A greener and sustainable flow chemistry protocol for the synthesis of 3,3-disubstituted indolenines through interrupted Fischer indolisation reaction is described. First, two model aldehydes were reacted with phenylhydrazine in order to explore the reaction feasibility in a ‘greener’ fashion in batch mode. The best outcomes were then used as the starting point for the implementation of the reaction in continuous flow. A thorough exploration of key parameters allowed the identification of the most efficient reagent mixing mode, and the optimum temperature and residence time. The newly developed method allowed straightforward reaction channelling towards the formation of the indolenines, thus reducing the competitive formation of side products. We further broadened the scope of the conceived methodology by exploring the possibility of a heterogeneous in-line reduction of the indolenines to their indoline counterparts. This rapid approach nicely complements known batch chemistry and could facilitate synthesis and scale up of 3,3-disubstituted indolenines and indolines, offering a coupling point for additional and subsequent flow reactions for multistep syntheses for further derivatization.

中文翻译：

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利用连续流动的中断Fischer：（螺）吲哚啉和（螺）吲哚啉特权支架的可持续合成

描述了一种通过中断的Fischer吲哚化反应合成3,3-二取代的吲哚胺的绿色环保可持续流方案。首先，使两种模型醛与苯肼反应，以“绿色”方式分批方式探索该反应的可行性。然后将最佳结果用作在连续流中进行反应的起点。通过对关键参数的深入研究，可以确定最有效的试剂混合模式以及最佳的温度和停留时间。新开发的方法允许直接的反应引导至吲哚胺的形成，从而减少了副产物的竞争性形成。我们通过探索将吲哚类药物异质在线还原成其吲哚类对应物的可能性，进一步扩大了所设想的方法的范围。这种快速方法很好地补充了已知的间歇化学，并且可以促进3,3-二取代的吲哚啉和二氢吲哚的合成和规模化，为进一步的衍生化提供了额外的和后续的流动反应的偶联点。