State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, People's Republic of China.
Nat Commun. 2021 Jun 10;12(1):3536. doi: 10.1038/s41467-021-23887-2.
Asymmetric C(sp)-H functionalization is a persistent challenge in organic synthesis. Here, we report an asymmetric benzylic C-H acylation of alkylarenes employing carboxylic acids as acyl surrogates for the synthesis of α-aryl ketones via nickel and photoredox dual catalysis. This mild yet straightforward protocol transforms a diverse array of feedstock carboxylic acids and simple alkyl benzenes into highly valuable α-aryl ketones with high enantioselectivities. The utility of this method is showcased in the gram-scale synthesis and late-stage modification of medicinally relevant molecules. Mechanistic studies suggest a photocatalytically generated bromine radical can perform benzylic C-H cleavage to activate alkylarenes as nucleophilic coupling partners which can then engage in a nickel-catalyzed asymmetric acyl cross-coupling reaction. This bromine-radical-mediated C-H activation strategy can be also applied to the enantioselective coupling of alkylarenes with chloroformate for the synthesis of chiral α-aryl esters.
不对称 C(sp^2)-H 官能化在有机合成中是一个持久的挑战。在这里，我们报道了一种通过镍和光氧化还原双重催化，利用羧酸作为酰基替代物对烷基芳烃进行不对称苄基 C-H 酰化反应，以合成 α-芳基酮。该温和而直接的方法可以将各种原料羧酸和简单的烷基苯转化为具有高对映选择性的高价值的 α-芳基酮。该方法的实用性在具有药用相关性的分子的克级合成和后期修饰中得到了展示。机理研究表明，光催化生成的溴自由基可以进行苄位 C-H 裂解，从而激活烷基芳烃作为亲核偶联试剂，然后进行镍催化的不对称酰基交叉偶联反应。这种溴自由基介导的 C-H 活化策略也可以应用于烷基芳烃与氯甲酸酯的对映选择性偶联，以合成手性的 α-芳基酯。
