康 · 学术｜Reaction of the Day No. 1445

转自：康龙化成

Translation of Nickel-Catalyzed C(sp2)−C(sp3)Cross-Electrophile Coupling to Non-Amide Solvents

Brett D. Akana-Schneider,∇ Julianna M. Mouat,∇ Sisi Zhang, Michelle E. Akana, Bin Wu,* and Daniel J. Weix*

Chemical & Analytical Development, Suzhou Novartis Technical Development Company Limited, Changshu, Jiangsu 215537, China;

Department of Chemistry, University of Wisconsin−Madison, Madison, Wisconsin

53706, United States;

—Org. Lett., 2025, https://doi.org/10.1021/acs.orglett.5c01011

Recommended by Murong Xu_MC3

KEYWORDS: Cross-Electrophile Coupling (XEC), Ni catalysis (反应类型),aryl bromide, alkyl bromide (原料), aryl alkane (产物), C(sp2)−C(sp3) (成键类型), 4,4′-bis(dimethylamino)-2,2′-bipyridine, Non-Amide Solvent (其他)

ABSTRACT: The cross-electrophile coupling of organobromides is widely utilized in organic synthesis but generally requires undesirable amide solvents (e.g., DMF, DMA, and NMP). We report that the combination of a strongly donating, bidentate nitrogen ligand, LiI, and 4-picoline enables coupling in a variety of alcohol, ester, and ethereal solvents at up to 50 g scale. An improved synthesis of the optimal ligand, 4,4′-bis(dimethylamino)-2,2′-bipyridine, is also reported on the basis ofthe reductive homocoupling of 4-dimethylamino-2-chloropyridine.

(A) Analysis of solvents used in 190 publications of aryl−alkyl XEC shows that amides and ethers are common. The use of metal reductants in non-amide solvents remains underdeveloped. (B) Lewis basic additives enable selective XEC in a variety of non-amide solvents.

ZnBr2 Limits Conversion in Non-Amide Solvents

Substrate Scope for the Cross-Electrophile Coupling of Aryl Bromides with Alkyl Bromides in Acetonitrile

Prof.Daniel J. Weix et al have demonstrated that the combination ofLiI and pyridine additives allows nickel-catalyzed C(sp2)−C(sp3) XEC reactions to be run in a variety of non-amide solvents by tempering the detrimental effects of zinc(II) salts. These reactions can be scaled to decagram scale in standard stirred reactors and provide good scope and selectivity. Finally, we developed an improved synthesis of 4,4′‑NMe2bpy, which is a promising new ligand for XEC reactions. The precise details of the effects of stoichiometric iodide and Lewis base additives are the subject of continuing study in our laboratories and will be reported in due course. However, we anticipate that the flexibility of these conditions will translate well to process chemistry contexts, serving as a complementary approach to photochemical, electrochemical, or organic reductant-driven systems by leveraging the low cost of metallic powder reductants.

（转自：康龙化成）