Batch Versus Flow Lithiation-Substitution of 1,3,4-Oxadiazoles: Exploitation of Unstable Intermediates Using Flow Chemistry

Jeff Y. F. Wong, John M. Tobin, Filipe Vilela, Graeme Barker

Research output: Contribution to journalArticle

Abstract

1,3,4‐Oxadiazoles are a common motif in pharmaceutical chemistry, but few convenient methods for their modification exist. A fast, convenient, high yielding and general α‐substitution of 1,3,4‐oxadiazoles has been developed using a metalation‐electrophilic trapping protocol both in batch and under continuous flow conditions in contradiction to previous reports which suggest that α‐metalation of this ring system results in ring fragmentation. In batch, lithiation is accomplished at an industrially convenient temperature, –30 °C, with subsequent trapping giving isolated yields of up to 91%. Under continuous flow conditions, metalation is carried out at room temperature, and subsequent in flow electrophilic trapping gave up to quantitative isolated yields. Notably, lithiation in batch at room temperature results only in ring fragmentation and we propose that the superior mixing in flow allows interception and exploitation of an unstable intermediate before decomposition can occur.
Original languageEnglish
Pages (from-to)12439-12445
Number of pages7
JournalChemistry - A European Journal
Volume25
Issue number53
Early online date30 Jul 2019
DOIs
Publication statusPublished - 20 Sep 2019

Fingerprint

Substitution reactions
Temperature
Decomposition
1,3,4-oxadiazole
Pharmaceutical Chemistry

Keywords

  • alkylation
  • flow chemistry
  • heterocycles
  • lithiation
  • synthetic methods

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Organic Chemistry

Cite this

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title = "Batch Versus Flow Lithiation-Substitution of 1,3,4-Oxadiazoles: Exploitation of Unstable Intermediates Using Flow Chemistry",
abstract = "1,3,4‐Oxadiazoles are a common motif in pharmaceutical chemistry, but few convenient methods for their modification exist. A fast, convenient, high yielding and general α‐substitution of 1,3,4‐oxadiazoles has been developed using a metalation‐electrophilic trapping protocol both in batch and under continuous flow conditions in contradiction to previous reports which suggest that α‐metalation of this ring system results in ring fragmentation. In batch, lithiation is accomplished at an industrially convenient temperature, –30 °C, with subsequent trapping giving isolated yields of up to 91{\%}. Under continuous flow conditions, metalation is carried out at room temperature, and subsequent in flow electrophilic trapping gave up to quantitative isolated yields. Notably, lithiation in batch at room temperature results only in ring fragmentation and we propose that the superior mixing in flow allows interception and exploitation of an unstable intermediate before decomposition can occur.",
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Batch Versus Flow Lithiation-Substitution of 1,3,4-Oxadiazoles: Exploitation of Unstable Intermediates Using Flow Chemistry. / Wong, Jeff Y. F.; Tobin, John M.; Vilela, Filipe; Barker, Graeme.

In: Chemistry - A European Journal, Vol. 25, No. 53, 20.09.2019, p. 12439-12445.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Barker, Graeme

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