Serendipitous synthesis of cross-conjugated dienes by cascade deconstructive esterification of thiomorpholinone-tethered alkenoic acids.

Abstract

Functionalized 1,3-dienes are ubiquitous structural motifs in biologically pertinent molecules. They are frequently employed as precursors for a broad range of chemical transformations, including Diels-Alder reactions. The stereoselective construction of highly decorated 1,3-dienes therefore represents an important research objective. Medicinal chemists are becoming increasingly interested in synthetic methodologies that not only achieve expedient construction and peripheral editing of heterocycles, but also seek to modify their core framework in order to achieve skeletal remodeling. In a succinct manifestation of this 'scaffold hopping' concept, we herein describe a cascade reaction, which converts thiomorpholinone-tethered alkenoic acids to 1,1-disubstituted amino-1,3-dienes. This domino process involves esterification of the acid, base-assisted ring-opening, and concomitant 1,2-migration of the α-amino alkenyl group. Several control experiments have revealed that the alkenyl substituent is necessary for deconstruction to occur. Inherently more activated N-aryl-substituted thiomorpholinone acids react significantly faster than their less activated N-alkyl congeners.