Facile Synthesis of Alkylthio-Benzaldehydes

During the course of our research we required various alkoxyl alkylthio substituted benzaldehydes. Examination of the Literature revealed that classical methods¹ might be suitable but cumbersome. Several workers² have developed efficient methods for the preparation of 2-alkylthiobenzaldehydes. However, attempted preparation of alkoxyl substituted benzaldehydes using these methods resulted in extensive O-dealkylation. Thus a method for the synthesis of alkylthio substituted benzaldehydes which would accommodate the presence of alkoxyl substituents was investigated. Reaction of the known alkoxyl substituted 2-bromobenzaldehydes 1a-e with the sodium salt of primary³ mercaptans in DMF provided good to excellent yields of the alkylthiobenzaldehydes shown in Table II and Table III.

The facile nature of this reaction is due presumably to the activation effect of the aldehyde group.⁴ Aldehydes with bromine substituted in the para position react similarly (see Table IV). However, aldehydes with bromine substituted in the meta position to the carbonyl are unreactive under these conditions.

The low yields of the methylenedioxy substituted products 2d and 3d result from cleavage of the ether by the nucleophilic sulfur reagent. In the case of the sterically congested 2-bromo-3,4,5-trimethoxybenzaldehyde (1f), reaction with the sodium salt of methyl mercaptan is very slow and affords a 80% yield of unreacted aldehyde 1f with the remainder being dehalogenated aldehyde. Reaction of 1f with the sodium salt of benzyl mercaptan gave only recovered starting aldehyde.

Although this method is limited to the use of primary mercaptans and sterically unhindered aldehydes, it offers a simple and efficient method for the preparation of oxygenated alkylthiosubstituted benzaldehydes from readily available precursors.