1- Methoxy-6-nitroindole

In the first route (Scheme 4), indoUne (5) is nitrated to 6-nitro-2,3-dUiydroindole (22, 92%). Apphcation of the tungstate method to 22 and subsequent methylation provide l-methoxy-6-nitroindole (9, 77%) via 8a. A Vilsmeier-Haack reaction (94%), followed by nitroaldol reaction (85%), leads 9 to l-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 l-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-l-methoxytryptamine (25, 30%). 

The values of the 1-hydroxy moiety of (5)-(- -)-iVb-acetyl- 1-hydroxytrypto-phan methyl ester (32), methyl l-hydroxyindole-3-butylate (33), iVb-methoxy-carbonyl-l-hydroxytryptamine (34), 1-hydroxymelatonm (19), l-hydroxy-6-nitroindole (35), and l-hydroxy-5-nitroindole (36) are determined to be 9.8, 8.4, 8.2, 8.1, 6.9, and 6.8, respectively (Fig. 2) (2000H1881). Thus, 1-hydroxyindoles are weak acids, stronger than phenol and weaker than succinimide. Therefore,... 

The effect of a nitro group at the 6 position on the nucleophilic substitution reaction has been examined using l-methoxy-6-nitroindole (82) as a substrate (2001H1151). The reaction with NaOMe in refluxing DMF generates 6-nitroin-dole (83, 57%), 2-methoxy- (199, 22%), and 3-methoxy-6-nitroindoles (84, 6%) (Scheme 29). The formation of 199 and 84 can be explained by the SN2 -type nucleophilic substitution reaction at the 2 and 3 positions, respectively, with the... 

Yamada K, Yamada F, Shiraishi T, Tomioka S, Somei M (2009) Nucleophilic substitution reaction in indole chemistry l-methoxy-6-nitroindole-3-carbaldehyde as a versatile building block for 2,3,6-trisubstitute indoles. Heterocycles 77 971-982... 

This new reaction is successfully applied for the preparation of 1-hydroxy-5-nitroindole-3-carbaldehyde (6a, 96%) from 6b that is obtained in 97% yield by the Vilsmeier-Haack reaction of readily available 1-methoxy-5-nitroindole (12) [5-7,9]. 

Methoxyindole-3-carbaldehyde (10a) undergoes nucleophilic substitution reactions in sharp contrast with indole-3-carbaldehyde that does not react with nucleophiles under forcing reaction conditions. The most reactive reactant among the thus-far obtained l-hydroxy and 1-methoxy derivatives is l-methoxy-6-nitroindole-3-carbaldehyde (10b) as shown in Fig. 2. So, the nudeophihc substitution reactions of 10b in DMF are examined for the synthesis of new 2,3,6-trisubstituted indoles. The representative results are shown in Scheme 14 [13]. 

In the reaction of 10b with piperidine in DMF, a novel methyl ether cleavage reaction of the 1-methoxy group occurs in addition to the nucleophilic substitution reaction, resulting in the formation of l-hydroxy-6-nitroindole-3-carbaldehyde (5a, 10%) and 2-piperidinyl product (109, 59%, Scheme 15) [11]. 

Scheme 14 Nucleophilic substitution reaction of l-methoxy-6-nitroindole-3-carbaldehyde...

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