Cyclisation of benzylaminoacetonitriles. Part 2. Evidence for two mechanisms of cyclisation

Abstract

Treatment of 3,4-dimethoxybenzylaminoacetonitriles with concentrated sulphuric acid gives 2,3-dihydroisoquinolin-4(1H)-ones. Cyclisation of 1-(3,4,5-trimethoxybenzylamino)cyclohexanecarbonitrile (2) at room temperature gave 3,4-dihydro-5,6,7-trimethoxyisoquinoline-3-spirocyclohexan-4(1H)-one (8)(22%) and 1-(3,4,5-trimethoxybenzylamino)cyclohexanecarboxamide (9)(7%). At 50 °C, cyclisation gave 3,4-dihydro-7-hydroxy-6,8-dimethoxyisoquinoline-3-spirocyclohexan-4(1H)-one (10) as the major product. A dual mechanism for cyclisation is postulated, one mode involving electrophilic attack para to the C-3 methoxy-substituent, the second attack para to the C-4 methoxy-substituent, giving a spiro-intermediate which undergoes rearrangement to an iminium ion, the fate of which is dependent on the proximity of differing nucleophiles. The latter mechanism is consistent with the formation of 1,2,3,4-tetrahydro-6,7-dimethoxy-2-(4-methoxyphenacyl)isoquinoline by treatment of 2-[N-(3,4-dimethoxyphenethyl)-4-methoxybenzylamino]acetonitrile (6) with sulphuric acid.