Rh(iii)-catalyzed simultaneous [3 + 3]/[5 + 1] annulation of 1-arylpyrazolidinones with gem-difluorocyclopropenes leading to fluorinated pyridopyrimidinone derivatives

Abstract

Exploitation of effective methodologies to construct the pyridopyrimidinone scaffold expediently has a significant impact on organic synthesis and drug development. Presented herein is an efficient and concise synthesis of fluorinated pyridopyrimidinone derivatives through formal [3 + 3]/[5 + 1] annulation of 1-arylpyrazolidinones with gem-difluorocyclopropenes. The assembly of the title products involves sequential C–H/N–H/N–N/C–C/C–F bond cleavage along with pyrazolidinone ring expansion, cyclopropene ring opening and pyridine ring forming reactions. For the [3 + 3] annulation, 1-arylpyrazolidinone acts as an enamine unit while gem-difluorocyclopropene acts as a β-fluorinated C3 synthon. For the [5 + 1] annulation, the former acts as a latent 3-aminopropanamide moiety while the latter acts as a C1 synthon. To our knowledge, this is the first report on the preparation of fluorinated pyridopyrimidinones through the simultaneous construction of both the pyridyl and the pyrimidinonyl scaffolds along with the introduction of the fluoro unit. In addition, structural derivatization of the products thus obtained readily furnished the pharmaceutically significant 3-fluoroquinoline derivatives.