Metrics & MoreArticle Recommendations CONSPECTUS:The functionalization of unactivated carbon− hydrogen bonds is a transformative strategy for the rapid construction of molecular complexity given the ubiquitous presence of C−H bonds in organic molecules. It represents a powerful tool for accelerating the synthesis of natural products and bioactive compounds while reducing the environmental and economic costs of synthesis. At the same time, the ubiquity and strength of C−H bonds also present major challenges toward the realization of transformations that are both highly selective and efficient. The development of practical C−H functionalization reactions has thus remained a compelling yet elusive goal in organic chemistry for over a century. Specifically, the capability to form useful new C−C, C−N, C−O, and C−X bonds via direct C−H functionalization would have wide-ranging impacts in organic synthesis. Palladium is especially attractive as a catalyst for such C−H functionalizations because of the diverse reactivity of intermediate palladium−carbon bonds. Early efforts using cyclopalladation with Pd(OAc) 2 and related salts led to the development of many Pd-catalyzed C−H functionalization reactions. However, Pd(OAc) 2 and other simple Pd salts perform only racemic transformations, which prompted a long search for effective chiral catalysts dating back to the 1970s. Pd salts also have low reactivity with synthetically useful substrates. To address these issues, effective and reliable ligands capable of accelerating and improving the selectivity of Pd-catalyzed C−H functionalizations are needed.In this Account, we highlight the discovery and development of bifunctional mono-N-protected amino acid (MPAA) ligands, which make great strides toward addressing these two challenges. MPAAs enable numerous Pd(II)-catalyzed C(sp 2 )−H and C(sp 3 )−H functionalization reactions of synthetically relevant substrates under operationally practical conditions with excellent stereoselectivity when applicable. Mechanistic studies indicate that MPAAs operate as unique bifunctional ligands for C−H activation in which both the carboxylate and amide are coordinated to Pd. The N-acyl group plays an active role in the C−H cleavage step, greatly accelerating C−H activation. The rigid MPAA chelation also results in a predictable transfer of chiral information from a single chiral center on the ligand to the substrate and permits the development of a rational stereomodel to predict the stereochemical outcome of enantioselective reactions. We also describe the application of MPAA-enabled C−H functionalization in total synthesis and provide an outlook for future development in this area. We anticipate that MPAAs and related next-generation ligands will continue to stimulate development in the field of Pd-catalyzed C−H functionalization.

Hydroxylation of aryl carbon–hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon–hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.

Dehydrogenative transformations of alkyl chains to alkenes through methylene carbon-hydrogen (C-H) activation remain a substantial challenge. We report two classes of pyridine-pyridone ligands that enable divergent dehydrogenation reactions through palladium-catalyzed b-methylene C-H activation of carboxylic acids, leading to the direct syntheses of a,b-unsaturated carboxylic acids or g-alkylidene butenolides. The directed nature of this pair of reactions allows chemoselective dehydrogenation of carboxylic acids in the presence of other enolizable functionalities such as ketones, providing chemoselectivity that is not possible by means of existing carbonyl desaturation protocols. Product inhibition is overcome through ligand-promoted preferential activation of C(sp 3 )-H bonds rather than C(sp 2 )-H bonds or a sequence of dehydrogenation and vinyl C-H alkynylation. The dehydrogenation reaction is compatible with molecular oxygen as the terminal oxidant.

Pd­(II)-catalyzed C–H lactonization of o-methyl benzoic acid substrates has been achieved using molecular oxygen as the oxidant. This finding provides a rare example of C–H oxygenation through Pd­(II)/Pd(0) catalysis as well as a method to construct biologically important benzolactone scaffolds. The use of a gas mixture of 5% oxygen in nitrogen demonstrated the possibility for its application in pharmaceutical manufacturing.

The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C–H oxidation reactions. Here, we reveal the stepwise intramolecular SN2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp3)–H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C–O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O2 oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η3-(π-benzylic)–Pd and K+–O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the η3-(π-benzylic)–Pd and η2-(π-phenyl)–Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K+ cation in the ortho-C–H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp3)–H bond lactonization in the presence of C(sp2)–H.