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<p>The development of continuous flow processes for the Staudinger synthesis of β-lactams was investigated in order to provide an alternative to cumbersome batch procedures. First, a model reaction based on acetoxyacetyl chloride and <i>N</i>-(phenylmethylidene)isopropylamine was selected for initial parameter evaluation and optimization. Assessment of a broad set of bases showed that the use of diisopropylethylamine, <i>N</i>-methylpiperidine or tributylamine in acetonitrile is recommended for obtaining the desired 3-acetoxy-1-isopropyl-4-phenyl-β-lactam in high <i>cis</i> diastereoselectivity. Next, the optimized reaction set-up was successfully translated to the continuous flow production of a set of differently substituted β-lactams which are known to be difficult to prepare via batch procedures. Interestingly, an unexpected base-induced diastereoselectivity was observed during this study, allowing for tuning of the reaction conditions to favor the formation of either the <i>cis</i> or the <i>trans</i> isomer in select cases.</p> Graphical Abstract <p></p>

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Staudinger β-lactam synthesis via continuous flow chemistry

  • 期刊论文

  • 发表日期：

    2025年11月17日

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  • Sari Deketelaere,
  • Stefan Desimpel,
  • Reinout Van Kerrebroeck,
  • Lander Delputte,
  • Emma Vandenheede,
  • Matthias D’hooghe,
  • Christian V. Stevens

摘要

The development of continuous flow processes for the Staudinger synthesis of β-lactams was investigated in order to provide an alternative to cumbersome batch procedures. First, a model reaction based on acetoxyacetyl chloride and N-(phenylmethylidene)isopropylamine was selected for initial parameter evaluation and optimization. Assessment of a broad set of bases showed that the use of diisopropylethylamine, N-methylpiperidine or tributylamine in acetonitrile is recommended for obtaining the desired 3-acetoxy-1-isopropyl-4-phenyl-β-lactam in high cis diastereoselectivity. Next, the optimized reaction set-up was successfully translated to the continuous flow production of a set of differently substituted β-lactams which are known to be difficult to prepare via batch procedures. Interestingly, an unexpected base-induced diastereoselectivity was observed during this study, allowing for tuning of the reaction conditions to favor the formation of either the cis or the trans isomer in select cases.

Graphical Abstract