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Nickel-Catalyzed Reductive Coupling of γ-Metalated Ketones with Unactivated Alkyl Bromides

Ning Cui, Tingzhi Lin, Yan-En Wang, Jian Wu, Yuheng Han, Xinyang Xu, Fei Xue, Dan Xiong, Patrick J. Walsh* and Jianyou Mao*

*University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States; Nanjing Tech University, Nanjing 211816, P. R. China, Email: pwalshsas.upenn.edu, ias_jymaonjtech.edu.cn

N. Cui, T. Lin, Y.-E. Wang, J. Wu, Y. Han, X. Xu, F. Xue, D. Xiong, P. J. Walsh, J. Mao, Org. Lett., 2022, 24, 3987-3992.

DOI: 10.1021/acs.orglett.2c01390


Abstract

A nickel-catalyzed reductive cross-coupling reaction of aryl cyclopropyl ketones with easily accessible unactivated alkyl bromides provides γ-alkyl-substituted ketones. Initial mechanistic studies revealed that the reaction proceeds via radical cleavage of the alkyl bromide.


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proposed mechanism



General Procedure

To an oven-dried microwave vial (10 mL) equipped with a stir bar (10 * 5 mm) was added Ni(ClO4)26H2O (3.6 mg, 0.01 mmol), bipy (2.3 mg, 0.015 mmol) under an argon atmosphere inside a glove box at 25 C. Next, 0.1 mL of dry DMA was added via syringe. After the catalyst/ligand solution was stirred for 1 hour at 25 C inside the glove box, Zn powder (13.1 mg, 0.2 mmol, 2 equiv) was added to the reaction vial followed by the cyclopropyl(phenyl)methanone (0.1 mmol, 1.0 equiv, 15 μL) and alkyl bromide (0.25 mmol, 2.5 equiv). The microwave vial was sealed with a cap containing a rubber septum and removed from the glove box. The reaction mixture was stirred (~800 rpm) at 40 C in an oil bath for 12 h. The resulting brown black solution was removed from the oil bath, cooled to room temperature, quenched by addition of 5 drops water through the septum via syringe, and then the vial opened to air. The reaction mixture was passed through a plug of silica gel (200-300 mesh) and the silica gel rinsed with 5 mL of ethyl acetate to afford a yellow solution. The solvent and volatile materials were removed by rotary evaporator. The crude residue was purified by flash column chromatography on silica gel to yield the corresponding product.


Key Words

alkylation, zinc, γ-substituted ketones


ID: J54-Y2022