Selective halogenation of pyridines using designed phosphine reagents
Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C–H precursors are lacking. We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phos...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2020
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| _version_ | 1826273897865019392 |
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| author | Levy, JN Alegre-Requena, JV Liu, R Paton, RS McNally, A |
| author_facet | Levy, JN Alegre-Requena, JV Liu, R Paton, RS McNally, A |
| author_sort | Levy, JN |
| collection | OXFORD |
| description | Halopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C–H precursors are lacking. We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. Computational studies indicate that C–halogen bond formation occurs via an SNAr pathway, and phosphine elimination is the rate-determining step. Steric interactions during C–P bond cleavage account for differences in reactivity between 2- and 3-substituted pyridines. |
| first_indexed | 2024-03-06T22:35:13Z |
| format | Journal article |
| id | oxford-uuid:59a85d20-9b7c-423f-a682-a0107a064c21 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:35:13Z |
| publishDate | 2020 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:59a85d20-9b7c-423f-a682-a0107a064c212022-03-26T17:11:02ZSelective halogenation of pyridines using designed phosphine reagentsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:59a85d20-9b7c-423f-a682-a0107a064c21EnglishSymplectic ElementsAmerican Chemical Society2020Levy, JNAlegre-Requena, JVLiu, RPaton, RSMcNally, AHalopyridines are key building blocks for synthesizing pharmaceuticals, agrochemicals, and ligands for metal complexes, but strategies to selectively halogenate pyridine C–H precursors are lacking. We designed a set of heterocyclic phosphines that are installed at the 4-position of pyridines as phosphonium salts and then displaced with halide nucleophiles. A broad range of unactivated pyridines can be halogenated, and the method is viable for late-stage halogenation of complex pharmaceuticals. Computational studies indicate that C–halogen bond formation occurs via an SNAr pathway, and phosphine elimination is the rate-determining step. Steric interactions during C–P bond cleavage account for differences in reactivity between 2- and 3-substituted pyridines. |
| spellingShingle | Levy, JN Alegre-Requena, JV Liu, R Paton, RS McNally, A Selective halogenation of pyridines using designed phosphine reagents |
| title | Selective halogenation of pyridines using designed phosphine reagents |
| title_full | Selective halogenation of pyridines using designed phosphine reagents |
| title_fullStr | Selective halogenation of pyridines using designed phosphine reagents |
| title_full_unstemmed | Selective halogenation of pyridines using designed phosphine reagents |
| title_short | Selective halogenation of pyridines using designed phosphine reagents |
| title_sort | selective halogenation of pyridines using designed phosphine reagents |
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