Combining Biginelli multicomponent and click chemistry: Generation of 6-(1,2,3-triazol-1-yl)-dihydropyrimidone libraries
Combining Biginelli multicomponent and click chemistry: Generation of 6-(1,2,3-triazol-1-yl)-dihydropyrimidone libraries
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DOI：
10.1021/cc0498938
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发表时间：
2004-11-01
影响因子：
--
通讯作者：
Kappe, CO
中科院分区：
文献类型：
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作者：
Khanetskyy, B;Dallinger, D;Kappe, CO
报道了高通量合成6-(1，2，3-三氮唑-1-基)-二氢嘧啶酮类化合物的高效液相合成方法。该多步骤序列包括在快速流动条件(停留时间为1分钟)下，使用可回收的聚合物支撑的溴化剂，在C6-甲基位置对二氢嘧啶类前体(DHPM、Biginelli化合物)进行初始溴化。6-溴甲基二氢嘧啶中间体随后经过微波辅助的叠氮化步骤(25分钟)，提供关键的6-叠氮甲基二氢嘧啶前体。在序列的最后一步，叠氮化合物在铜(I)催化(叠氮-乙炔连接，“点击化学”)下与末端乙炔反应，利用受控微波辐射(20分钟)以区域特定的方式(1，4-三氮唑)以中等的总收率提供目标6-(1，2，3-三唑-1-基)-二氢嘧啶酮。总共建立了一个包含27个化合物的文库，其中有4个多样性点。
Efficient solution-phase protocols for the high-throughput synthesis of 6-(1,2,3-triazol-1-yl)-dihydropyrimidones are reported. The multistep sequence involves the initial bromination of dihydropyrimidones precursors (DHPMs, Biginelli compounds) at the C6-methyl position, using a recyclable polymer-supported brominating agent under rapid flow-through conditions (residence time of 1 min). The 6-bromomethyldihydropyrimidone intermediates were subsequently subjected to a microwave-assisted azidation step (25 min), providing the key 6-azidomethyldihydropyrimidone precursors. In the final step of the sequence, the azides were treated with terminal acetylenes under Cu(I) catalysis (azide-acetylene ligation, "click chemistry") to provide the target 6-(1,2,3-triazol-1-yl)-dihydropyrimidones in a regiospecific fashion (1,4-triazoles) in moderate overall yield utilizing controlled microwave irradiation (20 min). In total, a library of 27 compounds was prepared with 4 points of diversity.