Catalytic N‑Alkylation of (Hetero)Aromatic Amines and Tandem Annulation Reactions

A general and practical approach for N-alkylation of heteroaromatic amines with heteroaromatic alcohols is always challenging and rarely reported. Here, we designed and synthesized phosphine-free, robust, and efficient N,N-bidentate-Co(II) complexes for a universal N-alkylation of amines strategy. This present catalytic methodology can be applied to a wide range of substrates by varying alcohols, including aryl, aliphatic, acyclic, and cyclic groups, with heteroaromatic amines such as aminopyridine, 2-aminopyrimidine, and aminoquinoline to provide diverse monoalkylated organonitrogen compounds in good to excellent yields (108 examples). In addition, the utility of the developed catalytic protocol was also extended successfully for the dehydrogenative synthesis of biologically important quinoline derivatives (11 examples). Particularly, 8-aminoquinoline reacted differently with tandem N-alkylated-transfer hydrogenative byproduct (N-benzyl-1,2,3,4-tetrahydroquinolin-8-amine) was obtained, revealing the catalytic activity of the complex I. The reaction proceeded under environmentally benign conditions, which liberates water as the sole byproduct. Notably, a concise synthesis of acetylcholinesterase inhibitors (AChEIs) scaffolds as potential cognition enhancers illustrated the utility of the present protocol. Interestingly, various control and deuterium-labeled experiments were performed, suggesting that the reaction proceeds via the borrowing hydrogen pathway.杂芳族胺与杂芳族醇的通用实用型N-烷基化（N-alkylation）方法始终极具挑战性，且相关研究报道极为罕见。本文中，我们设计并合成了无膦、稳健且高效的N,N-双齿钴(II)（N,N-bidentate-Co(II)）配合物，用于构建普适性的胺类N-烷基化催化策略。该催化方法可适配多种底物，可兼容芳基、脂肪族、无环及环基等不同结构的醇类，与氨基吡啶、2-氨基嘧啶、氨基喹啉等杂芳族胺类反应后，可获得结构多样的单烷基化有机氮化合物，产率处于良好至优异水平（共108个反应实例）。此外，所开发的催化方案还成功拓展至具有生物活性的喹啉衍生物的脱氢合成领域，共包含11个反应实例。尤为特别的是，8-氨基喹啉（8-aminoquinoline）表现出独特的反应路径，生成了串联N-烷基化-转移氢化副产物（N-苄基-1,2,3,4-四氢喹啉-8-胺），由此证实了配合物I的催化活性。该反应在环境友好的条件下进行，仅产生水作为唯一副产物。尤为值得关注的是，利用本方案可简洁合成作为潜在认知增强剂的乙酰胆碱酯酶抑制剂（AChEIs）骨架，进一步彰显了该催化方案的应用价值。有趣的是，我们开展了多种对照实验与氘标记实验，结果表明该反应遵循借氢（borrowing hydrogen）路径进行。