Development of efficient domino and C–H functionalization reactions toward fluorine-containing N-heterocycles for Life Science

这项联合提出的研究重点是开发原子效率高的合成方法，以开发具有抗癌和抗病毒性能的新型含氟(二氢)喹唑啉和异喹啉杂环化合物。与传统的走走停停的合成方法相比，一锅策略和涉及一系列C-H活化的多米诺骨牌反应为合成具有生物活性的杂环化合物提供了巨大的潜力。通过降低成本、工作时间和浪费，多米诺骨牌和一锅法有助于实现经济和生态兼容的现代合成化学的目标。使用富含地球的金属作为催化剂或无金属方法，进一步促进了设想的合成的可持续性。另外，C-H键的后期直接转化可以极快、高效地构建靶标文库。一些新的(二氢)喹唑啉和异喹啉的合成方法(多步多米诺骨牌和C-H键活化法)意味着使用氟化苯胺作为起始化合物。然而，一种方便、直接、环保的氟苯胺类化合物的合成方法仍然很难找到。因此，这项建议的第一个目标是合成氟苯胺骨架，这将通过一种新的无金属两组分四步多米诺骨牌工艺进行。随后，从新型的高官能化氟苯胺出发，合成了不同的含氟(二氢)喹唑啉和异喹啉衍生物。因此，这项联合研究的第二个目标是开发通过多米诺或一锅反应和C-H键活化方法(3D金属催化，金属电催化)作为关键步骤的(二氢)喹唑和异喹啉的高效合成。设想的后期电光催化三氟甲基化得到的喹唑啉将显著扩大现有的文库，需要最少的时间努力。设计的C-H官能化和多米诺反应的反应范围将在优化的条件下进行研究，产品将用于抗癌和抗病毒研究。由于杂化化合物可能比母体化合物更有效，因此还计划合成新的(二氢)喹唑啉、异喹啉和精选青蒿素的杂化化合物。通过不同的连接体将选定的母体化合物进行杂交，将开发出用于鉴定有效的抗癌和抗病毒候选药物的基本先导结构(第三个目标)。

This joint proposed research is focused on the development of atom-efficient synthetic methods toward novel fluorine-containing (dihydro)quinazoline and isoquinoline heterocyclic compounds with anticancer and antiviral properties. One-pot strategies and domino reactions involving a sequence of C–H activations offer enormous potential for generating bioactive heterocyclic compounds with low manual efforts, in contrast to the conventional stop-and-go synthesis. By lowering costs, working time and waste, domino, and one-pot processes contribute to the aim of economically and ecologically compatible modern synthetic chemistry. The use of earth-abundant metals as catalysts or metal-free approaches contributes further to the sustainability of the envisioned syntheses. Additional direct late-stage transformations of C–H bonds permit an extremely fast and efficient construction of target libraries. Some of the envisioned synthetic methods (multi-step domino and C–H bond activation methods) toward new (dihydro)quinazolines and isoquinolines imply the use of fluorinated anilines as starting compounds. However, a convenient, straightforward and environmentally friendly synthetic method towards fluoroaniline compounds remains elusive. The first objective of this proposal is, therefore, the synthesis of fluoroaniline frameworks, which will be performed via a new metal-free two-component four-step domino process. Subsequently, different fluorine-substituted (dihydro)quinazoline and isoquinoline derivatives will be synthesized starting from novel highly functionalized fluoroanilines. Thus, the second objective of this joint research is the development of efficient syntheses of (dihydro)quinazolines and isoquinolines via domino or one-pot reactions and C–H bond activation methods (3d metal-catalyzed, metalla-electrocatalyzed) as key steps. The envisioned late-stage electrophotocatalyzed trifluoromethylation of obtained quinazolines will significantly enlarge the available library, requiring a minimum time effort. The reaction scope for the devised C–H functionalizations and domino reactions will be investigated under optimized conditions and the products will be studied against cancer and viruses. Since hybrids can be even more effective than the parent compounds, hybrids of new (dihydro)quinazolines, isoquinolines, and selected artemisinins are furthermore planned to be synthesized. By hybridizing selected parent compounds via various linkers, fundamental lead structures for identifying efficient anticancer and antiviral drug candidates will be developed (third objective).