Regioselective synthesis of 4-functionalized pyridines

Summary

4-Functionalized pyridines are privileged scaffolds in various fields. The C-4 selective functionalization of pyridines is perhaps the most convenient protocol to pyridine derivatives. However, this reaction is still unexplored because of the inert property of pyridine and the challenge in the regioselectivity. Herein, we report an aromatic C-4 selective functionalization of pyridine N-oxides with DABCO and Tf₂O as the regioselective controller. The commercial availability of reagents, good tolerance of functional groups, and simple operability made it a promising approach to 4-functionalized pyridines. The mechanism studies revealed that the N-(4-pyridyl)-DABCO salt was the key intermediate, and the bulky steric hindrance of the CF₃SO₂ group and DABCO was the origin of C-4 selectivity. This intermediate can serve as a generic handle to realize C–X, C–N, C–O, C–S, and C–P bond formation.