz; CDCl3) 193.63 (CHO), 139.30 (C), 136.52 (C), 134.82 (C), 131.84 (CH), 128.09 (CH), 127.78 (C), 127.47 (CH), 125.43 (CH), 123.44 (CH), 121.35 (CH), 119.73 (CH), 111.96 (CH); m/z 221 (M+, 98%), 193 (100%), 165 (58%), 86 (24%), 84 (38%), 71 (15%), 57 (27%), 43 (25%) (Found: 221.2001. C15H11NO requires 221.0841). N H H O Chapter 4 Experimental Procedures 113 (j) 2-(5-Methoxy-1H-indol-3-yl)benzaldehyde (158) 2-(5-Methoxy-1-(phenylsulfonyl)-1H-indol-3- yl)benzaldehyde (146) (0.50 g, 1.28 mmol), K2CO3 (33.50 g, 240 mmol, 190 eq). Column chromatography gave a brown oil (158) 0.30 g (94%); vmax (Liquid)/cm-1 3359 (m, NH), 2830 (w, CH), 1680 (s, C=O), 1622 (m), 1597 (m), 1537 (m), 1448 (s), 1438 (s), 1389 (s), 1290 (s), 1258 (s), 1176 (m), 1117 (m), 1027 (s), 969 (s), 917 (s), 830 (m), 799 (s), 766 (s), 729 (s), 690 (s), 638 (m); ?H (300 MHz; CDCl3; Me4Si) 10.01 (1H, s, CHO), 8.51 (1H, s, NH), 8.06 (1H, d, J = 7.79, ArH), 7.70-7.62 (2H, m, 2 ? ArH), 7.56-7.46 (2H, m, 2 ? ArH), 7.35 (1H, d, J = 8.91, ArH), 7.21 (1H, s, ArH), 7.02 (1H, s, ArH), 6.94 (1H, d, J = 8.87, ArH), 3.80 (H, s, CH3O); ?C (75MHz; CDCl3) 194.29 (CHO), 156.15 (C), 140.05 (C), 135.26 (C), 134.91 (CH), 134.22 (C), 132.23 (CH), 130.30 (C), 128.67 (CH), 127.93 (CH), 126.60 (CH), 114.46 (CH), 113.34 (CH), 101.55 (CH), 56.85 (CH3O). (k) 1-(2-(1H-indol-3-yl) acetophenone (159) 1-(2-(1-(Phenylsulfonyl)-1H-indol-3-yl) acetophenone (147) (0.21 g, 0.56 mmol), K2CO3 (14.68 g, 106 mmol, 190 eq). Column chromatography gave a brown oil (159) 0.13 g (92%); vmax (Liquid)/cm-1 3329 (b, NH), 3057 (w, CH), 1670 (s, C=O), 1596 (m), 1544 (m), 1456 (m), 1352 (m), 1277 (m), 1224 (m), 1098 (m), 1009 (m), 739 (s); ?H (300 MHz; CDCl3; Me4Si) 8.61 (1H, s, NH), 7.66-7.50 (4H, m, 4 ? ArH), 7.42-7.36 (2H, m, 2 ? ArH), 7.27-7.14 (2H, m, 2 ? ArH), 7.09 (1H, d, J = 2.44, ArH), 2.02 (3H, s, CH3); ?C (75MHz; CDCl3) 206.60 (C=O), 142.03 (C), 136.68 (C), 133.44 (C), 131.28 (CH), 131.12 (CH), 128.07 (CH), 127.09 (CH), 126.83 (C), 124.27 (CH), 123.19 (CH), 120.98 (CH), 119.80 (CH), 116.72 (C), 111.94 (CH), 30.45 (CH3); m/z 236 (M+, 100%), 218 (18%), 194 (3%), 143 (3%), (Found: 235.2560. C16H13NO require 235.0997). N H O N H MeO H O Chapter 4 Experimental Procedures 114 (l) 1-(2-(5-Methoxy-1H-indol-3-yl) acetophenone (160) 1-(2-(5-Methoxy-1-(phenylsulfonyl)-1H-indol-3-yl) acetophenone (148) (0.17 g, 0.42 mmol), K2CO3 (11.01 g, 80 mmol, 190 eq). Column chromatography gave a cream white solid (160) 0.090 g (82%). Melting point 116-120 ?C; vmax (Solid)/cm-1 3268 (m, NH), 2987 (w, CH), 1666 (s, C=O), 1592 (m), 1537 (m), 1486 (m), 1353 (m), 1281 (s), 1214 (s), 1135 (m), 1031 (m), 920 (m), 842 (m), 805 (s), 764 (s), 701 (s), 645 (m); ?H (300 MHz; CDCl3; Me4Si) 8.56 (1H, s, NH), 7.59-7.51 (3H, m, 3 ? ArH), 7.42-7.37 (1H, m, ArH), 7.31-7.25 (1H, m, ArH), 7.10 (1H, d, J = 2.36, ArH), 7.05 (1H, d, J = 1.72, ArH), 6.91 (1H, dd, J = 2.14 and 2.11, ArH), 3.80 (3H, s, CH3O), 2.03 (3H, s, CH3); ?C (75MHz; CDCl3) 204.82 (C=O), 153.38 (C), 140.05 (C), 131.70 (C), 129.79 (C), 129.33 (CH), 129.20 (CH), 126.26 (CH), 125.34 (C), 125.17 (CH), 122.87 (CH), 114.70 (C), 111.77 (CH), 110.81 (CH), 99.21 (CH), 55.33 (CH3O), 28.49 (CH3). 4.8 Synthesis of 2,3-Diphenyl-1-(phenylsulfonyl)-1H-indole (161) To Pd(PPh3)4 (10%, 0.17 g) was added a deoxygenated mixture of the 2,3-dibromo-1-(phenylsulfonyl)-1H-indole (108) (0.50 g, 1.49 mmol) in DME (5 ml) and phenylylboronic acid (123) (0.27 g, 2.23 mmol, 1.5 eq) in ethanol (3 ml). The reaction mixture was stirred at rt for about 10 min followed by the addition of deoxygenated solution Na2CO3 (1.34 g, 12.7 mmol, 8.5 eq) in water (6.3 ml). The resulting reaction mixture was stirred for further 10 min at rt before being heated to reflux for 8 h. The reaction mixture was allowed to cool to rt, quenched with water (10 ml) and the organic extracts extracted with CH2Cl2 (3 ? 30 ml). The organic fractions were combined, dried over MgSO4, N H MeO O N S O O Chapter 4 Experimental Procedures 115 filtered through a celite plug and the excess solvent was removed on a rotary evaporator. The resulting black oil was purified by column chromatography using 10% EtOAc/Hexane as an eluent. This gave a light red solid (161) which was recrystallized from CH2Cl2 to give a cream white solid in 56% yield. Melting point: 173-175 ?C, lit. value 174-176 ?C69; vmax (Solid)/cm-1 3065 (m, CH), 1604 (w), 1447 (s), 1379 (s), 1184 (s), 1128 (m), 1087 (s), 910 (s), 733 (s); ?H (300 MHz; CDCl3; Me4Si) 8.41 (1H, d, J = 8.42, ArH), 7.50-7.43 (5H, m,5 ? ArH), 7.321-7.20 (11H, m, 11 ? ArH ), 7.09-7.06 (2H, m, 2 ? ArH); ?C (75 MHz; CDCl3) 138.20 (C), 137.45 (C), 136.88 (C), 133.56 (CH), 132.60 (C), 132.19 (2 ? CH), 130.87 (C), 130.44 (C), 129.83 (2 ? CH), 128.77 (2 ? CH), 128.61 (CH), 128.50 (2 ? CH), 127.34 (2 ? CH), 127.01 (CH), 126.95 (2 ? CH), 125.31 (CH), 124.93 (C), 124.38 (CH), 120.16 (CH), 116.33 (CH); m/z 409 (M+, 42%), 334 (7%), 269 (29%), 268 (100%), 267 (58%), 266 (13%), 219 (21%), 213 (10%), 193 (12%), 190 (7%), 165 (21%), 163 (10%), 77 (19%), 51 (7%) (Found: 409.1195. C26H19SO2N requires 409.1137). 4.9 Synthesis of 2,3-Diphenyl-1H indole (162) 2,3-Diphenyl-1-(phenylsulfonyl)-1H-indole (161) (0.28 g, 0.69 mmol) was dissolved in methanol (20 ml) at rt under N2 atmosphere, K2CO3 (17.80 g, 131.1 mmol, 190 eq) was added to the solution and the reaction mixture was heated to reflux under N2 for 18 h. The reaction mixture was then allowed to cool to rt and filtered through a celite plug and then the filtrate concentrated under reduced pressure. Water was added to the crude material and slowly acidified to pH 2-4 with aqueous 10% HCl. The aqueous portion was saturated with solid NaCl and the organic material extracted with CH2Cl2 (3 ? 30 ml). The combined organic extracts were washed two times with water (20.0 ml), brine (20.0 ml), dried over MgSO4 and concentrated under reduced pressure. This resulted in brown oils that were subjected to column chromatography using 10% EtOAc/Hexane as an eluent. Column chromatography gave a yellow oil (162) that solidified on standing in 60% yield. Melting point: 224-227?C; vmax (Solid)/cm-1 3461 (m, NH), 3062 (w, CH), 1603 (w), 1454 (m), 1330 (w), 1250 N H Chapter 4 Experimental Procedures 116 (w), 1184 (w), 1093 (w), 909 (s), 732 (s), 650 (m); ?H (300 MHz; CDCl3; Me4Si) 8.21 (1H, s, NH), 7.68 (1H, d, J = 7.90 ArH), 7.45-7.37 (6H, m, 6 ? ArH), 7.34-7.12 (7H, m, 7 ? ArH); ?C (75 MHz; CDCl3) 136.3 (C1), 135.5 (C1), 134.5 (C), 133.1 (C), 132.5 (C), 130.6 (2 ? CH), 130.3 (C), 129.1 (2 ? CH), 128.9 (2 ? CH), 128.6 (2 ? CH), 128.1 (CH), 126.7 (CH), 123.1 (CH), 120.9 (CH), 120.1 (CH), 111.3 (CH); m/z 269 (M+, 100%), 268 (17%), 267 (22%), 266 (5%), 254 (4%), 241 (3%), 193 (18%), 165 (13%), 163 (3%), 134 (7%), 133 (10%), 132 (5%), 127 (6%), 42 (4%) (Found: 269.1217. C20H15N requires 269.1205). 4.10 Synthesis of a novel class compounds 4.10.1 Synthesis of 2-arylindoles via one-pot synthesis 4.10.1.1 2-(4-Bromo-2,5-dimethoxyphenyl)-1-(phenylsulfonyl)-1-H-indole (164) To 1-(phenylsulfonyl)-1H-indole (36) (1.00 g, 3.89 mmol) in a dry flask was added isopropylmagnesium chloride solution in THF (~0.8 M in excess) and diisopropylamine (1 ml). The reaction mixture was maintained at rt under N2 atmosphere for 16 h. The reaction mixture was treated with 1,4-dibromo-2,5-dimethoxybenzene (2.30 g, 7.78 mmol, 2 eq) and Pd(PPh3)4 (0.23 g, 0.20 mmol, 0.050 eq). After stirring at rt for 48 h, the reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl. The mixture was extracted with CH2Cl2 (3 ? 30 ml), the organic layers combined and dried over MgSO4, filtered though celite plug and excess solvent removed on a rotary evaporator. This resultant black oil was subjected to column chromatography. The resultant light black oil was recrystallized from the mixture of CH2Cl2 and hexane to give white solid (164) (0.38 g, 21%). Melting point: 181-183 ?C; vmax (Solid)/cm-1 2838 (w, CH), 1585 (w), 1489 (s), 1439 (m), 1431 (m), 1367 (s), 1279 (m), 1213 (s), 1177 (s), 1118 (m), 1090 (m), 1068 (s), 1034 (s), 999 (s), 850 (s), 810 (s), 752 (s), 730 (s), 686 (s), 639 (s);?H (300 MHz; CDCl3; N S OO MeO Br OMe Chapter 4 Experimental Procedures 117 Me4Si) 8.25 (1H, d, J = 8.33, ArH), 7.51-7.44 (4H, m, 4 ? ArH), 7.37-7.23 (4H, m, 4 ? ArH), 7.12 (1H, s, ArH), 6.78 (1H, s, ArH), 6.58 (1H, s, ArH), 3.82 (3H, s, CH3O), 3.68 (3H, s, CH3O); ?C (75MHz; CDCl3) 153.08 (C), 149.63 (C), 139.05 (C), 137.99 (C), 137.04 (C), 133.85 (CH), 130.14 (C), 129.06 (2 ? CH), 127.13 (2 ? CH), 125.25 (CH), 124.32 (CH), 121.25 (CH), 116.72 (CH), 116.46 (CH), 113.13 (CH), 113.54 (CH), 57.36 (CH3O), 55.53 (CH3O); m/z 470 (M+, 46%, 79Br), 472 (M+, 44%, 81Br), 392 (12%), 373 (100%), 332 (14%), 317 (6%), 219 (4%), 113 (4%), (Found: 470.3100. C22H18NSO4Br requires 471.0140). 4.10.1.2 2-(4-Bromo-2,5-dimethoxyphenyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole (165) To 1-(phenylsulfonyl)-5-methoxy-1H-indole (102) (0.97 g, 3.89 mmol) in a dry flask was added isopropylmagnesium chloride solution in THF (~0.8 M in excess) and diisopropylamine (1 ml). The reaction mixture was maintained at rt under N2 atmosphere for 16 h. The reaction mixture was treated with 1,4-dibromo-2,5-dimethoxybenzene (1.93 g, 6.76 mmol, 2 eq) and Pd(PPh3)4 (0.20 g, 0.17 mmol, 0.050 eq). After stirring at rt for 48 h, the reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl. The mixture was extracted with CH2Cl2 (3 ? 30 ml), the organic layers combined and dried over MgSO4, filtered though celite plug and excess solvent removed on a rotary evaporator. This resulted in a black oil that was subjected to column chromatography. The resultant light black oil was recrystallized from the mixture of CH2Cl2 and hexane to give white solid (165) (0.60 g, 35%). Melting point: 159-162 ?C; vmax (Solid)/cm-1 2941 (w, CH), 1611 (m), 1494 (m), 1382 (m), 1207 (s), 1171 (s), 1027 (m), 1028 (m), 950 (w), 857 (m), 814 (s), 752 (s), 722 (m), 685 (s); ?H (300 MHz; CDCl3; Me4Si) 8.14 (1H, d, J = 8.92, ArH), 7.45 (3H, d, J = 8.13, 3 ? ArH), 7.31- 7.26 (2H, m, 2 ? ArH), 7.13 (1H, s, ArH), 6.97-6.92 (2H, m, 2 ? ArH), 6.77 (1H, s, ArH), 6.52 (1H, s, ArH); ?C (75MHz; CDCl3) 157.24 (C), 152.97 (C), 149.62 (C), 138.76 (C), 137.87 (C), 133.80 (CH), 132.64 (C), 131.55 (C), 128.99 (2 ? CH), 127.10 (2 ? CH), 121.49 (C), 117.20 N MeO S O O Br OMe MeO Chapter 4 Experimental Procedures 118 (CH), 116.75 (CH), 116.50 (CH), 114.08 (CH), 113.93 (CH), 113.29 (CH), 103.65 (CH), 57.36 (CH3O), 56.56 (CH3O), 56.05 (CH3O); 4.10.2 Synthesis of indolo-fused pyrans 4.10.2.1 2-Allyl-1-(phenylsulfonyl)-1H-indole (169) To 1-(phenylsulfonyl)-1H-indole (36) (3.00 g, 12 mmol) in a dry flask was added isopropylmagnesium chloride solution in THF (~0.8 M in excess) and diisopropylamine (1 ml). The reaction mixture was maintained at rt under N2 atmosphere for 16 h. Allyl bromide (4.23 g, 35 mmol, 3.1 ml, 2.9 eq) was added and the mixture was stirred at rt for an hour. The reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl. The mixture was extracted with CH2Cl2 (3 ? 30 ml), the organic layers combined and dried over MgSO4, filtered though celite plug and excess solvent removed on a rotary evaporator. This resulted in brown oil that was subjected to column chromatography. The resultant light brown oil was recrystallized from the mixture of CH2Cl2 and hexane to give white solid (169) (1.1 g, 31%). Melting point: 88-91 ?C, literature reported (169) as an oil89; vmax (Solid)/cm-1 3083 (w, CH), 1591 (w), 1448 (s), 1366 (s), 1270 (m), 1219 (m), 1170 (m), 1141 (s), 1092 (s), 1045 (s), 998 (s), 918 (m), 759 (s), 739 (s), 721 (s), 684 (s), 651 (s), 623 (s); ?H (300 MHz; CDCl3; Me4Si) 8.16 (1H, d, J = 7.87, ArH), 7.76 (2H, d, J = 7.63, 2 ? ArH), 7.54-7.38 (4H, m, 4 ? ArH), 7.29-7.18 (2H, m, 2 ? ArH), 6.40 (1H, s, ArH), 7.01-5.96 (1H, m, CH=C), 5.22-5.16 (2H, m, C=CH2), 3.78-3.76 (2H, m, CH2-C=C); ?C (75MHz; CDCl3) 140.53 (C), 139.56 (C), 137.66 (C), 134.49 (CH), 134.06 (CH), 130.04 (C), 129.63 (CH), 126.69 (CH), 124.49 (CH), 123.99 (CH), 120.69 (CH), 118.22 (CH2), 115.11 (CH), 109.99 (CH), 33.80 (CH2); m/z 298 (M+, 100%), 223 (6%), 157 (42%), 141 (4%), (Found: 297.0260. C17H15NO2S requires 297.0824). N S OO Chapter 4 Experimental Procedures 119 4.10.2.2 2-Allyl-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (171) 2-Allyl-1-(phenylsulfonyl)-indole (169) (0.7 g, 2.3mmol) in CH2CH2 (6 ml) was added to a solution of TiCl4 (0.51 ml, 4.7 mmol, 2 eq) and Cl2CHOCH3 (0.47 ml, 4.7 mmol, 2 eq) in CH2Cl2 (6 ml) at -78 ?C, and the resulting reaction mixture was stirred at ? 78 ?C for 3 h. The reaction mixture was allowed to warm to rt and diluted with water. The reaction mixture was made basic with 10% aqueous Na2CO3 and then extracted with CH2Cl2 (3 ? 30 ml). The organic extracts were combined, dried over MgSO4, filtered through celite plug and the excess solvent removed on a rotary evaporator to result in a brown oil residue. This oily residue was subjected to column chromatography using 10% EtOAc/Hexane as an eluent to give a brown oil (171) (0.61 g, 81%), literature reported (171) isolated as solid with melting point 157-158.5 ?C75. vmax (Liquid)/cm-1 3063 (w, CH), 1666 (s, C=O), 1553 (m), 1448 (s), 1372 (s), 1265 (w), 1172 (s), 1119 (m), 1087 (s), 1026 (m), 995 (s), 915 (s), 749 (s), 726 (s), 683 (s); ?H (300 MHz; CDCl3; Me4Si) 10.31 (1H, s, CHO), 8.32-8.29 (1H, m, ArH), 8.21-8.18 (1H, m, ArH), 7.88 (2H, d, J = 8.14, 2 ? ArH) 7.64-7.59 (1H, m, ArH), 7.52-7.46 (2H, m, 2 ? ArH), 7.41-7.38 (2H, m, 2 ? ArH), 6.15-6.02 (1H, m, HC=C), 5.17-5.06 (2H, m, C=CH2), 4.26- 4.24 (2H, m, CH2-C=C); ?C (75MHz; CDCl3) 186.18 (CHO), 149.31 (C), 138.96 (C), 136.41 (C), 134.90 (CH), 134.68 (CH), 129.94 (CH), 127.10 (CH), 126.53 (C), 126.17 (CH), 126.60 (CH), 121.91 (CH), 119.99 (C), 118.12 (CH2), 114.83 (CH), 29.89 (CH2); m/z 325 (M+, 7%), 264 (23%), 219 (100%), 184 (11%), 156 (7%), 131 (40%), 100 (15%), 69 (50%), (Found: 325.0771. C21H17NSO3 requires 325.0773). 4.10.2.3 (2-Allyl-1-(phenylsulfonyl)-1H-indol-3-yl) methanol (172) 2-Allyl-1-(phenylsulfonyl)-1H-indole-3-carbaldehyde (171) (0.50 g, 1.54 mmol) was dissolved in ethanol. NaBH4 (0.12 g, 3.08 mmol, 2 eq) was added during which time the temperature was not N S OO O N S OO OH Chapter 4 Experimental Procedures 120 allowed to rise above 20 ?C. Stirring was then continued for 6 h at rt, before the solvent was removed in vacuo. The residual white solid in round bottom flask was shaken up with 80 ml of aqueous 15% NaOH and the alkaline solution was extracted with CH2Cl2 (3 ? 30 ml). The combined organic extracts were dried over MgSO4, filtered with celite plug and the excess solvent removed on a rotary evaporator to give a yellow oil. The oil was subjected to column chromatography using 50% EtOAc/Hex as an eluent to get yellow oil (172) 0.36g (71%), literature reported (172) isolated as solid with melting point 82-83 ?C76; vmax (Liquid)/cm-1 3406 (b, OH), 2923 (w, CH), 1606 (w), 1448 (s), 1362 (s), 1217 (w), 1170 (s), 1089 (s), 993 (s), 778 (s), 745 (s), 723 (s), 684 (s); ?H (300 MHz; CDCl3; Me4Si) 8.47 (1H, d, J = 8.10, ArH), 8.04 ( 2H, d, J = 8.04, 2 ? ArH), 7.89 (1H, d, J = 7.54, ArH), 7.80-7.76 (1H, m, ArH), 7.69-7.63 (2H, m, 2 ? ArH), 7.60-7.52 (2H, m, 2 ? ArH), 7.38-6.25 (1H, m, C-CH=C), 5.33-5.26 (2H, m, C- C=CH2), 5.01 (2H, s, CH2O), 4.17 (2H, d, J = 5.67, CH2-C=C), 1.96 (1H, s, OH); ?C (75MHz; CDCl3) 139.45 (C), 136.93 (C), 136.90 (C), 136.06 (=CH-), 134.15 (CH), 129.61 (2 ? CH), 126.81 (2 ? CH), 125.10 (CH), 124.16 (CH), 121.10 (C), 119.37 (CH), 116.70 (=CH2), 115.34 (CH), 55.74 (CH2O), 30.38 (-CH2-); m/z 326 (M+, 24%), 310 (100%), 284 (5%), 185 (3%), 141 (3%), 109 (2%), (Found: 326.1990. C17H18NO3S requires 327.0929). 4.10.2.4 1-(2-Allyl-1-(phenylsulfonyl)-1H-indol-3-yl)ethanol (173) Magnesium turnings (0.030 g, 1.23 mmol, 4.0 eq) were placed in a two necked round bottom flask and dried in an oven. The flask fitted with a dropping funnel and cooled under N2. Dry ether was then placed into the round bottom flask and CH3I was added to the suspension. The mixture immediately started going cloudy with slight rise in temperature. Once all the magnesium has reacted, the dropping funnel was charged with the solution of 2-allyl-1- (phenylsulfonyl)-1H-indole-3-carbaldehyde (171) (0.10 g, 0.308 mmol) in ether, and this was added dropwise to the cloudy Grignard solution. The resulting yellow solution was left to stir for 18 h under N2 over which time the solution turned milky orange. Water was added to the reaction mixture to quench the excess Grignard reagent and this N S OO OH Chapter 4 Experimental Procedures 121 formed a white slurry of Mg(OH)2. The slurry was made soluble by adding an aqueous solution of NH4Cl and the mixture was transferred to the separating funnel and extracted with CH2Cl2 (3 ? 30 ml). The organic fractions were combined, dried over MgSO4, filtered through a celite plug and the excess solvent removed on a rotary evaporator. The resulting yellow oil was purified by column chromatography using 30% EtOAc/Hexane as an eluent to give yellow oil (173), 0.080 g (76%); vmax (Liquid)/cm-1 3567 (b, OH), 2977 (w, CH), 1603 (w), 1448 (s), 1364 (s), 1223 (w), 1171 (s), 1150 (m), 1089 (m), 1022 (m), 960 (w), 913 (m), 730(s), 685 (s); ?H (300 MHz; CDCl3; Me4Si) 8.19 (1H, d, J = 7.91, ArH), 7.81 (1H, d, J = 7.13, ArH), 7.73 (2H, d, J = 8.85, 2 ? ArH), 7.51-7.46 (1H, m, ArH), 7.40-7.35 (2H, m, 2 ? ArH), 7.29-7.22 (2H, m, 2 ? ArH), 6.03-5.93 (1H, m, CH2CHCH2), 5.18-5.12 (1H, m, CH(OH)CH3), 5.04-4.92 (2H, m, CH2CHCH2), 3.93 (1H, dd, J = 5.55 and 5.54, CH2CHCH2), 3.77 (1H, dd, J = 5.99 and 5.97, CH2CHCH2), 1.91 (1H, s, OH), 1.55 (3H, d, J = 6.57, CH(OH)CH3); ?C (75MHz; CDCl3) 1139. 48 (C), 137.29 (C), 135.85 (CH), 134.16 (C), 134.06 (CH), 129.56 (2 ? CH), 128.42 (C), 127.11 (C), 126.80 (2 ? CH), 125.14 (C), 124.80 (CH), 123.82 (CH), 122.02 (CH), 116.55 (CH), 115.17 (CH), 64.56 (CH(OH)CH3), 30.44 (CH2CHCH2), 23.57 (CH(OH)CH3); m/z 340 (M-, 10%), 324 (100%), 284 (2%), 198 (4%), 183 (30%), 168 (6%), 109 (2%), (Found: 341.2530. C19H19NO3S requires 341.1086). 4.10.2.5 3-Methyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (174) Hg(OAc)2 (2.34 g, 0.73 mmol, 1.5 eq) was added to (2-allyl-1- (phenylsulfonyl)-1H-indol-3-yl) methanol (172) (0.16 g, 0.49 mmol) dissolved in dry THF (15 ml). The resulting yellow mixture was stirred under N2 for 20 h at rt. A further portion of Hg(OAc)2 (0.23 g, 0.73 mmol, 1.5 eq) was added and the mixture was stirred at rt for further 18 h. A mixture of NaBH4 (0.042 g, 1.22 mmol, 2.5 eq) in aqueous NaOH (5 ml, 2.5 M) was added whilst stirring. After stirring for further 1 h, a saturated solution aqueous Na2CO3 (5 ml) was added and the mixture was stirred for further 20 minutes. The reaction mixture was allowed to stand for 30 minutes and the THF removed under reduced pressure. Saturated aqueous brine solution (20 ml) and CH2Cl2 N O S OO Chapter 4 Experimental Procedures 122 (20.0 ml) were added and the mixture was extracted with CH2Cl2 (3 ? 30 ml). The organic fractions were combined, dried over MgSO4, filtered with the celite plug and silica to remove traces of Hg and the excess solvent was removed on a rotary evaporator. This gave clear oil that solidified on standing and it was dissolved in CH2Cl2 and subjected to column chromatography using 20% EtOAc/Hexane as an eluent to give a clear solid (174) 0.05 g (31%), melting point 145-148 ?C; vmax (Solid)/cm-1 3061 (w, CH), 1620 (m), 1449 (m), 1404 (s), 1363 (s), 1304 (m), 1220 (s), 1201 (m), 1170 (s), 1119 (m), 1083 (s), 1049 (m), 1022 (m), 979 (m), 931 (s), 852 (s), 794 (m), 759 (s), 725 (s), 687 (s), 664 (s); ?H (300 MHz; CDCl3; Me4Si) 8.46 (1H, d, J = 8.18, ArH), 8.09 (1H, d, J = 8.61, 2 x ArH), 7.85-7.80 (1H, m, ArH), 7.74-7.69 (2H, m, 2 ? ArH), 7.63-7.52 (3H, m, 3 ? ArH), 5.19-5.03 (2H, m, CH2O), 4.17-4.10 (1H, m, CH), 3.56-3.55 (1H, m, CH), 3.16-3.07 (1H, m, CH), 1.75 (3H, d, J = 6.20, CH3); ?C (75MHz; CDCl3) 137.80 (C), 135.18 (C), 132.69 (CH), 131.68 (C), 128.28 (2 ? CH), 126.36 (C), 125.32 (2 ? CH), 123.33 (CH), 122.56 (CH), 116.99 (CH), 116.02 (C), 113.47 (CH), 69.81 (CH), 62.25 (CH2O), 31.78 (CH2), 20.38 (CH3); m/z 328 (M+, 37%), 284 (100%), 220 (3%), 187 (13%), 143 (7%), 109 (2%), (Found: 327.1570. C17H18NO3S requires 327.0929). 4.10.2.6 1,3-Dimethyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (175) Hg(OAc)2 (0.12 g, 0.37 mmol, 1.5 eq) was added to 1-(2-allyl-1- (phenylsulfonyl)-1H-indol-3-yl)ethanol (173) (0.080 g, 0.25 mmol) dissolved in dry THF (15 ml). The resulting yellow mixture was stirred under N2 for 20 h at rt. A further portion of Hg(OAc)2 (0.080 g, 0.25 mmol, 1 eq) was added and the mixture was stirred at rt for further 18 h. A mixture of NaBH4 (0.023 g, 0.61 mmol, 2.5 eq) in aqueous NaOH (5 ml, 2.5 M) was added whilst stirring. After stirring for further 1 h, a saturated solution aqueous Na2CO3 (5 ml) was added and the mixture was stirred for further 20 minutes. The reaction mixture was allowed to stand for 30 minutes before the THF removed under reduced pressure. An aqueous saturated brine solution (20 ml) and CH2Cl2 (20.0 ml) were added and the reaction mixture was extracted with CH2Cl2 (3 ? 30 ml). The organic fractions were combined, dried over MgSO4, filtered with the celite plug and silica N S O O O Chapter 4 Experimental Procedures 123 to remove traces of Hg and the excess was solvent removed on a rotary evaporator. This gave clear oil that solidified on standing and it was dissolved in CH2Cl2 and subjected to column chromatography using 20% EtOAc/Hexane as an eluent to give clear oil (175) 0.02 g (25%); vmax (Liquid)/cm-1 2920 (w, CH), 1615 (w), 1448 (s), 1369 (s), 1203 (m), 1171 (s), 1150 (s), 1090 (s), 1028 (s), 975 (m), 885 (m), 777 (s), 744 (s), 723 (s), 684 (s); ?H (300 MHz; CDCl3; Me4Si) 8.16 (1H, d, J = 8.12, ArH), 7.78 (2H, d, J = 7.39, 2 ? ArH), 7.55-7.750 (1H, m, ArH), 7.44-7.37 (2H, m, 2 ? ArH), 7.31-7.22 (2H, m, 2 ? ArH), 5.10-5.04 (1H, m, CH(O)CH3), 4.14-4.08 (1H, m, CH2CH(O)CH3), 3.26-3.16 (1H, m, CH2CH(O)CH3), 2.85-2.69 (1H, m, CH2CH(O)CH3), 1.60- 1.54 (3H, m, CH(O)CH3), 1.45-1.38 (3H, m, CH2CH(O)CH3); ?C (75MHz; CDCl3) 138.86 (C), 136.31 (C), 133.69 (CH), 132.28 (C), 129.29 (2 ? CH), 127.49 (C), 126.35 (2 ?CH), 124.18 (CH), 124.04 (C), 123.49 (CH), 120.97 (C), 119.18 (C), 118.43 (CH), 114.54 (CH), 67.55 (CH(O)CH3), 64.04 (CH2CH(O)CH3), 32.54 (CH2CH(O)CH3), 21.19 (CH(O)CH3), 19.98 (CH2CH(O)CH3); m/z 342 (M+, 66%), 298 (100%), 201(8%), 157 (10%), 130 (2%), (Found: 341.1290. C19H19NO3S requires 341.1086). References 124 References 1) G. A. Swan, An Introduction to the Alkaloids, Blackwell Scientific Publications, Oxford, 1967, 1-4. 2) R.H. F. Manske, The Alkaloids, Academic Press, Vol. 1, New York, 1950, 1. 3) M. Hesse, Alkaloid Chemistry, A Wiley-Interscience Publication, New York, 1981, 6-7. 4) M. Hesse, Alkaloids, Nature?s Curse or Blessing, Verlag Helvetica Chimica Acta, Z?rich and Wiley-VCH, Weinheim, 2002, 283-292. 5) http://waynesword.palomar.edu/ww0401.htm. 6) http://www.people.vcu.edu/~asneden/alkaloids.htm. 7) M. Frederich, M. Tits and L. Angenot, Transaction of the Royal Society of Tropical Medicine and Hygiene, 2008, 102, 11-19. 8) V. Birzniece, T. B?ckstr?ma, I. Johanssona, C. Lindblad, P. Lundgrena, M. L?fgren, T. Osslon, G. Ragagnina, M. Taubea, S. Turkmena, G. Wahlstr?mc, M. Wanga, A. Wihlb?cka, and D. Zhua, Brain Research Review, 2006, 51, 212-239. 9) V. H. Shukla, K. R. Dave and S. R. Katyare, Comparative Biochemistry and Physiology Part C, 2000, 127, 79-90. 10) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875-2911. 11) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873-2920. 12) J. J. Li and G. W. Gribble, Palladium in Heterocyclic Chemistry, Tetrahedron Organic Chemistry Series, Vol. 20, Oxford, 2000, 73-74. 13) A. R. Martin and Q. Zheng, Advances in Nitrogen Heterocycles, Volume 1, JAI Pres Inc., Greenwhich Connecticut, 1995, 71. 14) B. Sezen and D. Sames, J. Am. Chem. Soc., 2003, 125, 5274-5275. 15) www.unb.br/iq/labpseq/qo/olv/olv/about.htm-23k. 16) R. J. Sundberg, Indoles, Academic Press Limited, New York, 1996, 1. 17) www.unb.br/iq/labpseq/qo/olv/olv/indigo.htm. 18) J. A Joule and K. Mills, Heterocyclic Chemistry, Blackwell Science Ltd, 4th edition, Oxford, 2000, 353-361. 19) T. Eicher and S. Hauptmann, The Chemistry of Heterocycles, Georg Thieme Verlag, Stuttgart, New York, 1995, 99-110. References 125 20) S. Nakatsuka, O. Asano, K. Ueda and T Goto, Heterocycles, 1987, 26, 1471-1474. 21) Clayden, N. Greeves, S. Warren and P. Wothers, Organic Chemistry, Oxford University Press, Oxford, 2001, 1169-1170. 22) M. Alfonsi, A. Arcadi, M. Aschi, G. Bianchi and F. Marinelli, J. Org. Chem., 2005, 70, 2265-2273. 23) J. Sl?tt and J. Bergman, Tetrahedron, 2002, 58, 9187-9191. 24) M. R. Brennan, K. L. Erickson, F. S. Szamalc, M. J. Tansey and J. M. Thornton, Heterocycles, 1986, 24, 2879-2885. 25) M.G. Saulnier and G.W. Gribble, J. Org. Chem., 1982, 47, 757-761. 26) B. Danieli, G. Lesma, M. Martinelli, D. Pasarella, I. Peretto, and A. Silvani, Tetrahedron, 1998, 54, 14081-14088. 27) Y. Kondo, A. Yoshida, and T. Sakamoto, J. Chem. Soc., Perkin Trans. 1, 1996, 2331- 2332. 28) A. Dinsmore, D. Billing, K. Mandy, J. P. Michael, D. Mogano, and S. Patil, Org. Lett., 2004, 6, 293-296. 29) X. Wang, B. S. Lane and D. Sames, J. Am. Chem. Soc., 2005, 127, 4996-4997. 30) N. R. Deprez, D. Kalyani, A. Krause and M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 4972-4973. 31) J. Wang, Y. Shen, W. Hu, M. Hsieh, F. Lin, M. Hsu and M. Hsu, J. Med. Chem., 2006, 49, 4971-4980. 32) J. M. Berry, T. D. Bradshaw, I. Fichtner, R. Ren, C. H. Schwalbe, G. Wells, Eng-Hui Chew, M. F. G. Stevens, and A. D. Westwell, J. Med. Chem., 2005, 48, 639-644. 33) N. Misawa, R. Nakamura, Y. Kagiyama, H. Ikenaga, F. Furukawa and K. Shindo, Tetrahedron, 2005, 61, 195-204. 34) S. Mahboobi, S. Teller, H. Pongratz, H. Hufsky, A. Sellmer, A. Botzki, A. Uecker, T. Beckers, S. Baasner, C. Sch?chtele, F. ?berall, M. U. Kassack, S. Dove and F. D. B?hmer, J. Med. Chem., 2002, 45, 1002-1018. 35) A. Penoni, J. Volkmann and K. M. Nicholas, Org. Lett., 2002, 4, 699-701. 36) L. Ackermann and R. Born, Tetrahedron Lett., 2004, 45, 9541-9544. 37) J. S. Yadaf, B. V. S. Reddy and T. Swamy, Tetrahedron Lett., 2003, 44, 9121-9124. References 126 38) D. Mukherjee, S. K. Sarkar, U. S. Chowdhury and S. C. Taneja, Tetrahedron Lett., 2007, 48, 663-667. 39) J. S. Yadav, B. V. S. Reddy, P. M. Reddy and Ch. Srinivas, Tetrahedron Lett., 2002, 43, 5185-5187. 40) G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. SAmbri and P. Melchiorre, Org. Lett., 2007, 9, 1403-1405. 41) M. B. Smith, L. C. Guo, S. Okeyo, J. Stenzel, J. Yanella and E. LaChpelle, Org. Lett., 2002, 4, 2321-2323. 42) Z. Zhang, Z. Hu, Z. Yu, P. Lei, H. Chi, Y. Wang and R. He, Tetrahrdron Lett., 2007, 48, 2415-2419. 43) C. Peifer, T. Stoiber, E. Unger, F. Totzke, C. Sch?chtele, D. Marm?, R. Brenk, G. Klebe, D. Schollmeyer and G. Dannhardt, J. Med. Chem., 2006, 49, 1271-1281. 44) A. Uzan, G. Le Fur and J. Rataud, J. Med. Chem., 1980, 23, 1306-1310. 45) H. Wu, S. Lin and Y. Chen, J. Agric. Food Chem., 2005, 53, 5164-5169. 46) W. Chao, D. Yean, K. Amin, C. Green and L. Jong, J. Med. Chem., 2007, 50, 3412-3415. 47) J. A. Joule and K. Mills, Heterocyclic Chemistry at a Glance, Blackwell Publishing Ltd., Oxfoed, 2007, 132-143. 48) P. L. Julian, E. W. Meyer, A. Magnani and W. Cole, J. Am. Chem. Soc., 1945, 67, 1203- 1211. 49) Y. Tsuji, K. Huh and Y. Watanabe, J. Org. Chem., 1987, 52, 1673-1680. 50) M. Tokunaga, M. Ota, M. Haga and Y. Wakatsuki, Tetrahedron Lett., 2001, 42, 3865- 3868. 51) S. Chandrasekaran, A. M. Al-Ghananeem, R. M. Riggs and P. A. Crooks, Bioorg. Med. Chem. Lett., 2006, 16, 1874-1879. 52) W. Hu, Z. Guo, X. Li, C. Guo, F. Chu, and G. Cheng, Bioorg. Med. Chem., 2003, 11, 5539-5544. 53) R. Silvestri, G. DeMartino, G. LaRgina, M. Artoco, S. Massa, L. Vargiu, M. Mura, A. G. Loi, T. Marrceddu and P. La Colla, J. Med. Chem., 2003, 46, 2482-2493. 54) B. L. Flynn, E. Hamel and M. K. Jung, J. Med. Chem., 2002, 45, 2670-2673. 55) C. H. Merlic, Y. You, D. M. McInnes, A. L. Zechman, M. M. Miller and Q. Deng, Tetrahedron, 2001, 57, 5199-5212. References 127 56) R. Pathak, J. M. Nhlapo, S. Govender, J. P. Michael, W. A. L. van Otterlo and C. B. de Koning, Tetrahedron, 2006, 62, 2820-2830. 57) B. Hugon, B. Pfeiffer, P. Renard and M. Prudhomme, Tetrahedron Lett., 2003, 44, 3927- 3930. 58) A. Rahman and A. Basha, Biosynthesis of Indole Alkaloids, Oxford University Press, New York, 1983, 45-88. 59) S. E. Wolkenberg and D. L. Boger; Chem. Rev., 2002, 102, 4307-4403. 60) C. Aubry, A. Patel, S. Mahale, B. Chaudhuri, J.-D. Mar?chal, M. J. Sutcliffe and P. R. Jenkins, Tetrahedron Lett., 2005, 46, 1423-1425. 61) C. J. Pearce, T. W. Doyle, S. Forenza, K. S. Lam and D. R. Schroeder, J. Nat. Prod., 1988, 51, 937-940. 62) A. H?rmann, B. Chaudhuri and H. Fretz, Bioorg. Med. Chem., 2001, 9, 917-921. 63) G. Gribble, M. G. Saulnier, J. A. Obaza-Nataitis and D. M. Ketcha, J. Org. Chem., 1992, 57, 5891-5899. 64) T. Sakamoto, Y. Kondo, N. Takazawa and H. Yamanaka, J. Chem. Soc. Perkin Trans. 1, 1996, 1927-1934. 65) N. Murugesan, Z. Gu, P. D. Stein, S. Bisaha, S. Spergel, R. Girotra, V. G. Lee, J. Lloyd, R. N. Misra, J. Schmidt, A. Mathur, L. Stratton, Y. F. Kelly, E. Bird, T. Waldron, E. C. - K. Liu, R. Zhang, H. Lee, R. Serafino, B. Abboa-Offei, P. Mathers, M. Giancarli, A. A. Seymour, M. L. Webb, S. Moreland, J. C. Barrish and J. T. Hunt, J. Med. Chem., 1998, 41, 5198-5218. 66) D. M. Ketcha, D. A. Lieurance and D. F. J. Homan, J. Org. Chem., 1989, 54, 4350-4356. 67) G. W. Gribble and T. C. Barden, J. Org. Chem., 1985, 50, 5900-5902. 68) E. Wenkert, E. C. Angell, V. F. Ferreira, E. L. Michelotti, S. R. Piettre, J. Sheu and C. S. Swindell, J. Org. Chem., 1986, 51, 2343-2351. 69) Y. Liu and G. W. Gribble, Tetrahedron Lett., 2000, 41, 8717-8722. 70) S. C. Conway and G. W. Gribble, Heterocycles, 1992, 34, 2095-2108. 71) D. P. Steinhuebel, J. J. Fleming and J. Du Bois, Org. Lett., 2002, 4, 293-295. 72) B. Wang, M. Li, H. Song and B. Wang, J. Org. Chem., 2006, 71, 8291-8293. 73) W. Zhao and E. M. Carreira, Org. Lett., 2003, 5, 4153-4154. 74) M. L. Bennasar, E. Zulaica, D. Sol?, and S. Alonso, Tetrahedron, 2007, 63, 861-866. References 128 75) M. G. Saulnier and G. W. Gribble, Tetrahedron Lett., 1983, 24, 5435-5438. 76) G. W. Gribble, D. J. Keavy, D. A. Davis, M. G. Saulnier, B. Pelcman, T. C. Barden, M. P. Sibi, E. R. Olson and J. J. BelBruno, J. Org. Chem., 1992, 57, 5878-5891. 77) C. B. de Koning, J. P. Michael and W. A. L van Otterlo, Synlett., 2002, 2065-2067. 78) D. D. Perrin and W. L. Armerego, Purification of Laboratory Chemicals, Pergamon Press, Oxford, 1998. 79) A. B. Smith III, M. Visnick, J. N. Haseltine, P. A. Sprengeler, Tetrahedron, 1986, 42, 2957-2970. 80) C. S. Cho, C. S. Kim, J. H. Kim, T. Shim and S. Chul, J. Chem. Res. Synop., 2004, 9, 630-631. 81) Upjohn Co., BE 621047, 1963; cited in Chem. Abstr., 1963, 59, 11433b. 82) L. Buchman, Wiss. Z. Tech. Hochsch. Chem. Carl Schorlemmer Lenna-Mersebug, 1963, 5, 125-217. 83) N. R. Deprez, D. Kalyani, A. Krause and M. S. Sandford, J. Am. Chem. Soc., 2006, 128, 4972-4973. 84) M. D. Smith, A. F. Stepan, C. Ramarao, P. E. Brennan and S. V. Ley, Chem. Commun., 2003, 21, 2652-2653. 85) I. Fleming and M. Woolias, J. Chem. Soc. Perkin Trans. 1, 1979, 829-837. 86) W. H. Dekker, H. A. Selling and J. C. Overeem, J. Agric. Food, Chem., 1975, 23, 785- 791. 87) J. Bergman, Acta Chem. Scand., 1971, 25, 1277-1280. 88) P. Terent?ew, Dokl. Akad. Nauk, 1957, 114, 560, 563. 89) A. P. Kozikowski and X Cheng, J. Chem. Soc. Chem. Commun., 1987, 680-683. 90) J. C. Powers, J. Org. Chem., 1966, 31, 2627-2631. Appendix 129 Appendix Appendix 1: Selected 1H and 13C NMR spectra Compound Page 5-Methoxy-2-phenyl-1H-indole (129) 130 2-o-Tolyl-1H-indole (130) 131 5-Methoxy-2-o-tolyl-1H-indole (131) 132 2-(4-Methoxyphenyl)-1H-indole (134) 133 5-Methoxy-3-o-tolyl-1H-indole (152) 134 3-(4-Methoxyphenyl)-1H-indole (155) 135 1-(2-(1H-indol-3-yl) acetophenone (159) 136 1-(2-(5-Methoxy-1H-indol-3-yl) acetophenone (160) 137 2-(4-Bromo-2,5-dimethoxyphenyl)-1-(phenylsulfonyl)-1-H-indole (164) 138 2-(4-Bromo-2,5-dimethoxyphenyl)-5-methoxy-1-(phenylsulfonyl)-1H-indole (165) 139 2-(4-Bromo-2,5-dimethoxyphenyl)-1H-indole (166) 140 2-(4-Bromo-2,5-dimethoxyphenyl)-5-methoxy-1H-indole (167) 141 2-Allyl-1-(phenylsulfonyl)-1H-indole (169) 142 3-Methyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (174) 143 1,3-Dimethyl-5-(phenylsulfonyl)-1,3,4,5-tetrahydropyrano[4,3-b]indole (175) 144 Appendix 130 ppm (f1) 4.05.06.07.08.0 0 5000 8 .210 7 .653 7 .626 7 .454 7 .429 7 .403 7 .333 7 .308 7 .295 7 .266 7 .249 7 .091 7 .084 6 .872 6 .864 6 .843 6 .835 6 .757 3 .862 1. 00 1. 95 0. 97 1. 84 4. 41 2. 97 Tlabo : TLB85.01 : CDCl3 : 19/06/07 : 300K : 1H ppm (f1) 100150 0 10000 20000 30000 40000 154 .929 139 .012 132 .851 132 .426 130 .150 129 .404 128 .034 125 .454 113 .039 112 .011 102 .708 100 .260 56 .258 Tlabo : TLB85.01 : CDCl3 : 19/06/07 : 300K : 13C N H MeO N H MeO Appendix 131 ppm (f1) 3.04.05.06.07.08.0 0 5000 10000 8 .036 7 .648 7 .622 7 .436 7 .420 7 .407 7 .360 7 .334 7 .267 7 .247 7 .236 7 .186 7 .162 7 .147 7 .121 6 .590 2 .465 1. 00 1. 08 0. 89 7. 24 2. 84 Tlabo : TLB67.10 : CDCl3 : 27/03/07 : 300K : 1H ppm (f1) 50100 0 5000 10000 15000 20000 25000 137 .892 136 .612 136 .545 133 .090 131 .514 129 .441 129 .312 128 .411 126 .533 122 .498 120 .983 120 .500 111 .227 103 .418 21 .547 Tlabo : TLB67.10 : CDCl3 : 27/03/07 : 300K : 13C N H N H Appendix 132 ppm (t1) 3.04.05.06.07.08.0 8 .026 7 .473 7 .459 7 .445 7 .284 7 .274 7 .252 7 .112 6 .886 6 .879 6 .857 6 .850 6 .546 3 .869 2 .498 1. 00 1. 19 5. 05 1. 20 1. 18 1. 06 3. 36 3. 31 Tlabo : TLBO98.09 : CDCl3 : 13/08/07 : 300K : 1H ppm (t1) 50100150 154 .426 138 .240 136 .074 132 .711 131 .315 131 .083 129 .300 128 .904 127 .927 126 .099 112 .360 111 .477 102 .862 102 .249 55 .941 21 .132 Tlabo : TLBO98.09 : CDCl3 : 13/08/07 : 300K : 13C N H MeO N H MeO Appendix 133 ppm (f1) 4.05.06.07.08.09.010.011.0 0 5000 11 .401 7 .806 7 .777 7 .502 7 .476 7 .383 7 .357 7 .058 7 .046 7 .018 6 .996 6 .970 6 .759 3 .805 1. 00 2. 11 2. 45 4. 27 1. 05 3. 28 Tlabo : TLB66.1 : DMSO : 15/03/07 : 300K : 1H ppm (f1) 50100150 0 1000 2000 3000 4000 5000159 .148 138 .127 137 .280 129 .189 126 .717 125 .265 121 .386 120 .013 119 .576 114 .713 111 .421 97 .691 55 .570 Tlabo : TLB66.1 : DMSO : 19/03/07 : 300K : 13C N H OMe N H OMe A pp en di x 13 4 pp m (t1 ) 3. 0 4 . 0 5. 0 6. 0 7 . 0 8. 0 8.113 7.431 7.414 7.402 7.347 7.331 7.318 7.304 7.276 7.249 7.219 7.127 7.121 6.936 6.912 6.883 6.876 6.906 3.784 2.321 1.00 1.19 1.04 4.38 1.07 1.07 3.18 3.18 T la bo : TL B 12 2. 1 : C D C l3 : 01 /1 0/ 07 : 30 0K : 1H pp m (t1 ) 50 10 0 1 50 154.632 137.130 134.800 131.196 130.992 130.600 127.708 126.958 125.901 123.810 117.497 112.832 112.177 101.748 56.116 20.928 T la bo : T LB 12 2. 1 : C D C l3 : 01 /1 0/ 07 : 30 0K : 13 C /1 H N H M e O N H M e O Appendix 135 ppm (f1) 4.05.06.07.08.0 8 .149 7 .990 7 .965 7 .671 7 .642 7 .454 7 .428 7 .309 7 .301 7 .293 7 .283 7 .254 7 .090 7 .061 3 .921 1. 00 1. 13 2. 20 1. 13 2. 29 3. 44 3. 36 Tlabo : TLB43.12 : CDCl3 : 13/02/07 : 300K : 1H ppm (f1) 100150 158 .537 137 .033 129 .064 128 .587 126 .325 122 .746 121 .650 120 .593 120 .176 118 .385 114 .735 111 .825 55 .820 Tlabo : TLB43.12 : CDCl3 : 13/02/07 : 300K : 13C N H OMe N H OMe Appendix 136 ppm (f1) 2.03.04.05.06.07.08.0 0 5000 10000 8 .609 7 .655 7 .629 7 .579 7 .553 7 .521 7 .415 7 .404 7 .388 7 .380 7 .243 7 .161 7 .097 7 .089 2 .018 1. 00 2. 20 3. 24 4. 33 Tlabo : TLB88 : CDCl3 : 18/06/07 : 300K : 1H ppm (f1) 50100150200 0 50000 100000 206 .604 142 .025 136 .676 133 .440 131 .279 131 .119 128 .066 127 .087 126 .826 124 .267 123 .186 120 .980 119 .803 116 .722 111 .936 30 .446 Tlabo : TLB88 : CDCl3 : 18/06/07 : 300K : 13C N H O N H O A pp en di x 13 7 pp m (t1 ) 2 . 0 3. 0 4. 0 5. 0 6. 0 7 . 0 8. 0 8.556 7.585 7.561 7.537 7.512 7.415 7.391 7.366 7.310 7.281 7.249 7.100 7.092 7.053 7.047 6.925 6.917 6.895 6.888 3.804 2.026 1.00 3.00 3.30 3.16 2.40 2.13 1.04 T la bo : T LB 12 1 : C D C l3 : 29 /0 9/ 07 : 30 0K : 13 C pp m (t1 ) 50 10 0 15 0 20 0 204.824 153.376 140.052 131.701 129.790 129.334 129.197 126.264 125.343 125.169 122.871 114.700 111.771 110.811 99.214 54.329 28.493 T la bo : T LB 12 1 : C D C l3 : 29 /0 9/ 07 : 30 0K : 13 C N H M eO O N H M eO O Appendix 138 ppm (t1) 4.05.06.07.08.0 0 1000 2000 3000 4000 5000 6000 8 .261 8 .234 7 .509 7 .484 7 .462 7 .437 7 .373 7 .349 7 .325 7 .299 7 .280 7 .254 7 .232 7 .127 6 .777 6 .578 3 .820 3 .679 1. 00 0. 88 0. 91 4. 21 4. 00 6. 00 0. 89 Tlabo : TLB53.1 : CDCl3 : 14/12/06 : 300K : 1H/13C ppm (t1) 100150 0 500 1000 1500 2000 2500 3000153 .082 149 .628 139 .047 137 .998 137 .039 133 .847 130 .406 129 .055 127 .132 125 .249 124 .323 121 .252 116 .722 116 .455 116 .127 113 .535 57 .358 56 .533 Tlabo : TLB53.1 : CDCl3 : 14/12/06 : 300K : 1H/13C N S OO MeO Br OMe N S OO MeO Br OMe Appendix 139 ppm (f1) 4.05.06.07.08.0 -1000 0 1000 2000 3000 4000 5000 6000 70008 .151 8 .121 7 .468 7 .440 7 .309 7 .284 7 .256 7 .130 6 .967 6 .936 6 .924 6 .777 6 .516 3 .819 3 .691 1. 00 5. 33 0. 81 2. 84 0. 87 5. 71 2. 60 Tlabo: TLB92.1: CDCl3: 08/07/07: 300K: 1H ppm (f1) 50100150 0 500 1000 157 .241 152 .971 149 .620 138 .756 137 .867 133 .797 132 .640 131 .549 128 .990 127 .104 121 .488 117 .200 116 .755 116 .506 114 .083 113 .933 113 .291 103 .653 57 .363 56 .557 56 .047 Tlabo : TLB92.1 : CDCl3 : 09/070/07 : 300K : 13C N MeO S O O Br OMe MeO N MeO S O O Br OMe MeO Appendix 140 ppm (f1) 4.05.06.07.08.09.010.0 9 .625 7 .641 7 .615 7 .421 7 .394 7 .323 7 .243 7 .215 7 .200 7 .168 7 .133 7 .108 6 .883 3 .944 3 .923 1. 00 1. 10 1. 12 1. 07 3. 30 1. 03 6. 35 Tlabo : TLB56.1 : CDCl3 : 07/02/07 : 300K : 1H ppm (f1) 60708090100110120130140150 -5000 0 5000 10000 15000 20000 25000 30000151 .124 150 .515 136 .651 135 .514 128 .268 122 .680 120 .959 120 .453 118 .040 111 .814 111 .456 111 .115 100 .556 57 .306 57 .185 Tlabo : TLB56.1 : CDCl3 : 08/02/07 : 300K : 13C N H Br MeO OMe N H Br MeO OMe Appendix 141 ppm (t1) 4.05.06.07.08.09.0 -500 0 500 1000 1500 2000 2500 3000 3500 9 .542 7 .325 7 .313 7 .283 7 .256 7 .211 7 .077 6 .879 6 .850 6 .817 3 .967 3 .939 3 .863 1. 00 0. 87 1. 79 2. 55 2. 63 2. 63 3. 38 Tlabo : TLB105.03 : CDCl3 : 20/08/007 : 300K : 1H ppm (t1) 100150 154 .413 150 .771 150 .102 135 .693 131 .573 128 .315 120 .660 117 .674 112 .816 111 .803 111 .411 110 .631 101 .728 99 .891 56 .948 56 .806 55 .851 Tlabo : TLB105.03 : CDCl3 : 21/08/07 : 300K : 13C N H MeO Br OMe MeO N H MeO Br OMe MeO A pp endix 142 pp m (f1) 4 .0 5 .0 6 .0 7 .0 8 .0 8.174 8.148 7.769 7.744 7.739 7.517 7.492 7.429 7.403 7.383 7.378 7.268 7.264 7.252 7.241 7.236 7.229 7.225 7.204 7.201 6.404 6.075 6.053 6.043 6.039 6.022 6.017 6.007 5.985 5.963 5.222 5.217 5.212 5.201 5.164 3.779 3.776 3.757 1.00 1.94 6.18 0.91 0.95 1.94 2.01 Tlab o : TLB 46 .11 : C D C l3 : 10/11/06 : 300K : 1H pp m (f1) 50 100 140.525 139.556 137.656 134.498 134.055 130.042 129.630 126.687 124.490 123.998 120.690 118.219 115.106 109.992 33.795 Tlab o : TLB 46 .1 : C D C L3 : 14/11/06 : 300K : 13C NS O O NS O O A pp en di x 14 3 pp m (f1 ) 2. 0 3. 0 4. 0 5. 0 6. 0 7 . 0 8. 0 010 00 20 00 30 00 40 00 50 00 60 00 8.475 8.447 8.104 8.080 7.825 7.744 7.718 7.605 7.577 7.558 7.548 5.194 5.189 5.141 5.090 5.081 5.072 5.032 4.169 4.157 4.148 4.136 4.125 4.116 4.104 3.562 3.554 3.504 3.162 3.129 3.121 3.104 3.071 1.757 1.737 Tla bo : TL B7 3 : C DC l3 : 1 1/0 5/0 7 : 30 0K : 1H p pm (f1 ) 5 0 1 0 0 05 0 0 0 1 0 0 0 0 1 5 0 0 0 2 0 0 0 0 137.798 135.176 132.691 131.681 128.282 126.356 125.323 123.332 122.556 116.993 116.022 113.471 69.812 62.146 31.779 20.380 N O S O O N O S O O A pp en di x 14 4 pp m (f1 ) 0. 0 5. 0 010 00 2 00 0 30 00 4 00 0 8.176 8.149 7.791 7.766 7.761 7.526 7.443 7.416 7.392 7.292 7.258 7.250 7.246 7.221 5.078 5.057 4.127 4.118 4.107 4.096 4.087 4.076 3.264 3.252 3.222 3.206 3.195 3.174 3.166 3.156 2.781 2.750 2.746 2.724 2.719 2.693 2.688 1.579 1.557 1.535 1.448 1.427 1.402 1.381 Tla bo : TL B8 1.1 : CD Cl 3 : 06 /06 /07 : 30 0K : 1H pp m (f1 ) 50 1 00 050 0 1 00 0 1 50 0 133.691 129.285 126.346 124.183 124.036 123.492 123.447 119.176 118.429 114.578 114.541 70.326 70.012 67.552 64.040 33.134 32.535 29.694 21.526 21.188 21.119 19.978 Tla bo : T LB 81 .1 : C DC l3 : 0 6/0 6/0 7 : 30 0K : 1 3C N S O O O N S O O O