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.