PALLADIUM-CATALYZED HYDROARYLATION OF PROPIOLAMIDES - A REGIOCONTROLLED AND STEREOCONTROLLED METHOD FOR PREPARING 3,3-DIARYLACRYLAMIDES

A general regio- and stereoselective synthesis of 3,3-diarylacrylamide s is reported. Palladium-catalyzed coupling reactions of propiolamides with aryl halides provide arylpropiolamides. A subsequent hydroarylat ion reaction of these arylpropiolamides with aryl halides, catalytic p alladium, an amine base, and formic acid in refluxing ethyl acetate pr ovides 3,3-diarylacrylamides regio- and stereoselectively. The unique stereo- and regiocontrol is presumed to proceed through careful reacti on parameters that allow intramolecular coordination of the propiolami de amide functionality to the transient palladium-alkyne complex. Pall adium-catalyzed hydroarylation of propiolamides has not been studied; however, preliminary results from related systems suggest that regiose lective addition can be achieved. The methodology as a synthesis tool is demonstrated in an efficient route to previously difficult-to-prepa re potent, benzimidazole antiviral targets. In addition, the synthesis scope is explored where, by judicious choice of reaction sequence and aryl iodide, either the Z- or E-geometric isomer of a given pair of 3 ,3-diarylacrylamides is independently prepared.