This invention presents a groundbreaking method for meta-C-H functionalization using pyridine and quinoline-based directing groups. By overcoming selectivity issues and the need for prefunctionalized starting materials, this protocol enables efficient meta-C-H olefination and acetoxylation with excellent selectivity. The method's versatility is demonstrated across a wide substrate scope, including complex molecules and various substituted arenes. Additionally, the use of pyrimidine-based directing groups expands the scope of functionalization reactions beyond olefination and acetoxylation, offering a comprehensive solution for meta-C-H functionalization with broad applicability.
Figure (1) Schematic showing Template for Remote Meta-C-H Functionalization
The challenge lies in efficiently functionalizing inert C-H bonds in arenes to form C-C or C-X bonds, crucial for various applications. Traditional methods face selectivity issues, while transition metal-catalyzed reactions are limited by prefunctionalized starting materials. Additionally, achieving distal meta-C-H activation poses challenges due to macrocyclic intermediate formation and weak coordination. Thus, there's a pressing need for a robust directing group strategy to enable efficient meta-functionalization, overcoming coordination limitations and substrate specificity issues.
- Unique Strong σ-Coordination: Unlike prior methods relying on weak coordination, this approach capitalizes on robust σ-coordination between the directing group and the transition metal. This enhances reaction control, boosting selectivity & efficiency.
- Innovative Scaffold Design: The invention introduces a precisely crafted scaffold with sulfonyl linkers, optimizing the proximity between the directing group and the metal center. This design ensures accurate positioning of the catalyst, enabling effective meta-C-H activation across diverse substrates.
- Exceptional Selectivity: Through tailored engineering of pyridyl and quinoline- based directing groups, the method achieves outstanding selectivity for meta- functionalization.
- Versatility Across Substrates: The protocol accommodates a broad range of complex molecules and substituted arenes, demonstrating remarkable versatility. This expands its applicability in various fields, including pharmaceuticals and materials science.
The prototype for this invention involves a catalytic system utilizing transition metal catalysts such as palladium acetate, along with directing groups like quinoline or pyridine, sulfonyl linkers, ligands such as N-Ac-Gly-OH, and oxidants like silver acetate. The reactions are typically conducted in solvents like HFIP or DCE, under controlled temperature conditions ranging from 40°C to 100°C and at atmospheric pressure. The experimental setup ranges from small-scale benchtop vessels to larger reactors suitable for scale-up. Performance is evaluated based on parameters such as yield, selectivity, and reaction rate—where successful outcomes include high yields (typically above 75%) and strong monoselectivity (mono:di ratios exceeding 7:1).
The technology has been successfully validated in a laboratory environment through extensive experimentation. Multiple substrates have undergone meta-selective C–H functionalization using palladium-catalyzed processes in the presence of novel directing groups and sulfonyl linkers. The reactions have demonstrated high yields, excellent regioselectivity, and broad substrate applicability. This confirms the robustness and reproducibility of the method under standard lab-scale conditions. While no pilot-scale deployment has been reported, the chemistry is well-established for further development or optimization toward real-world applications.
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This technology accelerates drug development by enabling more efficient and selective synthesis, which can ultimately benefit public health. Its environmentally friendly approach reduces chemical waste and harmful byproducts, supporting sustainable practices. In materials science, it allows for the creation of precisely tailored compounds useful in advanced technologies. Collectively, these advantages can enhance industrial productivity and contribute to broader economic growth.
- Medicinal Chemistry: Facilitating the synthesis of pharmaceutical compounds.
- Crop Protection: Enhancing the development of agrochemicals for crop protection and enhancement.
- Material Sciences: Enabling the creation of specialized materials with tailored properties.
- Chemical Synthesis: Streamlining organic synthesis processes in chemical manufacturing.
- Biotechnology: Supporting research and development in biopharmaceuticals and biochemicals.
Geography of IP
Type of IP
201621029854
424544