Synthetic studies of indoles and related compounds. Part 22. The Vilsmeier–Haack reaction of N-benzyl-1,2,3,4-tetrahydrocarbazoles and its synthetic application to olivacine and ellipticine

Abstract

Vilsmeier–Haack reaction of 9-benzyl-1,2,3,4-tetrahydrocarbazole (18a) at 120 °C gave 9-benzyl-1-methylcarbazole-3-carbaldehyde (19a) and 9-benzyl-1 -[N,N-(dimethylamino)methyl]carbazole-3-carbaldehyde (22a) in moderate yields, whereas, the same reaction at 0 °C gave 9-benzyl-1,2,3,4-tetrahydrocarbazole-1-carbaldehyde (20a) in very good yield. The aldehyde (20a) was converted into 9-benzyl-1-methylcarbazole (21a) by another Vilsmeier–Haack reaction. This carbazole (21a) unexpectedly underwent non-regioselective formylation under similar reaction conditions to give a mixture of compound (19a) and 9-benzyl-8-methylcarbazole-3-carbaldehyde (23a). On the basis of the above results, a mechanism of the formation of the aromatic aldehyde (19a) was proposed, which involves 1,5-sigmatropic rearrangement of an N-methylidene dimethylammonium cation from the 4a-position to the 3-position as a key step. Vilsmeier–Haack reaction of 9-benzyl-1,2,3,4-tetrahydro-4-methylcarbazole (18b) at 100 °C also gave 9-benzyl-1,4-dimethylcarbazole-3-carb-aldehyde (19b) in moderate yield. The total syntheses of two antitumour alkaloids, olivacine (10) and ellipticine (11), were achieved by utilizing compounds (19a) and (19b) as key intermediates.