Copper‐Mediated Late‐Stage Functionalization of Heterocycle‐Containing Molecules

One long‐standing issue in directed C−H functionalization is that either nitrogen or sulfur atoms present in heterocyclic substrates may bind preferentially to a transition‐metal catalyst rather than to the desired directing group. This competitive binding has largely hindered the application of C−H functionalization in late‐stage heterocycle drug discovery. Reported here is the use of an oxazoline‐based directing group capable of overriding the poisoning effect of a wide range of heterocycle substrates. The potential use of this directing group in pharmaceutical drug discovery is illustrated by diversification of Telmisartan (an antagonist for the angiotensin II receptor) through copper‐mediated C−H amination, hydroxylation, thiolation, arylation, and trifluoromethylation. Override switch: A bidentate oxazoline‐based directing group (DG) allows copper‐mediated C−H amination, hydroxylation, thiolation, arylation, alkynylation, and trifluoromethylation. The directing group overrides the directing/poisoning effects of heterocyclic moieties.