Double Cu‐Catalyzed Direct Csp³−H Azidation/CuAAC Reaction: A Direct Approach towards Demanding Triazole Conjugates

Abstract

The first one-pot procedure for the double copper(I)-catalyzed oxidative Csp³ -H azidation-CuAAC process, implying unstable azide intermediates and easy-to-remove reagents under water-tolerant conditions, is presented. The combination of tert-butyl hydroperoxide as oxidant and TMSN₃ as azide source for the C-H bond azidation, which produces harmless side-products such as tBuOH and H₂ O, probed to be perfectly compatible with the following cycloaddition step. Highly demanding 1,2,3-triazoles could be then directly obtained in good overall yields by extraction or simple crystallization, thus avoiding chromatography purifications. The potential of this methodology, has also being highlighted by the successful reaction of alkynes presenting interesting complex biological moieties based for example on biotin, DNA base or cinchona alkaloid units.