International Letters of Chemistry, Physics and Astronomy Online: 2015-08-04

ISSN: 2299-3843, Vol. 57, pp 126-144

doi:10.18052/www.scipress.com/ILCPA.57.126
© 2015 SciPress Ltd., Switzerland

Malononitrile: A Versatile Active Methylene Group

R. S. Dhivare1, a *, S. S. Rajput2, b
1
Department of Chemistry, J.J.T. University, Jhunjhunu, Rajasthan, India
2
Department of Chemistry, SVS’s Dadasaheb Rawal College, Dondaicha, Maharashtra, India
E-mail address: aravii_1978@rediffmail.com, brajputss65@gmail.com

Keywords: Malononitrile, Active methylene group

Abstract: The title role of malononitrile in the development of Knoevenagel condensation of

organic synthesis and their new findings are explored in this review. The active methylene group of
malononitriles is very important attacking part in the heterocyclic conversions and also having a
great potency towards several microbial and biological systems.

Contents:
1. Introduction
2. Concept of active methylene group in malononitrile
3. Methods of synthesis of malononitrile derivatives
4. Chemical reactions of malononitriles
5. Miscellaneous Reactions with malononitrile
6. Conclusion

1. INTRODUCTION:
In the earlier 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 and
toxic-kinetic interactions with aldehyde components [1]. Some of the malononitrile derivatives
shows the significant antimicrobial [2] such as antibacterial [3] and antifungal [4] [5], anti-proliferative
activities on human breast adenocarcinoma, ovarian adenocarcinoma and lymphoblastic leukemia
cell [6]. They also acts as anticancer [7], mollucicidal [8], anti-inflammatory [9] and anti-oxidant [10]
agents. Besides these the definite complex molecules of malononitrile derivatives by copper metal
confers 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:

Active methylene group of malononitrile 1 analogs plays a vital and attacking role in the
heterocyclic synthesis. Malononitrile innumerate the unique interest in the organic synthesis due to
the conversion of different functional groups such as ketones, aldehydes, esters, Oxo and amines
corresponding carbanions of malononitrile molecule causes very essential for structural and spectral
changes [13]. The Knoevenagel condensation reaction offers most of the conversion between
carbonyl carbons with active methylene group of the nitrile analogs. Their molecular crystal acts as
phase transfer in the specific heat capacity at low temperature [14]. In the photochemical study of
malononitrile 1 measured by the photo absorption and fluorescence excitation in vacuum UV region
by Rydberg states. It was proved that CN (B2∑+) and CN (A2II) photo fragments increases by
decreasing the wavelength excitation in fluorescence spectrum [15].

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 International Letters of Chemistry, Physics and Astronomy Vol. 57 127

H H

C
C C
N 1 N

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)

R1 CN R1 CN
silica gel or NH4OAc
O +
solvent free
R2 CN R2 CN
2(a-c) 1 3(a-c)

1a, 3a: R1, R2 = fluorenyl: 1b, 3b: R1 = Ph, R2 = CH3 : 1c, 3c : R1 = R2 = Ph

Scheme - 01

Gupta R. 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) and
malononitrile 5(a-b) were reacted in presence of silica supported ammonium acetate catalyst
refluxed on 60ºC temperature in methylene dichloride solvent; furnished compound 6(a-l) gave
high quality and yields. (Scheme – 02)

O NC R1 CN
SiO2-NH4OAc
+
X CH2Cl2, 60C
R1 R2
R2 X
4(a-f) 5(a-b)
6(a-l)
X = CN, COOEt
Scheme - 02
Elison M. N. et al [18]have synthesized the different substituted tetracyanopropanes by the
elctrolysis of malononitrile and carbonyl groups (ketones / aldehydes) in presence of sodium
bromide undivided electrolytic cell reaction. (Scheme – 03 and Scheme – 04)

O R1 R2
electrolysis NC
CH2(CN)2 + CN
R1 R2 NaBr
NC CN
1 6(b-i) 7(b-i)
b R1 = Me, R2 = Et f R1 = Pr, R2 = Pr
c R1 = Me, R2 = Pr g R1 , R2 = (CH2)4
d R1 = Me, R2 = Bu h R1 , R2 = (CH2)6
e R1 = Me, R2 = Me(CH2)5 i R1 = Me, R2 = Ph
Scheme - 03
128 Volume 57

O R1 R2
electrolysis NC
CH2(CN)2 + CN
R H NaBr
NC CN
1 8(a-h) 9(a-h)
aR=H e R = 2-ClC6H4
b R = Me f R = 2-BrC6H4
c R = Pr g R = 2-IC6H4
d R = Ph h R = 3-MeOC6H4
Scheme - 04
3.2 Synthesis using aldehydes:
Bhuiyan M. M. H. et al [19] synthesized arylidene malononitrile derivatives 11(a-k) by parallel
mixture of substituted aromatic aldehydes 10(a-k) and malononitrile 1 using catalytic amount of
ammonium acetate under microwave irradiation. (Scheme -05)
Ar CN
Ar CN NH4OAc
O +
MWI
H H CN
CN
10 (1-11) 1 11 (1-11)
Scheme - 05
[20]
Sheibani H. and Saljoog A. S. have reported the ecofriendly high speed Knoevenagel
condensation synthesis. In the reaction condition, counterpart mixture of the substituted aldehydes
12(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)
Ar CN
Ar CN H2O/C2H5OH
O + H2O
+
KOH/NaOH
H R 50-60C H R
12(a-v) 13 14(a-t)
R = CN, COOEt
Scheme - 06

Rajendran A. et al [21] have reported the simple efficient and rapid Knoevenagel condensation
synthesis by using ionic liquid media. The mixture of aromatic aldehyde 15(a-f) and
dicyanomethane 1 were evenly carried out in pyridinium salicylate ionic liquid refluxed on 40ºC for
few minutes occupied the malononitrile 16(a-f) derivatives. (Scheme – 07)
CN CN
IL
ArCHO +
1-5 min Ar
CN CN
15(a-f) 16(a-f)
1
Scheme - 07

Pal R. [22] endured a new efficient method of Knoevenagel condensation reaction by using fruit juice
accelerators. The Parallel mixture of different substituted aldehydes 17(a-d) and malonic nitrile 1 by
tamarind juice catalyst in an aqueous media in presence visible light for few minutes afforded the
malononitrile 18(a-d) analogous. (Scheme – 08)
 International Letters of Chemistry, Physics and Astronomy Vol. 57 129

aq. tamarind juice Ar CN

Ar CN
hv, 2-7 min
O +
80-98%
H H CN
CN
17(a-d) 18(a-d)
1
R = aryl, cinnamyl
heteroaryl, alkyl
Scheme - 08
[23]
Pasha M. A. et al have fabricated the solvent free grindstone method of Knoevenagel
condensation. In the reaction condition, the substituted aldehyde 19 and nitriles 20 uniformly mixed
with Na2CO3 catalyst under grindstone method afforded aryl-methylidene 21. (Scheme – 09)
CN Grindstone method Ar CN
ArCHO + solvent-free
Na2CO3, 1-5 min
19 X 21
20 X
X = COOEt, CN
Scheme - 09
[24]
Tamami B. and Fadavi A. have synthesized the malononitrile derivatives 24 in presence of
modified form of polyacrylamide catalyst heated under water by using equimolar mixture of
aromatic aldehyde 22 and nitrile 23 analogs. (Scheme – 10)
O CN CN
Cat/solvent-free/60C
+
H Ar or Cat / Water/ 80C
R Ar CN
22 24
23
R = CN, CONH2 and CO2Et
Scheme - 10

Lin Q. et al [25] have designed a novel chemosensor of cyanide analogous 26 by the condensation
between napthaldehyde 25 with mlononitrile 1 heated at 90°C fro 2 hrs in aqueous media via green
synthesis. (Scheme – 11)
CN
O H
CN
1
CH2(CN)2

H2O 90C
25 26
Scheme - 11
Basude M. et al. [26] have prepared the methylene-dinitrile derivatives 29(a-i) under water. An
experimental section, substituted aryl aldehydes 27(a-i) reacts with malononitrile or ethyl
cyanoacetate 28(a-b) in presence of ZnO catalyst in an aqueous condition at ambient temperature
that gives end products (Scheme – 12)
CN
O CN
ZnO
OR +
O CN
R 27 (1-9) CN
28 (1-2) 29(1-9)
R = Cl or OCH3 or NO2
Scheme - 12
130 Volume 57

Jain S. 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) under
Knoevenagel condensation reaction catalyzed by L-proline refluxed on 60ºC in ethanol. (Scheme –
13)

R1 CHO L-proline CH=C(CN)2

CN R1
C2H5OH
N +
60C N
R2 CN
30(a-d) R2
31(a-e) 32(a-t)
Scheme - 13

Gutch P. K. et al [28] have formulated and reported the biologically active riot control agent
benzylidene malononitrile 34 groups. These are synthesized by the mixture of substituted aromatic
aldehydes 33 and malononitrile 1 in presence of highly alkaline catalyst like piperidine refluxed in
cyclohexane solvent. They are bio-significant riot-control agents. (Scheme – 14)
CN
CN
R2 CHO Piperidine R2 + H2O
CH=C
+
CN
R1 CN
34 R1
33 1
R1 = H, F, Cl, Br, NO2, CH3, OCH3, COOH R2 = H, F, Cl, Br, NO2, CH3, OCH3, OH, N(CH3)2
Scheme - 14

Gauda M. A. and Abu-Hasan A. [29] have intended the eco-friendly synthesis of malononitrile
derivatives 36, 38 in an aqueous media. In the Knoevenagel condensation synthesis of aromatic
aldehydes 35, 37 and malononitrile 1 were equally mixed by using lithium hydroxide monohydrate
catalyst which acts as dual-activator nature. (Scheme – 15)

35 CN
Ar-CHO
LiOH.H2O (0.05 equi)
Ar 36 CN
CN
H2O CHO
OH CN
CN 37
1
LiOH.H2O O NH
38
Scheme - 15

3.3 Synthesis from indole-1,3-diketones:

Riyaz S. D. et al [30] have formulated the differernt substituted isatins 41(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)
 International Letters of Chemistry, Physics and Astronomy Vol. 57 131

NC
R
R
O CN
N
Piperidinium
C acetate
+
O H2O, 30 min O
N X  / 100ºC N
R1 H 40(a-c) H
39a-s) R1 41(a-s)
a) X = CN
R = H, Cl, Br, F, I b) X = COOEt
R1 = H, F c) X = COOH
Scheme -16

Lashgari N. et al [31] have reported the Knoevenagel condensation of isatins 44(a-h) in an aqueous
condition. These products were synthesized by the parallel mixture of indoles 42(a-d) and nitriles
43(a-b) refluxed in presence of silica based sulphonic acid (SBA-Pr-SO3H) catalyst under water.
(Scheme – 17)

X
O CN
R X
R
SBA-Pr-SO3H
O +
H2O / Reflux O
C
N
H N N
H
42(a-d) 43(a-b) 44(a-h)
R = H, Cl, Br, NO2 X = CN, CO2Et
Scheme - 17

Katrizky A. R. et al [32] have formulated the novel dyestuffs. These compounds were carried out
from isatin 45(a-g) refluxed with alkyl halides and DMF which gave N-alkylisatins 46(a-g); then
further refluxed with malononitrile 1 under DMSO readily converted into corresponding 1-alkyl-
3cyanomethylideneindol-2-ones 47(a-g). (Scheme – 18)

X
O O CN
1
RX CH2(CN)2
O O
DMSO O
N NaH, DMF N
H R N
45(a-g) R
46(a-g) 47(a-g)
R : a = H, b = CH3, c = n-pr, d = n-hexyl, e = PhCH2, f = PhCHCH3, g = I-(benzotriazole)CH2-
Scheme - 18

3.4 Using cyclopentadienones:

Andrew T. L. et al [33] have synthesized 6,6-dicyanofulvenes 49, 51 derived from monomeric and
dimeric forms of cyclopentadienones 48, 50 with malononitrile 1 by using TiCl4 and pyridine
catalyst stirred from 0ºC to room temperature in the methylene dichloride solvent. (Scheme – 19)
132 Volume 57

O 1 NC CN
CH2(CN)2
Ph Ph TiCl4 , Py
Ph Ph
CH2Cl2, 0 C to rt
Ph Ph
45% Ph Ph
48 49

NC CN
O
1
Ph Ph CH2(CN)2 Ph Ph
TiCl4 , Py

CH2Cl2, 0 C to rt

50%

50 51
Scheme - 19

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

Taherkhani M. [34] reported the indenobenzoquinoxaline 53 in microwave assisted solvent free one
pot synthesis. The quinoxalines 53 derivatives was synthesized by the mixture of ninhydrin 51 and
napthalen-2,3-diamine 52 counterparts of malononitrile 1 with few drops of DMSO in solvent free
microwave conditions. (Scheme – 20)

CN
1 NC
O
OH CH2(CN)2, 1.2 eq. N
H2N DMSO (3drops)
+
OH MW (125-130C) N
H2N 3 min
51 O 52 53
Scheme - 20

3.6 Synthesis from chalcones:

Asiri A. M. [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 acetate
and acetic acid under benzene, the 2,5-bis-arylidene-1-dicyanomethylene-cyclopentane 55(a-g) are
produced. The afforded compounds have found promising antifungal activities. (Scheme – 21)

O NC CN
1
CH2(CN)2

AcOH-AcONH4
Me N N Me C6H6 Me
Me N N
Me Me
54(a-g) Me 55(a-g) Me
Scheme - 21

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

Sindhu A. et al [36] have assembled the chemoselective elimination of malononitrile derivatives.
The 2-benzylidinemalononitrile 58 was performed by the condensation of malononitrile 1 and 1-[4-
(benzylideneamino)-phenyl] ethanones 56 by the elimination of byproduct 59. (Scheme – 22)
 International Letters of Chemistry, Physics and Astronomy Vol. 57 133

NC
NC CN
1
HC C H NC CN
CN C COCH3

CH N COCH3 CH +
CH=N COCH3

R NH
R 58
R 57 59
56
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 chloranils 60 and malononitrile 61 (1:2) ration in presence
of triethylamine catalyst refluxed in ethanolic conditions. The selected compunds possesess the
significant antimicrobial activities. (Scheme – 23)

O O Cl
Cl Cl NC Cl
EtOH / Et3N Cl
+
NC reflux, 30 min Cl
Cl Cl Cl
61
O Cl O
60 62
Scheme - 23

3.9 From alkyl halides:

Diez-Barra E. Et al [38] have prepared the mono-alkyl-malononitrile 64 and di-alkyl-malononitriles
67 by using tetra-butyl ammonium bromide catalyst in solvent free basic medium. (Scheme – 24)
Base R2C(CN)2
CNCH2CN + R-X
TBAB
1 64
63
Base
RCH(CN)2 + R'-X RR' C(CN)2
TBAB
65 66 67
Scheme - 24

4. CHEMICAL REACTIONS:
Jayachandran M. and Shriram K. [39] have fortified the 5,5’-(arylalkene-1,1-diyl) bis(1H-
tetrazoles) 70(a-b) derived from (arylalkene)malononitrile 69(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)
R2 R1
O CN CN
R1
Piperidine NaN3 / NH4Cl H H
+ N N
R1 R2 ethanol /  DMF /  N N
CN R2 CN
68(a-b) N N N N
1 69(a-b) 70(a-b)
a) R = Phenyl, R1 = methyl
b) R = Phenyl, R1 = Phenyl
Scheme - 25
134 Volume 57

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-dihydro-
3H-pyrazol-3-ylide-ne) malononitrile 72(a-j) were afforded from 71(a-j) and 1 with the help of
piperidyl acetate catalyst, then accomplished with sulphur morphine at 60ºC for 6 min which form
73(a-j). By closing the final step, glacial acetic acid was catalyzed by the mixture of substituted
aldehydes and 52(a-j) furnishes the novel pyrazolo-pyrimidine 53(a-j) synthons are positive
antimicrobial agents. (Scheme – 26)
H N N
N H Sulfur
N N morphine
Piperidyl acetate N
O + 6 hrs

H3C
71(a-j) N H3C
1 72(a-j) N

H O
H N
N N N
N RCOCH3
Glacial acetic acid NH
Con. H2SO4
H3C 6 hrs H3C
S S N R
73(a-j) NH2 74(a-j) H
R= Phenyl, 2-hydroxy phenyl, 4-fluorophenyl, 4-chloro phenyl,
4-bromo phenyl, 4-nitro phenyl, 4-methyl phenyl4-methoxy phenyl
Scheme - 26
[41]
Dandia A. et al have constructed a novel indole derivatives by solventless method. The new
annulated 2-amino-3-carbonitrile-spiro[(indeno-1,2,b)pyran-4(5H),3‘-(3,H)indole]2‘,5(1’H)-diones
78(a-b) were carried out by 3-dicyano/carboethoxycyanomethylene-2H-indol-2-ones 77
intermediates from malononitrile derivatives 76 and substituted indoles 75 titles. (Scheme – 27)

O
NC
76 N CN O
O
N C C O
O O
O O NH2
Solid state X N
X N R.T. H
H
X N OCN
75 77 H
78
Scheme - 27
Abdel-megid M. et al [42] have developed diaminopyridone 82 of nitrogen substituted fused
heterocyclic 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 in
presence of piperidine catalyst refluxed in ethanol. The synthesized products emphasized the
substantial antimicrobial activities. (Scheme – 28)
1 O
O
H3C CHO CH2(CN)2 H3C CN

H2O CN
O O
79 80
EtOH NH2NHCOCH2CN
EtOH NH2NHCOCH2CN Piperidine O
1 NC NH2
O H CH2(CN)2 O
H3C N H3C
N CN EtOH NH2
O Piperidine CN
O O
81 82
Scheme - 28
 International Letters of Chemistry, Physics and Astronomy Vol. 57 135

Karimi-Jaberi Z. and Pooladian B. [43] have constructed a novel synthesis of 2-amino-4H-pyran-3-

carbonitrile 84(a-q) series by facile one pot reaction of α,α‘-bis(arylidene)cycloalkanones 83(a-q)
and malononitrile 1 were refluxed under alcoholic condition by using K2CO3 catalyst. (Scheme –
29)
O NH2
K2CO3
O CN
NC 5 mol%
Z +
R R EtOH, reflux
NC Z
83(a-q) 1 R R
84(a-q)
Z = CH2, CH2CH2, CH(CH3)CH2
Scheme - 29
Manikannan R. et al [44] have buildup the multicomponenet synthesis of polysubstituted pyridines
87 by using equivalent mixture of substituted ketones 85, dicyanomethane 1 and aromatic aldehydes
86 in presence of alcoholic sodium hydroxide stirred for 10-60 min. Then the formulated
compounds were screened their anti-tubercular activities on mycobactrium tuberculosis. These
compounds were found more potent activities than the standards. (Scheme – 30)
NC Ar N OR'
O NaOH/R'OH
+ + Ar'CHO
S r.t., 10-60 min S CN
Ar R NC 86
R Ar'
85 1
87
Scheme - 30
[45]
Shi F. et al have mounted the solvent free synthesis of 2-amino-cyanopyridines 90 by
microwave assisted method. The substituted aromatic aldehydes 88, ketones 89 and propanedinitrile
1 are uniformly mixed with the addition of ammonium acetate catalyst was irradiated in a single
component system intended the final products. (Scheme – 31)
Ar
ArCHO NC
NH4OAc NC
88 +
NC WI
RCOCH3 H2N N R
89 1 90
Scheme - 31
[46]
Datta B. and Pasha M. A. have reported the solvent free eco-friendly synthesis under thermal
condition. Malononitrile 1, substituted ketones 92 and aromatic aldehydes 91 were heated with
iodized K2CO3 catalyst, the polysubstituted dicyanoaniline 93 afforded in a very short time.
(Scheme – 33)
NH2
CHO NC CN
NC
O I2 / K2CO3
+ +
, 10 min CH3
NC
R 1 92 R
91 93
R = H, 4-OCH3, 3,4-(OCH3)2, 4-CH3, 4-Cl, 4-NO2, and Furan-2-yl
Scheme - 32

Desale K. R. et al [47] developed the candid one-pot multicomponent microwave synthesis. In these
neat reaction, the combination mixture of methylenedinitrile 1, aromatic aldehydes 94 and 1-napthol
95 were catalysed by p-dimethylaminopyridine which produces 2-amino-2-chromenes 96
derivatives. (Scheme – 33)
136 Volume 57

NH2
CN
OH O
CN
conditions
ArCHO + +
CN
94 96
1 95
Scheme - 33

Beheshtia Y. S. et al [48] have introduced the novel DABCO catalyst in one pot multicomponent
synthesis of pyridine dicarbonitrile 99 by the reaction mixture of paramethyl thiophenol 97, malonic
nitrile 1 and substituted aromatic aldehydes 98. (Scheme – 35)
Ar
Me
CN NC CN
DABCO
+ + ArCHO
r.t.
CN H2N S Me
SH 1 98 99
97 Scheme - 34

Heravi M. M. et al [49] have synthesized the novel 2-amino-4-H-chromene derivatives 102 and 103
in presence methanesulfonic acid catalyst refluxing with the mixture of aryl aldehydes 100,
malononitrile 1 and α,β-disubstituted napthols 101 in a single pot reaction. (Scheme – 35)
NH2 CN
CN Ar NH2
X O
CN CH3CN
Y O
reflux Ar
ArCHO + + +
methanesulfonic
CN acid
100
1 101 102 103
Scheme - 35
Hasaninejad A. et al [50] alumina supported recyclable potassium fluoride catalyst were created
and used for the synthesis of benzopyran 106 by using the uniform mixture malononitrile 1,
substituted cyclohexane-1,3-dione 105 and aromatic aldehydes 104 were refluxed under ethanolic
condition. (Scheme – 36)
O Ar
O
Ar CN CN
Supported-KF
O + + R R
O Solvent
H O NH2
CN R
104 R 106
1 105
Scheme - 36
[51]
Ahmadi S. A. and Maddahi M. have developed the 2-amino-4-hydroxy-1H pyrrole-3-
carbonitrile 108 from the reaction mixture of glycine 107 and malononitrile 1 accelerated by
piperidine under the microwave efficient conditions. (Scheme – 37)
NC OH
O CN
NH2 +
OEt CN H2N
N
107 1 H
108
Scheme - 37
 International Letters of Chemistry, Physics and Astronomy Vol. 57 137

Zirani G. M. et al [52] have prepared the pyrano[2,3-d]-pyrimidine diones 111 by the three
component reaction synthesis from barbituric acid 109, malononitrile 1 and substituted aldehydes
110 carried out withSBA-Pr-SO3H nanocatalyst under the solvent free conditions. The final
compounds possessed the considerable urease inhibitory activities. (Scheme – 38)
O O Ar
R2 R SBA-Pr-SO3H
N N +1 R2 CN
ArCHO + CH2(CN)2 Solvent free N
O O O N NH2
110 1
109 R1
Scheme - 38 111

Kibon Z. et al [53] have constructed the new 2-amino-3-cyanopyridines 155(a-d) through

enaminonitriles 113 intermediate from substituted ketones 112 and malononitrile 1 by the solvent
free microwave assisted method. (Scheme – 39)
NHR2
NC CN NC CN NC
O CN R2NH2 N
+ DMFDMA
R1 CH3 CN R1
R1 CH3 R1 N
114 115(a-d)
112 1 113
Scheme - 39

Khalify J. et al [54] have synthesized 3-amino-5-arylpyridazine-4-carbonitril 118 series by using

arylglyoxal 116 and hydrazine hydrate 117 in presence of malononitrile 1 stirred for 30 min at room
temperature under ethanol and water (1:1) ratio. (Scheme – 40)
CN
O NH2NH2.H2O
117 Ar NH2
+ CH2(CN)2
O r.t., / 1h / 72-88%
Ar 1 N
EtOH
N
116(a-g)
118 (a-g)
Scheme - 40

Kiyani H. et al [55] have developed the eco-friendly green facile four component reaction. In the
synthesis part, pyranopyrazoles 122(a-q) were prepared by equimolar mixture of aromatic aldehydes
119(a-q), hydrazines 120, ehtyl acetoacetate 121 and malononitrile 1 by using sodium acetoacetate
catalyst stirred under water at room temperature. (Scheme – 41)
O H2N CN
N
O C Sodium benzoate
15 mol%
O Ar
+ RNH-NH2 + +
Water, r.t.
Ar H 120 C
O O
N
119(a-q) 121 N
1 R
N
122(a-q)
Scheme - 41

Danish I. A. and Prasad K. J. R. [56] have synthesiszed 3-cyano-5,6-dihydro-2-ethoxy-4-phenyl-

pyrido[2,3-a](carbazoles 124 from the reaction mixture of 2-benzylidene-8-methyl-1-oxo-1,2,3,4-
tetrahydracarbazoles 123 and malononitrile 1 with anhydrous ethanol in presence of sodium hydride
catalyst refluxed under desicated benzene. (Scheme – 42)
138 Volume 57

1
R1 R1
CH2(CN)2

NaH, EtOH R2 N
R2 N C6H6
H H
R3 O R3 N
CN
123(a-e) 124(a-e) O-CH2-CH3
Scheme - 42
[57]
Varela J. A. et al have developed the novel series of spiropyridines 127 a symmetric chiral
ligands obtained from dual-cyclization between bis-alkynenitriles 125 and substituted alkynes 126
by using cobalt catalyst under single pot reaction. (Scheme – 43)
R1
n
R1

Co(I) R2 N
+ N R2
n n [2+2+2]

NC CN R2 n
R1 127
125 126
Scheme - 43
El-Emary T. I. et al [58] have synthesized a novel spiro segregated indole substituted heterocyclic
compounds like 3-benzoylcyanomethylidine-1(H)-indle-2-one 130, 3-thiosemicarbazide-1(H)-
indole-2-one 132 and indoline-2,3-dione-3-cyanoacetic hydrazone 134 derivatives. They are
procured by the condensation of 1-H-indole-2,3-dione 128 with benzoylacetonitrile 129,
thiosemicarbazide 131 and cyanoacetic hydrazide 133 heated with phsphoryl chloride catalyst.
(Scheme – 44)
O

O
N
128 H

131 133
129
NH3NHCSNH2
CH2(CN)(COPh) NH3NHCOCH2CN

NC
CO-Ph NNHCSNH2
NNHCOCH2CN

O O
O
N N
H N
130 H 132 134
H
Scheme - 44
[59]
Makarem S. et al 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 the
formation of 2-amino-4H-chromenes 137(a-h). (Scheme – 45)
OH R
RCHO
136(a-h) CN
Propanol, NaBr
+ +
50 mA
CH2(CN)2 HO O NH2
135 OH 1 137(a-h)
Scheme - 45
 International Letters of Chemistry, Physics and Astronomy Vol. 57 139

Fringulli F. et al [60] have developed the 7-hydroxy-3-carboxy coumarins 143 in a single pot
reaction in aqueous media by equimolar amount mixture of 2, 4, dihydroxy benzaldehyde 138 and
propane-dinitrile 1 were carried out under water in heterogeneous conditions. There are four types
of fundamental reaction are stepwise carried out such as Knoevenagel, aldol condensation, Pinner
reaction, acid catalyst, base catalyst and acid-base equilibrium synthesis simultaneously monitoring
pH scales from starting medium to the final coumarins. (Scheme – 46)
pH 8.3 CN CN
CHO CN (NaHCO3)
+ R.T. CN
HO OH HO HO O NH
CN 139 OH 140
138 1
pH 1.0
90C (HCl)
COOH COONa CN
R.T. 90C
pH 2.0 pH 8.3
HO 143 O O (HCl) HO 142 O O (NaHCO3) HO 141 O O

Scheme - 46

5. MISCELLANEOUS REACTIONS:
Hammam A. E. G. et al. [61] have synthesized pyrazole152, pyridine 150, pyrimidine 148 and
malononitrile 145, 146 derivatives. In the beginning bis-chalcone 144 derivatives were treated with
CH2(CN)2 1, NH=C(NH2)2.HCl 147, CN-CH2COOEt 149, PhNHNH2 151 in presence of
ammonium acetate affered pyroles, pyridine, pyrimidine, pyrazoline derivatives. (Scheme – 47)

X CH X CH
O OH O NH2

N N
Et CN Et CN

X
X
145 146
ammonium
acetate CH2(CN)2 O CH2(CN)2 EtOH / Pip
1 H H 1
AcOH C C

NH=C(NH2)2.HCl
147 EtOH / NaOH N
X X PhNHNH2
144
Et 151
EtOH / Et3N
CN-CH2COOEt
ammonium
acetate
149

CH CH CH
X
H N Ph
N NH2 N O
N

N N N N
Et Et CN Et

X
148 X 150 152
X
Scheme -47
Shaker R. M. et al. [62] have formulated the novel Spiro-fused pyran 157 derivatives by solvent less
microwave assisted synthesis. These pyran derivatives were made by the cyclization of three
components mixture of ninhydrin 154, malononitrile 1 and phenyl pyrazoline-3, 5-dione 153
irradiated in presence of the neutral Al2O3 catalyst. (Scheme – 48)
140 Volume 57

O
O O +3
153 + O
155
NC CN
NC MW
O O O
1 CN 3 min CN
O + +2
HN
O O N O NH2
HN O Ph 157
N O O
Ph 156
N NH
154
Ph
Scheme - 48
[63]
Rajput S. S. has reported the malononitrile derivatives azoflurorenes 160, 162 furnished by the
mixture of 4-chlorophenyl-succinimides 158, substituted aromatic aldehydes 159 and acetaldehyde
161 with methylene nitrile 1 by using piperidine catalyst refluxed under ethanolic conditions.
(Scheme – 49)
R R

CHO
N C C N

159 R H2N O N O NH2

1 CH2(CN)2
O N O Piperidine / C2H5OH
Cl
160
CH3-CHO CH3 CH3
Cl 161 N C C N
158
1 CH2(CN)2
Piperidine / C2H5OH H2N O N O NH2

Cl
Scheme - 49 162
Ameta K. L. et al. [64] have synthesized malononitrile analogous 166 by the mixture of substituted
aromatic aldehydes 164 and 2,4-dihydroxy-acetophenone 163 under microwave in presence of
montmorilonite K10 catalyst which form chalcones 165. On further treatment with malononitrile in
presence of catalytic amount of morpholine furnishes the required product. (Scheme – 50).
R2
HO OH
R1 R3
+
CH3 O

163 164
O Montmorilonite K10
R2 Microwave
HO OH R1 R3 R2
N 1 N HO OH R1 R3

Montmorilonite K10
Microwave and
N N Morpholine O 165
166 NH2
Scheme - 50
 International Letters of Chemistry, Physics and Astronomy Vol. 57 141

6. CONCLUSION

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

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Volume 57
10.18052/www.scipress.com/ILCPA.57

Malononitrile: A Versatile Active Methylene Group

10.18052/www.scipress.com/ILCPA.57.126

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