N-sulfonyl acrylamides are important synthetic intermediates for the construction of various complex heterocyclic organic molecules and potential drug targets for disease treatments. A striking example is DG 041 which is an N-sulfonyl acrylamide, is a potent and selective EP3 antagonist acting as an antiplatelet and antithrombotic. Herein we report the synthesis of α,β-disubstituted N-sulfonyl acrylamides through [2+2] cycloaddition reaction of Bestmann’s ylide with various N-tosyl protected imines. We discovered that this [2+2] cycloaddition results in the formation of β-lactams with an exocyclic phosphonium ylide, which upon thermal induction underwent a ring-opening reaction to selectively give zwitterionic phosphonium salts in excellent yields. Moreover, the latter species can be subjected to a Michael addition at the β-carbon to form a host of α-ylidic acrylamides. These salt-type structures have the potential to be used to carry a drug/antioxidant/probe into the biological system to put on a site-specific function in cells. Also, the α-ylidic acrylamides can be further utilized to carry out Wittig reaction with various aldehydes to give α,β-disubstituted N-sulfonyl acrylamides in one pot.

Use of Bestmann's ylide in the synthesis of highly substituted N-sulfonyl acrylamides

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