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Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine

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JournalTetrahedron
DateAccepted/In press - 21 Dec 2020
DateE-pub ahead of print - 24 Dec 2020
DatePublished (current) - 12 Feb 2021
Volume81
Number of pages6
Early online date24/12/20
Original languageEnglish

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.

Bibliographical note

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.

    Research areas

  • Amine synthesis, Flow chemistry, Lithiation, Pyrrolidines

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