Asymmetric Synthesis of 2‐Arylindolines and 2,2‐Disubstituted Indolines by Kinetic Resolution
Kinetic resolution of 2‐arylindolines (2,3‐dihydroindoles) was achieved by treatment of their N‐tert‐butoxycarbonyl (Boc) derivatives with n‐butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2‐disubstituted products...
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| Veröffentlicht in: | Chemistry : a European journal 2021-08, Vol.27 (45), p.11670-11675 |
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| creator | Choi, Anthony El‐Tunsi, Ashraf Wang, Yuhang Meijer, Anthony J. H. M. Li, Jia Li, Xiabing Proietti Silvestri, Ilaria Coldham, Iain |
| description | Kinetic resolution of 2‐arylindolines (2,3‐dihydroindoles) was achieved by treatment of their N‐tert‐butoxycarbonyl (Boc) derivatives with n‐butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2‐disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N‐Boc‐2‐arylindolines were converted to 2,2‐disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2‐disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation‐trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2‐aryl and 2,2‐disubstituted indolines.
Asymmetric synthesis of 2‐arylindolines was achieved by kinetic resolution with n‐butyllithium and the chiral ligand sparteine followed by electrophilic quench. The recovered starting materials and the 2,2‐disubstituted products were isolated with high enantiomer ratios. Variable temperature NMR spectroscopy and DFT studies were used to determine the rate of Boc rotation. |
| doi_str_mv | 10.1002/chem.202101248 |
| format | Article |
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Asymmetric synthesis of 2‐arylindolines was achieved by kinetic resolution with n‐butyllithium and the chiral ligand sparteine followed by electrophilic quench. The recovered starting materials and the 2,2‐disubstituted products were isolated with high enantiomer ratios. Variable temperature NMR spectroscopy and DFT studies were used to determine the rate of Boc rotation.</description><identifier>ISSN: 0947-6539</identifier><identifier>EISSN: 1521-3765</identifier><identifier>DOI: 10.1002/chem.202101248</identifier><identifier>PMID: 34110662</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Asymmetric synthesis ; Butyllithium ; Chemistry ; Enantiomers ; enantioselectivity ; heterocycles ; Heterocyclic compounds ; Indoles ; kinetic resolution ; Kinetics ; lithiation ; Magnetic resonance spectroscopy ; NMR ; NMR spectroscopy ; Nuclear magnetic resonance ; Selectivity ; Sparteine ; Spectroscopy ; Spectrum analysis ; Stereoisomerism ; Toluene</subject><ispartof>Chemistry : a European journal, 2021-08, Vol.27 (45), p.11670-11675</ispartof><rights>2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH</rights><rights>2021 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4688-56da1fe481aed6e7c0bfeb10809ef1457b213a2867a3c956cc80d644678de3e63</citedby><cites>FETCH-LOGICAL-c4688-56da1fe481aed6e7c0bfeb10809ef1457b213a2867a3c956cc80d644678de3e63</cites><orcidid>0000-0003-4803-3488 ; 0000-0003-4130-8805 ; 0000-0003-4602-6292</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fchem.202101248$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fchem.202101248$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34110662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Choi, Anthony</creatorcontrib><creatorcontrib>El‐Tunsi, Ashraf</creatorcontrib><creatorcontrib>Wang, Yuhang</creatorcontrib><creatorcontrib>Meijer, Anthony J. H. M.</creatorcontrib><creatorcontrib>Li, Jia</creatorcontrib><creatorcontrib>Li, Xiabing</creatorcontrib><creatorcontrib>Proietti Silvestri, Ilaria</creatorcontrib><creatorcontrib>Coldham, Iain</creatorcontrib><title>Asymmetric Synthesis of 2‐Arylindolines and 2,2‐Disubstituted Indolines by Kinetic Resolution</title><title>Chemistry : a European journal</title><addtitle>Chemistry</addtitle><description>Kinetic resolution of 2‐arylindolines (2,3‐dihydroindoles) was achieved by treatment of their N‐tert‐butoxycarbonyl (Boc) derivatives with n‐butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2‐disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N‐Boc‐2‐arylindolines were converted to 2,2‐disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2‐disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation‐trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2‐aryl and 2,2‐disubstituted indolines.
Asymmetric synthesis of 2‐arylindolines was achieved by kinetic resolution with n‐butyllithium and the chiral ligand sparteine followed by electrophilic quench. The recovered starting materials and the 2,2‐disubstituted products were isolated with high enantiomer ratios. Variable temperature NMR spectroscopy and DFT studies were used to determine the rate of Boc rotation.</description><subject>Asymmetric synthesis</subject><subject>Butyllithium</subject><subject>Chemistry</subject><subject>Enantiomers</subject><subject>enantioselectivity</subject><subject>heterocycles</subject><subject>Heterocyclic compounds</subject><subject>Indoles</subject><subject>kinetic resolution</subject><subject>Kinetics</subject><subject>lithiation</subject><subject>Magnetic resonance spectroscopy</subject><subject>NMR</subject><subject>NMR spectroscopy</subject><subject>Nuclear magnetic resonance</subject><subject>Selectivity</subject><subject>Sparteine</subject><subject>Spectroscopy</subject><subject>Spectrum analysis</subject><subject>Stereoisomerism</subject><subject>Toluene</subject><issn>0947-6539</issn><issn>1521-3765</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqFkctu1DAUhi0EokNhyxJFYsOCDL7H3iCNhkIripC4rC3HOWFcJXGxHVB2PALPyJPg0ZThsmHjY_l8_uTjH6GHBK8JxvSZ28G4ppgSTChXt9CKCEpq1khxG62w5k0tBdMn6F5KVxhjLRm7i04YJwRLSVfIbtIyjpCjd9X7Zco7SD5Voa_oj2_fN3EZ_NSFskCq7NRV9On-_IVPc5uyz3OGrro4Eu1SvS6bXFzvIIVhzj5M99Gd3g4JHtzUU_Tx5dmH7Xl9-fbVxXZzWTsulaqF7CzpgStioZPQONz20BKssIaecNG0lDBLlWwsc1pI5xTuJOeyUR0wkOwUPT94r-d2hM7BlKMdzHX0o42LCdabvzuT35lP4YtRXEjV8CJ4ciOI4fMMKZvRJwfDYCcIczK0fKRSXBNd0Mf_oFdhjlMZr1ASCymVFoVaHygXQ0oR-uNjCDb79Mw-PXNMr1x49OcIR_xXXAXQB-CrH2D5j85sz8_e_Jb_BCk7qbo</recordid><startdate>20210811</startdate><enddate>20210811</enddate><creator>Choi, Anthony</creator><creator>El‐Tunsi, Ashraf</creator><creator>Wang, Yuhang</creator><creator>Meijer, Anthony J. H. M.</creator><creator>Li, Jia</creator><creator>Li, Xiabing</creator><creator>Proietti Silvestri, Ilaria</creator><creator>Coldham, Iain</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SR</scope><scope>8BQ</scope><scope>8FD</scope><scope>JG9</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4803-3488</orcidid><orcidid>https://orcid.org/0000-0003-4130-8805</orcidid><orcidid>https://orcid.org/0000-0003-4602-6292</orcidid></search><sort><creationdate>20210811</creationdate><title>Asymmetric Synthesis of 2‐Arylindolines and 2,2‐Disubstituted Indolines by Kinetic Resolution</title><author>Choi, Anthony ; El‐Tunsi, Ashraf ; Wang, Yuhang ; Meijer, Anthony J. H. M. ; Li, Jia ; Li, Xiabing ; Proietti Silvestri, Ilaria ; Coldham, Iain</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4688-56da1fe481aed6e7c0bfeb10809ef1457b213a2867a3c956cc80d644678de3e63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Asymmetric synthesis</topic><topic>Butyllithium</topic><topic>Chemistry</topic><topic>Enantiomers</topic><topic>enantioselectivity</topic><topic>heterocycles</topic><topic>Heterocyclic compounds</topic><topic>Indoles</topic><topic>kinetic resolution</topic><topic>Kinetics</topic><topic>lithiation</topic><topic>Magnetic resonance spectroscopy</topic><topic>NMR</topic><topic>NMR spectroscopy</topic><topic>Nuclear magnetic resonance</topic><topic>Selectivity</topic><topic>Sparteine</topic><topic>Spectroscopy</topic><topic>Spectrum analysis</topic><topic>Stereoisomerism</topic><topic>Toluene</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Choi, Anthony</creatorcontrib><creatorcontrib>El‐Tunsi, Ashraf</creatorcontrib><creatorcontrib>Wang, Yuhang</creatorcontrib><creatorcontrib>Meijer, Anthony J. 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M.</creatorcontrib><creatorcontrib>Li, Jia</creatorcontrib><creatorcontrib>Li, Xiabing</creatorcontrib><creatorcontrib>Proietti Silvestri, Ilaria</creatorcontrib><creatorcontrib>Coldham, Iain</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Engineered Materials Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Materials Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Chemistry : a European journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Choi, Anthony</au><au>El‐Tunsi, Ashraf</au><au>Wang, Yuhang</au><au>Meijer, Anthony J. H. M.</au><au>Li, Jia</au><au>Li, Xiabing</au><au>Proietti Silvestri, Ilaria</au><au>Coldham, Iain</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Asymmetric Synthesis of 2‐Arylindolines and 2,2‐Disubstituted Indolines by Kinetic Resolution</atitle><jtitle>Chemistry : a European journal</jtitle><addtitle>Chemistry</addtitle><date>2021-08-11</date><risdate>2021</risdate><volume>27</volume><issue>45</issue><spage>11670</spage><epage>11675</epage><pages>11670-11675</pages><issn>0947-6539</issn><eissn>1521-3765</eissn><abstract>Kinetic resolution of 2‐arylindolines (2,3‐dihydroindoles) was achieved by treatment of their N‐tert‐butoxycarbonyl (Boc) derivatives with n‐butyllithium and sparteine in toluene at −78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2‐disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N‐Boc‐2‐arylindolines were converted to 2,2‐disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2‐disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation‐trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2‐aryl and 2,2‐disubstituted indolines.
Asymmetric synthesis of 2‐arylindolines was achieved by kinetic resolution with n‐butyllithium and the chiral ligand sparteine followed by electrophilic quench. The recovered starting materials and the 2,2‐disubstituted products were isolated with high enantiomer ratios. Variable temperature NMR spectroscopy and DFT studies were used to determine the rate of Boc rotation.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>34110662</pmid><doi>10.1002/chem.202101248</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0003-4803-3488</orcidid><orcidid>https://orcid.org/0000-0003-4130-8805</orcidid><orcidid>https://orcid.org/0000-0003-4602-6292</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Asymmetric synthesis Butyllithium Chemistry Enantiomers enantioselectivity heterocycles Heterocyclic compounds Indoles kinetic resolution Kinetics lithiation Magnetic resonance spectroscopy NMR NMR spectroscopy Nuclear magnetic resonance Selectivity Sparteine Spectroscopy Spectrum analysis Stereoisomerism Toluene |
| title | Asymmetric Synthesis of 2‐Arylindolines and 2,2‐Disubstituted Indolines by Kinetic Resolution |
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