N-三氟甲基酰胺合成方法的研究进展

doi:10.6023/cjoc202409003

摘要/Abstract

N-三氟甲基酰胺及其衍生物的分子含有可以带来独特物化性能的酰胺官能团和N-CF₃官能团, 在物理学和生命科学上具有重要的研究意义, 近年来越来越引起药物化学家、材料化学家和有机合成化学家的兴趣和重视. 然而从丰富易得的底物出发, 开发高效合成N-三氟甲基酰胺的新方法, 目前仍然是一个具有挑战性的科学问题, 正受到人们的持续关注. 在过去七十年中, 针对该类化合物的合成方法的开发取得了显著的发展, 这些合成方法可以归纳为以下四种策略: (1)电化学氧化氟化合成法, (2)应用(N-三氟甲基)二氟碳酰亚胺的合成砌块法, (3)应用异硫氰酸酯的合成砌块法, (4)氧化偶联法. 此综述专注于N-三氟甲基酰胺的合成研究, 总结了该类化合物的合成策略, 概述了近年来合成方法的发展现状, 对不同的合成策略进行了梳理与比较, 并且展望了未来可能的N-三氟甲基酰胺合成方法发展方向.

关键词: N-三氟甲基酰胺, 合成方法, 有机氟化学

Since N-trifluoromethylamide compounds contain both amide and N-CF₃ functional groups, which are of significant importance in physical and life science, N-trifluoromethylamides have become increasingly popular among pharmacists, materials chemists, and organic synthetic chemists in recent years. However, the development of new methods for efficient synthesis of N-trifluoromethylamides from abundant and readily available substrates remains a challenging scientific problem. Over the past 70 years, synthetic methodologies for these compounds have developed rapidly, utilizing four strategies: electrochemical oxidative fluorination, synthesis using the key synthetic building block (N-trifluoromethyl)difluoro-imide, synthesis using the building blocks isothiocyanates and oxidation coupling. This review focuses on the synthesis of N-trifluoromethylamides, summarizes the synthesis strategies of this kind of compounds, outlines the development status of synthesis methods in recent years, sorts out and compares various synthesis strategies, and anticipates the potential development direction for N-trifluoromethylamides synthesis methods in the future.

Key words: N-trifluoromethylamide, synthesis methods, organofluorine chemistry

引用此文

林天星, 刘天飞. N-三氟甲基酰胺合成方法的研究进展[J]. 有机化学, 2025, 45(6): 1995-2006.

Tianxing Lin, Tianfei Liu. Research Advances in the Synthetic Methodologies of N-Trifluoromethylamides[J]. Chinese Journal of Organic Chemistry, 2025, 45(6): 1995-2006.

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图/表 28

图1. 文献报道的功能性N-三氟甲基酰胺化合物 (A) Bioactive molecule reported in the literature; (B) functional material molecules

Figure 1. Functional N-trifluoromethylamides compounds

图式1. N-三氟甲基酰胺及其衍生物的合成策略

Scheme 1. Strategies for the synthesis of N-trifluoromethyl-amides and their derivatives

图式2. 全氟-N,N-二甲基乙酰胺的电化学合成法

Scheme 2. Electrochemical synthesis of perfluorine-N,N-dime-thylacetamides

图式3. 采用合成砌块(N-三氟甲基)二氟碳酰亚胺(12)的合成方法

Scheme 3. Synthesis method of building block (N-trifluoro-methyl) difluoroimide (12)

图式4. 温和条件碳酰氟合成

Scheme 4. Synthesis of carbonyl fluoride under mild conditions

图式5. (N-三氟甲基)二氟碳酰亚胺与羧酸的反应

Scheme 5. Reaction of (N-trifluoromethyl) difluoroimide with carboxylic acid

图式6. (N-三氟甲基)二氟碳酰亚胺与格氏试剂反应

Scheme 6. Reaction of (N-trifluoromethyl) difluoroimide with Grignard reagents

图式7. N-三氟甲基氨基甲酰氟的合成和可能机制

Scheme 7. Synthesis and the proposed mechanism of N-trifluo-romethyl carbamyl fluoride

图式8. N-三氟甲基氨基甲酰氟与格氏试剂的反应

Scheme 8. Reactions of N-trifluoromethyl carbamyl fluoride with Grignard reagents

图式9. 中间体AgOCF3的合成

Scheme 9. Synthesis of the intermediate AgOCF3

图式10. 通过中间体AgOCF3制备N-三氟甲基甲酰氟的合成法

Scheme 10. Synthetic method of N-trifluoromethyl formyl fluorides from intermediate AgOCF3

图式11. 通过中间体AgOCF3制备N-三氟甲基氨基甲酰氟的反应机理

Scheme 11. Reaction mechanism of synthesizing N-trifluoro-methyl carbamyl fluorides from intermediate AgOCF3

图式12. 镍催化N-三氟甲基氨基甲酰氟与炔基硅烷的交叉偶联反应

Scheme 12. Nickel-catalyzed cross-coupling reactions between N-trifluoromethyl carbamyl fluorides and alkynylsilanes

图式13. 化合物49的衍生化反应

Scheme 13. Derivatization of compound 49

图式14. NaBH4对N-三氟甲基氨基甲酰氟的还原反应

Scheme 14. Reductions of N-trifluoromethyl carbamyl fluoride by NaBH4

图式15. 氧化与还原条件对N-三氟甲基甲酰胺化学稳定性测试

Scheme 15. Tests on chemical stabilities of N-trifluoromethylformamides under redox conditions

图式16. N-三氟甲基氨基甲酰氟的叠氮化

Scheme 16. Azide of N-trifluoromethyl carbamoyl azides

图式17. 氨甲酰叠氮化物的光催化环化反应获得环N-三氟甲基脲

Scheme 17. Photocatalytic cyclization of carbamoyl azides to obtain cyclo-N-trifluoromethylureas

图式18. 光催化N-三氟甲基咪唑烷酮的合成

Scheme 18. Photocatalytic synthesis of N-trifluoromethyl imidazolidinones

图式19. 通过中间体N-三氟甲基胺基银与酰卤反应合成N-三氟甲基酰胺

Scheme 19. Synthesizing N-trifluoromethylamides by the reactions between the intermediate N-trifluoromethylamine silvers and the acyl halide derivatives

图式20. 通过关键中间体N-三氟甲基胺基银与酰卤反应合成N-三氟甲基酰胺的反应机理

Scheme 20. Reaction mechanism of synthesizing N-trifluoro-methylamides by the reactions between the intermediate N-tri-fluoromethylamine silvers and the acyl halide derivatives

图式21. 大位阻N-三氟甲基酰胺产物的合成

Scheme 21. Synthesis of N-trifluoromethylamides with steric groups

图式22. 通过3-氨基吡啶衍生氨基甲酸酯合成N-三氟甲基氨基甲酸硫酯和脲类化合物

Scheme 22. Synthesis of N-trifluoromethyl thiocarbamates and ureas from 3-aminopyridine-derived carbamates

图式23. 经历关键中间体硫代碳酸酰胺和三氟化溴反应的N-三氟甲基酰胺合成法

Scheme 23. Synthesis of N-trifluoromethylamides by the reaction between thiocarbonamides and bromine trifluoride

图式24. 氧化交叉偶联合成N-三氟甲基酰胺

Scheme 24. Oxidative cross-coupling for synthesizing N-tri-fluoromethylamides

图式25. N-三氟甲基琥珀酰亚胺合成法

Scheme 25. Synthesis of N-trifluoromethyl succinimide

图式26. 试剂108的合成

Scheme 26. Synthesis of reagent 108

图式27. 由试剂108和试剂112合成N-三氟甲基酰胺和衍生物

Scheme 27. Synthesis of N-trifluoromethylamides and derivatives from reagent 108 and reagent 112

参考文献 38

[1]	Xue, D.-X.; Wang, Q.; Bai, J. Coord. Chem. Rev. 2019, 378, 2.
[2]	Schneider, N.; Lowe, D. M.; Sayle, R. A.; Tarselli, M. A.; Landrum, G. A. J. Med. Chem. 2016, 59, 4385.
[3]	Scattolin, T.; Bouayad-Gervais, S.; Schoenebeck, F. Nature 2019, 573, 102.
[4]	Zivkovic, F. G.; Wycich, G.; Liu, L.; Schoenebeck, F. J. Am. Chem. Soc. 2024, 146, 1276.
[5]	Leo, A.; Hansch, C.; Elkins, D. Chem. Rev. 1971, 71, 525.
[6]	Sahu, K. K.; Ravichandran, V.; Mourya, V. K.; Agrawal, R. K. Med. Chem. Res. 2007, 15, 418.
[7]	Liu, J.; Parker, M. F. L.; Wang, S.; Flavell, R. R.; Toste, F. D.; Wilson, D. M. Chem 2021, 7, 2245.
[8]	Ikawa, M.; Lohith, T. G.; Shrestha, S.; Telu, S.; Zoghbi, S. S.; Castellano, S.; Taliani, S.; Da Settimo, F.; Fujita, M.; Pike, V. W.; Innis, R. B. J. Nucl. Med. 2017, 58, 320.
[9]	Tao, M.; Qian, J.; Chen, Z.; An, L.-K.; Wilson, D. M.; Liu, J. J. Org. Chem. 2023, 88, 15237.
[10]	Jäger, U.; Schwab, M.; Sundermeyer, W. Chem. Ber. 1986, 119, 1127.
[11]	Jacques, V.; Dumas, S.; Sun, W.; Troughton, J. S. Investigative Radiology 2010, 45, 613.
[12]	Lentz, D.; Brüdgam, I.; Hartl, H. Angew. Chem. 1987, 99, 951.
[13]	Lutz, W.; Sundermeyer, W. Chem. Ber. 1979, 112, 2158.
[14]	Yarovenko, N. N.; Vasil'eva, A. S. Zhurnal Obshchei Khimii 1958, 28, 2502
[15]	Mamone, M.; Morvan, E.; Milcent, T.; Ongeri, S.; Crousse, B. J. Org. Chem. 2015, 80, 1964.
[16]	Cao, T.; Retailleau, P.; Milcent, T.; Crousse, B. Chem. Commun. 2021, 57, 10351.
[17]	Young, J. A.; Simmons, T. C.; Hoffmann, F. W. J. Am. Chem. Soc. 1956, 78, 5637.
[18]	Ignat’ev, N. V.; Schmidt, M.; Heider, U.; Kucherina, A.; Sartori, P.; Helmy, F. M. J. Fluorine Chem. 2002, 113, 201.
[19]	Fawcett, F. S.; Tullock, C. W.; Coffman, D. D. J. Am. Chem. Soc. 1962, 84, 4275.
[20]	DesMarteau, D. D.; Lu, C. J. Fluorine Chem. 2011, 132, 1194.
[21]	(a) Til'kunova, N. A.; Gontar, A. F.; Sizov, Y. A.; Bykhovskaya, É. G.; Knunyants, I. L. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Transl.) 1977, 26, 2214.
	(b) Til'kunova, N. A., Slota, S. I., Gontar', A. F. Sizov, Y. A; Knunyants, I. L. Russ. Chem. Bull. 1978, 27, 2518.
[22]	Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
[23]	Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
[24]	van der, Werf, A.; Hribersek, M.; Selander, N. Org. Lett. 2017, 19, 2374.
[25]	Sheppard, W. A. J. Am. Chem. Soc. 1965, 87, 4338.
[26]	Turksoy, A.; Scattolin, T.; Bouayad-Gervais, S.; Schoenebeck, F., Chem.-Eur. J. 2020, 26, 2183.
[27]	Kolomeitsev, A. A.; Vorobyev, M.; Gillandt, H. Tetrahedron Lett. 2008, 49, 449.
[28]	Marrec, O.; Billard, T.; Vors, J.-P.; Pazenok, S.; Langlois, B. R. J. Fluorine Chem. 2010, 131, 200.
[29]	Nielsen, C. D. T.; Zivkovic, F. G.; Schoenebeck, F. J. Am. Chem. Soc. 2021, 143, 13029.
[30]	Zivkovic, F. G.; Nielsen, C. D.-T.; Schoenebeck, F. Angew. Chem., Int. Ed. 2022, 61, e202213829.
[31]	Bouayad-Gervais, S.; Scattolin, T.; Schoenebeck, F. Angew. Chem., Int. Ed. 2020, 59, 11908.
[32]	Bouayad-Gervais, S.; Nielsen, C. D. T.; Turksoy, A.; Sperger, T.; Deckers, K.; Schoenebeck, F. J. Am. Chem. Soc. 2022, 144, 6100.
[33]	Turksoy, A.; Bouayad-Gervais, S.; Schoenebeck, F. Chem.-Eur. J. 2022, 28, e202201435.
[34]	Liu, J.; He, X.; Deng, L.; You, Y.; Lai, Y. Synthesis 2024, 56, 2118.
[35]	Hagooly, Y.; Gatenyo, J.; Hagooly, A.; Rozen, S. J. Org. Chem. 2009, 74, 8578.
[39]	Lu, Z.; Ju, M.; Wang, Y.; Meinhardt, J. M.; Martinez Alvarado, J. I.; Villemure, E.; Terrett, J. A.; Lin, S. Nature 2023, 619, 514.
[40]	Liu, S.; Yang, Y.; Liu, T. Aggregate 2024, 5, e543.
[41]	Kong, X.; Liang, Y.; Guo, Z.; Lin, T.; Liu, S.; Liu, Z.; Liu, T.; Cheng, J. P. ChemSusChem 2024, e202402041.
[42]	Zhu, H.; Gao, C.; Yu, T.; Xu, C.; Wang, M. Angew. Chem., Int. Ed. 2024, 63, e202400449.
[43]	Zhang, R. Z.; Zhang, R. X.; Wang, S.; Xu, C.; Guan, W.; Wang, M., Angew. Chem., Int. Ed. 2022, 61, e202110749.
[44]	Spennacchio, M.; Bernús, M.; Stanić, J.; Mazzarella, D.; Colella, M.; Douglas, J. J.; Boutureira, O.; Noël, T. Science 2024, 385, 991.
[36]	Zhang, Z.; He, J.; Zhu, L.; Xiao, H.; Fang, Y.; Li, C. Chin. J. Chem. 2020, 38, 924.
[37]	Liu, H.; He, X.; Chen, Z.; Zhang, J.; Fang, X.; Sun, Z.; Chu, W. Chem. Asian J. 2023, 18, e202300039.
[38]	Liu, S.; Huang, Y.; Wang, J.; Qing, F.-L.; Xu, X.-H. J. Am. Chem. Soc. 2022, 144, 1962.