Electrochemical reactor dictates site selectivity in N-heteroarene carboxylations

Abstract

Pyridines and related N-heteroarenes are commonly found in pharmaceuticals, agrochemicals, and other bioactive compounds^1,2. Site-selective C–H functionalization would provide a direct way of making these medicinally-active products^3,4,5. For example, nicotinic acid derivatives could be made by C–H carboxylation, but this remains an elusive transformation^6,7,8. Here, we describe the development of an electrochemical strategy for the direct carboxylation of pyridines using CO₂. The choice of electrolysis setup gives rise to divergent site selectivity: a divided electrochemical cell leads to C5-carboxylation, whereas an undivided cell promotes C4-carboxylation. The undivided cell reaction is proposed to operate via a paired electrolysis mechanism^9,10, wherein both cathodic and anodic events play critical roles in altering the site selectivity. Specifically, anodically-generated iodine preferentially reacts with a key radical anion intermediate in the C4-carboxylation pathway via hydrogen-atom transfer, thus diverting the reaction selectivity via the Curtin-Hammett principle¹¹. The scope of the transformation was expanded to a wide range of N-heteroarenes including bi- and terpyridines, pyrimidines, pyrazines and quinolines.