Metal- and Solvent-Free Multicomponent Decarboxylative A3-Coupling for the Synthesis of Propargylamines: Experimental, Computational, and Biological Investigations

Decarboxylative A(3)-coupling of ortho-hydroxyben- zaldehydes, secondary amines, and alkynoic acids is performed under catalyst and solvent-free conditions. The developed methodology provided a waste-free method for the synthesis of hydroxylated propargylamines which are versatile precursors for various bioactive heterocyclic scaffolds. The experimental and density functional theory studies revealed that the in situ-formed ortho-quinonoid intermediate (formed from ortho-hydroxybenzal-dehyde and amine) undergoes a concerted Eschweiler-Clarke type decarboxylation with alkynoic acids. The synthesized compounds were evaluated for MAO-A, MAO-B, and AChE inhibitory activities as potential drug candidates for the treatment of various neurological disorders. Compound 4f was found to be the most potent and selective MAO-B (high selectivity over MAO-A) and AChE inhibitor in the series with IC50 values of 4.27 +/- 0.07 and 0.79 +/- 0.03 mu M, respectively.