Decarboxylative Cross-Electrophile Coupling of (Hetero)Aromatic Bromides and NHP Esters

DeCicco, Ethan M.; Berritt, Simon; Knauber, Thomas; Coffey, Steven B.; Hou, Jie; Dowling, Matthew S.

doi:10.1021/acs.joc.3c01072

Cited by 7 publications

(2 citation statements)

References 50 publications

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“…To the best of our knowledge, these are some of the highest yields for C(sp 2 )–C(sp 3 ) XEC reactions reported for 2-haloazines under similar conditions. We could find only a single example of the coupling of S8 with an alkyl N -hydroxyphthalimide ester using 20 mol % nickel and no examples of couplings with S10 – S12 . − …”

Section: Resultsmentioning

confidence: 96%

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

Tcyrulnikov,

Hubbell,

Pedro

et al. 2024

J. Am. Chem. Soc.

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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.

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Section: Resultsmentioning

confidence: 96%

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

Tcyrulnikov,

Hubbell,

Pedro

et al. 2024

J. Am. Chem. Soc.

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“…We found that L5 enables higher yields than L2 in the decarboxylative arylation of an N -hydroxyphthalimide ester with an aryl bromide (Table and Figure S4.12). Notably, the coupling of redox-active esters with bromoarenes often requires the use of carboxamidine-based ligands to enable high conversion and selectivity. − These results suggest that L5 may be widely useful in coupling a variety of electrophiles. Indeed, we were also able to directly substitute L5 for L2 in the reported coupling of N -alkyl 2,4,6-triphenylpyridiniums with aryl bromides (Table ).…”

Section: Resultsmentioning

confidence: 99%

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

Akana,

Tcyrulnikov,

Akana-Schneider

et al. 2024

J. Am. Chem. Soc.

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Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp 2 )−C(sp 3 ) 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 5fold 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.

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Nickel-catalyzed reductive formylation of aryl halides via formyl radical

Liu,

Bao

et al. 2024

Chinese Chemical Letters

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Decarboxylative Cross-Electrophile Coupling of (Hetero)Aromatic Bromides and NHP Esters

Cited by 7 publications

References 50 publications

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

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

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

Nickel-catalyzed reductive formylation of aryl halides via formyl radical

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