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

TY - JOUR

T1 - Rapid “high” temperature batch and flow lithiation-trapping of N-Boc pyrrolidine

AU - Kwong, Alice

AU - Firth, James D.

AU - Farmer, Thomas J.

AU - O'Brien, Peter

N1 - 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.

PY - 2021/2/12

Y1 - 2021/2/12

N2 - 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.

AB - 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.

KW - Amine synthesis

KW - Flow chemistry

KW - Lithiation

KW - Pyrrolidines

UR - http://www.scopus.com/inward/record.url?scp=85099534895&partnerID=8YFLogxK

U2 - 10.1016/j.tet.2020.131899

DO - 10.1016/j.tet.2020.131899

M3 - Article

AN - SCOPUS:85099534895

SN - 0040-4020

VL - 81

JO - Tetrahedron

JF - Tetrahedron

M1 - 131899

ER -