Oh

Scheme 3 Synthesis of Nb-acetyl-5-acetylamino-1-methoxytryptamine tained by nitration of 15, is then converted to Nb-acetyl-2,3-dihydro-5-nitrotryptamine (17, 93%).

Oxidation of 17 with m-chloroperbenzoic acid (MCPBA) gives rise to Nb-acetyl-1-hydroxy-5-nitrotryptamine (18, 70%). In this oxidation step, MCPBA is superior to the tungstate method. Methylation of the 1-hydroxy group with Me2SO4 and subsequent reduction of the resultant 19 (93%) with Sn/Ac2O/AcOH affords 13 (89%). Interestingly, reduction of 19 with Zn/Ac2O/AcOH generates 13 (34%) and 4-acetoxy-Nb-acetyl-5-acetylamino-1-methoxytryptamine (20, 16%), a Bamberger rearrangement product.

For the preparation of Nb-acetyl-6-acetylamino-1-methoxytryptamine (21) two routes have been developed [15]. The first is seven steps from indoline (5) with an overall yield of 38%. The second is eight steps with a 34% overall yield starting from tryptamine (14).

In the first route (Scheme 4), indoline (5) is nitrated to 6-nitro-2,3-dihydroindole (22, 92%). Application of the tungstate method to 22 and subsequent methylation provide 1-methoxy-6-nitroindole (9, 77%) via 8a. A Vilsmeier-Haack reaction (94%), followed by nitroaldol reaction (85%), leads 9 to 1-methoxy-6-nitro-3-(2-nitrovinyl)indole (23) through 1-methoxy-6-nitroindole-3-carbaldehyde (10b). After selective reduction of the nitro-vinyl part of 23 with NaBH4, the resultant 1-methoxy-6-nitro-3-(2-nitro-ethyl)indole (24,84%) is treated with Zn/HCl and then Ac2O to give 21 (81%). Reduction of 24 with Zn/AcOH produces 6-amino-1-methoxytryptamine (25, 30%).

In the second route (Scheme 5), tryptamine (14) is transformed to Nb-trifluoroacetyl-2,3-dihydro-6-nitrotryptamine (28) by the successive tri-fluoroacetylation (99%), reduction (99%), and nitration (75%) through 26 and 27. Application of the tungstate method to 28 and subsequent methyl-ation afford Nb-trifluoroacetyl-1-methoxy-6-nitrotryptamine (30, 73%) via Nb-trifluoroacetyl-1-hydroxy-6-nitrotryptamine (29). After alkaline hydrolysis, acetylation of the resultant 31 (99%) affords 32 (90%). Reduction of 32

1) Na2W04-2H20

1) Na2W04-2H20

Scheme 4 Synthesis of Nb-acetyl-6-acetylamino-1-methoxytryptamine from indoline

33 32 31 30

Scheme 5 Synthesis of Nb-acetyl-6-acetylamino-1-methoxytryptamine from tryptamine

33 32 31 30

Scheme 5 Synthesis of Nb-acetyl-6-acetylamino-1-methoxytryptamine from tryptamine with Zn/HCl provides Nb-acetyl-6-amino-1-methoxytryptamine (33, 91%). Finally, acetylation of the 6-amino group of 33 provides the desired product (21, 72%). Compounds (25 and 33) are useful building blocks for the future preparation of a variety of 6-substituted 1-methoxytryptamines.

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