One-pot multistep synthesis of 1-fluoroalkylisoquinolines and fused fluoroalkylpyridines from N-fluoroalkyl-1,2,3-triazoles

Abstract

An efficient one-pot microwave-assisted potassium fluoride-mediated synthesis of 1-fluoroalkyl-3-fluoroisoquinolines and fused fluoroalkylpyridines from N-fluoroalkylated 1,2,3-triazoles was developed. The reaction has a wide scope and allows the preparation of structurally diverse 3-fluoroisoquinolines with a fluoroalkyl group in position 1, a substituent in position 4 and a substituent on the fused benzene (or heteroaromatic) ring. N-Fluoroalkylated ketenimines, which undergo stereoselective formal 1,3-fluorine shift to difluoroazadienes, were identified as intermediates in the reaction sequence. The presence of fluorine in position 3 and a halogen in position 4 of the resulting isoquinolines allowed for further modification by nucleophilic aromatic substitution and cross-coupling reactions, respectively. The developed methodologies were utilized for the synthesis of derivatives of drug candidates.