One-Pot Parallel Solution-Phase Synthesis of 1-Substituted 4-(2-Aminoethyl)-1H-pyrazol-5-ols

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• 作者：David Kralj ; Ana Novak ; Georg Dahmann ; Uroš ; Groš ; elj ; Anton Meden ; Jurij Svete
• 刊名：Journal of Combinatorial Chemistry
• 出版年：2008
• 出版时间：September 8, 2008
• 年：2008
• 卷：10
• 期：5
• 页码：664-670
• 全文大小：154K
• 年卷期：v.10,no.5(September 8, 2008)
• ISSN：1520-4774

文摘

Two variations of enaminone-based parallel solution-phase synthesis of 1-substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols 8 and their NH-tautomers 8′ were developed. The synthetic strategy comprises a two step preparation of the N-protected α-enamino lactams 3a and 3b from 2-pyrrolidinone (1), “ring switching” transformation of 3a,b with monosubstituted hydrazines 4a−u, and acidolytic removal of the N-protecting group. In order to ensure a clean and fast conversion, reactions of Cbz-enaminone 3a with hydrazines 4a−k were carried out under microwave irradiation to afford the “ring-switched” intermediates 7a−k. Deprotection of 7a−k with HBr−AcOH at 50 °C gave a library of 11 analytically pure 4-(2-aminoethyl)-1H-pyrazol-5-ols (di)hydrobromides 8/8’a−k in 16−75% yields over two steps. The other reagent, Boc-enaminone 3b, was more reactive and ring switching transformations with hydrazines 4b,d,k proceeded smoothly and cleanly under conventional heating. Finally, a parallel one-pot transformation of the Boc-enaminone 3b with hydrazines 4a−u followed by subsequent deprotection of the intermediates 9a−u with HCl−EtOAc furnished a library of 21 analytically pure 4-(2-aminoethyl)-1H-pyrazol-5-ols (di)hydrochlorides 8/8’a−u in 40−100% yields.