Comparison of N-CF₃ and N-CH₃ Compounds

Compared to N-methyl (N-CH₃) substituted compounds, N-trifluoromethyl (N-CF₃) compounds exhibit higher lipophilicity, greater metabolic stability, and lower alkalinity. However, current methods for combining CF₃ with nitrogen are highly limited. As important building blocks for energetic materials and drug modifications, N-CF₃ secondary amines are prone to hydrolysis and conversion into isocyanates, making conventional column chromatography separation techniques unsuitable. This poses significant challenges in their synthesis and isolation.

Development of a Novel Synthetic Method for N-CF₃ Secondary Amines

Recently, Professor Wenbin Yi’s research group at Nanjing University of Science and Technology developed the first general method for synthesizing N-CF₃ secondary amines. This method utilizes triethylsilane (Et₃SiH) and silver fluoride (AgF) to generate hydrogen fluoride (HF) in situ, which reacts with isothiocyanates (R-NCS) and AgF to produce difluoromethylimines (R-N=CF₂). Subsequent addition yields the corresponding N-CF₃ secondary amines (Figure 1). The reaction achieves high conversion rates, and byproducts such as silver metal and triethylfluorosilane (Et₃SiF) can be easily removed via filtration and reduced pressure. This approach effectively addresses the synthesis and isolation challenges of N-CF₃ secondary amines, demonstrates excellent functional group compatibility, tolerates both strong electron-withdrawing and electron-donating aromatic substrates, enables the facile preparation of relatively unstable aliphatic products, and can be scaled up to gram-level production.

Application of N-CF₃ Secondary Amines and Advancement in N-CF₃ Sulfonamide Synthesis

N-CF₃ secondary amines, with their expandable N-H sites, serve as versatile precursors for constructing N-CF₃ amides, sulfonamides, and other derivatives. Professor Wenbin Yi’s research group further investigated the construction of N-CF₃ sulfonamides using N-CF₃ secondary amines as building blocks. Due to the strong electron-withdrawing nature and steric hindrance of the trifluoromethyl group, the activation of the N-H bond is challenging. The researchers discovered that using sulfonyl bromides with AgOTf to generate highly reactive RSO₂-OTf in situ was key to the reaction. These mixed anhydrides act as effective sulfonylating agents, facilitating the formation of N-S bonds with N-CF₃ secondary amines and enabling the synthesis of a series of N-CF₃ sulfonamide compounds. This also represents the first general method for synthesizing N-trifluoromethyl sulfonamides, applicable to the preparation of various trifluoromethylated pharmaceuticals, such as the antipyretic and analgesic drug phenacetin and the antibacterial agent sulfamethoxazole. Additionally, the synthesized perfluoro-tert-butyl compounds hold potential for applications in ¹⁹F MRI probes, contrast agents, and related fields.

Yi Wenbin is a Professor and Doctoral Supervisor at Nanjing University of Science and Technology, with long-term dedication to the research on synthetic principles, molecular design, and application technologies of fluorine-containing functional chemicals.

Over the past five years, he has led multiple national-level research projects, including the National Science and Technology Major Project, the National Defense Basic Strengthening Plan, the National Huoyan Action Plan Project, and three General Program grants from the National Natural Science Foundation of China. In terms of academic achievements, he has published over 30 papers as the first or corresponding author in prestigious international and domestic journals such as J. Am. Chem. Soc., Angew. Chem. Int. Ed., Nat. Commun., and CCS Chemistry. Additionally, he has been granted more than 20 invention patents, of which 3 have been scaled up for industrial production and 9 have been successfully commercialized.

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