钯催化的二氟甲基芳基化的研究进展
Research Progress on Palladium-Catalyzed Difluoromethyl Arylation
DOI: 10.12677/jocr.2025.131003, PDF,   
作者: 陈钰沣:浙江师范大学化学与材料科学学院,浙江 金华
关键词: 钯催化二氟甲基芳基化Palladium Catalysis Difluoromethyl Arylation
摘要: 增加生物活性分子的亲脂性、代谢稳定性、药代动力学特征的有效方法之一是在其分子结构中引入含氟基团,特别是二氟甲基。在过去的十年中,基于过渡金属催化完成二氟甲基芳基化的方法已经被证明是有效的策略。这些方法主要包括两类:一是芳烃的预官能团化,二是开发各类二氟甲基化试剂,其中由钯催化的二氟甲基芳基化的反应表现出优异的选择性、广泛的官能团耐受性、温和的反应条件等众多优点。鉴于二氟甲基在各个领域的重要性,本文主要总结了钯催化的二氟甲基芳基化的反应研究进展,反应涵盖至2024年。
Abstract: One of the effective methods to enhance the lipophilicity, metabolic stability, and pharmacokinetic properties of bioactive molecules is to introduce fluorine-containing groups, especially difluoromethyl groups, into their molecular structures. Over the past decade, transition metal-catalyzed methods for difluoromethyl arylation have been proven to be an effective strategy. These methods mainly fall into two categories: pre-functionalization of aromatic compounds and development of various difluoromethylating reagents. Among them, palladium-catalyzed difluoromethyl arylation reactions exhibit numerous advantages, such as excellent selectivity, broad functional group tolerance, and mild reaction conditions. Given the significance of difluoromethyl groups in various fields, this review mainly summarizes the research progress of palladium-catalyzed difluoromethyl arylation reactions, covering studies up to 2024.
文章引用:陈钰沣. 钯催化的二氟甲基芳基化的研究进展[J]. 有机化学研究, 2025, 13(1): 21-34. https://doi.org/10.12677/jocr.2025.131003

参考文献

[1] Silva, D.R., Daré, J.K. and Freitas, M.P. (2020) Conformational Preferences of Fluorine-Containing Agrochemicals and Their Implications for Lipophilicity Prediction. Beilstein Journal of Organic Chemistry, 16, 2469-2476. [Google Scholar] [CrossRef] [PubMed]
[2] Saranya, P.V., Aneeja, T. and Anilkumar, G. (2021) Palladium-Catalyzed Difluoromethylation and Difluoroalkylation Reactions: An Overview. Applied Organometallic Chemistry, 36, e6503. [Google Scholar] [CrossRef
[3] Johnson, B.M., Shu, Y., Zhuo, X. and Meanwell, N.A. (2020) Metabolic and Pharmaceutical Aspects of Fluorinated Compounds. Journal of Medicinal Chemistry, 63, 6315-6386. [Google Scholar] [CrossRef] [PubMed]
[4] O’Hagan, D. (2008) Understanding Organofluorine Chemistry. An Introduction to the C-F Bond. Chemical Society Reviews, 37, 308-319. [Google Scholar] [CrossRef] [PubMed]
[5] Yuan, C.C., Chen, X.L., Zhang, J.Y. and Zhao, Y.S. (2017) Meta-Selective C-H Difluoromethylation of Various Arenes with a Versatile Ruthenium Catalyst. Organic Chemistry Frontiers, 4, 1867-1871. [Google Scholar] [CrossRef
[6] Erickson, J.A. and McLoughlin, J.I. (1995) Hydrogen Bond Donor Properties of the Difluoromethyl Group. The Journal of Organic Chemistry, 60, 1626-1631. [Google Scholar] [CrossRef
[7] Pauling, L., Springall, H.D. and Palmer, K.J. (1939) The Electron Diffraction Investigation of Methylacetylene, Dimethylacetylene, Dimethyldiacetylene, Methyl Cyanide, Diacetylene, and Cyanogen. Journal of the American Chemical Society, 61, 927-937. [Google Scholar] [CrossRef
[8] Gillis, E.P., Eastman, K.J., Hill, M.D., Donnelly, D.J. and Meanwell, N.A. (2015) Applications of Fluorine in Medicinal Chemistry. Journal of Medicinal Chemistry, 58, 8315-8359. [Google Scholar] [CrossRef] [PubMed]
[9] Barroso, J., Andújar, D., Martín, C.S., Fernández-Quintanilla, C. and Dorado, J. (2012) Johnsongrass (Sorghum halepense) Seed Dispersal in Corn Crops under Mediterranean Conditions. Weed Science, 60, 34-41. [Google Scholar] [CrossRef
[10] Larkin, M. (2004) Malaria: Spreading Education and Advocacy on the Web. The Lancet Infectious Diseases, 4, Article 381. [Google Scholar] [CrossRef
[11] Zafrani, Y., Yeffet, D., Sod-Moriah, G., Berliner, A., Amir, D., Marciano, D., et al. (2017) Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor” Concept. Journal of Medicinal Chemistry, 60, 797-804. [Google Scholar] [CrossRef] [PubMed]
[12] Zhang, W., Wang, F. and Hu, J. (2009) N-Tosyl-S-difluoromethyl-s-phenylsulfoximine: A New Difluoromethylation Reagent for S-, N-, and C-nucleophiles. Organic Letters, 11, 2109-2112. [Google Scholar] [CrossRef] [PubMed]
[13] Zeng, X., Yan, W., Zacate, S.B., Cai, A., Wang, Y., Yang, D., et al. (2020) Copper-Catalyzed Deaminative Difluoromethylation. Angewandte Chemie International Edition, 59, 16398-16403. [Google Scholar] [CrossRef] [PubMed]
[14] Hua, H., Zhang, B., He, Y., Qiu, Y., Hu, J., Yang, Y., et al. (2016) Copper-Catalyzed Difluoromethylation of Propargylamide-Substituted Indoles: Synthesis of Mono and Bis-Difluoromethylated Indoloazepinone Derivatives. Chemical Communications, 52, 10396-10399. [Google Scholar] [CrossRef] [PubMed]
[15] Sheng, J., Ni, H., Bian, K., Li, Y., Wang, Y. and Wang, X. (2018) Nickel-Catalyzed Direct Difluoromethylation of Aryl Boronic Acids with BrCF2H. Organic Chemistry Frontiers, 5, 606-610. [Google Scholar] [CrossRef
[16] Liu, J., Zhuang, S., Gui, Q., Chen, X., Yang, Z. and Tan, Z. (2014) Synthesis of Oxindoles through Silver-Catalyzed Trifluoromethylation, Difluoromethylation and Arylsulfonylation-Cyclization Reaction of N-arylacrylamides. European Journal of Organic Chemistry, 2014, 3196-3202. [Google Scholar] [CrossRef
[17] Zhong, J., Yang, C., Chang, X., Zou, C., Lu, W. and Che, C. (2017) Platinum (II) Photo-Catalysis for Highly Selective Difluoroalkylation Reactions. Chemical Communications, 53, 8948-8951. [Google Scholar] [CrossRef] [PubMed]
[18] Rageot, D., Bohnacker, T., Melone, A., Langlois, J., Borsari, C., Hillmann, P., et al. (2018) Discovery and Preclinical Characterization of 5-[4,6-Bis({3-Oxa-8-Azabicyclo[3.2.1]octan-8-Yl})-1,3,5-Triazin-2-Yl]-4-(difluoromethyl)pyridin-2-Amine (PQR620), a Highly Potent and Selective mTORC1/2 Inhibitor for Cancer and Neurological Disorders. Journal of Medicinal Chemistry, 61, 10084-10105. [Google Scholar] [CrossRef] [PubMed]
[19] Fujikawa, K., Fujioka, Y., Kobayashi, A. and Amii, H. (2011) A New Method for Aromatic Difluoromethylation: Copper-Catalyzed Cross-Coupling and Decarboxylation Sequence from Aryl Iodides. Organic Letters, 13, 5560-5563. [Google Scholar] [CrossRef] [PubMed]
[20] Ge, S., Chaładaj, W. and Hartwig, J.F. (2014) Pd-Catalyzed Α-Arylation of Α, α-Difluoroketones with Aryl Bromides and Chlorides. A Route to Difluoromethylarenes. Journal of the American Chemical Society, 136, 4149-4152. [Google Scholar] [CrossRef] [PubMed]
[21] Belhomme, M., Poisson, T. and Pannecoucke, X. (2014) Copper-Catalyzed Direct C-2 Difluoromethylation of Furans and Benzofurans: Access to C-2 Cf2h Derivatives. The Journal of Organic Chemistry, 79, 7205-7211. [Google Scholar] [CrossRef] [PubMed]
[22] Sun, X. and Yu, S. (2014) Visible-Light-Mediated Fluoroalkylation of Isocyanides with Ethyl Bromofluoroacetates: Unified Synthesis of Mono and Difluoromethylated Phenanthridine Derivatives. Organic Letters, 16, 2938-2941. [Google Scholar] [CrossRef] [PubMed]
[23] Jung, J., Kim, E., You, Y. and Cho, E.J. (2014) Visible Light-Induced Aromatic Difluoroalkylation. Advanced Synthesis & Catalysis, 356, 2741-2748. [Google Scholar] [CrossRef
[24] Grushin, V.V. and Marshall, W.J. (2006) Unexpected H2O-Induced Ar-X Activation with Trifluoromethylpalladium (II) Aryls. Journal of the American Chemical Society, 128, 4632-4641. [Google Scholar] [CrossRef] [PubMed]
[25] Gu, Y., Leng, X. and Shen, Q. (2014) Cooperative Dual Palladium/Silver Catalyst for Direct Difluoromethylation of Aryl Bromides and Iodides. Nature Communications, 5, Article No. 5405. [Google Scholar] [CrossRef] [PubMed]
[26] Lu, C., Lu, H., Wu, J., Shen, H.C., Hu, T., Gu, Y., et al. (2018) Palladium-Catalyzed Difluoromethylation of Aryl Chlorides and Triflates and Its Applications in the Preparation of Difluoromethylated Derivatives of Drug/Agrochemical Molecules. The Journal of Organic Chemistry, 83, 1077-1083. [Google Scholar] [CrossRef] [PubMed]
[27] Lu, C., Gu, Y., Wu, J., Gu, Y. and Shen, Q. (2017) Palladium-Catalyzed Difluoromethylation of Heteroaryl Chlorides, Bromides and Iodides. Chemical Science, 8, 4848-4852. [Google Scholar] [CrossRef] [PubMed]
[28] Aikawa, K., Nakamura, Y., Yokota, Y., Toya, W. and Mikami, K. (2014) Stable but Reactive Perfluoroalkylzinc Reagents: Application in Ligand-Free Copper-Catalyzed Perfluoroalkylation of Aryl Iodides. ChemistryA European Journal, 21, 96-100. [Google Scholar] [CrossRef] [PubMed]
[29] Ferguson, D.M., Malapit, C.A., Bour, J.R. and Sanford, M.S. (2019) Palladium-Catalyzed Difluoromethylation of Aryl Chlorides and Bromides with TMSCF2H. The Journal of Organic Chemistry, 84, 3735-3740. [Google Scholar] [CrossRef] [PubMed]
[30] Deng, X., Lin, J. and Xiao, J. (2016) Pd-Catalyzed Transfer of Difluorocarbene. Organic Letters, 18, 4384-4387. [Google Scholar] [CrossRef] [PubMed]
[31] Feng, Z., Min, Q. and Zhang, X. (2015) Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of Arylboronic Acids with Bromodifluoroacetate. Organic Letters, 18, 44-47. [Google Scholar] [CrossRef] [PubMed]
[32] Feng, Z., Min, Q., Fu, X., An, L. and Zhang, X. (2017) Chlorodifluoromethane-triggered Formation of Difluoromethylated Arenes Catalysed by Palladium. Nature Chemistry, 9, 918-923. [Google Scholar] [CrossRef] [PubMed]
[33] Fu, X., Xue, X., Zhang, X., Xiao, Y., Zhang, S., Guo, Y., et al. (2019) Controllable Catalytic Difluorocarbene Transfer Enables Access to Diversified Fluoroalkylated Arenes. Nature Chemistry, 11, 948-956. [Google Scholar] [CrossRef] [PubMed]
[34] Hori, K., Motohashi, H., Saito, D. and Mikami, K. (2018) Precatalyst Effects on Pd-Catalyzed Cross-Coupling Difluoromethylation of Aryl Boronic Acids. ACS Catalysis, 9, 417-421. [Google Scholar] [CrossRef
[35] Zhao, H., Herbert, S., Kinzel, T., Zhang, W. and Shen, Q. (2020) Two Ligands Transfer from Ag to Pd: En Route to (SIPr)Pd(CF2H)(X) and Its Application in One-Pot C-H Borylation/Difluoromethylation. The Journal of Organic Chemistry, 85, 3596-3604. [Google Scholar] [CrossRef] [PubMed]
[36] Pan, F., Boursalian, G.B. and Ritter, T. (2018) Palladium-Catalyzed Decarbonylative Difluoromethylation of Acid Chlorides at Room Temperature. Angewandte Chemie International Edition, 57, 16871-16876. [Google Scholar] [CrossRef] [PubMed]
[37] Jiang, X., Gong, W., Li, X., Wang, S., Gu, Z., Yang, Y., et al. (2024) Pd-Catalyzed Divergent Site-Selective Difluoromethylation and Difluoromethylcarbonylation of Aryl Sulfonium Salts. ACS Catalysis, 14, 13557-13566. [Google Scholar] [CrossRef
[38] Chen, X., Liu, Y., Zhang, S., Li, Y., Zhou, X., Yu, X., et al. (2024) A Difluoromethylation Reagent: Access to Difluoromethyl Arenes through Palladium Catalysis. Organic Letters, 26, 6024-6029. [Google Scholar] [CrossRef] [PubMed]
[39] Tu, G., Wang, D., Yuan, C., Zhang, J. and Zhao, Y. (2020) Palladium-Catalyzed Para-Selective Difluoromethylation of Arene Esters. The Journal of Organic Chemistry, 85, 10740-10749. [Google Scholar] [CrossRef] [PubMed]
[40] Chen, X., Lu, H., Chen, C., Zeng, R., Wang, D., Shi, C., et al. (2022) Palladium-Catalyzed Gem-Difluoroallylation Reaction between Aryltributyltin and Bromodifluoromethylated Alkenes. The Journal of Organic Chemistry, 87, 2935-2946. [Google Scholar] [CrossRef] [PubMed]
[41] Choi, K., Mormino, M.G., Kalkman, E.D., Park, J. and Hartwig, J.F. (2022) Palladium-Catalyzed Aryldifluoromethylation of Aryl Halides with Aryldifluoromethyl Trimethylsilanes. Angewandte Chemie International Edition, 61, e202208204. [Google Scholar] [CrossRef] [PubMed]