ImageVerifierCode 换一换
格式:DOC , 页数:155 ,大小:5.29MB ,
资源ID:2438318      下载积分:15 金币
快捷下载
登录下载
邮箱/手机:
温馨提示:
快捷下载时,用户名和密码都是您填写的邮箱或者手机号,方便查询和重复下载(系统自动生成)。 如填写123,账号就是123,密码也是123。
特别说明:
请自助下载,系统不会自动发送文件的哦; 如果您已付费,想二次下载,请登录后访问:我的下载记录
支付方式: 支付宝    微信支付   
验证码:   换一换

加入VIP,免费下载
 

温馨提示:由于个人手机设置不同,如果发现不能下载,请复制以下地址【https://www.docduoduo.com/d-2438318.html】到电脑端继续下载(重复下载不扣费)。

已注册用户请登录:
账号:
密码:
验证码:   换一换
  忘记密码?
三方登录: 微信登录   QQ登录   微博登录 

下载须知

1: 本站所有资源如无特殊说明,都需要本地电脑安装OFFICE2007和PDF阅读器。
2: 试题试卷类文档,如果标题没有明确说明有答案则都视为没有答案,请知晓。
3: 文件的所有权益归上传用户所有。
4. 未经权益所有人同意不得将文件中的内容挪作商业或盈利用途。
5. 本站仅提供交流平台,并不能对任何下载内容负责。
6. 下载文件中如有侵权或不适当内容,请与我们联系,我们立即纠正。
7. 本站不保证下载资源的准确性、安全性和完整性, 同时也不承担用户因使用这些下载资源对自己和他人造成任何形式的伤害或损失。

版权提示 | 免责声明

本文(Synthesis and Properties of Acetylenic Derivatives of Pyrazoles.doc)为本站会员(dzzj200808)主动上传,道客多多仅提供信息存储空间,仅对用户上传内容的表现方式做保护处理,对上载内容本身不做任何修改或编辑。 若此文所含内容侵犯了您的版权或隐私,请立即通知道客多多(发送邮件至docduoduo@163.com或直接QQ联系客服),我们立即给予删除!

Synthesis and Properties of Acetylenic Derivatives of Pyrazoles.doc

1、1Synthesis and Properties of Acetylenic Derivatives of PyrazolesSERGEI F. VASILEVSKY AND EUGENE V. TRETYAKOVInstitute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences, 630090, Novosibirsk, Russian Federation.JOSE ELGUEROInstitutos de Qumica Fsica y Qumica Mdica

2、, Consejo Superior de Investigaciones Cientficas, 28006 Madrid, Spain.I. INTRODUCTION3II. SYNTHESIS OF ACETYLENYLPYRAZOLES4A. REACTIONS OF CYCLIZATION .4B. REACTIONS OF ELIMINATION29C. CROSS-COUPLING OF HALOGENOPYRAZOLES WITH TERMINAL ACETYLENES AND ITS COPPER(I) SALTS39D. PYROLYSIS.65III. CHEMICAL

3、PROPERTIES OF ACETYLENYLPYRAZOLES66A. REACTIONS OF TERMINAL ACETYLENES WITH PARTICIPATION OF C-H BOND .661. The Favorsky reaction .662. Homo-coupling 703. Cross-coupling.724. Aminomethylation765. Halogenation .806. Alkylation.827. Metalation82B. REACTIONS WITH PARTICIPATION OF CC BOND831. Halogenati

4、on .832. Hydration.833. Hydrohalogenation852. Hydratation854. Hydrazination 865. Oxidation .86C. REACTIONS WITH PARTICIPATION OF C-X BOND 911. Retro Favorsky reaction 912. Desilylation973. Destannylation.984. Decarboxylation 985. Cineamination .1006. Transhalogenation.101D. HETEROCYCLIZATIONS OF VIC

5、INAL FUNCTIONALLY SUBSTITUTED PYRAZOLYLACETYLENES 911. Aminopyrazolylacetylenes .1052. Nitroacetylenylpyrazoles .1073. Acetylenylpyrazolcarboxylic acids 1074. Amides of acetylenylpyrazolcarboxylic acids1155. Hydrazides of acetylenylpyrazolcarboxylic acids .11926. Diazonium salts of acetylenylpyrazol

6、es.123IV. STRUCTURE, SPECTRA AND PROPERTIES OF ACETYLENYLPYRAZOLES .129A. MOLECULAR DIMENSIONS .129C. IR SPECTRA130B. UV SPECTRA 131D. 1H NMR SPECTRA133E. 13C NMR SPECTRA .134F. THERMODYNAMIC CH-ACIDITY OF ETHYNYLPYRAZOLES.134G. MAGNETIC PROPERTIES OF SPIN-LABELLED ALKYNYLPYRAZOLES .137V. BIOLOGICAL

7、 PROPERTIES OF ACETYLENYLPYRAZOLES141VI. CONCLUSIONS .145REFERENCES 1463I. IntroductionThe acetylenic derivatives of the pyrazoles1 analogs have aroused great interest in recent years due to the wide variety of their biological and pharmacological properties (72IZV2524; 93MIP1; 96BMC797; 99USP592576

8、9, 99BMC979).On the other hand, acetylenylpyrazoles are highly valuable intermediates because a triple bond is susceptible to reactions of nucleophilic, electrophilic, radical and cycloaddition, and terminal acetylenes display the unusually high CH-acidity which can be used for both functionalizing

9、and building up C-C bonds. In addition, compounds with a vicinal arrangement of a multiple bond and a functional group prone to intramolecular addition, make it possible to produce the annealed heterocyclic systems. This predetermines the potentialities of alkynylpyrazoles as highly reactive syntons

10、 (83IZV688; 85IZV1367; 98HC519; 99JCS(P1)3721).At the same time, the results of works on the chemistry of acetylenic derivatives of pyrazole are scattered over original papers, patents, dissertations and are unavailable for a wide circle of chemists. This review is aimed at compensating this gap.1 T

11、he review described syntheses and properties of alkynylpyrazoles and its annelated analogs in which triple bond directly connected with the heterocycle.4II. Synthesis of acetylenylpyrazolesA. Reactions of cyclizationThis type of reactions is represented by 1,3-dipolar addition classified by Huzgen (

12、69MI1). The 1,3-bipolar addition is the interaction between 1,3-dipole and a multiple system d=e, i.e. “dipolarophyl”, followed by a cyclic shift of electrons and completed with a 5-membered ring closure (Scheme 1). adecb adecbScheme 1The first representative of acetylenic derivatives 3(5)-ethynylpy

13、razole, was produced by condensation of diacetylene with diazomethane by Kuhn and Henkel (41LA279), and later by other authors (69IZV2546), or of acetylene with diazopropyne (62AG252; 68LA113) (Scheme 2). HCCCCH+ N+N-HCCH+HCCN+N- NHCCHScheme 2The mixture of products of different composition forms de

14、pending on the diacetylene-diazomethane ratio (68LA124).HCCCCH NHCCHCH2N20 oC NCCHNCH NNHHNN+ + +Scheme 3With ratio 1:1 of butadiyne and diazomethane, 3(5)-ethynylpyrazole dominates (55%). The yields of isomeric 3- and 5-ethynyl-1-methylpyrazoles are 8 and 11%, respectively. The double excess of dia

15、zomethane leads mainly to the mixture of N-methylated isomers (81%), 10% of 3(5)-ethynylpyrazole and a small amount (3%) of bipyrazole (68LA124) (Scheme 3).The monosubstituted diacetylenes including the 3-triethylstannyl derivative (81%) (71ZOB2230) reacts with 1,3-dipole, first, with a terminal ace

16、tylenic group with a 3(5)-alkyn-1-ylpyrazole closure (65ZOR610; 68KGS695) (Scheme 4).5CCCCH NHCCCH2N2R RR = Me, Et, C(H3)2OCH(Me)OBu, Sn(Et)3Scheme 41,3-Dipolar additions of diazomethane to acetylenes under the mild conditions are restricted to monosubstituted acetylenes, and thus the formation of p

17、yrazole derivatives 1 (1,3-dipolar additions, C=C isomerization, then methylation) reinforces the existence of the terminal acetylene in caryoynencins (87TL3981) (Scheme 5).HCCCC OH OHO CC OH OONNR3 3CH2N2 1 R = Me,2 = HScheme 5While Kakisawa et al. (87TL3981) reported formation of N-methylpyrazole

18、1, later Yamaguchi et al. obtained N-H derivative 2 by reaction of caryoynencins with diazomethane in ethyl acetate at 0 oC (94BSJ1717; 95JMC5015). The 1,3-dipolar addition was quite sensitive to the solvent employed, and very low yield of pyrazole derivative 2 was formed in ether or methanol (Schem

19、e 5).As compared with monosubstituted diacetylenes, the disubstituted ones add diazomethane to form 4-alkynylpyrazoles (58CB1841; 60CB1931; 68LA124). Diazomethane reacts similarly with either ethers of polyacetylenic acids (57JCS2012) or free acids (57CB124; 60CB1931; 68LA124), which is the method f

20、or synthesizing the esters of pyrazole-3-carboxylic acids with acetylenic substituent at position 4 of the cycle (Scheme 6).NHNCH2N2 CCR1COMeCCR1 COR2nR1 = Et, R2 = Me, n = 2;R1 = Me, R2 = H, n = 2;R1 = Me, R2 = H, n = 3 n-1Scheme 6Thus, 1,4-dibenzoylbutadiyne-1,3 with dizomethane forms 3(5)-benzoyl

21、ethynylpyrazole (yield 59%) (68LA124). In a similar way, the reaction of 2,7-dimethyl-octadiyne-2,7-diol-2,7 with diazomethane leads to 4-3-(1-hydroxy-1-methyl-ethyl)-1H-pyrazol-4-yl-2-methyl-but-3-yn-2-ol in 64% yield (58CB1841) (Scheme 7).6 NHNCH2N2 CCRRCCR CCRR = C(O)-C6H5, C(H3)2OH, CH2O-C(O)-C6

22、H5, CH2O-C(O)-p-Br-C6H4, CH2-()-m-Br-64,Scheme 71,6-Dicarboaryloxyhexadiynes-1,6 react like the 1,4-disubstituted butadiynes giving rise to the corresponding 3-(aroyloxymethylene)-4-(3-aroyloxypropynyl-1)pyrazole in a 84-89% yield (87MI1). Reaction of symmetric diacetylene esters of aromatic acids w

23、ith diazomethane gave 3-(benzoyloxymethyl)-4-(benzoyloxypropyn-1-yl-1)pyrazoles (Scheme 7 with R = -CH2OC(O)C6H4-Y; Y = H, Br-2, Br-4, NO2-2, NO2-4, (NO2)2-3,5, OMe-2, OMe-3, OMe-4 (87MI2); R = -3-Py, -4-Py (84MI1) and with R = CH2OC(O)C6H4-Y; Y = Cl-4, Cl-2, Cl2-2,4, I-2, 3-I (86MI2).Note that the

24、1,4-substituted butadiynes with diazomethane can form two isomers. Kuznetsov with co-workers have considered in detail this problem and established that diphenyldiacetylene with diazomethane form, in standard conditions (ether, 0oC, 9 days), only one of two possible regioisomers, i.e., 4-phenyl-3(5)

25、-phenylethynylpyrazole (yield 86%) (93ZOB1107). The cyclization of derivatives of phenoxy-2,4-hexadiyn-6-oles with diazomethane leads only to one isomer of alkynylpyrazole (Scheme 8) (76MI1; 77MI1).NHNCH2N2 CCCCCCAr = o-Br-C6H4, p-Br-C6H4, 2,4-Br2-C6H3, o-NO2-C6H4, m-NO2-C6H4, p-NO2-C6H4OHOAr OHOArS

26、cheme 8At the same time, according to the data (68LA113; 71CAS1731), the disubstituted diacetylenes with diazomethane form both the 3- and 4-acetylenylsubstituted pyrazoles. In this case, the former are formed in trace amounts (cheme 9).NHNCH2N2 CCArCCAr CCAr = C6H5, p-Br-C6H4, p-Cl-C6H4, p-CH3-C6H4

27、; R = CH3Ar = 65, R = 65;Ar = C6H5, = OCH3RORO + NHNCCArROmaijor product minor productcheme 97As follows from the Table I, the 4-acetylenylderivative yields depend on both the reaction time and the structure of aromatic and acylic components (molecule polarity). If more than one equivalent of diazom

28、ethane used the N-methylation of pyrazole occurs.TABLE IDependence of the Yield of Alkynylpyrazoles and Its N-Methyl Derivatives on the Composition of Diyne/Diazomethane Mixture and Reaction TimeaNR1R3 R4R5Diyne and reaction condition R1 R3 R4 R5 m.p., oC Yield (%)C6H5-CC-CC-COCH33 min.HHCOCH3CC-C6H

29、5CC-C6H5COCH3HH157 526C6H5-CC-CC-COCH340 min.HHCOCH3CC-C6H5CC-C6H5COCH3HH157 747C6H5-CC-CC-COCH324 h, 2 equivalents of CH2N2HCH3CH3COCH3HCOCH3CC-C6H5CC-C6H5CC-C6H5HCOCH3H157 44429p-Br-C6H5-CC-CC-COCH340 min.H COCH3 CC-p-BrC6H5 H 210 92p-Br-C6H5-CC-CC-COCH316 h, 2 equivalents of CH2N2HCH3CH3HCOCH3HCO

30、CH3CC-p-BrC6H5CC-p-Br-C6H5CC-p-Br-C6H5CC-p-Br-C6H5COCH3HCOCH3HH210 5119121.7p-Cl-C6H5-CC-CC-COCH340 min.H COCH3 CC-p-Cl-C6H5 H 205 90p-Cl-C6H5-CC-CC-COCH37 days, 2 equivalents of CH2N2HCH3CH3COCH3HCOCH3CC-p-Cl-C6H5CC-p-Cl-C6H5CC-p-Cl-C6H5HCOCH3H205 383227p-CH3-C6H5-CC-CC-COCH340 min.HHCOCH3HCC-p-CH3

31、-C6H5CC-p-CH3-C6H5HCOCH3199 815p-CH3-C6H5-CC-CC-COCH316 daysHCH3CH3HCOCH3HCOCH3CC-p-CH3-C6H5CC-p-CH3-C6H5CC-p-CH3-C6H5CC-p-CH3-C6H5COCH3HCOCH3HH199 3821135(continued)8TABLE I (continued)Diyne and reaction condition R1 R3 R4 R5 m.p., oC Yield (%)p-CH3-C6H5-CC-CC-COCH317 h, 2 equivalents of CH2N2HCH3C

32、H3HCOCH3HCOCH3CC-p-CH3-C6H5CC-p-CH3-C6H5CC-p-CH3-C6H5CC-p-CH3-C6H5COCH3HCOCH3HH199 531477C6H5-CC-CC-COC6H53 min.H COC6H5 CC-C6H5 H 130 33C6H5-CC-CC-COC6H540 min.HHCOC6H5CC-C6H5CC-C6H5COC6H5HH130 706C6H5-CC-CC-COC6H519 days, 2 equivalents of CH2N2HCH3CH3COC6H5HCOC6H5CC-C6H5CC-C6H5CC-C6H5HCOC6H5H130 1

33、45034C6H5-CC-CC-COOCH33 min.HCH3HCOOCH3HCC-C6H5CC-C6H5CC-C6H5COOCH3HCOOCH3H3643C6H5-CC-CC-COOCH340 min.HCH3HCOOCH3HCC-C6H5CC-C6H5CC-C6H5COOCH3HCOOCH3H720.86C6H5-CC-CC-COOCH319 days, 2 equivalents of CH2N2CH3CH3HCOOCH3CC-C6H5CC-C6H5COOCH3H4916a From reference (71CAS1731).The standard technique for ob

34、taining alkynylpyrazoles consists in mixing up the ether solutions of diazoalkane and diacetylene or its derivatives (or diazopropyne and acetylene) and keeping reaction mass for either several hours or three weeks within a narrow temperature range (0-20 oC).According to the literature data, the sel

35、ectivity degree of interaction between diazoalkanes and diacetylenes is high enough. The main products can be represented by both of the regioisomeric ethynylpyrazoles. However, the reaction course substantially depends on the structures of both diazoalkane and diacetylene (91ZOB2286). Thus, the add

36、ition of diazomethane to the activated CC bond in arylacyldiacetylenes leads, according to the Auwers rule (29LA284) mainly or exclusively to 4-arylethynyl-3(5)-acylpyrazoles (68LA124; 71CAS1731). The interaction between diazomethane and diacetylene, its mono- and disubstituted derivative (of both a

37、liphatic and aromatic series) (93ZOB1107; 91ZOB2286) gives 3-alkynylpyrazoles which can also regioselectively react with the second diazoalkane molecule to form symmetric bipyrazoles.In case of reaction between 2-diazopropane and diphenyldiacetylene the reverse (as compared with other diynes) orient

38、ation of addition of the first molecule of diazocompound with a predominant formation of 4-phenylethynylpyrazole is observed. Therefore, it is noteworthy that whereas the regiodirectedness of the addition of diazoalkanes to alkenes is well studied and its products have, as a rule, the structure pred

39、icted with respect to electron effects, the problem of orientation of 1,3-dipoles in reactions with a triple carbon-carbon bond is not solved. Authors 9(91ZOB2286; 93ZOB1107) consider not the electron (the Auwers rule) but steric factors that are most likely to determine the courses of both of the r

40、eactions with 2-diazopropane. Indeed, in each case, the adducts form in which the bulky group C(CH3)2 adds to the triple bond carbon atom containing the less sterically bulk substituent (H -CCR Ph pyrazolyl). No wonder that the main product in the reaction between 2-diazopropane and diphenyldiacetyl

41、ene is 4-phenylethynylpyrazole. At the same time the interaction between diacetylene and diazomethane leads to the corresponding 5-ethynylpyrazole. The authors (91ZOB2286; 93ZOB1107) attribute this to the space effect.Diazopropyne reacts similarly with a monosubstituted acetylene to form 3(5)-alkyny

42、lpyrazoles (68LA113). Thus, the reaction of diazopropyne with methyl ether of acetylenecarboxylic acid results in 5-ethynyl-1H-pyrazole-3-carboxylic asid methyl ether in 48 h in 62% yield. 5-Ethynyl-1H-pyrazole-3,4-dicarboxylic acid dimethyl ester was prepared by reaction of diazopropyne with methyl

43、 ether of acetylenedicarboxylic acid (Scheme 10).CCR NHCCHH3CO2CRH3CO2C HCCCHN2R = CO2CH3, HScheme 10Under similar conditions, the interaction between diacetylene and diazoethane (68CB3700) gives rise to 5-ethynyl-3-methyl-1H-pyrazole in 34% yield (Scheme 11).HCCCCH NHCCHCH3CHN2 NNHHNN+Scheme 11Ethy

44、l diazoacetate is added endo to Me3Si(CC)2SiMe3 to give 3-ethoxyarbonyl-4-trimethylsilylethynyl-5-trimethylsilylpyrazole (88JOM247).10TABLE IIAlkynylpyrazoles Prepared by Cyclizations of 1,3-Diynes with Diazomethane1,3-DiyneRCCCCRAlkynylpyrazoles Structural formula Formula index m.p., oC b.p., oC/mm

45、 HgReported yield (%)LiteratureUnsubstitutedHCCCCH 3-Ethynyl-1H-pyrazoleab CHNH C5H4N2 45-46 86-87/455-56 65-67/0.553.5-55 (petroleum ether)4155c41LA27969IZV254668LA12471ZOB2230MonosubstitutedRCC-CCHR = CH3 3-Prop-1-ynyl-1H-pyrazole CNH C6H6N2 71-72 112-114/6 65ZOR610R = C2H5 3-But-1-ynyl-1H-pyrazol

46、e CNH C7H8N2 38-39 120-122/5 65ZOR610R = SnEt3 3-Triethylstannanylethynyl-1H-pyrazole CNH SnEt3C11H18N2Sn 141-143/0.8d420 1.3873nD20 1.547581 71ZOB2230A mixture of 7E, 9E; 7Z, 9E; 7E, 9Z;H-(CC)4-(CH=CH)2-CHOH(CH2)4CO2CH36-Hydroxy-16-(1H-pyrazol-3-yl)-hexadeca-7,9-diene-11,13,15-triynoic acid methyl

47、esterCNH RR = corresponding (CC)2(CH=CH)2CHOH(CH2)4CO2CH3C20H20N2O3 - 59d 94BSJ1717eA mixture of 2E,4E and 2E,4Z-isomers of H-(CC)4CH(OH)-(CH=CH)2-CH312-(1H-Pyrazol-3-yl)-dodeca-2,4-diene-7,9,11-triyn-6-olR = (CC)3CH(OH)-(CH=CH)2-CH3 C15H12N2O - 32f 95JMC5015111,3-DiyneRCCCCRAlkynylpyrazoles Structu

48、ral formula Formula index m.p., oC b.p., oC/mm HgReported yield (%)LiteratureA 1:1 mixture of 3E,5E and 3E,5Z-isomers ofH-(CC)4-(CH=CH)2-CH(OH)-CH312-(1H-Pyrazol-3-yl)-dodeca-3,5-diene-7,9,11-triyn-2-olA 2:1 mixture of 3E,5E and 3E,5Z-isomers R = (CC)3(CH=CH)2CH(OH)CH3C15H12N2O - 56g 95JMC5015A 1:1

49、mixture of 3E,5E and 3E,5Z-isomers ofH-(CC)4-(CH=CH)2-CH(OAc)-CH3Acetic acid 1-methyl-11-(1H-pyrazol-3-yl)-undeca-2,4-diene-6,8,10-triynyl esterA 1:1 mixture of 3E,5E and 3E,5Z-isomers R = (CC)3(CH=CH)2CH(OAc)CH3C17H14N2O2 - 69h 95JMC5015Symmetrically disubstitutedRCC-CCR CRHNRR = CH2OC(=O)-CH3 Acetic acid 4-(3-acetoxy-prop-1-ynyl)-2H-pyrazol-3-ylmethyl esterR = CH2OC(=O)-CH3 C11H12N2O4 oil 72 78MI3R = (CH3)2OH 4-5-(1-Hydroxy-1-methyl-ethyl)-1H-pyrazol-4-yl-2-meth

本站链接:文库   一言   我酷   合作


客服QQ:2549714901微博号:道客多多官方知乎号:道客多多

经营许可证编号: 粤ICP备2021046453号世界地图

道客多多©版权所有2020-2025营业执照举报