Cobalt-electrocatalytic C-H hydroxyalkylation of N-heteroarenes with trifluoromethyl ketones.

Abstract

Trifluoromethyl carbinols and N-heteroarenes are both prevalent in bioactive molecules. However, access to high-value pharmacophores combining these two functional groups still remains a challenge. Herein, we report an electro-chemical redox-neutral coupling for the synthesis of N-heteroaryl trifluoromethyl carbinols from readily available N-heteroarenes and trifluoromethyl ketones. The reaction starts with reversing the polarity of ketones to nucleophilic ketyl radicals through an electrocatalytic proton-coupled electron transfer (PCET), followed by radical addition to heteroarenes and rearomatization to afford tertiary alcohol products. Importantly, the merging of paired electrolysis and cobalt catalysis is crucial to this regioselective C-H hydroxyalkylation of heteroarenes, and thus avoids several known competing pathways including the spin-center shift (SCS) process. Collectively, this protocol provides straightforward access to heteroaryl trifluoromethyl carbinols, featuring ideal atom economy, excellent regioselectivity, and paired redox-neutral electrolysis.