Safe and Efficient Tetrazole Synthesis in a Continuous-Flow Microreactor


  • We are grateful to the Novartis-MIT Center for Continuous Manufacturing for financial support and to several colleagues at MIT (Stephen L. Buchwald, Klavs F. Jensen, and their co-workers) and Novartis (Gerhard Penn, Berthold Schenkel, Oljan Repic, Thierry Schlama, Mike Girgis, Lukas Padeste, and Felix Kollmer) for insightful discussions.


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Safer flow: The synthesis of 5-substituted tetrazoles in flow (see scheme) is safe, efficient, scalable, requires no metal promoter, and uses a near-equimolar amount of NaN3, yet nonetheless displays a broad substrate scope. The hazards associated with HN3 are essentially eliminated, shock-sensitive metal azides such as Zn(N3)2 are avoided, and residual NaN3 is quenched in-line with NaNO2.