Brønsted acid-catalyzed alkylation of tetrazoles with alcohols

Tetrazoles are prominent in medicinal chemistry, yet their efficient alkylation remains a challenge. Common methods for the alkylation of tetrazoles include base-catalyzed reactions with alkyl halides or acid-catalyzed alkylation of tetrazoles. However, these approaches are associated with harsh reaction conditions, poor functional group tolerance and low regioselectivity. Herein, we report an efficient methodology for the alkylation of 5-substituted tetrazoles with primary, secondary and tertiary alcohols using 5 mol% of aqueous tetrafluoroboric acid HBF₄ (aq.) as a catalyst. The reaction exhibits one to one ratio of starting materials, short reaction times, excellent functional group tolerance and high N2 regioselectivity.