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

本联合提议的研究重点是开发具有抗癌和抗病毒特性的新型含氟（二氢）喹唑啉和异喹啉杂环化合物的原子高效合成方法。与传统的走走停停合成相比，涉及一系列碳氢化合物活化的一锅策略和多米诺骨牌反应为低人工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，多米诺骨牌和一锅工艺有助于实现经济和生态相容的现代合成化学的目标。使用地球上丰富的金属作为催化剂或无金属的方法进一步有助于所设想的合成的可持续性。另外，C-H键的后期直接转化可以非常快速和有效地构建目标库。一些设想的合成新（二氢）喹唑啉和异喹唑啉的方法（多步多米诺骨牌法和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、直接和环保的合成氟苯胺化合物的方法仍然难以实现。因此，本提案的第一个目标是合成氟苯胺框架，这将通过一种新的无金属双组分四步多米诺骨牌工艺进行。随后，以新型高官能化氟苯胺为原料，合成不同的氟取代（二氢）喹唑啉和异喹啉衍生物。因此，本联合研究的第二个目标是开发通过多米诺骨牌反应或一锅反应和C-H键活化方法（三维金属催化，金属电催化）高效合成（二氢）喹唑啉和异喹唑啉的关键步骤。设想的后期光电催化得到的喹唑啉的三氟甲基化将大大扩大可用的文库，需要最小的时间努力。在优化的条件下，将研究所设计的C-H功能化和多米诺反应的反应范围，并研究产物对癌症和病毒的作用。由于杂合物甚至可能比母体化合物更有效，因此进一步计划合成新的（二氢）喹唑啉、异喹啉和选定的青蒿素的杂合物。通过各种连接物杂交选定的亲本化合物，将开发用于识别有效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).