Electrochemical C(sp2)-H Deuterodifluoromethylation of Quinoxalinones and 2H-Indazoles with CF2DSO2Na

Abstract

With the growing enthusiasm for the green chemistry, the efficient and convenient introduction of the deuterodifluoromethyl group (-CF2D) into drug molecules has become a research hotspot of great interest. Herein, a green and efficient electrochemical method for C(sp2)-H deuterodifluoromethylation of quinoxalinones and 2H-indazoles with CF2DSO2Na has been developed. This strategy proceeds in the mixture solution of acetonitrile/water at 25 o C without any transition-metal catalysts or stoichiometric oxidants. The value of this method is underscored by a wide range of substrates (45 examples), high yields (up to 84%) and high deuteration incorporations (approximately 96%). Radical trapping experiments and cyclic voltammetry experiments indicate that a radical pathway is involved during the reaction. Moreover, the deuteriation step in the synthesis of CF2DSO2Na has been achieved using a NaOD/D2O solution, which enables the reuse of D2O, reducing waste and further enhancing the commercial potential of this method.Green foundation1. This study presents an efficient electrochemical method for C(sp2)-H deuterodifluoromethylation of quinoxalinones and 2Hindazoles with CF2DSO2Na. Notably, this process does not require transition-metal catalysts or external oxidants, and proceeds in the green mixture solution of acetonitrile/water at 25 o C. 2. As a green synthetic approach, the green chemistry metrics of this reaction were quantified, yielding satisfactory results: the environmental factors (E-factor) were 3.27 and 2.68, the process mass intensities (PMI) were 4.27 and 3.68, the reaction mass efficiencies (RME) were 23.4% and 27.2%, the atom economies (AE) were 69.2% and 73.6%, and the carbon efficiencies (CE) were 66.0% and 68.4%. 3. Future research will focus on expanding the substrate scope, like other (hetero)aromatics, while also exploring suitable electrode materials to efficiently synthesize deuterodifluoromethylated compounds for potential use in pharmaceutical and materials science.