Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction
The first mechanistic investigation of electrophilic amide activation of α,α-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler–Napieralski-based synthetic strategy to the aspidosperma alkaloids, including...
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/110277 https://orcid.org/0000-0003-3080-1063 |
| _version_ | 1811071677837082624 |
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| author | White, Kolby L. Mewald, Marius Movassaghi, Mohammad |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry White, Kolby L. Mewald, Marius Movassaghi, Mohammad |
| author_sort | White, Kolby L. |
| collection | MIT |
| description | The first mechanistic investigation of electrophilic amide activation of α,α-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler–Napieralski-based synthetic strategy to the aspidosperma alkaloids, including a complex tetracyclic diiminium ion, is discussed. The reactivity of a wide range of pyridines with trifluoromethanesulfonic anhydride was systematically examined, and characteristic IR absorption bands for the corresponding N-trifluoromethanesulfonylated pyridinium trifluoromethanesulfonates were assigned. The reversible formation of diiminium ether intermediates was studied, providing insight into divergent mechanistic pathways as a function of the steric environment of the amide substrate and stoichiometry of reagents. Importantly, when considering base additives during electrophilic amide activation, more hindered α-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. |
| first_indexed | 2024-09-23T08:54:55Z |
| format | Article |
| id | mit-1721.1/110277 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:54:55Z |
| publishDate | 2017 |
| publisher | American Chemical Society (ACS) |
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| spelling | mit-1721.1/1102772022-09-30T12:09:02Z Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction White, Kolby L. Mewald, Marius Movassaghi, Mohammad Massachusetts Institute of Technology. Department of Chemistry White, Kolby L. Mewald, Marius Movassaghi, Mohammad The first mechanistic investigation of electrophilic amide activation of α,α-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in our interrupted Bischler–Napieralski-based synthetic strategy to the aspidosperma alkaloids, including a complex tetracyclic diiminium ion, is discussed. The reactivity of a wide range of pyridines with trifluoromethanesulfonic anhydride was systematically examined, and characteristic IR absorption bands for the corresponding N-trifluoromethanesulfonylated pyridinium trifluoromethanesulfonates were assigned. The reversible formation of diiminium ether intermediates was studied, providing insight into divergent mechanistic pathways as a function of the steric environment of the amide substrate and stoichiometry of reagents. Importantly, when considering base additives during electrophilic amide activation, more hindered α-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation. National Institute of General Medical Sciences (U.S.) (GM074825) National Science Foundation (U.S.). Graduate Research Fellowship Program German Academic Exchange Service 2017-06-26T19:56:57Z 2017-06-26T19:56:57Z 2015-07 Article http://purl.org/eprint/type/JournalArticle 0022-3263 1520-6904 http://hdl.handle.net/1721.1/110277 White, Kolby L., Marius Mewald, and Mohammad Movassaghi. “Direct Observation of Intermediates Involved in the Interruption of the Bischler?Napieralski Reaction.” The Journal of Organic Chemistry 80.15 (2015): 7403–7411. https://orcid.org/0000-0003-3080-1063 en_US http://dx.doi.org/10.1021/acs.joc.5b01023 Journal of Organic Chemistry Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | White, Kolby L. Mewald, Marius Movassaghi, Mohammad Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction |
| title | Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction |
| title_full | Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction |
| title_fullStr | Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction |
| title_full_unstemmed | Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction |
| title_short | Direct Observation of Intermediates Involved in the Interruption of the Bischler–Napieralski Reaction |
| title_sort | direct observation of intermediates involved in the interruption of the bischler napieralski reaction |
| url | http://hdl.handle.net/1721.1/110277 https://orcid.org/0000-0003-3080-1063 |
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