Enantio- and Diastereoselective Rh(I)-Catalyzed Defluorinative Arylation of Pentafluoroethyl Alkenes to Access Fluoroalkenes Featuring a Unique F- and CF₃-Substituted sp²-Carbon

Abstract

We herein describe an enantio- and diastereoselective rhodium(I)-catalyzed defluorinative arylation of pentafluoroethyl alkenes with arylboronic acids. A new class of previously inaccessible functionalized fluoroalkenes featuring a sp²-carbon connected to F and CF₃ can be synthesized. Using both 1,1- and 1,2-disubstituted alkene substrates, tetra- and trisubstituted fluoroalkene products are obtained in excellent Z/E selectivities with well-defined alkene geometry. These fluoroalkenes are potential synthons for accessing chiral compounds containing a stereogenic centre with F and CF₃ group.

Keywords

Rhodium / Arylation / Defluorination / Fluoroalkene / Pentafluoroethyl / Asymmetric catalysis / Insertion / Stereochemistry

References

[1] For representative reviews, see: (a) Britton, R.; Gouverneur, V.; Lin, J.-H.; Meanwell, M.; Ni, C.; Pupo, G.; Xiao, J.-C.; Hu, J. Contemporary Synthetic Strategies in Organofluorine Chemistry. Nat. Rev. Methods Primers 2021, 1, 47; (b) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH, Weinheim, Germany, 2004; (c) Uneyama, K. Organofluorine Chemistry, Blackwell Publishing, Oxford, U.K., 2006; (d) Tsui, G. C.; Hu, J. Organofluorine Chemistry. Asian J. Org. Chem. 2019, 8, 566–567; (e) Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881–1886; (f) Thayer, A. M. Fabulous Fluorine. Chem. Eng. News 2006, 84, 15–24.

[2] Ma, J.-A.; Cahard, D. Emerging Fluorinated Motifs: Synthesis, Properties, and Applications, Wiley-VCH, Weinheim, Germany, 2020.

[3] For a recent analysis of FDA approved fluorine-containing drugs in 2023, see: Wang, Q.; Bian, Y.; Dhawan, G.; Zhang, W.; Sorochinsky, A. E.; Makarem, A.; Soloshonok, V. A.; Han, J. FDA approved fluorine-containing drugs in 2023. Chin. Chem. Lett. 2024, 35, 109780.

[4] For reviews on C-F bond functionalization, see: (a) Coates, G.; Rekhroukh, F.; Crimmin, M. R. Breaking Carbon–Fluorine Bonds with Main Group Nucleophiles. Synlett 2019, 30, 2233–2246; (b) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of Fluorinated Molecules by Transition-Metal-Mediated C–F Bond Activation to Access Fluorinated Building Blocks. Chem. Rev. 2015, 115, 931–972; (c) Uneyama, K.; Amii, H. C–F Bond Activation in Organic Synthesis. Chem. Rev. 2009, 109, 2119–2183; (d) Stahl, T.; Klare, H. F. T.; Oestreich, M. Main-Group Lewis Acids for C–F Bond Activation. ACS Catal. 2013, 3, 1578–1587; (e) Clot, E.; Eisenstein, O.; Jasim, N.; MacGregor, S. A.; McGrady, J. E.; Perutz, R. N. C–F and C–H Bond Activation of Fluorobenzenes and Fluoropyridines at Transition- Metal Centers: How Fluorine Tips the Scales. Acc. Chem. Res. 2011, 44, 333–348; (f) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Activation of Carbon–Fluorine Bonds by Metal Complexes. Chem. Rev. 1994, 94, 373–431; (g) Whittlesey, M. K.; Peris, E. Catalytic Hydrodefluorination with Late Transition-Metal Complexes. ACS Catal. 2014, 4, 3152–3159; (h) Kühnel, M. F.; Lentz, D.; Braun, T. Synthesis of Fluorinated Building Blocks by Transition-Metal-Mediated Hydrodefluorination Reactions. Angew. Chem. Int. Ed. 2013, 52, 3328–3348.

[5] For a recent review on defluorinative C-F bond functionalization, see: Hooker, L. V.; Bandar, J. S. Synthetic Advantages of Defluorinative C−F Bond Functionalization. Angew. Chem. Int. Ed. 2023, 62, e202308880.

[6] (a) Luo, Y.-R. Comprehensive Handbook of Chemical Bond Energies, CRC Press, Boca Raton, FL, 2007; (b) O’Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 2008, 37, 308–319.

[7] For selected reviews on transition metal-catalyzed C-F bond functionalization, see: (a) Koley, S.; Altman, R. A. Recent Advances in Transition Metal-Catalyzed Functionalization of gem-Difluoroalkenes. Isr. J. Chem. 2020, 60, 313–339; (b) Fujita, T.; Fuchibe, K.; Ichikawa, J. Transition-Metal-Mediated and -Catalyzed C–F Bond Activation by Fluorine Elimination. Angew. Chem. Int. Ed. 2019, 58, 390–402.

[8] For selected reviews, see: (a) Song, S.; Xu, S. Recent Progress in Selective C-F Bond Activation of Trifluoromethyl Alkenes. Chin. J. Org. Chem. 2023, 43, 411–425; (b) Paioti, P. H. S.; Gonsales, S. A.; Xu, S.; Nikbakht, A.; Fager, D. C.; Liu, Q.; Hoveyda, A. H. Catalytic and Stereoselective Transformations with Easily Accessible and Purchasable Allyl and Alkenyl Fluorides. Angew. Chem. Int. Ed. 2022, 61, e202208742; (c) Wang, M.; Shi, Z. Catalytic Enantioselective Allylic C–F Bond Functionalization. Chem. Lett. 2021, 50, 553–559.

[9] For selected reviews, see: (a) Drouin, M.; Hamel, J.-D.; Paquin, J.-F. Synthesis of Monofluoroalkenes: A Leap Forward. Synthesis 2018, 50, 881–955; (b) Barata-Vallejo, S.; Lantaño, B.; Postigo, A. Recent Advances in Trifluoromethylation Reactions with Electrophilic Trifluoromethylating Reagents. Chem. Eur. J. 2014, 20, 16806–16829.

[10] For our contribution to the synthesis of pentafluoroethylated compounds, see: (a) Dong, T.; Shen, Q.; Tsui, G. C. Synthesis and application of well-defined [Ph₄P]⁺[Cu(CF₂CF₃)₂]^- complex as a versatile pentafluoroethylating reagent. Chem. Sci. 2024, 15, 11550–11556; (b) Tang, Y.; Tsui, G. C. Copper-catalyzed pentafluoroethylation of aryl/ alkenyl iodides with pentafluoroethylsilane. Org. Chem. Front. 2024, 11, 4366–4370; (c) Fu, Z.; Tsui, G. C. Divergent pentafluoroethylation of styrene derivatives using CuCF₂CF₃. Org. Chem. Front. 2024, 11, 4697–4701; (d) Dong, T.; Tang, Y.; Tsui, G. C. Thermal N–O bond heterolysis of TEMPO-CF₂CF₃ towards trifluoroacetylation of alcohols and amines. Org. Chem. Front. 2023, 10, 5092–5098.

[11] For leading examples, see: (a) Sano, K.; Fukuhara, T.; Hara, S. Regioselective synthesis of β-fluoro-α,β-unsaturated ketones by the reaction of β-diketones with DFMBA. J. Fluor. Chem. 2009, 130, 708–713; (b) Zhang, Y.; Raugh, N.; Koert, U. Fluorotrifluoromethyl Group Installation: Tetrasubstituted Tertiary Stereocenters Containing C–F and C–CF₃ Bonds via Copper-Mediated Allylic Substitution. Org. Lett. 2023, 25, 5641–5645; (c) Huang, H.; Gou, F.; Pu, Y.; Yuan, J.; Bai, M.; Zhu, J.; Li, S.; Feng, Z. Silyl Radical-Promoted Defluorination of Fluoroalkyl Ketones to Access Fluorinated 1,3-Dienes. Chin. J. Chem. 2025, 43, 2901–2908; (d) Xu, S.; del Pozo, J.; Romiti, F.; Fu, Y.; Mai, B. K.; Morrison, R. J.; Lee, K. A.; Hu, S.; Koh, M. J.; Lee, J.; Li, X.; Liu, P.; Hoveyda, A. H. Diastereo- and enantioselective synthesis of compounds with a trifluoromethyl- and fluoro-substituted carbon centre. Nat. Chem. 2022, 14, 1459–1469. For other related examples, see: (e) Liu, S.; Yang, Y.; Song, Q.; Liu, Z.; Lu, Y.; Wang, Z.; Sivaguru, P.; Bi, X. Tunable molecular editing of indoles with fluoroalkyl carbenes. Nat. Chem. 2024, 16, 988–997; (f) Wu, Y.; Lu, G.; Yuan, T.; Xu, Z.; Wan, L.; Cai, C. Oxidative trifluoromethylation and fluoroolefination of unactivated olefins. Chem. Commun. 2016, 52, 13668–13670; (g) Sang, J.; Feng, L.; Hu, R.; Chen, J.; Shang, D.; Bao, Q.; Rao, W. Sc(OTf)₃-Catalyzed C2-Selective Cyanation/Defluorination Cascade of Perfluoroalkylated 3-Indolylmethanols and Application to the Synthesis of 3-Fluoro(perfluoroalkyl)-β-carbolines. Org. Lett. 2021, 23, 7666–7671.

[12] For leading reviews, see: (a) Hayashi, T.; Yamasaki, K. Rhodium-Catalyzed Asymmetric 1,4-Addition and Its Related Asymmetric Reactions. Chem. Rev. 2003, 103, 2829–2844; (b) Fagnou, K.; Lautens, M. Rhodium-Catalyzed Carbon−Carbon Bond Forming Reactions of Organometallic Compounds. Chem. Rev. 2003, 103, 169–196.

[13] (a) Miura, T.; Ito, Y.; Murakami, M. Synthesis of gem-difluoroalkenes via β-fluoride elimination of organorhodium(I). Chem. Lett. 2008, 37, 1006–1007; (b) Huang, Y.; Hayashi, T. Rhodium-Catalyzed Asymmetric Arylation/Defluorination of 1-(Trifluoromethyl)alkenes Forming Enantioenriched 1,1-Difluoroalkenes. J. Am. Chem. Soc. 2016, 138, 12340–12343; (c) Jang, Y. J.; Rose, D.; Mirabi, B.; Lautens, M. Rhodium-Catalyzed Enantioselective Defluorinative α-Arylation of Secondary Amides. Angew. Chem. Int. Ed. 2018, 57, 16147–16151; (d) Pan, Y.; Lu, X.; Qiu, H.; Hayashi, T.; Huang, Y. Highly Enantioselective Synthesis of Monofluoroalkenes by Rhodium-Catalyzed Asymmetric Arylation/Defluorination of Allyl Difluorides. Org. Lett. 2020, 22, 8413–8418.

[14] (a) Zong, Y.; Tang, Y.; Tsui, G. C. Rhodium(I)-Catalyzed Defluorinative Coupling of Boronic Acids with Monofluoroalkenes. Org. Lett. 2022, 24, 6380–6385; (b) Li, M.; Tsui, G. C. Rhodium(I)-Catalyzed Defluorinative Bisarylation of Monofluorodienes with Boronic Acids. Org. Lett. 2024, 26, 2223–2227; (c) Tan, H.; Zong, Y.; Tang, Y.; Tsui, G. C. Stereoselective Rhodium(I)-Catalyzed C–F Bond Arylation of Tri- and Tetrasubstituted gem-Difluoroalkenes with Boronic Acids. Org. Lett. 2023, 25, 877–882.

[15] See the Supporting Information (SI) for full details.

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2025 The Author(s). Chinese Journal of Chemistry published by SIOC, CAS, Shanghai and Wiley-VCH GmbH