Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis
Copyright © 2020 American Chemical Society. C3-substituted 1H-indazoles are useful and important substructures in many pharmaceuticals. Methods for direct C3-functionalization of indazoles are relatively rare, compared to reactions developed for the more nucleophilic N1 and N2 positions. Herein, we...
| Main Authors: | , , , , |
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| Format: | Article |
| Sprog: | English |
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American Chemical Society (ACS)
2021
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| Online adgang: | https://hdl.handle.net/1721.1/132536 |
| _version_ | 1826208800636403712 |
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| author | Ye, Yuxuan Kevlishvili, Ilia Feng, Sheng Liu, Peng Buchwald, Stephen L |
| author_facet | Ye, Yuxuan Kevlishvili, Ilia Feng, Sheng Liu, Peng Buchwald, Stephen L |
| author_sort | Ye, Yuxuan |
| collection | MIT |
| description | Copyright © 2020 American Chemical Society. C3-substituted 1H-indazoles are useful and important substructures in many pharmaceuticals. Methods for direct C3-functionalization of indazoles are relatively rare, compared to reactions developed for the more nucleophilic N1 and N2 positions. Herein, we report a highly C3-selective allylation reaction of 1H-N-(benzoyloxy)indazoles using CuH catalysis. A variety of C3-allyl 1H-indazoles with quaternary stereocenters were efficiently prepared with high levels of enantioselectivity. Density functional theory (DFT) calculations were performed to explain the reactivity differences between indazole and indole electrophiles, the latter of which was used in our previously reported method. The calculations suggest that the indazole allylation reaction proceeds through an enantioselectivity-determining six-membered Zimmerman-Traxler-type transition state, rather than an oxidative addition/reductive elimination sequence, as we proposed in the case of indole alkylation. The enantioselectivity of the reaction is governed by both ligand-substrate steric interactions and steric repulsions involving the pseudoaxial substituent in the six-membered allylation transition state. |
| first_indexed | 2024-09-23T14:12:51Z |
| format | Article |
| id | mit-1721.1/132536 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:12:51Z |
| publishDate | 2021 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/1325362021-09-21T03:22:59Z Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis Ye, Yuxuan Kevlishvili, Ilia Feng, Sheng Liu, Peng Buchwald, Stephen L Copyright © 2020 American Chemical Society. C3-substituted 1H-indazoles are useful and important substructures in many pharmaceuticals. Methods for direct C3-functionalization of indazoles are relatively rare, compared to reactions developed for the more nucleophilic N1 and N2 positions. Herein, we report a highly C3-selective allylation reaction of 1H-N-(benzoyloxy)indazoles using CuH catalysis. A variety of C3-allyl 1H-indazoles with quaternary stereocenters were efficiently prepared with high levels of enantioselectivity. Density functional theory (DFT) calculations were performed to explain the reactivity differences between indazole and indole electrophiles, the latter of which was used in our previously reported method. The calculations suggest that the indazole allylation reaction proceeds through an enantioselectivity-determining six-membered Zimmerman-Traxler-type transition state, rather than an oxidative addition/reductive elimination sequence, as we proposed in the case of indole alkylation. The enantioselectivity of the reaction is governed by both ligand-substrate steric interactions and steric repulsions involving the pseudoaxial substituent in the six-membered allylation transition state. 2021-09-20T18:22:54Z 2021-09-20T18:22:54Z 2020-11-16T15:19:03Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/132536 en 10.1021/JACS.0C04286 Journal of the American Chemical Society Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Chemical Society (ACS) chemRxiv |
| spellingShingle | Ye, Yuxuan Kevlishvili, Ilia Feng, Sheng Liu, Peng Buchwald, Stephen L Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis |
| title | Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis |
| title_full | Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis |
| title_fullStr | Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis |
| title_full_unstemmed | Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis |
| title_short | Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis |
| title_sort | highly enantioselective synthesis of indazoles with a c3 quaternary chiral center using cuh catalysis |
| url | https://hdl.handle.net/1721.1/132536 |
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