美国科罗拉多州立大学Andrew McNally和Robert S. Paton研究组开发出了磷介导的吖嗪（azine）的C-H氟烷基化sp2-sp3偶联反应。该项研究成果发表在2021年4月28日出版的《自然》上。
氟烷基官能团深刻地影响药物的物理性质，并从各个方面影响它们的药代动力学和药效学特征。候选药物中越来越多地含有CF3和CF2H基团，而农用化学发展的趋势同样表明，氟烷基化效应可转化为在人类、昆虫和植物中的应用。新的氟烷基化反应无疑加速了这一趋势；然而，在复杂的药物类分子中，将C-H键直接转化为C-CF2X (X = F或H)基团的方法却很少。对于吡啶这种药物中最常见的杂环芳烃，只有一种方法，即通过氟烷基自由基，可以在药物开发过程中遇到的复杂结构中实现吡啶C-H氟烷基化。
有鉴于此，课题组人员开发了一套常规条件下稳定的氟烷基膦，可以直接将吡啶构建模块、类药物片段和药物中的C-H键转化为氟烷基衍生物。这一方法不需要预先安装的官能团或定位基团，且该反应可耐受多种空间和电子分布上不同的吡啶，并且在大多数情况下对4-位具有极高的选择性。进一步研究表明，该反应先形成磷盐，然后进行sp2-sp3磷配体偶联，这是一种尚未开发的C–C键形成方式。
附：英文原文
Title: Phosphorus-mediated sp 2 - sp 3 couplings for C–H fluoroalkylation of azines
Author: Xuan Zhang, Kyle G. Nottingham, Chirag Patel, Juan V. Alegre-Requena, Jeffrey N. Levy, Robert S. Paton, Andrew McNally
Issue&Volume: 2021-04-28
Abstract: Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence virtually all metrics associated with their pharmacokinetic and pharmacodynamic profiles. Drug candidates increasingly contain CF3 and CF2H groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect, and plant life. New fluoroalkylation reactions have undoubtedly stimulated this uptake; however, methods that directly convert C–H bonds into C–CF2X (X = F or H) groups in complex drug-like molecules are rare. For pyridine, the most common aromatic heterocycle in pharmaceuticals, only one approach, via fluoroalkyl radicals, is viable for pyridyl C–H fluoroalkylation in the elaborate structures encountered during drug development. Here, we have developed a set of bench-stable fluoroalkylphosphines that directly convert the C–H bonds in pyridine building blocks, drug-like fragments, and pharmaceuticals into fluoroalkyl derivatives. No pre-installed functional groups or directing groups are required; the reaction tolerates a variety of sterically and electronically distinct pyridines and is exclusively selective for the 4-position in most cases. The reaction proceeds via initial phosphonium salt formation followed by sp2-sp3 phosphorus ligand-coupling, an underdeveloped manifold for C–C bond formation.
DOI: 10.1038/s41586-021-03567-3
Source: https://www.nature.com/articles/s41586-021-03567-3