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Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling 1,2 . The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond 3-12 . As one of the oldest known Csp 3 -Csp 3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates 13 . In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century 5 , thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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 β-methylene C–H activation of carboxylic acids, leading to the direct syntheses of α,β-unsaturated carboxylic acids or γ-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.

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., Competing Interests: Competing interests: US Patent application 63/124,544 is pending.

Pd II -catalyzed enantioselective C(sp 3 )-H cross-coupling of free carboxylic acids with organoborons has been realized using either mono-protected amino acid (MPAA) ligands or mono-protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl- and vinyl-boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α-chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An acetyl-protected aminoethyl phenyl thioether has been developed to promote C(sp 3 )-H activation. Significant ligand enhancement is demonstrated by the realization of the first Pd(II)-catalyzed olefination of C(sp 3 )-H bonds of free carboxylic acids without using an auxiliary. Subsequent lactonization of the olefinated product via 1,4 addition provided exclusively monoselectivity in the presence of multiple β-C-H bonds. The product γ-lactone can be readily opened to give either the highly valuable β-olefinated or γ-hydroxylated aliphatic acids. Considering the challenges in developing Heck couplings using alkyl halides, this reaction offers a useful alternative.

The development of C(sp3)−H functionalization reactions that use common protecting groups and practical oxidants remains a significant challenge. Herein we report a monoprotected aminoethyl thioether (MPAThio) ligand‐enabled β‐C(sp3)−H lactamization of tosyl‐protected aliphatic amides using tert‐butyl hydrogen peroxide (TBHP) as the sole oxidant. This protocol features exceedingly mild reaction conditions, reliable scalability, and the use of practical oxidants and protecting groups. Further derivatization of the β‐lactam products enables the synthesis of a range of biologically important motifs including β‐amino acids, γ‐amino alcohols, and azetidines. [ABSTRACT FROM AUTHOR]

PdII‐catalyzed enantioselective C(sp3)−H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α‐chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity. Worth protecting: PdII‐catalyzed enantioselective C(sp3)−H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. [ABSTRACT FROM AUTHOR]

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