Geri Jacob B, Wade Wolfe Michael M, Szymczak Nathaniel K
Department of Chemistry , University of Michigan , 930 N. University , Ann Arbor , Michigan 48109 , United States.
J Am Chem Soc. 2018 Aug 1;140(30):9404-9408. doi: 10.1021/jacs.8b06093. Epub 2018 Jul 24.
The difluoromethyl group (R-CFH) 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-CFH starting materials to expose nucleophilic Ar-CF synthons represents an unexplored, yet promising route to construct benzylic Ar-CF-R linkages. Here we show that the combination of a Brønsted superbase with a weak Lewis acid enables deprotonation of Ar-CFH groups and capture of reactive Ar-CF fragments. This route provides access to isolable and reactive Ar-CF 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-CF-R) linkages, which are useful lipophilic and metabolically resistant replacements for benzylic linkages in medicinal chemistry.
二氟甲基（R-CFH）赋予药物分子理想的药代动力学性质，并且通常作为一个不宜进一步修饰的末端官能团被作为目标。将广泛可得的Ar-CFH起始原料去质子化以暴露出亲核性的Ar-CF合成子，这代表了一条构建苄基Ar-CF-R键的尚未探索但很有前景的途径。在此我们表明，布朗斯特超强碱与弱路易斯酸的组合能够使Ar-CFH基团去质子化并捕获活性Ar-CF片段。这条途径提供了获得可分离且具反应性的Ar-CF合成子的方法，这些合成子在室温下能与多种亲电试剂发生反应。该方法在亲电试剂和二氟甲基（杂）芳烃方面都具有高度通用性，并且可直接应用于苄基二氟亚甲基（Ar-CF-R）键的合成，这些键在药物化学中是用于替代苄基键的有用的亲脂性且代谢稳定的基团。
