Palladium-Catalyzed Enantioselective β-C(sp³)–H Activation Reactions of Aliphatic Acids: A Retrosynthetic Surrogate for Enolate Alkylation and Conjugate Addition

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Enolate alkylation and conjugate addition into an α,β-unsaturated system have served as long-standing strategic disconnections for the installation of αor β-substituents on carbonyl-containing compounds. At the onset of our efforts to develop C−H activation reactions for organic synthesis, we set our eye toward developing asymmetric β-C−H activation reactions of aliphatic acids with the perspective that this bond-forming event could serve as a more flexible retrosynthetic surrogate for both canonical carbonyl-related asymmetric transformations.In this Account, we describe our early efforts using strongly coordinating chiral oxazolines to probe reaction mechanism and the stereochemical nature of the C−H cleavage transition state. The characterization of key reactive intermediates through Xray crystallography and computational studies suggested a transition state with C−H and Pd−OAc bonds being approximately coplanar for optimum interaction. We then moved forward to develop more practical, weakly coordinating monodentate amide directing groups, a necessary advance toward achieving the β-C−H activation of weakly coordinating native carboxylic acids. Throughout this journey, gradual deconvolution between a substrate's directing effect and its intimate interplay with ligand properties has culminated in the design of new ligand classes that ultimately allowed the competency of native carboxylic acids in β-C−H activation. These efforts established the importance of ligand acceleration in Pd-catalyzed C−H activation, where the substrate's weak coordination is responsible for positioning the catalyst for C−H cleavage, while the direct participation from the bifunctional ligand is responsible for enthalpically stabilizing the C−H cleavage transition state. Building upon these principles, we developed five classes of chiral ligands (MPAA, MPAQ, MPAO, MPAThio, MPAAM) to enable enantioselective β-C−H activation reactions, including carbon−carbon and carbon−heteroatom bond formation. The accumulated data from our developed enantioselective C−H activation reactions indicate that ligands possessing point chirality are most effective for imparting stereoinduction in the C−H activation step, the application of which enabled the desymmetrization and subsequent C−H functionalization of enantiotopic carbon and protons across a range of weakly coordinating arylamides and, more recently, free carboxylic acids. Progress in ligand design, in conjunction with the enabling nature of alkali metal countercations, led to the realization of a suite of β-methyl and now methylene C(sp 3 )−H activation reactions. These advancements also enabled the use of economical oxidants, such as peroxides and molecular oxygen, to facilitate catalyst turnover. In the future, continued progress in designing more efficient bifunctional chiral ligands is likely to provide a myriad of enantioselective β-C−H activation reactions of readily available native substrates.

Hydride Relay Exchange Mechanism for the Heterocyclic C–H Arylation of Benzofuran and Benzothiophene Catalyzed by Pd Complexes

“…The C–H bond activation is one of the most promising strategies in organic synthesis to realize atomic economy . However, there exist two challenges to be solved: one is that most of the C–H bonds are inert to be broken, and another is that it is hard to distinguish C–H bonds to be activated at different positions of organic molecules.…”

Ligand-ligated Ni–Al bimetallic catalysis for C–H and C–C bond activation

“…Compared with C(sp 2 )–H bonds, enantioselective activation of C(sp 3 )–H bonds was more challenging. Although precious metals such as Pd succeeded in catalyzing enantioselective C(sp 3 )–H bond activation reactions by subtle selection of chiral ligands, 32 same strategies are in general ineffective for most 3d-transition metals, whose catalytic activity was very sensitive to the structure of ligands. The only example was reported by Matsunaga, Yoshino and co-workers, 33 who realized enantioselective Co( iii )-catalyzed amidation of primary C(sp 3 )–H bonds of thioamides with an amino acid derivative as a chiral anion.…”

Direct acylation and alkynylation of hydrocarbons via synergistic decatungstate photo-HAT/nickel catalysis

“…4 Such a strategy overcomes the limitations associated with classical C-H activation, such as the requirement for coordination directing groups, excess oxidizing or reducing agents, and high reaction temperatures, thereby providing an attractive strategic alternative to conventional metal-catalyzed C(sp 3 )-H activation. 5 In this context, tetrabutylammonium decatungstate (TBADT) is a versatile and cheap hydrogen atom transfer (HAT) photocatalyst that can extract hydrogen atoms from hydrocarbons to generate the corresponding carbon-centered radicals. 6 In 2018, the MacMillan group disclosed the direct arylation of strong aliphatic C(sp 3 )-H bonds via a dual TBADT-HAT and nickel catalytic manifold.…”

“…4 Such a strategy overcomes the limitations associated with classical C–H activation, such as the requirement for coordination directing groups, excess oxidizing or reducing agents, and high reaction temperatures, thereby providing an attractive strategic alternative to conventional metal-catalyzed C(sp 3 )–H activation. 5…”