Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives
Abstract Difluorocarbene, an important reactive intermediate in organic synthesis, exhibits intriguing properties and synthetic versatility. However, great challenges in modulating reaction pathways limit its widespread application in synthetic chemistry. While metal-catalyzed difluorocarbene transf...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61947-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849235163840512000 |
|---|---|
| author | Jiuling Li Baofan Wang Taichen Liu Qinghong Wen Tongfei Jing Xiang Fu Yingming Pan Kai Wei Xiaoyu Zhou Wenhao Hu Zhenghui Kang |
| author_facet | Jiuling Li Baofan Wang Taichen Liu Qinghong Wen Tongfei Jing Xiang Fu Yingming Pan Kai Wei Xiaoyu Zhou Wenhao Hu Zhenghui Kang |
| author_sort | Jiuling Li |
| collection | DOAJ |
| description | Abstract Difluorocarbene, an important reactive intermediate in organic synthesis, exhibits intriguing properties and synthetic versatility. However, great challenges in modulating reaction pathways limit its widespread application in synthetic chemistry. While metal-catalyzed difluorocarbene transfer offers a promising strategy but remains a formidable challenge. Herein, we disclose a copper-mediated multicomponent reaction of amine, aldehyde and BrCF2CO2K for synthesis of α- aminoamide derivatives, wherein copper-difluorocarbene serve as carbonyl source. Control experiments and DFT calculations support the pathway initiated by formation of a copper-difluorocarbene from BrCF2CO2K, followed by nucleophilic attack of the amine to produce an ammonium ylide, interception of the ylide with imine, and defluorination via carbonyl migration. This transformation demonstrates broad substrate scope, accommodating not only aromatic aldehydes but also alkyl aldehydes and drug-modified arylamines, highlighting its synthetic applicability. Furthermore, the method provides a practical and ideal alternative to classical Ugi or Strecker reactions, circumventing the need for toxic cyanide salts or unstable isonitriles. |
| format | Article |
| id | doaj-art-b56701a38b4542c4bed4c9d5dea954b9 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b56701a38b4542c4bed4c9d5dea954b92025-08-20T04:02:54ZengNature PortfolioNature Communications2041-17232025-07-0116111010.1038/s41467-025-61947-zMulti-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivativesJiuling Li0Baofan Wang1Taichen Liu2Qinghong Wen3Tongfei Jing4Xiang Fu5Yingming Pan6Kai Wei7Xiaoyu Zhou8Wenhao Hu9Zhenghui Kang10School of Medical Sciences, Pingdingshan UniversityZhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of SciencesSchool of Medical Sciences, Pingdingshan UniversityZhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of SciencesZhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of SciencesSchool of Pharmaceutical Sciences, Sun Yat-sen UniversitySchool of Chemistry and Pharmaceutical Sciences, Guangxi Normal UniversitySchool of Medical Sciences, Pingdingshan UniversitySchool of Pharmaceutical and Chemical Engineering, Taizhou UniversitySchool of Pharmaceutical Sciences, Sun Yat-sen UniversityZhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of SciencesAbstract Difluorocarbene, an important reactive intermediate in organic synthesis, exhibits intriguing properties and synthetic versatility. However, great challenges in modulating reaction pathways limit its widespread application in synthetic chemistry. While metal-catalyzed difluorocarbene transfer offers a promising strategy but remains a formidable challenge. Herein, we disclose a copper-mediated multicomponent reaction of amine, aldehyde and BrCF2CO2K for synthesis of α- aminoamide derivatives, wherein copper-difluorocarbene serve as carbonyl source. Control experiments and DFT calculations support the pathway initiated by formation of a copper-difluorocarbene from BrCF2CO2K, followed by nucleophilic attack of the amine to produce an ammonium ylide, interception of the ylide with imine, and defluorination via carbonyl migration. This transformation demonstrates broad substrate scope, accommodating not only aromatic aldehydes but also alkyl aldehydes and drug-modified arylamines, highlighting its synthetic applicability. Furthermore, the method provides a practical and ideal alternative to classical Ugi or Strecker reactions, circumventing the need for toxic cyanide salts or unstable isonitriles.https://doi.org/10.1038/s41467-025-61947-z |
| spellingShingle | Jiuling Li Baofan Wang Taichen Liu Qinghong Wen Tongfei Jing Xiang Fu Yingming Pan Kai Wei Xiaoyu Zhou Wenhao Hu Zhenghui Kang Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives Nature Communications |
| title | Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives |
| title_full | Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives |
| title_fullStr | Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives |
| title_full_unstemmed | Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives |
| title_short | Multi-component reactions via copper(I) difluorocarbene as carbonyl source for constructing α—aminoamide derivatives |
| title_sort | multi component reactions via copper i difluorocarbene as carbonyl source for constructing α aminoamide derivatives |
| url | https://doi.org/10.1038/s41467-025-61947-z |
| work_keys_str_mv | AT jiulingli multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT baofanwang multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT taichenliu multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT qinghongwen multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT tongfeijing multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT xiangfu multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT yingmingpan multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT kaiwei multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT xiaoyuzhou multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT wenhaohu multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives AT zhenghuikang multicomponentreactionsviacopperidifluorocarbeneascarbonylsourceforconstructingaaminoamidederivatives |