Conversion of lactams to the corresponding azacycles are efficient synthetic routes for the preparation of α-functionalized azacycle. Those conversions essentially involve the amide bond manipulations. α-Aminoalkylation of reactive iminium ion species is a powerful method for such conversions to provide azacycles with a scaffold diversity. Five and six-membered lactams and azacycles are prevalent in nature, so the conversion of five- and six-membered lactams via α-aminoalkylation have been extensively studied. For instance, approaches involved in thioamides, sulfonyl amides, N-alkoxylactams, formamidines, enamine triflates and phosphates, lactim ethers, and N,O-acetals have been developed for such conversions to provide α-vinylated or α-acetylated azacycles, which can be useful intermediates for the assembly of structurally diverse azacycles ranging from simple bicyclic to complex polycyclic systems by using various synthetic methods, such as metathesis and aza-Claisen rearrangement. In contrast, conversion of medium- to macrocyclic lactams to the corresponding azacycles were relatively less explored. Indeed, a major challenge continues to be the lack of concise and efficient methods for such conversions of medium- to macrocyclic lactams avoiding undesirable ring openings. We also have suffered from a series of synthetic steps for the preparation of medium sized 2-vinylazacycles in our previous report. In the context of our interest in medium- to macrocyclic lactams and azacycles, we became attracted to the issue of direct conversion of medium-sized lactams to provide corresponding α-vinylated or α-acetylenylated azacycles. Herewith, we report a direct synthetic method for the conversion of medium-sized lactam rings to α-acetylenylated azacycles employing N,O-acetal TMS ethers as N-acyliminium ion precursors.

Vinylation and acetylenylation of N,O-acetal TMS ethers derived from medium-sized lactams

2019 Spring National Meeting

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