Reaction development and mechanistic investigation of rhodium-catalyzed pyridine synthesis via C-H activation

Abstract

Described herein are two complementary rhodium-catalyzed methods for the synthesis of substituted pyridines from unsaturated oxime derivatives and alkenes. In the first, formal [4+2] cycloaddition of O-pivaloyl α, β-unsaturated oxime esters and activated terminal alkenes was discovered to proceed in high yields and with excellent selectivity for 6-substituted pyridine products. Mechanistic experiments were found to be consistent with a reversible C-H activation step and a C-N bond forming, N-O bond cleaving process en route to pyridine formation. Rhodium-catalyzed coupling using unactivated alkene substrates was shown to present important information regarding the influence of the alkene component on product distribution. In a second method, access to 5-substituted pyridine derivatives was achieved by decarboxylative annulation of α, β-unsaturated oxime esters and β-substituted acrylic acid derivatives. In this case, carboxylic acids were found to serve as traceless activating groups for selective alkene incorporation. A wealth of mechanistic insight was gained by identification of and decomposition studies regarding catalytically relevant rhodium complexes.