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

• Applicants: Professor Dr. Lutz Ackermann; Professorin Dr. Svetlana Tsogoeva
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535144216

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).

• DFG Programme: Research Grants