The Difluoromethyl Group as a Masked Nucleophile: A Lewis Acid/Base Approach
The Difluoromethyl Group as a Masked Nucleophile: A Lewis Acid/Base Approach
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DOI：
10.1021/jacs.8b06093
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发表时间：
2018-08-01
影响因子：
15
通讯作者：
Szymczak, Nathaniel K.
中科院分区：
文献类型：
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作者：
Geri, Jacob B.;Wolfe, Michael M. Wade;Szymczak, Nathaniel K.
二氟甲基（R-CF2H）赋予药物分子理想的药代动力学特性，通常作为不能进一步修饰的末端官能团作为靶标。广泛使用的Ar-CF2H起始材料去质子化以暴露亲核的Ar-CF2-合成子，这是一条尚未开发但有希望构建苯基Ar-CF2- r键的途径。在这里，我们证明了Bronsted超碱与弱Lewis酸的结合可以使Ar-CF2H基团去质子化并捕获活性Ar-CF2-片段。这条途径提供了分离的和活性的Ar-CF2-合成子的途径，这些合成子可以在室温下与大量的亲电试剂反应。该方法在亲电和二氟甲基（杂）芳烃中都是高度通用的，可以直接应用于苯基二氟乙烯（Ar-CF2-R）键的合成，这是药物化学中有用的亲脂性和代谢抗性苯基键的替代品。
The difluoromethyl group (R-CF2H) imparts desirable pharmacokinetic properties to drug molecules and is commonly targeted as a terminal functional group that is not amenable to further modification. Deprotonation of widely available Ar-CF2H starting materials to expose nucleophilic Ar-CF2- synthons represents an unexplored, yet promising route to construct benzylic Ar-CF2-R linkages. Here we show that the combination of a Bronsted superbase with a weak Lewis acid enables deprotonation of Ar-CF2H groups and capture of reactive Ar-CF2- fragments. This route provides access to isolable and reactive Ar-CF2- synthons that react with a broad array of electrophiles at room temperature. The methodology is highly general in both electrophile and difluoromethyl (hetero)arene and can be applied directly to the synthesis of benzylic difluoromethylene (Ar-CF2-R) linkages, which are useful lipophilic and metabolically resistant replacements for benzylic linkages in medicinal chemistry.