Indole-3-carbaldehyde, 1-methoxy

The aza-Diels-Alder reaction of substituted lf/-indole-2-carbaldehydes 1323 with Danishevsky s diene 1324 proceeds with a high degree of diastereoselectivity providing highly functionalized l-R -2-(Tmethyl-lf/-indol-2-yl)-2,3-dihydro-4(l//)-pyridinones 1325 which were further elaborated into novel polycyclic heterocycles (Equation 289) <2002TL29>. Attempts to form the imine of 12/-indole-2-carbaldehyde 1326 in situ in the presence of diene 1324 and zinc chloride or zinc triflate at 0 °C or at room temperature did not afford the expected cycloadduct 1327. Instead, 2-(177-indol-2-yl)-2,3-dihydro-477-pyran-4-one 1328 and the 5-hydroxy-l-methoxy-5-(l/7-indol-2-yl)-Tpenten-3-one 1329 were isolated in 45% and 25% yields, respectively (Equation 290). 

The indole-2-carbaldehyde 101 reacts with sulfur, oxygen, and nitrogen nucleophiles with loss of the methoxy-protecting group to produce the 3-substituted indole-2-carbaldehydes 102 in good yields [42]. 

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... 

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%). 

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]. 

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