Reaction of quinidine acetate, epiquinidine and its acetate in superacid: formation of gem-difluoro derivatives with or without rearrangement

In HF–SbF5, quinidine 1a or its dihydrochloride cyclises previously obtained with usual acids. A similar reaction is observed in the presence of CCl4. Under similar conditions quinidine acetate 1b and epiquinidine acetate 2b dihydrochlorides both yield 10,10-difluoro derivatives epimeric at C-3, 6 and 7, and 9c and 10b, and a rearranged difluoro derivative 8b and 11b, respectively. Epiquinidine 2a leads to the expected analogues 10a and 11a and to a ketone 9a. Formation of gem-difluoro compounds implies chloro intermediates at C-10, precursors of α-chlorocarbenium ions, which are trapped by a fluoride ion and which lead by halogen exchange to the products.

Graphical AbstractFigure optionsDownload as PowerPoint slide