Development of an Air-Stable, Broadly Applicable Nickel Source for Nickel-Catalyzed Cross-Coupling

The synthesis of NiCl­(<i>o</i>-tolyl)­(TMEDA) (<b>3</b>; TMEDA = tetramethylethylenediamine) and its application in coupling reactions is described. In combination with a suitable ligand, precatalyst <b>3</b> was applied to a wide range of transformations, such as Suzuki, amination, Kumada, Negishi, Heck, borylation, and reductive coupling. Yields of products obtained with <b>3</b> are equal or superior to those obtained with common Ni sources such as Ni­(cod)₂ (<b>1</b>) and NiCl₂(dme) (<b>2</b>). Importantly, and unlike <b>1</b>, complex <b>3</b> is stable for months in air as a solid, which eliminates the need for a glovebox and greatly facilitates the reaction setup. Thus, complex <b>3</b> is the first highly versatile Ni source that combines the broad applicability of <b>1</b> with the air stability of <b>2</b>

Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling

The synthesis, characterization, and reactivity of intermediates formed in the Ni-catalyzed Suzuki–Miyaura cross-coupling (SMC) of an aryl chloride are described. Oxidative addition of 1-chloro-4-trifluoromethylbenzene (<b>1</b>) to a mixture of Ni­(cod)₂ and PCy₃ afforded NiCl­(4-CF₃Ph)­(PCy₃)₂ (<b>2</b>), which then cleanly provided dimeric [Ni­(4-CF₃Ph)­(μ–OH)­(PCy₃)]₂ (<b>3</b>) by reaction with aqueous KOH. Reactivity studies of <b>2</b> and <b>3</b> with phenylboronic acid (<b>4</b>) revealed that, while <b>2</b> affords only traces of the biphenyl coupling product after 24 h, the same reaction with <b>3</b> is complete within minutes at room temperature. In contrast, the reaction of <b>3</b> with potassium phenyltrihydroxyborate (<b>6</b>) is much slower than that with boronic acid <b>4</b>, and significantly lower yields of the cross-coupling product are obtained. We show that formation of the hydroxo species <b>3</b> is the rate-determining step in the present SMC

Nickel Hydroxo Complexes as Intermediates in Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling

The synthesis, characterization, and reactivity of intermediates formed in the Ni-catalyzed Suzuki–Miyaura cross-coupling (SMC) of an aryl chloride are described. Oxidative addition of 1-chloro-4-trifluoromethylbenzene (<b>1</b>) to a mixture of Ni­(cod)₂ and PCy₃ afforded NiCl­(4-CF₃Ph)­(PCy₃)₂ (<b>2</b>), which then cleanly provided dimeric [Ni­(4-CF₃Ph)­(μ–OH)­(PCy₃)]₂ (<b>3</b>) by reaction with aqueous KOH. Reactivity studies of <b>2</b> and <b>3</b> with phenylboronic acid (<b>4</b>) revealed that, while <b>2</b> affords only traces of the biphenyl coupling product after 24 h, the same reaction with <b>3</b> is complete within minutes at room temperature. In contrast, the reaction of <b>3</b> with potassium phenyltrihydroxyborate (<b>6</b>) is much slower than that with boronic acid <b>4</b>, and significantly lower yields of the cross-coupling product are obtained. We show that formation of the hydroxo species <b>3</b> is the rate-determining step in the present SMC

Enantiopure <i>C</i>₁-Symmetric Bis(imino)pyridine Cobalt Complexes for Asymmetric Alkene Hydrogenation

Enantiopure <i>C</i>₁-symmetric bis­(imino)­pyridine cobalt chloride, methyl, hydride, and cyclometalated complexes have been synthesized and characterized. These complexes are active as catalysts for the enantioselective hydrogenation of geminal-disubstituted olefins

Enantiopure <i>C</i>₁-Symmetric Bis(imino)pyridine Cobalt Complexes for Asymmetric Alkene Hydrogenation

Enantiopure <i>C</i>₁-symmetric bis­(imino)­pyridine cobalt chloride, methyl, hydride, and cyclometalated complexes have been synthesized and characterized. These complexes are active as catalysts for the enantioselective hydrogenation of geminal-disubstituted olefins

Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible

Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible

Computationally Guided Ligand Discovery from Compound Libraries and Discovery of a New Class of Ligands for Ni-Catalyzed Cross-Electrophile Coupling of Challenging Quinoline Halides

Although screening technology has heavily impacted the fields of metal catalysis and drug discovery, its application to the discovery of new catalyst classes has been limited. The diversity of on- and off-cycle pathways, combined with incomplete mechanistic understanding, means that screens of potential new ligands have thus far been guided by intuitive analysis of the metal binding potential. This has resulted in the discovery of new classes of ligands, but the low hit rates have limited the use of this strategy because large screens require considerable cost and effort. Here, we demonstrate a method to identify promising screening directions via simple and scalable computational and linear regression tools that leads to a substantial improvement in hit rate, enabling the use of smaller screens to find new ligands. The application of this approach to a particular example of Ni-catalyzed cross-electrophile coupling of aryl halides with alkyl halides revealed a previously overlooked trend: reactions with more electron-poor amidine ligands result in a higher yield. Focused screens utilizing this trend were more successful than serendipity-based screening and led to the discovery of two new types of ligands, pyridyl oxadiazoles and pyridyl oximes. These ligands are especially effective for couplings of bromo- and chloroquinolines and isoquinolines, where they are now the state of the art. The simplicity of these models with parameters derived from metal-free ligand structures should make this approach scalable and widely accessible

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2′-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt

Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling

Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2′-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parameterization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational ligand library, correlation of observed reaction outcomes with features of the ligands, and the in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a 5-fold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt