Nickel-Catalyzed Cross-Electrophile Coupling of the Difluoromethyl Group for Fluorinated Cyclopropane Synthesis

Abstract

Herein, we report a new strategy for fluorinated cyclopropane synthesis. Photocatalytic olefin difluoromethylation is coupled with a nickel-catalyzed intramolecular cross-electrophile coupling (XEC) reaction between a difluoromethyl moiety and a benzylic ether. To the best of our knowledge, this is the first example of a XEC reaction employing a difluoromethyl group as an electrophile. A plausible mechanism is highlighted, and DFT calculations are included to support the observed stereochemical outcome.

Key words

nickel - cross-electrophile coupling - fluorinated cyclopropane - difluoromethyl

Publication History

Received: 29 July 2020

Accepted after revision: 30 December 2020

Article published online:
28 January 2021

• References and Notes

• 1 Present address: Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA.
• 2 Present address: Department of Chemistry and Biochemistry, California State University, Los Angeles, CA 90032, USA.

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• 35 2-(cis-2-Fluorocyclopropyl)naphthalene (cis-6) – Typical Procedure In a glovebox, an oven-dried 7 mL vial equipped with a stir bar was charged with substrate 5 (24 mg, 0.10 mmol, 1.0 equiv), Ni(cod)₂ (1.4 mg, 5.0 μmol, 5.0 mol%), rac-BINAP (3.1 mg, 5.0 μmol, 5.0 mol%), and PhMe (0.50 mL, 0.20 M in substrate). MeMgI (77 μL, 0.20 mmol, 2.0 equiv) was then added dropwise. After 24 h, the reaction vial was removed from the glovebox, quenched with MeOH, filtered through a plug of silica gel eluting with Et₂O, and concentrated in vacuo. Phenyltrimethylsilane (PhTMS; 8.6 μL, 50 μmol) was added, and a ¹H NMR yield of 39% (5:1 dr, cis/trans) was obtained based on comparison to PhTMS as internal standard. The product was purified by column chromatography (100% pentane) to yield the title compound as a white semisolid. An isolated yield was not reported due to volatility. The dr was determined based on the integration of the resonances in the ¹H NMR spectrum attributed to the hydrogens geminal to the fluorine atom. The relative configuration was assigned based on NOE analysis. TLC R_f = 0.6 (2% Et₂O/pentane). ¹H NMR (500 MHz, CDCl₃): δ = 7.81–7.77 (m, 3 H), 7.71 (s, 1 H), 7.46–7.39 (m, 3 H), 4.85 (dtd, J = 66.0, 6.2, 2.9 Hz, 1 H), 2.25–2.19 (m, 1 H), 1.43 (dtd, J = 22.5, 7.7, 2.8 Hz, 1 H), 1.30–1.23 (m, 1 H). ¹³C NMR (125.4 MHz, CDCl₃): δ = 133.7 (d, J = 3.0 Hz), 133.5, 132.4, 127.8, 127.73, 127.68, 127.23 (d, J = 1.4 Hz), 127.17 (d, J = 1.1 Hz), 126.1, 125.5, 72.7 (d, J = 221.9 Hz), 21.8 (d, J = 11.1 Hz), 11.9 (d, J = 10.4 Hz). ¹⁹F NMR (365.4 MHz, CDCl₃): δ = –222.2. HRMS (TOF MS ES+): m/z [M]⁺ calcd for C₁₃FH₁₁: 186.0845; found: 186.0840.