吲唑的简便合成

第29卷第1期蔡可迎等吲唑的简便合成53化学试剂2007 29(1 )53 ~54吲唑的简便合成蔡可迎”宗志敏魏贤勇(中国矿业大学化工学院江苏徐州221008 )摘要:以邻硝基甲苯为原料在乙醇钠催化下与草酸二乙酯缩合然后经水解、双氧水氧化、盐酸酸化得到邻硝基苯乙酸,收率62%。邻硝基苯乙酸用8%硫化铵溶液在回流温度下还原2h后再进行重氮化反应将得到的重氮盐溶液于室温放置24 h得到吲唑收率71%。两步总收率44%。关键词吲唑邻硝基苯乙酸合成中图分类号:0626文献标识码:A文章编号0258-3283( 2007 )01 -0053-02吲唑是重要的有机合成中间体其许多衍生反应瓶中在搅拌下分批投入1.6 g( 70 mmol )切物具有药物活性[3。例如,吲唑环在Cu( II )催碎的金属钠待金属钠全溶后冷却至室温，得到化下与芳基硼酸反应可得1-芳基吲唑4] ,1芳基乙醇钠的无水乙醇溶液。加入8.8 g( 60 mmol )吲唑可作避孕药[5] ;吲唑与酸酐或酰氯反应可得草酸二乙酯搅拌待物料混合均匀后滴加8.2 gN_酰基吲唑[°]其中一些N-酰基吲唑具有驱虫活( 60 mmol )邻硝基甲苯,約0.5 h加完然后于室性。吲唑的合成方法主要有: )以吲唑-3~羧酸为温反应0.5 h ,升温回流反应1.0 h。稍冷加入原料进行脱羧反应得到72 )以3-腈基吲唑为原30 mL水进行水解加热回流1.5 h。水解完毕料进行脱腈基反应得到7]3)以3-氯吲唑为原料经水蒸气蒸馏回收未反应的邻硝基甲苯。冷至室经脱氯得到[8];4)邻甲基苯胺与乙酐、醋酸钾和温滴加30%双氧水,同时不断取反应液用氢氧亚硝酸异戊酯的混合物料反应得到9] 5 )4-醛基化钠溶液检测,当 反应液遇氢氧化钠溶液不变色吡唑与丁二酸二乙酯在叔丁醇钾催化下缩合得时表明反应已完成。将物料冷至室温用盐酸酸到101。方法1 )2 )和3 )的问题是原料不易获得;化至pH2静置有结晶析出。抽滤所得固体用方法4 )的反应体系复杂,导致后处理困难收率乙醇/水(体积比1: 3 )重结晶,干燥后得白色针低;方法5 )需在强碱催化下进行条件苛刻。状晶体6.74g收率62%。m.p. 138~140 C(文以价廉易得的邻硝基甲苯为原料,在乙醇钠献'2]值:140~141 C )。IR( KBr压片)n cm-':催化下与草酸二乙酯进行缩合反应再经水解、氧3 20( - -COOH); 700( C=0);1 600 ,1 500 ,1化及酸化制得邻硝基苯乙酸后者通过还原、重氮450(苯环)。化、环合及脱羧可得到吲唑:1.2.2吲唑的合成将1.2.1制得的3.62g(20mmol)邻硝基苯C00HLCOCJHJ,NnOC.H.-NO,_ (NH)S乙酸和35 mL 8%( NH, )S溶液加入100 mL烧凸m,2.H,0.HO,H瓶中,回流反应2 h。将反应液冷却、过滤缓慢滴NaNO,H*.加浓盐酸至pH <3。用冰盐浴冷却至5 C以下,搅拌下缓慢滴加4.2mL30%的亚硝酸钠水溶液,1实验部分约10 min加完。加完后再反应10min,用KI淀1.1主要仪器与试剂粉试纸检验NaNO2是否过量，如过量可加入少量惠普HP6890/5973型气相色谱/质谱联用尿素。反应结束后讨滤除去未反应的邻硝基苯乙仪美国Nicolet公司Magna-IR 560红外光谱仪。中国煤化工断有固体析出并且有邻硝基甲苯为工业品(质量分数>99.7% ),TYHCNMHG其他试剂均为分析纯。收稿日期2006-05-251.2实验步骤基金项目江苏省高新技术产业发展项目( JHB05-33 )。1.2.1邻硝基苯乙酸的合成作者简介蔡可迎( 1970-)男江苏沛县人,博士生,讲师,参照文献11 ]制备:将 20 mL无水乙醇加入从事有机中间体的合成研究。54化学试剂2007年1月气体逸出。抽滤得鳞片状固体热水重结晶、真空dazoles[ J ] Tetrahedron Lett. ,2005 ,46( 21 ):3 771-3干燥得淡黄色粉末1. 68 g收率71%(以邻硝基774.苯乙酸计)。m.p. 145~147 C(文献8]值:145 ~[5 ]LEBEDEV A Y ,KHARTULYARI A s ,VOSKOBOYNIK-OV A Z. Synthesis of 1-aryl-1H-indazoles via palladium-146.5C)。IR(KBr压片),v,cm-1:3400catalyzed intramolecular amination of aryl halide[ J] J.(- -NH-);3 300(- -NH- 缔合);1 600 ,1 550 ,Org. Chem. 2005 70( 2 ) 596-602.1 500(苯环);700(苯的1 2-二取代)。 MS ,m/z[ 6 ]KINGSBURY W D GYURIK R J ,THEODORIDES V J ,( % ):118( M* ,100)91(37 );78(5 );63(21 )52et al. Synthesis of l-and 2-substituted indazoles as anthel-(8 )。mintic agents[ J ] J. Med. Chem. ,1976 ,19( 6 ) :839-840.2结果与讨论. [ 7 ]ROUSSEAU V ,LINDWALL H G. Strueture and ultravio-重氮盐能和许多具有活泼氢原子的化合物进let absorption spectra of indazole ,3-substituted indazole行偶合反应而在邻氨基苯乙酸形成的重氮盐中and some of their derivatives[ J ] J. Am. Chem. Soc.苯环.上重氮基邻位的亚甲基由于羧基吸电子效应1950 72(7 ) 3047-3 048.而具有活泼氢原子,因此重氮盐能进行分子内偶[ 8 ]徐克勋.精细有机化工原料及中间体手册M]北京:化学工业出版社,1998. 431-432.合形成稳定的五元环羧基同时脱去,生 成吲唑,[ 9 ]CHRISTOPH R ,VOLKER H. Simplifcation of the jacob-其过程如下。son indazole synthesis[ J ] Synthesis ,1972 ( 7 ) :375-,C00H~376.“CO0H[ 10 ]GIOVANNI B P ,BARBARA C GIAMPIEROS et al.AN≈N°Crnew synthetic approach to indazole synthesis[ J ] Syn-在吲唑合成过程中,重氮盐溶液须置于室温.thesis ,1997 ( 10):1 140-1 142.(约20C)使其缓慢反应才能有较高的收率。温[ 11 ]DICARLO F J. Synethesis of oxindole[ J ] J. Am. Chem.度较低反应缓慢,且有重氮盐分解造成吲唑收Soc. ,1944 66( 8)1 420.率降低温度较高,反应速度加快,但有焦油状副[ 12 ]WILIAM B ,WRICHT JR ,KENNETH H C. Cyelie产物生成也使吲唑收率降低。hydroxamic acids derived from indole[ J ] J. Am. Chem.Soc. 1956 78( 1 )221-224.参考文献:[ 1 ]SONGJJ ,YEE N K. Synthesis of 1-aryl-1 H-indazoles viaSimple synthesis of indazole CAI Ke-ying* ,ZONG Zhi-min ,WEI Xian-yong ( School of Chemical Engineering ,Chinathe palladium-catalyzed cyclization of N-aryl-N'< o-bro-University of Mining and Technology ,Xuzhou 221008 ,Chi-mobenzyl )hydrazines and[ N-aryl-N'< o-bromobenzyI )-hydrazinato-N" ]-triphenyl-phosphonium bromides[ J ]na) ,Huaxue Shiji 2007 29( 1 ) 53 ~54Abstract :o-Nitrophenylacetic acid was synthesized by con-Tetrahedron Lett. 2001 42( 16 ) 2937-2 940.[2 ]HUANG Li-jau ,SHIH Mei-ling ,CHEN Hua-sin ,et al.densation of o-nitrotoluene with diethyl oxalate catalyzed bySynthesis of N2 ( substituted benzyl )-3( 4-methylphe-Cz HAONa followed by hydrolysis poxidation with H2O2 and a-cidification with HCI resulting in an approximate 62% yield.nyl ) indazoles as novel anti-angiogenic agents[ J ].Indazole was synthesized in 71% yield by keeping the diazo-Bioorg. Med. Chem. 2006 ,14( 2 ) 528 536.[ 3 ]HEINZ R S ,BLECKMAN ,MICHAEL T K et al. Synthe-nation solution for 24 h at room temperature ,which was pre-pared from reducing o-nitrophenylacetic acid with 8%sis of disubstituted indazole compounds as cyclin depend-( NH, )2S solution upon refluxing for 2 h and diazotizing withent kinase inhibitors and methods for inhibiting cell pro-HCl and NaNO2. The overall yield was around 44%.liferation :WO 2 001 053 268[ P ].2001 -07-26.[4 ]HARI Y SHOJI Y ,AOYAMA T. Regioselective synthesisKev wnrds indavnle. 'n-nitrnnhenvlacetic acid synthesis中国煤化工of I-arylindazoles via N-arylation of 3-trimethylsilylin-TYHCNMH G .请您继续支持关心本刊共同进步