Second‐Generation One‐Pot Enantioselective Heck‐Matsuda Arylations of Unactivated Olefins Directly from Anilines and Nitroarenes

Abstract A highly improved second generation of the one‐pot enantioselective Heck‐Matsuda reaction directly from anilines and nitroarenes is reported. This practical arylation method, featuring 56 examples, relies on the in situ diazotization of anilines and 3‐aminothiophenes, or from the in situ reduction‐diazotization of nitrobenzene derivatives. The in situ diazotization of the aniline, directly or from the in‐situ reduction of the nitroarene, synchronizes smoothly with the enantioselective Heck‐Matsuda reaction under mildly acidic conditions, bypassing the synthesis and handling of some unstable and/or difficult‐to‐prepare arenediazonium salts. The protocol was applied to the desymmetrization of unactivated olefins leading to the synthesis of functionalized spirocyclopentenyl hydantoins, aryl cyclopentenes, and β ‐aryl‐ γ ‐lactones, in high yields (up to 99%) and er (up to 99:1). The efficiency of the method is showcased by the formal total synthesis of the bioactive compound VPC01091, a potential drug candidate for multiple sclerosis treatment at the gram scale in excellent yield (94%), in 97:3 er and 20>1 dr .