Photochemical Perfluoroalkylation with Pyridine N-Oxides: Mechanistic Insights and Performance on a Kilogram Scale.
Photochemical Perfluoroalkylation with Pyridine N-Oxides: Mechanistic Insights and Performance on a Kilogram Scale.
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DOI：
10.1016/j.chempr.2016.08.002
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发表时间：
2016-09-08
期刊：
影响因子：
23.5
通讯作者：
Stephenson CRJ
中科院分区：
文献类型：
--
作者：
Beatty JW;Douglas JJ;Miller R;McAtee RC;Cole KP;Stephenson CRJ
（杂）芳烃的直接三氟甲基化对制药工业具有重要意义。为此目的存在许多试剂，并在发现工作中被广泛使用；然而，这些试剂的步骤密集制备及其相应的成本导致这些方法在大规模应用中的使用很少。为了使直接三氟甲基化方法迅速过渡到大规模应用，非常需要进一步开发利用公吨规模上可获得的廉价CF3源的工艺。我们报道了吡啶n -氧化物衍生物与三氟乙酸酐协同使用，以促进高产和可扩展的三氟甲基化反应。关键的机制见解包括观察溶液中的电子供体-受体复合物以及对光子通量的高度依赖。这些观察结果最终导致了这种化学在千克规模上的应用，证明了这种试剂组合在制备应用中的实用性。近几十年来，氟掺入已成为药物合成技术的一个非常重要的特征。虽然已经为小规模的发现工作开发了许多方法，但直接的、真正可扩展的全氟烷基化通常仅限于涉及超化学计量量的铜的反应。为了尽量减少这些过程的相关环境成本，Stephenson和他的同事们展示了一种改进的全氟烷基化方法，该方法需要最少的催化剂负荷，并在千克规模上利用可见光。
The direct trifluoromethylation of (hetero)arenes is a process of high importance to the pharmaceutical industry. Many reagents exist for this purpose and have found widespread use in discovery efforts; however, the step-intensive preparation of these reagents and their corresponding cost have resulted in minimal use of these methods in large-scale applications. For the ready transition of direct trifluoromethylation methodologies to large-scale application, the further development of processes utilizing inexpensive CF3 sources available on a metric ton scale is highly desirable. We report the use of pyridine N-oxide derivatives in concert with trifluoroacetic anhydride to promote a high-yielding and scalable trifluoromethylation reaction. Key mechanistic insights include the observation of electron donor-acceptor complexes in solution as well as a high dependence on photon flux. These observations have culminated in the application of this chemistry on a kilogram scale, demonstrating the utility of this reagent combination for preparative applications. Fluorine incorporation has become a highly important feature of drug-synthesis technology in recent decades. Although a multitude of methods have been developed for small-scale discovery efforts, direct, truly scalable perfluoroalkylation has been generally limited to reactions involving superstoichiometric amounts of copper. In an effort to minimize the associated environmental cost of these processes, Stephenson and colleagues demonstrate an improved perfluoroalkylation method requiring minimal catalyst loadings and utilizing visible light on a kilogram scale.