串联炔-异氰[3+2]环加成/Boulton-Katritzky重排/扩环反应构建吡咯并[3,2-d]嘧啶-4-酮化合物  

Synthesis of Pyrrolo[3,2-d]pyrimidin-4-ones via Cascade Alkyne−isocyanide[3+2]Cycloaddition/Boulton-Katritzky Rearrangement/Ring Expansion Process

作　　者：罗江浩 马浩文 张杰豪 周伟 蔡倩 Luo Jianghao;Ma Haowen;Zhang Jiehao;Zhou Wei;Cai Qian(International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China,College of Pharmacy,Jinan University,Guangzhou 510530)

机构地区：[1]暨南大学药学院教育部中药现代化与创新药物研究国际合作联合实验室,广州510530

出　　处：《化学学报》2023年第8期898-904,共7页Acta Chimica Sinica

基　　金：国家自然科学基金(Nos.22001093,21971087);广东省基础与应用基础研究项目(No.2022A1515010200)资助。

摘　　要：吡咯并[3,2-d]嘧啶-4-酮骨架在药物设计中广受关注,该骨架是众多生物活性分子的核心结构单元.目前已报道的吡咯并[3,2-d]嘧啶-4-酮骨架的合成方法有限且存在原料不易得、反应条件苛刻、合成步骤长、产率低和产物结构不易修饰等缺陷.因此,发展吡咯并[3,2-d]嘧啶-4-酮骨架的新型高效合成策略在合成化学与药物化学领域均具有重要的研究意义.最近,一种通过串联炔-异氰[3+2]环加成/Boulton-Katritzky重排/酰基迁移扩环反应构建9-去氮鸟嘌呤化合物的新方法被报道,该方法以氮杂异噁唑衍生的炔丙酰胺化合物和异氰化合物为原料.鉴于异噁唑化合物也是Boulton-Katritzky重排反应常使用的底物,此工作进一步研究了一系列异噁唑衍生的炔丙酰胺化合物与异氰化合物的上述串联反应,成功构建了一系列吡咯并[3,2-d]嘧啶-4-酮化合物.Pyrrolo[3,2-d]pyrimidin-4-ones are valuable structural motifs in many bioactive compounds and pharmaceuticals.Such structures have received extensive attentions from synthetic community.Two general strategies have been developed for the formation of the fused pyrimidine-pyrrole structure:one is to construct the pyrimidine ring from substituted pyrroles,and the other is to construct the pyrrole ring from 5,6-functionalized pyrimidines.However,these methods have generally required multiple synthetic steps and the use of starting materials with uncommon functional groups,and also suffered with other drawbacks such as harsh reaction conditions and limited substrate scope.Thus,it is highly desirable to develop facile and practical approaches for the construction of structural diversified pyrrolo[3,2-d]pyrimidin-4-ones.Very recently,we have developed an alkyne-isocyanide[3+2]cycloaddition/Boulton-Katritzky rearrangement/ring expansion reaction for the synthesis of 9-deazaguanines from 1,2,4-oxadiazole-derived propiolamides with isocyanides.Different from traditional Boulton-Katritzky rearrangement(BKR),which is to form stable five-membered rings,the method provides a facile access to fused heterocycles via forming an unstable BKR spirocyclic intermediate and followed by a spontaneous ring expansion via acyl migration.In this work,to further expand the scope of this method,the[3+2]cycloaddition/BKR-ring expansion reactions of isoxazole-derived propiolamides with isocyanides were developed.The reactions were performed with CuI as the catalyst and Cs_(2)CO_(3) as the base in toluene/N,N-dimethylformamide(DMF)(1∶3,V∶V)at room temperature for the alkyne-isocyanide[3+2]cycloaddition and then at 110℃ for the BKR-ring expansion process.A variety of isoxazolederived propiolamides and isocyanides were well tolerated in the reactions and afforded the desired pyrrolo[3,2-d]pyrimidin-4-one products in satisfactory yields.The control experiments were performed to elucidate the reaction process:copper catalyst is used only for

关 键 词：炔-异氰[3+2]环加成 Boulton-Katritzky重排 扩环反应 [3 2-d]嘧啶-4-酮 串联反应 

分 类 号：O626[理学—有机化学]