Ming Shang

Cu(II)-Mediated C–H Amidation and Amination of Arenes: Exceptional Compatibility with Heterocycles

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.

Overcoming the limitations of directed C–H functionalizations of heterocycles

In directed C–H activation reactions, any nitrogen or sulphur atoms present in heterocyclic substrates will coordinate strongly with metal catalysts. This coordination, which can lead to catalyst poisoning or C–H functionalization at an undesired position, limits the application of C–H activation reactions in heterocycle-based drug discovery, in which regard they have attracted much interest from pharmaceutical companies. Here we report a robust and synthetically useful method that overcomes the complications associated with performing C–H functionalization reactions on heterocycles. Our approach employs a simple N-methoxy amide group, which serves as both a directing group and an anionic ligand that promotes the in situ generation of the reactive PdX2 (X = ArCONOMe) species from a Pd(0) source using air as the sole oxidant. In this way, the PdX2 species is localized near the target C–H bond, avoiding interference from any nitrogen or sulphur atoms present in the heterocyclic substrates. This reaction overrides the conventional positional selectivity patterns observed with substrates containing strongly coordinating heteroatoms, including nitrogen, sulphur and phosphorus. Thus, this operationally simple aerobic reaction demonstrates that it is possible to bypass a fundamental limitation that has long plagued applications of directed C–H activation in medicinal chemistry.

Ru(II)-catalyzed ortho-C-H amination of arenes and heteroarenes at room temperature.

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.

Exceedingly Fast Copper(II)‐Promoted ortho CH Trifluoromethylation of Arenes using TMSCF3

The direct ortho-trifluoromethylation of arenes, including heteroarenes, with TMSCF3 has been accomplished by a copper(II)-promoted C-H activation reaction which completes within 30 minutes. Mechanistic investigations are consistent with the involvement of C-H activation, rather than a simple electrophilic aromatic substitution (SE Ar), as the key step.

Remote Meta-C–H Activation Using a Pyridine-Based Template: Achieving Site-Selectivity via the Recognition of Distance and Geometry

The pyridyl group has been extensively employed to direct transition-metal-catalyzed C–H activation reactions in the past half-century. The typical cyclic transition states involved in these cyclometalation processes have only enabled the activation of ortho-C–H bonds. Here, we report that pyridine is adapted to direct meta-C–H activation of benzyl and phenyl ethyl alcohols through engineering the distance and geometry of a directing template. This template takes advantage of a stronger σ-coordinating pyridine to recruit Pd catalysts to the desired site for functionalization. The U-shaped structure accommodates the otherwise highly strained cyclophane-like transition state. This development illustrates the potential of achieving site selectivity in C–H activation via the recognition of distal and geometric relationship between existing functional groups and multiple C–H bonds in organic molecules.

Cu(OAc)2-Catalyzed Coupling of Aromatic C–H Bonds with Arylboron Reagents

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.

Cu(II)-Catalyzed Coupling of Aromatic C–H Bonds with Malonates

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(sp(2))-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.

Cu(II)-Mediated C(sp2)–H Hydroxylation

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.

Ligand-Controlled Para-Selective C–H Arylation of Monosubstituted Arenes

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.

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.