Vilsmeier-Haack Reaction Of α-acyl Ketene-S,S-acetals: Synthesis Of Polysubstituted β-Lactams

Since Kelber first synthesized the a-benzoyl ketene-(S,S)-acetal in 1910,α-oxo ketene-(S,S)-acetals chemistry has become an important division in organic chemistry through the development of near one hundred years. Particular in recent three decades, quite amount of documents have been published in this area, and several reviews were successively reported to summarize these results.G?enerally,α-Oxo ketenedithioacetals are applied extensively as a kind of versatile intermediates and are widely studied in organic synthesis.β-Lactam has a long history of development starting from the discovery of monocyclicβ-lactams (monobactams) by Imada and his coworkers in 1981, the quest for new synthetic methods and refinement of those already known remains appealing. And the research into the application of theses methods in synthesizing novel biologically active zetidinone derivatives still constitutes an active area in organic synthesis. Recent years have seen a resurgence of interest in the development of stereo- and enantioselective methodologies.Over the past few decades, the utility ofα-oxo ketene-S,S acetals as versatile intermediates in organic synthesis has been recognized. During the course of our studies on the Vilsmeier-Haack reaction ofα-acyl ketene-S,S-acetals, we noted that the readily synthesizedα-(1-chlorovinyl)ketene-S,S-acetals showed promising structural characteristics that could be exploited in further organic transformations. Inspired by these findings and our continuing interest in the utilization ofβ-oxo amide derivatives in the synthesis of carbo- and heterocycles, we synthesizedα-carbamoyl,α-(1-chlorovinyl) ketene-S,S acetals fromα-acyl,α-carbamoyl ketene-S,S-acetals and explored their synthetic potential. As a result, an efficient one-pot synthesis of highly substitutedα-alkylidene-β-lactams was developed from readily available in aqueous media.This work mainly based on the following two aspects:1. Halogenation or haloformylation reactions ofα-oxo ketenedithioacetals could be controlled through the control of the temperature and the quantity of Vilsmeier reagents.α-carbamoyl,α-Halovinyl ketenedithioacetals were obtained in moderate to high isolated yields.2. Theα-alkylidene-β-lactams were prepared simply by treating theα-carbamoyl,α-halovinyl ketenedithioacetals with sodium hydroxide in aqueous media, and proposed an aza-Michael addition mechanism.In summary, a facile and convenient one-pot synthesis of polysubstitutedβ-lactams was developed. The simplicity of execution, mild conditions, high yields, ready availability of substrates, flexible substituted patterns, and broad range of potential synthetic utility of the products, make the protocol attractive for academic research and practical applications.