Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds Functionalization
Abstract Introducing distinctive functional groups to expand the structural diversity and improve the intrinsic properties of parent molecules has been an essential pursuit in organic chemistry. By using perfluoroalkyl halide (PFAH) as a nontraditional, readily available, ideal 1,2‐difluoroalkenyl c...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202404738 |
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| author | Yu‐Lan Chen Wei Han Yuan‐Yuan Ren Mengtao Ma Danhua Ge Zhi‐Liang Shen Kai Guo Xue‐Qiang Chu |
| author_facet | Yu‐Lan Chen Wei Han Yuan‐Yuan Ren Mengtao Ma Danhua Ge Zhi‐Liang Shen Kai Guo Xue‐Qiang Chu |
| author_sort | Yu‐Lan Chen |
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| description | Abstract Introducing distinctive functional groups to expand the structural diversity and improve the intrinsic properties of parent molecules has been an essential pursuit in organic chemistry. By using perfluoroalkyl halide (PFAH) as a nontraditional, readily available, ideal 1,2‐difluoroalkenyl coupling partner, a defluorinative cyclization reaction of enamides for the construction of fluoroalkenyl oxazoles is first developed. The selective and controllable two‐fold cleavage of vicinal C(sp3)─F bonds in PFAH not only enables the introduction of a specific 1,2‐difluoroalkenyl moiety with ease but also results in the functionalization of two C(sp2)─H bonds of enamides without the need for metal catalyst, photocatalyst, oxidant, or light. The method can be applied to the late‐stage modification of complex molecules, synthesis of biological‐relevant oxazole analoges, and scale‐up synthesis, which all further highlight the real‐world utility of this protocol. Mechanistic studies reveal that the reaction possibly proceeds through a radical perfluoroalkylation, consecutive C─F bond heterolytic cleavage, and cyclization process. In addition, the in situ formed perfluoroalkyl radical which may also serve as an essential hydrogen abstractor. |
| format | Article |
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| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Advanced Science |
| spelling | doaj-art-7aa3592db4e444b4bbe29686ddba7cb82025-08-20T02:30:35ZengWileyAdvanced Science2198-38442025-02-01128n/an/a10.1002/advs.202404738Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds FunctionalizationYu‐Lan Chen0Wei Han1Yuan‐Yuan Ren2Mengtao Ma3Danhua Ge4Zhi‐Liang Shen5Kai Guo6Xue‐Qiang Chu7Technical Institute of Fluorochemistry School of Chemistry and Molecular Engineering Nanjing Tech University Nanjing 211816 ChinaTechnical Institute of Fluorochemistry School of Chemistry and Molecular Engineering Nanjing Tech University Nanjing 211816 ChinaTechnical Institute of Fluorochemistry School of Chemistry and Molecular Engineering Nanjing Tech University Nanjing 211816 ChinaDepartment of Chemistry and Materials Science College of Science Nanjing Forestry University Nanjing 210037 ChinaTechnical Institute of Fluorochemistry School of Chemistry and Molecular Engineering Nanjing Tech University Nanjing 211816 ChinaTechnical Institute of Fluorochemistry School of Chemistry and Molecular Engineering Nanjing Tech University Nanjing 211816 ChinaCollege of Biotechnology and Pharmaceutical Engineering Nanjing Tech University Nanjing 211816 ChinaTechnical Institute of Fluorochemistry School of Chemistry and Molecular Engineering Nanjing Tech University Nanjing 211816 ChinaAbstract Introducing distinctive functional groups to expand the structural diversity and improve the intrinsic properties of parent molecules has been an essential pursuit in organic chemistry. By using perfluoroalkyl halide (PFAH) as a nontraditional, readily available, ideal 1,2‐difluoroalkenyl coupling partner, a defluorinative cyclization reaction of enamides for the construction of fluoroalkenyl oxazoles is first developed. The selective and controllable two‐fold cleavage of vicinal C(sp3)─F bonds in PFAH not only enables the introduction of a specific 1,2‐difluoroalkenyl moiety with ease but also results in the functionalization of two C(sp2)─H bonds of enamides without the need for metal catalyst, photocatalyst, oxidant, or light. The method can be applied to the late‐stage modification of complex molecules, synthesis of biological‐relevant oxazole analoges, and scale‐up synthesis, which all further highlight the real‐world utility of this protocol. Mechanistic studies reveal that the reaction possibly proceeds through a radical perfluoroalkylation, consecutive C─F bond heterolytic cleavage, and cyclization process. In addition, the in situ formed perfluoroalkyl radical which may also serve as an essential hydrogen abstractor.https://doi.org/10.1002/advs.2024047381,2‐difluoroalkenyl groupC─F bond functionalizationdefluorinative cyclizationfluoroalkyl halidesoxazole |
| spellingShingle | Yu‐Lan Chen Wei Han Yuan‐Yuan Ren Mengtao Ma Danhua Ge Zhi‐Liang Shen Kai Guo Xue‐Qiang Chu Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds Functionalization Advanced Science 1,2‐difluoroalkenyl group C─F bond functionalization defluorinative cyclization fluoroalkyl halides oxazole |
| title | Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds Functionalization |
| title_full | Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds Functionalization |
| title_fullStr | Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds Functionalization |
| title_full_unstemmed | Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds Functionalization |
| title_short | Defluorinative Cyclization of Enamides with Fluoroalkyl Halides Through Two Vicinal C(sp3)─F Bonds Functionalization |
| title_sort | defluorinative cyclization of enamides with fluoroalkyl halides through two vicinal c sp3 ─f bonds functionalization |
| topic | 1,2‐difluoroalkenyl group C─F bond functionalization defluorinative cyclization fluoroalkyl halides oxazole |
| url | https://doi.org/10.1002/advs.202404738 |
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