Application of salicylic acid as an eco-friendly and efficient catalyst for the synthesis of 2,4,6-triaryl pyridine, 2-amino-3-cyanopyridine, and polyhydroquinoline derivatives

Article abstract of DOI:10.1002/jhet.4242

In this study, three eco-friendly, efficient, and convenient protocols have been reported for one-pot synthesis of 2,4,6-triaryl pyridine, 2-amino-3-cyanopyridine, and polyhydroquinoline derivatives using salicylic acid as a catalyst under solvent-free condition. The reported protocols offer several significant advantages such as the application of a nontoxic, neutral, and cheap catalyst, environmentally friendly conditions, the easy isolation of products by filtering, short reaction times, simple methodology, and good yields.

Full text of DOI:10.1002/jhet.4242

Received: 11 October 2020
DOI: 10.1002/jhet.4242
Revised: 5 January 2021
Accepted: 2 February 2021
A R T I C L E
Application of salicylic acid as an eco-friendly and efficient
catalyst for the synthesis of 2,4,6-triaryl pyridine, 2-amino-
3-cyanopyridine, and polyhydroquinoline derivatives
Majid Roozifar | Nourallah Hazeri
| Homayoun Faroughi Niya
Department of Chemistry, Faculty of
In this study, three eco-friendly, efficient, and convenient protocols have been
reported for one-pot synthesis of 2,4,6-triaryl pyridine, 2-amino-
3-cyanopyridine, and polyhydroquinoline derivatives using salicylic acid as a
catalyst under solvent-free condition. The reported protocols offer several sig-
nificant advantages such as the application of a nontoxic, neutral, and cheap
catalyst, environmentally friendly conditions, the easy isolation of products by
filtering, short reaction times, simple methodology, and good yields.
Science, University of Sistan and
Baluchestan, Zahedan, Iran
Correspondence
Nourallah Hazeri, Department of
Chemistry, Faculty of Science, University
of Sistan and Baluchestan, P.O. Box
98135-674, Zahedan, Iran.
Email: nhazeri@chem.usb.ac.ir;
n_hazeri@yahoo.com
Funding information
University of Sistan and Baluchestan
1 | INTRODUCTION
In recent years, significant attention has been focused on
the synthesis of polyfunctionalized heterocyclic materials
In recent years, the management, development, and design of
chemical processes are the most important goals of green
chemistry to remove or decrease the generation and use of
substances that are hazardous to the environment and
health.[1] Green chemistry has been widely used in all industry
areas such as agriculture, household products, cosmetic, aero-
space, pharmaceutical, electronics, and aerospace for their
approach striving to obtain sustainability at the molecular
level.[2] Hence, most investigations have focused on the design
of synthetic strategies containing environmentally friendly
conditions such as using a green catalyst, low temperature,
using the green solvents or solvent-free condition.[3–7]
Multicomponent reactions (MCRs) are useful strategies
for the preparation of structurally different complex mole-
cules with significant pharmacological and biological prop-
erties that at least three components are involved to
generate a single product containing all the atoms of the
starting materials. Also, multicomponent reactions have ide-
ally exploratory power for the generation of organic mole-
cules because they are step efficient, atom economic, so
these reactions have been found to have an important role
in drug discovery projects and have received significant
attention from industries and academia.[8–12]
because they are essential in the drug production process,
and 68% of the produced drugs are heterocyclic.[13,14] The
ability to construct various structures is the most important
reason for the widespread application of heterocyclic com-
pounds to obtain the desired functions.[15,16] Among the vari-
ous heterocyclic compounds, nitrogen-bearing heterocyclic
molecules such as pyridine and quinoline derivatives are
more important because of their various pharmaceutical and
biological activities. Among the various pyridine ring,
2-amino-3-cyanopyridines and 2,4,6-triaryl pyridines are
famous as Kröhnke pyridine motifs that are individually
attractive.[17,18] Furthermore, it has been observed which pyri-
dines be employed as dyes, pesticides, additives, herbicides,
fungicides, and medicinally active compounds with properties
such as antibacterial, anticonvulsant, antimalarial, antioxi-
dant, and antiparasitic.[19–23] Other valuable nitrogen-
containing heterocycles are polyhydroquinoline derivatives
with a variety of biological activities.[24] Also, these com-
pounds are well known as one of the most valuable classes of
drugs that have a variety of biological properties such as Ca2+
channel blockers, antidiabetic agent, antitumor, bronchodila-
tor, hepatoprotective, antiatherosclerotic, geroprotective, and
vasodilator.[25,26]
J Heterocyclic Chem. 2021;58:1117–1129.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1117

1118
ROOZIFAR ET AL.
SCHEME 1 Salicylic acid catalyzed one-pot multicomponent reaction of 2,4,6-triaryl pyridine, 2-amino-3-cyanopyridine, and
polyhydroquinoline derivatives [Colour figure can be viewed at wileyonlinelibrary.com]
In this research, in continuation of the earlier
study,[27–29] three eco-friendly, efficient, and convenient
methods have been developed for the one-pot pseudo-
four-component synthesis of 2,4,6-triaryl pyridines via var-
ious acetophenones 2, ammonium acetate 3, and various
arylaldehydes 1, the one-pot four-component synthesis of
2-amino-3-cyanopyridines via various acetophenones 2,
ammonium acetate 3, various arylaldehydes 1, and
malononitrile 5, and also the one-pot four-component syn-
thesis of polyhydroquinolines via various arylaldehydes 1,
ammonium acetate 3, ethyl or methyl acetoacetate 7, and
dimedone 8 in the percent of salicylic acid as a catalyst
under solvent-free condition (Scheme 1).
derivatives (1.0 mmol), and 15 mol% of salicylic acid was
heated at 110ꢀC under solvent-free condition and the pro-
gress of the reaction was controlled by TLC. After a suit-
able time, the mixture of the reaction was cooled to room
temperature and 2 mL of ethanol was added to the reac-
tion mixture, and the corresponding product was filtered
by Whatman filter paper. In order to further purify, the
corresponding product was recrystallized in hot ethanol.
2.3 | General procedure for the four-
component synthesis of 2-amino-
3-cyanopyridine derivatives
In a vial, a mixture of ammonium acetate (1.5 mmol),
acetophenone derivatives (1.0 mmol), malononitrile
(1.0 mmol), arylaldehyde derivatives (1.0 mmol), and
5 mol% of salicylic acid was stirred at 90ꢀC under the
solvent-free condition, and the progress of the reaction
was controlled by TLC. After enough time, the mixture of
the reaction was allowed to cool to room temperature
and 2 mL of ethanol was added to the reaction mixture,
and the desired product was separated by filtering.
Finally, the pure product was obtained by recrystalliza-
tion from ethanol.
2 | EXPERIMENTAL
2.1 | General
Melting points of pure products were obtained using an Elec-
trothermal melting point apparatus (type 9100). All applied
chemicals were prepared from Merck and Aldrich companies
in high purity. BRUKER DRX-300 Avance instrument in
DMSO at 300 Hz, BRUKER DRX-300 Avance instrument in
DMSO at 75.6 MHz, and FT-IR-JASCO-460 plus spectrome-
1
ter were applied to record H NMR, 13C NMR, and FT-IR
spectra related to known compounds, respectively.
2.4 | General procedure for the four-
component synthesis of
polyhydroquinoline derivatives
2.2 | General procedure for the pseudo-
four-component synthesis of 2,4,6-triaryl
pyridine derivatives
In a vial, a mixture of ammonium acetate (1.5 mmol),
ethyl or methyl acetoacetate (1.0 mmol), dimedone
(1.0 mmol), arylaldehyde derivatives (1.0 mmol), and
10 mol% of salicylic acid was stirred at 70ꢀC under
In a vial, a mixture of ammonium acetate (1.5 mmol),
acetophenone derivatives (2.0 mmol), arylaldehyde

ROOZIFAR ET AL.
1119
solvent-free condition, and the progress of the reaction
was controlled by TLC. After an appropriate time, the
mixture of the reaction was allowed to cool to room tem-
perature and the desired product was washed by ethanol
and separated by filtering. Finally, the product was puri-
fied by recrystallization from ethanol.
NMR (300 MHz, DMSO d6): δ = 159.39, 155.55, 150.08,
138.05, 134.51, 129.16, 128.29, 116.35, 116.29. MS (EI,
70ev): MZ, M+ = 391.9.
2.5.5 | 2-amino-4-(4-bromophenyl)-
6-(4-chlorophenyl)nicotinonitril (6m)
2.5 | Selected spectra for the products
are given as follows
White solid; IR (KBr): ν: 3499, 3376, 2208, 1545, 1010,
1
820, 498 cm−1; H-NMR (300 MHz, DMSO-d6) (δ, ppm):
7.12 (s, 2H, NH2), 7.33 (s, 1H, Haromatic), 7.56 to 8.19 (m,
8H, Haromatic); 13C NMR (300 MHz, DMSO-d6): (δ, ppm):
161.25, 157.87, 154.35, 136.73, 136.51, 135.50, 132.42,
132.17, 131.02, 129.52, 129.17, 123.77, 117.23, 109.51,
87.21. MS (EI, 70 ev): MZ, M+ = 383.9.
2.5.1 | 2,6-bis(4-chlorophenyl)-
4-(4-methoxyphenyl)pyridine (4b)
White solid; IR(KBr): v: 3435, 3070, 2837, 1897, 1601,
1
1252, 825 cm−1; H NMR (300 MHZ, DMSO) (δ, ppm):
3.86 (s, 3H, OCH3), 7.11 (d, 2H, J = 8.7 Hz, Haromatic),
7.60 (d, 4H, J = 8.7 Hz, Haromatic), 8.05 (d, 2H, J = 8.7 Hz,
Haromatic), 8.21 (s, 2H, Haromatic), 8.37 (d, 4H, J = 8.7 Hz,
2.5.6 | 2-amino-4-(naphthalen-2-yl)-6-(p-
tolyl)nicotinonitrile (6n)
H
aromatic).
Yellow solid; IR (KBr): ν: 3485, 3307, 2206, 3192,
3039 cm−1 1H-NMR (300 MHz, DMSO-d6) (δ, ppm):
;
2.5.2 | 2,6-bis(4-methylphenyl)-
4-(4-fluorophenyl)pyridine (4c)
2.38 (s, 3H, CH3), 7.04 (s, 2H, NH2), 7.33 (d, 2H,
J = 8.1 Hz, Haromatic), 7.39 (s, 1H, Haromatic), 7.61 to 7.67
(m, 2H, Haromatic), 7.80 (dd, 1H J = 8.4 Hz, J = 1.8 Hz,
Haromatic), 8.02 to 8.12 (m, 5H, Haromatic), 8.27 (s, 1H,
Yellow solid; IR (KBr): v: 3424, 2918, 1605, 1507,
1
818, 555 cm−1; H NMR (300 MHZ, DMSO-d6) (δ, ppm):
H
aromatic); 13C NMR (300 MHz, DMSO-d6): δ = 161.36,
2.40 (s, 6H, 2CH3), 7.36 (d, 4H, J = 8.1 Hz, Haromatic), 7.42
(d, 2H, J = 8.7 Hz, Haromatic), 8.10 to 8.15 (m, 4H,
159.08, 155.26, 140.42, 135.28, 135.00, 133.56, 133.08,
129.74, 128.94, 128.73, 128.39, 128.13, 127.70, 127.24,
126.29, 117.68, 109.65, 86.99, 21.40. MS (EI, 70 ev): MZ,
M+ = 336.1.
H
aromatic), 8.25 (d, 2H, J = 8.1 Hz, Haromatic).
2.5.3 | 2,6-bis(4-bromophenyl)-
4-(4-hydroxyphenyl)pyridine (4o)
2.5.7 | 2-amino-4-(4-methylphenyl)-
6-(4-methoxyphenyl)nicotinonitril (6o)
1
Yellow solid; IR (KBr): 3129, 1604, 1209, 820 cm−1; H
NMR (300 MHz, DMSO-d6) (δ, ppm): 6.96 (d, 2H,
J = 8.4 Hz, Haromatic), 7.73 (d, 4H, J = 8.4), 7.93 (d, 2H,
J = 8.7 Hz, Haromatic), 8.16 (s, 2H, Haromatic), 8.28 (d, 4H
J = 8.4 Hz, Haromatic), 9.91 (s, 1H, OH); 13C NMR
(300 MHz, DMSO-d6): δ = 159.40, 155.66, 150.11, 138.41,
132.08, 129.41, 129.18, 128.30, 123.30, 116.33. MS (EI,
70 ev): MZ, M+ = 479.9.
White solid; IR (KBr): ν: 3499, 3376, 2208 cm−1 1H-
;
NMR (300 MHz, DMSO-d6) (δ, ppm): 2.38 (s, 3H, CH3),
3.86 (s, 3H, OCH3), 6.93 (s, 2H, NH2), 7.12 (d, 2H,
J = 9 Hz, Haromatic), 7.23 (s, 1H, Haromatic), 7.31 (d, 2H,
J = 8.1 Hz, Haromatic), 7.66 (dd, 2H, J = 9.1 Hz,
J = 1.8 Hz, Haromatic), 8.05 (d, 2H, J = 8.1 Hz, Haromatic);
13C NMR (300 MHz, DMSO-d6): δ = 161.41, 160.86,
158.89, 154.83, 140.30, 135.34, 130.31, 129.71, 129.62,
127.64, 117.88, 114.62, 109.16, 86.48, 55.83, 21.39; MS
(EI, 70 ev); MZ, M+ = 316.
2.5.4 | 2,6-bis(4-chlorophenyl)-
4-(4-hydroxyphenyl)pyridine (4p)
Yellow solid; IR(KBr): v: 3102, 1897, 1601, 1212,
2.5.8 | 2-amino-6-(4-chlorophenyl)-
4-(naphthalen-2-yl)nicotinonitrile (6q)
1
828 cm−1; H NMR (300 MHz, DMSO-d6) (δ, ppm): 6.95
(d, 2H, J = 8.7 Hz, Haromatic), 7.60 (d, 4H, J = 8.4 Hz),
7.95 (d, 2H, J = 8.4 Hz Haromatic), 8.18 (s, 2H, Haromatic),
8.36 (d, 4H, J = 8.4 Hz, Haromatic), 9.91 (s, 1H, OH); 13C
White solid; IR (KBr): ν: 3460, 3372, 2209 cm−1; 1H-NMR
(300 MHz, DMSO-d6) (δ, ppm): 7.13 (s, 2H, NH2), 7.46 (s,

1120
ROOZIFAR ET AL.
2H, Haromatic), 7.58 to 7.66 (m, 4H, Haromatic), 7.82 (dd,
1H, J = 8.4 Hz, J = 1.8 Hz, Haromatic), 8.03 to 8.13 (m, 3H,
Haromatic), 8.22 (d, 2H, J = 8.4 Hz, Haromatic), 8.29 (s, 1H,
2.5.9 | Ethyl 2,7,7-trimethyl-5-oxo-
4-phenyl-1,4,5,6,7,8-hexahydroquinoline-
3-carboxylate (9a)
H
aromatic); 13C NMR (62.5 MHz, DMSO-d6): δ = 161.32,
157.76, 155.59, 136.89, 135.46, 134.81, 133.60, 133.06,
129.54, 129.18, 128.95, 128.75, 128.48, 128.14, 127.73,
127.29126.26, 117.47, 109.98, 87.73. MS (EI, 70ev); MZ,
M+ = 355.2.
White solid; IR (KBr): ν: 3290, 2963, 1698, 1620, 1484,
1
1211 cm−1; H NMR (300 MHz, CDCl3) (δ, ppm): 0.86 (s,
3H, CH3), 1.02 (s,3H, CH3), 1.14 (t, 3H, J = 7.2 Hz, CH3),
1.96 to 2.33 (m, 4H, CH2), 2.33 (s, 3H, CH3), 3.99 (q, 2H,
TABLE 1 Investigation of the synthesis of 2,4,6-triaryl pyridines in the presence of the different catalysts at 110ꢀC
Entry
Catalyst (15 mol%)
Salicylic acid
DABCO
Solvent
Time (min)
Isolated yield (%)
1
2
3
4
5
6
7
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
25
150
180
100
90
90
45
35
42
65
48
54
Lactose
Tannic acid
Benzilic acid
Bismuth chloride
Cobalt (II) nitrate hexahydrate
240
240
Note: Bold indicates optimized conditions.
TABLE 2 Optimization of reaction conditions for the synthesis of 2,4,6-triaryl pyridines [Colour figure can be viewed
atwileyonlinelibrary.com]
Entry
1
Catalyst (mol%)
Solvent
Temperature (ꢀC)
Time (min)
Yield (%)
65
5
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
110
110
110
110
110
110
110
25
50
35
2
10
15
20
25
30
35
15
15
15
15
15
15
15
15
15
80
3
25
90
4
25
88
5
22
83
6
25
79
7
25
73
8
360
240
180
100
60
Trace
20
9
50
10
11
12
13
14
15
16
60
35
70
48
80
54
90
45
63
100
120
130
35
77
25
87
20
86
Note: Bold indicates optimized conditions.

ROOZIFAR ET AL.
1121
J = 7.2 Hz, OCH2), 4.87 (s, 1H, CH), 7.05 to 7.22 (m, 5H,
Haromatic), 9.07 (s, 1H, NH).
0.87 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.89 to 2.53 (m, 4H,
CH2), 2.28 (s, 3H, CH3-C=), 3.35 (s, 3H, OMe), 3.50 (s,
3H, OMe), 3.70 (s, 3H, OMe), 4.98 (s, 1H, CH), 6.33 to
6.98 (m, 3H, Haromatic), 8.94 (s, 1H, NH); 13C NMR
(300 MHZ, DMSO-d6): δ = 194.30, 168.34, 159.09, 158.41,
150.25, 144.19, 130.97, 128.26, 109.28, 104.70, 103.67,
98.71, 55.81, 55.41, 50.90, 50.82, 32.46, 32.67, 29.82, 26.75,
18.46, MS(EI, 70 ev): MZ, M+ = 386.
2.5.10 | Methyl 4-(3,4-dimethoxyphenyl)-
2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-
3-carboxylate (9o)
White solid; IR (KBr): ν: 3276, 3202, 3076, 2945, 1699, 1602,
1380, 1217, cm−1; 1H NMR (300 MHz, DMSO) (δ, ppm): 0.89
(s, 3H, CH3), 1.03 (s,3H, CH3), 1.99 to 2.41 (m, 4H, CH2-
CMe2-CH2), 2.30 (s 3H, CH3-C=), 3.57 (s, 3H, CO2Me), 3.67
(s, 3H, OCH3), 3.68 (s, 3H, OCH3), 4.83 (s, 1H, CH), 6.61 to
6.79 (m, 3H, Haromatic), 9.07 (s, 1H, NH); 13C NMR (300 MHZ,
DMSO-d6): δ = 194.94, 167.92, 149.92, 148.54, 147.42, 145.41,
140.76, 119.45, 111.93, 103.97, 55.85, 55.75, 51.11, 50.73, 35.41,
32.59, 29.70, 26.85, 18.73; MS (EI, 70 ev): MZ, M+ = 386.
2.5.12 | Methyl 2,7,7-trimethyl-5-oxo-
4-(3,4,5-trimethoxyphenyl)-
1,4,5,6,7,8-hexahydroquinoline-
3-carboxylate (9q)
White solid; IR (KBr): ν: 3283, 3077, 2960, 2933, 1699,
1
1648, 1503, 1221 cm−1; H NMR (300 MHz, DMSO) (δ,
ppm): 0.95 (s, 3H, CH3), 1.04 (s,3H, CH3), 2.02 to 2.53 (m,
4H, CH2), 2.29 (s, 3H, CH3-C=), 3.35 (s, 3H, CO2Me),
3.61 (s, 3H, OCH3), 3.69 (s, 6H, 2OCH3), 4.85 (s, 1H, CH),
6.42 (s, 2H, Haromatic), 9.11 (s, 1H, NH); 13C NMR
(300 MHz, DMSO-d6): δ = 194.95, 167.89, 152.85, 150.33,
145.52, 143.66, 136.24, 110.08, 104.93, 103.86, 60.35,
56.12, 51.13, 50.73, 36.03, 32.59, 29.74, 26.84, 18.73.
MS(EI, 70 ev): MZ, M+ = 416.
2.5.11 | Methyl4-(2,4-dimethoxyphenyl)-
2,7,7-trimethyl-5-oxo-
1,4,5,6,7,8-hexahydroquinoline-
3-carboxylate (9p)
White solid; IR(KBr): ν: 3290, 3082, 2963,1698, 1640,
1
1484, 1211, cm−1; H NMR (300 MHz, DMSO) (δ, ppm):
TABLE 3 Synthesis of 2,4,6-triaryl pyridine derivatives in the presence of salicylic acid (15 mol%) as catalyst under solvent-free
condition at 110ꢀC [Colour figure can be viewed atwileyonlinelibrary.com]
Entry
1
R1
R2
Product
4a
Time (min)
Isolated yield (%)
M.p (ꢀC)
162-164
191-192
185-186
243-245
250-252
190-191
227-229
202-204
235-237
175-177
200-202
197-200
113-115
147-149
258-260
263-264
M.p (ꢀC) [References]
164-165 [34]
188-190 [30]
202-204 [34]
242-244 [34]
250-252 [34]
188-190 [34]
230-232 [30]
201-203 [31]
243-245 [31]
180-182 [30]
196-198 [35]
200-202 [35]
103-105 [35]
139-140 [32]
This work
4-OH-Ph
4-OMe-Ph
4-F-Ph
4-Me-Ph
4-Cl-Ph
4-Me-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-OMe-Ph
4-Cl-Ph
Ph
70
10
30
25
15
45
55
40
50
25
60
30
50
75
40
30
86
90
85
90
95
87
58
82
90
84
87
75
88
72
82
88
2
4b
3
4c
4
4-F-Ph
4d
4e
5
3-F-Ph
6
4-NO2-Ph
3-NO2-Ph
4-Me-Ph
4-OH-Ph
Ph
4f
7
4g
8
4h
4i
9
10
11
12
13
14
15
16
4j
4-NO2-Ph
4-Cl-Ph
4-Br-Ph
4-N(CH3)2-Ph
4-OH-Ph
4-OH-Ph
4k
4l
4-Me-Ph
Ph
4m
4n
4o
4-Cl-Ph
4-Br-Ph
4-Cl-Ph
4p
This work

1122
ROOZIFAR ET AL.
3 | RESULTS AND DISCUSSION
pyridines at 110ꢀC under solvent-free condition
(Table 1). It has been found which salicylic acid is a suit-
able catalyst for the synthesis of 2,4,6-triaryl pyridines
with short reaction times and high yields. Subsequently,
the model reaction was investigated using various
amounts of salicylic acid and different temperatures
under solvent-free condition, and the results are sum-
marized in Table 2. Observably, when the model reac-
tion was performed in the percent of 15 mol% of catalyst
at 110ꢀC under solvent-free condition (entire 3), the best
yield and time reaction were achieved.
In this article, we describe three practical protocols
using salicylic acid as an efficient catalyst. It is notewor-
thy that according to the previous studies in the
literature,[28,30–33] the synthesis of 2,4,6-triaryl pyridines,
2-amino-3-cyanopyridines, and polyhydroquinolines has
not progressed well in the presence of solvents such as
water, ethanol, and water:ethanol, so the solvent-free
condition was chosen as a good and green condition in
this study. In the first protocol, to study the optimal per-
formance in the synthesis of 2,4,6-triaryl pyridines,
ammonium acetate (1.5 mmol), 4-F-acetophenone
(2.0 mmol), and 4-Cl-benzaldehyde (1.0 mmol) were
chosen as model substrates. Initially, the different cata-
lysts were tested for the synthesis of 2,4,6-triaryl
After optimization, optimized reaction conditions
were applied for the preparation of 2, 4, 6-triaryl pyridine
derivatives
using
various
acetophenones
and
arylaldehydes with electron-donating or electron-
withdrawing groups to investigate the efficiency of this
SCHEME 2 The proposed synthetic pathway for the synthesis of 2,4,6-triaryl pyridine derivatives [Colour figure can be viewed at
wileyonlinelibrary.com]

ROOZIFAR ET AL.
1123
TABLE 4 Optimization of reaction conditions for the synthesis of 2-amino-3-cyanopyridines [Colour figure can be viewed
atwileyonlinelibrary.com]
Entry
Catalyst (mol%)
Solvent
Temperature (ꢀC)
Time (min)
Yield (%)
1
5
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
90
20
20
20
20
20
20
300
150
85
45
25
20
20
92
2
10
15
20
25
30
5
90
92
3
90
90
4
90
85
5
90
76
6
90
72
7
25
Trace
55
8
5
50
9
5
70
75
10
11
12
13
5
80
82
5
100
110
120
92
5
90
5
88
Note: Bold indicates optimized conditions.
TABLE 5 Synthesis of 2-amino-3-cyanopyridine derivatives in the presence of salicylic acid (5 mol%) as catalyst under solvent-free
condition at 90ꢀC [Colour figure can be viewed atwileyonlinelibrary.com]
Entry
1
R1
R2
Product
6a
Time (min)
Isolated yield (%)
M.p (ꢀC)
186-187
173-174
144-146
150-151
210-212
194-196
237-239
198-200
230-232
170-172
192-195
238-240
240-242
210-212
142-144
210-212
M.p (ꢀC) [References]
186-187 [36]
180-182 [36]
148-150 [37]
173-175 [36]
212-213 [37]
205-207 [38]
238-240 [37]
195-197 [37]
234-236 [37]
172-174 [39]
194-197 [37]
242-243 [40]
This work
Ph
Ph
25
35
10
20
50
30
35
25
15
20
40
20
20
60
40
35
92
92
95
90
88
80
86
96
93
91
80
90
94
73
80
86
2
4-OMe-Ph
4-F-Ph
4-Me-Ph
4-NO2-Ph
4-OMe-Ph
Ph
Ph
6b
3
Ph
6c
4
Ph
6d
6e
5
Ph
6
4-Cl-Ph
4-Cl-Ph
Ph
6f
7
6g
8
4-Br-Ph
4-Cl-Ph
Ph
6h
6i
9
Ph
10
11
12
13
14
15
16
4-Me-Ph
Ph
6j
2-Cl-Ph
4-F-Ph
4-Br-Ph
2-Nph
4-OMe-Ph
2-Nph
6k
6l
4-Cl-Ph
4-Cl-Ph
4-Me-Ph
4-Me-Ph
4-Cl-Ph
6m
6n
6o
This work
This work
6p
This work

1124
ROOZIFAR ET AL.
SCHEME 3 The proposed synthetic pathway for the synthesis of 2-amino-3-cyanopyridines [Colour figure can be viewed at
wileyonlinelibrary.com]
protocol (Table 3). As expected, all of the 2,4,6-triaryl pyr-
idine derivatives were easily synthesized in excellent to
good yields that make this method be useful for the syn-
thesis of 2,4,6-triaryl pyridine.
addition between another equivalent of activated
acetophenone and 1,3-diaryl-2-propen-1-one A. Next,
NH3 formed from the destruction of ammonium acetate
3 attacked intermediate B in the presence of salicylic acid
as a Brønsted acid catalyst to form intermediate C.
Finally, The formation of the final desired product (4a-p)
has been followed by cyclized, dehydrogenated, and
tautomerization of intermediate C and the generated H+
of catalyst is released back into the catalytic route.
In the second protocol, the one-pot synthesis of
2-amino-3-cyanopyridins has been developed using salicylic
acid as a green catalyst under solvent-free condition. To
study the optimal performance in the synthesis of 2-amino-
The mechanism for the synthesis of 2,4,6-triaryl pyri-
dine derivatives is not clear enough. According to previ-
ous studies in the literature,[32,35] a catalyzed proposed
mechanism with salicylic acid is suggested in Scheme 2.
Mechanistically, carbonyl groups of the desired
arylaldehyde 1 and acetophenone 2 have been protonated
and activated by salicylic acid (a Brønsted acid catalyst)
and the reaction has been initially progressed by an aldol
condensation to generate a 1,3-diaryl-2-propen-1-one A.
Then, intermediate B has been achieved by Michael
3-cyanopyridines,
ammonium
acetate
(1.5 mmol),

ROOZIFAR ET AL.
1125
TABLE 6 Optimization of reaction conditions for the synthesis of polyhydroquinolines [Colour figure can be viewed
atwileyonlinelibrary.com]
Entry
Catalyst (mol%)
Solvent
Temperature (ꢀC)
Time (min)
Yield (%)
1
10
15
20
25
30
10
10
10
10
10
10
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
Solvent free
70
70
70
70
70
25
30
40
50
60
80
7
93
93
93
90
85
40
50
65
73
85
94
2
7
3
10
20
25
240
180
90
20
15
7
4
5
6
7
8
9
10
11
Note: Bold indicates optimized conditions.
acetophenone (1.0 mmol), benzaldehyde (1.0 mmol), and
malononitrile (1.0 mmol) were chosen as model substrates.
For this purpose, the different amounts of catalyst and vari-
ous temperatures were tested in the model reaction under
solvent-free condition, and the best result was achieved by
5 mol% of catalyst at 90ꢀC (Table 4, entry 1).
activated acetophenone to form the enamine intermedi-
ate B. Afterward, this enamine intermediate B reacts
with intermediate A to give intermediate C. Here, the
presence of salicylic acid as a catalyst helps to afford the
desired products (6a-p) after intramolecular cyclization,
tautomerization, and aromatization.
After optimization, in order to check the efficiency of this
protocol, optimized reaction conditions were applied for the
preparation of 2-amino-3-cyanopyridine derivatives using
various acetophenones and arylaldehydes with electron-
donating or electron-withdrawing groups. As evident from
Table 5, salicylic acid shows high catalytic activity in the syn-
thesis of all derivatives of 2-amino-3-cyanopyridines.
The mechanism for the synthesis of 2-amino-
3-cyanopyridin derivatives is not clear enough. According
to the literature review,[28,37] a catalyzed proposed mech-
anism with salicylic acid is suggested in Scheme 3. The
acid-base interactions between salicylic acid as a Lewis
acid, arylaldehyde, and acetophenone lead to active C O
groups of arylaldehyde 1 and acetophenone 2. Immedi-
ately, malononitrile 5 reacts with activated arylaldehyde
via Knoevenagel condensation followed by dehydration
to generate intermediate A. On the other hand, generated
Finally, the attractive results achieved in the synthesis
of 2,4,6-triaryl pyridines and 2-amino-3-cyanopyridines
led us to investigate the ability of salicylic acid in the syn-
thesis of polyhydroquinoline derivatives. Therefore, the
reaction between 4-OMe-benzaldehyde, ammonium ace-
tate, ethyl acetoacetate, and dimedone was chosen as a
model to study the optimization of the reaction parame-
ters such as temperature and amount of catalyst, and the
results are presented in Table 6. According to the results
summarized in Table 6, the optimized conditions were
obtained to be as follows: 4-OMe-benzaldehyde
(1.0 mmol), ammonium acetate (1.5 mmol), ethyl
acetoacetate (1.0 mmol), dimedone (1.0 mmol), and sali-
cylic acid (10 mol%) at 70ꢀC under solvent-free condition
(Table 6, entry 1).
In an attempt to generalize the utility of this method-
ology, a series of polyhydroquinolines were synthesized
using many types of benzaldehydes containing electron-
ammonia from ammonium acetate
3 reacts with

1126
ROOZIFAR ET AL.
TABLE 7 Synthesis of polyhydroquinoline derivatives in the presence of salicylic acid (10 mol%) as catalyst under solvent-free condition
at 70ꢀC [Colour figure can be viewed atwileyonlinelibrary.com]
Entry
1
R1
R3
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Product
9a
Time (min)
Isolated yield (%)
M.p (ꢀC)
206-208
210-212
247-249
252-254
222-224
242-244
180-181
198-200
201-203
255-257
253-256
230-232
210-212
218-220
200-202
246-248
262-264
M.p (ꢀC) [References]
205-207 [33]
206-208 [33]
244-246 [33]
255-257 [33]
234-236 [33]
242-244 [41]
175-177 [42]
207-209 [33]
209-211 [42]
259-261 [33]
258-259 [33]
231-233 [42]
206-208 [41]
217-219 [42]
This work
H
7
92
88
85
89
80
88
92
85
90
90
93
90
91
85
90
80
92
2
3-F
9b
8
3
4-Cl
9c
5
4
4-Br
9d
9e
5
5
4-OH
8
6
4-NO2
3-NO2
2-NO2
2-Cl
9f
10
9
7
9g
8
9h
9i
8
9
6
10
11
12
13
14
15
16
17
4-Me
9j
5
4-OMe
4-N(CH3)2
3-OMe-4-OH
3-OH
9k
9l
7
8
9m
9n
9o
5
7
3,4-di-OMe
2,4-di-OMe
3,4,5-tri-OMe
8
9p
9q
10
9
This work
This work
withdrawing and electron-donating moieties. As tabu-
lated in Table 7, all of the polyhydroquinolines deriva-
tives were efficiently synthesized in excellent to good
yields and short reaction times that make this methodol-
ogy useful for the synthesis of polyhydroquinolines.
The mechanism for the synthesis of polyhydroquinoline
derivatives is not clear enough. Based on the literature
review,[33,41,42] a catalyzed proposed mechanism with sali-
cylic acid is suggested in Scheme 4. Carbonyl groups of the
desired arylaldehydes 1, ethyl or methyl acetoacetate 7, and
dimedone 8 have been protonated and activated by salicylic
acid (a Brønsted acid catalyst), and the reaction has been
acid to generate enamine B. Afterward, intermediate
C has been achieved by Michael addition between
enamine B and 2-benzylidenedimedone A. Then,
intermediate C has been changed to intermediate
D by tautomerization. Finally, the presence of sali-
cylic acid as a catalyst helps to afford the desired
product (9a-q) after intramolecular cyclization,
dehydrogenated, and aromatization.
4 | COMPARISON
initially progressed by
a
Knoevenagel condensation
In order to highlight the importance and efficiency of these
protocols, the present results were compared with several
reported data. Based on Table 8, our catalytic protocols
show a high catalytic activity and are superior in terms of
reaction conditions, product yield, and reaction time.
between enol form of dimedone with activated arylaldehyde
to form a 2-benzylidenedimedone A. On the other hand,
NH3 obtained from ammonium acetate 3 linked to
activated ethyl or methyl acetoacetate with salicylic

ROOZIFAR ET AL.
1127
SCHEME 4 The proposed mechanism for the synthesis of polyhydroquinolines [Colour figure can be viewed at wileyonlinelibrary.com]
TABLE 8 Comparison of the efficiency of salicylic acid with other catalysts in the literature
Entry
Product
4k
Catalyst
Amount
2.5 mol%
5 mol%
4 mol%
15 mol%
20 mol%
20 mg
Condition
Time (min)
Yield (%)
References
1
CoCl2.6H2O
Solvent-free, 110ꢀC
AcOH, 90ꢀC
—
55
89
25
20
20
40
25
8
84
98
60
84
91
73
86
92
91
95
90
92
35
Nanocrystalline MgAl2O4
CMC-CeIV
32
Solvent-free, 80ꢀC
Solvent-free, 110ꢀC
Solvent-free, 100ꢀC
Solvent-free, 100ꢀC
Solvent-free, 100ꢀC
Solvent-free, 90ꢀC
Solvent-free, 60ꢀC
Solvent-free, r.t
EtOH, r.t
31
Salicylic acid
This work
2
6a
9a
Cobalt (II) nitrate hexahydrate
ClO4/Al-MCM-41
{Fe3O4@SiO2@(CH2)3Im}C(CN)3
Salicylic acid
28
36
7 mg
37
5 mol%
15 mg
This work
Chitosan
33
{[TPPSP]OTf}
0.5 mol%
5 mol%
10 mol%
13
300
7
42
Yb(OTf)3
43
Salicylic acid
Solvent-free, 70ꢀC
This work

1128
ROOZIFAR ET AL.
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In brief, we present three versatile and simple protocols
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2,4,6-triaryl
pyridine,
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3-cyanopyridine, and polyhydroquinoline derivatives
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ORCID
Nourallah Hazeri https://orcid.org/0000-0002-0560-
7245
Homayoun Faroughi Niya https://orcid.org/0000-0002-
2220-4288
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How to cite this article: Roozifar M, Hazeri N,
Faroughi Niya H. Application of salicylic acid as an
eco-friendly and efficient catalyst for the synthesis
of 2,4,6-triaryl pyridine, 2-amino-3-cyanopyridine,
and polyhydroquinoline derivatives. J Heterocyclic
Chem. 2021;58:1117–1129. https://doi.org/10.1002/
jhet.4242
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