Electrochemical reactor dictates site selectivity in N -heteroarene carboxylations

Pyridines and related N -heteroarenes are commonly found in pharmaceuticals, agrochemicals and other biologically active compounds 1 , 2 . Site-selective C–H functionalization would provide a direct way of making these medicinally active products 3 – 5 . For example, nicotinic acid derivatives could be made by C–H carboxylation, but this remains an elusive transformation 6 – 8 . Here we describe the development of an electrochemical strategy for the direct carboxylation of pyridines using CO 2 . The choice of the 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 through a paired-electrolysis mechanism 9 , 10 , in which 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 through hydrogen-atom transfer, thus diverting the reaction selectivity by means of the Curtin–Hammett principle 11 . The scope of the transformation was expanded to a wide range of N -heteroarenes, including bipyridines and terpyridines, pyrimidines, pyrazines and quinolines.