A general strategy for C(sp(3))-H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor.
A general strategy for C(sp(3))-H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor.
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DOI：
10.1038/s41467-021-27165-z
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发表时间：
2021-11-29
影响因子：
16.6
通讯作者：
Doyle AG
中科院分区：
文献类型：
--
作者：
Leibler IN;Tekle-Smith MA;Doyle AG
光氧化还原催化提供了许多 C(sp3)-H 官能化方法，可以通过碳中心自由基进行选择性氧化和 C(sp3)-C 键形成。虽然高度可行，但以碳为中心的自由基的官能化很大程度上是由亲电试剂介导的。值得注意的是，亲核试剂代表了丰富且实用的试剂类别，激发了开发通用亲核试剂 C(sp3)–H 官能化策略的兴趣。在这里，我们描述了一种通过顺序氢原子转移（HAT）和氧化自由基-极性交叉将 C(sp3)-H 键转化为碳正离子的策略。所得碳正离子被多种亲核试剂（包括卤化物、水、醇、硫醇、富电子芳烃和叠氮化物）官能化，以形成不同的键。机理研究表明，HAT 由甲基自由基介导，甲基自由基是一种先前未开发的 HAT 试剂，其极性与光氧化还原催化中使用的许多试剂不同，为后期 C(sp3)-H 功能化提供了新的位点选择性。当碳基单元在光氧化还原催化中功能化时，通常使用亲电子偶联配偶体，以使两个片段的极性适当匹配。在这里，作者展示了一种通用方法，通过连续的氢原子转移和氧化自由基-极性交叉来代替使用亲核偶联伙伴，这种偶联伙伴更便宜且通常更简单。
Photoredox catalysis has provided many approaches to C(sp3)–H functionalization that enable selective oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp3)–H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical—a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis—enabling new site-selectivity for late-stage C(sp3)–H functionalization. When carbon-based units are functionalized in photoredox catalysis, electrophilic coupling partners are often used, such that the polarities of the two fragments are appropriately matched. Here the authors show a generalized methodology to instead use nucleophilic coupling partners, which are cheaper and often simpler, via successive hydrogen atom transfer and oxidative radical-polar crossover.
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影响因子：
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通讯作者：
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