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Synlett 2021; 32(15): 1525-1530
DOI: 10.1055/s-0040-1706013
DOI: 10.1055/s-0040-1706013
cluster
Modern Nickel-Catalyzed Reactions
Nickel-Catalyzed Cross-Electrophile Coupling of the Difluoromethyl Group for Fluorinated Cyclopropane Synthesis
Financial support from the Center for Scientific Review (NIH NIGMS R01GM100212) is gratefully acknowledged.
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.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1706013.
- Supporting Information
Publication History
Received: 29 July 2020
Accepted after revision: 30 December 2020
Article published online:
28 January 2021
© 2021. Thieme. All rights reserved
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References and Notes
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1 Present address: Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA.
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2 Present address: Department of Chemistry and Biochemistry, California State University, Los Angeles, CA 90032, USA.
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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 Rf
= 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.
For reviews, see:
For selected examples of fluorinated cyclopropane synthesis, see:
For recent reviews of photochemical difluoromethylation reactions, see:
This principle has previously been successful in facilitating the oxidative addition of benzylic C–O bonds, see: