Overview on the synthetic routes to nicotine nitriles

Abstract

The biological and medicinal properties of nicotinonitrile and its analogues have prompted enormous research aimed at developing synthetic routes to these heterocyclic. This review highlights the different synthetic routes to nicotine nitriles.

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Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Overview on the synthetic routes to nicotine
nitriles
M. A. Salem, M. H. Helel, M. A. Gouda, Y. A. Ammar & M. S. A. El-Gaby
To cite this article: M. A. Salem, M. H. Helel, M. A. Gouda, Y. A. Ammar & M. S. A. El-Gaby
(2018): Overview on the synthetic routes to nicotine nitriles, Synthetic Communications, DOI:
10.1080/00397911.2017.1394468
To link to this article: https://doi.org/10.1080/00397911.2017.1394468
Published online: 23 Jan 2018.
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SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1394468
Overview on the synthetic routes to nicotine nitriles
M. A. Salema,b, M. H. Helelc, M. A. Goudad,e, Y. A. Ammarb, and M. S. A. El-Gabyf
aDepartment of Chemistry, Faculty of Science and Arts, King Khalid University, Mohail Assir, KSA; bDepartment
of Chemistry, Faculty of Science, Al-Azhar University, Cairo, Egypt; cDepartment of Chemistry, Faculty of Arts
and Science, Northern Border University, Rafha, KSA; dDepartment of Chemistry, Faculty of Science and Arts,
Taibah University, Ulla, KSA; eDepartment of Chemistry, Faculty of Science, Mansoura University, Mansoura,
Egypt; fDepartment of Chemistry, Faculty of Science, Al-Azhar University, Assiut, Egypt
ABSTRACT
The biological and medicinal properties of nicotinonitrile and its
analogues have prompted enormous research aimed at developing
synthetic routes to these heterocyclic. This review highlights the
different synthetic routes to nicotine nitriles.
GRAPHICAL ABSTRACT
ARTICLE HISTORY
Received 27 September 2017
KEYWORDS
Chalcone; enaminone;
enaminonitriles; Micheal
addition; nicotinonitrile
Introduction
Pyridine derivatives occur in numerous natural products which are of fundamental
importance to living systems (e.g., nicotinamide adenine dinucleotide). They display
interesting physiological activities with attractive applications as pharmaceuticals and
agro-chemicals as well as general synthetic building blocks.
[1,2]
Nicotinonitrile like pyridine
derivatives are of special synthetic importance,
[3–7]
the interest in further developing novel
routes for the synthesis of these compounds has been revived.
[8–12]
The potent biological
activity of various vitamins and drugs
[13–15]
is primarily contributed to the presence of
pyridine ring in their molecular makeup. Also, the pyridine ring was found in the
skeleton of many compounds that have potent antibacterial, antifungal, and anticancer
properties.
[16]
The anticancer activity of nicotinonitrile derivatives is of much interest
owing to the different types of biological targets they might interfere with, e.g., PDE3,
PIM1 kinase, and survivin (Fig. 1).
[17]
none defined
CONTACT M. A. Salem m_eltayyeb@hotmail.com Department of Chemistry, Faculty of Science, Al-Azhar University,
Nasr City, Cairo 11284, Egypt; Department of Chemistry, Faculty of Arts and Science, King Khalid University, Mohail Assir,
KSA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
© 2018 Taylor & Francis

Synthesis
One-pot synthesis of nicotinonitriles
2-Oxo-nicotinonitriles 6
a–p
were found to be obtained by one-pot reaction of an
equimolar mixture of 2-acetylnaphthalene 1a, 2-acetyl-5,6,7,8-tetrahydro-naphthalene 1b,
or 3-acetyl-2-methyl-1,8-naphthyridine 1c as ketone part and aromatic aldehyde 2 with
ethyl cyanoacetate in ethanol in the presence of ammonium acetate under reflux
condition.
[18–21]
The formation of compounds 6 possibly takes place as shown in Scheme 2, where the
aldehyde condenses with the more reactive methylene group in ethyl cyanoacetate rather
than with the less reactive methyl group in 2-acetylnaphthalene. The Michael addition
of the 2-acetylnaphthalene on the produced cyanoacrylate takes place, followed by the
replacement of enolic OH by NH
2
, then cyclization takes place with elimination of ethanol
and finally dehydrogenation to produce compounds 6a–p.
Also, the one-pot synthesis of 2-oxo-pyridine-3-carbonitrile 8 was achieved upon the
refluxing of 2-butanone, p-anisaldehyde, and ethyl cyanoacetate in ethanolic ammonium
acetate solution for 10h.
[22]
The reaction proceeded through a Michael-type addition of
Figure 1. Various nicotinonitrile derivatives with potential growth inhibitory and/or antiangiogenic
actions through PDE3 inhibition; PIM-1 kinase inhibition; or survivin inhibition.
Scheme 1. One-pot synthesis of 2-oxo-nicotinonitriles 3.
2 M. A. SALEM ET AL.

the ethyl cyanoacetate to the unsaturated system, followed by cyclization under the reaction
condition (Scheme 3).
In addition, 2-oxo-6-indolypyridine-3-carbonitrilile derivatives 11a–e were synthesized
through one-pot multicomponent reaction of 3-acetylindole 9, aromatic aldehydes 10,
ethylcyanoacetate, and ammonium acetate in the presence of piperidine as a catalyst using
microwave irradiation method or a traditional thermal method.
[23]
Scheme 3. One-pot synthesis of 2-oxo-nicotinonitrile 8.
Scheme 2. The plausible mechanism for the formation of substituted compound 6.
SYNTHETIC COMMUNICATIONS®3

Rong et al.
[24]
reported the synthesis of 4-aryl-2-oxo-2,5-dihydro-1H-indeno[1,2-b]
pyridine-3-carbonitrile 14a–g and 4-aryl-2-oxo-1,2,5,6-tetrahydrobenzo[h]quinoline-3-
carbonitrile 14h–o through the reaction of 2,3-dihydroinden-1-one 12a or 3,4-
dihydronaphthalen-1(2H)-one 12b, aromatic aldehydes 13, and malononitrile in the
presence of NaOH under solvent-free condition.
Salem et al.
[25]
reported that 2-oxo-6-amino-crotinonitrile 16 was achieved through
ternary condensation of 2-(2-cyanoacetamido)benzoate 15, acetaldehyde, and
malononitrile in refluxing ethanol containing catalytic amount of piperidine.
Similarly, interaction of N,N0-(4,40-sulfonylbis(4,1-phenylene))bis(2-cyanoacetamid) 16
with appropriate aldehydes 17 and malononitrile in the presence of catalytic amounts of
piperidine afforded bis-2-oxo-crotinonitrile 18 (yield 68–81).
[26]
2-Alkoxynicotinonitriles 21a–l were found to be synthesized through ternary
condensation of aromatic aldehydes 19, acetophenones 20, and malononitrile in the
presence of sodium alkoxide under microwave conditions (Scheme 9). The formation of
products 21 was presupposed to proceed through production of chalcone 22 by reaction
between acetophenones 20 and aromatic aldehydes 19, then a Michael addition of the
malononitrile anion at α, β-unsaturated ketones to generate adduct A which react with
alkoxide anion to form intermediate B, followed by intramolecular cyclization through loss
of water to produce C, and subsequent dehydrogenation of the cyclized product C procures
to the 2-alkoxy cyanopyridines 21.
[27]
Table 2. Synthesis of product 14 under solvent-free conditions.
Compd. no. Ar° Time (min) Yield
14a 4-FC
6
H
4
10 88
14b 4-BrC
6
H
4
10 89
14c 4-ClC
6
H
4
10 95
14d 2-ClC
6
H
4
10 90
14e 2,4-Cl
2
C
6
H
3
10 86
14f 3,4-Cl
2
C
6
H
3
10 88
14g 4-OCH
3
C
6
H
4
10 89
14h 4-FC
6
H
4
10 91
14i 4-BrC
6
H
4
10 93
14j 4-ClC
6
H
4
10 92
14k 2-ClC
6
H
4
10 89
14l 3,4-Cl
2
C
6
H
3
10 81
144m 4-CH
3
C
6
H
4
15 85
14n 4-OCH
3
C
6
H
4
15 89
14b 3,4-(CH
3
)
2
C
6
H
3
15 86
Table 1. Comparative synthesis of 2-oxo-1,2-dihydropyridine-3-carbonitrile derivatives (11a–e) by
microwave irradiation and thermal heating.
Compd. no. Ar0
Time Yield
Mp (°C) M
w
a
(min) T
h
b
(h) M
w
T
h
b
(h)
11a 2-C
4
H
3
S 20 17 77 44 <300
11b 4-OCH
3
C
6
H
4
20 18 79 45 <300
11c 4-FC
6
H
4
15 10 87 56 <300
11d 4-ClC
6
H
4
17 15 82 63 <300
11e 4-BrC
6
H
4
17 14 83 61 <300
a
The reaction was performed by microwave irradiation at 250 W and 150 °C.
b
The reaction was performed by thermal heating at 150 °C in an oil bath.
c
Isolated yields.
4 M. A. SALEM ET AL.

Scheme 4. One-pot synthesis of 2-oxo-nicotinonitriles derivative 11.
Scheme 5. One-pot synthesis of 2-oxo-nicotinonitrile 14.
Scheme 6. One-pot synthesis of 2-oxo-nicotinonitrile 16.
Scheme 7. One-pot synthesis of bis-2-oxo-nicotinonitrile 18.
SYNTHETIC COMMUNICATIONS®5

Under the same reaction conditions, a one-pot reaction of 3-acetylpyridine 23,
malononitrile, benzaldehyde 24, and sodium ethoxide afforded 2-alkoxynicotinonitriles
25.
[27]
Ternary reaction of cyanothioacetamide derivative 26, cyclohexanone, and
malononitrile afforded 2-thioxo-crotinonitrile 27.
[28]
Heravi et al.
[29]
reported four-component condensations of acetophenone, aromatic
aldehydes 28, arylthiol 29, and malononitrile in the presence of Triton X-100 (5 mol%)
aqueous micelles. This reaction led to the formation of 4,6-diaryl-2-(arylthio)
nicotinonitrile 30 in good yields (80–95%).
Scheme 8. One-pot synthesis of 2-alkoxy-nicotinonitrile 21.
Scheme 9. One-pot synthesis of 2-alkoxy-nicotinonitrile 25.
6 M. A. SALEM ET AL.

2-Amino-nicotinonitriles 33a–g were obtained according to Hantzsch-type synthesis
through multicomponent reaction of the appreciate aromatic aldehydes 31, substituted
acetophenone 32, malononitrile, and ammounium acetate as nitrogen sources.
[30,31]
Also, 2-amino-5-isoprpoyl-4-aryl-6-methylnicotinonitriles 35a–f were obtained in
high yield through one-pot condensation of malononitrile, 4-methylpentan-2-one, aryl
carboxaldehyde 34, and ammonium acetate in ethanol under reflux for 24 h.
[32]
Multicomponent reaction of malononitrile, aromatic aldehyde 35 and 3-acetyl–2-
methyl-1,8-naphthyridine 1c
[21]
or 3-acetylcoumarin-2-one 36
[33]
or 1-(3,5-diphenyl-4,
5-dihydro-1H-pyrazol-1-yl)ethanone 37
[34]
in the presence of ammonium acetate under
reflux afforded 2-amino-nicotinonitrile derivatives 38–40.
In 2012, Safari et al.
[35]
reported a green and convenient approach to the synthesis of
2-amino-nicotinonitriles 43 through four-component reaction of aromatic aldehydes 41, acet-
ophenone derivatives 42, malononitrile, and ammonium acetate in water under ultrasound
irradiation.
The combinatorial synthesis was achieved for this methodology with applying
ultrasound irradiation while making use of water as a green solvent. In comparison to
conventional methods, experimental simplicity, excellent yields, and selectivity without
the need for a transition metal or base catalyst are prominent features of this sonocatalyzed
procedure.
In addition, Khalifeh et al.
[36]
developed the synthesis of 2-amino-pyridine-3-
carbonitrile derivatives 46 through the four-component coupling reaction between
aldehyde 44, ketone 45, malononitrile, and ammonium acetate in the presence of 2 mol%
copper nanoparticles on charcoal (Cu/C) catalyst.
Table 3. Synthesis of 2-amino-3-cyanopyridine derivatives 43 under sonication and conventional
conditions.
Product Ar Ar0
With sonication Without sonication
Time (min) Yield (%) Time (h) Yield (%)
43a H C
6
H
5
25 91 1.5 80
43b H 4-MeC
6
H
4
20 89 2.5 79
43c OH C
6
H
5
25 93 1.5 74
43d OH 4-MeOC
6
H
4
23 85 2.5 86
43e OH 4-ClC
6
H
4
18 93 1.2 76
43f OH 3-NO
2
C
6
H
4
30 95 1.2 77
43g H 4-ClC
6
H
4
20 95 1.0 85
43h H 4-MeOC
6
H
4
20 87 3.0 70
43i H 4-BrC
6
H
4
22 98 1.5 85
43j H 4-pyridyl 15 95 1.2 75
43k OH 2-MeOC
6
H
4
30 75 3.0 -d
a
43l OH 2-FC
6
H
4
35 80 3.0 -d
43m OH 2-ClC
6
H
4
35 78 3.0 -d
43n OH 3-FC
6
H
4
15 96 1.5 82
43o OH 3-MeOC
6
H
4
17 90 2.0 80
43p OH 3-BrC
6
H
4
15 90 1.5 76
43q OH 3-ClC
6
H
4
15 95 1.5 82
43r OH 3-OHC
6
H
4
20 97 2.0 82
43s OH 4-BrC
6
H
4
18 97 1.5 84
43t OH 4-NO
2
C
6
H
4
10 99 1.5 85
43u OH 4-pyridyl 15 98 2.2 77
43v OH 4-FC
6
H
4
15 97 1.3 88
43w OH 2-Furyl 18 90 2.5 73
43x OH 2-thienyl 15 93 2.3 76
a
Only obtained the intermediate benzylidenemalononitrile.
SYNTHETIC COMMUNICATIONS®7

2-Amino-4-aryl-6-(phenylthio)pyridine-3,5-dicarbonitriles 48a–d have been prepared by
an efficient stepwise one-pot three multicomponent reactions of aromatic aldehydes 47a–d,
malononitrile, and benzenethiol in the presence of base catalysts such as triethylamine,
HSA-MgO, or nanocrystalline magnesium oxide in moderate to good yields.
[37]
Also, 2-amino-4-aryl-6-(pyrrolidin-1-yl)pyridine-3,5-dicarbonitriles 50 are accessible
from a multicomponent reaction of aromatic aldehydes 49 with 2 equiv. to each
malononitrile and pyrrolidine in ethanol.
[38]
From enaminonitriles
When 3-oxo-5-phenyl-4enenitrile 51 was allowed to react with trichloroacetonitrile,
nicotinonitrile 53 had afforded in 85% yields. It was believed that this product was formed
through intermediate 52.
[39]
Reaction of cyanoacetanilide 54 with arylidene malononitrile 55 in refluxing ethanol
containing a catalytic amount of triethyl amine furnished the nicotinonitrile derivatives
57.
[40,41]
Compounds 57 are assumed to be formed by the addition of active methylene
to cyano group of the arylidene malononitrile followed by cyclization by the addition of
amide nitrogen to the other cyano group.
Similarly, the reaction of cyanoacetic acid hydrazide 58 with (4-methoxybenzylidene)
malononitrile 59 in ethanolic triethylamine solution afforded 1-aminopyridine derivative
60, which rearranged upon heating in 95% aqueous ethanolic triethylamine to give 1,
4-diamino-5-cyano-2-(4methoxyphenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid 61.
[42]
On the other hand, the reaction of cyanoacetamide derivatives 62 with arylidene
malononitriles 63 in ethanolic piperidine under reflux for 4 h afforded nicotinonitriles
65 through Michael adducts 64.
[25,28,43–49]
Similarly, Salem et al.
[25]
reported the synthesis of 6-amino-4-(furan-2-yl)-2-
oxonicotinonitrile 70 and 5-cyano-4-(4-(dimethylamino)phenyl)-6-hydroxy-2-oxopyridine
71 through the reaction of cyanoacetamide derivatives 66 with α-substituted cinnamoni-
triles 67 in refluxing ethanol in the presence of catalytic amount of piperidine. The
formation of nicotinonitrile derivatives 70 and 71 was assumed to be proceeded through
the Michael addition of active methylene group of compound 66 on the β-carbon atom
of cinnamonitrile derivatives to give the Michael adducts 68 and 69 followed by
intramolecular cyclization and elimination of HX.
On the other hand, when cyanoacetamide derivative 66 was reacted with α-substituted
cinnamonitriles 67 in refluxing DMF in the presence of catalytic amount of piperidine,
quinazolines 73a–e were obtained through the formation of pyridine intermediate 72
followed by the elimination of methanol molecule.
[25]
In addition, bisnicotinonitriles 75 were found to be obtained through the Micheal
addition of cyanoacetanilide 65e on bisbenzylidene 74.
[43]
Also, bisnicotinonitriles 77 were found to be achieved in good yield through the reaction
of bis(aminopyridone) derivatives 76 with malononitrile and/or ethylcyanoacetate in
ethanol in the presence of piperidine under reflux condition.
[50]
In a similar manner, 66a, b was allowed to react with 1, 3-indandione malononitrile 78
and the corresponding spiro-nictinonitrile derivative 79 was obtained.
[25]
Reaction of 2-cyano-N-(4-substitutedphenyl)-3-arylacrylamide 80 with cyanoacetamide deri-
vatives 81a, b in dry ethanol containing a catalytic amount of piperidine under reflux afforded
8 M. A. SALEM ET AL.

nicotinonitriles 83 instead of compound 82.
[51]
On the other hand, when cyanoacetohydrazide
was allowed to react with 2-cyano-N-(4-methylphenyl)-3-phenylacrylamide 80c in dry ethanol
containing a catalytic amount of piperidine under reflux, the nicotinonitrile derivative 85 was
achieved instead of compound 84.
[52]
Michael addition of active methylene in acrylonitrile 86
to activated double bond of 2-cyano-N-(4-substituted phenyl)-3-arylacryl-amide 80 afforded
the corresponding dihydropyridine derivatives 88 through Michael adduct 87.
[51]
Reaction of cyanoacetamide derivative 65e, f with tetracyanoethylene 89 in refluxing diox-
ane containing few drops of trimethylamine afforded nicotinonitrile derivative 90a, b.
[28,43]
Similarly, Michael addition of cyanoacetamide derivative 65e on 2-(bis(methylthio)
methylene)malononitrile (91) in ethanol in the presence of sodium ethoxide under reflux
condition gave the nicotinonitrile derivative 92.
[43]
Also, nicotinonitrile derivative 95 was found to be formed in good yield through the
reaction of 2-cyano-N-(benzothiazol-2-yl)acetamide (93) with 3-aminocrotonitrile (94)
in refluxing ethanol containing a catalytic amount of trimethylamine.
[53]
It was found that enaminonitrile 96 reacts with dimethylformamide dimethyl acetal
(DMF-DMA) to give 2-((dimethylamino)methylene)-3-iminopentane-nitrile (97), which
was converted to a nicotinonitrile 100 by refluxing with malononitrile in ethanol
containing a catalytic amount of piperidine instead of intermediates 98 and 99. Formation
of 100 was believed to be formed through initial addition of malononitrile on the double-
bond system of enaminonitrile 96 to give the acyclic intermediate 98 which reacts with
another mole of malononitrile to give 100 through intermediate 99. On the other hand,
when enaminonitrile 96 was allowed to react with ethoxymethylenemalononitrile in
ethanol containing a catalytic amount of piperidine under reflux condition, nicotinonitrile
derivative 102 was obtained through intermediacy of nonisolable intermediates 101.
Also, treatment of 96 with triethylorthoformate in refluxing acetic anhydride afforded
enaminonitrile derivative 103. When 103 is allowed to reflux with benzylidenemalononi-
trile 104 in ethanol containing a catalytic amount of piperidine, a tetrahydronicotinonitrile
derivative 106 was obtained instead of intermediate 105.
[54]
In addition, nicotinonitrile derivatives 109a–l were found to be obtained through the
reaction of enaminonitrile 96 with arylidenes 107a–h or arylidene cyanothioacetamide
107i–l under reflux in ethanol containing a catalytic amount of piperidine.
[54]
Furthermore, coupling of enaminonitrile 96 with aryl diazonium salts 110 afforded aryl
diazenyl 111 which fused with malononitrile in domestic microwave oven for 3 min to
afford nicotinonitrile derivatives 113a–c through intermediacy of 112 that cyclizes and
tautomerizes into 113. In contrast to this, aryl diazenyl 111b, d, e reacted with ethyl
cyanoacetate under fusion condition to give nicotinonitrile derivative 115 through
intermediacy of 114 that cyclizes and tautomerizes through elimination of ethanol.
[54]
Reaction of ylidene cyanoacetic acid esters 116 with DMF-DMA produced
dimethylaminovinyl derivatives 117a–c with good yields. Obtained 117 when refluxed with
primary amines (bp over 100 °C) in anhydrous xylene form targeted nicotinonitriles 118a–l
in good yields.
[55]
2-Chloronicotinonitriles 121 were obtained from the Vilsmeier reaction of alkylidene
malononitriles 119 (In these reactions, the iminoalkylated intermediate 120 undergoes
cyclization reaction to afford the corresponding nicotinonitriles.).
[56]
On the other hand, the penultimate enamine 123 results by treating
isopropylidenemalononitrile 122 with DMF-DMA in the presence of acetic anhydride,
SYNTHETIC COMMUNICATIONS®9

and ultimately 2-bromo-4-methylnicotinonitrile 125 is produced after enamine 123 is
treated with HBr in acetic acid. Transferring the batch synthesis into a semicontinuous
process requires one to consider solvent exchanges and by-products that might complicate
downstream operations.
[57]
From enamines
Treatment of ethyl phenyl acetate 126a or ethyl p-nitrophenyl acetate 126b with
DMF-DMA under microwave condition gave the enaminoesters 127a, b in a good yield.
When compounds 127 were allowed to react with malononitrile under microwave
condition, a nucleophilic substitution took place to led directly to the formation of
enaminonitrile derivatives 128a, b. Compound 128 underwent intramolecular cyclization
in refluxing acetic acid containing a catalytic amount of ammonium acetate to afford
the nicotinonitriles 130 through intermediate 129.
[58]
But, when the symmetrical vinamidinium salts 131a–d were allowed to react with
malononitrile in refluxing ethanol in the presence of ammonium acetate for 12 h, the
2-amino-5-aryl or formylnicotinonitriles 132a–d were obtained in a good yield.
[59]
Abdelriheem et al.
[60]
reported that the reaction of 1-(5-bromobenzofuran-2-yl)-
3-(dimethylamino)prop-2-en-1-one (133) with each cyanothioacetamide or
2-cyanoacetohydrazide in a solution of piperidinum acetate [piperidine (2.5 mL), water
(5 mL), and acetic acid (2 mL)] was heated under reflux for about 10 min and afforded
6-(5-bromobenzofuran-2-yl)-2-thioxo-1,2-dihydropyridine-3-carbonitrile (134) and
1-amino-6-(5-bromo-benzofuran-2-yl)-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (135),
respectively, in a good yield.
Similarly, Abu-Shanab et al.
[61]
and Hussein et al.
[62]
reported the treatment of
enaminone 137 with cyanothioacetamide in ethanol in the presence of sodium ethoxide
or piperidine under reflux gave 6-methyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile
138a, b with a very good yield.
In 2014, Al-Omran et al.
[63]
discussed the reactivity of 3-anilinoenone 140 (prepared,
by reactions of 3-enaminones 139 with aniline in ethanol) toward the activated nitrile.
Therefore, the reaction of anilinoenone 140a, b with malononitrile in acetic acid gave
2-anilinonicotinonitrile derivatives 144a, b. The nicotinonotrile 144 formed most likely
through initial 1,4-addition of malononitrile to the activated double bond in 140, followed
by the elimination of aniline molecule under acidic conditions to give the intermediate 141.
Scheme 10. One-pot synthesis of 2-thioxo-nicotinonitrile 27.
10 M. A. SALEM ET AL.

The latter then undergoes ring closure through its enolized form to yield the imidoester
142. The aniline molecules that are still present in the reaction medium is attacked to
C-2 of imidoester 142 to yield the intermediate 143, which then undergoes cyclization
through elimination of water to give the final nicotinonotrile derivative 144.
It was also noted that 6-aryl-2-chloronicotinonitriles 148 are formed from enaminoke-
tones 145 through a chlorosubstituted intermediate 146 (Scheme 43).
[64]
Apparently, under
Vilsmeier–Haack reaction condition, the addition of malononitrile to vinamidinium salt
145 resulted in the formation of 146 which on cycloaromatization with the elimination
of dimethylamine afforded 2-chloro-6-phenylnicotinonitrile 148.
Scheme 13. One-pot synthesis of 2-amino-nicotinonitrile 35.
Scheme 12. One-pot synthesis of 2-amino-nicotinonitrile 33.
Scheme 11. One-pot synthesis of 2-arylthio-nicotinonitrile 30.
SYNTHETIC COMMUNICATIONS®11

Similarly, Vilsmeier–Haack reagent can act as a Knoevenagel base/buffer for the
synthesis of 5-aroyl-2-chloro-6-(methylsulfanyl)nicotinonitriles 150 from α-oxoketene
dithioacetals 149.
[65]
Scheme 16. One-pot synthesis of 2-amino-nicotinonitrile 46.
Scheme 15. One-pot synthesis of 2-amino-nicotinonitrile 43.
Scheme 14. One-pot synthesis of 2-amino-nicotinonitrile 38–40.
12 M. A. SALEM ET AL.

From chalcones
Shah et al.
[66–68]
reported the synthesis of 2-oxo-4,6-diaryl-1,2-dihydropyridine-3-
carbonitrile 152 by refluxing corresponding chalcones 151 with ethyl cyanoacetate in etha-
nol in the presence of ammonium acetate.
Michael addition of malononitrile on β-carbon atom of chalcone derivative 153 in
the presence of ammonium acetate under M.W
[69]
or under reflux condition yielded
2-amino-nicotinonitriles 154.
[70]
Scheme 20. Synthesis of 4-amino-5-(arylmethylene)-nicotinonitrile 57.
Scheme 19. Synthesis of 4-oxo-nicotinonitrile 53.
Scheme 18. One-pot synthesis of 2-amino-nicotinonitrile 50.
Scheme 17. One-pot synthesis of 2-amino-nicotinonitrile 48.
SYNTHETIC COMMUNICATIONS®13

El-Sharkawy et al.
[71]
reported the uses of chalcone derivative 155 in the synthesis of
different nicotinonitriles depending on basic medium exchange. Thus, the reaction of
155 with equimolar amounts of malononitrile in ethanolic sodium ethoxide solutions gave
Scheme 22. Synthesis of 6-amino nicotinonitrile 65.
Scheme 21. Synthesis of 1,4-diamino-nicotinonitrile 61.
14 M. A. SALEM ET AL.

the corresponding 2-amino-6-oxo-nicotinonitrile 157 through intermediate 156.
However, carrying the reaction of 155 with either malononitrile or ethyl cyanoacetate in
the presence of anhydrous ammonium acetate and heating in an oil bath at 140 °C gave
the nicotinonitriles 159a–d. The reaction took place through the intermediate formation
of 158 followed by intramolecular cyclization.
From β-dicarbonyl compounds
Seifi et al. have reported that the nicotinonitrile 161 was prepared in the reaction
of malononitrile with 1,3-dicarbonyl compounds. Unsymmetrical 1,3-diketones such
as 1-phenyl-1,3-butanedione (160c), 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione
(160d), and 1,1,1-trifluoropentane-2,4-dione (160e) exist mainly in two enol forms.
[72]
Based on the
1
H NMR and
13
C NMR, only one product was obtained from the nucleophilic
reaction of malononitrile on the acetyl group of unsymmetrical, 1,3-diketones 160c, d;
however, the reaction of 1,1,1-trifluoropentane-2,4-dione (160e) with malononitrile in
the same reaction condition afforded the mixture of nicotinonitrile 161(I)e and 161(II)e
in different yields.
Scheme 23. Synthesis of 6-amino (hydroxyl)- nicotinonitriles 70 and 71.
Scheme 24. Synthesis of quinazoline 73.
SYNTHETIC COMMUNICATIONS®15

Also, nicotinonitrile 163 was found to be obtained by the reaction of malononitrile with
3-oxo-N-p-tolyl-butyramide 162 in ethanolic piperidine solution under reflux.
[73]
Under the same reaction condition, treatment of 4,4-trifluoro-1-(4-methoxyphenyl)
butane-1,3-dione 164 with 2-cyanoacetohydrazide afforded nicotinonitrile 165.
[74]
Also, the reaction of 2-cyanoacetohydrazide with benzoylacetone and/or benzoyl
trifluoroacetone 166 in refluxing ethanol containing a catalytic amount of diethyl amine
afforded regioselectively nicotinonitrile derivatives 167.
[75,76]
Scheme 26. Synthesis of bis-2-oxo-nicotinonitrile 77.
Scheme 27. Synthesis of spiro-nictinonitrile 79.
Scheme 25. Synthesis of bis-2-oxo-nicotinonitrile 75.
16 M. A. SALEM ET AL.

Scheme 28. Synthesis of nictinonitriles 83, 85, and 88.
Scheme 29. Synthesis of 6-amino-nictinonitrile 90.
Scheme 30. Synthesis of 6-amino-nictinonitrile 92.
SYNTHETIC COMMUNICATIONS®17

Furthermore, cyclocondensation of cyanoacetamide derivatives 168a, b with with
acetylacetone, benzoylacetone, or ethyl acetoacetates 169 in ethanol solution containing
catalytic amounts of piperidine
[77]
or trimethylamine
[78]
under reflux furnished the
corresponding nicotinonitrile derivatives 170a–e.
On the other hand, cyclocondensation of cyanoacetamide derivatives 62e, f with
acetylacetone under fusion condition yielded nicotinonitrile derivatives 171.
[28,43]
Scheme 31. Synthesis of 6-amino-nictinonitrile 95.
Scheme 32. Synthesis of 2-amino-nictinonitriles 100, 102, and 106.
18 M. A. SALEM ET AL.

In 2009, Al-Zaydi et al.
[79]
have reported the synthesis of nicotinonitrile derivatives 173
through the reaction of cyanoacetamide derivatives 172 with β-ketoester either through
long reflux of neat reagents or by short-time microwave or by US for 5–7 h at 40 °C to
afford in each case the same product 173a–d which may be exist in another tautomeric
form 174.
In different manners, nicotinonitrile derivatives 177 and 178 were obtained by the
reaction of sodium-3-(2,5-dichloro thiophene-3-yl)prop-3-oxo-1-en-1-olate 176 [formed
by the treatment of 1-(2,5-dichlorothiophene-3-yl)ethanone 175 with ethyl formate
in the presence of sodium methoxide] with each cyanothioacetamide, cyanoacetamide,
and/or cyanoacetohydrazide in the presence of piperidine acetate under reflux.
[80]
Scheme 33. Synthesis of 2-amino-nictinonitrile 109.
Scheme 34. Synthesis of 2-amino(hudroxy)-nictinonitriles 113 and 115.
SYNTHETIC COMMUNICATIONS®19

From phenacylcyanide
A Michael addition of the active methylene of one molecule of phenacylcyanide to
the cyano function of another afforded the 1,5-dione intermediate 179, which is
transformed into the nicotinonitrile 180 under the effect of ammonia.
[81]
Also,
phenacylcyanide was converted into 3-amino-3-ethoxy-1-phenylprop-2-en-1-one
hydrochloride 181 by reaction with ethanol in ether in the presence of HCl. The latter
compound was allowed to react with arylidenemalononitrile 182 to give 2-amino-5-
benzoylnicotinonitriles 183.
[82]
Scheme 35. Synthesis of 2-oxo-nictinonitrile 118.
Scheme 36. Synthesis of 2-chloro-nictinonitrile 121.
Scheme 37. Synthesis of 2-bromo-nictinonitrile 125.
20 M. A. SALEM ET AL.

Scheme 38. Synthesis of 2-amino-nictinonitrile 130.
Scheme 39. Synthesis of 2-amino-nictinonitrile 132.
Scheme 40. Synthesis of 2-oxo(thioxo)-nictinonitriles 134 and 135.
SYNTHETIC COMMUNICATIONS®21

From pyran
Finally, a series of aminonicotinonitriles derivatives 186 were synthesized by the reaction of
2H-pyran-2-one 184 and the N-aryl amidine 185 using KOH as a catalyst in DMF at room
temperature.
[83,84]
Scheme 41. Synthesis of 2-thioxo-nictinonitrile 138.
Scheme 42. Synthesis of nictinonitrile 144.
Scheme 43. Synthesis of 2-chloro-nictinonitrile 148.
22 M. A. SALEM ET AL.

Scheme 44. Synthesis of 2-chloro-nictinonitrile 150.
Scheme 45. Synthesis of 2-oxo-nictinonitrile 152.
Scheme 46. Synthesis of 2-amino-nictinonitrile 154.
SYNTHETIC COMMUNICATIONS®23

Scheme 47. Synthesis of nictinonitriles 157 and 159.
Scheme 48. Synthesis of 2-oxo-nictinonitrile 161.
Scheme 49. Synthesis of 6-amino-4-methyl-2-oxo-1-p-tolyl-1,2-dihydro nictinonitrile (163).
24 M. A. SALEM ET AL.

The synthesis of 2,6-diaryl nicotonitrile involves the nucleophilic attack by more basic
N-1 of amidine 185 at C-6 of 2H-pyran-2-one 184. The attack of amidine N-1 leads to
form unstable intermediate 187 followed by ring closure and a retro [2 + 2] process with
the elimination of carbon dioxide to form 2,6-diaryl nicotonitrile 186 (Scheme 58).
[85]
Scheme 50. Synthesis of 1-amino-6-(4-methoxyphenyl)-2-oxo-4-(trifluoromethyl)-1,2-dihydro nictino-
nitrile (165).
Scheme 51. Synthesis of 2-oxo-nictinonitrile 167.
Scheme 52. Synthesis of 2-oxo-nictinonitrile 170.
Scheme 53. Synthesis of 2-oxo(thioxo)-nictinonitrile 171.
SYNTHETIC COMMUNICATIONS®25

Scheme 54. Synthesis of 2-oxo-nictinonitrile 174.
Scheme 55. Synthesis of 2-oxo-(thioxo)-nictinonitriles 177 and 178.
Scheme 56. Synthesis of 4-amino-nictinonitrile 180 and 2-amino-nictinonitrile 183.
26 M. A. SALEM ET AL.

Conclusion
The synthesis of nicotinonitrile derivatives was achieved by different methods as outlined
in Schemes 1–58. Reviewing the reaction output in previous methods indicated that
one-pot synthesis and reaction with β-dicarbonyl compounds methods are easy to perform
and use almost all the available starting materials to give product in high yield.
Scheme 57. Synthesis of 2,6-diarylnicotinonitrile 186.
Scheme 58. The plausible mechanism for the formation of substituted compounds 186.
Table 4. Preparation of 2,6-diaryl-4-secondary aminonicotinonitriles 186 from 2H-pyran-2-one 184 and
N-aryl amidine 185.
Entry Ar Ar0Ar00 Yield (%) Mp (°C)
186a C
6
H
5
Piperidine C
6
H
5
C
6
H
4
F-4 48 160
186a C
6
H
5
Piperidine C
6
H
5
C
6
H
5
48 161
186b C
6
H
4
Br-4 Piperidine C
6
H
5
C
6
H
5
48 173
186b C
6
H
4
Br-4 Piperidine C
6
H
5
C
6
H
4
F-4 42 173
186c C
6
H
4
Br-4 Morpholine C
6
H
5
C
6
H
4
F-4 46 172
186c C
6
H
4
Br-4 Morpholine C
6
H
5
C
6
H
5
44 172
186d C
6
H
4
Cl-4 Morpholine C
6
H
5
C
6
H
4
F-4 39 198
186e C
6
H
4
Br-4 Piperidine C
6
H
4
Br-4 H 22 168
186f C
6
H
4
Cl-4 Piperidine C
6
H
5
H 16 172
186g C
6
H
4
Cl-4 Pyrolidine C
6
H
5
C
6
H
4
Br-4 22 156
186h C
6
H
4
OCH
3–
4 Piperidine C
6
H
5
H 38 166
SYNTHETIC COMMUNICATIONS®27

References
[1] Balasubramanian, M.; Keay, J. G. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; 5, Chapter 5.06, 245.
[2] Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, 1996; l.5, Chapter 5.05, 167.
[3] Palacios, F.; Alonso, C.; Rubiales, G. J. Org. Chem. 1997, 62, 1146–1154.
[4] Reich, S. H.; Melnick, M.; Pino, M. J.; Fuhry, M. A. N.; Trippe, A. J.; Appelt, K.; Davies, J. F.;
Wu, B. W.; Musick, L. J. Med. Chem. 1996, 39, 2781–2794.
[5] Lavilla, R.; Gotsens, T.; Guerrero, M.; Bosch, J. Synthesis 1995, 382.
[6] Vohra, R.; MacLean, D. B. Heterocycles 1994, 39, 445–448.
[7] Nakajima, T.; Izawa, T.; Kashiwabara, T.; Nakajima, S.; Munezuka, Y. Chem. Pharm. Bull. 1994,
42, 2475–2482.
[8] Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.; Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K.
Synthesis 1997, 1321–1324.
[9] Petrich, S. A.; Hicks, F. A.; Wilkinson, D. R.; Tarrant, J. G.; Bruno, S. M.; Vargas, M.; Hosein,
K. N.; Gupton, J. T.; Sikorski, J. A. Tetrahedron 1995, 51, 1575–1584.
[10] Sakakibara, Y.; Ido, Y.; Sasaki, K.; Sakai, M.; Uchino, N. Bull. Chem. Soc. Jpn. 1993, 66,
2776–2778.
[11] Matsui, M.; Oji, A.; Hiramatsu, K.; Shibata, K.; Muramatsu, H. J. Chem. Soc., Perkin Trans. 2,
1992, 201–206.
[12] Gundersen, L.-L.; Rise, F.; Undheim, K. Tetrahedron 1992, 48, 5647–5656.
[13] Joule, J. A.; Smith, G.; Mills, K. Heterocyclic Chemistry, 3rd ed.; Chapman and Hall: London,
1995; 72–119.
[14] Donohoe, T. J.; Basutto, J. A.; John, F.; Bower, J. F.; Rathi, A. Org. Lett. 2011, 13, 1036–1039.
[15] Henry, G. D. Tetrahedron 2004, 60, 6043–6061.
[16] Millet, J.; Torrentino-Mdamet, M.; Alibert, S.; Rogier, C.; Santelli-Rouvier, C.; Mosnier, J.;
Baret, E.; Barbe, J.; Parzy, D.; Pradines, B. Antimicrob. Agents Chemother. 2004, 48, 2753–2756.
[17] Ghosh, P. S.; Manna, K.; Banik, U.; Das, M.; Sarkar, P. Int. J. Pharm. Pharm. Sci. 2014, 6, 39–42.
[18] Kotb, E. R.; El-Hashash, M. A.; Salama, M. A.; Kalf, H. S.; Abdel Wahed, N. A. M. Acta Chim.
Slov. 2009, 56, 908–919.
[19] Mohamed, S. F.; Youssef, M. M.; Kotb, E. R.; Amr, A. E. Sci. Pharm. 2008, 76, 279–303.
[20] Hamdy, N. A.; Anwar, M. M.; Abu-Zaid, K. M.; Awad, H. M. Acta Pol. Pharm. Drug Res. 2013,
70, 987–1001.
[21] Karabasanagouda, T.; Adhikari, A. V. Org. Chem. An Ind. J. 2006, 2, 67–74.
[22] Swelam, S. A.; El-Said, N. S.; Aly, A. S.; Abdel-Fatth, A. M. Int. J. Pharm. Technol. Res. 2009, 1,
445–453.
[23] El-Sayed, N. S.; Shirazi, A. N.; El-Meligy, M. G.; El-Ziaty, A. K.; Nagib, Z. A.; Parang, K.
Tetrahedron Lett. 2014, 55, 1154–1158.
[24] Rong, L.; Han, H.; Jiang, H.; Tu, S. J. Heterocycl. Chem. 2009, 46, 465–468.
[25] Salem, M. A.; Helal, M. H.; Eldebss, T. M. A.; Abd-Elaziz, T. A.; El-Sherif, A. A.; Mohamed,
G. A. M. J. Iran. Chem. Soc. 2015, 12, 1693–1707.
[26] Al-Said, M. S.; Ghorab, M. M.; Nissan, Y. M. Chem. Central J. 2012, 6, 1–14.
[27] Amer, A. A.; Abdelhamid, A. A. J. Heterocycl. Chem. 2017 [Online].
[28] Salem, M. A.; Thabet, H. K.; Ismail, M. A.; Ammar, Y. A. Chem. Sci. J. 2011, 36, 1–11.
[29] Heravi, M. R. P.; Soufi, A. Chin. Chem. Lett. 2015, 26, 263–266.
[30] Faidallah, H. M.; Rostom, S. A. F.; Khan, K. H. J. Chem. 2016, 2016, 1–12.
[31] Mahmoud, M. R.; Derbala, H. A.; Madkour, H. M. F.; Habashy, M. M.; Nassar, M. H. Eur.
Chem. Bull. 2013, 2, 662–669.
[32] Gouda, M. A.; Helal, M. H. Eur. J. Chem. 2015, 6, 84–87.
[33] Fikry, R. M.; Ismail, N. A.; El-Garby, M.; Kamel, E. M.; Deeb, A. D. H. Eur. Chem. Bull. 2015, 4,
240–245.
[34] Siddiqui, N.; Ahsan, W.; Alam, M. S. H.; Ali, R.; Srivastava, K.; Ahmed, S. H. Bull. Korean
Chem. Soc. 2011, 32, 576–582.
28 M. A. SALEM ET AL.

[35] Safari, J.; Banitaba, S. H.; Khalili, S. H. D. Ultrasonics Sonochem. 2012, 19, 1061–1069.
[36] Khalifeh, R.; Ghamari, M. J. Braz. Chem. Soc. 2016, 27, 759–768.
[37] Alinaghizadeh, F.; Zahedifar, M.; Seii, M.; Sheibani, H. J. Braz. Chem. Soc. 2016, 27, 663–669.
[38] Raghukumar, V.; Thirumalai, D.; Ramakrishnan, V. T.; Karunakarac, V.; Ramamurthy, P.
Tetrahedron 2003, 59, 3761–3768.
[39] Nawwar, G. A. M.; Osman, S. A.; El-Bayanki, K. A. M.; Elgemeie, G. E. H.; Elnagdi, M. H.
Heterocycles 1985, 23, 2983–2988.
[40] Mustafa, N.; Elnagdi, M. H.; Abdel-Aziz, E. H.; Ibrahim, E. J. Heterocycl. Chem. 1984, 21,
1261–1264.
[41] Abdel-Latif, F. F. Rev. Roum. Chim. 1990, 35, 679–682; Chem. Abstr. 1991, 114, 228683h.
[42] Zayed, E. M.; Hafez, E. A.; Ghozlan, S. A. S.; Ibrahim, A. A. H. Heterocycles 1984, 22, 2553–2558.
[43] Ammar, Y. A.; El-Gaby, M. S. A.; Salem, M. A. Arab. J. Chem. 2014, 7, 615–622.
[44] Al-Arab, M. M. J. Heterocycl. Chem. 1989, 26, 1665–1673.
[45] Basyouni, W. M. Acta Chem. Slov. 2003, 50, 223–238.
[46] Elgemeie, G. H.; Sayed, S. H. Phosphorus Sulfur Silicon Relat. Elem. 2003, 178, 465–473.
[47] Abdel Motaal, E. A.; EL-Gaby, M. S. A.; Salem, M. A. Orient. J. Chem. 2015, 31, 1–10.
[48] Martin, N.; Seoane, C.; Soto, J. L. Heterocycles 1987, 26, 2811–2816.
[49] Beckmann, S.; Schefczik, E. Eur. Patent 1994, 628, 547; Chem. Abstr. 1995, 122, 213936.
[50] Helal, M. H.; Salem, M. A.; Ali, H. M. J. Heterocycl. Chem. 2017, 54, 2614–2626.
[51] Ammar, Y. A.; El-Sharief, A. M. S. H.; Mohamed, Y. A.; Salem, M. A.; Al-Sehemi, A. G.;
El-Gaby, M. S. A. J. Chin. Chem. Soc. 2004, 51, 975–981.
[52] El-Rady, E. A.; Khalil, M. A. J. Chin. Chem. Soc. 2004, 51, 779–784.
[53] Hussin, A. M.; Abu-Shanab, F. A.; Abd-Elraheim, M. A. M.; Gaby, M. S. A. Phosphorus Sulfur
Silicon Relat. Elem. 2008, 183, 1722–1734.
[54] Ramiz, M. M. M.; Abdel Hafizb, I. S.; Elian, M. A. J. Chin. Chem. Soc. 2012, 59, 758–767.
[55] Hovhannisyan, A. A.; Aristakesyan, L. H.; Hakobyan, R. M.; Melikyan, G. S. Chem. Biol. 2015,
2, 9–13.
[56] Sreenivasulu, M.; Rao, G. S. K. Ind. J. Chem. 1989, 28B, 584–586.
[57] Longstreet, A. R.; Opalka, S. M.; Campbell, B. S.; Gupton, B. F.; McQuade, D. T. Beilstein J. Org.
Chem. 2013, 9, 2570–2578.
[58] Al-Sheikh, M. A. J. Saud. Chem. Soc. 2011, 15, 155–159.
[59] Jemmezi, F.; Kether, F. B.; Amri, I.; Bassem, J.; Khiari, J. E. J. Appl. Chem. 2014, 7, 62–66.
[60] Abdelriheem, N. A.; Ahmad, S. A.; Abdelhamid, A. O. Molecules 2015, 20, 822–838.
[61] Abu-Shanab, F. A.; Mousa, S. A. S.; Sherif, S. H. M.; Hassan, M. I. Int. J. Org. Chem. 2014, 4,
319–330.
[62] Hussein, A. M.; Ishak, E. A.; Atalla, A. A.; Abdel Hafiz, S.; Elnagdi, M. H. Phosphorus Sulfur
Silicon Relat. Elem. 2007, 182, 2897–2917.
[63] Al-Omran, F.; El-Khair, A. Org. Chem. Curr. Res. 2014, 3, 1–10.
[64] Asokan, C. V.; Anabha, E. R.; Thomas, A. D.; Jose, A. M.; Lethesh, K. C.; Prasanth, M.;
Krishanraj, K. U. Tetrahedron Lett. 2007, 48, 5641–5643.
[65] Anabha, E. R.; Nirmala, K. N.; Thomas, A.; Asokan, C. V. Synthesis 2007, 3, 428–432.
[66] Shah, H. C.; Shah, V. H.; Desai, N. D. ARKIVOC 2009, ii, 76–87.
[67] Flefel, E. M.; Abbas, H. S.; Abdel Mageid, R. E.; Zaghary, W. A. Molecules 2016, 21, 2–15.
[68] Pawar, M. P.; Nimavat, K. Org. Chem. An Ind. J. 2013, 9(12), 516–519.
[69] Yadav, J. S.; Srivastava, Y. K. Der Chem. Sin. 2011, 2(1), 1–7.
[70] Lahsasni, S. A.; Al korbi, F. H.; Aljaber, N. A. Chem. Cent. J. 2014, 8(32), 1–10.
[71] El-Sharkawy, K. A.; Ibrahim, R. A. Eur. Chem. Bull. 2013, 2(8), 530–537.
[72] Seifi, M.; Sheibani, H. Arab. J. Chem. 2017, 10, S2453–S2456.
[73] Hussein, A. M.; El-Gaby, M. S. A.; Abd El-Maged, A. A.; El-Sharief, A. M.; Ammar, Y. A. Open
Access Library J. 2015, 2, e1439.
[74] Khunt, H. R.; Babariya, J. S.; Dedakiya, C. H. D.; Maniar, C. H. A.; Naliapara, Y. T. Int. Lett.
Chem. Phys. Astronomy 2014, 11, 185–192.
[75] Elgemeie, G. E. H.; El-Ezbawy, S. R.; Ramiz, M. M.; Mansour, O. A. Org. Prep. Proced. Int. 1991,
23, 645–650.
SYNTHETIC COMMUNICATIONS®29

[76] Gutcait, A.; Belyakov, S. V.; Gudriniece, E.; Bleidelis, J.; Mishnev, A. F.; Kramina, M. Kimijas
Serija 1986, 5, 607; Chem. Abstr. 1987, 107, 58776.
[77] Farag, A. A. Der Pharma Chem. 2015, 7(11), 130–141.
[78] Nasr, T.; Bondock, S.; Eid, S. E. J. Med. Chem. 2014, 84, 491–504.
[79] Al-Zaydi, K. H. M.; Borik, R. M.; Elnagdi, M. H. Ultrasonics Sonochem. 2009, 16, 660–668.
[80] Ahmed, S. A.; Ahmed, O. M.; Elgendy, H. S. J. Pharm. Res. 2014, 8(9), 1303–1313.
[81] Kelly, T. R.; Liu, H. J. Am. Chem. Soc. 1985, 107, 4998–4999.
[82] Elghandour, A. H. H.; Ramiz, M. M. M.; Elnagdi, M. H. Synthesis 1989, 10, 775–777.
[83] Bhosale, S. V.; Patil, U. D.; Kalyankar, M. B.; Nalage, S. V.; Patil, V. S.; Desale, K. R. J.
Heterocycl. Chem. 2010, 47, 691–696.
[84] Patil, U. D.; Nikum, A. P.; Nagle, P. S.; Mahulikar, P. P. J. Pharm. Res. 2012, 5(3), 1383–1386.
[85] Pratap, R.; Kumar, B.; Ram, V. J. Tetrahedron 2007, 63, 10309–10319.
30 M. A. SALEM ET AL.