Abstract
Grushin’s reagent, (bpy)Cu(CF3)3, is a well-known trifluoromethylation agent, but its potential as a difluorocarbene source has remained largely unexplored. Here, we present a photo- and acid-mediated strategy that repurposes Grushin’s reagent as an efficient difluorocarbene precursor for the difluoromethylation of diverse alcohols, including complex primary, secondary, and tertiary alcohols bearing multiple polar functional groups. This method exhibits broad functional group compatibility and has been successfully applied to the late-stage modification of complex natural products and bioactive molecules. A notable achievement is the regioselective difluoromethylation of saccharides and polyols, a challenging transformation enabled by Me2SnCl2, which serves a dual role as a hydroxyl activator and an in situ source of hydrogen chloride. Antifungal activity evaluation reveals that compounds 3c and 3n possess good efficacy, highlighting their potential as promising leads for antifungal development.
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The full experimental details for the preparation of all new compounds, and their spectroscopic and chromatographic data generated in this study, are provided in the Supplementary Information. Data supporting the findings of this manuscript are also available from the corresponding author upon request.
References
Sessler, C. D. et al. CF2H, A Hydrogen Bond Donor. J. Am. Chem. Soc. 139, 9325–9332 (2017).
Zafrani, Y. et al. CF2H, A Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH3? J. Med. Chem. 62, 5628–5637 (2019).
Zafrani, Y. et al. Modulation of the H-Bond Basicity of Functional Groups by α-fluorine-Containing Functions and its Implications for Lipophilicity and Bioisosterism. J. Med. Chem. 64, 4516–4531 (2021).
Zhang, W. et al. Application of Difluoromethyl Isosteres in the Design of Pesticide Active Molecules. J. Agric. Food Chem. 72, 21344–21363 (2024).
Gillis, E. P. et al. Applications of Fluorine in Medicinal Chemistry. J. Med. Chem. 58, 8315–8359 (2015).
Müller, K., Faeh, C. & Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 317, 1881–1886 (2007).
Elkamhawy, A. et al. Discovery of Novel Naphthalene‑Based Diarylamides as Pan‑Raf Kinase Inhibitors with Promising Anti‑Melanoma Activity: Rational Design, Synthesis, In Vitro and In Silico Screening. Arch. Pharm. Res. 48, 150–165 (2025).
Li, Y. et al. Discovery of a Potent, Selective Renal Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitor (HSK0935) for the Treatment of Type 2 Diabetes. J. Med. Chem. 317, 1881–1886 (2017).
Patel, K. J., Lee, C., Tan, Q. & Tannock, L. F. Use of the Proton Pump Inhibitor Pantoprazole to Modify the Distribution and Activity of Doxorubicin: A Potential Strategy to Improve the Therapy of Solid Tumors. Clin. Cancer Res. 19, 6766–6776 (2013).
Li, L., Wang, F., Ni, C. & Hu, J. Synthesis of Gem-Difluorocyclopropa(e)nes and O-, S-, N-, and P-Difluoromethylated Compounds with TMSCF2Br. Angew. Chem. Int. Ed. 52, 12390–12394 (2013).
Xie, Q. & Hu, J. A Journey of the Development of Privileged Difluorocarbene Reagents TMSCF2X (X = Br, F, Cl) for Organic Synthesis. Acc. Chem. Res. 57, 693–713 (2024).
Mizukado, J. et al. Reactions of Aliphatic Fluoro-Alcohols with CHClF2 at Atmospheric Pressure. J. Fluor. Chem. 127, 400–404 (2006).
Gershonov, E. et al. Regio- and Chemoselectivity in S- and O- Difluoromethylation Reactions Using Diethyl (bromodifluoromethyl)phosphonate. J. Fluor. Chem. 250, 109867 (2021).
Mitsch, R. A. Difluorodiazirine. III. Synthesis of Difluorocyclopropanes. J. Am. Chem. Soc. 87, 758–761 (1965).
Pasenok, S. V. et al. Carbenoide Reaktionen von Trifluormethylelement-Verbindungen. 3. Die Reaktionen von Zn(CF3)Br·2CH3CN mit Phenol, Pentafluorphenol, deren Kalium- und Ammoniumsalzen. Z. Anorg. Allg. Chem. 625, 831–833 (1999).
Mizukado, J. et al. Insertion Reactions of Difluorocarbene Generated by Pyrolysis of Hexafluoropropene Oxide to O-H Bond. J. Fluor. Chem. 126, 365–369 (2005).
Levchenko, K. et al. Copper-Catalyzed O-Difluoromethylation of Functionalized Aliphatic Alcohols: Access to Complex Organic Molecules with an OCF2H Group. J. Org. Chem. 81, 5803–5813 (2016).
Liu, S. et al. Difluorocarbene Generation via a Spin-Forbidden Excitation under Visible Light Irradiation. J. Am. Chem. Soc. 146, 31094–31105 (2024).
Sap, J. B. et al. [18F]Difluorocarbene for Positron Emission Tomography. Nature 606, 102–108 (2022).
Zhu, J., Liu, Y. & Shen, Q. Direct Difluoromethylation of Alcohols with an Electrophilic Difluoromethylated Sulfonium Ylide. Angew. Chem. Int. Ed. 55, 9050–9054 (2016).
Xie, Q. et al. Efficient Difluoromethylation of Alcohols Using TMSCF2Br as a Unique and Practical Difluorocarbene Reagent under Mild Conditions. Angew. Chem. Int. Ed. 56, 3206–3210 (2017).
Bonn, P. et al. Mechanochemical Difluoromethylations of Alcohols. CCS Chem. 5, 1737–1744 (2023).
Liu, G.-K. et al. Facile Difluoromethylation of Aliphatic Alcohols with an S-(difluoro-methyl)sulfonium Salt: Reaction, Scope and Mechanistic Study. Chem. Commun. 55, 7446–7449 (2019).
Seeberger, P. H. & Werz, D. B. Synthesis and Medical Applications of Oligosaccharides. Nature 446, 1046–1051 (2007).
Bertozzi, C. R. & Kiessling, L. L. Chemical Glycobiology. Science 291, 2357–2364 (2001).
Ernst, B. & Magnani, J. L. From Carbohydrate leads to Glycomimetic Drugs. Nat. Rev. Drug Discov. 8, 661–677 (2009).
Liu, Y.-G. et al. Carbene-Catalyzed Chirality-Controlled Site-Selective Acylation of Saccharides. Nat. Commun. 16, 54 (2025).
Lv, W.-X. et al. Programmable Selective Acylation of Saccharides Mediated by Carbene and Boronic Acid. Chem 8, 1518–1534 (2022).
Wang, G. et al. Site-Selective C–O Bond Editing of Unprotected Saccharides. J. Am. Chem. Soc. 146, 824–832 (2024).
Lv, J. et al. Catalytic Regioselective Acylation of Unprotected Nucleosides for Quick Access to COVID and Other Nucleoside Prodrugs. ACS Catal. 13, 9567–9576 (2023).
Romine, A. M. et al. Easy Access to the Copper(III) Anion [Cu(CF3)4]−. Angew. Chem. Int. Ed. 54, 2745–2749 (2015).
Shen, H. et al. Trifluoromethylation of Alkyl Radicals in Aqueous Solution. J. Am. Chem. Soc. 139, 9843–9846 (2017).
Guo, S., AbuSalim, D. I. & Cook, S. P. Aqueous Benzylic C–H Trifluoromethylation for Late-Stage Functionalization. J. Am. Chem. Soc. 140, 12378–12382 (2018).
Choi, G. et al. Direct C(sp3)-H Trifluoromethylation of Unactivated Alkanes Enabled by Multifunctional Trifluoromethyl Copper Complexes. Angew. Chem. Int. Ed. 60, 5467–5474 (2021).
Xue, J.-H. et al. Site-Specific Deaminative Trifluoromethylation of Aliphatic Primary Amines. Angew. Chem. Int. Ed. 63, e202319030 (2024).
Sun, J. et al. Sulfonyl Hydrazides as a General Redox-Neutral Platform for Radical Cross-Coupling. Science 387, 1377–1383 (2025).
Ferguson, D. M. et al. Stoichiometric and Catalytic Aryl-Perfluoroalkyl Coupling at Tri-tert-butylphosphine Palladium(II) Complexes. J. Am. Chem. Soc. 139, 11662–11665 (2017).
Leclerc, M. C. et al. Perfluoroalkyl Cobalt(III) Fluoride and Bis(perfluoroalkyl) Complexes: Catalytic Fluorination and Selective Difluorocarbene Formation. J. Am. Chem. Soc. 137, 16064–16073 (2015).
Harrison, D. J. et al. Cobalt Fluorocarbene Complexes. Organometallics 32, 12–15 (2013).
Brothers, P. J. & Roper, W. R. Transition-Metal Dihalocarbene Complexes. Chem. Rev. 88, 1293–1326 (1988).
Xie, Q. et al. Controllable Double CF2-Insertion into sp2 C–Cu Bond Using TMSCF3: A Facile Access to Tetrafluoroethylene-Bridged Structures. Chem. Sci. 11, 276–280 (2020).
Xie, Q. et al. From C1 to C2: TMSCF3 as a Precursor for Pentafluoroethylation. Angew. Chem. Int. Ed. 57, 13211–13215 (2018).
Wang, Q. et al. From C1 to C3: Copper-Catalyzed Gem-Bis(trifluoromethyl)olefination of α-Diazo Esters with TMSCF3. Angew. Chem. 132, 8585–8589 (2020).
Demizu, Y. et al. Regioselective Protection of Sugars Catalyzed by Dimethyltin Dichloride. Org. Lett. 10, 5075–5077 (2008).
Martinelli, M. J. et al. Catalytic Regioselective Sulfonylation of α-Chelatable Alcohols: Scope and Mechanistic Insight. J. Am. Chem. Soc. 124, 3578–3585 (2002).
Jin, J. et al. NHC/B(OH)3-Mediated C3-Selective Acylation of Unprotected Monosaccharides: Mechanistic Insights and Toward Simpler/Greener Solutions. Green. Chem. 26, 5997–6004 (2024).
Dai, S. et al. Saccharide-Assisted Resolution of Bioactive Chiral Carboxylic Acids via NHC-Catalyzed Regioselective Transesterification. ACS Catal. 14, 14043–14047 (2024).
Dai, S. et al. Boronic Acid and Phosphoyl Chloride-Mediated Site-Selective Ketalization of Unprotected Saccharides: In Situ Generation of a Proton Catalyst and Multiple Roles of Reagents. Org. Lett. 26, 10910–10914 (2024).
Dimakos, V. & Taylor, M. S. Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives. Chem. Rev. 118, 11457–11517 (2018).
Hughes, R. P. Conversion of Carbon–Fluorine Bonds α to Transition Metal Centers to Carbon–Hydrogen, Carbon–Carbon, and Carbon–Heteroatom Bonds. Eur. J. Inorg. Chem. 4591-4606 (2009).
Lishchynskyi, A. et al. Trifluoromethylation of Aryl and Heteroaryl Halides with Fluoroform Derived CuCF3: Scope, Limitations, and Mechanistic Features. J. Org. Chem. 78, 11126–11146 (2013).
Zeng, X. et al. Copper-Catalysed Difluorocarbene Transfer Enables Modular Synthesis. Nat. Chem. 15, 1064–1073 (2023).
Zhang, S.-L. & Dong, J.-J. Hydrogen-Bonding-Assisted α‑F Elimination from Cu−CF3 for in Situ Generation of R3N·HF Reagents: Reaction Design and Applications. Org. Lett. 21, 6893–6896 (2019).
Luo, Y. et al. Oxidative Addition of an Alkyl Halide to Form a Stable Cu(III) Product. Science 381, 1072–1079 (2023).
Luo, Y. et al. Decoding the Redox Behaviour of Copper in Ullmann-type Coupling Reactions. Nature 646, 1105–1113 (2025).
Yang, X. et al. Discovery of Novel Piperidine-Containing Thymol Derivatives as Potent Antifungal Agents for Crop Protection. Pest. Manag. Sci. 80, 4906–4914 (2024).
Nie, G. et al. Enantioselective Synthesis of Pyrazolo[3,4-b]pyridone Derivatives with Antifungal Activities against Phytophthora Capsici and Colletotrichum Fructicola. Org. Lett. 25, 134–139 (2023).
Acknowledgements
We acknowledge financial support from the National Key Research and Development Program of China (2024YFD2001100), National Natural Science Foundation of China (32502555 for W.-X.L., U23A20201 for Y.R.C.); National Natural Science Fund for Excellent Young Scientists Fund Program (Overseas for W.-X.L.); the starting grant of Guizhou University [(2024) 01 for W.-X.L.]; Scientific and Technological Innovation Platform Research Project of Guizhou Province [CXPTXM(2025)012 for Y.R.C.]; the Science and Technology Department of Guizhou Province [QiankehejichuZD(2026)013 for Y.R.C.]; Singapore National Research Foundation under its NRF Competitive Research Program (NRF-CRP22-2019-0002 for Y.R.C., NRF-CRP31-0005 for Y.R.C.); Ministry of Education, Singapore, under its MOE AcRF Tier 1 Award (RG11/24, RG102/25 for Y.R.C.), MOE AcRF Tier 2 (MOE-T2EP10222-0006 for Y.R.C., MOE-T2EP10125-0008 for Y.R.C.); a Chair Professorship Grant, and Nanyang Technological University (for Y.R.C.); the Program of Introducing Talents of Discipline to Universities of China (111 Program, D20023) at Guizhou University, the Central Government Guides Local Science and Technology Development Fund Projects [Qiankehezhongyindi (2024) 007, (2023)001]. The authors extend their appreciation to the group of Prof. Qilong Shen (Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences) for their valuable help in providing copper (I) complex F5 (bpyCu(I)CF3).
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S. D. performed main methodology development, scope evaluation, and synthetic application; C. X., S. L. contributed to scope evaluation; M. L., C. C., and T. L. contributed to synthetic application; Y. R. C. and W.-X. L. conceptualized and directed the project and drafted the manuscript with assistance from all co-authors.
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Dai, S., Xie, C., Long, S. et al. Repurposing trifluoromethyl copper (III) complexes for difluoromethylation of saccharides and complex alcohols. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71706-3
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DOI: https://doi.org/10.1038/s41467-026-71706-3
