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

用于生命科学的含氟氮杂环的高效多米诺骨牌和 CâH 官能化反应的开发

• 批准号: 535144216
• 负责人: Professor Dr. Lutz Ackermann
• 金额: --
• 依托单位: Institut für Organische und Biomolekulare Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/535144216?language=en
• 关键词: Development; efficient; domino; functionalization; reactions

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).

这项联合提出的研究集中在开发含氟的新型（二氢）喹啉唑啉和异喹啉异源化合物具有抗癌和抗病毒特性的新型合成方法上。与常规的停止和go合成相比，涉及一系列C – H激活的一台策略和多米诺反应为产生生物活性杂环化合物的巨大潜力。通过降低成本，工作时间和浪费，多米诺骨牌和一锅过程，有助于经济和生态兼容的现代合成化学的目标。用作催化剂或无金属方法的使用土质金属进一步有助于构成合成的可持续性。 C – H键的其他直接晚期转换允许目标库的快速和高效构建。一些设想的合成方法（多步多键和C – H键激活方法）朝向新的（二氢）喹啉唑啉和等喹啉，这意味着将氟化苯胺作为起始化合物的使用。但是，一种方便，直接且环保的合成方法，用于氟氨基化合物仍然难以捉摸。因此，该提案的第一个目的是氟氨基框架的合成，该框架将通过新的无金属两组分四步多米诺骨牌进行。随后，将从新型高度官能化的氟氨基素开始合成不同的氟取代（二氢）喹唑啉和异喹啉衍生物。这是这项联合研究的第二个目标是开发（二氢）喹唑啉和异喹啉的有效合成，通过多米诺或一汤匙反应以及C – H键激活方法（3D金属催化，金属 - 电蛋白含量）作为关键步骤。所设想的后期电催化的三氟甲基化获得的喹啉唑啉将大大增加可用的文库，需要最少的时间努力。在优化的条件下将研究设计的C – H功能化和多米诺反应的反应范围，并将研究产物针对癌症和病毒。由于杂化可以比父级化合物更有效，因此，新（二氢）喹啉唑啉，等喹啉的混合体以及通过各种连接器杂交所选的父型化合物的杂交素还可以通过各种接头结构来识别有效的抗药性药物和抗病毒药物候选者。