Brønsted Acid‐Catalyzed Tandem Aldol Condensation/1,4‐Aza‐Michael Addition: N 2 ‐Selective Alkylation of Tetrazoles

Herein, we disclose a Brønsted acid‐catalyzed tandem aldol condensation/1,4‐aza‐Michael addition strategy to achieve highly N 2 ‐selective alkylation of tetrazoles (N 2 /N 1 > 25:1), and the N 2 ‐selectivity was unambiguously confirmed by single‐crystal X‐ray diffraction. Control experiments verify that in situ generated α,β‐unsaturated ketones act as key intermediates, and acid catalysis is indispensable for the condensation and conjugate addition steps. With p‐toluenesulfonic acid (TsOH) as the optimal catalyst, this transformation tolerates a broad spectrum of tetrazole derivatives with aryl, aliphatic, hydroxyl, pyridyl, and thioether substituents, and the reaction is scalable to gram scale. This straightforward method employs readily available ketones and aldehydes without the need for presynthesized α,β‐unsaturated ketones, offering an efficient and regioselective route to N 2 ‐alkyl tetrazoles.