Tuning Catalytic Activity of Palladium in Direct C−H Arylation of Biologically Active Xanthines using Silver Additive.

Abstract

We describe an efficient and versatile method for the direct C−H arylation of xanthines with aryl halides using Pd/P(o‐tolyl)3 as catalyst and Ag2O as an additive. Silver salts have been frequently used as an additive in the Pd‐catalyzed C−H bond activation reactions albeit in excessive amounts (2 to 4 eq.). Herein, we use of a stoichiometric amount (0.1 to 1 eq.) of Ag2O to obtain the optimum yields of C‐8 arylated products. This method exhibits broad substrate scope and enables synthesis of a wide range of xanthine derivatives by variation of aryl component at the C‐8 position. A key advantage of silver additive is that it reduces the catalyst loading and time required for the completion of reactions. Although kinetic experiments show that the inclusion of silver salt accelerates the rate of reaction, catalytic role of silver salt could not be conceived since the C−H bond cleavage is not a rate determining step. Silver salt presumably act as a terminal oxidant in the catalytic cycle and assist the regeneration of Pd catalyst. Moreover, preliminary assessment of biological activities of xanthines demonstrates that the C‐8 arylated xanthines derivatives efficiently inhibit the α‐Synuclein fibrillation, a key factor behind Parkinson's disease.