The C4-dimethylaminomethyl Mannich adducts of 3-substituted 5-hydroxyindoles undergo a facile, amine catalyzed carbon-carbon bond cleavage to yield the corresponding Ca-hydrogen indole derivatives. Reverse Mannich condensation occurs most readily in Cs-carbethoxy substrates, then in ðyl derivatives; no reverse reaction was observed for Cs-hydrogen derivatives. An indole N-H group is not required for reverse reaction. This transformation is catalyzed by primary (most efficient), secondary, and tertiary amines. The role of the C3 substituent is discussed in terms of both steric and electronic effects. It is concluded that a steric CrCa peri interaction is responsible for the observed difference in behavior between the Cs-carbethoxy and Ca-hydrogen derivatives.
Formation of a new carbon-carbon bond resulting in addition of a one carbon substituent to an existing skeleton by means of the Mannich reaction is a welldocumented synthetic tool. 3 Recently it has been established4 that Mannich condensation of 5-hydroxyindoles (e.g., 1) results in selective introduction of an
aminomethyl substituent at the Cd position (e.g., l a ) . It was anticipated that these Cb indole adducts (e.g., la) would undergo net substitution via an eliminationaddition mechanism (eq 1) analogous to that pro-posed315 for gramine (2), the NIannich adduct of indole. In support of this hypothesis Mannich adducts of this general type have been used as synthetic intermediates in the construction of more complex hydroxyindole derivatives.O
(1) Financial support of this research