N,N'-Dimethylurea as an efficient ligand for the synthesis of pharma-relevant motifs through Chan-Lam cross-coupling strategy.

Abstract

N,N'-Dimethylurea (DMU) is introduced as a ligand to aid the Chan-Lam N-arylation of primary amides, amines, and 3-aminophenols with arylboronic acids and its ester derivative as the arylating associate. The developed methodology is catalyzed by Cu and its in situ complexation with DMU brings about efficient synthesis of N-arylated anilines, 3-aminophenols, and primary amides in moderate to good yields (50-90%). The [Cu2(OAc)4(DMU)2] complex is synthesized and characterized by single crystal structure elucidation. The catalyst is cheap, free from prior synthesis of a metal complex, provides chemoselectivity towards the N-arylation of 3-aminophenols, and is suitable for mono-arylation of primary amides. The synthetic utility of the methodology is tested in the post-modification of two active pharmaceutical ingredients (APIs). The developed catalytic system extends the scope of N,N'-dimethylurea as an auxiliary in inexpensive and versatile Cu catalysis.