TBHP-mediated denitrogenative synthesis of pyridine carboxamides from pyridine carbohydrazides and amines in water,Organic Chemistry Frontiers

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TBHP-mediated denitrogenative synthesis of pyridine carboxamides from pyridine carbohydrazides and amines in water
Organic Chemistry Frontiers ( IF 4.6 ) Pub Date : 2022-11-01 , DOI: 10.1039/d2qo01465c
Joydev K. Laha ₁ , Anjali Gupta ₁ , Upma Gulati ₁ , Mandeep Kaur Hunjan ₁ , J. Patrick Weber ₂ , Martin Breugst ₂

Affiliation

Isoniazid (isonicotinic acid hydrazide) is used as an antibiotic to treat tuberculosis and mechanistic studies indicate that the intermediately formed isonicotinoyl radical is the active form of the drug. However, the application of this and other pyridine acyl radicals in organic synthesis is largely unexplored. We have now studied the generation of these radicals and their subsequent reactivity with polarity-matched coupling partners. The radicals can be generated in situ through a tert-butyl hydroperoxide (TBHP)-mediated denitrogenation of the corresponding pyridine carbohydrazides. Those radicals then react with various amines yielding pyridine carboxamides in 50–93% yield. The key advantages of this synthetic method include the use of mild and metal-free reactions conditions, water as the solvent, a wide substrate scope, and an excellent functional-group tolerance, which was demonstrated in the synthesis of primary, secondary, and tertiary amides and pharmaceuticals. Further experimental studies revealed that this method is extendable to other acyl radicals and, thus, provides a complementary method to the available protocols. Computational studies further support the electronic nature and predicted reactivity of these pyridine acyl radicals.

中文翻译：

TBHP介导的吡啶甲酰肼和胺在水中脱氮合成吡啶甲酰胺

异烟肼（异烟酸酰肼）用作治疗结核病的抗生素，机理研究表明中间形成的异烟酰自由基是该药物的活性形式。然而，这种和其他吡啶酰基自由基在有机合成中的应用在很大程度上是未开发的。我们现在已经研究了这些自由基的产生以及它们随后与极性匹配的偶联伙伴的反应性。自由基可以通过叔-丁基过氧化氢（TBHP）介导的相应吡啶碳酰肼的脱氮作用。然后这些自由基与各种胺反应，以 50-93% 的收率产生吡啶甲酰胺。这种合成方法的主要优点包括使用温和且不含金属的反应条件、水作为溶剂、底物范围广和优异的官能团耐受性，这在伯、仲和叔的合成中得到了证明酰胺和药物。进一步的实验研究表明，这种方法可扩展到其他酰基，因此，为现有协议提供了一种补充方法。计算研究进一步支持这些吡啶酰基自由基的电子性质和预测的反应性。

更新日期：2022-11-01

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