Highly efficient four-component synthesis of 2-amino-3-cyanopyridines using doped nano-sized copper(I) oxide (Cu2O) on melamine-formaldehyde resin

Article abstract of DOI:10.3184/174751916X14709292404728

A convenient and facile four-component synthesis is described of 2-amino-3-cyanopyridine derivatives from readily available starting materials catalysed by doped nano-sized Cu₂O on melamine-formaldehyde resin (nano-Cu₂O-MFR). In this method, treatment of different aldehydes, ketones, malononitrile, and ammonium acetate in refluxing H₂O/EtOH (1:1) in the presence of doped nano-Cu₂O-MFR as a highly efficient heterogeneous catalyst affords the corresponding 2-amino-3-cyanopyridines in good to excellent yields. The nano-Cu₂O-MFR is a cheap and stable nano-catalyst that could be easily recovered and reused for many consecutive reaction runs without considerable decrease in its activity.

Full text of DOI:10.3184/174751916X14709292404728

540 RESEARCH PAPER
VOL. 40 SEPTEMBER, 540–544 JOURNAL OF CHEMICAL RESEARCH 2016
Highly efficient four-component synthesis of 2-amino-3-cyanopyridines using
doped nano-sized copper(I) oxide (Cu2O) on melamine–formaldehyde resin
Somayeh Behrouz*
Medicinal Chemistry Research laboratory, Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
A convenient and facile four-component synthesis is described of 2-amino-3-cyanopyridine derivatives from readily available starting
materials catalysed by doped nano-sized Cu2O on melamine–formaldehyde resin (nano-Cu2O–MFR). In this method, treatment of different
aldehydes, ketones, malononitrile, and ammonium acetate in refluxing H2O/EtOH (1:1) in the presence of doped nano-Cu2O–MFR as
a highly efficient heterogeneous catalyst affords the corresponding 2-amino-3-cyanopyridines in good to excellent yields. The nano-
Cu2O–MFR is a cheap and stable nano-catalyst that could be easily recovered and reused for many consecutive reaction runs without
considerable decrease in its activity.
Keywords: 2-amino-3-cyanopyridine, heterogeneous nano-catalyst, multi-component reaction, nano-Cu2O–MFR, one-pot synthesis,
pyridine derivatives
Due to numerous applications of heterocyclic compounds
especiallyN-heterocyclicderivativesindifferentareaofsciences,
a great deal of research effort has been focused on developing
simple and efficient synthetic procedures for their construction.
Among heterocyclic compounds, the pyridine substructure is
well known as an important sub-structure found in a variety
of natural and synthetic products exhibiting a wide range of
biological and pharmacological properties.1 The naturally
occurring compounds like vitamins B3 and B6, nicotine, and
nicotinamide adenine dinucleotide phosphate (NADP) contain
a pyridine moiety in their structures. In addition, the pyridine
ring is a key structural motif present in plenty of drugs having
a broad range of biological and pharmacological properties.
Moreover, some pyridine derivatives are also involved in
coordination chemistry, organocatalysis, supramolecular
structures, polymers, non-linear optical materials, electrical
materials and agrochemicals.1 Among pyridine derivatives,
2-amino-3-cyanopyridines have attracted considerable attention
due to their remarkable biological properties. 2-Amino-3-
cyanopyridine derivatives display abundant biological activities
such as anticancer, anti-inflammatory, antiviral, antimicrobial,
antihypertensive, antitubercular and antioxidant properties.
They have also proved to be potent inhibitors of HIV-1 itegrase
and IKK-β as well as A2A adenosine receptor antagonists.
Moreover, they have been frequently used as valuable
intermediates for the construction of a variety of heterocyclic
derivatives.1
Due to the remarkable biological properties associated with
2-amino-3-cyanopyridines, many synthetic approaches have
been developed to access structurally diverse 2-amino-3-
cyanopyridine derivatives.2 Although most of these procedures
are useful and efficient, they are accompanied by one or more
drawbacks such as the use of toxic solvents, utilising expensive
metal catalysts, long reaction times, complicated reaction
procedures, harsh reaction conditions, tedious work-ups, multi-
step syntheses, and unsatisfactory yield of the desired products.
Multi-component reactions (MCRs) have emerged as
powerful and attractive strategies in medicinal, combinatorial,
and organic chemistry.3 These reactions provide straightforward
and rapid access to complex molecules from simple, available
precursors in a single step without the isolation of intermediates.
Therefore, MCRs are associated with many advantages like
atom economy, minimisation of chemical waste and thus
lower environmental costs, quantitative yields, and simple
experimental procedures. Particularly, MCRs have been widely
applied for the construction of structurally diverse heterocyclic
compounds.3 In this regard, the most extensively used strategy
for synthesis of 2-amino-3-cyanopyridine derivatives involves
the four-component reaction (4CR) of diverse aldehydes,
ketones, malononitrile, and ammonium acetate in different
conditions.2 However, the applicability of these methods were
restricted by one or more drawbacks like the use of expensive
and nonreusable catalysts, unsatisfactory yields, long reaction
times, limited scope of substrates, and the use of microwave
or ultrasound irradiations. Hence, the development of efficient
and applicable methods with suitable generality for synthesis
of 2-amino-3-cyanopyridines still remains of great importance.
In recent years, the use of heterogeneous catalysts has
attracted much more attention from both environmental and
economic concerns. The use of heterogeneous catalysts in
organic synthesis offers attractive advantages like thermal
stability of the catalyst, minimisation of the chemical wastes,
ease of operation, mild reaction conditions, recyclability and
reusability of the catalyst. Heterogeneous catalysts have been
efficiently employed in various multi-component reactions.4
It was recently reported that the application of copper
nanoparticles on a charcoal catalyst (Cu/C) for the 4CR of
aldehyde, ketone, malononitrile, and ammonium acetate in
refluxing MeCN afforded the corresponding 2-amino-3-
cyanopyridines.5
Melamine–formaldehyde resin (MFR) has a unique chemical
structure which makes it a suitable and useful solid support for
absorbing different metal salts to afford valuable heterogeneous
catalysts. The schematic view for the potential hosting of cation
and anion by MFR is shown in Fig. 1.6 Previously, we reported
the synthesis and application of doped nano-sized Cu2O on
melamine–formaldehyde resin (nano-Cu2O–MFR) as a novel
and highly efficient heterogeneous catalyst in click syntheses of
1,4-disubstituted-1H-1,2,3-triazoles having antibacterial activity.6
Inspired by the remarkable biological activities of 2-amino-
3-cyanopyridines and in continuation of our effort to discover
the new applications for nano-Cu2O–MFR in organic synthesis,
hereby, we would like report a facile and straightforward
synthesis of structurally diverse 2-amino-3-cyanopyridine
derivatives via the four-component reaction of different
aldehydes, ketones, malononitrile, and ammonium acetate
in refluxing H2O/EtOH (1:1) in the presence of doped nano-
Cu2O–MFR (Scheme 1).
* Correspondent. E-mail: behrouz@sutech.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2016 541
NH
NH
N
N
N
N
NH
N
N
HN
N
H
N
H
N
N
NH
N
N
HN
N
N
N
N
N
N
NH
H
H
N
N
NH
N
N
H
H
H
N
N
H
NH
N
N
H
H
HN
N
NH
N
N
HN
N
N
N
N
N
NH
NH
Fig. 1 The schematic view for the potential hosting of cation (left) and anion (right) by MFR.
R1
O
O
CN
NH2
nano Cu O MFR
−
−
2
NH
4OAc
NC
R2
CN
R1
H
CH3
H2O/EtOH (1:1), reflux
R2
N
1
2
3
4
5a p
−
1
2
1
2
5a
5b
5c
5d
5e
: R = C6H5; R = C6H5
5h
5i
: R = C6H5; R = (Me)3C
1
2
1
2
: R = 4-Cl C H ; R = C H
6
5
−
: R = 2-Cl C H ; R = 4-OH C H
4
−
−
−
−
6
−
6
6
4
6
4
6
1
2
1
2
: R = pyridin-4-yl; R = C6H5
5j
: R = 3-Br C H ; R = 4-OH C H
6
4
4
1
2
1
2
: R = thiophen-3-yl; R = C6H5
5k
: R = 4-Me C H ; R = 4-Br C H
−
6
4
4
1
2
1
2
: R = Me; R = C6H5
5l
: R = 4-OMe C H ; R = 4-Cl C H
−
−
6
6
4
4
1
2
1
2
5f
: R = C6H5; R = naphthalen-2-yl
5m:
5n:
R = 4-Cl C H ; R = 4-Cl C H
−
−
−
6
4
6
4
1
2
1
2
5g
: R = C6H5; R = Me
R = furan-2-yl; R = 4-Me C H
6
4
O
O
5o:
5p:
H
3C
N
O
N
CN
CN
O2N
N
NH2
N
NH2
MeO
Scheme 1 Four-component synthesis of 2-amino-3-cyanopyridines 5 using nano-Cu2O–MFR and reactants 1–4.
Results and discussion
entries 2–7). As the results in Table 1 indicate, the use of water
in combination with the examined solvents afforded low to
moderate yields of the desired product 5a (entries 2 and 4–7).
The best result was obtained when a solution of H2O/EtOH (1:1)
was employed as the solvent (Table 1, entry 3). Consequently, it
was the solvent of choice for achieving all subsequent reactions.
In the same circumstances, the use of pure EtOH under reflux
conditions did not affect the reaction efficiency (Table 1, entry 8).
We further studied the effect of different temperatures on the
progress of the model reaction (Table 1, entries 3 and 9–11).
As the data in Table 1 demonstrates, increasing the reaction
temperature up to reflux conditions dramatically improved the
reaction efficiency (entries 3, 9, and 10). However, a further
raise of the reaction temperature led to no distinguishable effect
on the progress of the reaction (Table 1, entry 11).
The first step of this synthetic approach was begun with
the optimisation of the reaction conditions. To identify
the optimised reaction conditions, 4CR of benzaldehyde,
acetophenone, malononitrile, and ammonium acetate in the
presence of doped nano-Cu2O–MFR was investigated as a
sample reaction. Therefore, the influence of several effective
reaction parameters on the progress of the reaction including
solvent type, temperature, and catalyst loading were studied in
sample reactions to afford 2-amino-4,6-diphenylnicotinonitrile
(5a). The results obtained are shown in Table 1.
The choice of a suitable solvent is important for the satisfactory
conduct of the reaction. In recent years, the use of water as
a solvent in reactions has attracted increasingly significant
interest mainly from the viewpoints of green chemistry and
economic factors. Thus, our initial attempt was to carry out
the model reaction in pure water as the green solvent. Thus the
model reaction was carried out in refluxing water which affords
81% of 2-amino-4,6-diphenylnicotinonitrile after 2.5 h (Table 1,
entry 1). To improve the yield, the effect of water with several
polar and nonpolar solvents in 1:1 ratio was screened (Table 1,
In another complementary experiment, the effect of
different amounts of nano-Cu2O–MFR was examined in
the current protocol (Table 1, entries 3, 12, and 13). As it is
clear from Table 1, when the catalyst loading was increased
up to 0.072 mol%, higher yields of product in shorter reaction
times were attained (entries 3 and 12). Increasing the catalyst

542 JOURNAL OF CHEMICAL RESEARCH 2016
Table 1 Effect of various reaction parameters on the model reaction
Entry
1
2
3
4
5
6
7
8
Solvent
H2O
Catalyst/mol%
Temperature/°C
reflux
reflux
reflux
reflux
100
Time/h
2.5
Yieldc/%
81
67
92
70
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.072)
nano-Cu2O–MFR (0.048)
nano-Cu2O–MFR (0.096)
CuI
H2O/toluenea
H2O/EtOHa
H2O/EtOAca
H2O/DMFa
H2O/THFa
H2O/MeCNa
EtOH
3
1
2
4
5
4
3
5
2
1
1.8
1
3
65
46
reflux
reflux
reflux
r.t.
70
110b
reflux
reflux
reflux
reflux
reflux
79
83
69
85
92
89
92
75
71
9
H2O/EtOHa
H2O/EtOHa
H2O/EtOHa
H2O/EtOHa
H2O/EtOHa
H2O/EtOHa
H2O/EtOHa
H2O/EtOHa
10
11
12
13
14
15
16
Cu(OAc)2
3
3
CuO
70
aA mixture of 1:1 solvents were used.
bSealed tube was used.
cIsolated yield.
Table 2 Doped nano-Cu2O–MFR-catalysed synthesis of 2-amino-3-
resulted in no improvement in the yield of 5 (Table 1, entry 13).
Consequently, 0.072 mol% of nano-Cu2O–MFR was employed
for efficient performance of all reactions.
cyanopyridines
Entryref.
Producta
5a
5b
5c
5d
5e
5f
5g
Time/h
1
1
Yieldb/%
92
94
93
89
80
87
85
82
17
To evaluate the catalytic potency of nano-Cu2O–MFR, 4CR
of model substrates was investigated using several copper
catalysts under the optimised conditions (Table 1, entries 3 and
14–16). As shown in Table 1, the model reaction was efficiently
achieved using nano-Cu2O–MFR to afford 92% of the desired
product 5a (entry 3). The use of other catalysts, such as CuI,
Cu(OAc)2 and CuO, provided moderate yields of 5a (entries
14–16). The satisfactory outcome attained by nano-Cu2O–MFR
can be attributed to the presence of a large surface area and the
chemical and thermal stability of nano-Cu2O–MFR under the
optimised reaction conditions.
An appropriate stoichiometric ratio for aldehyde 1, ketone 2,
malononitrile 3, and ammonium acetate 4 to afford 2-amino-
4,6-diphenylnicotinonitrile 5 in excellent yield under the
optimised conditions was found to be 1:1:1.3:1.5 respectively.
With optimised reaction conditions in hand, we then screened
the scope, versatility and general applicability of the present
protocol in 4CR of structurally diverse aldehydes, ketones,
malononitrile, and ammonium acetate in the presence of doped
nano-Cu2O–MFR (Table 2). As is clear from Table 2, doped
nano-Cu2O–MFR was shown to be a suitable nano-catalyst that
effectively catalyses the present four-component synthesis of
2-amino-3-cyanopyridines.
As shown in Table 2, all reactions proceeded smoothly
to afford the desired 2-amino-3-cyanopyridine derivatives
in good to excellent yields. Aliphatic, heteroaromatic, and
aromatic aldehydes bearing electron rich or electron deficient
substituents were used and led to the desired products in good
to excellent yields. The application to sterically hindered
ortho-substituted benzaldehydes provides the desired products
5i and 5o in reasonable yields (Table 2, entries 9 and 15). In
a further exploration of the reaction scope, the optimised
reaction conditions were exploited for different aliphatic and
aromatic ketones. It was found that structurally diverse ketones
successfully underwent this transformation resulting in good to
excellent yields of the desired products in short reaction times.
The applicability of the present protocol on a large scale was
investigated by its application for the model reaction under the
27
38
1
45
1.4
1.6
1.6
1.7
2
55
65
75
85
5h
5i
98
2
77
108
119
127
139
149
15
16
5j
5k
5l
5m
5n
5o
5p
1.3
1.3
1.2
1
1.5
2
91
87
88
93
75
74
1.3
90
aAll products were characterised by 1H and 13C NMR, IR, CHN, and MS analysis.
bIsolated yield.
optimised reaction conditions on a 50 mmol scale which led to
the formation of 5a in 90% yield.
We also studied the reusability of doped nano-Cu2O–MFR
under the optimised reaction conditions (Table 3). The ease
of recovery, chemical and thermal stability of nano-Cu2O–
MFR allows it to be a recyclable and reusable catalyst which
can be efficiently applied for at least 7 reaction runs (Table 3).
According to the ICP analysis, the amount of leached copper
from nano-Cu2O–MFR is 0.0016% after seven consecutive runs
which is essentially negligible.
It is well-established that 1,4-dihydropyridines (1,4-DHPs)
are obtained as the main intermediates in the 4CR of aldehydes,
ketones, malononitrile, and ammonium acetate and then their
subsequent oxidation leads to the formation of the corresponding
pyridine derivatives.1 In the present protocol, the reaction was
performed in an open flask under an air atmosphere. Thus,
oxidative aromatisation of the 1,4-DHPs efficiently affords the
desired pyridine derivatives.

JOURNAL OF CHEMICAL RESEARCH 2016 543
1
Table 3 The reusability of nano-Cu2O–MFR
3037, 2204, 1621, 1566, 1454; H NMR (CDCl3, 250 MHz) δ 5.68 (s,
Runa
1
Time/h
1
Yieldb/%
92
92
91
91
90
89
89
2H, NH2), 7.21 (s, 1H, pyridine–H5), 7.45–7.61 (m, 8H, ArH), 7.73
(d, J = 8.1 Hz, 2H, ArH); 13C NMR (CDCl3, 62.5 MHz) δ 92.4, 109.8,
115.0, 115.9, 126.7, 127.3, 128.1, 128.7, 129.5, 130.4, 135.1, 154.9, 157.8,
160.4; MS (EI) m/z (%): 271 (11.5) [M]+; Anal. calcd for C18H13N3: C,
79.68; H, 4.83; N, 15.49; found: C, 79.76; H, 4.95; N, 15.57%.
2-Amino-4-(4-chlorophenyl)-6-phenylnicotinonitrile (5b): Pale
yellow solid; yield 94%; m.p. 192–193 °C (lit.7 190 °C); IR (νmax/cm–1):
3400, 3267, 3050, 2201, 1624, 1576, 1470, 1078; 1H NMR (CDCl3, 250
MHz) δ 5.71 (s, 2H, NH2), 7.18 (s, 1H, pyridine–H5), 7.27–7.36 (m, 7H,
ArH), 7.51 (d, J = 8.3 Hz, 2H, ArH); 13C NMR (CDCl3, 62.5 MHz) δ
91.8, 109.1, 114.8, 115.6, 127.3, 128.0, 128.7, 130.6, 134.0, 135.2, 136.1,
153.9, 157.8, 160.7; MS (EI) m/z (%): 271 (14.8) [M]+; Anal. calcd for
C18H12ClN3: C, 70.71; H, 3.96; N, 13.74; found: C, 70.85; H, 4.07; N,
13.82%.
2
1
3
1
4
5
6
7
1.1
1.1
1.3
1.3
aThe entry number corresponds to the trial number.
bIsolated yield.
In conclusion, we have described a direct and simple one-pot
procedure for synthesis of 2-amino-3-cyanopyridins via four-
component reaction of aldehydes, ketones, malononitrile, and
ammonium acetate in refluxing H2O/EtOH (1:1) in the presence
of doped nano-Cu2O–MFR as a highly efficient heterogeneous
catalyst. In this protocol, structurally diverse aldehydes and
ketones were used successfully to afford the desired pyridine
derivatives in good to excellent yields. The nano-Cu2O–MFR
is a cheap and stable heterogeneous nano-catalyst that could be
simply prepared, recovered, and reused for many reaction runs
without considerable reduction in activity.
2-Amino-6-phenyl-4,4’-bipyridine-3-carbonitrile (5c): White solid;
yield 93%; m.p. 217–218 °C (lit.8 215–218 °C); IR (νmax/cm–1): 3360,
1
3280, 3037, 2214, 1629, 1571, 1456; H NMR (DMSO-d6, 250 MHz)
δ 5.93 (s, 2H, NH2), 7.24–7.50 (m, 6H, ArH), 7.69–7.74 (m, 4H, ArH);
13C NMR (DMSO-d6, 62.5 MHz) δ 95.2, 110.9, 113.8, 123.8, 126.0,
127.1, 130.5, 138.7, 145.0, 149.6, 152.1, 156.7, 163.4; MS (EI) m/z (%):
272 (17.5) [M]+; Anal. calcd for C17H12N4: C, 74.98; H, 4.44; N, 20.58;
found: C, 75.04; H, 4.51; N, 20.67%.
2-Amino-6-phenyl-4-(thiophen-3-yl)nicotinonitrile (5d): White
solid; yield 89%; m.p. 212–213 °C (lit.5 213–214 °C); IR (νmax/cm–1):
3400, 3304, 3025, 2213, 1643, 1575, 1450; 1H NMR (CDCl3, 250 MHz)
δ 5.48 (s, 2H, NH2), 7.12 (s, 1H, pyridine-H5), 7.31–7.38 (m, 6H, ArH),
7.54 (d, J = 8.0 Hz, 1H, thiophene-H5), 7.85 (s, 1H, thiophene-H2);
13C NMR (CDCl3, 62.5 MHz) δ 94.0, 111.6, 119.8, 121.5, 126.8, 127.9,
128.7, 129.2, 131.1, 132.9, 138.3, 152.6, 157.2, 162.0; MS (EI) m/z (%):
277 (21.6) (M +); Anal. calcd for C16H11N3S: C, 69.29; H, 4.00; N, 15.15;
Found: C, 69.38; H, 4.13; N, 15.26%.
2-Amino-4-methyl-6-phenylnicotinonitrile (5e): White solid; yield
80%; m.p. 121–122 °C (lit.5 121–122 °C); IR (νmax/cm–1): 3455, 3349,
3060, 2985, 2213, 1635, 1558, 1461; 1H NMR (CDCl3, 250 MHz) δ 2.29
(s, 3H, CH3), 5.37 (s, 2H, NH2), 7.15 (s, 1H, pyridine-H5), 7.24–7.31
(m, 3H, ArH), 7.72–7.78 (m, 2H, ArH); 13C NMR (CDCl3, 62.5 MHz)
δ 22.0, 93.7, 114.6, 117.8, 127.0, 128.2, 129.7, 136.4, 152.9, 157.0, 161.8;
MS (EI) m/z (%): 209 (18.7) [M]+; Anal. calcd for C13H11N3: C, 74.62;
H, 5.30; N, 20.08; found: C, 74.53; H, 5.36; N, 20.17%.
2-Amino-6-(naphthalen-2-yl)-4-phenylnicotinonitrile (5f): White
solid; yield 87%; m.p. 169–170 °C (lit.5 171–172 °C); IR (νmax/cm–1):
3460, 3353, 3081, 2210, 1658, 1546, 1459; 1H NMR (CDCl3, 250 MHz)
δ 5.26 (s, 2H, NH2), 7.11 (s, 1H, pyridine-H5), 7.29–7.37 (m, 4H, ArH),
7.57–7.65 (m, 4H, ArH), 7.80–7.86 (m, 3H, ArH), 8.23 (s, 1H, ArH);
13C NMR (CDCl3, 62.5 MHz) δ 95.4, 112.0, 118.1, 124.6, 126.1, 127.0,
127.6, 128.0, 128.5, 128.8, 129.2, 129.7, 130.2, 130.8, 133.8, 134.5,
136.3, 154.7, 158.0, 162.7; MS (EI) m/z (%): 321 (25.8) [M]+; Anal.
calcd for C22H15N3: C, 82.22; H, 4.70; N, 13.08; found: C, 82.35; H,
4.79; N, 12.98%.
Experimental
All chemical reagents were purchased from either Fluka or Merck.
Nano-Cu2O–MFR was prepared due to the established procedure.6
Solvents were purified by standard procedures, and stored over 3Å
molecular sieves. Reactions were followed by TLC using SILG/UV
254 silica gel plates. Column chromatography was performed on silica
gel 60 (0.063–0.200 mm, 70-230 mesh; ASTM). Melting points were
measured using Electrothermal IA 9000 melting point apparatus in
open capillary tubes and are uncorrected. IR spectra were obtained
1
using a Shimadzu FTIR-8300 spectrophotometer. H and 13C NMR
spectra were recorded on Brüker Avance-DPX-250/400 spectrometer
operating at 250/62.5 MHz, respectively. Chemical shifts are given in
δ relative to tetramethylsilane (TMS) as an internal standard, coupling
constants J are given in Hz. GC/MS was performed on a Shimadzu
GC/MS-QP 1000-EX apparatus (m/z; rel.%). Elemental analyses were
performed on a Perkin–Elmer 240-B micro-analyser.
Synthesis of 2-amino-3-cyanopyridines using nano-Cu2O–MFR;
general procedure
In a two-neck round-bottom flask (50 mL) equipped with a condenser
was added a mixture of aldehyde (10 mmol), ketone (10 mmol),
malononitrile (13 mmol), ammonium acetate (15 mmol), and nano-
Cu2O–MFR (0.3 g, 0.072 mol%) in refluxing H2O/EtOH (1:1). After
completion of the reaction as indicated by TLC monitoring (Table 2),
the reaction mixture was vacuum-filtered using a sintered-glass
funnel and the residue was washed with hot EtOH (2 × 10 mL). The
filtrate was then evaporated under vacuum to remove the solvent. The
remaining foam was dissolved in CHCl3 (100 mL) and subsequently
washed with water (2 × 100 mL). Afterward, the organic layer was
dried over anhydrous sodium sulfate and evaporated. The crude
product was purified by short column chromatography on silica gel
eluting with n-hexane:EtOAc.
2-Amino-6-methyl-4-phenylnicotinonitrile (5g): White solid; yield
85%; m.p. 189–190 °C (lit.5 188–189 °C); IR (νmax/cm–1): 3465, 3340,
1
3036, 2955, 2214, 1652, 1552, 1475; H NMR (CDCl3, 250 MHz) δ
2.32 (s, 3H, CH3), 5.65 (s, 2H, NH2), 7.21-7.26 (m, 4H, ArH), 7.53–7.60
(m, 2H, ArH); 13C NMR (CDCl3, 62.5 MHz) δ 24.9, 92.8, 109.1, 115.6,
127.7, 128.3, 129.7, 136.8, 152.9, 158.5, 161.3; MS (EI) m/z (%): 209
(13.7) [M]+; Anal. calcd for C13H11N3: C, 74.62; H, 5.30; N, 20.08;
found: C, 74.76; H, 5.38; N, 20.19%.
2-Amino-6-tert-butyl-4-phenylnicotinonitrile (5h): White solid;
yield 82%; m.p. 168–169 °C (lit.5 169–170 °C); IR (νmax/cm–1): 3427,
3361, 3050, 2949, 2211, 1658, 1541, 1443; 1H NMR (CDCl3, 250 MHz)
δ 1.34 (s, 9H, 3 × CH3), 5.21 (s, 2H, NH2), 7.05 (s, 1H, pyridine-H5),
7.48–7.56 (m, 5H, ArH); 13C NMR (CDCl3, 62.5 MHz) δ 30.73, 35.29,
92.6, 108.5, 115.7, 127.4, 128.1, 129.0, 136.8, 153.6, 159.1, 160.7; MS
(EI) m/z (%): 251 (18.3) [M]+; Anal. calcd for C16H17N3: C, 76.46; H,
6.82; N, 16.72; found: C, 76.58; H, 6.90; N, 16.81%.
Recycling the catalyst
After completion of the reaction, the catalyst was vacuum-filtered
from the reaction mixture using a sintered glass funnel followed by
successive washing with hot EtOH (2 × 10 mL). The catalyst was then
kept in a vacuum oven at 100 °C for 30 minutes and stored in a sealed
vessel in a refrigerator.
2-Amino-4,6-diphenylnicotinonitrile (5a): Pale yellow solid;
yield 92%; m.p. 186–187 °C (lit.7 186 °C); IR (νmax/cm–1): 3427, 3304,
2-Amino-4-(2-chlorophenyl)-6-(4-hydroxyphenyl)nicotinonitrile
(5i): White solid; yield 77%; m.p. 193–194 °C (lit.8 194–196 °C); IR

544 JOURNAL OF CHEMICAL RESEARCH 2016
(νmax/cm–1): 3450, 3370, 3218, 3049, 2219, 1652, 1564, 1471, 1082;
1H NMR (DMSO-d6, 250 MHz) δ 6.21 (s, 2H, NH2), 7.10 (s, 1H,
pyridine-H5), 7.36–7.41 (m, 4H, ArH), 7.57–7.62 (m, 2H, ArH), 7.82
(d, J = 8.4 Hz, 2H, ArH), 9.98 (s, 1H, OH); 13C NMR (DMSO-d6, 62.5
MHz) δ 94.0, 109.7, 116.1, 117.8, 124.9, 127.2, 128.0, 128.5, 129.3,
130.7, 132.3, 136.6, 154.4, 158.9, 160.8, 162.5; MS (EI) m/z (%): 321
(25.1) [M]+; Anal. calcd for C18H12ClN3O: C, 67.19; H, 3.76; N, 13.06;
found: C, 67.08; H, 3.85; N, 13.14%.
(CDCl3, 62.5 MHz) δ 21.7, 97.1, 112.8, 113.5, 117.9, 127.4, 129.0, 135.0,
139.2, 141.8, 145.4, 146.1, 148.2, 158.9, 162.7; MS (EI) m/z (%): 275
(16.8) [M]+; Anal. calcd for C17H13N3O: C, 74.17; H, 4.76; N, 15.26;
found: C, 74.26; H, 4.87; N, 15.17%.
2-Amino-6-(4-methoxyphenyl)-4-{2-[5-(2-methyl-4-nitro-1H-
imidazol-1-yl)pentyloxy] phenyl} nicotinonitrile (5o): Yellow foam;
yield 74%; IR (νmax/cm–1): 3400, 3376, 3100, 2969, 2218, 1664, 1552,
1
1539, 1470, 1348, 1124; H NMR (CDCl3, 250 MHz) δ 1.21–1.27
2-Amino-4-(3-bromophenyl)-6-(4-hydroxyphenyl)nicotinonitrile
(5j): White solid; yield 91%; m.p. 227–228 °C (lit.8 226–229 °C); IR
(νmax/cm–1): 3410, 3385, 3348, 3050, 2223, 1659, 1546, 1464, 1070;
1H NMR (DMSO-d6, 250 MHz) δ 6.29 (s, 2H, NH2), 7.21 (s, 1H,
pyridine-H5), 7.35–7.42 (m, 3H, ArH), 7.60 (d, J = 8.2 Hz, 2H, ArH),
7.81 (s, 1H, ArH), 7.98 (d, J = 8.2 Hz, 2H, ArH), 10.02 (s, 1H, OH);
13C NMR (DMSO-d6, 62.5 MHz) δ 91.8, 108.9, 115.7, 116.5, 123.0,
126.1, 127.2, 128.0, 129.1, 129.7, 130.4, 137.5, 156.2, 159.6, 161.3,
163.0; MS (EI) m/z (%): 366 (29.4) [M]+; Anal. calcd for C18H12BrN3O:
C, 59.03; H, 3.30; N, 11.47; found: C, 59.15; H, 3.38; N, 11.60%.
2-Amino-6-(4-bromophenyl)-4-p-tolylnicotinonitrile (5k): Yellow
solid; yield 87%; m.p. 236–237 °C (lit.9 235–237 °C); IR (νmax/cm–1):
3435, 3371, 3085, 2948, 2210, 1634, 1570, 1439, 1061; 1H NMR
(CDCl3, 250 MHz) δ 2.28 (s, 3H, CH3), 6.05 (s, 2H, NH2), 7.15 (s,
1H, pyridine-H5), 7.37 (d, J = 8.1 Hz, 2H, ArH), 7.50 (d, J = 8.3 Hz,
2H, ArH), 7.74 (d, J = 8.1 Hz, 2H, a ArH), 7.81–7.85 (m, 2H, ArH);
13C NMR (CDCl3, 62.5 MHz) δ 23.5, 91.3, 108.4, 117.6, 123.9, 127.8,
128.3, 129.0, 132.1, 134.0, 136.8, 138.1, 154.9, 158.0, 162.1; MS (EI)
m/z (%): 364 (23.3) [M]+; Anal. calcd for C19H14BrN3: C, 62.65; H,
3.87; N, 11.54; found: C, 62.54; H, 3.76; N, 11.60%.
(m, 2H, CH2), 1.86–1.93 (m, 4H, 2 × CH2), 2.45 (s, 3H, CH3), 3.47 (t,
J = 7.5 Hz, 2H, NCH2), 3.65 (s, 3H, OCH3), 3.82 (t, J = 7.5 Hz, 2H,
OCH2), 6.08 (s, 2H, NH2), 7.14 (s, 1H, pyridine-H5), 7.29–7.53 (m,
6H, ArH), 7.85 (s, 1H, imidazole-H5), 7.97 (d, J = 8.1 Hz, 2H, ArH);
13C NMR (CDCl3, 62.5 MHz) δ 15.8, 24.1, 29.7, 32.0, 48.1, 54.5, 67.0,
96.1, 112.0, 115.2, 116.8, 120.1, 120.8, 127.4, 128.1, 128.9, 129.2, 129.6,
136.8, 146.3, 150.9, 153.6, 156.7, 158.6, 160.2, 163.4; MS (EI) m/z
(%): 512 (27.4) [M]+; Anal. calcd for C28H28N6O4: C, 65.61; H, 5.51; N,
16.40; found: C, 65.70; H, 5.43; N, 16.52%.
2-Amino-4-[4-(2-phenoxyethoxy)phenyl]-6-phenylnicotinonitrile
(5p): Pale yellow oil; yield 90%; IR (νmax/cm–1): 3415, 3370, 3056,
1
2972, 2210, 1659, 1540, 1461, 1128; H NMR (CDCl3, 250 MHz) δ
3.97 (t, J = 7.3 Hz, 2H, OCH2), 4.12 (t, J = 7.3 Hz, 2H, OCH2), 5.91 (s,
2H, NH2), 7.17–7.41 (m, 4H, ArH), 7.50–7.56 (m, 3H, ArH), 7.80–7.87
(m, 4H, ArH), 7.91 (d, J = 8.1 Hz, 2H, ArH), 8.04 (d, J = 8.1 Hz, 2H,
ArH); 13C NMR (CDCl3, 62.5 MHz) δ 59.8, 60.1, 97.0, 110.3, 114.8,
115.3, 116.9, 120.1, 124.7, 126.9, 127.2, 128.0, 128.6, 129.9, 130.1, 138.1,
154.0, 156.6, 158.0, 162.5; MS (EI) m/z (%): 407 (23.6) [M]+; Anal.
calcd for C26H21N3O2: C, 76.64; H, 5.19; N, 10.31; found: C, 76.78; H,
5.27; N, 10.40%.
2-Amino-6-(4-chlorophenyl)-4-(4-methoxyphenyl)nicotinonitrile
(5l): Yellow solid; yield 88%; m.p. 175–176 °C (lit.7 177 °C); IR
(νmax/cm–1): 3410, 3365, 3100, 2941, 2215, 1653, 1568, 1457, 1126, 1080;
1H NMR (CDCl3, 250 MHz) δ 3.47 (s, 3H, CH3), 5.72 (s, 2H, NH2),
7.24 (s, 1H, pyridine-H5), 7.47–7.56 (m, 4H, ArH), 7.70 (d, J = 8.0 Hz,
2H, ArH), 7.83 (m, 2H, ArH); 13C NMR (CDCl3, 62.5 MHz) δ 58.2,
94.0, 108.9, 114.3, 115.6, 127.2, 127.9, 128.4, 129.0, 129.7, 130.8, 134.7,
153.9, 158.0, 162.6; MS (EI) m/z (%): 335 (27.1) [M]+; Anal. calcd for
C19H14ClN3O: C, 67.96; H, 4.20; N, 12.51; found: C, 67.82; H, 4.27; N,
12.64%.
2-Amino-4,6-bis(4-chlorophenyl)nicotinonitrile (5m): Yellow
solid; yield 93%; m.p. 248–249 °C (lit.9 248–250 °C); IR (νmax/cm–1):
3400, 3352, 3064, 2207, 1657, 1535, 1426, 1088; 1H NMR (CDCl3, 250
MHz) δ 5.78 (s, 2H, NH2), 7.19 (s, 1H, pyridine-H5), 7.25–7.33 (m, 4H,
ArH), 7.69–7.76 (m, 4H, ArH); 13C NMR (CDCl3, 62.5 MHz) δ 95.7,
110.5, 116.9, 126.3, 127.7, 128.0, 128.8, 129.4, 130.0, 132.1, 136.6,
154.1, 158.8, 162.9; MS (EI) m/z (%): 340 (31.4) [M]+; Anal. calcd for
C18H11Cl2N3: C, 63.55; H, 3.26; N, 12.35; found: C, 63.64; H, 3.37; N,
12.41%.
The author is grateful to Shiraz University of Technology
Research Council for partial support of this work.
Received 29 May 2016; accepted 4 July 2016
Paper 1604121 doi: 10.3184/174751916X14709292404728
Published online: 26 August 2016
References
1
2
3
C. Allais, J.–M. Grassot, J. Rodriguez and T. Constantieux, Chem. Rev.,
2014, 114, 10829.
M.A. Gouda, M.A. Berghot, G.E. Abd El Ghania and Abd El-Galil M.
Khalil, Synth. Commun., 2014, 44, 297.
J. Zhu and H. Bienyamé, Multicomponent reactions, Wiley-VCH,
Weinheim, 2005.
4
5
6
M.J. Climent, A. Corma and S. Iborra, RSC Adv., 2012, 2, 16.
R. Khalifeh and M. Ghamari, J. Braz. Chem. Soc., 2016, 27, 759.
M.N. Soltani Rad, S. Behrouz, A. Movahedian, M.M. Doroodmand, Y.
Ghasemi, S. Rasoul–Amini, A.–R. Ahmadi Gandomani and R. Rezaiee,
Helv. Chim. Acta, 2013, 96, 688.
7
8
9
R. Gupta, A. Jain, M. Jain and R. Joshi, Bull. Korean Chem. Soc., 2010,
31, 3180.
J. Safari, S.H. Banitaba and S. Dehghan Khalili, Ultrason. Sonochem.,
2012, 19, 1061.
R. Ghorbani–Vaghei, Z. Toghraei–Semiromi and R. Karimi–Nami, C. R.
Chim., 2013, 16, 1111.
2-Amino-4-(furan-2-yl)-6-p-tolylnicotinonitrile (5n): Pale yellow
solid; yield 75%; m.p. 147–148 °C (lit.9 149–151 °C); IR (νmax/cm–1):
3407, 3359, 3050, 2947, 2205, 1651, 1545, 1463 cm–1; 1H NMR (CDCl3,
250 MHz) δ 2.41 (s, 3H, CH3), 5.93 (s, 2H, NH2), 7.18–7.26 (m, 3H,
ArH), 7.40–7.46 (m, 2H, ArH), 7.79–7.85 (m, 2H, ArH); 13C NMR