Selective Ring Omethylation of Hydroxybenzaldehydes Via Their Mannich Bases

Abstract In connection with our synthesis of analogs of serotonin neuro-toxins1 we needed access to 4-hydroxy-3-methoxy-5-methylbenzaldehyde (1) in quantities. The only previous method for the synthesis of 1 involved conversion of o-vanillin to 2-hydroxy-3-methoxytoluene followed by formylation using CHCl3/NaOH in 12% overall yield. We thought a more efficient process would result if we could introduce a methyl group selectively in the position ortho to the hydroxyl group of vanillin (2). However, no direct and selective method for introducing a methyl group into a benzene ring containing a hydroxyl as well as an aldehyde group has been described in the literature. In this paper we describe the development of a method for the synthesis of 1 from vanillin (2) without requiring the protection of either the hydroxyl or the aldehyde function and demonstrate the generality of such a method.