The use of a weakly coordinating monodentate directing group for copper mediated ortho-hydroxylation and amination reactions allows for the identification of an external oxazoline ligand as a promoter.

AbstractOne 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.

Pd-catalyzed α-olefinic C–H activation of simple α,β-unsaturated olefins has been developed. 4-imino-β-lactam derivatives were readily synthesized via activation of α-olefinic C–H bonds with excellent cis stereoselectivity. A wide range of heterocycles at the β-position are compatible with this reaction. The product of 4-imino-β-lactam derivatives can be readily converted to 2-aminoquinoline which exists extensively in pharmaceutical drugs and natural products.

In a Pd-catalyzed double C–H activation reaction, a pyridine-type ligand is identified, for the first time, to enable a highly para-selective C–H arylation of monosubstituted arenes. Excellent para-selectivity is achieved with a variety of arenes containing alkyl, methoxyl, and halo substituents.

A new Cu(II)-catalyzed oxidative coupling of arenes with malonates has been developed using an amide-oxazoline directing group. The reaction proceeds via C(sp2)–H activation and malonate coupling, followed by intramolecular oxidative N–C bond formation. A variety of arenes bearing different substituents are shown to be compatible with this reaction.

A Cu(II)-mediated ortho-C–H hydroxylation using a removable directing group has been developed. The reaction exhibits considerable functional group tolerance. The use of O2 as an oxidant is crucial for the reactivity. Water is also found to significantly improve this reaction.

Cu(II)-promoted ortho alkynylation of arenes and heteroarenes with terminal alkynes has been developed to prepare aryl alkynes. A variety of arenes and terminal alkynes bearing different substituents are compatible with this reaction, thus providing an alternative disconnection to Sonogashira coupling.

A Cu(OAc)2-mediated C–H amidation and amination of arenes and heteroarenes has been developed using a readily removable directing group. A wide range of sulfonamides, amides, and anilines function as amine donors in this reaction. Heterocycles present in both reactants are tolerated, making this a broadly applicable method for the synthesis of a family of inhibitors including 2-benzamidobenzoic acids and N-phenylaminobenzoates.

Cu-catalyzed coupling of aryl C–H bonds with arylboron reagents was accomplished using a readily removable directing group, which provides a useful method for the synthesis of biaryl compounds. The distinct transmetalation step in this Cu-catalyzed C–H coupling with aryl borons provides unique evidence for the formation of an aryl cupperate intermediate.

The Ru(II)-catalyzed ortho-C–H amination directed by a weakly coordinating amide auxiliary with O-benzoyl hydroxylamines at room temperature has been achieved. This reaction is compatible with heterocycles including pyrazole, thiophene, benzothiophene, furan, benzofuran, and indole.

The use of a weakly coordinating monodentate directing group for copper mediated ortho-hydroxylation and amination reactions allows for the identification of an external oxazoline ligand as a promoter.