Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA.
Molecules. 2022 Oct 18;27(20):6998. doi: 10.3390/molecules27206998.
A new synthesis of C5-substituted 1-alkyl-1-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards SAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. Initially, the sequence was expected to produce indoline products, but oxidative heteroaromatization intervened to generate the indoles. The reaction proceeded under anhydrous conditions in DMF at 23-90 °C using equimolar quantities of the acrylate and the amine with 2 equiv. of KCO to give 61-92% of the indole products. The reaction involves an aza-Michael addition, followed by SAr ring closure and heteroaromatization. Since the reactions were run under nitrogen, the final oxidation to the indole likely results from reaction with dissolved oxygen in the DMF. Substrates incorporating a 2-arylacrylonitrile proved too reactive to prepare using our protocol. The synthesis of the reaction substrates, their relative reactivities, and mechanistic details of the conversion are discussed.
本文报道了 C5-取代的 1-烷基-1-吲哚-3-羧酸酯的新合成方法。通过芳香取代制备了一系列甲基 2-芳基丙烯酰胺氮杂迈克尔受体，使其对 SAr 反应具有活性。随后与一系列伯胺反应生成标题化合物。最初，该序列预计会产生吲哚啉产物，但氧化杂芳构化会生成吲哚。反应在无水条件下，在 23-90°C 的 DMF 中，使用等摩尔量的丙烯酰胺和胺，并用 2 当量的 KCO 进行，得到 61-92%的吲哚产物。反应涉及氮杂迈克尔加成，随后是 SAr 环闭合和杂芳构化。由于反应在氮气下进行，最终的氧化为吲哚可能是与 DMF 中的溶解氧反应的结果。含有 2-芳基丙烯腈的底物反应过于活泼，无法按照我们的方案制备。讨论了反应底物的合成、它们的相对反应活性以及转化的机理细节。
