Ghosh Subrata K, He Lizhe, Tang Zilu, Comito Robert J
The University of Houston, 4800 Calhoun Road, Houston, Texas 77004, United States.
J Org Chem. 2023 Nov 3;88(21):15209-15217. doi: 10.1021/acs.joc.3c01722. Epub 2023 Oct 24.
Basic amines show broad bioactivity and remain a promising source of new medicines. The direct photoalkylation of imines offers a promising strategy for complex amines. However, the lack of efficient imine photoreactivity hinders this reaction and remains a fundamental limitation in organic photochemistry. We report an efficient photoalkylation of imines that provides primary amines directly without protecting or leaving groups. The transformation effects C-H addition across -H imines under energy-transfer photocatalysis by a ketone. Our method is distinguished from organometallic, metal-catalyzed, and photoredox approaches to imine alkylation by its lack of protecting groups and its broad scope, which includes unactivated alkanes, protic substrates, basic amines, heterocycles, and ketone imines. We highlight this scope through the condensation and alkylation of two pharmaceutical ketones, providing complex amines succinctly. Our mechanistic analysis supports a three-step process, involving hydrogen-atom transfer to an imine triplet excited state, intersystem crossing, and radical recombination, with photocatalytic enhancement through energy transfer. We further show that -H imines are more photoreactive than -substituted imines, a distinction partially explained by sterics and side reactions. To fully explain this distinction, we introduce the thermodynamic parameter excited-state hydrogen-atom affinity, which is highly effective at predicting the photoreactivity of imines.
伯胺具有广泛的生物活性，仍然是新药的一个有前景的来源。亚胺的直接光烷基化反应为合成复杂胺类化合物提供了一种很有前景的策略。然而，亚胺缺乏有效的光反应活性阻碍了该反应，并且仍然是有机光化学中的一个基本限制。我们报道了一种亚胺的高效光烷基化反应，该反应无需保护基或离去基团即可直接生成伯胺。该转化反应通过酮在能量转移光催化下实现了对α - H亚胺的C - H加成。我们的方法与用于亚胺烷基化的有机金属、金属催化和光氧化还原方法不同，其特点是无需保护基且适用范围广泛，包括未活化的烷烃、质子性底物、伯胺、杂环化合物和酮亚胺。我们通过两种药物酮的缩合和烷基化反应突出了这一适用范围，简洁地合成了复杂胺类化合物。我们的机理分析支持一个三步过程，包括氢原子转移到亚胺三重态激发态、系间窜越和自由基重组，并通过能量转移实现光催化增强。我们进一步表明，α - H亚胺比α - 取代亚胺具有更高的光反应活性，这种差异部分由空间位阻和副反应解释。为了全面解释这种差异，我们引入了热力学参数激发态氢原子亲和力，它在预测亚胺的光反应活性方面非常有效。
