Electrophilic substitution in indoles. Part 10. The mechanism of substitution in 4,6- and 5,6-dimethoxyindoles

Abstract

Deuterium-labelling experiments show that the boron trifluoride-catalysed cyclisation (at 80 °C) of 4-(4,6-dimethoxyindol-3-yl)butanol (3c) to 5,7-dimethoxytetrahydrocarbazole (9c) occurs by two simultaneous pathways. The main route (61.5%) involves initial cyclisation at the 3-position of (3c) to give an intermediate spirocyclic indole which then rearranges to the tetrahydrocarbazole; the minor pathway (38.5%) involves direct attack at the 2-position. The cyclisation of 4-(5,6-dimethoxyindol-3-yl)butanol (3d) to 6,7-dimethoxytetrahydrocarbazole (9d) also occurs by two routes, but in this case a much lower proportion (13.5%) arises by direct attack at the 2-position. Kinetic studies of the overall rates of cyclisation of the indolylbutanols (3) to tetrahydrocarbazoles (9) were facilitated by the use of high-pressure liquid chromatography, and showed that the relative rates were as follows: 4-indol-3-ylbutanol (3a) > 4-(6-methoxyindol-3-yl)butanol (3b) > 4-(4,6-dimethoxyindol-3-yl)butanol (3c) > 4-(5,6-dimethoxyindol-3-yl)butanol (3d). The differences in rates were tentatively attributed to the effects of the methoxy-groups on the rates of rearrangement of the protonated spirocyclic indole intermediates (5) formed by direct attack at the indole 3-position.