Ren Meng-Meng, Yang Yin, Wang Fei
State Key Laboratory of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University Weijin Rd. 94 Tianjin 300071 China
Chem Sci. 2025 Sep 22. doi: 10.1039/d5sc03780h.
The strategic incorporation of deuterium atoms into pharmaceutical compounds can profoundly influence their pharmacokinetic profiles and metabolic stability. This is particularly relevant for the ubiquitous N-methyl motif in bioactive molecules, where metabolic oxidation of the methyl group often represents a major pathway. Despite this potential, synthetic methods for the direct introduction of the N-CD group through C-H functionalization remain elusive. We report herein an iron-catalysed protocol for the synthesis of N-CD anilines through site-selective aromatic C-H amination. An iron-aminyl radical is proposed as the key intermediate that facilitates site-selective homolytic aromatic substitution (HAS) through chelating with basic functional groups, including amides, urea and carbamate. The resulting -amino products serve as versatile synthetic intermediates for valuable heterocycles. Importantly, the Weinreb amide proves effective as a directing group, offering the advantage of transforming into diverse carbonyl molecules.
将氘原子策略性地引入药物化合物中可深刻影响其药代动力学特征和代谢稳定性。这对于生物活性分子中普遍存在的N-甲基基序尤为重要，其中甲基的代谢氧化往往是主要途径。尽管有这种潜力，但通过C-H官能化直接引入N-CD基团的合成方法仍然难以捉摸。我们在此报告一种通过位点选择性芳族C-H胺化合成N-CD苯胺的铁催化方案。提出铁-氨基自由基作为关键中间体，通过与包括酰胺、尿素和氨基甲酸酯在内的碱性官能团螯合来促进位点选择性均裂芳族取代（HAS）。所得的α-氨基产物作为有价值杂环的通用合成中间体。重要的是，Weinreb酰胺被证明是一种有效的导向基团，具有转化为多种羰基分子的优势。
