The cyclisation of benzylaminonitriles. Part 6. Evidence for exclusive participation of a spirocyclic intermediate

Abstract

Cyclisation of 3,4-dialkoxybenzylaminoacetonitriles to 6,7-dialkoxy-1,2-dihydroisoquinolin-4(3H)-ones can occur by two mechanisms. The first involves electrophilic attack para to the 3-alkoxy substituent, and the second proceeds via formation of a spirocyclic intermediate with the participation of the 4-alkoxy group. In order to assess the relative contribution of these two mechanisms the cyclisation of 1-(4-ethoxy-3-methoxybenzylamino)cyclohexanecarbonitrile (12) and the isomer with the reverse orientation of alkoxy substituents (13) was studied. The benzylamino nitrile (12) on treatment with concentrated sulphuric acid at –10 °C, room temperature, and 50°C gave a mixture of the 7-ethoxy-6-methoxyisoquinolinone (27) and the 7-hydroxy-6-methoxyisoquinolinone (26). Identical treatment of the isomeric 3-ethoxy-4-methoxybenzylamino nitrile (13) produced the 6-ethoxy-7-methoxyisoquinolinone (28), the 6-hydroxy-7-methoxyisoquinolinone (29), and the 6-ethoxy-7-hydroxyisoquinolinone (30). The relative proportion of phenolic products increased with rise in temperature of cyclisation.

The profile of O-dealkylation that occurred during cyclisation differed from that of the 6,7-dialkoxyisoquinolinones under identical conditions, and a case is argued that cyclisation proceeds no further than the spirocyclic intermediate in concentrated acid. Rearrangement to the iminium ion and conversion of the latter into the isoquinolinone via a Pictet-Spengler reaction therefore occur during subsequent stages in dilute aqueous conditions.