Nucleophilic Dearomatization of N‑Heteroaromatics Enabled by Lewis Acids and Copper Catalysis

Dearomative functionalization of heteroaromatics, a readily available chemical feedstock, is one of the most straightforward approaches for the synthesis of three-dimensional, chiral heterocyclic systems, important synthetic building blocks for both synthetic chemistry and drug discovery. Despite significant efforts, direct nucleophilic additions to heteroaromatics have remained challenging because of the low reactivity of aromatic substrates associated with the loss of aromaticity, as well the regio- and stereoselectivities of the reaction. Here we present a catalytic system that leads to unprecedented, high-yielding dearomative C-4 functionalization of quinolines with organometallics with nearly absolute regio- and stereoselectivities and with a catalyst turnover number (TON) as high as 1000. The synergistic action of the chiral copper catalyst, Lewis acid, and Grignard reagents allows us to overcome the energetic barrier of the dearomatization process and leads to chiral products with selectivities reaching 99% in most cases. Molecular modeling provides important insights into the speciation and the origin of the regio- and enantioselectivity of the catalytic process. The results reveal that the role of the Lewis acid is not only to activate the substrate toward a potential nucleophilic addition but also to subtly control the regiochemistry by preventing the C-2 addition from happening.作为一类易得的化工原料，杂芳烃（heteroaromatics）的去芳构化官能化反应是构建三维手性杂环体系的最简策略之一，而该类杂环体系正是合成化学与药物研发领域的关键合成砌块。尽管已有大量研究探索，直接对杂芳烃进行亲核加成仍颇具挑战：一方面，芳香底物因丧失芳香性而活性较低；另一方面，反应的区域选择性与立体选择性亦难以精准调控。本研究报道了一种催化体系，可实现喹啉与有机金属试剂间前所未有的高收率去芳构化C-4位官能化反应，该反应具备近乎绝对的区域与立体选择性，催化剂转化数（turnover number, TON）最高可达1000。手性铜催化剂、路易斯酸（Lewis acid）与格氏试剂（Grignard reagents）的协同作用，可有效克服去芳构化过程的能垒，最终生成的手性产物在多数情况下选择性可达99%。分子建模（molecular modeling）为解析该催化过程的物种分布、区域选择性与对映选择性起源提供了重要见解。研究结果表明，路易斯酸的作用不仅在于活化底物以促进亲核加成反应，更可通过抑制C-2位加成反应，精准调控反应的区域选择性。