二氟卡宾试剂在有机合成中的应用研究进展
Research Progress on the Application of Difluorocarbene Reagents in Organic Synthesis
DOI: 10.12677/jocr.2024.121007, PDF,   
作者: 洪雨微：浙江师范大学，化学与材料科学学院，浙江 金华
关键词: 二氟卡宾；二氟甲基化；有机合成；Difluorocarbene； Difluoromethylation； Organic Synthesis
摘要: 氟作为最强电负性的非金属元素，将其引入到有机分子中能赋予分子独特的物理化学性质。含氟及三氟甲基(CF3)的分子在药物化学领域已被广泛研究应用，近年来，含二氟甲基(CHF2)的分子也日益受到关注。研究显示，二氟甲基基团的引入不仅能增强药物的生物活性、改善其溶解度和生物可利用性，还能优化代谢稳定性和细胞膜透过性，降低毒性。本文总结了近年来二氟卡宾试剂在C-二氟甲基化、N-二氟甲基化、O-二氟甲基化以及S-二氟甲基化等反应中的应用。
Abstract: Fluorine, as the most electronegative non-metal element, imparts unique physicochemical properties to organic molecules when introduced into them. Molecules containing fluorine and trifluoromethyl (CF3) have been extensively studied and applied in the field of medicinal chemistry. In recent years, molecules containing difluoromethyl (CHF2) groups have also attracted increasing attention. Studies have shown that the introduction of difluoromethyl groups can not only enhance the biological activity of drugs, improve their solubility and bioavailability, but also optimize metabolic stability and cell membrane permeability, and reduce toxicity. This article summarizes the applications of difluorocarbene reagents in C-difluoromethylation, N-difluoromethylation, O-dif- luoromethylation, and S-difluoromethylation reactions in recent years.
文章引用：洪雨微. 二氟卡宾试剂在有机合成中的应用研究进展[J]. 有机化学研究, 2024, 12(1): 85-95. https://doi.org/10.12677/jocr.2024.121007

参考文献

[1] Zafrani, Y., Sod-Moriah, G., Yeffet, D., et al. (2019) CF2H, a Functional Group-Dependent Hydrogen-Bond Donor: Is It a More or Less Lipophilic Bioisostere of OH, SH, and CH3? Journal of Medicinal Chemistry, 62, 5628-5637. [Google Scholar] [CrossRef] [PubMed]
[2] Singh, A., Maqbool, M., Mobashir, M., et al. (2017) Corrigendum to ‘Dihydroorotate ‘Dehydrogenase: A Drug Target for the Development of Antimalarials’ [Eur. J. Med. Chem. 125 (2017) 640-651]. European Journal of Medicinal Chemistry, 128, 346-347. [Google Scholar] [CrossRef] [PubMed]
[3] Sessler, C.D., Rahm, M., Becker, S., et al. (2017) CF2H, a Hydrogen Bond Donor. Journal of the American Chemical Society, 139, 9325-9332. [Google Scholar] [CrossRef] [PubMed]
[4] Thompson, S., McMahon, S.A., Naismith, J.H., et al. (2016) Exploration of a Potential Difluoromethyl-Nucleoside Substrate with the Fluorinase Enzyme. Bioorganic Chemistry, 64, 37-41. [Google Scholar] [CrossRef] [PubMed]
[5] Müller, K., Faeh, C. and Diederich, F. (2007) Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science, 317, 1881-1886. [Google Scholar] [CrossRef] [PubMed]
[6] Zhou, Y., Wang, J., Gu, Z., et al. (2016) Next Generation of Fluorine-Containing Pharmaceuticals, Compounds Currently in Phase II-III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. Chemical Reviews, 116, 422-518. [Google Scholar] [CrossRef] [PubMed]
[7] Casero Jr., R.A. and Woster, P.M. (2009) Recent Advances in the Development of Polyamine Analogues as Antitumor Agents. Journal of Medicinal Chemistry, 52, 4551-4573. [Google Scholar] [CrossRef] [PubMed]
[8] Cheer, S.M., Prakash, A., Faulds, D. and Lamb, H.M. (2003) Pantoprazole. Drugs, 63, 101-132. [Google Scholar] [CrossRef] [PubMed]
[9] Takagi, H., Tanaka, K., Tsuda, H. and Kobayashi H., (2008) Clinical Studies of Garenoxacin. International Journal of Antimicrobial Agents, 32, 468-474. [Google Scholar] [CrossRef] [PubMed]
[10] Brahms, D.L.S. and Dailey, W.P. (1996) Fluorinated Carbenes. Chemical Reviews, 96, 1585-1632. [Google Scholar] [CrossRef] [PubMed]
[11] Wang, F., Luo, T., Hu, J., et al. (2011) Synthesis of Gem-Difluorinated Cyclopropanes and Cyclopropenes: Trifluoromethyltrimethylsilane as a Difluorocarbene Source. Angewandte Chemie International Edition, 50, 7153-7157. [Google Scholar] [CrossRef] [PubMed]
[12] Konno, T. and Kitazume, T. (1996) Novel Synthesis and Application of γ-Difluoromethylated Prop-2-Ynylic and Allylic Alcohols. Chemical Communications, 19, 2227-2228. [Google Scholar] [CrossRef] 
[13] Wang, F., Huang, W. and Hu, J. (2011) Difluoromethylation of O-, S-, N-, C-Nucleophiles Using Difluoromethyltri(N-Butyl)Ammonium Chloride as a New Difluorocarbene Source. Chinese Journal of Chemistry, 29, 2717-2721. [Google Scholar] [CrossRef] 
[14] Okusu, S., Tokunaga, E. and Shibata, N. (2015) Difluoromethylation of Terminal Alkynes by Fluoroform. Organic Letters, 17, 3802-3805. [Google Scholar] [CrossRef] [PubMed]
[15] Wang, J., Tokunaga, E. and Shibata, N. (2018) Highly C-Selective Difluoromethylation of β-Ketoesters by Using TMSCF2Br/Lithium Hydroxide/N, N, N-Trimethylhexadecan-1-Ammonium Bromide. Chemical Communications, 54, 8881-8884. [Google Scholar] [CrossRef] 
[16] Zhu, J., Zheng, H., Xue, X.S., et al. (2018) Carbon-Selective Difluoromethylation of Soft Carbon Nucleophiles with Difluoromethylated Sulfonium Ylide. Chinese Journal of Chemistry, 36, 1069-1074. [Google Scholar] [CrossRef] 
[17] Zhang, X.Y., Fu, X.P., Zhang, S. and Zhang, X.G. (2020) Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes. CCS Chemistry, 2, 293-304. [Google Scholar] [CrossRef] 
[18] Ando, M., Wada, T. and Sato, N. (2006) Facile One-Pot Synthesis of N-Difluoromethyl-2-Pyridone Derivatives. Organic Letters, 8, 3805-3808. [Google Scholar] [CrossRef] [PubMed]
[19] Prakash, G.K.S., Krishnamoorthy, S., Ganesh, S.K., et al. (2014) N-Difluoromethylation of Imidazoles and Benzimidazoles Using the Ruppert-Prakash Reagent Under Neutral Conditions. Organic Letters, 16, 54-57. [Google Scholar] [CrossRef] [PubMed]
[20] Thomoson, C.S., Wang, L. and Dolbier, W.R. (2014) Use of Fluoroform as a Source of Difluorocarbene in the Synthesis of N-CF2H Heterocycles and Difluoromethoxypyridines. Journal of Fluorine Chemistry, 168, 34-39. [Google Scholar] [CrossRef] 
[21] Li, Z., Dong, J., Yuan, Z., et al. (2018) One-Pot Synthesis of 3-Difluoromethyl Benzoxazole-2-Thiones. Organic Letters, 20, 6407-6410. [Google Scholar] [CrossRef] [PubMed]
[22] Huang, Y., Lin, Z., Chen, Y., et al. (2019) Transition-Metal-Free N-Difluoromethylation of Hydrazones with TMSCF2Br as the Difluoromethylation Reagent. Organic Chemistry Frontiers, 6, 2462-2466. [Google Scholar] [CrossRef] 
[23] Fier, P.S. and Hartwig, J.F. (2013) Synthesis of Difluoromethyl Ethers with Difluoromethyltriflate. Angewandte Chemie International Edition, 52, 2092-2095. [Google Scholar] [CrossRef] [PubMed]
[24] Xie, Q., Ni, C., Zhang, R., et al. (2017) Efficient Difluoromethylation of Alcohols Using TMSCF2Br as a Unique and Practical Difluorocarbene Reagent under Mild Conditions. Angewandte Chemie International Edition, 56, 3206-3210. [Google Scholar] [CrossRef] [PubMed]
[25] Van Bonn, P., Ke, J., Weike, C., et al. (2023) Mechanochemical Difluoromethylations of Alcohols. CCS Chemistry, 5, 1737-1744. [Google Scholar] [CrossRef] 
[26] 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]
[27] Liu, G.K., Qin, W.B., Li, X., et al. (2019) Difluoromethylation of Phenols and Thiophenols with the S-(Difluo-Romethyl)Sulfonium Salt: Reaction, Scope, and Mechanistic Study. The Journal of Organic Chemistry, 84, 15948-15957. [Google Scholar] [CrossRef] [PubMed]
[28] Peng, L., Wang, H. and Guo, C. (2021) Copper-Catalyzed Enantioselective Difluoromethylation of Amino Acids via Difluorocarbene. Journal of the American Chemical Society, 143, 6376-6381. [Google Scholar] [CrossRef] [PubMed]
[29] Song, H., Li, W., Wang, X., et al. (2023) Pentacoordinate Phosphoranes as Versatile Reagents in Fluoroalkylation Reactions. CCS Chemistry, 6, 165-176. [Google Scholar] [CrossRef] 
[30] Song, H., Li, J., Zhang, Y., et al. (2023) Photoredox Catalysis-Enabled C-H Difluoromethylation of Heteroarenes with Pentacoordinate Phosphorane as the Reagent. The Journal of Organic Chemistry, 88, 12013-12023. [Google Scholar] [CrossRef] [PubMed]

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