Kawai Koki, Usui Mai, Ikawa Sota, Hoshiya Naoyuki, Kishikawa Yosuke, Shibata Norio
Department of Nanopharmaceutical Sciences, Nagoya Institute of Technology Gokiso, Showa-ku Nagoya 466-8555 Japan
Department of Engineering, Nagoya Institute of Technology Gokiso, Showa-ku Nagoya 466-8555 Japan.
Chem Sci. 2025 Jan 13;16(6):2830-2836. doi: 10.1039/d4sc07788a. eCollection 2025 Feb 5.
In this study, we explore the potential of the difluoro(trifluoromethoxy)methyl group, CF-O-CF, an underexplored but promising structural analog of the trifluoromethoxy group (OCF). This moiety offers unique electronic properties and enhanced chemical stability due to its multiple C-F bonds, along with the added advantage of C-O bond cleavage, making it an attractive option in fluorine chemistry. We have succeeded in synthesizing difluoro(trifluoromethoxy)methyl compounds radical amino- and hydroxy-trifluoromethoxylations of β,β-difluorostyrenes. Control experiments, including radical clock experiments, support a free radical mechanism. The synthetic utility of the resulting difluoro(trifluoromethoxy)methyl compounds is also demonstrated through transformations into bioactive analogs, such as pyrrole derivatives, fendiline analogs, and carpropamid analogs, highlighting their potential in drug development.
在本研究中，我们探索了二氟（三氟甲氧基）甲基基团（CF-O-CF）的潜力，它是三氟甲氧基（OCF）一种未被充分研究但很有前景的结构类似物。由于其多个碳氟键，该部分具有独特的电子性质和增强的化学稳定性，同时还具有碳氧键断裂的额外优势，使其成为氟化学中一个有吸引力的选择。我们成功地合成了二氟（三氟甲氧基）甲基化合物，通过β,β-二氟苯乙烯的自由基氨基化和羟基三氟甲氧基化反应。包括自由基钟实验在内的对照实验支持自由基机理。所得二氟（三氟甲氧基）甲基化合物的合成效用还通过转化为生物活性类似物得到证明，如吡咯衍生物、芬地林类似物和甲霜灵类似物，突出了它们在药物开发中的潜力。
