{"title":"将硼酰基自由基介导的卤素原子转移与铜催化相结合,实现酰胺与烷基卤化物烷基化的自由基策略。","authors":"Zhenhua Zhang, Lorenzo Poletti, Daniele Leonori","doi":"10.1021/jacs.4c05487","DOIUrl":null,"url":null,"abstract":"<p><p>Amide alkylation is a fundamental process in organic chemistry. However, the low nucleophilicity of amides means that divergent coupling with alkyl electrophiles is often not achievable. To circumvent this reactivity challenge, individual amine synthesis followed by amidation with standard coupling agents is generally required. Herein, we demonstrate a radical solution to this challenge by using an amine-borane complex and copper catalysis under oxidative conditions. While borohydride reagents are generally used as reducing agents in ionic chemistry, their conversion into amine-ligated boryl radicals diverts their reactivity toward halogen-atom transfer. This enables the conversion of alkyl halides into the corresponding alkyl radicals for amide functionalization via copper catalysis. The process is applicable to the <i>N</i>-alkylation of primary amides employing unactivated alkyl iodides and bromides, and it was also showcased in the late-state functionalization of both complex amide- and halide-containing drugs.</p>","PeriodicalId":49,"journal":{"name":"Journal of the American Chemical Society","volume":null,"pages":null},"PeriodicalIF":14.4000,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A Radical Strategy for the Alkylation of Amides with Alkyl Halides by Merging Boryl Radical-Mediated Halogen-Atom Transfer and Copper Catalysis.\",\"authors\":\"Zhenhua Zhang, Lorenzo Poletti, Daniele Leonori\",\"doi\":\"10.1021/jacs.4c05487\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Amide alkylation is a fundamental process in organic chemistry. However, the low nucleophilicity of amides means that divergent coupling with alkyl electrophiles is often not achievable. To circumvent this reactivity challenge, individual amine synthesis followed by amidation with standard coupling agents is generally required. Herein, we demonstrate a radical solution to this challenge by using an amine-borane complex and copper catalysis under oxidative conditions. While borohydride reagents are generally used as reducing agents in ionic chemistry, their conversion into amine-ligated boryl radicals diverts their reactivity toward halogen-atom transfer. This enables the conversion of alkyl halides into the corresponding alkyl radicals for amide functionalization via copper catalysis. The process is applicable to the <i>N</i>-alkylation of primary amides employing unactivated alkyl iodides and bromides, and it was also showcased in the late-state functionalization of both complex amide- and halide-containing drugs.</p>\",\"PeriodicalId\":49,\"journal\":{\"name\":\"Journal of the American Chemical Society\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":14.4000,\"publicationDate\":\"2024-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of the American Chemical Society\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1021/jacs.4c05487\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/1 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the American Chemical Society","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/jacs.4c05487","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/1 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
A Radical Strategy for the Alkylation of Amides with Alkyl Halides by Merging Boryl Radical-Mediated Halogen-Atom Transfer and Copper Catalysis.
Amide alkylation is a fundamental process in organic chemistry. However, the low nucleophilicity of amides means that divergent coupling with alkyl electrophiles is often not achievable. To circumvent this reactivity challenge, individual amine synthesis followed by amidation with standard coupling agents is generally required. Herein, we demonstrate a radical solution to this challenge by using an amine-borane complex and copper catalysis under oxidative conditions. While borohydride reagents are generally used as reducing agents in ionic chemistry, their conversion into amine-ligated boryl radicals diverts their reactivity toward halogen-atom transfer. This enables the conversion of alkyl halides into the corresponding alkyl radicals for amide functionalization via copper catalysis. The process is applicable to the N-alkylation of primary amides employing unactivated alkyl iodides and bromides, and it was also showcased in the late-state functionalization of both complex amide- and halide-containing drugs.
期刊介绍:
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