Zhang Pengpeng, Wang Jin, Robertson Zoe R, Newhouse Timothy R
Department of Chemistry, Yale University, 225 Prospect Street, PO Box 208107, New Haven, CT 06511, USA.
Angew Chem Int Ed Engl. 2022 May 23;61(22):e202200602. doi: 10.1002/anie.202200602. Epub 2022 Mar 30.
Heterocycles are widespread in pharmaceuticals but methods for their transition metal-catalyzed functionalization remain limited. This report describes a general, mild, and effective nickel-catalyzed benzylic allylation and benzylation of 14 types of heterocyclic aromatic compounds, including pyridines, pyrazines, pyrimidines, pyridazines, triazines, benzimidazoles, oxazoles, thiazoles, as well as 3,3-dimethyl-indoles. The exquisite selectivity for benzylic sites at the 2-position is hypothesized to be controlled by coordination of a heterocyclic nitrogen to Zn(TMP) subverting generally presumed pK 's of benzylic protons. Furthermore, the broad range of heterocyclic substrates, the diversity of electrophiles, and excellent functional group compatibility suggest its future application to synthesis of complex molecules and library diversification in drug discovery.
杂环化合物在药物中广泛存在，但过渡金属催化其官能化的方法仍然有限。本报告描述了一种通用、温和且有效的镍催化14种杂环芳香化合物的苄基烯丙基化和苄基化反应，这些化合物包括吡啶、吡嗪、嘧啶、哒嗪、三嗪、苯并咪唑、恶唑、噻唑以及3,3 - 二甲基吲哚。推测在2 - 位苄基位点的优异选择性是由杂环氮与Zn(TMP)的配位作用控制的，这颠覆了通常认为的苄基质子的pK值。此外，广泛的杂环底物、亲电试剂的多样性以及出色的官能团兼容性表明其在复杂分子合成和药物发现中的库多样化方面具有未来应用前景。
