Catalytic Vilsmeier-Haack Reactions for C1-Deuterated Formylation of Indoles

The Vilsmeier-Haack reaction is a powerful tool to introduce formyl groups into electron-rich arenes, but its wide application is significantly restricted by stoichiometric employment of caustic POCl3. Herein, we reported a catalytic version of the Vilsmeier-Haack reaction enabled by a P(III)/P(V)=O cycle. This catalytic reaction provides a facile and efficient route for the direct construction of C1-deuterated indol-3-carboxaldehyde under mild conditions with stoichiometric DMF-d7 as the deuterium source. The products feature a remarkably higher deuteration level (>99%) than previously reported ones and are not contaminated by the likely unselective deuteration at other sites. The present transformation can also be used to transfer other carbonyl groups. Further downstream derivatizations of these deuterated products manifested their potential applications in the synthesis of deuterated bioactive molecules. Mechanistic insight was disclosed from studies of kinetics and intermediates.

Automated summary

In this study, a catalytic version of the Vilsmeier-Haack reaction enabled by a P(III)/P(V)=O cycle was reported. The reaction provides a convenient and efficient route for the direct construction of C1-deuterated indol-3-carboxaldehyde under mild conditions. The products have a high deuteration level and are not affected by non-selective deuteration. Furthermore, this transformation can be used to transfer other carbonyl groups.