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A Ball-Milling-Enabled Cross-Electrophile Coupling

Andrew C. Jones, William I. Nicholson, Jamie A. Leitch and Duncan L. Browne*

*Department of Pharmaceutical and Biological Chemistry, School of Pharmacy, 29-39 Brunswick Square, Bloomsbury, London, WC1N 1AX, United Kingdom, Email: Duncan.Browneucl.ac.uk

A. C. Jones, W. I. Nicholson, J. A. Leitch, D. L. Browne, Org. Lett., 2021, 23, 6337-6341.

DOI: 10.1021/acs.orglett.1c02096


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Abstract

Ball-milling enables a nickel-catalyzed cross-electrophile coupling of aryl halides and alkyl halides. Under a mechanochemical manifold, the reductive C-C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive setups, in reaction times of 2 h. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the nickel catalytic cycle.

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General Procedure A: Mechanochemical cross coupling of aryl halides with alkylhalides

To a 15 mL stainless steel Jar was added a 3 g stainless steel milling ball. Aryl halide (1 mmol), alkyl halide (1.5 mmol, 1.5 equiv.), NiCl26H2O (0.024 g, 0.1 mmol, 10 mol%), 1,10-phenanthroline (0.036 g, 0.2 mmol, 20 mol%), Zinc granular (20-30 mesh, 0.130 g, 2 mmol, 2 equiv.) and N,N-dimethylacetamide (0.180 mL, 3 mmol, 3 equiv.) were all added to the jar (for alkyl bromide examples NaI (0.150 g, 1.0 mmol, 1.0 equiv.) was also added). The jar was closed and placed on the mixer mill. The reaction was milled for 2 hours at 30 Hz. After the milling period the jar was opened and rinsed from the jar into a conical flask using CH2Cl2 (~20 mL). 1M HCl was added to the flask and stirred for 10 minutes. The resulting biphasic mixture was transferred to a separating funnel where the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic layers were washed with brine (~40 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the crude product as a yellow/orange oil. The crude product was purified by flash column chromatography to afford the cross-electrophile coupled product.

On some occasions when small quantities of homo-coupled biaryl products co-elute during column chromatography, the mixture can be further purified using Kugelrohr distillation (Buchi b-585 glass oven kugelrohr) with the pressure and temperature ranges given where appropriate.


Key Words

alkylation, zinc, mechanochemistry


ID: J54-Y2021