Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan.
Nat Commun. 2022 Nov 9;13(1):6505. doi: 10.1038/s41467-022-34176-x.
Regioselective transformations of tertiary amines, which are ubiquitously present in natural products and drugs, are important for the development of novel medicines. In particular, the oxidative α-C-H functionalisation of tertiary amines with nucleophiles via iminium cations is a promising approach because, theoretically, there is almost no limit to the type of amine and functionalisation. However, most of the reports on oxidative α-C-H functionalisations are limited to α-methyl-selective or non-selective reactions, despite the frequent appearance of α-methylene-substituted amines in pharmaceutical fields. Herein, we develop an unusual oxidative regiospecific α-methylene functionalisation of structurally diverse tertiary amines with alkynes to synthesise various propargylic amines using a catalyst comprising Zn salts and hydroxyapatite-supported Au nanoparticles. Thorough experimental investigations suggest that the unusual α-methylene regiospecificity is probably due to a concerted one-proton/two-electron transfer from amines to O on the Au nanoparticle catalyst, which paves the way to other α-methylene-specific functionalisations.
叔胺在天然产物和药物中普遍存在，其区域选择性转化对于新型药物的开发非常重要。特别是，通过亚胺阳离子使叔胺与亲核试剂发生氧化 α-C-H 官能化是一种很有前途的方法，因为从理论上讲，胺和官能团的类型几乎没有限制。然而，尽管在药物领域中经常出现α-亚甲基取代的胺，但大多数关于氧化 α-C-H 官能化的报道仅限于α-甲基选择性或非选择性反应。在此，我们开发了一种使用包含 Zn 盐和负载在羟基磷灰石上的 Au 纳米颗粒的催化剂，对结构多样的叔胺与炔烃进行不寻常的氧化区域选择性α-亚甲基官能化，以合成各种丙炔基胺。深入的实验研究表明，这种不寻常的α-亚甲基区域选择性可能是由于胺向 Au 纳米颗粒催化剂上的 O 发生协同的一质子/两电子转移，这为其他α-亚甲基特异性官能化开辟了道路。
