Copper difluorocarbene-involved catalytic gem-difluoropropargylation
Abstract The use of metal for catalytic difluorocarbene transfer reactions has long been hindered by the lack of understanding of metal difluorocarbene chemistry, despite the potential implications for medicinal chemistry and advanced materials science. Here, we report a copper-catalyzed difluorocar...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59903-y |
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| author | Xin Zeng Shi-Ping Sun Hai-Yang Zhao Xingang Zhang |
| author_facet | Xin Zeng Shi-Ping Sun Hai-Yang Zhao Xingang Zhang |
| author_sort | Xin Zeng |
| collection | DOAJ |
| description | Abstract The use of metal for catalytic difluorocarbene transfer reactions has long been hindered by the lack of understanding of metal difluorocarbene chemistry, despite the potential implications for medicinal chemistry and advanced materials science. Here, we report a copper-catalyzed difluorocarbene transfer reaction via 1,1-migration of copper difluorocarbene, in contrast to the previous nucleophilic addition of copper difluorocarbene pathway. This reaction enables the development of a modular catalytic gem-difluoropropargylation reaction using a variety of simple and widely available potassium propiolates, terminal alkynes, and allyl/propargyl electrophiles to couple difluorocarbene, opening an avenue to the precise synthesis of organofluorine compounds without tedious synthetic procedures. The impact of this protocol is demonstrated by the efficient synthesis of complex fluorinated skeletons and the rapid synthesis of key intermediates for pheromone derivatives and PGF2 agonists. Mechanistic studies reveal that the migratory insertion of difluorocarbene into the C-Cu bond of the alkynylcopper species is a key step in the reaction. |
| format | Article |
| id | doaj-art-23d238b754dd4e3bb009bac51504c505 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-23d238b754dd4e3bb009bac51504c5052025-08-20T02:25:16ZengNature PortfolioNature Communications2041-17232025-05-0116111010.1038/s41467-025-59903-yCopper difluorocarbene-involved catalytic gem-difluoropropargylationXin Zeng0Shi-Ping Sun1Hai-Yang Zhao2Xingang Zhang3State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of SciencesState Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of SciencesAbstract The use of metal for catalytic difluorocarbene transfer reactions has long been hindered by the lack of understanding of metal difluorocarbene chemistry, despite the potential implications for medicinal chemistry and advanced materials science. Here, we report a copper-catalyzed difluorocarbene transfer reaction via 1,1-migration of copper difluorocarbene, in contrast to the previous nucleophilic addition of copper difluorocarbene pathway. This reaction enables the development of a modular catalytic gem-difluoropropargylation reaction using a variety of simple and widely available potassium propiolates, terminal alkynes, and allyl/propargyl electrophiles to couple difluorocarbene, opening an avenue to the precise synthesis of organofluorine compounds without tedious synthetic procedures. The impact of this protocol is demonstrated by the efficient synthesis of complex fluorinated skeletons and the rapid synthesis of key intermediates for pheromone derivatives and PGF2 agonists. Mechanistic studies reveal that the migratory insertion of difluorocarbene into the C-Cu bond of the alkynylcopper species is a key step in the reaction.https://doi.org/10.1038/s41467-025-59903-y |
| spellingShingle | Xin Zeng Shi-Ping Sun Hai-Yang Zhao Xingang Zhang Copper difluorocarbene-involved catalytic gem-difluoropropargylation Nature Communications |
| title | Copper difluorocarbene-involved catalytic gem-difluoropropargylation |
| title_full | Copper difluorocarbene-involved catalytic gem-difluoropropargylation |
| title_fullStr | Copper difluorocarbene-involved catalytic gem-difluoropropargylation |
| title_full_unstemmed | Copper difluorocarbene-involved catalytic gem-difluoropropargylation |
| title_short | Copper difluorocarbene-involved catalytic gem-difluoropropargylation |
| title_sort | copper difluorocarbene involved catalytic gem difluoropropargylation |
| url | https://doi.org/10.1038/s41467-025-59903-y |
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