One-pot synthesis of 2-amino-3-cyanopyridine derivatives under solvent-free conditions

Article abstract of DOI:10.1016/j.crci.2013.06.006

A series of 2-amino-3-cyanopyridines were obtained from aryl aldehydes, substituted acetophenones, malononitrile and ammonium acetate in good to excellent yields by proceeding through a simple, mild and efficient procedure utilizing N,N,N′,N′-tetrabromobe

Full text of DOI:10.1016/j.crci.2013.06.006

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CRAS2C-3785; No. of Pages 7
C. R. Chimie xxx (2013) xxx–xxx
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´
Full paper/Memoire
One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions
a
b
Ramin Ghorbani-Vaghei a, , Zahra Toghraei-Semiromi , Rahman Karimi-Nami
*
a Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, 65174 Hamedan, Iran
b School of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of 2-amino-3-cyanopyridines were obtained from aryl aldehydes, substituted
acetophenones, malononitrile and ammonium acetate in good to excellent yields by
proceeding through a simple, mild and efficient procedure utilizing N,N,N0,N0-tetra-
bromobenzene-1,3-disulfonamide [TBBDA] and poly(N-bromo-N-ethylbenzene-1,3-dis-
ulfonamide) [PBBS] as catalysts.
Received 5 March 2013
Accepted after revision 3 June 2013
Available online xxx
Keywords:
ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
2-Amino-3-cyanopyridine
Multicomponent reaction
Aldehyde
Ketone
Malononitrile
Ammonium acetate
Solvent-free
TBBDA
PBBS
1. Introduction
or toluene as the solvent [7,10], microwave assistance [11],
resulting in unsatisfactorily low yields. Due to the
Heteroaromatic rings containing nitrogen atoms often
play important roles as the scaffolds of bioactive sub-
stances. [1] The pyridine ring system is one of the most
popular N-heteroaromatics incorporated into the structure
of many pharmaceuticals. Among them, 2-amino-3-
cyanopyridine derivatives are known to have multiple
biological activities, such as anti-microbial [2], cardiotonic,
[3] anti-inflammatory [4,5], anti-parkinsonism [6] and
anti-tumor properties. [7] Also, they have been identified
interesting properties of pyridines, the development of
synthetic methods that enable a facile access to these
heterocycles is desirable.
2. Experimental
All commercially available chemicals were obtained
from Merck and Fluka companies, and used without
further purification unless otherwise stated. Nuclear
magnetic resonance (NMR) spectra were recorded in
DMSO-d6 on Bruker Avance 300 MHz FT and Varian
90 MHz NMR spectrometers using TMS as an internal
standard. Chemical shifts were expressed in parts per
million (ppm). Infrared (IR) spectroscopy was conducted
on a PerkinElmer GX FT–IR spectrometer. Mass spectra
were recorded on a Shimadzu QP 1100 BX Mass Spectro-
meter. Elemental analyses (C, H, N) were performed with a
Heraeus CHN-O-Rapid analyzer.
as novel IKK-
b inhibitors [4], A2A adenosine receptor
antagonists [6] and potent inhibitor of HIV-1 integrase
(Fig. 1) [8]. Despite the existence of extensive literature for
the synthesis of 2-amino-3-cyanopyridines, the most
common procedures need multiple steps [9], toxic benzene
*
Corresponding author.
E-mail address: rgvaghei@yahoo.com (R. Ghorbani-Vaghei).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.06.006
Please cite this article in press as: Ghorbani-Vaghei R, et al. One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.06.006

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H
N
OEt
R1
R
N
NC
H2N
Br
O
NC
H2N
R1
N
Br
R3
N
NC
NC
NC
CN
S
N
OMe
Br
H2N
N
H2N
R2
R
Br
H2N
N
R2
HO
O
O
a
b
c
d
e
Fig. 1. a: anti-tumor; b: anti-microbial; c: novel IKK-
b inhibitors; d: A2A adenosine receptor antagonists; e: HIV-1 integrase.
2.1. General procedure for the synthesis of 2-amino-3-
cyanopyridines
C18H11Cl2N3: C, 63.55; H, 3.26; N, 12.35. Found: C, 63.86; H,
2.89; N, 12.46. MS: m/z 339 (Table 1, 5c).
A mixture of aldehyde (2 mmol), substituted acetophe-
none (2 mmol), malononitrile (2 mmol), ammonium acet-
ate (2.5 mmol) and TBBDA or PBBS (0.05 g) was heated
under stirring at 100 8C for appropriate times (Table 1). The
progress of the reaction was monitored by TLC (10:4, n-
hexane/acetone). After completion of the reaction, the
reaction mixture was allowed to cool to room temperature,
and 95% cold EtOH (5 mL) was added. The precipitate was
filtered off and washed with cold ethanol. After drying, the
pure product was obtained. Removal of the solvent under
reduced pressure gave back the catalysts.
2.2.4. 2-Amino-6-(4-fluorophenyl)-4-p-tolylnicotinonitrile
Yellow solid, mp: 198–200 8C. IR (KBr): 3495, 3394,
2207, 1610, 1583, 1549, 1510, 1223, 1161, 819 cmꢀ1 1H
;
NMR (90 MHz, DMSO-d6):
(s, NH2, 2H), 7.29–8.18 (m, CH aromatic, 9H). 13C NMR
(75 MHz, DMSO-d6): c (ppm) 21.33, 86.91, 109.36, 115.84,
dH (ppm) 2.38 (s, CH3, 3H), 6.95
d
116.13, 117.59, 128.72, 129.73, 129.96, 130.08, 134.49,
139.85, 155.40, 157.86, 161.31, 162.19. Anal. calcd for
C
19H14FN3: C, 75.23; H, 4.65; N, 13.85. Found: C, 75.23; H,
4.16; N, 13.61. MS: m/z 303 (Table 1, 5d).
2.2.5. 2-Amino-6-(4-bromophenyl)-4-p-tolylnicotinonitrile
Yellow solid, mp: 235–237 8C. IR (KBr): 3496, 3391,
2207, 1608, 1583, 1547, 1009, 815 cmꢀ1; 1H NMR (90 MHz,
DMSO-d6): dH (ppm) 2.40 (s, CH3, 3H), 7.02 (s, NH2, 2H),
7.30–8.13 (m, CH aromatic, 9H). 13C NMR (75 MHz, DMSO-
2.2. Physical and spectroscopic data
2.2.1. 2-Amino-4,6-bis(3-chlorophenyl)nicotinonitrile
Cream solid, mp: 170–173 8C. IR (KBr): 3435, 33.9,
3215, 2210, 1646, 1567, 1477, 1081, 784 cmꢀ1
;
1H NMR
d6): dc (ppm) 21.34, 87.34, 109.47, 117.53, 124.24, 128.73,
(90 MHz, DMSO-d6):
d
H (ppm) 7.11 (s, NH2, 2H), 7.57–8.19
129.73, 132.05, 134.41, 137.20, 139.89, 155.49, 157.70,
161.32. Anal. calcd for C19H14BrN3: C, 62.65; H, 3.87; N,
11.54. Found: C, 62.75; H, 3.41; N, 11.29. MS: m/z 363
(Table 1, 5e).
(m, CH aromatic, 9H). 13C NMR (75 MHz, DMSO-d6): dc
(ppm) 87.72, 109.89, 117.05, 126.35, 127.41, 127.69,
128.70, 129.96, 130.34, 130.99, 133.87, 134.13, 139.23,
139.95, 154.03, 157.46, 161.15. Anal. calcd for
C
18H11Cl2N3: C, 63.55; H, 3.26; N, 12.35. Found: C,
2.2.6. 2-Amino-6-(4-fluorophenyl)-4-(4-
methoxyphenyl)nicotinonitrile
63.93; H, 2.95; N, 12.21. MS: m/z 339 (Table 1, 5a).
Brown solid, mp: 186–189 8C. IR (KBr): 3491, 3390,
2.2.2. 2-Amino-4-(3-chlorophenyl)-6-(4-
chlorophenyl)nicotinonitrile
2209, 1609, 1584, 1548, 1509, 1220, 826 cmꢀ1 1H NMR
;
(90 MHz, DMSO-d6): dH (ppm) 3.82 (s, CH3, 3H), 6.94–7.69
Yellow solid, mp: 222–224 8C. IR (KBr): 3449, 3327,
(m, CH aromatic, 9H), 8.07 (s, NH2, 2H). 13C NMR (75 MHz,
DMSO-d6): dc (ppm) 55.78, 86.81, 109.48, 114.59, 117.83,
127.68, 129.07, 129.52, 130.32, 130.47, 138.11, 154.92,
158.92, 160.86, 161.44. Anal. calcd for C19H14FN3O: C,
71.46; H, 4.42; N, 13.16. Found: C, 71.08; H, 4.16; N, 13.25.
MS: m/z 319 (Table 1, 5f).
3214, 2209, 1639, 1568, 1549, 1481, 1082, 786 cmꢀ1 1H
;
NMR (90 MHz, DMSO-d6): dH (ppm) 7.09 (s, NH2, 2H), 7.35–
8.23 (m, CH aromatic, 9H). 13C NMR (75 MHz, DMSO-d6): dc
(ppm) 87.28, 109.60, 117.18, 127.62, 128.65, 129.08,
129.50, 129.92, 130.98, 133.88, 135.50, 136.63, 139.28,
153.85, 157.87, 161.19. Anal. calcd for C18H11Cl2N3: C,
63.55; H, 3.26; N, 12.35. Found: C, 63.71; H, 2.97; N, 12.16.
MS: m/z 339 (Table 1, 5b).
2.2.7. 2-Amino-6-(4-fluorophenyl)-4-(3-
methoxyphenyl)nicotinonitrile
Brown solid, mp: 172–174 8C. IR (KBr): 3475, 3378,
2.2.3. 2-Amino-4,6-bis(4-chlorophenyl)nicotinonitrile
2207, 1634, 1601, 1575, 1510, 1258, 834 cmꢀ1 1H NMR
;
Yellow solid, mp: 248–250 8C. IR (KBr): 3507, 3701,
(90 MHz, DMSO-d6): dH (ppm) 3.83 (s, CH3, 3H), 7.01 (s,
2204, 1614, 1578, 1567, 1549, 1088, 829 cmꢀ1
;
1H NMR
NH2, 2H), 7.21–8.27 (m, CH aromatic, 9H). 13C NMR
(90 MHz, DMSO-d6):
d
H (ppm) 7.06 (s, NH2, 2H), 7.35–8.24
(75 MHz, DMSO-d6): dc (ppm) 55.74, 87.09, 109.49, 114.26,
(m, CH aromatic, 9H). 13C NMR (75 MHz, DMSO-d6): dc
(ppm) 87.65, 109.86, 117.09, 126.36, 127.41, 127.71,
128.72, 129.74, 129.97, 130.36, 130.99, 133.86, 134.12,
139.22, 139.93, 154.03, 157.43, 161.16. Anal. calcd for
115.83, 116.12, 117.43, 120.98, 130.01, 130.12, 130.34,
134.48, 138.67, 155.27, 157.96, 159.75, 161.23. Anal. calcd
for C19H14FN3O: C, 71.46; H, 4.42; N, 13.16. Found: C,
71.28; H, 4.30; N, 13.09. MS: m/z 319 (Table 1 5g).
Please cite this article in press as: Ghorbani-Vaghei R, et al. One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.06.006

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3
Table 1
Synthesis of 2-amino-3-cyanopyridine derivatives.
R
O
NC
CHO
TBBDA or PBBS
R′
NC
CN
R
NH4OAc
H2N
Solvent-free, 100 ºC
N
R′
1
2
3
4
5(a-k)
Br
N
Br
N Br
Br
N
Br
N
Br
S
S
(
)
S
S
CH2CH2
n
O O
O O
O O
O O
PBBS
TBBDA
Entry
A
B
Product
TBBDA
Time (min)
10
PBBS
Mp (8C)
CHO
Yield (%)
90
Time (min)
10
Yield (%)
85
5a
170–173
O
Cl
Cl
Cl
NC
Cl
H2N
N
5b
10
92
10
80
222–224
CHO
O
Cl
Cl
Cl
NC
H2N
N
Cl
5c
5
94
5
90
248–250
O
CHO
Cl
Cl
Cl
NC
H2N
N
Cl
5d
30
90
40
90
198–200
CHO
O
F
NC
H2N
N
F
5e
30
88
40
85
235–237
O
CHO
Br
NC
H2N
N
Br
Please cite this article in press as: Ghorbani-Vaghei R, et al. One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.06.006

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Table 1 (Continued )
Entry
A
B
Product
TBBDA
Time (min)
25
PBBS
Mp (8C)
Yield (%)
94
Time (min)
25
Yield (%)
90
5f
186–189
CHO
OMe
OMe
O
F
NC
H2N
N
F
5g
15
86
15
85
172–174
O
O
OMe
MeO
F
NC
H2N
N
F
5h
35
85
40
85
235–237
O
O
OMe
MeO
MeO
MeO
OMe
F
OMe
NC
H2N
N
F
5i
10
89
10
85
207–210
CHO
Cl
O
Cl
NC
F
H2N
N
F
F
5j
15
85
15
79
269–273
CHO
O
N
F
O
NC
H2N
N
N
5k
25
89
25
80
149–151
O
O
CHO
NC
H2N
N
2.2.8. 2-amino-6-(4-fluorophenyl)-4-(3,4,5-
trimethoxyphenyl)nicotinonitrile
2.2.9. 2-amino-4-(3-chlorophenyl)-6-(4-
fluorophenyl)nicotinonitrile
Cream solid, mp: 235–237 8C. IR (KBr): 3497, 3370,
2213, 1635, 1555, 1508, 1130, 811 cmꢀ1; 1H NMR (90 MHz,
DMSO-d6): dH (ppm) 3.74 (s, CH3, 3H), 3.86 (s, CH3, 6H),
6.99–8.21 (m, CH aromatic and NH2, 11H). 13C NMR
Cream solid, mp: 207–210 8C. IR (KBr): 3513, 3409,
2204, 1646, 1579, 1512, 1159, 834 cmꢀ1; 1H NMR (90 MHz,
DMSO-d6):
d
H (ppm) 6.83–8.19 (m, CH aromatic and NH2,
c (ppm) 86.88, 94.50,
11H). 13C NMR (75 MHz, DMSO-d6):
d
(75 MHz, DMSO-d6):
d
c (ppm) 56.53, 60.56, 87.01, 106.47,
109.46, 115.87, 116.13, 118.97, 127.64, 128.66, 129.77,
130.06, 131.00, 133.86, 139.36, 148.61, 153.81, 154.49,
158.10, 161.19. Anal. calcd for C18H11ClFN3: C, 66.78; H,
3.42; N, 12.98. Found: C, 67.33; H, 3.16; N, 12.20. MS: m/z
323 (Table 1 5i).
109.42, 115.85, 116.13, 117.71, 130.02, 130.14, 132.63,
134.52, 138.91, 153.31, 155.36, 157.80, 161.27. Anal. calcd
for C21H18FN3O3: C, 66.48; H, 4.78; N, 11.08. Found: C,
66.18; H, 4.54; N, 10.62. MS: m/z 379 (Table 1 5h).
Please cite this article in press as: Ghorbani-Vaghei R, et al. One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.06.006

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Scheme 1. One-pot synthesis of 2-amino-3-cyanopyridine derivatives.
6.98 (s, NH2,2H), 7.31–7.33 (d, CH, 2H), 7.52–7.53 (d, CH,
2H), 8.01–8.04 (m, CH, 3H). 13C NMR (100 MHz, DMSO-d6):
dc (ppm) 20.90, 103.95, 112.72, 113.00, 117.30, 127.00,
129.26, 134.63, 139.97, 141.18, 145.45, 145.46, 148.72,
158.7, 161.14. Anal. calcd for C17H13N3O: C, 74.17; H, 4.76;
N, 15.26. Found: C, 74.72; H, 4.56; N, 15.58. MS: m/z 275
(Table 1 5k).
2.2.10. 2-amino-4-(4-fluorophenyl)-6-(pyridin-3-
yl)nicotinonitrile
Cream solid, mp: 269–273 8C. IR (KBr):3476, 3362, 2215,
1650, 1578, 1514, 1193, 838 cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6): dH (ppm) 6.96 (s, CH, 1H), 7.03 (s, NH2,2H), 7.42–
7.47 (t, CH, 2H), 7.61–7.65 (m, CH, 1H), 7.77–7.80 (m, CH,
3H), 8.14–8.17 (m, CH, 1H), 8.76–8.77 (m, CH, 1H). 13C NMR
(100 MHz, DMSO-d6): dc (ppm) 115.55, 115.77, 115.81,
118.58, 123.51, 130.97, 131.06, 133.28, 133.97, 146.58,
148.79, 149.01, 150.28,153.96,154.03, 161.59,164.05. Anal.
calcd for C17H11FN4: C, 70.34; H, 3.82; N, 19.30. Found: C,
70.06; H, 3.99; N, 19.58. MS: m/z 290 (Table 1 5j).
3. Results and discussion
In continuation of our interest in the application of
N,N,N0,N0-tetrabromobenzene-1,3-disulfonamide [TBBDA]
and
poly(N-bromo-N-ethylbenzene-1,3-disulfonamide)
[PBBS] [12] in organic synthesis [13–22], we report a
new and efficient method for the one-pot synthesis of 2-
amino-3-cyanopyridine derivatives by the condensation of
substituted acetophenone with various arylaldehydes,
malononitrile and ammonium acetate in the presence of
2.2.11. 2-amino-4-(furan-2-yl)-6-p-tolylnicotinonitrile
Cream solid, mp: 149–151 8C. IR (KBr): 3477, 3311, 2204,
1642, 1542, 1508, 1264, 805 cmꢀ1 1H NMR (400 MHz,
;
DMSO-d6):dH (ppm)2.38(s, CH3, 3H), 6.78–6.80(m, CH,1H),
Table 2
Reaction times and yields in various conditions.
Cl
O
NC
CHO
TBBDA or PBBS
Solvent-free, 100 ºC
NC
CN
NH4OAc
H2N
N
Cl
Cl
Cl
Entry
Catalyst
Solvent
Amount of catalyst (mol%)
Temperature
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
None
Ethanol
–
Reflux
Reflux
Reflux
Reflux
Reflux
100 8C
100 8C
100 8C
720
720
720
720
90
38
ZnCl2
Ethanol
12.83
13.12
9.22
4.53
4.53
3.62
6.34
36
AlCl3
Ethanol
18
SnCl2
Ethanol
34
TBBDA
TBBDA
TBBDA
TBBDA
Ethanol
80
Solvent-free
Solvent-free
Solvent-free
10
92 (92, 90, 89)b
10
88
90
20
a
Isolated yield.
b
The catalyst was reused for three times.
Please cite this article in press as: Ghorbani-Vaghei R, et al. One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.06.006

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TBBDA
NC
O
Br
O
Br
Br
N
O
H
N Br
Br
+
H
S
S
O
O
O
R
R
CN
Br
N
NH
R'
CN
CN
CN
R
Br
R
TBBDA
R'
N
C
NH2
CN
CH2
R'
H
N
NH
CN
R
O
R'
CH3
NH4OAc
+
R
TBBDA
Br
R'
R'
H
N
R'
H
N
NH2
CN
NH2
CN
N
N
H
CN
TBBDA
H
TBBDA
R
R
R
Scheme 2. Suggested mechanism for the synthesis of 2-amino-3-cyanopyridine derivatives.
TBBDA and PBBS as the efficient catalysts at 100 8C in good
yields, as shown in Scheme 1.
Surprisingly, while para-substituted, the meta-substituted
aromatic aldehydes, the heteroaromatic aldehyde and the
heteroaromatic ketone gave 2-amino-3-cyanopyridines in
good to excellent yields, the ortho-substituted aromatic
aldehydes, the aliphatic aldehyde (hexanale) and the
aliphatic ketone (acetone) gave no products. Obviously,
the reactivity of aldehydes is the key factor for this one-pot
transformation.
Mechanistically, it is likely that these catalysts release
Br+ in situ, which can act as an electrophilic species and the
mechanism shown in Scheme 2 is proposed for the
synthesis of 2-amino-3-cyanopyridine derivatives [17,20].
Initially, we decided to examine various catalysts for the
synthesis of 2-amino-4,6-bis(4-chlorophenyl)nicotinoni-
trile as a model compound (Table 2). We investigated the
effects of various catalysts, including ZnCl2, SnCl2, AlCl3 and
N,N,N0,N0-tetrabromobenzene-1,3-disulfonamide [TBBDA]
under various conditions. The results are summarized in
Table 2. The reaction without catalyst provided little
amounts of product (Table 2, Entry 1). The best result in
ethanol was achieved using N,N,N0,N0-tetrabromobenzene-
1,3-disulfonamide (Table 2, entry 5). In recent years, the
synthesis of compounds under solvent-free conditions is an
importantchallenge inheterocyclic synthesis. Therefore, we
decided to test this solvent-free reaction with various ratios
of TBBDA. We found that the reaction was rapid and gave
excellent yield of the product when using N,N,N0,N0-
tetrabromobenzene-1,3-disulfonamide [TBBDA] (10 min,
92%, Entry 6). In the light of this, subsequent studies were
carried out under the following optimized conditions, that
is, with 4.53 mol% TBBDA at 100 8C.
4. Conclusion
In conclusion, we have developed a simple procedure for
the synthesis of novel 2-amino-3-cyanopyridine derivatives
from the reaction of various aryl aldehydes, substituted
acetophenones, malononitrile and ammonium acetate in the
presence of TBBDA and PBBS as the catalysts under solvent-
free conditions. Moreover, the method has advantages in
terms of product yields, recyclable catalyst, operational
simplicity (easy work-up of reactions),environmental
These results encouraged us to investigate the scope
and generality of this new protocol for various aromatic
aldehydes and ketones under optimized conditions.
Please cite this article in press as: Ghorbani-Vaghei R, et al. One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.06.006

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Acknowledgments
We are thankful to Bu-Ali Sina University, Center of
Excellence in Development of Environmentally Friendly
Methods for Chemical Synthesis (CEDEFMCS) for financial
support.
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Appendix A. Supplementary data
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Supplementary data associated with this article can be
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j.crci.2013.06.006.
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Please cite this article in press as: Ghorbani-Vaghei R, et al. One-pot synthesis of 2-amino-3-cyanopyridine derivatives
under solvent-free conditions. C. R. Chimie (2013), http://dx.doi.org/10.1016/j.crci.2013.06.006