Kwong, Alice, Firth, James D., Farmer, Thomas J. orcid.org/0000-0002-1039-7684 et al. (1 more author) (2021) Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine. Tetrahedron. 131899. ISSN 0040-4020
Abstract
The development of suitable reaction conditions for the rapid “high” temperature lithiation-trapping of N-Boc pyrrolidine under batch and flow conditions is described. For optimisation of batch conditions, the lithiation-trapping was explored using s-BuLi at temperatures of −30 to 20 °C. Two new batch lithiation conditions were discovered using the biomass-derived, sustainable solvent, 2-MeTHF: diamine-free lithiation in 2-MeTHF gave α-substituted pyrrolidines in 50–69% yields at −20 °C or 0 °C. The requirement for very short lithiation times is explained by the chemical instability of the lithiated intermediate at high temperatures. A practical flow chemistry reaction manifold (s-BuLi, TMEDA, THF, 0 °C, 5 s) has been developed which delivered an α-substituted pyrrolidine in 59% yield. This flow process opens up new opportunities for scaling-up of lithiation-trapping reactions of N-Boc heterocycles.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Funding Information: We thank the University of York and the Wild Fund for funding (AK). Publisher Copyright: © 2021 Elsevier Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. |
Keywords: | Amine synthesis,Flow chemistry,Lithiation,Pyrrolidines |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Depositing User: | Pure (York) |
Date Deposited: | 25 Feb 2021 11:28 |
Last Modified: | 28 Mar 2025 00:11 |
Published Version: | https://doi.org/10.1016/j.tet.2020.131899 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1016/j.tet.2020.131899 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:171578 |