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During the course of this work, several synthetic procedures were repeatedly used to obtain indole analogues with different substitution patterns. This section describes those general procedures. Each method is described using a specific example. Individual synthetic methods are described separately, where applicable.

Method 1 : General synthetic procedure for lndole-3-carboxaldehydes. The Vilsmeier- Haack Reaction

The general procedure is illustrated by the preparation of 5-methoxy-2-phenyl-indol-3-

carboxaldehyde 264b.

Phosphoryl chloride (0.02 mol,3.10 g,1.88 ml) was slowly added to DMF (0.077 mol,5.67 g,6.00

ml) under nitrogen at 0 °C at such a rate that the internal temperature was maintained at 0 °C . After 10 minutes a solution of 5-methoxy-2-phenyl-1 H-indole 264a (4.0 g, 0.018 mol) In DMF (6 ml) was added dropwise. The reaction mixture was stirred vigorously and allowed to attain room temperature over a 90 minute period. The mixture was subsequently poured into 2N NaOH (50 ml). The product crystallised as pale yellow flakes which were isolated by vacuum filtration.

Method 2 : General synthetic procedure for Nitro-oiefins. The Henry Nitroaidoi Reaction.

5-Methoxy-2-phenyl-1H-indol-3-carboxaldehyde 264b (2.0 g, 7.96 mmol) was dissolved in

nitromethane (4 ml). To this solution was added NH4OAC (1.0 g) and the mixture was heated at 101 °C for 2.5 hours. During this process the reaction mixture became bright red in colour. The cooled mixture was poured into ice cold water (150 ml), extracted with EtOAc (100 ml) and dried over MgS0 4 . Removal of the solvent under reduced pressure furnished the title compound as fine red crystals.

Method 3 : General synthetic procedure for Tryptamines. Method A : From NItriles.

The general procedure for 2-phenyitryptamlne 250b is described .

2-Pheny!-indo!-3-acetonitriie 250a (2,0 g,8.62 mmol), dissolved in dry diethyl ether (50 ml) was added dropwise under a steady stream of nitrogen to a suspension of lithium aluminium hydride (0.132 mol, 5.01 g) in dry diethyl ether (100 ml). Stirring was maintained for several hours at room temperature until thin layer chromatographic analysis revealed that all starting material had been reduced. The reaction was subsequently quenched by the dropwise addition of saturated NH4CI solution. Solid inorganic material was removed by vacuum filtration. Volatile components of the filtrate were removed under reduced pressure and the residual material was dissolved in EtOAc (100 ml). The organic extract was washed with water (2x30 ml) followed by sat. NaCI solution and dried over anhydrous MgS0 4 . Removal of the EtOAc yielded the product as a clear oil.

Many of the tryptamine intermediates obtained in this way were subsequently transformed into amide analogues without further characterisation.

Method B : From Nitro-olefins

The general procedure for 2-phenyl-5-methoxytryptamine 266 is described.

Under a steady stream of N2(g), lithium aluminium hydride (0.013 mol, 0.5 g) was added to an anhydrous 50/50 THF, diethyl ether (40 ml) solvent system. 5-Methoxy-2-phenyl-3-(2’-nitrovinyl)-

1 H-indole 265 (1.50 g, 5.1 mmol) In anhydrous THF (30 ml) was added dropwise to this

suspension. The mixture was stirred under nitrogen for 15 hours before being quenched by the cautious addition of saturated NH4CI solution. The resultant inorganic precipitate was filtered off and repeatedly washed with THF. The THF was removed under vacuum and the residual yellow oil was dissolved in EtOAc (100 ml). The EtOAc solution was repeatedly extracted with 2M HOI. The aqueous isolate was neutralised with 2M NaOH and extracted with EtOAc. This organic extract was washed with brine and dried over MgS0 4 . Gravity filtration followed by removal of the solvent from the filtrate under reduced pressure yielded a pale yellow oil which gave a white foam under vacuum.

Method 4 : General synthetic procedure for N-Acyl amides.

described. In many cases of acid anhydride was used as the acylating reagent instead of an acid chloride.

Tryptamine (5.0 g,0.031 mol) was dissolved in dry CH2CI2 (150 ml) under a stream of nitrogen. Triethylamine (0.037 mol,3.76 g,2.92 ml) was added dropwise and the mixture was stirred at room temperature for 10 minutes. Acetyl chloride (leqv.,0.031 mol,2.43 g,2.69 ml) in C H 2CI2 (30 ml) was added dropwise to the solution which was stirred and maintained at room temperature for 3 hours. The solid inorganic by-products were removed by filtration and the yellow filtrate was washed successively with H2O (50 ml), 10% HCI (50 ml), 2 M NaOH (2x30 ml), H2O (50 ml) and brine. The solution was dried over anhydrous Na2S0 4 , filtered and the CH2CI2 removed under reduced pressure to give a colourless oil which produced colourless crystals on standing at room temperature.

Method 5 : General synthetic procedure for N-Fluoroacyl amides.

The method adopted for the synthesis of N-[2-(indol-3-yl)ethyl]-trifluoroacetamide 64 is

described. Other homologated fluoroacyl amides were synthesised using fluoroacylating reagents of general formula CnF2n+iC 0 2 CH2CH3.

Tryptamine (1.0 g, 6.25 mmol)was dissoived in methanol (6 ml) at room temperature. Triethylamine (1 eqv.,6.25 mmol,0.81 mi,0.63 g) was added and the reaction mixture was stirred at room temperature for 5 minutes, under N2(g). Ethyl trifluoroacetate (1.25 eqv., 1.11 g, 0.93 ml, 7.81 mmol) was added dropwise and stirring maintained for a further 30 minutes. MeOH was removed under reduced pressure and the resultant brown oil was subjected to flash column chromatography [60-80 hexane:EtOAc, 2 :1].

Method 6 : General synthetic procedure for Gramines. The Mannich Reaction.

The general procedure adopted for the synthesis of 2-phenylgramine 249 is described.

2-Phenyl-1 H-indole 247 (10.0 g,0.052 mol) in 1,4-dioxane (52 cm^) was added dropwise over a

30 minute period to an ice cold solution of 1,4-dioxane (50 cm^), glacial acetic acid (50 cm^), 36% aqueous formaldehyde solution and dimethylamine (11.5 cm^). The mixture was stirred at 0 °C for 2 hours and then at room temperature for 5 hours. Volatile components were subsequently removed under reduced pressure to yield a white solid mass. The solid was partially dissolved in water and extracted with EtOAc (3x50 ml). The organic layer was washed repeatedly with 2M HCI and the aqueous extract neutralised with 2M NaOH. The neutral solution

was extracted with EtOAc, washed with saturated NaCI solution and dried over MgS0 4 . Removal of the solvent under reduced pressure yielded the gramine derivative.

Method 7 : General synthetic procedure for synthesis of lndol-3-acetonitriles.

The general procedure for the synthesis of 2-phenyl-indol-3-acetonitrile 250 a is described.

2-Phenylgramine 249 (6.0 g, 0.024 mol) was dissolved in MeOH (80 ml) with stirring. Mel (0.12 mol,7.47 ml) was added in one portion, followed after 30 minutes by KON (0.25 mol, 16.28 g) dissolved in H2O (10 ml) and DMF (10 ml). The solution was heated at 80 °C for 10 hours on an oil bath. Volatile components were removed under reduced pressure and the resultant solid mass was partially dissolved in water. The suspension was extracted with Et2 0 (2x100 ml), washed with water, brine and dried over Na2S0 4 .

Method 8 : General Procedure for Preparation of N-[2-(lndol-3-yl)ethyl]-alkylureas.

General method illustrated by the preparation of N-[2-(indol-3-yl)ethyl]-allylthiourea 70.

Tryptamine (1.0 g, 6.25 mmol) was dissolved in anhydrous CH2CI2 (50 ml) under a stream of nitrogen. Allylthioisocyanate (1 eqv., 0.62 g, 0.61 ml) in anhydrous CH2CI2 (30 ml) was added dropwise and the mixture was stirred for 2 hours at room temperature. Removal of volatile components under reduced pressure yielded a clear oil which when triturated with ether gave the title compound as white crystals.