Understanding the regioselectivity of 5-substituted 1H-tetrazoles alkylation

Abstract

The synthesis of disubstituted tetrazoles is described from 1H-5-monosubstituted tetrazoles via the aliphatic amine diazotization reaction, which forms a transient alkyl diazonium intermediate, acting as an alkylating agent. Although the 2,5-disubstituted tetrazole (2,5-Tz) is preferentially formed in moderate to excellent yields, it is also possible to isolate the minor 1,5-disubstituted tetrazole (1,5-Tz) in several cases. The regioselectivities (1,5-Tz:2,5-Tz) are highly variable and cannot be exclusively attributed to the steric hindrance of the electrophile. A new rationale to explain the observed regioselectivity, based on the difference in mechanism between first- and second-order nucleophilic substitutions, is thus proposed. In addition, in some cases the intramolecular stabilization of the resulting diazonium influences the regioselectivity.