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 |
| Language: | English |
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American Chemical Society (ACS)
2022
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| Online Access: | https://hdl.handle.net/1721.1/132536.2 |
| _version_ | 1811093724319449088 |
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| author | Ye, Yuxuan Kevlishvili, Illia Feng, Sheng Liu, Peng Buchwald, Stephen Leffler |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Ye, Yuxuan Kevlishvili, Illia Feng, Sheng Liu, Peng Buchwald, Stephen Leffler |
| 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 | 2024-09-23T15:49:38Z |
| format | Article |
| id | mit-1721.1/132536.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:49:38Z |
| publishDate | 2022 |
| publisher | American Chemical Society (ACS) |
| record_format | dspace |
| spelling | mit-1721.1/132536.22022-08-04T20:35:19Z Highly Enantioselective Synthesis of Indazoles with a C3-Quaternary Chiral Center Using CuH Catalysis Ye, Yuxuan Kevlishvili, Illia Feng, Sheng Liu, Peng Buchwald, Stephen Leffler Massachusetts Institute of Technology. Department of Chemistry 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. 2022-08-04T20:35:17Z 2021-09-20T18:22:54Z 2022-08-04T20:35:17Z 2020 2020-11-16T15:19:03Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/132536.2 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/octet-stream American Chemical Society (ACS) chemRxiv |
| spellingShingle | Ye, Yuxuan Kevlishvili, Illia Feng, Sheng Liu, Peng Buchwald, Stephen Leffler 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/1721.1/132536.2 |
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