Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA.
Medicine Design, Pfizer Inc, Groton, CT, USA.
Nat Chem. 2022 Jan;14(1):94-99. doi: 10.1038/s41557-021-00834-8. Epub 2022 Jan 5.
Reactions that enable carbon-nitrogen, carbon-oxygen and carbon-carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(II) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.
反应使碳-氮、碳-氧和碳-碳键的形成成为合成化学的核心。然而，为了在不强制反应条件的情况下实现这些转化，通常需要对底物进行预官能化。因此，直接偶联丰富的原料化学品的方法的发展对于快速构建复杂的分子支架是非常可取的。在这里，我们报道了一种铜介导的、在可见光照射下羧酸与各种亲核试剂的净氧化脱羧偶联。初步的机理研究表明，该反应中的相关发色团是原位组装的 Cu(II) 羧酸盐物种。我们提出可见光激发到配体到金属电荷转移 (LMCT) 态导致引发氧化交叉偶联的自由基脱羧过程。该反应适用于各种偶联试剂，包括复杂的药物分子，这表明这种交叉亲核试剂偶联策略将有助于快速合成化合物库，以发现新的药物制剂。
