1、有机化学有机化学 Chinese Journal of Organic Chemistry ARTICLE *Corresponding authors.E-mail:; Received June 12,2022;revised August 16,2022;published online September 15,2022.Project supported by the National Natural Science Foundation of China(Nos.21563025,22162022).国家自然科学基金(Nos.21563025,22162022)资助项目.Chin.
2、J.Org.Chem.2023,43,195201 2023 Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences http:/sioc- DOI:10.6023/cjoc202206017 研究论文研究论文 I2催化-酮腈与 1H-吡唑-5-胺的环化反应 桑 田 贾 帆 何 静 李春天 刘 岩*刘 平*(石河子大学化学化工学院 化工绿色过程兵团重点实验室 新疆石河子 832003)摘要摘要 开发了一种碘催化的 1H-吡唑-5-胺和-酮基腈的环化反应,用来合成吡唑并1,5-a嘧啶.该方法提供了获得结构多样的吡唑并
3、1,5-a嘧啶衍生物的有效途径,其产率可达到良好至优秀.该方法具有反应条件简单温和、底物范围广等优点,并可以克级规模放大反应.关键词关键词 I2催化;环化反应;吡唑并1,5-a嘧啶 I2-Catalyzed Cyclization of-Ketonitrile with 1H-Pyrazol-5-amine Sang,Tian Jia,Fan He,Jing Li,Chuntian Liu,Yan*Liu,Ping*(Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan,School o
4、f Chemistry and Chemical Engineering,Shihezi University,Shihezi,Xinjiang 832003)Abstract An I2-catalyzed cyclization reaction of 1H-pyrazol-5-amine and-ketonitrile for the synthesis of pyrazolo1,5-apyrimidines was developed.This method provides an efficient way to obtain structurally diverse pyrazol
5、o1,5-apyrimidine derivatives in good to excellent yields.The method has the advantages of simple operation,mild reaction conditions and a wide range of substrates.It can also be scaled up.Keywords I2-catalyzed;cyclization reaction;pyrazolo1,5-apyrimidines 1 Introduction Pyrazolo1,5-apyrimidines are
6、an important class of heterocyclic compounds that have been widely used in medicine and agrochemicals,1 such as the sleeping drugs Indiplon2 and Zaleplon,3 the anxiolytic drug Ocinaplon,4 and the fungicide Pyrazophos5(Figure 1).6-7 Therefore,the construction of pyrazolo1,5-apyrimidines has attracted
7、 extensive attention in the field of organic synthesis.In 2006,Barsy et al.8 used 5-amino-3-phenylpyrazole and tri-phenylphosphine as raw materials to obtain 5-(triphenyl-orthophosphorylimino)-3-phenylpyrazole,and then pyra-zolo1,5-apyrimidines were produced by the intermolecu-lar Azido-Wittig react
8、ion of 5-(triphenylorthophospho-rylimino)-3-phenylpyrazole with-carbonitrile(Scheme 1a).However,the toxic triphenylphosphine and the organic base triethylamine are necessary for this process.In 2015,Aggarwals group reported the synthesis of pyrazolo1,5-apyrimidines by the reaction of 5-amino-3-hydra
9、zino-pyrazole dihydrochloride with-ketonitrile in the presence of sodium acetate(Scheme 1b).9 But the substrate 5-amino-3-hydrazinopyrazole dihydrochloride is not readily available.In 2016,Tus group reported the I2-catalyzed multicomponent bicyclization reaction of-ketonitrile with aryl sulfonyl hyd
10、razides for the synthesis of pyrazolo-1,5-apyrimidin-4-ium sulfonates,which were subse-quently converted to pyrazolo1,5-apyrimidines in the presence of NaOH(Scheme 1c).10 However,this reaction is only suitable for the preparation of 2,5-identical diaryl-substituted pyrazolo1,5-apyrimidines.On the ba
11、sis of the above work and our continuous research interests,11-12 we report herein the iodine-catalyzed reactions of 1H-pyrazol-5-amine and-ketonitriles.A series of novel 2,5-different-ly diaryl-substituted pyrazolo1,5-apyrimidine derivatives(Scheme 1d).2 Results and discussion Firstly,the reaction
12、conditions for the reaction of 3-phenyl-1H-pyrazol-5-amine 1a with-ketonitrile 2a to form 2,5-diphenylpyrazolo1,5-apyrimidin-7-amine 3a(Table 1)were optimized.When using 20 mol%I2 as the catalyst and ethanol as the solvent,the target product 3a was obtained in 87%yield at a reaction temperature of 8
13、0 有机化学 研究论文 196 http:/sioc- Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences Chin.J.Org.Chem.2023,43,195201 Figure 1 Some pyrazolo1,5-apyrimidine-containing drugs Scheme 1 Synthesis of pyrazolo1,5-apyrimidinesTable 1 Optimization of the reaction conditionsa Entry Catalyst(mol%)Sol
14、vent/mL T/t/h Yieldb/%1 I2(20)EtOH 80 12 87 2c I2(20)EtOH 80 12 Trace 3 I2(20)DMSO 80 12 94 4d I2(20)EtOH 80 12 75 5 I2(20)DMF 80 12 56 6 I2(20)CH3CN 80 12 28 7 TBAI(40)EtOH 80 12 11 8 NIS(40)EtOH 80 12 35 9 NBS(40)EtOH 80 12 42 10 NCS(40)EtOH 80 12 37 11 FeCl3(40)DMSO 80 12 54 12 AlCl3(40)DMSO 80 1
15、2 79 13 I2(10)DMSO 80 12 64 14 I2(40)DMSO 80 12 57 15 I2(20)DMSO 100 12 63 16 I2(20)DMSO 60 12 39 17 I2(20)DMSO 80 8 48 a Reaction conditions:1a(0.2 mmol),2a(0.3 mmol),solvent(2 mL),catalyst(20 mol%),under air.b Isolated yield.c Additive K2CO3(50 mol%).d Catalyst DMSO(20 mol%).(Entry 1).Adding 50 mo
16、l%K2CO3 to the system can only afford a trace amount of the target product 3a(Entry 2).Then,the reaction solvents such as dimethyl sulfoxide(DMSO),N,N-dimethylformamide(DMF)and CH3CN(Entries 35)were screened.The experimental results showed that DMSO was the best solvent for the reaction,and the target product 3a was obtained in 94%yield(Entry 3).Next,the types of catalysts were screened.When the catalyst was changed from I2 to tetrabutylammonium iodide(TBAI)and N-iodo-succininide(NIS),the target
