普林斯顿大学David W. C. MacMillan团队揭示了通过自由基交叉偶联推广芳烃CH烷基化反应。2025年3月24日出版的《自然》杂志发表了这项成果。

在此，研究组报告了一种新策略的应用，用于不同杂交自由基的选择性耦合，研究组称之为动态轨道选择。这种机制模式克服了Friedel-Crafts烷基化的常见限制，通过原位形成两种不同的自由基，随后根据其各自的结合特性由铜基催化剂区分。因此，该课题组研究人员在此证明了天然芳烃C直接烷基化的一般和高度模块化反应。氢键以丰富的良性醇和羧酸为烷基化剂。最终，该解决方案克服了在后期将复杂的烷基支架引入高度复杂的药物支架的合成挑战，从而获得了广阔的新化学空间。基于潜在耦合机制的通用性，动态轨道选择有望成为一种广泛适用的耦合平台，用于进一步挑战涉及两种不同自由基的转化。

据悉，分子支架的高效和模块化多样化，特别是不同分子文库的合成，仍然是药物优化活动中的一个重大挑战。后期引入烷基片段是特别可取的，因为这些图案具有较高的sp³特征和结构的通用性考虑到它们在分子框架中的普遍性，C(sp²)氢键是有吸引力的多样化目标，尽管这一过程往往需要困难的预功能化或漫长的从头合成。传统上，芳烃的直接烷基化是通过采用Friedel-Crafts或路易斯酸反应条件来实现的。然而，这些方法的功能基耐受性差，选择性低，限制了它们在后期功能化和药物优化运动中的广泛实施。

附：英文原文

Title: Generalizing arene CH alkylations by radicalradical cross-coupling

Author: Grokopf, Johannes, Gopatta, Chawanansaya, Martin, Robert T., Haseloer, Alexander, MacMillan, David W. C.

Issue&Volume: 2025-03-24

Abstract: The efficient and modular diversification of molecular scaffolds, particularly for the synthesis of diverse molecular libraries, remains a significant challenge in drug optimization campaigns.1–3 The late-stage introduction of alkyl fragments is especially desirable due to the high sp3-character and structural versatility of these motifs.4 Given their prevalence in molecular frameworks, C(sp2)H bonds serve as attractive targets for diversification, though this process often requires difficult pre-functionalization or lengthy de novo syntheses. Traditionally, direct alkylations of arenes are achieved by employing Friedel–Crafts reaction conditions using strong Brnsted or Lewis acids.5,6 However, these methods suffer from poor functional group tolerance and low selectivity, limiting their broad implementation in late-stage functionalization and drug optimization campaigns. Herein, we report the application of a novel strategy for the selective coupling of differently hybridized radical species, which we term dynamic orbital selection. This mechanistic paradigm overcomes common limitations of Friedel-Crafts alkylations via the in situ formation of two distinct radical species, which are subsequently differentiated by a copper-based catalyst based on their respective binding properties. As a result, we demonstrate herein a general and highly modular reaction for the direct alkylation of native arene CH bonds using abundant and benign alcohols and carboxylic acids as the alkylating agents. Ultimately, this solution overcomes the synthetic challenges associated with the introduction of complex alkyl scaffolds into highly sophisticated drug scaffolds in a late-stage fashion, thereby granting access to vast new chemical space. Based on the generality of the underlying coupling mechanism, dynamic orbital selection is expected to be a broadly applicable coupling platform for further challenging transformations involving two distinct radical species.

DOI: 10.1038/s41586-025-08887-2

Source: https://www.nature.com/articles/s41586-025-08887-2