Research Advances in the Synthetic Methodologies of N-Trifluoromethylamides

doi:10.6023/cjoc202409003

Abstract

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

Cite this article

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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Fig. & Tab. 28

Figure 1. Functional N-trifluoromethylamides compounds

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

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

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

Scheme 4. Synthesis of carbonyl fluoride under mild conditions

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

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

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

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

Scheme 9. Synthesis of the intermediate AgOCF3

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

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

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

Scheme 13. Derivatization of compound 49

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

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

Scheme 16. Azide of N-trifluoromethyl carbamoyl azides

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

Scheme 18. Photocatalytic synthesis of N-trifluoromethyl imidazolidinones

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

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

Scheme 21. Synthesis of N-trifluoromethylamides with steric groups

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

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

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

Scheme 25. Synthesis of N-trifluoromethyl succinimide

Scheme 26. Synthesis of reagent 108

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

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