Abstract
Benzoylacetonitriles are easily available and have high chemical reactivity due to the presence of three active moieties; nitrile, carbonyl, and active methylene functions. This review article represents a survey covering the synthetic strategies leading to five six-membered heterocycles; pyrans, pyridazines, pyrimidines, pyrazines, and triazine compounds; utilizing benzoylacetonitriles as starting precursor since 1985. The reactions are subdivided into groups that cover the synthetic methods of these heterocycles.
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Introduction
Benzoylacetonitrile, known as phenacylcyanide or ω-cyanoacetophenone, was named as 3-oxo-3-phenylpropanenitrile as using the IUPAC system. Benzoylacetonitrile is a versatile and convenient intermediate for preparation of various organic and, especially, six-membered heterocyclic compounds possessing diverse biological activities and many other practically useful properties, e.g. antimicrobial [1–5], photochemotherapic [6], antimalarial [7], anti-inflammatory [8], anti-HIV agents [9], anticancer agents [10], anti-T. cruzi activity [11], anti-HCV, antioxidant, and peroxynitrite inhibitory activity [12]; and as electron-transporting layer [13, 14]. Despite this versatile importance, and in connection to our previous review articles [15–19], benzoylacetonitrile have not been previously reviewed. The present review aims to demonstrate the synthetic potential of benzoylacetonitrile in the synthesis of pyrans, pyridazines, pyrazines and triazine compounds in the period from 1985 till now. The synthetic methods of benzoylacetonitriles and its utility in synthesis of pyridine derivatives were mentioned previously [18].
Pyrans and their fused derivatives
Michael addition reaction
The enantioselective Michael addition of 1 to α,β-unsaturated trichloromethyl ketones 2 was reported with a phenylalanine-derived bifunctional piperazine/thiourea catalyst, a series of α-trichloromethyldihydropyrans 3 were obtained with excellent yields (Scheme 1) [20].
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Similarly, enantioselective Michael addition of 1 to (E)-1,1,1-trifluoro-4-arylbut-3-en-2-one 4a,b gave (2S,4R)-2-hydroxy-2-(trifluoromethyl)-3,4-dihydro-2H-pyran-5-carbonitriles 5a,b in 71–95 % yield (Scheme 2) [21, 22]. The structure of compound 5b was established by the X-ray diffraction analyses.
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In a similar fashion, an asymmetric Michael addition of 1 to β,γ-unsaturated α-keto ester to form chiral dihydropyrans was reported. Thus Michael addition of 1 to (E)-methyl 2-oxo-4-phenylbut-3-enoate 6 led to (2S,4R)-methyl 5-cyano-2-hydroxy-4,6-diphenyl-3,4-dihydro-2H-pyran-2-carboxylate 7 in 95 % yield (Scheme 3) [23].
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The DABCO(1,4-diazabicyclo[2.2.2]octane)-catalyzed (3 + 3) annulations of 1 with 2-(acetoxymethyl)buta-2,3-dienoate 8 smoothly proceeded to construct benzyl 5-cyano-2-methyl-6-phenyl-4H-pyran-3-carboxylate 9 in excellent yields (Scheme 4) [24].
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Three-component one pot reaction of compound 1, 3-acetyl-1-ethyl-4-hydroxyquinolin-2(1H)-one 10, and formaldehyde yielded 2-amino-3-benzoyl-6-ethyl-4H-pyrano[3,2-c]quinolin-5(6H)-one 11 in 80 % yield [25]. Similarly, 6-amino-5-(2,3-dihydrobenzo[d]thiazol-2-yl)-2-phenyl-4H-pyran-3-carbonitrile 12 was prepared by three-component one pot reaction of compound 1, 2-cyanomethylbenzothiazole and, formaldehyde in refluxed ethanol containing triethylamine as catalyst [26]. 3-Methyl-6-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 13 was synthesized via three-component one pot reaction of compound 1; 2,5-dimethoxybenzaldehyde; and 3-methyl-1H-pyrazol-5(4H)-one in refluxed ethanol containing piperidine as catalyst (Scheme 5) [10].
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Treatment of 1 with 2-[(3-oxo-3,4-dihydroquinoxalin-2-yl)methylene]malononitrile 14 gave 2-amino-4-(3-oxo-3,4-dihydroquinoxalin-2-yl)-6-phenyl-4H-pyran-3,5-dicarbonitrile 15 in 79 % yield (Scheme 6) [27].
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Benzylidenemalononitrile 16 was reacted with 1 in refluxed ethanol in the presence of piperidine to yield 2-amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile 17 (Scheme 7) [28].
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Pyrano[2,3-c]pyrazole-5-carbonitrile 19 was obtained from Michael addition cyclocondensation of 1 to 4-(furan-2-ylmethylene)-3-methyl-1H-pyrazol-5(4H)-one 18 in refluxed ethanol in the presence of piperidine (Scheme 8) [29].
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Michael addition of compound 1 to 2,6-di(m-nitrophenylmethylene)cyclohexanone 20 followed by 6-exo-dig cyclization furnished (2-amino-8-(3-nitrobenzylidene)-4-(3-nitrophenyl)-5,6,7,8-tetrahydro-4H-chromen-3-yl)(phenyl)methanone 21 in 73 % yield (Scheme 9) [9].
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The asymmetric Michael addition of 1 to α-cyanocinnamate 22 gave (R) 23 and (S) 2-amino-5-cyano-4,6-diphenyl-4H-pyran-3-carboxylate 24 in moderate diastereomeric mixture and good yield (Scheme 10) [30].
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4-(2-Oxo-1,2-dihydroquinolin-3-yl)-2,6-diphenyl-4H-pyran-3,5-dicarbonitrile 26 was synthesized via Knoevenagel reaction between 1 and 2-chloroquinoline-3-carbaldehyde 25 followed by Michael addition of second molecule of 1 and cyclization. The structure of compound 26 was confirmed by the X-ray diffraction analyses (Scheme 11) [8].
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The mechanism of formation 26 probably takes place through a consecutive Michael addition of second molecule of compound 1, to the initially formed α,β-unsaturated carbonyl compound 27 followed by cyclization and elimination of a molecule of H2O and HCl to afford the target compounds 26 as describe in Scheme 12.
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Cycloaddition reaction
Recently, enantioselective synthesis of substituted pyrans using compound 1 was reported. A variety of substituents compound, prepared from condensation of 1 and aldehyde, were well tolerated in Cinchona-based primary amine catalytic system, providing the substituted pyran adducts 35 in high yields, high diastereoselectivity (up to 9.0:1) and excellent enantioselectivities (up to 96 %) (Scheme 13) [31].
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Catalyzed [4 + 2] annulation between activated terminal alkynes and oxo-dienes intermediated using triphenylphosphine catalyst (20 mol %) was reported. Thus, Diels–Alder reaction between 1-phenylprop-2-yn-1-one 34 and 1-phenylprop-2-yn-1-one gave the corresponding highly functionalized dihydropyrans 36 in good to excellent yields (Scheme 14) [32].
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Knoevenagel condensation of compound 1 with appropriate cycloalkanone 37 in refluxing toluene or xylene for 4–6 h in the presence of β-alanine and acetic acid as catalyst gave 2-cycloalkylidene-3-oxo-3-phenylpropionitriles 38. The cycloaddition reaction of compound 38 with enol ethers 39 was performed in toluene solution at 110 °C for 24 h and the spiropyrans 40 were obtained in 78–93 % yields (Scheme 15) [33].
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The manganese(III) initiated oxidative free radical reaction between 2-amino-1,4-benzoquinone 41 and 1 was reported. When 5,6-dimethyl-2-(methylamino)-1,4-benzoquinone 41 was treated with 1 and manganese(III) acetate in acetic acid at room temperature, a yellow product 1-(1-cyano-2-oxo-2-p-tolylethylidene)-2,7,8-trimethyl-6,9-dioxo-3-p-tolyl-2-azaspiro[4.4]nona-3,7-diene-4-carbonitrile 42 and 1′,3,4-trimethyl-5-oxo-2′,6′-dip-tolyl-1′H,5H-spiro[furan-2,4′-pyrano[4,3-b]pyrrole]-3′,7′-dicarbonitrile 43 were obtained in 55 % yield (Scheme 16) [34].
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Initiation occurs with the manganese(III) acetate oxidation of 1 to produce radical 1a. This radical intermediate undergoes intermolecular addition to quinone ring followed by oxidation to generate 44, which was then oxidized by manganese(III) acetate to produce radical 45. Radical 45 undergoes 1,2-carbonyl group migration followed by oxidation and intermolecular nucleophilic addition of another molecule of 1a to give 46, which then undergoes a further intramolecular condensation reaction to produce 42. The solvent effects play an important role in the manganese(III) acetate initiated oxidative free radical reaction. Reaction between 1a and 41 was next performed in other solvents. The change of solvent to benzene, 2,2,2-trifluoroethanol, and acetonitrile gave 42 as the only product. It gave best result (69 % yield) when acetonitrile was used as the solvent (Scheme 17) [34].
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Reaction with 2-hydroxybenzaldehydes
Reaction of compound 1 with salicylaldehyde in isopropyl alcohol in the presence of piperidine afforded 3-benzoyl-2-iminocoumarin 52. Treatment of the latter compound with HCl/EtOH gave the 3-benzoylcoumarins 53 (Scheme 18) [35, 36]. The cyclocondensation reaction of 7-hydroxy-5-methoxy-2-methyl-4-oxo-4H-chromene-6-carbaldehydes 54 with compound 1 in ethanol in the presence of piperidine yielded 7-benzoyl-8-imino-5-methoxy-2-methylpyrano[3,2-g]chromen-4(8H)-ones 55 (Scheme 18) [38, 39].
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The reaction of 2-(allyloxy)benzaldehyde or 2-(allyloxy)-1-naphthaldehyde 56 with compound 1 carried out at room temperature gave rise to the formation of the Knoevenagel aduct 57 in good yield. The intramolecular hetero-Diels–Alder cycloaddition of 57 was accomplished in boiling xylene and afforded 3-phenyl-tetrahydropyrano[3,4-c]pyran-4-carbonitriles 58 in good yield (Scheme 19) [40].
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A new strategy involving domino Knoevenagel hetero-Diels–Alder reaction is described for the preparation of the pyrano[3,4-c]chromene scaffold. Thus, reaction of 2-(prop-2-ynyloxy)benzaldehyde 59 with compound 1 in the presence of CuI and (NH4)2HPO4 afforded pyrano[3,4-c]chromenes 61, via intermediate 60, with good yields (Scheme 20) [41].
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The condensation reaction of ethyl 3-ethoxy-3-iminopropanoate hydrochloride 62 with 1 gave ethyl 3-amino-4-cyano-5-oxo-5-phenylpent-3-enoate 63. Then the latter compound was reacted with salicylaldehyde to afford 3-amino-2-benzoyl-3-(2-oxo-2H-chromen-3-yl)acrylonitrile 64 in 85 % yield (Scheme 21) [42].
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Reaction with enaminones
2-Dimethylaminomethylene-3-(phenylhydrazono)-indan-1-one 65 was allowed to react with compound 1 to afford [2-imino-5-(2-phenylhydrazono)-2,5-dihydroindeno[1,2-b]pyran-3-yl](phenyl)methanone 66 (Scheme 22) [43].
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Miscellaneous methods
Treatment of 2-fluoro-5-nitrobenzyl bromide 67 with compound 1 in the presence of excess potassium carbonate led to the formation of 6-nitro-2-phenyl-4H-chromene-3-carbonitrile 68 (Scheme 23) [44].
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Elgemeie et al. [45] reported the reaction of 1 with malononitrile in refluxing pyridine to give 2-phenylprop-1-ene-1,1,3-tricarbonitrile 70. But Abdelrazek and Michael [46] reinvestigated the same reaction and a mixture of two products 69 and 70 was obtained (Scheme 24).
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The formation of these two products 69 and 70 from compound 1 and malononitrile involved Knoevenagel condensation reaction which gave directly to compound 70 and Michael addition of the active methylene of malononitrile to the cyano function of 1 will lead to the tautomerized intermediate 71a/71b which undergoes a 6-exo-dig cyclization [47] to afford the iminopyran 69 as shown in Scheme 25.
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3-Benzyl-4-methyl-2-oxo-6-phenyl-2H-pyran-5-carbonitrile 73 was synthesized via reaction between ethyl 2-benzylbuta-2,3-dienoate 72 and 1 through a tandem nucleophilic addition/lactonization process (Scheme 26) [48].
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4-(Methylthio)-2-oxo-6-phenyl-2H-pyran-5-carbonitrile 75, showed very strong fluorescence in the solid state, was synthesized via reaction of compound 1 with ketene dithioacetal 74 in DMSO in the presence of sodium hydroxide (Scheme 27) [49].
.
Pyridazines and their fused derivatives
Reaction with α-diazo-β-diketones
Cyclocondensation reaction of 1 with α-hydrazonopropanal 76, in refluxed ethanol containing pipreidine yielded pyridazin-6-imines 77 (Scheme 28) [50–52].
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Similarly, 2-(2-furyl)-hydrazonopropanal 78 was condensed with 1 in dioxane in the presence of piperidine to yield 4-benzoyl-6H-pyridazino[1,6-a]quinazolin-6-one 80 via intermediate 79 (Scheme 29) [54].
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6-(1H-Benzo[d][1,2,3]triazol-1-yl)-4-benzoyl-5-methyl-2-phenylpyridazin-3(2H)-one 82 was obtained in 71 % yield from reaction between 1 and benzotriazolhydrazone 81 in benzene in the presence of acetic acid and ammonium acetate (Scheme 30) [55].
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Ethyl 3-oxo-2-(2-phenylhydrazono)butanoate 83 was reacted with compound 1 in the presence ammonium acetate to yield 5-cyano-4-methyl-1,6-diphenylpyridazin-1-ium-3-carboxylate 84 (Scheme 31) [56].
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Miscellaneous methods
Knoevenagel condensation of compound 1 with malononitrile afforded 2-phenylprop-1-ene-1,1,3-tricarbonitrile 70 which converted into 6-imino-1,4-diphenyl-1,6-dihydropyridazine-3,5-dicarbonitrile 85 when treated with benzene diazonium chloride followed by cyclization (Scheme 32) [45].
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Coupling of compound 63 with substituted benzene diazonium chloride to give ethyl 3-amino-4-cyano-5-oxo-5-phenyl-2-(2-arylhydrazono)pent-3-enoate 86. Then treatment of 86 with NaOH gave aminopyridazinium carboxylates 87 (Scheme 33) [46].
.
Pyrimidines and their fused derivatives
Reaction with 3(5)-aminopyrazoles, 2-aminothiophenes, 2-aminobenzimidazoles or 2-aminopyrimidines
Pyrazolo[1,5-a]pyrimidine 89 was synthesized by condensation of compound 1 with 3-amino-1,5-dihydro-1-(p-tosyl)pyrazole 88 in refluxed ethanol containing TEA [57]. Cyclocondensation of 1 with either ethyl 3,5-diamino-1H-pyrazole-4-carboxylate 90a [58] or ethyl 5-amino-3-phenyl-1H-pyrazole-4-carboxylate 90b [59] to give ethyl 7-amino-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxylate 91a,b; respectively. One pot three-component cyclocondensation reaction of compound 1, 4-(4-chlorophenyl)-5-methyl-1H-pyrazol-3-amine 92, and triethylorthoformate gave 3-(4-chlorophenyl)-2-methyl-7-phenylpyrazolo[1,5-a]pyrimidine-6-carbonitrile 93 [60]. Pyrazolo[1,5-a]pyrimidine 95 was synthesized in70 % yield via aza-Wittig reaction of compound 1 with 5-(triphenylphosphoranylideneamino)-3-phenylpyrazole 94 (Scheme 34) [61].
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2-(6-Acetyl-4-amino-5-phenylthieno[2,3-d]pyrimidin-2-yl)-1-phenylethanone 97 was synthesized, as inhibit the production of mycotoxins and fungal growth, from reaction of 5-acetyl-2-amino-4-phenylthiophene-3-carbonitrile 96 with compound 1 in DMF in the presence of piperidine [62]. 5,6-Dimethyl-2-(2-oxo-2-phenylethyl)thieno[2,3-d]pyrimidin-4(1H)-one 99 was prepared by treating aminothiophenecarboxylate 98 with 1 at room temperature (Scheme 35) [63].
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2-Benzoyl-3-phenylacrylonitrile 132 was reacted with 2-aminobenzoimidazole 100 in refluxed ethanol in the presence of pipredine to give 2,4-diphenyl-3,4-dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile 101 in excellent yield (Scheme 36) [64].
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Three-component one pot cyclocondensation reaction of compound 1, 1-(benzo[d]thiazol-2-yl)guanidine 102, and triethylorthoformate afforded 2-(benzo[d]thiazol-2-ylamino)-4-phenylpyrimidine-5-carbonitrile 103 (Scheme 37) [65].
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4-Phenyl-5-cyano-2-aminopyrimidines 106 were synthesized and found to have potent vascular endothelial growth factor (VEGF)-R2 kinase inhibitory activity. The key step involved reaction of a vinylogous amide with a guanidinium salt to form the pyrimidine ring. Specifically, treatment of 1 with N,N-dimethylformamide diethyl acetal (DMF-DEA) formed a vinylogous amide in situ that was reacted with guanidine nitrate in DMF at 100 °C to form the 2-amino-4-aryl-5-cyanopyrimidine 104. The Sandmeyer reaction of the aminopyrimidine 104 was accomplished by treatment with antimony trichloride and t-butylnitrite in 1,2-dichloroethane at 25 °C to smoothly afford the 2-chloropyrimidine 105. The displacement of the Cl of 105 with aliphatic amines proceeded at 25 °C and with aromatic amines in refluxing THF to afford the pharmacophores 106 (Scheme 38) [66].
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Miscellaneous methods
Pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine 108 was prepared in 68 % yield by reaction of 1 with formamidine 107 (Scheme 39) [67].
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The synthesis of substituted pyrazolo[1,5-a]quinazolin-5(4H)-one 110, as potent poly (ADP-ribose)polymerase-1 (PARP-1) inhibitors, has been reported. Thus, compound 1 was reacted with 2-hydrazinylbenzoic acid hydrochloride 109 under microwave condition in acetic acid to give 2-phenylpyrazolo[1,5-a]quinazolin-5(4H)-one 110 (Scheme 40) [68–71].
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Pyrimidinethiones 113 were synthesized from reaction of 3-amino-3-ethoxy-1-phenylprop-2-en-1-one hydrochloride 112 with isothiocyanate in refluxing acetone (Scheme 41) [72].
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Multi-component one pot reaction of compound 1, hydrazine hydrate, benzaldehyde, and malononitrile gave 7-amino-5-phenylpyrazolo[1,5-a]pyrimidine-6-carbonitrile 114 in good yields (Scheme 42) [73].
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Treatment of compound 1 with NaH-THF for 30-40 min and then with trifluoroacetonitrile for 5 h gave 4-phenyl-2,6-bis(trifluoromethyl)pyrimidine-5-carbonitrile 115 in 62 % yield (Scheme 43) [74, 75].
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Pyrazines and their fused derivatives
Benzo[c][1,2,5]oxadiazole 1-oxides 116 were reacted with compound 1 in different solvent, such as chloroform [7], dichloromethane [11] ethanol [76] in the presence of triethylamine at room temperature to give 2-cyano-3-arylquinoxaline 1,4-dioxide 117 in 45–61 % yield (Scheme 44). Quinoxaline 1,4-dioxide derivatives showed superior antimalarial [7] and anti-T. cruzi activity [11].
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Nitrosobenzothiazoleacetonitrile 118 was reacted with compound 1 in ethanol in the presence of triethylamine to yield 4-imino-3-(phenylcarbonyl)-4H-pyrazino[2,1-b][1,3]benzothiazole-1-carbonitrile 119 in 75 % yield (Scheme 45) [77].
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Triazines and their fused derivatives
Pyrazolo[5,1-c][1,2,4]triazines 121, 123, and 125 were synthesized from coupling of compound 1 with pyrazole diazonium chloride 120 [ 78], 122 [ 79], and 124 [80], respectively (Scheme 46).
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In a similar fashion, coupling diazotized of compound 1 with pyrazolediazonium chlorides 126, 128, and 130 in ethanol in the presence of sodium acetate yielded pyrazolo[5,1-c][1,2,4]triazine 127, [81] 129, [82] and 131 [ 83] (Scheme 47).
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Cyclocondensation reactions of compound 1 with pyrazole diazonium salt 132 afforded substituted triazine 288 [84]. 2-Thiazolediazonium salt 134 underwent coupling diazotized reaction with 1 to give ethyl 3-benzoyl-4-imino-6-methyl-4H-thiazolo[2,3-c][1,2,4]triazine-7-carboxylate 135 (Scheme 48) [85].
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Conclusion
This survey is attempted to summarize the synthetic potential of benzoylacetonitrile in the synthesis five six-memderd ring heterocycles, pyrans, pyridazines, pyrimidine, pyrazines and triazine compounds, during the period from 1985 till now. The literature survey of the synthetic potential of benzoylacetonitrile in the synthesis of five-memberd heterocycles was submitted as a separate review article [19].
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Abdel-Wahab, B.F., El-Mansy, M.F. & Khidre, R.E. Production of pyrans, pyridazines, pyrimidines, pyrazines and triazine compounds using benzoylacetonitriles as a precursor. J IRAN CHEM SOC 10, 1085–1102 (2013). https://doi.org/10.1007/s13738-013-0244-2
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DOI: https://doi.org/10.1007/s13738-013-0244-2