Pate Sophie, Taujanskas Joshua, Wells Robyn, Robertson Craig M, O'Neill Paul M, Stachulski Andrew V
Department of Chemistry, University of Liverpool Liverpool L69 7ZD UK
RSC Adv. 2024 Sep 2;14(38):27894-27903. doi: 10.1039/d4ra04959d. eCollection 2024 Aug 29.
The 2-aminothiazole grouping is a significant feature of many series of biologically active molecules, including antibiotics, anticancer agents and NSAIDs. We have a longstanding interest in the synthesis and biological evaluation of thiazolides, [2-hydroxyaroyl--(thiazol-2-yl)-amides] which have broad spectrum antiinfective, especially antiviral, properties. However, 2-amino-4-substituted thiazoles, especially 4-halo examples, are not easily available. We now report practical, efficient syntheses of this class from readily available pseudothiohydantoin, or 2-aminothiazol-4(5)-one: the key intermediate was its Boc derivative, from which, under Appel-related conditions, Br, Cl and I could all be introduced at C(4). Whereas 2-amino-4-Br/4-Cl thiazoles gave low yields of mixed products on acylation, including a bis-acyl product, further acylation of the Boc intermediates, with a final mild deprotection step, afforded the desired thiazolides cleanly and in good yields. In contrast, even mild hydrolysis of 2-acetamido-4-chlorothiazole led to decomposition with fast reversion to 2-aminothiazol-4(5)-one. We also present a correction of a claimed synthesis of 2-acetamido-4-chlorothiazole, which in fact produces its 5-chloro isomer.
2-氨基噻唑基团是许多系列生物活性分子的一个重要特征，这些分子包括抗生素、抗癌剂和非甾体抗炎药。我们长期以来一直对噻唑酯[2-羟基芳酰基-(噻唑-2-基)-酰胺]的合成和生物学评价感兴趣，这类化合物具有广谱抗感染特性，尤其是抗病毒特性。然而，2-氨基-4-取代噻唑，特别是4-卤代的例子，并不容易获得。我们现在报道了从容易获得的假硫代乙内酰脲或2-氨基噻唑-4(5)-酮出发，实用、高效地合成这类化合物：关键中间体是其Boc衍生物，在与阿佩尔反应相关的条件下，可在C(4)位引入Br、Cl和I。虽然2-氨基-4-溴/4-氯噻唑在酰化时得到的混合产物产率较低，包括一种双酰化产物，但Boc中间体的进一步酰化，经过最后的温和脱保护步骤，能干净地得到所需的噻唑酯，且产率良好。相比之下，即使是2-乙酰氨基-4-氯噻唑的温和水解也会导致分解，并迅速转化回2-氨基噻唑-4(5)-酮。我们还对所声称的2-乙酰氨基-4-氯噻唑的合成进行了修正，实际上该合成得到的是其5-氯异构体。
