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The asymmetric version of the Buchwald–Hartwig reaction has been developed as a powerful asymmetric-catalysis tool bolstered by the great success of its achiral version in the pharmaceuticals, materials, and catalysis fields. This review showcases research into the use of the asymmetric Buchwald–Hartwig reaction for constructing centered, axial, and planar chiralities. A brief overview of the chemistry is also provided based on this research.

Abstract

Over the past few decades, the Buchwald–Hartwig reaction has emerged as a powerful tool for forging C−N bonds, and has been vital to the pharmaceuticals, materials, and catalysis fields. However, asymmetric Buchwald–Hartwig amination reactions for constructing centered chirality, planar chirality, and axial chirality remain in their infancy owing to limited substrate scope and laggard ligand design. The recent surge in interest in the synthesis of C−N/N−N atropisomers, has witnessed a renaissance in asymmetric Buchwald–Hartwig amination chemistry as the first practical protocol for the preparation of C−N atropisomers. This review highlights reported asymmetric Buchwald–Hartwig amination protocols and provides a brief overview of their chemical practicality.

Nature Chemistry, Published online: 15 December 2022; doi:10.1038/s41557-022-01109-6

Abstract

An acceptorless dehydrogenative methodology for the synthesis of amides, aldehydes and ketones from hemiaminal and alcohols in the presence of manganese(I) based photocatalyst is developed. Several aromatic, aliphatic, heterocyclic aldehydes and primary aryl amines as well as secondary alkyl amines were coupled, providing the corresponding amides. The methodology was also extended for dehydrogenation of various alcohols to get the corresponding carbonyls. The proposed catalytic cycle was supported by various control experiments as well as different analytical techniques such as NMR, IR and ESI-MS.

A Ni-catalyzed site-selective intermolecular C(sp³)−H amidation has been developed. This protocol is characterized by its mild conditions, broad substrate scope, and excellent chemo- and site-selectivity, thus unlocking a complementary technique to conventional C(sp³)−N bond-forming reactions for accessing amine architectures from simple building blocks.

Abstract

A nickel-catalyzed site-selective intermolecular amidation of saturated C(sp³)−H bonds is reported. This mild protocol exhibits a predictable reactivity pattern to incorporate amide functions at C(sp³)−H sites adjacent to nitrogen and oxygen atoms in either cyclic or acyclic frameworks, thus offering a complementary reactivity profile to existing oxidative-type processes or metal-catalyzed C(sp³)−N bond-forming reactions operating via two-electron manifolds.

The first donor-free bis(amidophenolato)phosphonium ions were prepared, and their reactivity was investigated. The compounds possess extreme Lewis acidity up to the strongest monocationic phosphonium-based fluoride ion acceptor isolable to date. Numerous novel phosphorus-ligand cooperative reaction modes were observed toward silanes and unsaturated carbon-carbon bonds.

Abstract

The first bis(amidophenolato)phosphonium salts are prepared and fully characterized. The perfluorinated derivative represents the strongest monocationic phosphorus Lewis acid on the fluoride and hydride ion affinity scale isolable to date. This affinity enables new reactions, such as hydride abstraction from Et₃SiH, the first phosphaalkoxylation of an alkyne or a phosphorus catalyzed intramolecular hydroarylation. All properties and reactions are scrutinized by theory and experiment. Substantial σ- and π-acidity provides the required affinity for substrate activation, while phosphorus-ligand cooperativity substantially enriches the reactivity portfolio of phosphonium ions.

An enantioselective carboxylation reaction using CO₂ has been demonstrated as efficient for the synthesis of chiral carboxylic acids including profen family anti-inflammatory drugs. The reaction takes place under atmospheric pressure and benefits from mild conditions using nickel-catalysis in combination with a chiral 2,2′-bipyridine ligand, namely Me-Sbpy.

Abstract

In contrast to previous approaches to chiral α-aryl carboxylic acids that based on reactions using hazardous gases, pressurized setup and mostly noble metal catalysts, in this work, a nickel-catalyzed general, efficient and highly enantioselective carboxylation reaction of racemic benzylic (pseudo)halides under mild conditions using atmospheric CO₂ has been developed. A unique chiral 2,2′-bipyridine ligand named Me-SBpy featuring compact polycyclic skeleton enabled both high reactivity and stereoselectivity. The utility of this method has been demonstrated by synthesis of various chiral α-aryl carboxylic acids (30 examples, up to 95 % yield and 99 : 1 er), including profen family anti-inflammatory drugs and transformations using the acids as key intermediates. Based on mechanistic experimental results, a plausible catalytic cycle involving Ni-complex/radical equilibrium and Lewis acid-assisted CO₂ activation has been proposed.

Boron-centered radicals, generated by reduction of R₂BCl derivatives, react with N₂ all the way to borylamine formation. DFT calculations rationalize the reduction/functionalization process, involving N−N bond splitting. Hydrolysis of the mixture yields NH₄ ⁺. Radical addition to N₂ provides a new strategy for N₂ fixation.

Abstract

Ammonia, NH₃, is an essential molecule, being part of fertilizers. It is currently synthesized via the Haber–Bosch process, from the very stable dinitrogen molecule, N₂ and dihydrogen, H₂. This process requires high temperatures and pressures, thereby generating ca 1.6 % of the global CO₂ emissions. Alternative strategies are needed to realize the functionalization of N₂ to NH₃ under mild conditions. Here, we show that boron-centered radicals provide a means of activating N₂ at room temperature and atmospheric pressure whilst allowing a radical process to occur, leading to the production of borylamines. Subsequent hydrolysis released NH₄ ⁺, the acidic form of NH₃. EPR spectroscopy supported the intermediacy of radicals in the process, corroborated by DFT calculations, which rationalized the mechanism of the N₂ functionalization by R₂B radicals.

Intraligand charge transfer activation of Ni(Czbpy)Cl₂ gives access to visible-light-mediated carbon–heteroatom cross-couplings in the absence of exogenous photocatalysts. Details of the study are reported by Renske M. van der Veen, Arne Thomas, Bartholomäus Pieber, and co-workers in their Research Article (e202211433).