Streamlined Synthesis of 6-((1H-1,2,3-Triazol-4-yl)methyl)-1H-pyrrolo [3,4-d]pyridazin-1-one System via Sequential N-Alkylation, CuAAC, and [4 + 2] Cyclization Reactions

An efficient sequential three-step reaction methodology for the synthesis of three new series-1-(prop-2-yn-1-yl)-1H-pyrroles, methyl 4-acetyl-1-((1H-1,2,3-triazol-4-yl)methyl)-1H-pyrrole-3-carboxylates and 6-((1H-1,2,3-triazol-4-yl)methyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-ones-is reported. The methodology comprises: (i) N-alkylation reactions of polyfunctionalized 1H-pyrroles-which were previously obtained from (E)-methyl 2-azido-3-arylacrylates-with propargyl bromide in order to obtain 1H-pyrroles; (ii) standard copper-catalyzed azide-alkyne cycloaddition (CuAAC) involving organic azides (benzyl-, 4-methoxybenzyl- and 4-chlorobenzyl, as well as n-octyl azide) and N-propargylated 1H-pyrroles to give triazolyl derivatives, as methyl 1H-pyrrole-3-carboxylates (click chemistry); and (iii) [4 + 2] cyclocondensation reactions of the ketoesters in the presence of hydrazine hydrochloride in order to furnish the desired series of pyrrolo[3,4-d]pyridazin-1-ones at total yields up to 54%.

本研究报道了一种高效的三步连续反应方法，用于合成三类新型化合物：1-(丙-2-炔-1-基)-1H-吡咯、4-乙酰基-1-((1H-1,2,3-三唑-4-基)甲基)-1H-吡咯-3-羧酸甲酯，以及6-((1H-1,2,3-三唑-4-基)甲基)-2,6-二氢-1H-吡咯并[3,4-d]哒嗪-1-酮。该方法包含如下步骤：(i) N-烷基化反应：以炔丙基溴为烷基化试剂，对由(E)-2-叠氮基-3-芳基丙烯酸甲酯预先制备得到的多官能团化1H-吡咯进行N-烷基化，得到N-炔丙基取代的1H-吡咯；(ii) 铜催化叠氮-炔环加成反应（CuAAC）：以有机叠氮化物（包括苄基叠氮、4-甲氧基苄基叠氮、4-氯苄基叠氮以及正辛基叠氮）与上述N-炔丙基化1H-吡咯为底物，通过经典点击化学合成得到三唑取代的1H-吡咯-3-羧酸甲酯衍生物；(iii) [4+2]环缩合反应：以酮酸酯为底物，在盐酸肼存在下发生[4+2]环缩合反应，最终得到目标吡咯并[3,4-d]哒嗪-1-酮类化合物，总收率最高可达54%。