An Efficient Method for the Conversion of Phenolic Mannich Bases to C-Methylated Phenols. Synthesis of 3,6-Dimethylcatechol

Abstract

In connection with our synthesis of analogs of serotonin neurotoxins¹ we needed access to 3,6-dimethylcatechol (1) in quantities. This deceptively simple compound is not available commercially and is extremely inaccessible by the existing methods.^2–5 One of these methods⁵ involves conversion of catechol (2) to 3,6-bis(morpholinomethyl)catechol (3) followed by hydrogenolysis using Pd/C as the catalyst. The latter step required high temperature, long reaction time and a very high catalyst (10% Pd/C) to substrate ratio (1:3 by wt.). In addition, this procedure of hydrogenolysis gave highly variable results in our hands. The difficulty encountered in the conversion of 3 to 1 is not an isolated case. Resistance of phenolic Mannich bases to direct hydrogenolysis is a general^6–10 phenomenon although the exact reason for such resistance is not known and no general solution for this problem has been developed. It has been suggested⁸ that intramolecular hydrogen bonding between phenolic OH and the nitrogen atom of the amine function (cf. 3)may