A base-mediated synthesis of N-hydroxy- and N-alkoxyindoles from 2-nitrostyrenes

Abstract

Sequential treatment of alkyl 2-(2-nitroaryl)-2-butenoates with potassium tert-butoxide and an electrophile, such as methyl iodide, benzyl bromide and allyl bromide, afforded N-alkoxyindoles. In related reactions, using sodium tert-pentoxide as the base with or without in situ addition of an electrophile afforded N-alkoxy- and N-hydroxyindoles, respectively. Electrophiles such as dimethylsulfate, p-tosyl chloride, and acetic anhydride afforded moderate yields of the respective N-methoxy-, N-tosyloxy, and N-acetoxyindoles, while methyl iodide, benzyl bromide, and 1-bromohexane failed to form alkylated products using sodium tert-pentoxide as the base.

Figure 1.

Structures of bioactive natural products 1-3 and synthetic compounds 4 and 5.

Scheme 1.

Cyclization of 6 to N-methoxyindole 8 and of 7 to quinoline N-oxide 9.

Scheme 2.

Cyclization of a tert-butyl 2-(5-chloro/methoxy-2-nitrophenyl)-2-butenoate.

Scheme 3.

Synthesis of compound 10.

Scheme 4.

Formation and attempted cyclizations of precursor 21. ^a) Using 2.3 equiv of sodium tert-pentoxide in toluene. Circa 5% of 21 was recovered. ^b) Using 2.3 equiv of sodium tert-pentoxide in toluene, then dimethyl sulfate (3 equiv). Circa 54% of 21 was recovered.

Scheme 5

Kosugi-Migita-Stille coupling of 32 to give 34–39 and Barluenga coupling of 33 to give 40-42.

Scheme 6.

Methylation of N-hydroxyindole 47 to give N-methoxyindole 48.

Scheme 7.

Proposed mechanism for the formation of N-hydroxy- and N-alkoxyindoles.

Scheme 8.

Methanal trapping experiment.