A concise and versatile synthesis of 2-amino-3-cyanopyridine derivatives in 2,2,2-trifluoroethanol

Article abstract of DOI:10.1016/j.jfluchem.2012.06.009

Trifluoroethanol (TFE) is found to be an efficient and recyclable medium in promoting one-pot, four-component coupling reactions of aldehydes, ketones, malononitrile, and ammonium acetate to afford the corresponding 2-amino-3-cyanopyridine derivatives in high yields. The solvent (TFE) can be readily separated from reaction products and recovered in excellent purity for direct reuse.

Full text of DOI:10.1016/j.jfluchem.2012.06.009

Journal of Fluorine Chemistry 142 (2012) 41–44
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A concise and versatile synthesis of 2-amino-3-cyanopyridine derivatives
in 2,2,2-trifluoroethanol
*
Samad Khaksar , Mandana Yaghoobi
Department of Chemistry, Ayatollah Amoli Branch, Islamic Azad University, Amol, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
Trifluoroethanol (TFE) is found to be an efficient and recyclable medium in promoting one-pot, four-
component coupling reactions of aldehydes, ketones, malononitrile, and ammonium acetate to afford the
corresponding 2-amino-3-cyanopyridine derivatives in high yields. The solvent (TFE) can be readily
separated from reaction products and recovered in excellent purity for direct reuse.
ß 2012 Elsevier B.V. All rights reserved.
Received 4 April 2012
Received in revised form 16 May 2012
Accepted 12 June 2012
Available online 11 July 2012
Keywords:
Pyridine
Fluorinated solvent
Malononitrile
Recyclable
1. Introduction
However, the development of novel methods for the synthesis
of 2-amino-3-cyanopyridines is of great importance because of
The pyridine substructure is one of the most prevalent
heterocycles found in natural products, pharmaceuticals, and
functional materials [1–4]. Among these compounds, 2-amino-3-
cyanopyridine derivatives have been reported to possess antiviral,
antibacterial, and fungicidal activities [5–8]. 2-Amino-3-cyano-
pyridine derivatives were also reported as novel IKK-b inhibitors
[9], A2A adenosine receptor antagonists [10], potent inhibitor of
HIV-1 integrase [11], and so on. 2-Amino-3-cyanopyridines are
important and useful intermediates in preparing variety of
heterocyclic compounds [12,13]. Therefore, the synthesis of these
compounds is of great significance. A number of reports on this
topic have appeared in the literature [14–17]. However, some of
these procedures have certain limitations such as harsh reaction
conditions, long reaction time, toxic benzene as solvent, high
temperature or microwave assistance, tedious work-up, and low
yields. Murata et al. have reported the synthesis of 2-amino-6-aryl-
3-cyano-4-piperidinylpyridine derivatives through four-compo-
nent coupling reaction of acetophenone, N-Boc-formylpiperidine,
malononitrile and ammonium acetate in conventional heating
mode [18]. Nevertheless, the protocol gives comparatively lower
yields and longer reaction time. Very recently, Wang et al. reported
a one-pot synthesis of 2-amino-3-cyanopyridines using ytterbium
perfluorooctanoate in ethanol under reflux condition [19].
their potential biological and pharmaceutical activities. Over the
last years, fluorinated alcohols have received recognition as green
media in organic synthesis, because they display many advantages
over common organic solvents, such as high hydrogen bonding
donor ability, nonvolatility, nonflammability, polarity, high ioniz-
ing power, and low nucleophilicity [20]. A more attractive feature
of fluorinated alcohols is the possibility to recycle them and to
easily recover the product (by simple distillation). Fluorinated
alcohols are attracting increasing attention as alternative solvents
for a wide range of catalytic and organic reactions [21–34]. In
continuation of our interest using of fluorinated solvents as
efficient medium in various organic transformations [35–40], we
turned our attention toward the four-component condensation of
aldehydes, ketones, malononitrile, and ammonium acetate in TFE
as solvent. Herein, we describe a novel, efficient, and green
procedure for the synthesis of 2-amino-3-cyanopyridine deriva-
tives 5 via the four-component condensation (Scheme 1).
2. Results and discussion
Initially, we carried out the four-component condensation of
benzaldehyde (1 mmol), acetophenone (1 mmol), malononitrile
(1 mmol), and ammonium acetate (1.5 mmol) in trifluoroethanol
(2 mL) at refluxing temperature for 6 h. At the beginning of the
reaction, the reagents itself were dissolved completely in the
medium to form a homogeneous mixture (Fig. 1a), but near the
completion of the reaction, the system became a suspension, and
the product precipitated at the end of the reaction (Fig. 1b).
* Corresponding author. Fax: +98 121 2517071.
E-mail addresses: samadkhaksar@yahoo.com, s.khaksar@iauamol.ac.ir
(S. Khaksar).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.06.009

42
S. Khaksar, M. Yaghoobi / Journal of Fluorine Chemistry 142 (2012) 41–44
R
R2
R1
O
NC
H2N
O
CN
TFE
Reflux, 6 h
NH4OAc
+
+
+
R1
CH2R2
R
H
CN
N
1
2
4
3
5a-q
Scheme 1. One-pot four component condensation of aldehydes, ketones, malononitrile, and ammonium acetate in TFE.
Fig. 1. (a) Homogeneous mixture during the reaction, and (b) at the end of the reaction; the product has precipitated.
The products were isolated after selective evaporation of the
condition. The electronic effect seemed to have a slight influence
on the reaction since either the electron-withdrawing or the
electron-donating groups on the different aromatic ring resulted in
the hardly discriminate yields. We also examined this four-
component condensation with 2-substituted benzaldehyde, find-
ing that the reaction time was longer and yields were somewhat
lower than other aldehydes which were probably attributed to the
steric hindrance (Table 1, entries 3 and 4). To expand the scope of
ketone substrates, aromatic ketones with substituents or not, as
well as aliphatic and cyclic ketones, were applied to this protocol.
TFE and were purified by recrystallization from tetrahydrofuran to
afford the pure product. The products 2-amino-3-cyanopyridine
derivatives 5a, shown in Scheme 1 and confirmed by NMR
measurements, were obtained in good yield (90%). The scope and
generality of this four-component condensation was examined in
more detail. Both the electron-rich and -deficient aldehydes
worked well leading to good yields of products 5. Aromatic
aldehydes with several functionalities such as Cl, Me, OMe, and
NO2 were found to be compatible under the optimized reaction
O
CF3CH2
TFE
H
NH2
O
NH
R2
NH4OAc
R2
R2
R1
R1
R1
-H2O
I
O
CF3CH2
H
R
CN
CN
O
O
H
-H2O
CN
+
R
N
NH4OAc
CN
II
H
NH
R1
CH2CF3
I
II
+
R2
CN
H
III
H
N
H
R1
R2
R1
R2
N
R
R1
R2
N
NH2
CN
NH
CN
NH2
CN
O2 (air)
-H2
H
R
R
Scheme 2. Proposed mechanism for the synthesis of 2-amino-3-cyanopyridines.

S. Khaksar, M. Yaghoobi / Journal of Fluorine Chemistry 142 (2012) 41–44
43
Table 1
acetate (Table 1, entry 1) afforded the corresponding 2-amino-3-
cyanopyridine derivative in 90%, 90%, 88%, 88% and 85% isolated
yield over five cycles. When we carried out the reaction in TFE at
room temperature, the reaction proceeded very slowly to give very
poor yields. A plausible mechanism for the formation of 2-amino-3-
cyanopyridine is shown in Scheme 2.
Synthesis of 2-amino-3-cyanopyridine in TFE.
Entry
1
Ketones
Aldehydes
Product
Yield %
90
Refs.
[15]
5a
CHO
O
In this process, TFE act as Bronsted acid [41] and plays a
significant role in increasing the electrophilic character of the
electrophiles. The hydrogen bond donor ability might not be
important in this case. Actually the hydrogen bond donating ability
of these solvents drops as temperature rises owing to the fact that
hydrogen-bond formation is exothermic [42,43]. The polar
transition state of the reaction could be stabilized well by the
high ionizing solvent TFE. The reaction may proceed via enamine I,
which formed from ketone and ammonium acetate, and then
activated by TFE, reacts with alkylidene malononitrile II (from
condensation of aldehyde with malononitrile) to give intermediate
III, followed by cycloaddition, isomerization, and aromatization to
afford the final product. It may be assumed that the water-
exclusion of TFE may favor both imine and alkylidene malononi-
trile formation.
2
3
4
5
6
7
8
5b
5c
5d
5e
5f
90
80
82
88
90
90
95
[19]
[19]
[17]
[19]
[17]
[19]
[19]
O
O
O
O
O
O
CHO
Cl
CHO
Cl
CHO
Cl
Cl
CHO
O2N
MeO
CHO
CHO
5g
5h
Me
3. Conclusion
O
O
CHO
In conclusion, an extremely efficient and green process has been
developed for the synthesis of 2-amino-3-cyanopyridine deriva-
tives via one-pot condensation of aldehydes, ketones, malononi-
trile, and ammonium acetate in TFE without using any catalyst or
additives. This method is bestowed with merits like avoiding the
use of any base, metal or Lewis acid catalyst, ease of product
isolation/purification by non-aqueous work-up, high chemoselec-
tivity, no side reaction, low costs and simplicity in process and
handling and environmentally benign nature. These advantages of
TFE made this process very useful for the synthesis of 2-amino-3-
cyanopyridine derivatives. Further exploration of the scope of
fluorinated solvent to other type of reactions is underway.
MeO
MeO
9
5i
5j
95
85
85
[17]
[14]
[14]
CHO
Cl
10
11
O
CHO
Br
5k
O
CHO
Cl
Br
O
12
13
5l
90
95
[19]
[17]
CHO
4. Experimental
5m
O
O
CHO
CHO
Typical experimental procedure. A mixture of aldehyde (1 mmol),
ketone (1 mmol), malononitrile (1 mmol), and ammonium acetate
(1.5 mmol) were stirred in one-pot in TFE (2 mL) at refluxing
temperature for the stipulated time. The progress of the reaction is
monitored by TLC. After completion of the reaction, the corre-
sponding solid product 5 was obtained through simple filtering,
and recrystallized from tetrahydrofuran affording the highly pure
2-amino-3-cyanopyridine derivatives. The physical data (mp, IR,
NMR) of known compounds were found to be identical with those
reported in the literature. Spectroscopic data for selected examples
are shown below.
Cl
14
5n
85
[17]
Me
15
16
5o
5p
80
80
[19]
[19]
O
CHO
CHO
O
O
17
5q
85
[19]
CHO
Cl
2-Amino-4,6-diphenyl-nicotinonitrile (5a). mp: 186–187 8C. IR
(KBr): 3461, 3301, 3176, 2202, 1637, 1546, 1257 cmÀ1 1H NMR
.
In all cases, the desired reactions took place successfully to afford a
series of 2-amino-3-cyanopyridine derivatives in moderate to good
yields. The results are summarized in Table 1.
(400 MHz, CDCl3):
(m, 6H), 7.64 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 4.0 Hz, 2H). 13C NMR
(100 MHz, CDCl3): = 91.2, 116.5, 121.3, 125.2, 127.1, 128.1, 129.3,
d = 5.35 (br s, 2H, NH2), 7.21 (s, 1H), 7.46–7.52
d
Satisfactorily, the reactions displayed high functional group
tolerance and afforded the corresponding pyridines with great
efficiency. Thestructureoftheproducts(5a–q)wasestablishedfrom
their IR spectral data and comparison of their melting points with
those of authentic samples. Also, the structure of some products was
confirmed by 1H NMR and 13C NMR spectral data. Interestingly, the
reaction didnotproceed tocompletion wheneitherethanolor water
alone was used as solvent, even at reflux conditions. After the
reaction, TFE can be easily separated (by distillation) and reused
without decrease in its activity. For example, the reaction of
benzaldehyde, acetophenone, malononitrile, and ammonium
130.1, 131.2, 133.3, 157.5, 165.5, 164.7, 166.2.
2-Amino-4-(4-chlorophenyl)-6-phenylnicotinonitrile (5b). mp:
233–235 8C. IR (KBr): 3496, 3305, 3183, 2204, 1641, 1606,
1257 cmÀ1
.
1H NMR (400 MHz, CDCl3):
d
= 5.37 (br s, 2H, NH2),
7.18 (s, 1H), 7.48–7.60 (m, 10H). 13C NMR (100 MHz, CDCl3):
= 93.2, 116.3, 119.3, 125.2, 126.3, 127.5, 127.8, 132.2, 133.4,
d
134.5, 135.4, 154.3, 164.5, 166.2.
2-Amino-4-(2-chlorophenyl)-6-phenylnicotinonitrile (5c). mp:
193–196 8C. IR (KBr): 3480, 3336, 3180, 2221, 1621, 1562,
1241 cmÀ1
.
1H NMR (400 MHz, CDCl3):
d
= 5.48 (br s, 2H, NH2),
7.07 (s, 1H), 7.48–7.60 (m, 7H), 7.92–7.94 (m, 2H). 13C NMR

44
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129.8, 133.8, 134.1, 135.6, 136.5, 138.5, 155.3, 160.2, 166.1.
2-Amino-6-phenyl-4-p-tolylnicotinonitrile (5g). mp: 175–176 8C.
IR (KBr): 3463, 3293, 3168, 2202, 1631, 1575, 1257 cmÀ1. 1H NMR
(400 MHz, CDCl3):
7.32–7.99 (m, 9H). 13C NMR (100 MHz, CDCl3):
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= 2.43 (s, 3H), 5.35 (br s, 2H, NH2), 7.21 (s, 1H),
= 20.3, 91.2,
d
116.5, 120.1, 125.2, 125.7, 128.1, 129.2, 133.5, 133.8, 134.5, 136.5,
156.8, 162.3, 166.5.
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2-Amino-4-(4-chlorophenyl)-6-methylnicotinonitrile (5m). mp:
255–256 8C. IR (KBr): 3479, 3401, 3318, 3168, 2210, 1645, 1573,
1251 cmÀ1
.
1H NMR (400 MHz, CDCl3):
d
= 2.46 (s, 3H), 5.29 (br s,
2H, NH2), 6.63 (s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz,
2H). 1H NMR (400 MHz, CDCl3):
= 21.2, 91.3, 116.2, 120.4, 126.8,
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d
130.1, 133.2, 141.3, 157.6, 164.2, 166.2.
2-Amino-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile
(5p). mp: 230–233 8C. 1H NMR (400 MHz, CDCl3):
d = 1.65–1.69 (m,
2H), 1.82–1.88 (m, 2H), 2.35 (t, J = 6.4 HZ, 2H), 2.82 (t, J = 6.4 Hz,
2H), 5.20 (br s, 2H, NH2), 7.28–7.50 (m, 5H). 1H NMR (400 MHz,
CDCl3):
136.5, 154.5, 157.1, 161.43.
d = 22.5, 22.8, 26.5, 33.2, 90.4, 116.7, 120.7, 128.5, 128.8,
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Acknowledgment
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This research is supported by the Islamic Azad University,
Ayatollah Amoli Branch.
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