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 Brønsted 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 C−H 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.

分子支架的高效和模块化多样化，特别是对于不同分子文库的合成，仍然是药物优化活动中的重大挑战。^1-3烷基片段的后期引入特别可取，因为这些基序具有高 sp³ 特性和结构多功能性。⁴ 鉴于它们在分子框架中普遍存在，C（sp²）-H 键是有吸引力的多元化靶标，尽管这个过程通常需要困难的官能团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 反应条件使用强 Brønsted 或 Lewis 酸来实现的。^5,6 然而，这些方法存在官能团耐受性差和选择性低的问题，限制了它们在后期功能化和药物优化活动中的广泛实施。在此，我们报道了一种新策略在不同杂交自由基物种的选择性偶联中的应用，我们称之为动态轨道选择。这种机理范式通过原位形成两种不同的自由基物质克服了 Friedel-Crafts 烷基化的常见限制，随后根据它们各自的结合特性通过铜基催化剂进行区分。因此，我们在此展示了一种通用且高度模块化的反应，用于使用丰富且良性的醇和羧酸作为烷化剂对天然芳烃 C-H 键进行直接烷基化。最终，该解决方案克服了与在后期将复杂的烷基支架引入高度复杂的药物支架相关的合成挑战，从而获得了广阔的新化学空间。 基于潜在耦合机制的普遍性，动态轨道选择有望成为一个广泛适用的耦合平台，用于涉及两种不同自由基物种的进一步具有挑战性的转化。