Utility of cyanoacetic acid hydrazide in heterocyclic synthesis

General Papers ARKIVOC 2006 (ix) 113-156 Utility of cyanoacetic acid hydrazide in heterocyclic synthesis Samir Bondock,*Abd El-Gaber Tarhoni, and Ahmed A. Fadda Department of Chemistry, Faculty of Science, Mansoura University, ET-35516 Mansoura, Egypt E-mail: Bondock@mans.edu.eg Abstract This review describes the synthesis and reactions of cyanoacetic acid hydrazide as building block for the synthesis of polyfunctionalized heterocyclic compounds with pharmacological interest. Keywords: Cyanoacetic acid hydrazide, pyrazoles, thiadiazoles, pyridines, pyrans, pyridazines, pyrimidines, annelated heterocycles Contents 1. Introduction 2. Synthesis of Cyanoacetic Acid Hydrazide 3. Chemical Reactivity 4. Reactions of Cyanoacetic Acid Hydrazide 4.1. Synthesis of five-membered rings with one heteroatom 4.1.1. Thiophenes and their fused derivatives 4.2. Synthesis of five-membered rings with two heteroatoms 4.2.1. Pyrazoles and their fused derivatives 4.2.2. Thiazoles and their fused derivatives 4.3. Synthesis of five-membered rings with three heteroatoms 4.3.1. Triazoles and their fused derivatives 4.3.2. Thiadiazoles 4.4. Synthesis of six-membered rings with one heteroatom 4.4.1 Pyridines and their fused derivatives 4.4.2. Pyrans and their fused derivatives 4.4.3. Thiopyrans 4.5. Synthesis of six-membered rings with two heteroatoms 4.5.1 Pyridazines and their fused derivatives 4.5.2 Pyrimidines and their fused derivatives 4.6. Synthesis of six-membered rings with three heteroatoms ISSN 1424-6376 Page 113 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 4.6.1. Thiadiazines 4.6.2. Triazine 5. Conclusions 6. References 1. Introduction Cyanoacetic acid hydrazide is a versatile and convenient intermediate for the synthesis of wide variety of heterocyclic compounds. The β-functional nitrile1-4 moiety of the molecule is a favorable unit for addition followed by cyclization or via cycloaddition with numerous reagents providing heterocyclic compounds of different ring sizes with one or several heteroatoms that are interesting as pharmaceuticals,5,6 as herbicides,7 as antibacterial agents,8 and as dyes.9,10 Their reactions with dinucleophiles usually result in the formation of polycyclic ring systems which may be the skeleton of important heterocylic compounds. In previous publications, novel synthesis of azoles,11,12 azines,13 and azoloazines,14 had been reported utilizing β-functional nitriles as starting components. Among the β-functional nitriles, cyanoacetic acid hydrazide and their analogues are especially important starting materials or intermediates for the synthesis of various nitrogen-containing heterocyclic compounds. Our research deals with the effective use of cyanoacetic acid hydrazide in the synthesis of a variety of polyfunctional heterocyclic compounds with biological interest. 2. Synthesis of Cyanoacetic Acid Hydrazide Cyanoacetic acid hydrazide was obtained by careful addition of hydrazine hydrate to ethyl cyanoacetate in ethanol with stirring at 0°C.15 Scheme 1 ISSN 1424-6376 Page 114 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 3. Chemical Reactivity Cyanoacetic acid hydrazide can act as an ambident nucleophile, that is, as both an N- and a Cnucleophile. On treatment of cyanoacetic acid hydrazide with various reagents, the attack can take place at five possible sites: the nucleophile is able to attack the carbon of the carbonyl function (position 3) and the carbon atom of the nitrile function (position 5). While the active methylene group (position 4) and amino groups (positions 1 and 2) are able to attack electrophiles. (4) N (5) H (3) N (1) (2) NH2 O 4. Reactions of Cyanoacetic Acid Hydrazide The reactions of cyanoacetic acid hydrazide with numerous reagents are classified separately in one category due to the huge number of references. We have arranged this huge volume of data in terms of the type of the heterocycles formed, starting with five and six membered rings in order of increasing number of heteroatoms. Such systematic treatment provides a clear idea about the synthetic possibilities of the method and may be useful in selecting the direction of further research. 4.1. Synthesis of five-membered rings with one heteroatom 4.1.1. Thiophenes and their fused derivatives Reaction of compound 2 with cyclic ketones and sulfur in the presence of morpholine under Gewald reaction conditions afforded thiophene derivatives 3 and 4.16 ISSN 1424-6376 Page 115 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O O NHNH2 + (CH2)n + S CN 2 EtOH morpholine n = 1, 2, 3 O O N n(H2C) S O (CH2)n NH2 N H n(H2C) NH2 S N H (CH2)n 4 NH2 3 Scheme 2 4.2. Synthesis of five-membered rings with two heteroatoms 4.2.1. Pyrazoles and their fused derivatives Treatment of 2 in water containing a catalytic amount of conc. HCl with acetyl acetone at room temperature afforded 1-cyanoacetyl-3, 5-dimethyl pyrazole 5.15 O O O N H CN NH2 + O Me H2O/HCl r.t N N Me CN Me Me 2 5 Scheme 3 The reaction of 2 with alkylisocyanate yields alkylcarbamoyl derivative 6 that cyclized into pyrazole derivative 7 up on treatment with 2N sodium hydroxide.17 ISSN 1424-6376 Page 116 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 R N C O NHNH2 NC NC O O H N N H O 6 2 6,7 a b c NHR NH2 O R H Me Ph N NHR NaOH N HO 7 Scheme 4 Refluxing of 2 with phenyl isothiocyanate in basic dioxane solution afforded pyrazolinone derivative 8. Treatment of 8 with malononitrile in DMF in the presence of piperidine gave [(3amino-5-imino-4,5-dihydro-1H-pyrazol-1-yl)(anilino)methylene]malononitrile 9, which underwent cyclocondensation with hydrazine hydrate to give pyrazolo[1,5-a]pyrimidine derivative 10.18 O O NHNH2 CN + Ph N C S dioxane S N NHPh N H2N 2 8 NC H2N DMF/piperidine N CN HN N NHPh O NH2NH2 NC CN NHPh N N N H2N CN H2N 10 9 Scheme 5 5-Amino-3-hydroxypyrazole derivatives 12 were prepared from the reaction of 2 with ketones in the presence of a basic catalyst via the cyclization of hydrazone derivatives 11.19 ISSN 1424-6376 Page 117 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O O R1 + NHNH2 base O R2 CN NH CN 2 . N R2 11 CHR1R2 CHMe2 CHMeEt cyclopentyl cyclohexyl heterocycl 11,12 a b c d e R1 OH N N H2N CHR1R2 12 Scheme 6 Elnagdi and coworkers have reported the reaction of 2-(1-phenylethylidene)malononitrile with 2 furnished pyrazoline derivative 13.20 H2N O NC CN + Me NH CN HN NH2 Ph NH NC Me Ph 13 2 Scheme 7 Pyrazolidinone derivative 14 was obtained by treatment of 2 with ethyl 2-cyano-3phenylbut-2-enoate.20 NC Me OEt + Ph O O O NH CN HN NH NC NH2 Me Ph 14 2 Scheme 8 Cyanoaceto-N-arylsulfonylhydrazide 15 on refluxing in ethanol containing a catalytic amount of piperidine,21 or in presence of potassium hydroxide,22 undergo intramolecular ISSN 1424-6376 Page 118 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 cyclization to give the 5-amino-1-arylsulfonyl-4-pyrazolin-3-one or the tautomeric 5-amino-1arylsulfonyl-3-hydroxypyrazole structure 17. NC NH HN O O O EtOH/piperidine HN heat NH N H2N NH N O S O O S O Ar O S O Ar Ar 16 15 15-17 a b c d e f 17 Ar Ph C6H4-4-Cl C6H4-4-Br C6H4-4-Me C6H4-4-OMe C6H4-4-NO2 OH H2N N N O S O Ar Scheme 9 The reaction of 2 with isatin in ethanol containing a catalytic amount of triethylamine at room temperature furnished the isolated intermediate (2E)-2-cyano-2-(2-oxo-1,2-dihydro-3Hindol-3-ylidene)acetohydrazide 18 which cyclized under heating to give (2E)-3-(3-amino-5-oxo1,5-dihydro-4H-pyrazol-4-ylidene)-1,3-dihydro-2H-indol-2-one 19.23 ISSN 1424-6376 Page 119 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O NHNH2 O O CN N H 2 EtOH/Et3N EtOH/Et3N boiling H N O NHNH2 N O NH2 EtOH/Et3N boiling O CN O N H N H 18 19 Scheme 10 Condensation of hydrazone derivative 11d with aromatic aldehyde in ethanolic triethyl amine gave the unexpected 3-aryl-4,5,6,7-tetrahydro-1H-indazole 21.24 O Ar NHN CN O NHN CN 11d 20 ArCHO EtOH/Et3N 21 a b c d Ar Ar Ph p-Cl-C6H4 o-Cl-C6H4 p-anisyl N N H 21 Scheme 11 Treatment of 2 with phenyl 7-fluoro-4-chromone-3-sulfonate in presence of sodium acetate and glacial acetic acid at 100°C afforded a mixture of 7-fluoro-2H-[1,2]benzoxathiino[4,3c]pyrazole 4,4-dioxide 22 and 1-amino-8-fluoro-2-oxo-1,2,3,10b-tetrahydro[1,2] benzoxathiino[4,3-b]pyridine-3-carbonitrile 5,5-dioxide 23.25 ISSN 1424-6376 Page 120 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O O SO2OPh NHNH2 + CN F 2 O AcONa AcOH O N O F NH H2N SO2 F O 22 CN N SO2 23 Scheme 12 Reaction of 2 with ethyl benzoylacetate at 140-150°C yield 1N-cyanoacetyl-2Nbenzoylacetylhydrazine 24 which underwent cyclocondensation with 3-hydrazino-5,6-diphenyl1,2,4-triazine in absolute ethanol to yield compound 25 that when treated with dil. hydrochloric acid gives 1-[1-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-phenyl-1H-pyrazol-3-yl]pyrazolidine-3,5dione 26.26 O Ph NHNH2 NC O OEt H N NC O O O N H Ph Ph N Ph N N N dil.HCl N Ph O N Ph N NH N Ph N Ph 24 2 Ph O N N NHNH2 N N N Ph N H NH O O 25 26 CN Scheme 13 ISSN 1424-6376 Page 121 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Cycloaddition of 2 with arylidene of 2-cyanomethyl-1,3-benzothiazole yielded 3-aryl-2(1,3-benzothiazol-2-yl)-3-(5-imino-3-oxopyrazolidin-1-yl)propanenitrile 27.27 N N H2N CN S + NH O NC CN S Ar Ar HN Ar Ph 2-thienyl 2-furyl 27 a b c 2 Scheme 14 N NH O 27 Scheme 14 Compound 2 reacts with hydrazone derivatives in refluxing dioxane containing a catalytic amount of triethylamine to yield pyrazoloazine derivatives 30.28 O R NH2 R N H CO2Et N + HN O dioxane/Et3N N H N X _ CN X NH EtOH HN O NC 2 28 a, X = CN b, X = COCH3 CONH2 R= S R N N X OH N H2N N R N N X NC OH 30 OH N N O 29 a, X = N b, X = CH a, X = NH2 b, X = CH3 Scheme 15 ISSN 1424-6376 Page 122 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 4.2.2. Thiazoles and their fused derivatives Reaction of 2 with carbon disulfide in DMF and potassium hydroxide had been reported to afford nonisolable intermediate 31 that transformed into thiazole derivative 32 by the action of phenacyl bromide. On the other hand treatment of compound 32 with salicylaldehyde gave the 2H-chromen-2-one derivative 34 via the nonisolable arylidene 33 followed by intramolecular addition of hydroxy group to the nitrile function.29 NHNH2 NC O CS2 / KOH DMF H N NC O 2 O S N H SK Ph Br H N NC S N S O 31 Ph 32 CHO OH O O H N OH S N S O 34 CN H N S N S O Ph Ph 33 Scheme 16 Condensation of 2 with 3,5_dimethyl_1_phenyl_1H_pyrazole_4_carbaldehyde in ethanol under reflux afforded N_(3,5_dimethyl_1_phenyl_1H_pyrazole_4_methylidene) cyanoacetic acid hydrazide 35. The conversion of 35 into thiazole derivatives 36 was achieved by Gewald reaction, by reacting 35 with sulfur and appropriate aryl isothiocyanate in the presence of mixture of dimethylformamide and ethanol containing triethylamine as a basic catalyst.30 ISSN 1424-6376 Page 123 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 H3C CHO N + CH3 N H2N CN H N H3C N EtOH N N O Ph O CH3 Ph 2 CN H N 35 DMF/EtOH S, ArNCS Et3N H2N 36 Ar a b c C6H5 4-Cl-C6H4 4-CH3-C6H4 H3C N N N H N Ar N S O O CH3 Ph 36 Scheme 17 4.3. Synthesis of five-membered rings with three heteroatoms 4.3.1. Triazoles and their fused derivatives Cyclocondensation of 1-cyanoacetyl-4-phenylthiosemicarbazide 37 under basic conditions afforded 1, 2, 4-triazole derivative 38.31 H N NC O S N H N H Ph Ph OHheat 37 NC N S N NH 38 Scheme 18 Scheme 18 By treating compound 2 with tert-butoxycarbonylhydrazone esters in an oil bath at 115°C, 1,2,4-triazole derivative 42 was obtained.32 ISSN 1424-6376 Page 124 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O H N N CO O NHNH2 t-Bu t R + O H N N CO 115°C R H HN N OEt CN t-Bu CN O 39 2 O t-Bu NH2 N R O H HN N CO NH N H2O R heat CN N N O N 42 CN R H N N N 41 t-Bu CN O 40 Scheme 19 The reaction of 1-cyanoacetyl-4-phenylthiosemicarbazide 37 with ethyl iodide in DMF and in the presence of anhydrous potassium carbonate at room temperature gave 3-ethylsulfanyl-5cyanomethyl-4-phenyl-1,2,4-triazole 43.33 H N NC O S Ph Me N H NHPh I K2CO3 / DMF N NC S Me N N 43 37 Scheme 20 The reaction of 2 with different hydrazones delivered 1,2,4-triazole derivatives 44.34 NHCO2Et N O NC HN NH2 + NHCO2Et R N NC R N N OEt 44 a b c d 2 R Me Et Pr Bz 44 Scheme 21 ISSN 1424-6376 Page 125 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Golovko and coworkers published the reaction of 2 with lactim ether furnished the 5,6dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-ylacetonitrile 45.35 H N NC N NH2 N NC OEt base + N N O 2 45 Scheme 22 Treatment of 2 with 7-chloro-5-phenyl-1,3-dihydro-2H-1,4 benzodiazepine-2-thione in the presence of a basic catalyst afforded 8-chloro-6-phenyl-4H-s- triazolo [4,3-a] [1,4] 36 benzodiazepine-1-acetonitrile 46. S H N H N NC + Cl NH2 N N base N O N NC N Cl ph Ph 46 2 Scheme 23 Refluxing of compound 25 in glacial acetic acid and anhydrous sodium acetate yielded [5(5,6-diphenyl-1,2,4-triazin-3-yl)-6-phenyl-5H-pyrazolo[5,1-c][1,2,4]triazol-3-yl]acetonitrile 47.26 Ph N Ph N Ph N N Ph 25 AcONa AcOH N NH N H N Ph N N N N Ph O CN N N 47 CN Scheme 24 ISSN 1424-6376 Page 126 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 4.3.2. Thiadiazoles The reaction of 2 with phenylisothiocyanate in DMF in presence of sodium hydride gave nonisolable intermediate 48 that was converted into 1-cyanoacetyl-4-phenylthiosemicarbazide 37 by treatment with conc. hydrochloric acid. Heating of 37 with phosphorous oxychloride yielded (5anilino-1,3,4-thiadiazol-2-yl)acetonitrile 49.31,33 O O NHNH2 + Ph DMF NaOH N C S CN CN N N H 2 SNa NHPh 48 conc.HCl NC S H N O POCl3 Ph N N CN H N N H S NHPh 37 49 Scheme 25 Condensation of acylisothiocyanate with 2 in refluxing acetone gave 45% of thiocarbamoyl derivative 50 which underwent intramolecular cyclization in refluxing acetic acid to give 55% N-[5-(cyanomethyl)-1,3,4-thiadiazol-2-yl]acetamide 51.37 O NC HN 2 NH2 AcNCS acetone O NC HN N H S acetic acid N H Ac 50 NC S H N Ac N N 51 Scheme 26 4.4. Synthesis of six-membered ring with one heteroatom 4.4.1. Pyridines and their fused derivatives Cyclocondensation of 2 with ethyl 3-aminocrotonate in methanol in the presence of potassium hydroxide under reflux afforded 1-amino-3-cyano-6-hydroxy-4-methyl-pyridine-2-one 52.38 ISSN 1424-6376 Page 127 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Me Me NC + O NC H2N NH MeOH KOH EtO O O N OH NH2 NH2 2 52 Scheme 27 Cyclocondensation of 2 with benzoylacetone and/or benzoyl trifluoroacetone in refluxing ethanol containing a catalytic amount of diethyl amine yielded regioselectively 1-amino-4-alkyl2-oxo-6-phenyl-1,2-dihydropyridine-3-carbonitrile 53.39-40 O NC R + O R NH NC EtOH Ph O NH2 Et2NH O N 53 R a CH3 b CF3 2 Ph NH2 53 Scheme 28 Refluxing of 2 with benzylidenemalononitrile in ethanol in presence of piperidine gave pyridone derivative 54.41 NH2 NC NC CN + O NH EtOH/piperidine Ph NC O CN N Ph NH2 NH2 2 54 Scheme 29 Scheme 29 On heating 2 and arylidene of ethyl cyanoacetate in ethanol containing triethyl amine under reflux afforded diaminopyridine derivative 58 rather than aminopyridine derivative 56.42,43 ISSN 1424-6376 Page 128 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Ar NC CO2Et + O CN NH 2 NH2 EtOH Et3N Ar Ar NC O NC CO2Et N O NH2 -H2 Ar Ar CO2Et N OH 55 -H2 O N NH2 NH2 57 NC CN NH2 55-58 a b c Ar Ph 4-Cl-C6H4 furyl NC O CN N NH2 NH2 58 OH 56 Scheme 30 The one-pot reaction of 2 with aldehyde and an activated nitrile in ethanol containing a catalytic amount of piperidine yielded pyridine-2-one derivative 60.44-46 ISSN 1424-6376 Page 129 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 R NC X O NH + NH2 R CHO NC EtOH/piperidine + NC O R = H, Me, p-NO2C6H4, p-MeOC6H4 X = CN, COPh,CO2Ph 2 NH CN NH2 R 59 NC O X X N NH2 NH2 60 Scheme 31 Compound 2 reacted with (2E)-2-cyano-N-(4-methylphenyl)-3-phenylacrylamide in dry ethanol containing catalytic amount of piperidine under reflux to afford pyridine derivative 63 instead of compound 62.47 NHAr NHAr NC + O NH NH2 2 Ph O EtOH/piperidine NC CN O Ph NH CN NH2 61 Ar = 4-MeC6H4 NHAr NHAr NC O Ph N NH2 63 NH NC O CN N Ph NH2 62 Scheme 32 Cyclocondensation of 2 with (4-methoxybenzylidene)malononitrile in ethanol in the presence of triethylamine afforded 1-aminopyridine derivative 64, which rearranged on heating ISSN 1424-6376 Page 130 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 in 95% aqueous ethanol/triethylamine to give 1,4-diamino-5-cyano-2-(4-methoxyphenyl)-6-oxo1,6-dihydropyridine-3-carboxylic acid 65.48 NH2 NC NC O NH NH2 + NC EtOH/Et3N CN OMe O N NH NH2 2 OMe 64 NH2 NC O CO2H N NH2 EtOH(95%)/Et3N OMe 65 Scheme 33 Scheme 33 Martin and coworkers reinvestigated the cyclocondensation of 2 with (4methoxybenzylidene)malononitrile. They have found that prolonged heating lead only to the formation of 1,6-diamino-4-(4-methoxyphenyl)-3,5-dicyano-2-pyridone 66. The structure of compound 66 had been confirmed on the basis of chemical and spectroscopic evidence.49 OMe OMe NC + O NH NH2 CN EtOH/Et3N NC CN 24h, CN O 2 N NH2 NH2 66 Scheme 34 Treatment of 2 with arylidene cyanothioacetamide in ethanol containing catalytic amount of piperidine yielded pyridine-thione derivatives 69.46 ISSN 1424-6376 Page 131 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 R S R O NC base EtOH NHNH2 + CN NH2 S NHNH2 N 2 NC N H -H2 R O O NC NHNH2 S NH2 67 67-69 R a H b Me R O NC NH2 S NHNH2 N NH2 68 69 Scheme 35 Reaction of cyanoaceto-N-arylsulfonylhydrazide 15a with 2-((thiophen-2-yl)methylene) malononitrile in ethanol containing a catalytic amount of piperidine furnished pyridin-2-one derivative 70.50 S S NC CN O + NH HN EtOH/piperidine NC O NC SO2Ph 15a CN N HN NH2 SO2Ph 70 Scheme 36 Refluxing of cyanoaceto-N-arylsulfonylhydrazide 15 with arylidenecyanoacetate in presence of pyridine51,52 afforded pyridone derivative 73, while in the presence of ethanol containing a catalytic amount of piperidine51 afforded pyridine-2-one derivative 75.52 ISSN 1424-6376 Page 132 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Ar Ar CN NC OEt NC O CN + O O NH HN NH O HN SO2Ph 15 OEt SO2Ph 71 pyridine EtOH/piperidine Ar Ar NC O N HN 74 CN NC CO2Et O NH2 HN SO2Ph -H2 Ar Ar 72-75 a b c d e CO2Et NC N HN SO2Ph 72 -H2 O OH N NH2 Ar Ph 4-ClC6H4 4-MeC6H4 4-MeOC6H4 4-NO2C6H4 CN NC O HN SO2Ph OH N 75 SO2Ph 73 Scheme 37 Substituted N-benzoylaminopyridone 76 was prepared by cyclocondensation of Nbenzoylcyanoacetohydrazide 6c with ethyl acetoacetate in presence of sodium methoxide.52 Me NC + O NH Me NC O NaOCH3 O OEt NHCOPh O N OH NHCOPh 6c 76 Scheme 38 ISSN 1424-6376 Page 133 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Cyclocondensation of 3-indolylidenecyanoacetohydrazide 77 with ethyl benzylidenecyanoacetate in the presence of a base gave the corresponding 4-phenyl-3,5-dicyano6-hydroxyl-1N-(3-indolylidene) pyridin-2-ones 78.53 Ph NC NC Ph NH O N CN CN + EtO O base N OH N O N H N H 77 78 Scheme 39 On heating 2 with phenylhydrazono-3-oxobutyronitrile in refluxing ethanol containing a catalytic amount of triethyl amine yielded pyridine-2,6-dione derivative 79.54,55 O NC + O Me NNHPh Me CN NH NC EtOH Et3N NNHPh O N O NH2 NH2 2 79 Scheme 40 Elzanate et al. have been reported a novel synthetic route to nitrosopyridinone derivative 80 via the reaction of oxime derivative of β-ketoester with N-benzoylcyanoacetohydrazide.56 Me NC + O NH Me N O O OH OEt NHCOPh NC NO NaOH O N OH NHCOPh 6c 80 Scheme 41 ISSN 1424-6376 Page 134 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 The reaction of N-cyanoacetylhydrazone of epiandrosterone 81 with malononitrile in ethanol in the presence of a catalytic amount of piperidine afforded pyridine-2-one derivative 82.57 NH2 NC O Me Me Me NC Me H HO CN HN N CN Me EtOH/piperidine H HO H 81 O NH2 N N Me H H H 82 Scheme 42 Refluxing of 2 with 2-(4,5-dihydro-4-oxothiazol-2-yl)-3-phenylacrylonitrile in ethanol containing catalytic amount of piperidine gave 5-amino-8-cyano-3-oxo-7-phenyl-2,3-dihydro7H-[1,3]thiazolo[3,2-a]pyridine-6-carboxylic acid 83.41 CN CN Ph H2NHN CN O Ph S + S EtOH/piperidine HO N O 2 N O NH2 O 83 Scheme 43 Cyclocondensation of 2 with 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde yielded 7-amino-3-methyl-6-oxo-1-phenyl-6,7-dihydro-1H-pyrazolo[3,4-b]pyridine-558 carbonitrile 84. ISSN 1424-6376 Page 135 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 H NC Me O + O Cl NH NH2 N Ph NC N Me O N NH2 N Ph N 84 2 Scheme 44 Condensation of cyanoacetic acid hydrazones 85 with 1-aminoanthraquinone under Vilsmeier reaction conditions afforded 3-azabenzanthrone derivatives 86.59 O HN NH2 HN + N NH O NC Me N Me Ar N POCl3 DMF Ar NC O Ar 86 a ferrocenyl b 2-thienyl 85 86 Scheme 45 Cyclocondensation of 2 with (2E)-2-(1H-benzimidazol-2-yl)-3-arylacrylonitrile under reflux in the presence of a base gave 1-amino-3-aryl-4-cyanopyrido[1,2-a]benzimidazole-2carbohydrazide 87.60 O NH N CN NHNH2 + Ar NH2 O base CN NHNH2 N Ar N 2 87 87 a b c d CN Ar Ph 4-MeC6H4 4-MeOC6H4 1-naphthyl Scheme 46 ISSN 1424-6376 Page 136 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 The reaction of 2 with α,β-unsaturated ketones in the presence of a base gave pyrazolo[3,4b]pyridine-3-one derivative 89.61 NH2 O CN Ar base + HN NH2 O 2 CN O Ar Ar HN HN O Ar N N O Ar 89 Ar a 2-furyl b 2-thienyl 88 Ar 89 Scheme 47 Pyrazolopyridines 90 were obtained via cyclocondensation of β-ketoaldehyde with 2 in alkaline medium.62 H O R OH O base + NC O H2N NH N R 90 a b c 2 Scheme 48 R Me Ph 3-pyridyl N H N 90 Scheme 48 Pyrazolo[3,4-b]pyridine derivative 92 was prepared benzoylcinnamonitrile with N-acetyl cyanoacetohydrazide 91.63 via the reaction of α- Ph NC Ph O Ph O + CN NH HN Ac 91 NC Ph O N N H NH 92 Scheme 49 Cyclocondensation of 2 with β-aminocrotononitrile in acidic medium yielded pyrazolo[3,4-b]pyridine derivative 93.64 ISSN 1424-6376 Page 137 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 N NH2 CN Me H2N + NH NC H+ O NH HN O Me NH2 2 93 Scheme 50 The reaction of 2 with 3-acetylcoumarin in ethanol containing a catalytic amount of piperidine under reflux afforded 5-methyl-2,11c-dihydrochromeno[4,3-d]pyrazolo[3,4b]pyridine-1,6-dione 95.65 HN O Me O O NH2 HN + N NH2 O O C N EtOH/piperidine O Me 2 HN O N O 94 O N Me O Scheme 51 -H2O O 95 Scheme 51 Reaction of 2 with different aromatic aldehydes in ethanol under reflux afforded 1Narylmethylidene-2-cyanoacetohydrazides 96 that were treated with benzylidenemalononitrile to give [1,2,4]triazolo[1,5-a]pyridin-5(3H)-one derivatives 97.66 ISSN 1424-6376 Page 138 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Scheme 52 [1,2,4]Triazolo[1,5-a]pyridin-5(1H)-one derivatives 99 were prepared in one pot reaction in excellent yields by the reaction of 2 with malononitrile and an aromatic aldehyde.67 O NC O NC N NH2 + H NC CN + O N Ar H2N H 2 N Ar NH2 98 99 a b C Ar Ph 4-ClC4H6 4-MeOC4H6 O NC N H2N 99 N Ar N H Scheme 53 Martin and coworkers have reported that an unexpected reaction between N-acetyl cyanoacetohydrazide 91 and α-cyanocinnamonitrile in ethanol containing catalytic amount of piperidine afforded a novel 2-methyl-5-oxo-7-phenyl-1,5-dihydro[1,2,4]triazolo[1,5-a]pyridine6,8-dicarbonitrile 100.68 ISSN 1424-6376 Page 139 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O Ph CN NC N H + O H N CN EtOH/piperidine O NC N N Ph Me N H CN 100 91 Me Scheme 54 Refluxing of hydrazone derivative 11d and appropriate arylidenes of activated nitriles in ethanolic piperidine yielded spiro[cyclohexane-1,2`-[1,2,4]triazolo[1,5-a]pyridine]-5`-(1`H)-one derivatives 102.24,69 O NC N O NC N H Ar N 11d CN Ar O X NC 102 a b c d e f NH2 X 101 EtOH piperidine + Ar Ph p-anisyl p-Cl-C6H4 furyl Ph p-anisyl X CN CN CN CN CO2Et CSNH2 N N Ar X 102 H N N H Scheme 55 On the other hand, 3-indolylidenecyanoacetohydrazide 77 condensed with different arylidenemalononitriles in presence of a base to give 7-aryl-6,8-dicyano-2-(3indolyl)[1,2,4]triazolo[1,5-a]-pyridin-5-ones 103.53 ISSN 1424-6376 Page 140 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O O N CN N H base + N C N H N N Ar CN N H Ar CN N CN 103 78 Scheme 56 When anthranilonitrile was fused on an oil bath at 170 °C with different N-arylidenes of cyanoacetohydrazide 96 in presence of triethyl amine, it afforded triazolo[4,3-a]quinoline derivatives 106. Compounds 106 are assumed to be formed by the initial Thorpe-Ziegler addition65 of the methylene group 96 to the CN group of anthranilonitrile to afford the acyclic intermediates 104, followed by loss of a water molecule to afford the acyclic intermediates 105, which in turn undergo a further cyclization via addition of the NH to the activated C=N to give the final products 106.70 Scheme 57 ISSN 1424-6376 Page 141 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 4.4.2. Pyrans and their fused derivatives Refluxing of hydrazone derivative 11d and salicylaldehyde in ethanol containing a catalytic amount of sodium hydroxide afforded N`-cyclohexylidene-2-imino-4-oxochromane-3carbohydrazide 107.71 O HN H OH N O + HN O O EtOH NaOH CN N O 11d NH 107 Scheme 58 3-Methyl-6-oxo-4-phenyl-1,6-dihydropyran[2,3-c]pyrazole-5-carbonitrile 108 prepared via cyclocondensation of 2 with 4-benzylidene-3-methyl-2-pyrazolin-5-one.72 O NHNH2 O O NH + N NC 2 Ph -NH2NH2 O was NH N NC Ph Me 108 Me Scheme 59 Refluxing of 2 with pyrazolinone in ethanol in the presence of piperidine gave 6-amino-3methyl-4-phenyl-1,4-dihydropyran[2,3-c]pyrazole-5-carbohydrazide 109.41 O CN H2NHN N + O H2N NH EtOH/piperidine Ph Me H2NHN NH N O 2 O Ph Me 109 Scheme 60 ISSN 1424-6376 Page 142 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Cyclocondensation of 2 with benzofuranyl derivatives under Claisen-Schmidt reaction yielded 4-aryl-6-(6-hydroxy-2,3-diphenyl-1-benzofuran-5-yl)-2-imino-3,4-dihydro-5-phenyl-2Hpyran-3-carbohydrazide 110.73 O Ph O CN H2NHN Ph Ar + Ph 2 O OH base O 110 Ar a p-MeC6H4 b p-ClC6H4 NH Ph O H2NHN Ph Ar Ph OH O 110 Scheme 61 Reaction of 2 with benzopyranone in ethanol containing a catalytic amount of triethyl amine under reflux afforded 2-imino-5-methoxy-8-methyl-6-oxo-4-(2-oxo-2-phenylethyl)-3,4dihydro-2H,6H-pyrano[3,2-g]chromene-3-carbohydrazide 111.74 O O O H2N Ph MeO Et3N EtOH + N H CN 2 Ph O HO O Me MeO O H2NHNCO HN O Me O 111 Scheme 62 Reaction of bisdithiolobenzoquinone with 2 in a 1: 2 molar ratio in alkaline medium gave dispiro[4H-pyran-4,2`-[1,3]dithiolo[4,5-f][1,3]benzodithiole-6`,4``-[4H]pyran]-3,3``dicarbonitrile derivative 112. 75 ISSN 1424-6376 Page 143 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Me Me O H N NC + NH2 O S NH2 O Me S O S O alk.med. S CN O O O S 2 S O NC S S O Me H2N Me O Me 112 Scheme 63 4.4.3. Thiopyran The reaction of 2 with benzalcyanothioacetamide in ethanol containing a catalytic amount of triethyl amine gave thiopyran derivative 113.76 Ph Ph CN NC + H2N S O EtOH Et3N NHNH2 2 NC H2N CN S O 113 Scheme 64 4.5. Synthesis of Six-Membered Ring with Two Heteroatoms 4.5.1. Pyridazines and their fused derivatives Reaction of 2 with biacetyl in ethanol at room temperature yielded pyridazin-3-one derivative 115.77 ISSN 1424-6376 Page 144 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 O HN Me NH2 O HN Me Me O N HN -H2O O -H2O O N O Me Me CN CN 2 Me CN 115 114 Scheme 65 Refluxing of 2 with aceanthraquinone in acetic acid gave 116 that transformed into aceanthryleno[1,2-c]pyridazine derivative 117 when treated with potassium hydroxide.78 H2N NH O AcOH H2N NHO + O CN O KOH O HN O CN 2 N CN 117 116 Scheme 66 Cyclocondensation of α-(ethoxymethylene)-2,3,4,5-tetrafluoro-β-oxobenzenepropanoic acid ethyl ester with 2 led to the formation of fluorinated 1,3,4-oxadiazino[6,5,4-i,j]quinolines 118.79 F HN 2 F F O NC F + NH2 N F F O NC N O O CO2Et CO2Et 118 Scheme 67 ISSN 1424-6376 Page 145 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 The reaction of 2 with 2-phenyl-1,1,3-tricyano-3-bromopropene in a basic medium gave the nonisolable acyclic intermediate 119, which underwent cyclization via the addition of the active methylene to the CN group to afford the pyrrolo[1,2-b]pyridazine derivative 120.80 Ph H N NC CN Ph NH2 + NH NH NC Br 2 CN H2N CN NC CN DMF NC O TEA Ph CN NH2 N N NC O OH 119 120 Scheme 68 Scheme 68 4.5.2. Pyrimidine and their fused derivatives Barbituric acid derivative 121 could be obtained by the reaction of chlorocarbonylisocyanate with 2.81 CN CN O H2N + N NH O O Cl C O base H2N N NH O O 2 121 Scheme 69 Mohareb and coworkers reported that the reaction of N-benzylidene cyanoacetohydrazide 97a with ethyl cyanoacetate afforded pyrimidine derivative 122.82 O O CN of N H N Ph + OEt NC O N base H2N 96a N Ph CO2Et N 122 Scheme 70 ISSN 1424-6376 Page 146 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Cinnamoyl isothiocyanate reacts with 2 to give the corresponding cinnamoyl thiourea 123 which undergo cyclization in refluxing sodium ethoxide solution to give the corresponding 1-(5oxo-4,5-dihydro-1H-pyrazol-3-yl-)-6-phenyl-2-thioxotetrahydropyrimidin-4(1H)-one 124.83 N C N S S + O H2N NH NH HN NC N H O O Ph O Ph 2 123 N S HN NH N O NaOEt O Ph 124 Scheme 71 Scheme 71 Abdel Rahman et al. reported that treatment of 3-chloro-5,6-diphenyl-1,2,4-triazine with 2 in pyridine gave compound 125 which underwent dehydrocyclization by boiling in acetic acid containing catalytic amount of anhydrous sodium acetate to give 6-methyl-8-oxo-2,3-diphenyl8H-pyrimido[1,6-b][1,2,4]triazine-9-carbonitrile 126.84 Ph Ph N HN N N pyridine + O Cl Ph N Ph NH2 N N HN NH2 O CN CN 2 125 Me Ph N Ph N N AcONa AcOH N O CN Scheme 72 126 Scheme 72 The reaction of 2 with arylhydrazonomalononitrile in ethanol under reflux afforded pyrazolo[1,5-a]pyrimidine derivative 130.85 ISSN 1424-6376 Page 147 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 H N N Ar CN Ar N N N Ar N N NH2 H2N 129-130 a b c d N N N 127 Ph N N CN O Ar Ph 4-ClC6H4 4-MeC6H4 4-MeOC6H4 NH2 N N N N NH 129 H2N O 2 NH2 H2N Ar H2N + CN CN H N N N Ar H2N NH2 N N N NH2 O 128 130 Scheme 73 4-Amino-5-arylidenehydrazinocarbonylthiazole-2(3H)-thiones 131 were prepared by the reaction of N-arylidene cyanoacetic acid hydrazides 96 with sulphur and phenyl isothiocyanate in the presence of triethyl amine. These compounds were cyclized by acetic anhydride to give the corresponding thiazolo[4,5-d]pyrimidines 132.86 Ar1 N NH NC O 97 H2N S / PhNCS Et3N / DMF 1 Ar N H N Ph N H3C Ac2O S Ar1 S N N 131 131-132 Ar1 a b c S N O Ph N S O 132 C6H5 4-Cl-C6H4 4-OCH3-C6H4 Scheme 74 ISSN 1424-6376 Page 148 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Treatment of 2 with pentane-2,4-dione in ethanol in the presence of acetic acid led to the formation of 5,7-dimethylpyrazolo[1,5-a]pyrimidin-2-ol 133.87 Me Me O + Me O H2N NH NC N EtOH/AcOH O Me N OH N 2 133 Scheme 75 2-(2-Bromo-1-phenyl-2-thiocyanatoethylidene)malononitrile reacts with 2 to afford 4Hpyrrolo[1`,2`:4,5][1,3,4]thiadiazolo[3,2-a]pyrimidin-4-one derivative 134.88 O O CN N H 2 NH2 + CN Br NC CN S Ph N base H2N N NH2 N CN S 134 Ph Scheme 76 Heating of cyclopentylidene hydrazide of cyanoacetic acid 11c with salicylaldehyde in presence of a base afforded 3H-chromeno[2,3-d]pyrimidin-4(5H)-one derivatives 137.89 Scheme 77 ISSN 1424-6376 Page 149 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 4.6. Synthesis of Six-Membered Ring with Three Heteroatoms 4.6.1. Thiadiazine The reaction of 1-cyanoceto-4-phenylthiosemicarbazide 37 with ethyl bromoacetate in DMF and in the presence of anhydrous potassium carbonate at room temperature gave 1,3,4-thiadiazine derivative 138.33 NHPh NHPh HN NH NC Br S + N K2CO3 EtO O O N NC DMF S O 37 O 138 Scheme 78 4.6.2. Triazine Nucleophilic addition reaction of 3-thiophen-2-yl-acryloylisothiocyanate with 2 afforded thiocarbamoyl derivative 139 which gave pyrazolo[1,5-a][1,3,5]triazine derivative 140 on treatment with 5% potassium hydroxide.90 N S C O S S H2N + HN NH NC S O 2 N H O NC NH O 139 HS N S Scheme 79 N N 5%KOH N OH 140 Scheme 79 5. Conclusions The data considered in this review clearly demonstrate the high synthetic potential of cyanoacetic acid hydrazide. Many biologically active heterocyclic compounds have been ISSN 1424-6376 Page 150 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 obtained based on these reagents.1-10 This suggests that cyanoacetic acid hydrazide can be particularly promising synthons in combinatorial synthesis of functionalized carbo- and heterocyclic compounds used in the design of novel highly effective pharmaceuticals with a broad spectrum of bioresponses. The great interest of chemists in such reagents is confirmed by the facts that more than 80 articles of 90 cited in this review are dated in the last two decades, along with a multitude of patents. 6. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. Elnagdi, M. H.; Elmoghayar, M. R. H.; Elgemeie, G. E. H. Synthesis 1984, 1. Gaber, A. M.; El-Gaby, M. S. A.; El-Dean, A. M. K.; Eyada, H. A.; Al-Kamali, A. S. N. J. Chin. Chem. Soc. 2004, 51, 1325. Elagamey, A. G. A.; El-Taweel, F. M.; Khodeir, M. N. M.; Elnagdi, M. H. Bull. Chem. Soc. 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M.; El-Taweel, F. M.; Elmougi, S. M.; Elagamey, A. J. Heterocycl. Chem. 2004, 41, 655. ISSN 1424-6376 Page 154 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 90. Abed, N. M.; Elagamey, A. G. A.; Harb, A. F. A. J. Chem. Soc. Pak. 1988, 10, 151; Chem. Abstr. 1989, 110, 173140p. Biographical Sketches Dr. Samir Bondock Samir Bondock was born in 1970 in Mansoura, Egypt and received his M.Sc. thesis on synthesis of some new azo disperse dyes for dyeing synthetic fibers from the University of Mansoura in 1995 under the supervision of professor A. A. Fadda. He performed his Ph.D. thesis in the research group of Professor A. G. Griesbeck in Cologne, Germany where he graduated in 2003 on spin-mapping effects and photoaldol reactions. Since 2003, he has been a lecturer at the University of Mansoura. His research interest is the synthesis of heterocyclic compounds with pharmaceutical interest using thermal and [2+2] photochemical reactions. Abd El-Gaber El-Tarhoni Abd El-Gaber El-Tarhoni was born in 1964 in Mansoura, Egypt and studied chemistry at the University of Mansoura. In 1986, he obtained his B.Sc. He performed his M.Sc. thesis in the research group of Professor A. A. Fadda on azo disperse dyes and their availability for dyeing synthetic fibers. ISSN 1424-6376 Page 155 © ARKAT General Papers ARKIVOC 2006 (ix) 113-156 Prof. Ahmed Ali Fadda Prof. A. A. Fadda was born in 1950 in Cairo, Egypt. He received both his B.Sc. degree (1971) from Cairo University and his M.Sc. (1976) degree from Mansoura University. He performed his Ph.D. thesis in the research group of Professor A. N. Kost at Moscow University, Russia where he graduated in 1981 chemistry of pyridine rearrangement. Since 1991, he has been a professor of organic chemistry at the University of Mansoura. Prof. Fadda is the author of over 130 scientific papers on heterocyclic chemistry, dyes chemistry and synthetic methodology. His research interests cover the development and mechanistic understanding of organic reactions and their applications in dyes and medicinal chemistry. ISSN 1424-6376 Page 156 © ARKAT