Sun Chao, Shen Yinpu, Li Heyin, Wang Zhen, Li Yifan, Huang Mengjun, Zou Zhenlei, Liu Jing, Liu Ao, Pan Yi, Zhang Weigang, Wang Yi
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, Collaborative Innovation Center of Advanced Microstructures, School of Chemistry and Chemical Engineering, Nanjing University Nanjing 210023 China
Chem Sci. 2025 Aug 6. doi: 10.1039/d5sc02691a.
The difluoromethyl group (CFH) has garnered significant interest in medicinal chemistry owing to its unique biochemical and physicochemical properties. Its deuterated counterpart (CFD), building on the established utility of CFH, exhibits multifaceted potential for advancing biomedical research and therapeutic development. While the incorporation of the difluoromethyl group (CFH) into drug molecules has matured, efficient installation of its deuterated counterpart (CFD) remains a formidable challenge in medicinal chemistry. This study reports a novel (deuterio)difluoromethyl imidazolate reagent IMDN-SOCFX (X = D, H), which is used to successfully construct various highly selective (deuterio)difluoromethyl compounds in the form of (deuterio)difluoromethyl radicals while maintaining high deuteration rates, achieving >99% isotopic purity in deuterium incorporation. The reagent enables precise CFD and CFH installation in natural products and synthetic bioactive compounds, showing broad substrate compatibility. This establishes a robust deuteration platform for drug discovery.
二氟甲基（CFH）因其独特的生化和物理化学性质而在药物化学领域引起了广泛关注。其氘代类似物（CFD）在CFH已确立的效用基础上，在推进生物医学研究和治疗开发方面展现出多方面的潜力。虽然将二氟甲基（CFH）引入药物分子的方法已经成熟，但在药物化学中，有效引入其氘代类似物（CFD）仍然是一项艰巨的挑战。本研究报道了一种新型的（氘代）二氟甲基咪唑酸酯试剂IMDN-SOCFX（X = D，H），该试剂用于以（氘代）二氟甲基自由基的形式成功构建各种高选择性的（氘代）二氟甲基化合物，同时保持高氘代率，在氘掺入中实现>99%的同位素纯度。该试剂能够在天然产物和合成生物活性化合物中精确引入CFD和CFH，显示出广泛的底物兼容性。这为药物发现建立了一个强大的氘代平台。
