Carbon Dioxide Activation Center (CADIAC), The Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus, Denmark.
Center for Materials Crystallography, Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus, Denmark.
J Am Chem Soc. 2021 Oct 27;143(42):17816-17824. doi: 10.1021/jacs.1c09170. Epub 2021 Oct 13.
Many commercial drugs, as well as upcoming pharmaceutically active compounds in the pipeline, display aliphatic carboxylic acids or derivatives thereof as key structural entities. Synthetic methods for rapidly accessing isotopologues of such compounds are highly relevant for undertaking critical pharmacological studies. In this paper, we disclose a direct synthetic route allowing for full carbon isotope replacement via a nickel-mediated alkoxycarbonylation. Employing a nickel pincer complex ([(NN)Ni-Cl]) in combination with carbon-13 labeled CO, alkyl iodide, sodium methoxide, photocatalyst, and blue LED light, it was possible to generate the corresponding isotopically labeled aliphatic carboxylates in good yields. Furthermore, the developed methodology was applied to the carbon isotope substitution of several pharmaceutically active compounds, whereby complete carbon-13 labeling was successfully accomplished. It was initially proposed that the carboxylation step would proceed via the formation of a nickellacarboxylate, generated by CO insertion into the Ni-alkoxide bond. However, preliminary mechanistic investigations suggest an alternative pathway involving attack of an open shell species generated from the alkyl halide to a metal ligated CO to generate an acyl Ni species. Subsequent reductive elimination involving the alkoxide eventually leads to carboxylate formation. An excess of the alkoxide was essential for obtaining a high yield of the product. In general, the presented methodology provides a simple and convenient setup for the synthesis and carbon isotope labeling of aliphatic carboxylates, while providing new insights about the reactivity of the NN nickel pincer complex applied.
许多商业药物，以及即将上市的药物管道中的活性化合物，都将脂肪族羧酸或其衍生物作为关键结构实体。快速获得此类化合物的同位素类似物的合成方法对于进行关键的药理学研究非常重要。在本文中，我们披露了一种直接的合成途径，通过镍介导的烷氧基羰基化作用可以实现完全的碳同位素取代。使用镍钳形配合物([(NN)Ni-Cl])与碳-13 标记的 CO、烷基碘化物、甲醇钠、光催化剂和蓝色 LED 光结合，就有可能以良好的收率生成相应的同位素标记的脂肪族羧酸酯。此外，所开发的方法学还应用于几种药物活性化合物的碳同位素取代，成功地完成了完全的碳-13 标记。最初提出的羧化步骤将通过 CO 插入 Ni-烷氧基键生成的镍-羧酸盐来进行。然而，初步的机理研究表明，涉及从烷基卤化物攻击与金属配位的 CO 生成酰基 Ni 物种的替代途径。随后涉及烷氧基的还原消除最终导致羧酸盐的形成。需要过量的烷氧基才能获得高产率的产物。总的来说，所提出的方法为脂肪族羧酸酯的合成和碳同位素标记提供了一种简单方便的方法，同时为所应用的 NN 镍钳形配合物的反应性提供了新的见解。
