Convergent Paired Electrolysis for [3+2] Cycloaddition of Azidotrimethylsilane with N-Heterocycles.

Abstract

A widely used method to obtain tetrazoles is through the azide and nitrile [3+2] cycloaddition. However, this process often involves using non-recyclable transition metals or Lewis acid catalysts and stoichiometric amounts of oxidants and additives, which reduces atom efficiency. We have discovered a convergent paired electrochemical reaction to perform this cycloaddition reaction, without the need for metal catalysts or oxidants. This tetrazolation strategy uses azidotrimethylsilane (TMSN3) and N-heterocycles in an undivided cell at a constant current. We use a mixture of CH3CN and equivalent amounts of H2O as co-solvent at room temperature. It is crucial to produce a stoichiometric amount of active hydroxyl ions through the cathodic reduction of water. Cyclic voltammetry (CV) studies and control experiments confirm that the cycloaddition reaction is specific to the electrode electron transfer process, eliminating the need for a mediator to shuttle electrons. This metal- and oxidant-free strategy is highly compatible with different functional groups and produces products with moderate to good yields. We have successfully tetrazolated bioactive compounds at a late stage, scaled up batches efficiently, and synthesized free amino-containing N-heterocycles via denitrogenation of tetrazoles.