Rhodium-Catalyzed [3 + 2] Cycloaddition of in situ Generated Nitrile Ylides with Alkenes: A Route to Quaternary 2-Trifluoromethyl-1-Pyrrolines

Trifluoromethylated heterocycles with a C−CF3 stereogenic center are prevalent scaffolds in many bioactive small molecules and pharmaceutical and agrochemical libraries. However, efficient methods for the construction of 2-trifluoromethyl-1-pyrroline scaffolds have remained elusive. Here we report the first rhodium-catalyzed three-component reaction of α-trifluoromethyl-N-triftosylhydrazones with nitriles and alkenes, providing rapid access to 2-trifluoromethyl-1-pyrrolines with a quaternary stereocenter from readily available starting materials. This method features mild reaction conditions, good functional group tolerance, high yields, and excellent diastereoselectivity. The synthetic utility has been further demonstrated by late-stage diversification of five complex bioactive molecules, scale-up reactions, and diverse post-synthetic transformations, yielding valuable trifluoromethylated pyrrolidine and pyrroline scaffolds. DFT calculation elucidates the origins of chemo- and diastereoselectivity and the mechanism that proceeds via the key nitrile ylide intermediate.