1. INTRODUCTION:

In the previous periods, the nitrile derivative differs and proved their multiple practices in the heterocyclic synthesis. Furthermore they performed as an intermediary part in a number of reaction conversions. The malononitrile derivatives exhibits the synergistic toxicity in the toxic-dynamic andtoxic-kinetic interactions with aldehyde components^[1]. Some of the malononitrile derivativesshows the significant antimicrobial^[2]such as antibacterial^[3]and antifungal^{[4] [5]}, anti-proliferativeactivities on human breast adenocarcinoma, ovarian adenocarcinoma and lymphoblastic leukemiacell^[6]. They also act as anticancer^[7], molluscicidal^[8], anti-inflammatory^[9]and anti-oxidant^[10] agents.

Besides these the definite complex molecules of malononitrile derivatives by copper metalconfers the virtuous anticancer activities^[11]and similarly acts as G protein-coupled receptor 35(GPR35) agonists^[12].

2. CONCEPT OF ACTIVE METHYLENE GROUP IN MALONONITRILE:

The Active methylene group of malononitrile plays a vital and attacking role in the heterocyclic synthesis. Malononitrile innumerate the unique interest in the organic synthesis due tothe conversion of different functional groups such as ketones, aldehydes, esters, Oxo and aminescorresponding carbanions of malononitrile molecule causes very essential for structural and spectralchanges^[13]. The Knoevenagel condensation reaction offers most of the conversion betweencarbonyl carbons with active methylene group of the nitrile analogs. Their molecular crystal acts asphase transfer in the specific heat capacity at low temperature^[14]. In the photochemical study ofmalononitrile 1 measured by the photo absorption and fluorescence excitation in vacuum UV regionby Rydberg states. It was proved that CN (B2Σ+) and CN (A2II) photo fragments increases bydecreasing the wavelength excitation in fluorescence spectrum^[15].

3.METHODS OF SYNTHESIS OF MALONONITRILE:

3.1 Synthesis using ketones:

Wang G. and Cheng B.^[16] have synthesized the arylidene 3(a-c) malononitrile analogs by uniform mixture of substituted ketones 2 (a-c) and dicyanomethane 1 catalyzed by ammonium acetate or silica gel under the microwave assisted solvent free synthesis. (Scheme-01)

Gupta Y.K. et al ^[17] have buildup the simple and efficient silica supported method of Knoevenagel condensation method. Identical molar mixture of different substituted ketones 4(a-f)andmalononitrile5(a-b) were reacted in presence of silica supported ammonium acetate catalystrefluxed on 60ºC temperature in methylene dichloride solvent; furnished compound 6(a-l)gavehigh quality and yields. (Scheme – 02)

Elison M. N. et al^[18]have synthesized the different substituted tetra cyanopropanes by the elctrolysis of malononitrile and carbonyl groups (ketones / aldehydes) in presence of sodiumbromide undivided electrolytic cell reaction. (Scheme – 03 and Scheme – 04)

3.2 Synthesis using aldehydes:

Bhuiyan M. M. H. et al^[19] synthesized arylidenemalononitrile derivatives 11(a-k) by parallelmixture of substituted aromatic aldehydes 10(a-k) and malononitrile 1 using catalytic amount of ammonium acetate under microwave irradiation. (Scheme -05)

Sheibani H. and Saljoog A. S ^[20]has reported the eco-friendly high speed Knoevenagel condensation synthesis. In the reaction condition, counterpart mixture of the substituted aldehydes12(a-v) and nitrile groups 13(a-b) were carried out under ethanol-aqueous media in presence of KOH or NaOH catalyst at 50-60ºC temperature afforded the productive 14(a-t) derivatives.(Scheme – 06)

Rajendran A. et al ^[21]have reported the simple efficient and rapid Knoevenagel condensationsynthesis by using ionic liquid media. The mixture of aromatic aldehyde 15(a-f) anddicyanomethane1 were evenly carried out in pyridinium salicylate ionic liquid refluxed on 40ºC forfew minutes occupied the malononitrile 16(a-f) derivatives. (Scheme – 07)

Pal R. ^[22]endured a new efficient method of Knoevenagel condensation reaction by using fruit juiceaccelerators. The Parallel mixture of different substituted aldehydes 17(a-d) and malonic nitrile 1 bytamarind juice catalyst in an aqueous media in presence visible light for few minutes afforded themalononitrile18(a-d) analogous. (Scheme – 08)

Pasha M. A. et al ^[23]have fabricated the solvent free grindstone method of Knoevenagelcondensation. In the reaction condition, the substituted aldehyde 19 and nitriles 20 uniformly mixedwith Na2CO3 catalyst under grindstone method afforded aryl-methylidene21. (Scheme – 9)

Tamami B. and Fadavi A. ^[24]have synthesized the malononitrile derivatives 24 in presence ofmodified form of polyacrylamide catalyst heated under water by using equimolar mixture ofaromatic aldehyde 22 and nitrile 23 analogs. (Scheme – 10)

Lin Q. et al ^[25]have designed a novel chemosensor of cyanide analogous 26 by the condensation between napthaldehyde25 with mlononitrile1 heated at 90°C from 2 hrs in aqueous media via greensynthesis. (Scheme – 11)

Basude M. et al. ^[26]have prepared the methylene-dinitrile derivatives 29(a-i) under water. Anexperimental section, substituted aryl aldehydes 27(a-i) reacts with malononitrile or ethylcyanoacetate28(a-b) in presence of ZnO catalyst in an aqueous condition at ambient temperaturethat gives end products (Scheme – 12)

Gupta Y.K. et al ^[27] have established a new indole derivatives 32(a-t) promoted by L-proline catalyst.Indole aldehydes 30(a-d) evenly mixed with active methylene nitrile groups 31(a-e) underKnoevenagel condensation reaction catalyzed by L-proline refluxed on 60⁰C in ethanol. (Scheme –13)

Gutch P. K. et al ^[28]have formulated and reported the biologically active riot control agentbenzylidenemalononitrile34 groups. These are synthesized by the mixture of substituted aromaticaldehydes33 and malononitrile 1 in presence of highly alkaline catalyst like piperidine refluxed in cyclohexane solvent. They are bio-significant riot-control agents. (Scheme – 14)

Gauda M. A. and Abu-Hasan A. ^[29]have intended the eco-friendly synthesis of malononitrilederivatives36, 38 in an aqueous media. In the Knoevenagel condensation synthesis of aromaticaldehydes35, 37 and malononitrile 1 were equally mixed by using lithium hydroxide monohydratecatalyst which acts as dual-activator nature. (Scheme – 15)

3.3 Synthesis from indole-1,3-diketones:

Riyaz S. D. et al ^[30]have formulated the different substituted isatins41(a-s) were afforded by appropriate amount of substituted indole-1,3-diketone 40(a-s) reacts with active methylene malononitrile or ethyl cyanoacetate or cyanoacetic acid 39(a-c) in presence of piperidinium acetate catalyst heated at 100ºC for 30 min in aqueous media. (Scheme – 16)

Lashgari N. et al ^[31]have reported the Knoevenagel condensation of isatins44(a-h) in an aqueouscondition. These products were synthesized by the parallel mixture of indoles 42(a-d) and nitriles43(a-b) refluxed in presence of silica based sulphonic acid (SBA-Pr-SO3H) catalyst under water.(Scheme – 17)

Katrizky A. R. et al ^[32]have formulated the novel dyestuffs. These compounds were carried outfromisatin45(a-g) refluxed with alkyl halides and DMF which gave N-alkylisatins46(a-g); then further refluxed with malononitrile 1 under DMSO readily converted into corresponding 1-alkyl- 3cyanomethylideneindol-2-ones 47(a-g). (Scheme – 18)

3.4 Using cyclopentadienones:

Andrew T. L. et al ^[33]have synthesized 6,6-dicyanofulvenes 49, 51 derived from monomeric anddimeric forms of cyclopentadienones 48, 50 with malononitrile 1 by using TiCl4 and pyridinecatalyst stirred from 0ºC to room temperature in the methylene dichloride solvent. (Scheme –9)

3.5 Using ninhydrin and napthalen-2,3-diamine:

Taherkhani M. ^[34]reported the indenobenzoquinoxaline53 in microwave assisted solvent free onepot synthesis. The quinoxalines53 derivatives was synthesized by the mixture of ninhydrin51 andnapthalen-2,3-diamine 52 counterparts of malononitrile 1 with few drops of DMSO in solvent freemicrowave conditions. (Scheme – 20)

3.6 Synthesis from chalcones:

Gupta Y.K. et al^[35] has synthesized the bis-methine dyes from chalcones and malononitrile. A solution of afforded chalcones 54(a-g) were refluxed with malononitrile 1 catalyzed by ammonium acetateand acetic acid under benzene, the 2,5-bis-arylidene-1-dicyanomethylene-cyclopentane 55(a-g) areproduced. The afforded compounds have found promising antifungal activities. (Scheme – 21)

3.7 From 1-[4-(benzylideneamino)-phenyl] ethanones:

Sindhu A. et al ^[36]have assembled the chemo selective elimination of malononitrile derivatives.The 2-benzylidinemalononitrile 58 was performed by the condensation of malononitrile 1 and 1-4-(benzylideneamino)-phenyl] ethanones56 by the elimination of byproduct 59. (Scheme – 22)

3.8 Using chloranils:

Hammam A. S. et al ^[37]have formulated pyrrolo [2,3-f]indole-3,7-dicarbonitrile 62 derivatives. These are gained by the reaction mixture chloranils60 and malononitrile61 (1:2) ration in presenceof triethylamine catalyst refluxed in ethanolic conditions. The selected compounds possesess the significant antimicrobial activities. (Scheme – 23)

3.9 From alkyl halides:

Diez-Barra E. Et al ^[38]have prepared the mono-alkyl-malononitrile 64 and di-alkyl-malononitriles67 by using tetra-butyl ammonium bromide catalyst in solvent free basic medium. (Scheme – 24)

4. CHEMICAL REACTIONS:

Jayachandran M. and Shriram K.^[39]have fortified the 5,5’-(arylalkene-1,1-diyl) bis(1Htetrazoles) 70(a-b) derived from (arylalkene)malononitrile69(a-b) intermediates. The (arylalkene) malononitriles were prepared by substituted ketones 68 and propane-di-nitrile 1 with piperidine refluxed in presence of ethanolic condition. Then further cyclization was done by using sodium azide with ammonium chloride catalyst heated in DMF solvent acquired the final products which reveals the significant antibacterial activities. (Scheme – 25)

Dodiya D. K. et al^[40]have synthesized some novel pyrazolo[3’,4’:4,5]thieno[2,3-d] pyrimidine-8-ones 74(a-j) via malononitrile intermediates by three-step Gewald reaction. (5-methyl-2,4-ihydro-3H-pyrazol-3-ylide-ne) malononitrile72(a-j) were afforded from 71(a-j) and 1 with the help ofpiperidyl acetate catalyst, then accomplished with sulphur morphine at 60⁰C for 6 min which form73(a-j). By closing the final step, glacial acetic acid was catalyzed by the mixture of substitutedaldehydes and 52(a-j) furnishes the novel pyrazolo-pyrimidine 53(a-j) synthons are positiveantimicrobial agents. (Scheme – 26)

Dandia A. et al ^[41]have constructed a novel indole derivatives by solventless method. The newannulated2-amino-3-carbonitrile-spiro[(indeno-1,2,b)pyran-4(5H),3‘-(3,H)indole]2‘,5(1’H)-iones78(a-b) were carried out by 3-dicyano/carboethoxycyanomethylene-2H-indol-2-ones 77intermediates from malononitrile derivatives 76 and substituted indoles 75 titles. (Scheme – 27)

Abdel-megid M. et al ^[42]have developed diaminopyridone82 of nitrogen substituted fusedheterocyclic compounds derived from 1 and 79 starting components. The final derivatives 82 were gained by [(6-methyl-4-oxo-4H-chromene-3-yl) methylene] malononitrile 80 intermediates inpresence of piperidine catalyst refluxed in ethanol. The synthesized products emphasized thesubstantial antimicrobial activities. (Scheme – 28)

Karimi-Jaberi Z. and Pooladian B. ^[43] have constructed a novel synthesis of 2-amino-4H-pyran-3-carbonitrile84 (a-q) series by facile one pot reaction of α,α‘-bis(arylidene)cycloalkanones83(a-q) and malononitrile 1 were refluxed under alcoholic condition by using K2CO3 catalyst. (Scheme –29)

Manikannan R. et al ^[44]have buildup the multi component synthesis of poly substituted pyridines87 by using equivalent mixture of substituted ketones 85, dicyanomethane1 and aromatic aldehydes86 in presence of alcoholic sodium hydroxide stirred for 10-60 min. Then the formulated compounds were screened their anti-tubercular activities on mycobactrium tuberculosis. Thesecompounds were found more potent activities than the standards. (Scheme- 30)

Shi F. et al ^[45]have mounted the solvent free synthesis of 2-amino-cyanopyridines 90 bymicrowave assisted method. The substituted aromatic aldehydes 88, ketones 89 and propanedinitrile1 are uniformly mixed with the addition of ammonium acetate catalyst was irradiated in a singlecomponent system intended the final products. (Scheme – 31)

Datta B. and Pasha M. A. ^[46]have reported the solvent free eco-friendly synthesis under thermalcondition. Malononitrile 1, substituted ketones 92 and aromatic aldehydes 91 were heated with iodized K2CO3 catalyst, the polysubstituteddicyanoaniline93 afforded in a very short time.(Scheme – 32)

Gupta Y.K. et al^[47]developed the candid one-pot multicomponent microwave synthesis. In theseneat reaction, the combination mixture of methylenedinitrile1, aromatic aldehydes 94 and 1-napthol95 were catalysed by p-dimethylaminopyridine which produces 2-amino-2-chromenes 96derivatives. (Scheme – 33)

Beheshtia Y. S. et al ^[48]have introduced the novel DABCO catalyst in one pot multicomponentsynthesis of pyridine dicarbonitrile99 by the reaction mixture of paramethylthiophenol97, malonicnitrile1 and substituted aromatic aldehydes 98. (Scheme – 34)

Heravi M. M. et al ^[49]have synthesized the novel 2-amino-4-H-chromene derivatives 102 and 103in presence methanesulfonic acid catalyst refluxing with the mixture of aryl aldehydes 100,malononitrile1 and α,β-disubstitutednapthols101 in a single pot reaction. (Scheme – 35)

Hasaninejad A. et al ^[50]alumina supported recyclable potassium fluoride catalyst were created

and used for the synthesis of benzopyran106 by using the uniform mixture malononitrile 1,substituted cyclohexane-1,3-dione 105 and aromatic aldehydes 104 were refluxed under ethanoliccondition. (Scheme – 36)

Ahmadi S. A. and Maddahi M. ^[51]have developed the 2-amino-4-hydroxy-1H pyrrole-3-carbonitrile108 from the reaction mixture of glycine 107 and malononitrile 1 accelerated by

piperidine under the microwave efficient conditions. (Scheme – 37)

Zirani G. M. et al ^[52]have prepared the pyrano[2,3-d]-pyrimidine diones111 by the threecomponent reaction synthesis from barbituric acid 109, malononitrile1 and substituted aldehydes110 carried out withSBA-Pr-SO3H nanocatalyst under the solvent free conditions. The finalcompounds possessed the considerable urease inhibitory activities. (Scheme – 38)

Kibon Z. et al ^[53]have constructed the new 2-amino-3-cyanopyridines 155(a-d) throughenaminonitriles113 intermediate from substituted ketones 112 and malononitrile 1 by the solventfree microwave assisted method. (Scheme – 39)

Khalify J. et al ^[54]have synthesized 3-amino-5-arylpyridazine-4-carbonitril 118 series by usingarylglyoxal116 and hydrazine hydrate 117 in presence of malononitrile 1 stirred for 30 min at roomtemperature under ethanol and water (1:1) ratio. (Scheme – 40)

Kiyani H. et al^[55]have developed the eco-friendly green facile four component reaction. In thesynthesis part, pyranopyrazoles122(a-q) were prepared by equimolar mixture of aromatic aldehydes119(a-q), hydrazines120, ehtyl acetoacetate 121 and malononitrile 1 by using sodium acetoacetatecatalyst stirred under water at room temperature. (Scheme – 41)

Danish I. A. and Prasad K. J. R. ^[56]havesynthesiszed 3-cyano-5,6-dihydro-2-ethoxy-4-phenylpyrido[2,3-a](carbazoles124 from the reaction mixture of 2-benzylidene-8-methyl-1-oxo-1,2,3,4-tetrahydracarbazoles123 and malononitrile1 with anhydrous ethanol in presence of sodium hydridecatalyst refluxed under desicated benzene. (Scheme – 42).

Varela J. A. et al ^[57]have developed the novel series of spiropyridines127 a symmetric chiralligands obtained from dual-cyclization between bis-alkynenitriles125 and substituted alkynes 126by using cobalt catalyst under single pot reaction. (Scheme – 43)

El-Emary T. I. et al ^[58]have synthesized a novel spiro segregated indole substituted heterocycliccompounds like 3-benzoylcyanomethylidine-1(H)-indle-2-one 130, 3-thiosemicarbazide-1(H) -indole-2-one 132 and indoline-2,3-dione-3-cyanoacetic hydrazone134 derivatives. They areprocured by the condensation of 1-H-indole-2,3-dione 128 with benzoylacetonitrile129,thiosemicarbazide131 and cyanoacetic hydrazide 133 heated with phsphoryl chloride catalyst.(Scheme – 44)

Makarem S. et al ^[59]have developed the electrochemical induced multicomponent condensation

reaction. In the experimental section, a mixture of resorcinol 135, substituted aldehydes 136(a-h)and malononitrile 1 were evenly condensed in propanol by using NaBr electrolytes resulting in theformation of 2-amino-4H-chromenes 137(a-h). (Scheme – 45)

Fringulli F. et al ^[60]have developed the 7-hydroxy-3-carboxy coumarins143 in a single potreaction in aqueous media by equimolar amount mixture of 2, 4, dihydroxy benzaldehyde 138 andpropane-dinitrile1 were carried out under water in heterogeneous conditions. There are four typesof fundamental reaction are stepwise carried out such as Knoevenagel, aldol condensation, Pinnerreaction, acid catalyst, base catalyst and acid-base equilibrium synthesis simultaneously monitoringpH scales from starting medium to the final coumarins. (Scheme – 46)

5. MISCELLANEOUS REACTIONS:

Hammam A. E. G. et al. ^[61]have synthesized pyrazole152, pyridine 150, pyrimidine 148 andmalononitrile145, 146 derivatives. In the beginning bis-chalcone144 derivatives were treated withCH2(CN)2 1, NH=C(NH2)2.HCl147, CN-CH2COOEt 149, PhNHNH2 151 in presence ofammonium acetate afferedpyroles, pyridine, pyrimidine, pyrazoline derivatives. (Scheme – 47)

Gupta Y.K. et al^[62]have formulated the novel Spiro-fused pyran157 derivatives by solvent lessmicrowave assisted synthesis. These pyran derivatives were made by the cyclization of three components mixture of ninhydrin154, malononitrile1 and phenyl pyrazoline-3, 5-dione 153irradiated in presence of the neutral Al2O3 catalyst. (Scheme – 48)

Rajput S. S.^[63]has reported the malononitrile derivatives azoflurorenes160, 162 furnished by themixture of 4-chlorophenyl-succinimides 158, substituted aromatic aldehydes 159 and acetaldehyde161 with methylene nitrile 1 by using piperidine catalyst refluxed under ethanolic conditions.(Scheme – 49)

Gupta Y.K. et al.^[64]have synthesized malononitrile analogous 166 by the mixture of substitutedaromatic aldehydes 164 and 2,4-dihydroxy-acetophenone 163 under microwave in presence ofmontmorilonite K10 catalyst which form chalcones165. On further treatment with malononitrile inpresence of catalytic amount of morpholine furnishes the required product. (Scheme – 50).

6. CONCLUSION:

This review has attempted to summarize the synthetic methods and reactions of malononitrilegroups. Many biologically active heterocyclic compounds have been synthesized from that group. These reactions greatly extended synthetic possibilities in organic chemistry.

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Received on 05.12.2018 Modified on 12.12.2018

Asian J. Research Chem. 2018; 11(6):876-886.

DOI:10.5958/0974-4150.2018.00153.0