Direct, One-pot Sequential Reductive Alkylation of Lactams/Amides with Grignard and Organolithium Reagents through Lactam/Amide Activation

摘要

Simplicity is one of the major goals in current organic synthesis. The development of versatile methods using simple starting materials and multicomponent reactions leading to the formation of two or more carbon-carbon bonds in a one-pot process are two powerful strategies directed at this goal. The transformation of lactams and amides into the corresponding tert-alkylamines by a one-pot reductive bisal-kylation with different organometallic reagents is both a highly desirable and a challenging objective (Scheme 1). The merit of such a process is linked to the high stability of lactams/amides and the ready availability of both lactams/ amides and Grignard/organolithium reagents. Moreover, tert-alkylamines are important target compounds in synthetic chemistry. The research groups of Murai and Renaud have recently reported their synthesis of tert-alkylamines from thioamide derivatives. To develop a more convenient and less noxious general method, the direct use of readily available lactams and amides is highly desirable (Scheme 1). In this regard, de Meijere and co-workers recently reported an addition to formamides mediated by Ti(OiPr)4/TMSCl, but their method is restricted to N,N-dialkylformamides. Herein we report the first general and direct one-pot method for the conversion of lactams and amides into tert-alkylamines by the sequential addition of two organometallic reagents, which may be the same or different from one another.