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

Alice Kwong, James D. Firth, Thomas J. Farmer, Peter O'Brien*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number131899
Number of pages6
Early online date24 Dec 2020
Publication statusPublished - 12 Feb 2021

Bibliographical note

Funding Information:
We thank the University of York and the Wild Fund for funding (AK).

Publisher Copyright:
© 2021 Elsevier Ltd

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.


  • Amine synthesis
  • Flow chemistry
  • Lithiation
  • Pyrrolidines

Cite this