Abbreviated Ibogaine Congeners. Synthesis and Reactions of Tropan-3-yl-2- and -3-indoles. Investigation of an Unusual Isomerization of 2-Substituted Indoles Using Computational and Spectroscopic Techniques

Article abstract of DOI:10.1021/jo00087a037

The syntheses of several N-methyltropan-3-ylindoles, designated as congeners of ibogaine, are described.The synthetic approach to N-methyltropan-3-yl-2-indole revealed that the tropanyl 3'-center was quite sensitive to acid-catalyzed epimerization.The carbocyclic analog, N-methyl-2--oct-3-anyl>indole, also underwent this rearrangement.However, N-methyltropan-3-yl-3-indole was insensitive to acid or base, even under more vigorous conditions.This simple isomerization is quite rare for 2-substituted indoles, especially for cases where the center of reaction is not additionally activated, and normally only takes place under extreme reaction conditions.The mechanism of this reaction was investigated using ab initio molecular orbital calculations, NMR spectroscopy, and deuterium labeling studies.These results indicate that, in contrast to those previously obtained for more reactive 2-substituted indoles, the reaction can best be explained using a simple exchange mechanism involving the exocyclic enamine tautomer of the indole ring as an intermediate.The difference in reactivity is suggested to arise from a decrease in a relative energy of the exocyclic enamine tautomer due to the presence of increased strain in the endo bicyclic 2-substituent.The title compounds displayed modest pharmacological activity in a variety of biological assays.