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
