New Methods for Site-Selective Trifluoromethylation of Aromatic Heterocycles

描述（由申请人提供）：含有三氟甲基官能团的杂环分子支架在制药工业靶向的生物活性化合物中越来越常见。从抗抑郁药到抗癌药物，各种化疗药物都成功地利用了三氟甲基的掺入，因为它们的存在引起了独特的性质。因此，化学学界一直致力于开发将三氟甲基安装到药学上相关的杂环支架中的化学方法。本研究旨在通过高通量筛选和机制分析相结合，开发和完善芳香杂环选择性三氟甲基化的新化学策略。高通量筛选将有效地测试和突破最近报道的限制，但不发达的三氟甲基化方案已被证明比以前的方法具有显着优势。DFT计算将与反应筛选一起进行，以开发基于基态衬底性质的反应性和位点选择性的预测模型。包括动力学分析和动力学同位素效应研究在内的机理研究将有助于更好地理解这一重要反应类别，从而进一步开发和发现相关过程。最后，拟议研究的长期目标是开发一套通用的实验程序，用于各种杂环类的高收率和高位点选择性的三氟甲基化。发展稳健

DESCRIPTION (provided by applicant): Heterocyclic molecular scaffolds containing the trifluoromethyl functional group have become increasingly common in biologically active compounds targeted by the pharmaceutical industry. Chemotherapeutics ranging from antidepressants to anticancer agents have successfully utilized the incorporation of trifluoromethyl groups due to the unique properties their presence elicits. For this reason, there has been a consistent drive within the chemical community towards the development of chemical methods for the installation of the trifluoromethyl group into pharmaceutically relevant heterocyclic scaffolds. The proposed research aims to develop and refine novel chemical strategies for site-selective trifluoromethylations of aromatic heterocycles through a combination of high-throughput screening and mechanistic analysis. High-throughput screening will efficiently test and push the limits of a recently reported, but underdeveloped trifluoromethylatio protocol that has been show to have significant advantages over previous methods. DFT calculations will be performed in tandem with reaction screens to develop a predictive model of reactivity and site-selectivity based on ground-state substrate properties. Mechanistic investigation involving kinetic analysis and kinetic isotope effect studies will lead to better understanding of this important reaction class, allowing for further development and the discovery of related processes. Finally, the long term goal of the proposed research is the development of a suite of general experimental procedures for the trifluoromethylation of a variety of heterocyclic classes in high yield with high site-selectivity. The development of robust chemical strategies for the selective installation of trifluoromethyl groups into pharmaceutically relevant scaffolds would have a significant and immediate impact on the medical community as trifluoromethyl- containing chemotherapeutics may be targeted more efficiently and in greater numbers by medicinal chemists and pharmaceutical industries.