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

• 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.

For reviews, see:
• 3a David E, Milanole G, Ivashkin P, Couve-Bonnaire S, Jubault P, Pannecoucke X. Chem. Eur. J. 2012; 18: 14904
• 3b Pons A, Poisson T, Pannecoucke X, Charette AB, Jubault P. Synthesis 2016; 48: 4060
• 3c Dolbier WR, Battiste MA. Chem. Rev. 2003; 103: 1071
• 4 Lemonnier G, Lion C, Quirion J.-C, Pin J.-P, Goudet C, Jubault P. Bioorg. Med. Chem. 2012; 20: 4716
• 5 Taele TT. J. Med. Chem. 2016; 59: 8712

For selected examples of fluorinated cyclopropane synthesis, see:
• 6a Meyer OG. J, Fröhlich R, Haufe G. Synthesis 2000; 1479
• 6b Navuluri C, Charette AB. Org. Lett. 2015; 17: 4288
• 6c Pons A, Ivashkin P, Poisson T, Charette AB, Pannecoucke X, Jubault P. Chem. Eur. J. 2016; 22: 6239
• 6d Fang F, Cordes DB, Slawin AM. Z, O’Hagan D. Chem. Commun. 2019; 55: 10539
• 6e Delion L, Poisson T, Jubault P, Pannecoucke X, Charette AB. Can. J. Chem. 2020; 98: 516
• 6f Kazia A, Melngaile R, Mishnew A, Veliks J. Org. Biomol. Chem. 2020; 18: 1384

For recent reviews of photochemical difluoromethylation reactions, see:
• 7a Koike T, Akita M. Org. Biomol. Chem. 2019; 17: 5413
• 7b Pan X, Xia H, Wu J. Org. Chem. Front. 2016; 3: 1163
• 8 Erickson LW, Lucas EL, Tollefson EJ, Jarvo ER. J. Am. Chem. Soc. 2016; 138: 14006
• 9 O’Hagan D. Chem. Soc. Rev. 2008; 37: 308
• 10 Caron S. Org. Process Res. Dev. 2020; 24: 470
• 11a Ran Y, Lin Q.-Y, Xu X.-H, Qing F.-L. J. Org. Chem. 2016; 81: 7001
• 11b Arai Y, Tomita R, Ando G, Koike T, Akita M. Chem. Eur. J. 2016; 22: 1262
• 11c Noto N, Koike T, Akita M. ACS Catal. 2019; 9: 4382
• 12 Noto N, Koike T, Akita M. J. Org. Chem. 2016; 81: 7064
• 13a Zhang Z, Tang X, Thomoson CS, Dolbier WR. Org. Lett. 2015; 17: 3528
• 13b Noto N, Koike T, Akita M. Chem. Sci. 2017; 8: 6375
• 13c Noto N, Tanaka Y, Koike T, Akita M. ACS Catal. 2018; 8: 9408
• 14a Cao P, Duan J.-X, Chen Q.-Y. J. Chem. Soc., Chem. Commun. 1994; 737
• 14b Thomoson CS, Tang X.-J, Dolbier WR. J. Org. Chem. 2015; 80: 1264
• 14c Tang XJ, Dolbier WR. Angew. Chem. Int. Ed. 2015; 54: 4246
• 14d Lin Q.-Y, Ran Y, Xu X.-H, Qing F.-L. Org. Lett. 2016; 18: 2419
• 15 Yatham VR, Shen Y, Martin R. Angew. Chem. Int. Ed. 2017; 56: 10915
• 16a Tang X.-J, Thomoson CS, Dolbier WR. Org. Lett. 2014; 16: 4594
• 16b Liu J, Zhuang S, Gui Q, Chen X, Yang Z, Tan Z. Eur. J. Org. Chem. 2014; 3196
• 16c He Z, Tan P, Ni C, Hu J. Org. Lett. 2015; 17: 1838
• 16d Zhang Z, Martinez H, Dolbier WR. J. Org. Chem. 2017; 82: 2589
• 16e Zou G, Wang X. Org. Biomol. Chem. 2017; 15: 8748
• 16f Zhu M, You Q, Li R. J. Fluorine Chem. 2019; 228: 109391
• 17a Zhang Z, Tang X.-J, Dolbier WR. Org. Lett. 2016; 18: 1048
• 17b Kim YJ, Kim DY. J. Fluorine Chem. 2018; 211: 119
• 18 Zhang M, Lin J.-H, Xiao J.-C. Angew. Chem. Int. Ed. 2019; 58: 6079
• 19a Tang X.-J, Zhang Z, Dolbier WR. Chem. Eur. J. 2015; 21: 18961
• 19b Lin Q.-Y, Xu X.-H, Zhang K, Qing F.-L. Angew. Chem. Int. Ed. 2016; 55: 1479
• 19c Hu W.-Q, Xu X.-H, Qing F.-L. J. Fluorine Chem. 2018; 208: 73
• 20 For reviews on photochemical difluoromethylation reactions, see refs. 7, 11, and: Koike T, Akita M. Chem 2018; 4: 409
• 21 Zheng J, Cai J, Lin J, Guo Y, Xiao J. Chem. Commun. 2013; 49: 7513
• 22 Deng Z, Lin J, Cai J, Xiao J. Org. Lett. 2016; 18: 3206
• 23 Tamayo AB, Alleyne BD, Djurovich PI, Lamansky S, Tsyba I, Ho NN, Bau R, Thompson ME. J. Am. Chem. Soc. 2003; 125: 7377
• 24 Chen P.-P, Lucas EL, Greene MA, Zhang S.-Q, Tollefson EJ, Erickson LW, Taylor BL. H, Jarvo ER, Hong X. J. Am. Chem. Soc. 2019; 141: 5835
• 25 Schlenk W, Schlenk W. Ber. Dtsch. Chem. Ges. B 1929; 62: 920

This principle has previously been successful in facilitating the oxidative addition of benzylic C–O bonds, see:
• 26a Greene MA, Yonova IM, Williams FJ, Jarvo ER. Org. Lett. 2012; 14: 4293
• 26b Wisniewska HM, Swift EC, Jarvo ER. J. Am. Chem. Soc. 2013; 135: 9083
• 27 Liang Z, Xue W, Lin K, Gong H. Org. Lett. 2014; 16: 5620
• 28 Knappke CE. I, Grupe S, Gärtner D, Corpet M, Gosmini C, Jacobi von Wangelin A. Chem. Eur. J. 2014; 20: 6828
• 29 Lucas EL, Hewitt KA, Chen P.-P, Castro AJ, Hong X, Jarvo ER. J. Org. Chem. 2019; 85: 1775
• 30 Xu Z, Yang Y, Jiang J, Fu Y. Organometallics 2018; 37: 1114
• 31 Becke AD. J. Chem. Phys. 1993; 98: 5648
• 32 Lee C, Yang W, Parr RG. Phys. Rev. B. 1998; 37: 785
• 33 Hehre WJ, Radom L, Schleyer P. vR, Pople JA. Ab Initio Molecular Orbital Theory . Wiley; New York: 1986
• 34a Kirby AJ. Stereoelectronic Effects . Compton RG, Davies SG, Evans J, Gladden LF. Oxford University Press; New York: 1996
• 34b Fleming I. Molecular Orbitals and Organic Chemical Reactions, Student Edition. John Wiley & Sons; Chichester: 2009
• 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.