Catalytic alkylation of remote C-H bonds enabled by proton-coupled electron transfer.
Catalytic alkylation of remote C-H bonds enabled by proton-coupled electron transfer.
复制标题
DOI：
10.1038/nature19811
复制
发表时间：
2016-11-10
期刊：
影响因子：
64.8
通讯作者：
Knowles RR
中科院分区：
文献类型：
--
作者：
Choi GJ;Zhu Q;Miller DC;Gu CJ;Knowles RR
尽管在氢原子转移（HAT）催化方面取得了重大进展，但目前还没有能够均解N-烷基酰胺的强N-H键的分子HAT催化剂（图1a）。开发酰胺均解方案的动机源于所得酰胺基自由基的合成效用，其参与各种合成有用的转化，包括烯烃胺化和定向C-H键官能化。后一个过程是众所周知的霍夫曼-洛夫勒-弗雷塔格（HLF）反应的一个子集，它依赖于有利的键强度差异，使酰胺基能够从未活化的脂肪族C-H键中夺取H·（图1b）。虽然这些转化是有效的，但通常需要酰胺起始材料的氧化N-预官能化以实现有效的酰胺基生成。此外，由于这些N-活化基团通常被掺入最终产物中，因此这些方法通常不适于直接构建C-C键。在这里，我们报告了一种新的方法，克服了这些限制，通过质子耦合电子转移（PCET）事件的N-烷基酰胺的N-H键的均解。在该方案中，激发态铱光催化剂和弱磷酸盐碱协同作用，以在一致的基本步骤中从酰胺底物中除去质子和电子。所得到的酰胺基自由基中间体被证明能够促进随后的C-H提取和自由基烷基化步骤（图1c）。因此，这种C-H烷基化代表了HLF反应的一种新的催化变体，其利用简单的未官能化的酰胺来指导新的C-C键的形成。鉴于酰胺在药物和天然产物中的普遍存在，我们预计这种方法将简化含胺目标的合成和结构阐述。此外，这些研究进一步证明，协同PCET可以使普通有机官能团的均裂活化，这些官能团是使用传统的基于HAT的方法在能量上不可接近的。
Despite significant advances in hydrogen atom transfer (HAT) catalysis, there are currently no molecular HAT catalysts capable of homolyzing the strong N-H bonds of N-alkyl amides (Figure 1a). The motivation to develop amide homolysis protocols stems from the synthetic utility of the resulting amidyl radicals, which engage in a variety of synthetically useful transformations, including olefin amination and directed C-H bond functionalization. The latter process, a subset of the well-known Hofmann-Löffler-Freytag (HLF) reaction, relies on a favorable bond strength differential to enable amidyls to abstract H• from unactivated aliphatic C-H bonds (Figure 1b). While powerful, these transforms typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, as these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of C-C bonds. Here we report a new approach that overcomes these limitations by homolyzing the N-H bonds of N-alkyl amides through a proton-coupled electron transfer (PCET) event. In this protocol, an excited state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resulting amidyl radical intermediates are shown to be competent to promote subsequent C-H abstraction and radical alkylation steps (Figure 1c). As such, this C-H alkylation represents a novel catalytic variant of the HLF reaction that makes use of simple, unfunctionalized amides to direct the formation of new C-C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, these studies further demonstrate that concerted PCET can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.
登录
查看更多内容
影响因子：
15
作者：
Choi GJ;Knowles RR
通讯作者：
Knowles RR
影响因子：
62.1
作者：
WOLFF, ME
通讯作者：
WOLFF, ME
影响因子：
15
作者：
Horner, JH;Musa, OM;Newcomb, M
通讯作者：
Newcomb, M
影响因子：
6.6
作者：
Bortolamei, Nicola;Isse, Abdirisak A.;Gennaro, Armando
通讯作者：
Gennaro, Armando
影响因子：
16.6
作者：
Reece SY;Nocera DG
通讯作者：
Nocera DG