Synthesis of 2-Substituted Pyridine N-Oxides via Directed ortho-Metalation

Significance

Reported is the directed ortho-­metalation of pyridine N-oxides using i-PrMgCl to give 2-substituted Grignard species which may be trapped with electrophiles to give the corresponding 2-substituted pyridine N-oxides in low to excellent yields. The method appears to be an improvement on the use of alkyllithium reagents at -78 ˚C which is known to produce mainly 2,6-di­substituted products in low to moderate yields (14-45%) (R. A. Abramovitch et al. J. Org. Chem. 1972, 37, 1690; see Review below). In the case of 3,5-di­methylpyridine N-oxide, the 2-magnesiated species was subjected to interesting cross-coupling conditions using a diphenyliodonium partner to give a 2-phenyl product in a moderate yield of 51%.

Review: M. Schlosser, F. Mongin Chem. Soc. Rev. 2007, 36, 1161-1172.