Solvent-Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII-Catalyzed C-H Activation

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N-methoxy benzamides and ,-difluoromethylene alkynes is enabled by C-H activation with a chiral CpRhIII catalyst. Remarkably, product formation is solvent-dependent; alkynyl isoindolinones are afforded in MeOH (up to 86% yield, 99.6% ee) whereas monofluoroalkenyl isoindolinones are generated in (PrCN)-Pr-i (up to 98:2 Z/E, 93% yield, 86% ee). Mechanistic studies revealed chiral allene and E-configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z-configured monofluoroalkene upon protonation in the (PrCN)-Pr-i system and into an alkyne by an unusual anti -F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z-monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.