Johannes Großkopf, Chawanansaya Gopatta, Robert T. Martin, Alexander Haseloer, David W. C. MacMillan
{"title":"Generalizing arene C–H alkylations by radical–radical cross-coupling","authors":"Johannes Großkopf, Chawanansaya Gopatta, Robert T. Martin, Alexander Haseloer, David W. C. MacMillan","doi":"10.1038/s41586-025-08887-2","DOIUrl":null,"url":null,"abstract":"The efficient and modular diversification of molecular scaffolds, particularly for the synthesis of diverse molecular libraries, remains a notable challenge in drug optimization campaigns1–3. The late-stage introduction of alkyl fragments is especially desirable due to the high sp3 character and structural versatility of these motifs4. Given their prevalence in molecular frameworks, C(sp2)–H bonds serve as attractive targets for diversification, although this process often requires difficult prefunctionalization or lengthy de novo syntheses. Traditionally, direct alkylations of arenes are achieved by using Friedel–Crafts reaction conditions with strong Brønsted or Lewis acids5,6. However, these methods suffer from poor functional group tolerance and low selectivity, limiting their broad implementation in late-stage functionalization and drug optimization campaigns. Here we report the application of a new strategy for the selective coupling of differently hybridized radical species, which we term ‘dynamic orbital selection’. This mechanistic model 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 on the basis of their respective binding properties. As a result, we demonstrate here 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 groups 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. Using the concept of dynamic orbital selection distinct organic radical species can be differentiated, enabling direct coupling of aromatics with alcohols or carboxylic acids.","PeriodicalId":18787,"journal":{"name":"Nature","volume":"641 8061","pages":"112-121"},"PeriodicalIF":48.5000,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature","FirstCategoryId":"103","ListUrlMain":"https://www.nature.com/articles/s41586-025-08887-2","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
The efficient and modular diversification of molecular scaffolds, particularly for the synthesis of diverse molecular libraries, remains a notable challenge in drug optimization campaigns1–3. The late-stage introduction of alkyl fragments is especially desirable due to the high sp3 character and structural versatility of these motifs4. Given their prevalence in molecular frameworks, C(sp2)–H bonds serve as attractive targets for diversification, although this process often requires difficult prefunctionalization or lengthy de novo syntheses. Traditionally, direct alkylations of arenes are achieved by using Friedel–Crafts reaction conditions with strong Brønsted or Lewis acids5,6. However, these methods suffer from poor functional group tolerance and low selectivity, limiting their broad implementation in late-stage functionalization and drug optimization campaigns. Here we report the application of a new strategy for the selective coupling of differently hybridized radical species, which we term ‘dynamic orbital selection’. This mechanistic model 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 on the basis of their respective binding properties. As a result, we demonstrate here 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 groups 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. Using the concept of dynamic orbital selection distinct organic radical species can be differentiated, enabling direct coupling of aromatics with alcohols or carboxylic acids.
期刊介绍:
Nature is a prestigious international journal that publishes peer-reviewed research in various scientific and technological fields. The selection of articles is based on criteria such as originality, importance, interdisciplinary relevance, timeliness, accessibility, elegance, and surprising conclusions. In addition to showcasing significant scientific advances, Nature delivers rapid, authoritative, insightful news, and interpretation of current and upcoming trends impacting science, scientists, and the broader public. The journal serves a dual purpose: firstly, to promptly share noteworthy scientific advances and foster discussions among scientists, and secondly, to ensure the swift dissemination of scientific results globally, emphasizing their significance for knowledge, culture, and daily life.