单氟甲基化试剂研究进展：从单氟甲基化试剂到合成策略与应用
Research Progress in Monofluoromethylating Reagents: From Reagents to Synthetic Strategies and Applications
摘要: 单氟甲基(-CH2F)作为甲基的生物电子等排体及羟甲基的结构模拟物，在药物化学中占据重要地位。本文系统梳理了单氟甲基化试剂从1963年氟代乙酸乙酯的合成，到2026年光氧化还原开环氟磺酰化反应的发展历程，分析了现有试剂在合成路线、成本、安全性和底物适用范围等方面的不足。在此基础上，重点总结了三大合成策略的最新进展：其一，N-单氟甲基砌块模块化策略(包括可分离的N-CH2F氨基甲酰氟/硫代氨基甲酰氟，以及连续酰化–氟化方法)，实现了N-单氟甲基酰胺、甲酰胺、氨基甲酸酯和炔酰胺的高效构建；其二，烯烃单氟甲基化策略(涵盖钯催化氨基氟化、银催化自由基串联、钴肟/钴光催化、无光催化ATRA等多种模式)，实现了从苯乙烯到未活化烯烃的转化；其三，炔烃单氟甲基化策略(包括金催化条件驱动发散合成和光催化XAT介导的高Z/E选择性反应)，以及芳环过渡金属催化的交叉偶联策略(镍催化、铜催化等)。当前研究呈现出试剂创新、策略多样化、绿色化学与理性设计四大趋势，但仍面临发展普适性方法、实现复杂分子后期选择性修饰以及深入理解反应机理等挑战。
Abstract: The monofluoromethyl group (-CH2F) is a pivotal bioisostere of methyl and a structural mimic of hydroxymethyl in medicinal chemistry. This review traces the evolution of monofluoromethylating reagents from ethyl fluoroacetate (1963) to photoredox ring-opening fluorosulfonylation (2026), critiquing their limitations in synthetic routes, cost, safety, and scope. It then spotlights three key strategic advances: (i) modular NCH2F building blocks (isolable carbamoyl/thiocarbamoyl fluorides and sequential acylation–fluorination) for efficient access to Nmonofluoromethyl amides, formamides, carbamates, and alkynamides; (ii) alkene monofluoromethylation (Pd catalysis, Ag radical cascades, Co/photocatalysis, and photocatalystfree ATRA) enabling transformations from styrenes to unactivated alkenes; and (iii) alkyne monofluoromethylation (Aucatalyzed divergent synthesis and photocatalytic XAT with high Z/E selectivity), along with transition metalcatalyzed crosscoupling on arenes (Ni, Cu). Current trends—reagent innovation, strategic diversification, green chemistry, and rational design—are evident, yet challenges persist in developing general methods, achieving latestage selective modification of complex molecules, and elucidating reaction mechanisms.
文章引用：阿卜拉江·麦麦提敏, 阿布都热西提·阿布力克木. 单氟甲基化试剂研究进展：从单氟甲基化试剂到合成策略与应用[J]. 化学工程与技术, 2026, 16(3): 149-161. https://doi.org/10.12677/hjcet.2026.163015

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