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

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 general6–10 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