An efficient and ecofriendly synthesis of highly functionalized pyridones: Via a one-pot three-component reaction

Article abstract of DOI:10.1039/c8ra05690k

A simple and convenient protocol has been developed for the synthesis of N-amino-3-cyano-2-pyridone derivatives by a one-pot reaction of cyanoacetohydrazide, activated nitrile substrates (malononitrile, ethyl cyanoacetate, cyanoacetamide) and aromatic ald

Full text of DOI:10.1039/c8ra05690k

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An efficient and ecofriendly synthesis of highly
functionalized pyridones via a one-pot three-
component reaction†
Cite this: RSC Adv., 2018, 8, 27131
*
Hajar Hosseini
and Mohammad Bayat
A simple and convenient protocol has been developed for the synthesis of N-amino-3-cyano-2-pyridone
derivatives by a one-pot reaction of cyanoacetohydrazide, activated nitrile substrates (malononitrile, ethyl
cyanoacetate, cyanoacetamide) and aromatic aldehydes in the presence of piperidine in water or a mixture
of water and ethanol. The sequence of cascade reactions includes Knoevenagel condensation, Michael
addition, intramolecular cyclization, imine-enamine tautomerization and oxidative aromatization. The
main advantages of this procedure are availability of starting compounds, simple procedure, mild
conditions, easy purification of products and the use of water or water/ethanol as green solvents.
Received 3rd July 2018
Accepted 24th July 2018
DOI: 10.1039/c8ra05690k
rsc.li/rsc-advances
highly desired. There are some strategies for the synthesis of 3-
cyano-2-pyridone derivatives which already have been reported,
Introduction
most of them proceed through the regioselective cyclo-
condensation of an acetonitrile derivative (cyanoacetate ester,
cyanoacetamide or malononitrile) with a suitable carbonyl
substrate in a [3 + 3] mode. In fact, Michael addition of aceto-
nitrile derivatives to an appropriate carbonyl substrate (1,3-
dicarbonyl or a,b-unsaturated compound) and subsequent
hydrolytic cyclization followed by oxidative aromatization leads
to the corresponding 3-cyano-2-pyridones. Here, we outline
some of the most efficient methods (Scheme 2).
Reaction of malononitrile, ethyl cyanoacetate and aromatic
aldehydes in a two-step reaction led to corresponding 3-cyano-2-
pyridones (A).29 In another work the reaction of various enones
with cyanoacetamide, led to 3-cyano-2-pyridones by operating
The chemistry and applications of pyridine structures have
recently attracted a lot of attention due to their uses as synthetic
intermediates and their biological importance as agrochemi-
cals,1–3 pharmaceuticals,4–8 dye intermediates,9,10 insecticides,
adhesives,11 antifungals, antibacterials,12–14 antidepressant
agents,15,16 and antitumor agents.17 In fact the pyridine ring has
been found in more than 7000 drugs which are already in
existence.18
Furthermore, 2-pyridones are a unique category of pharma-
cophores which exhibit several biological activities such as
antitumoral,19 antimalarial,20 analgesic,21 and anti-HIV.22
Also cyanopyridines are important intermediates for the
synthesis of nicotinamide, nicotinic acid and isonicotinic acid.
3-Cyano-2-pyridones are one of the biodynamic cyanopyridine
derivatives (Scheme 1).23 The signicance of 3-cyano-2-pyridone
frameworks in the past few decades is undeniable. For example
they are the structural basis of the alkaloid ricinine, the rst
known alkaloid containing a cyano group. Milrinone is a 3-
cyano-2-pyridone derivative that has been used for the treat-
ment of congestive heart failure.24,25 Another derivative 3-cyano-
2-pyridone has shown anticancer activity which might be due to
the interference of the molecule with PDE-3,26 PIM-1 kinase,27
and survivin protein.28
Due to the great importance of this skeleton, the develop-
ment of efficient and environmentally benign methodologies
for the synthesis of diverse functionalized 2-pyridones is still
Department of Chemistry, Faculty of Science, Imam Khomeini International University,
Qazvin, Iran. E-mail: bayat_mo@yahoo.com; m.bayat@sci.ikiu.ac.ir; Tel: +98(28)
33780040
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra05690k
Scheme 1 Biodynamic activities of different derivatives of 3-cyano-2-
pyridone.
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reactions (MCRs) are extremely convergent one-pot processes,
in which three or more reagents are combined sequentially to
create complex products, with almost all the atoms coming
from the starting reagents.36–39
The reaction of cyanoacetohydrazide, malononitrile or ethyl
cyanoacetate and aldehydes has been reported in 1984 and 1997
with different procedure and there are no complete spectral
data about the structures of products.40,41 Furthermore,
synthesis of pyridones using of both cyanoacetamide and cya-
noacetohydrazide has not been reported so far.
We succeeded in synthesizing three categories of highly
functionalized 2-pyridone structures containing 1,6-diamino-4-
aryl-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile, ethyl 1,6-
diamino-4-aryl-3-cyano-2-oxo-1,2-dihydropyridine-5-carboxylate
and
1,6-diamino-4-aryl-3-cyano-2-oxo-1,2-dihydropyridine-5-
carboxamide.
Continuing our research on multi-component reactions
using cyanoacetohydrazide, we will describe in this paper a very
efficient and environmentally benign strategy for the synthesis
of N-amino-3-cyano-2-pyridone derivatives by a one-pot three
component reaction of cyanoacetohydrazide 1, acetonitrile
derivatives 2 (malononitrile 2a, ethyl cyanoacetate 2b, cyanoa-
cetamide 2c) and aromatic aldehydes 3 (Scheme 3).
For the better study of reactions and procedures and more
detailed examination of structures, we divide the reactions into
three class based on malononitrile 2a, ethyl cyanoacetate 2b
and cyanoacetamide 2c.
As the rst group of reactions, we used cyanoacetohydrazide
1, malononitrile 2a and aromatic aldehydes 3a–l in different
conditions. The best results were obtained in water in the
presence of piperidine as catalyst at room temperature. We
could synthesize 12 pyridone derivatives with various alde-
hydes. In all of these reactions, 1,6-diamino-4-aryl-3,5-dicyano-
2-pyridone 4a–l were obtained with high efficiency and rela-
tively short time (Table 1). The structures of compounds 4a–l
were derived from their IR, 1H NMR, 13C NMR spectroscopic
and mass spectrometric data (see the ESI†).
Scheme 2 Summary of previous studies of 3-cyano-2-pyridones
synthesis.
in DMSO and in the presence of excess t-BuOK under an oxygen
atmosphere (B).30 The Knoevenagel product of aromatic ketones
and ethyl acetoacetate reacted with N,N-dimethylformamide-
dimethylacetal (DMF-DMA) to produce enaminonitriles. By
adding various types of primary nucleophilic amines to enam-
inonitrile, 3-cyano-2-pyridone derivatives were formed (C).31
Condensation of acetylacetone and corresponding N-
substituted cyanoacetamide using microwave irradiation led to
pyridones (D).32 In a two-step reaction, rstly acrylamides were
obtained via the reaction of aromatic aldehydes and cyanoace-
tamide in water, then acrylamides were reacted with enolates to
produce corresponding 2-pyridones (E).33
Also 3-cyano-2-pyridinone derivatives were prepared in the
reaction of 1,3-dicarbonyl compounds with malononitrile fol-
lowed by cycloaddition and isomerization (F).34 In another study
a one-pot reaction of acetophenone derivatives, malononitrile
or ethyl cyanoacetate, an aldehyde, and ammonium acetate in
the presence of K2CO3 led to the corresponding structures (G).35
Many of the established procedures carried out under harsh
reaction conditions. On the other hand, one of the goals in
modern synthetic organic chemistry includes the use of safer,
easier and more effective methods.
By comparing the reaction rates in the table above, it is
found that for aldehydes with an electron withdrawing group on
the ring (nitro and halogens), the reaction rate is the highest
and with electron donating groups (methoxy), the speed is the
lowest.
1
Here we investigate the H and 13C NMR spectra of product
4a. As shown in Fig. 1, the 1H NMR spectrum of 4a showed two
signals at d 5.65 and 8.51 ppm identied as N–NH2 and NH2
Results and discussion
Here we report a one-pot three-component reaction between
cyanoacetohydrazide, acetonitrile derivatives (malononitrile,
ethyl cyanoacetate, cyanoacetamide) and aromatic aldehydes.
This strategy led to the N-amino-3-cyano-2-pyridones in good
yields via
a multicomponent reaction. Multicomponent Scheme 3 Synthetic scheme for generation of products 4, 5, 6.
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Table 1 Synthesis of 1,6-diamino-4-aryl-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile 4a–la
Entry
Aromatic aldehyde
Product
Time (h)
Yield (%)
M.p. (ꢀC)
1
12
93
340 (dec.)41
2
12
88
355 (dec.)
3
12
91
360 (dec.)41
4
16
83
321–323 (ref. 41)
5
15
85
265–267
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Table 1 (Contd.)
Entry
Aromatic aldehyde
Product
Time (h)
Yield (%)
M.p. (ꢀC)
6
12
90
332–334 (ref. 41)
7
11
87
305–307 (ref. 41)
8
12
85
292–294
9
13
80
365 (dec.)
10
17
75
290–292 (ref. 41)
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Table 1 (Contd.)
Entry
Aromatic aldehyde
Product
Time (h)
Yield (%)
M.p. (ꢀC)
11
11
83
338–340
12
13
78
324–326
a
All reactions were carried out with cyanoacetohydrazide 1 (1 mmol), malononitrile 2a (1 mmol), aromatic aldehydes 3 (1 mmol) and piperidine
(0.02 mmol) in water (10 ml).
groups respectively. These peaks were exchangeable with D2O.
The four protons of aromatic ring appeared at d 7.50 and
7.62 ppm as two doublets. The 1H-decoupled 13C NMR spec-
trum of 4a indicated 11 distinct resonances in accordance to
desired structure. Two signals of C-5 and C-3 of pyridone ring
were observed at d 74.7 and 86.8 ppm respectively. The signals
at d 115.8 and 116.6 ppm were related to two nitrile groups. The
signals at d 129.2, 130.4, 133.8 and 135.5 ppm were assigned to
carbons of aryl ring. The carbons of C-4 and C-6 appeared at
d 157.0 and 158.8 ppm. The carbonyl group (C-2) was observed
at d 159.5 ppm (Fig. 1).
The mass spectrum of 4a displayed the molecular-ion peak at
m/z 285 (100%) in agreement with the proposed structure. The
IR spectrum of this compound showed absorption bands at
3390, 3283 due to the NH2 groups, stretching vibration of nitrile
groups at 2216, strong absorption of carbonyl group at 1623,
N–H bending band at 1525, stretching vibration of C]C of
aromatic ring at 1465 and C–N band at 1227 cmꢁ1
.
According to the above ndings, we used ethyl cyanoacetate
instead of malononitrile. As a result, ethyl 1,6-diamino-4-aryl-3-
cyano-2-pyridone-5-carboxylate derivatives 5a–e were synthe-
sized via the reaction of cyanoacetohydrazide 1, ethyl cyanoa-
cetate 2b and the ve aldehydes 3 (Table 2). The best results in
Fig. 1 The 1H and 13C NMR spectrums of 4a.
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Table 2 Synthesis of ethyl 1,6-diamino-4-aryl-3-cyano-2-oxo-1,2-dihydropyridine-5-carboxylate 5a–ea
Entry
Aromatic aldehyde
Product
Time (h)
Yield (%)
M.p. (ꢀC)
1
20
87
245–247
2
20
85
280–282
3
4
22
24
80
75
322–324
218–220
5
24
75
237–239
a
All reactions were carried out with cyanoacetohydrazide 1 (1 mmol), ethyl cyanoacetate 2b (1 mmol), aromatic aldehydes 3 (1 mmol) and
piperidine (0.02 mmol) in water/EtOH (5 : 5 mL).
this type of reactions were obtained in the mixture of water and
The reaction with other aromatic aldehydes was carried out
ethanol (1 : 1, v/v) in the presence of piperidine at reux similar to the high work, but did not result in the expected
conditions (these reactions in water led to the hydrazone products and the reaction mixture showed several spots in TLC
products without participation of ethyl cyanoacetate).
(the desired product was not isolable).
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It is interesting to note that when methyl cyanoacetate was cyanoacetohydrazide 1, cyanoacetamide 2c and some aromatic
used instead of ethyl cyanoacetate in the above reaction, the aldehydes 3 led to 1,6-diamino-4-aryl-3-cyano-2-pyridone-5-
same ethyl carboxylate products 5a–e were obtained.
carboxamide derivatives 6a–e (Table 3). It was investigated
The spectral analysis of IR, 1H NMR, 13C NMR and mass that the best results were obtained in the mixture of water and
spectrums of 5a–e conrmed the formation of expected struc- ethanol (1 : 2, v/v) in the presence of piperidine at reux
1
tures (see the ESI†). For example the H NMR spectrum of 5a conditions (similar to the previous reactions, when water was
showed a triplet at d 0.57 and a quartet at d 3.73 ppm related to used alone, the hydrazone compounds were formed as only
the CH3 and CH2 groups. Protons of N–NH2 group was observed products).
at d 5.56 ppm. The signals of aromatic ring specied at d 7.25
This reaction with other aromatic aldehydes was carried out
and 7.48 ppm as two doublets. Two broad signals related to the similar to the rst work, but did not led to the pure products
NH2 group (position 6) appeared at d 8.42 and 8.72 ppm sepa- and the reaction mixture contained several spots in TLC (the
1
rately as a result of intramolecular hydrogen bonding. The H- expected product was not separable).
decoupled 13C NMR spectrum of 5a displayed 13 distinct
The structures of products 6a–e were deduced from their IR,
signals in accordance with expected structure. The carbons of 1H NMR, 13C NMR spectroscopic and mass spectrometric data
methyl and methylene groups appeared at d 13.2 and 60.5 ppm (see the ESI†). Here we study the 1H and 13C NMR spectra of 6a.
respectively. The signals of C-3 and C-5 of pyridone ring were As seen in Fig. 3, the 1H NMR spectrum of 6a indicated a singlet
observed at d 88.1 and 91.4 ppm. The nitrile group was assigned at d 5.67 ppm identied as the N–NH2 group. Two singlet broad
at d 117.0 The signals at d 129.2, 130.4, 133.8 and 135.5 ppm signals at d 6.85 and 7.22 ppm were assigned to the amino group
were related to carbons of aryl ring. The carbons of C-4 and C-6 (on C-6). Two doublets at d 7.28 and 7.65 ppm were related to
appeared at d 156.6 and 158.6 ppm. Two carbonyl groups (C-2 aryl ring. The amidic NH2 group appeared at d 7.78 ppm. The
and CO2Et) were observed at d 159.2 and 166.16 ppm respec- 1H-decoupled 13C NMR spectrum of 6a showed 11 resonances
tively (Fig. 2).
which conrmed the assumed structure. The signals of C-3 and
The mass spectrum of 5a afforded a molecular-ion peak at m/ C-5 were observed at d 83.7 and 99.4 ppm respectively. The
z 332 (100%) in conformity with the proposed product. The IR nitrile group appeared at d 118.1 ppm. The signals at d 123.0,
spectrum of this compound indicated absorption bands due to 130.8, 131.6 and 136.1 were related to aryl ring. The carbons of
NH2 groups broadly at 3387 and 3266, stretching vibrations of C-4 and C-6 were observed at d 153.8 and 154.0 ppm. Two
aliphatic C–H bands at 2984, 2923, one vibration of nitrile group carbonyl groups (C-2 and CONH2) were assigned at d 159.6 and
at 2215, strong absorptions of carbonyl groups at 1686 and 167.3 ppm respectively (Fig. 3).
1651, N–H bending band at 1536, stretching vibration of C]C
of aromatic ring at 1473 and C–N stretching band at 1207 cmꢁ1
The mass spectrum of 6a showed the molecular-ion peak at
m/z 347 (100%) that was in accordance with the desired struc-
.
In the third section, we used cyanoacetamide as activated ture. The IR spectrum of compound 6a showed absorption
nitrile compound. As
a
result, the reaction of broad bands at 3394, 3290 related to the NH2 groups, stretching
vibrations of nitrile group at 2205, strong absorption of
carbonyl groups at 1662 and 1612, N–H bending band at 1571,
stretching vibration of C]C of aromatic ring at 1463 and C–N
stretching band at 1213 cmꢁ1
.
A plausible mechanism for the formation of 2-pyridones 4, 5
and 6 is depicted in Scheme 4. Initial condensation of activated
nitriles 2 with aromatic aldehydes 3 in the presence of piperi-
dine, leads to the Knoevenagel products 7. The methylene group
of cyanoacetohydrazide loses proton with the catalyst so
subsequent Michael addition of cyanoacetohydrazide 1 to
adduct 7 affords intermediate 8 which undergoes intra-
molecular cyclisation via nucleophilic addition of –NH to nitrile
group to give the corresponding 1-amino-6-imino-2-
piperidinone 9. Successive imine–enamine tautomerization
followed by dehydrogenation affords desired products (Scheme
4).
It is necessary to mention this point that cyanoacetohy-
drazide could conceivably lead to condensation at the hydrazide
group with aldehydes, but even when the hydrazone structures
were synthesized and added to compounds 2, the same pyr-
idone products were obtained. In fact, the most important part
of these reactions was the prevention of hydrazone formation,
which was controlled with the mentioned conditions.
Fig. 2 The 1H and 13C NMR spectrums of 5a.
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Table 3 Synthesis of 1,6-diamino-4-aryl-3-cyano-2-oxo-1,2-dihydropyridine-5-carboxamide 6a–ea
Entry
Aromatic aldehyde
Product
Time (h)
Yield (%)
M.p. (ꢀC)
1
20
80
245–247
2
20
78
280–282
3
22
75
322–324
4
24
70
218–220
5
24
65
237–239
a
All reactions were carried out with cyanoacetohydrazide 1 (1 mmol), cyanoacetamide 2c (1 mmol), aromatic aldehydes 3 (1 mmol) and piperidine
(0.02 mmol) in water/EtOH (3 : 6 mL).
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d 74.7 (C–CN), 86.8 (C–CN), 115.8 (CN), 116.6 (CN), 129.2, 130.4,
133.8, 135.5 (Ar), 157 (C-4), 158.8 (C–NH2), 159.5 (C]O); MS (EI,
70 eV): m/z (%) ¼ 287 (35) [M + 2]+, 286 (18) [M + 1]+, 285 (100)
[M]+, 256 (19), 241 (20), 205 (13), 193 (7), 161 (10), 138 (5), 111
(4), 88 (3), 75 (6), 58 (3), 43 (2); anal. calcd for C13H8ClN5O: C,
54.65; H, 2.82; N, 24.51. Found: C, 54.65; H, 2.71; N, 24.39.
1,6-Diamino-4-(4-bromophenyl)-2-oxo-1,2-dihydropyridine-
3,5-dicarbonitrile (4b). White solid; yield: 0.289 g (88%); mp:
355 ꢀC (dec.); IR (KBr) (nmax/cmꢁ1): 3450, 3396, 3258, 2212, 1600,
1522, 1466, 1297, 829, 613; 1H NMR (300 MHz, DMSO): d 5.64 (s,
2H, N–NH2), 7.43 (d, J ¼ 8.1 Hz, 2H, ArH), 7.59 (d, J ¼ 8.1 Hz, 2H,
ArH), 8.50 (brs, 2H, NH2); 13C{1H} NMR (75.4 MHz, DMSO):
d 74.7 (C–CN), 86.7 (C–CN), 115.8 (CN), 116.6 (CN), 124.3, 130.6,
132.1, 134.2 (Ar), 157 (C-4), 158.8 (C–NH2), 159.5 (C]O); MS (EI,
70 eV): m/z (%) ¼ 331 (98) [M + 2]+, 330 (21) [M + 1]+, 329 (100)
[M]+, 300 (12), 285 (17), 258 (6), 222 (14), 205 (26), 193 (14), 165
(12), 152 (13), 126 (14), 100 (9), 88 (7), 75 (10), 58 (6), 43 (3); anal.
calcd for C13H8BrN5O: C, 47.29; H, 2.44; N, 21.21. Found: C,
47.26; H, 2.28; N, 21.07.
1,6-Diamino-4-(4-nitrophenyl)-2-oxo-1,2-dihydropyridine-3,5-
dicarbonitrile (4c). Yellow solid; yield: 0.269 g (91%); mp: 360 ꢀC
(dec.); 1H NMR (300 MHz, DMSO): d 5.50 (s, 2H, N–NH2), 7.84 (d,
J ¼ 9 Hz, 2H, ArH), 8.06 (brs, 2H, NH2); 8.44 (d, J ¼ 9 Hz, 2H,
ArH), 13C{1H} NMR (75.4 MHz, DMSO): d 74.6 (C–CN), 86.7 (C–
CN), 115.5 (CN), 116.4 (CN), 124.3, 130.2, 141.3, 148.9 (Ar), 157.0
(C-4), 158 (C–NH2), 159.4 (C]O); MS (EI, 70 eV): m/z (%) ¼ 297
(17) [M + 1]+, 296 (100) [M]+, 267 (11), 252 (14), 230 (3), 205 (4),
193 (5), 165 (8), 152 (7), 126 (5), 100 (4), 88 (4), 58 (3), 43 (2); anal.
calcd for C13H8N6O3: C, 52.71; H, 2.72; N, 28.37. Found: C,
52.64; H, 2.53; N, 28.19.
Fig. 3 The 1H and 13C NMR spectrums of 6a.
Experimental
Materials
All commercially available reagents and other solvents were
purchased and used without further purication. The NMR
spectra were recorded with a Bruker DRX-300 Avance instru-
ment (300 MHz for 1H and 75.4 MHz for 13C) with DMSO-d6 as
solvent. Chemical shis are given in ppm (d), and coupling
constant (J) are reported in hertz (Hz). Melting points were
measured with an electrotherma1 9100 apparatus. Mass spectra
were recorded with an Agilent 5975C VL MSD with Triple-Axis
Detector operating at an ionization potential of 70 eV. IR
spectra were measured with, Bruker Tensor 27 spectrometer (nꢀ
in cmꢁ1). Elemental analyses for C, H and N were performed
using a PerkinElmer 2004 series [II] CHN elemental analyzer.
1,6-Diamino-4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-
3,5-dicarbonitꢀrile (4d). Pale yellow solid; yield: 0.233 g (83%);
mp: 321–323 C; IR (KBr) (nmax/cmꢁ1): 3393, 3316, 3264, 2211,
1
1640, 1513, 1419, 1256, 1023, 837; H NMR (300 MHz, DMSO):
d 3.81 (s, 3H, OCH3), 5.62 (s, 2H, N–NH2), 7.07 (d, J ¼ 8.7 Hz, 2H,
ArH), 7.43 (d, J ¼ 8.7 Hz, 2H, ArH), 8.40 (brs, 2H, NH2); 13C{1H}
NMR (75.4 MHz, DMSO): d 55.79 (OCH3), 74.7 (C–CN), 86.7 (C–
CN), 114.4 (CN), 116.2 (CN), 117, 126.9, 130.3, 157.7 (Ar), 159.7
(C-4), 159.8 (C–NH2), 161.1 (C]O); MS (EI, 70 eV): m/z (%) ¼ 282
(18) [M + 1]+, 281 (100) [M]+, 266 (4), 252 (18), 237 (27), 210 (13),
195 (8), 180 (6), 167 (5), 140 (3), 114 (9), 88 (6), 58 (4), 43 (7); anal.
calcd for C14H11N5O2: C, 59.78; H, 3.94; N, 24.90. Found: C,
59.39; H, 3.79; N, 24.85.
General procedure for the synthesis of 1,6-diamino-4-aryl-2-
oxo-1,2-dihydropyridine-3,5-dicarbonitrile (4a–l)
The stoichiometric mixture of cyanoacetohydrazide 1 (1 mmol,
1,6-Diamino-4-(3-methoxyphenyl)-2-oxo-1,2-dihydropyridine-
0.99 g), malononitrile 2a (1 mmol, 0.66 g), aromatic aldehyde 3,5-dicarbonitrile (4e). White solid; yield: 0.238 g (85%); mp:
3a–l (1 mmol) and piperidine (20% mol, 0.019 ml) in H2O (10 265–267 ꢀC; IR (KBr) (nmax/cmꢁ1): 3425, 3314, 3194, 2954, 2205,
ml) was stirred at room temperature. The progress of the reac- 1682, 1617, 1526, 1464, 1292, 1159, 884; 1H NMR (300 MHz,
tion was monitored by TLC using ethyl acetate/n-hexane (1 : 1). DMSO): d 3.78 (s, 3H, OCH3), 5.57 (s, 2H, N–NH2), 6.99–7.10 (m,
Aer completion of the reaction, the precipitated product was 3H, ArH), 7.44 (t, J ¼ 8.1 Hz, 1H, ArH), 8.44 (brs, 2H, NH2); 13
C
collected by ltration and washed with warm ethanol to give the {1H} NMR (75.4 MHz, DMSO): d 55.78 (OCH3), 74.7 (C–CN), 86.8
pure products 4a–l.
(C–CN), 114.1 (CN), 115.8 (CN), 116, 116.7, 120.5, 130.3, 136.2,
1,6-Diamino-4-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine- 157 (Ar), 159.4 (C-4), 159.6 (C–NH2), 159.7 (C]O); MS (EI, 70
3,5-dicarbonitrile (4a). White solid; yield: 0.265 g (93%); mp: eV): m/z (%) ¼ 282 (18) [M + 1]+, 281 (100) [M]+, 280 (22), 265 (5),
340 ꢀC (dec.); IR (KBr) (nmax/cmꢁ1): 3390, 3283, 3197, 2216, 1623, 252 (18), 237 (16), 210 (3), 195 (7), 180 (6), 167 (5), 140 (6), 114
1525, 1465, 1227, 841, 766; 1H NMR (300 MHz, DMSO): d 5.65 (s, (6), 88 (5), 63 (5), 43 (2); anal. calcd for C14H11N5O2: C, 59.78; H,
2H, N–NH2), 7.51 (d, J ¼ 8.4 Hz, 2H, ArH), 7.62 (d, J ¼ 8.4 Hz, 2H, 3.94; N, 24.90. Found: C, 59.60; H, 3.84; N, 24.85.
ArH), 8.51 (brs, 2H, NH2); 13C{1H} NMR (75.4 MHz, DMSO):
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Scheme 4 Proposed mechanism for the formation of products 4, 5, 6.
(d, J ¼ 8.1 Hz, 2H, ArH), 8.57 (brs, 2H, NH2); 13C{1H} NMR (75.4
MHz, DMSO): d 74.7 (C–CN), 86.8 (C–CN), 115.6 (CN), 116.5
(CN), 122.5 (CF3), 126.1, 129.5, 131.03, 139.1, 135.5 (Ar), 157.1
(C-4), 158.6 (C–NH2), 159.5 (C]O); MS (EI, 70 eV): m/z (%) ¼ 320
(17) [M + 1]+, 319 (100) [M]+, 300 (12), 275 (24), 248 (10), 195 (11),
176 (10), 145 (9), 111 (4), 99 (6), 88 (5), 69 (15), 57 (8), 43 (11);
anal. calcd for C14H8F3N5O: C, 52.67; H, 2.53; N, 21.94. Found:
C, 52.35; H, 2.81; N, 21.67.
1,6-Diamino-4-phenyl-2-oxo-1,2-dihydropyridine-3,5-
dicarbonitrile (4f). White solid; yield: 0.225 g (90%); mp: 332–
334 ꢀC; IR (KBr) (nmax/cmꢁ1): 3444, 3397, 3240, 2212, 1630, 1525,
1469, 1219, 858, 739; 1H NMR (300 MHz, DMSO): d 5.64 (s, 2H,
N–NH2), 7.36–7.52 (m, 5H, ArH), 8.45 (brs, 2H, NH2); 13C{1H}
NMR (75.4 MHz, DMSO): d 74.7 (C–CN), 86.8 (C–CN), 115.9 (CN),
116.8 (CN), 128.4, 129, 130.6, 135 (Ar), 157.1 (C-4), 159.7 (C–
NH2), 160 (C]O); MS (EI, 70 eV): m/z (%) ¼ 252 (18) [M + 1]+, 251
(100) [M]+, 236 (2), 222 (21), 207 (26), 194 (7), 180 (17), 165 (8),
127 (14), 88 (5), 77 (12), 51 (10), 43 (4); anal. calcd for C13H9N5O:
C, 62.15; H, 3.61; N, 27.87. Found: C, 61.79; H, 3.56; N, 27.62.
1,6-Diamino-4-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-
3,5-dicarbonitrile (4g). White solid; yield: 0.247 g (87%); mp:
305–307 ꢀC; IR (KBr) (nmax/cmꢁ1): 3411, 3305, 3205, 2213, 1678,
1561, 1466, 1228, 880, 757; 1H NMR (300 MHz, DMSO): d 5.66 (s,
2H, N–NH2), 7.41–7.66 (m, 4H, ArH), 8.59 (brs, 2H, NH2); 13C
{1H} NMR (75.4 MHz, DMSO): d 75.3 (C–CN), 87.5 (C–CN), 115.1
(CN), 116 (CN), 128.2, 130.1, 130.2, 131, 132.1, 134.2 (Ar), 157 (C-
4), 157.7 (C–NH2), 159.5 (C]O); MS (EI, 70 eV): m/z (%) ¼ 287
(37) [M + 2]+, 286 (30) [M + 1]+, 285 (100) [M]+, 276 (3), 250 (23),
222 (4), 205 (13), 193 (10), 161 (12), 138 (10), 111 (5), 88 (6), 67
(3), 58 (4), 43 (2); anal. calcd for C13H8ClN5O: C, 54.65; H,
2.82; N, 24.51. Found: C, 55.14; H, 2.45; N, 24.31.
1,6-Diamino-4-(3-chlorophenyl)-2-oxo-1,2-dihydropyridine-
3,5-dicarbonitrile (4h). White solid; yield: 0.242 g (85%); mp:
292–294 ꢀC; 1H NMR (300 MHz, DMSO): d 5.66 (s, 2H, N–NH2),
7.42–7.62 (m, 4H, ArH), 8.52 (brs, 2H, NH2); 13C{1H} NMR (75.4
MHz, DMSO): d 74.8 (C–CN), 86.9 (C–CN), 115.7 (CN), 116.6
(CN), 127.2, 128.2, 130.5, 131.1, 133.6, 137 (Ar), 157 (C-4), 158.4
(C–NH2), 159.5 (C]O); anal. calcd for C13H8ClN5O: C, 54.65; H,
2.82; N, 24.51. Found: C, 55.53; H, 2.67; N, 24.50.
1,6-Diamino-2-oxo-4-(4-(triuoromethyl)phenyl)-1,2-
dihydropyridine-3,5-dicarbonitrile (4i). Pale brown solid;
yield: 0.255 g (80%); mp: 290–293 ꢀC; 1H NMR (300 MHz,
DMSO): d 5.61 (s, 2H, N–NH2), 7.72 (d, J ¼ 8.1 Hz, 2H, ArH), 7.93
1,6-Diamino-4-(3,4-dimethoxyphenyl)-2-oxo-1,2-dihydropyridine-
3,5-dicarbonitrile (4j). Pale yellow solid; yield: 0.233 g (75%); mp:
290–292 ꢀC; IR (KBr) (nmax/cmꢁ1): 3402, 3291, 2966, 2845, 2215,
1673, 1613, 152, 1464, 1269, 1153, 1019, 866, 762; 1H NMR (300
MHz, DMSO): d 3.77 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 5.64 (s,
2H, N–NH2), 7.02–7.10 (m, 3H, ArH), 8.40 (brs, 2H, NH2); 13C
{1H} NMR (75.4 MHz, DMSO): d 56 (OCH3), 56.1 (OCH3), 74.7 (C–
CN), 86.7 (C–CN), 111.84, 112.4 (Ar), 116.2 (CN), 117.1 (CN),
121.6, 126.9, 148.6, 150.7 (Ar), 157.1 (C-4), 159.7 (C–NH2), 159.8
(C]O); MS (EI, 70 eV): m/z (%) ¼ 312 (24) [M + 1]+, 311 (100)
[M]+, 296 (7), 268 (13), 237 (5), 209 (4), 181 (4), 151 (10), 127 (3),
101 (3), 88 (2), 77 (3), 58 (2), 43 (3); anal. calcd for C15H13N5O3: C,
57.87; H, 4.21; N, 22.50. Found: C, 57.60; H, 4.20; N, 22.22.
1,6-Diamino-4-(4-uorophenyl)-2-oxo-1,2-dihydropyridine-3,5-
dicarbonitrile (4k). White solid; yield: 0.223 g (83%); mp: 338–
340 ꢀC; IR (KBr) (nmax/cmꢁ1):3390, 3287, 3196, 2211, 1627, 1516,
1463, 1224, 1157, 945, 848, 616; 1H NMR (300 MHz, DMSO):
d 5.65 (s, 2H, N–NH2), 7.35–7.57 (m, 4H, ArH), 8.49 (brs, 2H,
NH2); 13C{1H} NMR (75.4 MHz, DMSO): d 74.9 (C–CN), 87 (C–
CN), 115.9 (CN), 116 (CN), 116.5, 131.1, 131.4, 163.4 (Ar), 157 (C-
4), 159 (C–NH2), 159.6 (C]O); anal. calcd for C13H8FN5O: C,
57.99; H, 2.99; N, 26.01. Found: C, 57.95, 2.89; 25.87.
1,6-Diamino-4-(3-uorophenyl)-2-oxo-1,2-dihydropyridine-3,5-
dicarbonitrile (4l). White solid; yield: 0.209 g (78%); mp: 340 ꢀC
(dec.); IR (KBr) (nmax/cmꢁ1): 3382, 3298, 3206, 2215, 1619, 1527,
1465, 1244, 1019, 965, 884, 761; 1H NMR (300 MHz, DMSO):
d 5.66 (s, 2H, N–NH2), 7.29–7.62 (m, 4H, ArH), 8.52 (brs, 2H,
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NH2); 13C{1H} NMR (75.4 MHz, DMSO): d 74.8 (C–CN), 86.9 (C– 334 (6) [M + 2]+, 333 (3) [M + 1]+, 332 (17) [M]+, 297 (100), 269
CN), 115.6 (Ar), 115.8 (CN), 116.5 (CN), 117.5, 124.7, 131.4, (95), 253 (12), 224 (11), 174 (6), 138 (7), 113 (3), 99 (3), 75 (3), 58
137.1, 162.1 (Ar), 157 (C-4), 158.5 (C–NH2), 159.5 (C]O); anal. (2), 43 (2); anal. calcd for C15H13ClN4O3: C, 54.14; H, 3.94; N,
calcd for C13H8FN5O: C, 57.99; H, 2.99; N, 26.01. Found: C, 16.84. Found: C, 56.05; H, 4.04; N, 16.71.
56.73; H, 3.83; N, 24.11.
Ethyl 1,6-diamino-4-(3-uorophenyl)-3-cyano-2-oxo-1,2-
dihydropyridine-5-carboxylate (5d). White solid; yield:
0.237 g (75%); mp: 218–220 ꢀC; IR (KBr) (nmax/cmꢁ1): 3390, 3268,
2217, 1687, 1652, 1537, 1456, 1310, 1208, 1096, 884; H NMR
(300 MHz, DMSO): d 0.57 (t, J ¼ 7.2 Hz, 3H, CH3), 3.74 (q, J ¼
General procedure for the synthesis of ethyl 1,6-diamino-4-
aryl-3-cyano-2-oxo-1,2-dihydropyridine-5-carboxylate (5a–e)
1
The stoichiometric mixture of cyanoacetohydrazide 1 (1 mmol, 7.2 Hz, 2H, CH2), 5.68 (s, 2H, N–NH2), 7.05 (d, J ¼ 7.8 Hz, 1H,
0.99 g), ethyl cyanoacetate 2b (1 mmol, 0.113 g), aromatic ArH), 7.14 (d, J ¼ 9.6 Hz, 1H, ArH), 7.25 (t, J ¼ 8.4 Hz, 1H, ArH),
aldehyde (1 mmol) and piperidine (20% mol, 0.019 ml) in 7.45 (q, J ¼ 8.1 Hz, 1H, ArH), 8.43 (brs, 1H, NH2), 8.78 (brs, 1H,
a mixture of H2O and ethanol (5 : 5 ml) was stirred at 80 ꢀC. NH2); 13C{1H} NMR (75.4 MHz, DMSO): d 13.2 (CH3), 60.4 (O–
Upon completion the reaction as monitored by TLC (using ethyl CH2), 88.2 (C–CN), 91.3 (C–CO2Et), 116.9 (CN), 114.5, 115.3,
acetate/n-hexane (1 : 1)), the precipitated product was collected 123.6, 130.5, 141.4, 163.8 (Ar), 156.7 (C-4), 158.3 (C–NH2), 159.1
by ltration and washed with H2O/EtOH to give the pure (C]O), 166.1 (CO2Et); MS (EI, 70 eV): m/z (%) ¼ 317 (19) [M +
products 5a–e.
1]+, 316 (100) [M]+, 287 (4), 270 (30), 213 (26), 171 (6), 146 (13),
Ethyl 1,6-diamino-4-(4-chlorophenyl)-3-cyano-2-oxo-1,2- 111 (2), 75 (3), 58 (2), 43 (2); anal. calcd for C15H13FN4O3: C,
dihydropyridine-5-carboxylate (5a). White solid; yield: 56.96; H, 4.14; N, 17.71. Found: C, 56.42; H, 4.28; N, 17.34.
0.288 g (87%); mp: 245–247 ꢀC; IR (KBr) (nmax/cmꢁ1): 3387, 3226,
Ethyl 1,6-diamino-4-(4-uorophenyl)-3-cyano-2-oxo-1,2-
2984, 2923, 2215, 1686, 1651, 1585, 1473, 1207, 1092, 839, 618; dihydropyridine-5-carboxylate (5e). White solid; yield:
1H NMR (300 MHz, DMSO): d 0.57 (t, J ¼ 7.2 Hz, 3H, CH3), 3.73 0.237 g (75%); mp: 237–239 ꢀC; 1H NMR (300 MHz, DMSO):
(q, J ¼ 7.2 Hz, 2H, CH2), 5.67 (s, 2H, N–NH2), 7.25 (d, J ¼ 8.4 Hz, d 0.59 (t, J ¼ 7.2 Hz, 3H, CH3), 3.73 (q, J ¼ 7.2 Hz, 2H, CH2), 5.66
2H, ArH), 7.49 (d, J ¼ 8.4 Hz, 2H, ArH), 8.42 (brs, 1H, NH2), 8.72 (s, 2H, N–NH2), 7.26 (d, J ¼ 7.8 Hz, 4H, ArH), 8.55 (br, 2H, NH2);
(brs, 1H, NH2); 13C{1H} NMR (75.4 MHz, DMSO): d 13.2 (CH3), 13C{1H} NMR (75.4 MHz, DMSO): d 13.2 (CH3), 60.5 (O–CH2),
60.5 (O–CH2), 88.1 (C–CN), 91.4 (C–CO2Et), 117 (CN), 128.4, 88.2 (C–CN), 91.7 (C–CO2Et), 117.1 (CN), 115.4, 129.5, 135.5,
129.2, 133.4, 138.1 (Ar), 156.6 (C-4), 158.6 (C–NH2), 159.2 (C] 163.2 (Ar), 156.5 (C-4), 158.9 (C–NH2), 159.3 (C]O), 166.2
O), 166.1 (CO2Et); MS (EI, 70 eV): m/z (%) ¼ 334 (35) [M + 2]+, 333 (CO2Et); anal. calcd for C15H13FN4O3: C, 56.96; H, 4.14; N, 17.71.
(21) [M + 1]+, 332 (100) [M]+, 303 (5), 286 (13), 251 (13), 229 (21), Found: C, 56.14; H, 4.08; N, 17.61.
187 (5), 162 (12), 138 (7), 111 (4), 75 (4), 58 (3), 43 (5); anal. calcd
for C15H13ClN4O3: C, 54.14; H, 3.94; N, 16.84. Found: C, 53.86;
H, 3.74; N, 16.47.
General procedure for the synthesis of 1,6-diamino-4-aryl-3-
cyano-2-oxo-1,2-dihydropyridine-5-carboxamide (6a–e)
Ethyl 1,6-diamino-4-(4-bromophenyl)-3-cyano-2-oxo-1,2-
dihydropyridine-5-carboxylate (5b). White solid; yield: The stoichiometric mixture of cyanoacetohydrazide 1 (1 mmol,
0.319 g (85%); mp: 245–247 ꢀC; IR (KBr) (nmax/cmꢁ1): 3391, 3270, 0.99 g), cyanoacetamide 2c (1 mmol, 0.084 g), aromatic alde-
2216, 1686, 1588, 1537, 1471, 1207, 1091, 878, 768, 615; 1H NMR hyde (1 mmol) and piperidine (20% mol, 0.019 ml) in a mixture
(300 MHz, DMSO): d 0.57 (t, J ¼ 6.9 Hz, 3H, CH3), 3.73 (q, J ¼ of H2O and ethanol (3 : 6 ml) was stirred at 80 ꢀC. Aer
6.9 Hz, 2H, CH2), 5.66 (s, 2H, N–NH2), 7.19 (d, J ¼ 8.1 Hz, 2H, completion of the reaction that was monitored by TLC (using
ArH), 7.62 (d, J ¼ 8.1 Hz, 2H, ArH), 8.42 (brs, 1H, NH2), 8.72 (brs, ethyl acetate/n-hexane (1 : 1)), the precipitated product was
1H, NH2); 13C{1H} NMR (75.4 MHz, DMSO): d 13.1 (CH3), 60.5 collected by ltration and washed with H2O/EtOH to give the
(O–CH2), 88 (C–CN), 91.3 (C–CO2Et), 117 (CN), 121.9, 129.5, pure products 6a–e.
131.3, 138.5 (Ar), 156.6 (C-4), 158.6 (C–NH2), 159.2 (C]O), 166.1
1,6-Diamino-4-(4-bromophenyl)-3-cyano-2-oxo-1,2-dihydropyridine-5-
(CO2Et); MS (EI, 70 eV): m/z (%) ¼ 379 (19) [M+2]+, 378 (100) carboxamide (6a). Brown solid; yield: 0.278 g (80%); mp: 245–
[M+1]+, 377 (21) [M]+, 376 (99), 349 (4), 332 (9), 304 (9), 275 (18), 247 ꢀC; IR (KBr) (nmax/cmꢁ1): 3394, 3290, 2205, 1662, 1612, 1571,
223 (18), 194 (14), 152 (8), 127 (12), 100 (5), 88 (5), 43 (3); anal. 1463, 1399, 1267, 886, 579; 1H NMR (300 MHz, DMSO): d 5.67 (s,
calcd for C15H13BrN4O3: C, 47.76; H, 3.47; N, 14.85. Found: C, 2H, N–NH2), 6.85 (brs, 1H, NH2), 7.22 (brs, 1H, NH2), 7.28 (d, J ¼
47.43; H, 3.75; N, 14.53.
8.4 Hz, 2H, ArH), 7.65 (d, J ¼ 8.4 Hz, 2H, ArH), 7.78 (s, 2H,
Ethyl 1,6-diamino-4-(2-chlorophenyl)-3-cyano-2-oxo-1,2- CONH2); 13C{1H} NMR (75.4 MHz, DMSO): d 83.7 (C–CN), 99.4
dihydropyridine-5-carboxylate (5c). White solid; yield: (C–CONH2), 118.1 (CN), 123, 130.8, 131.6, 136.1 (Ar), 153.8 (C-4),
0.265 g (80%); mp: 322–324 ꢀC; IR (KBr) (nmax/cmꢁ1): 3386, 3269, 154 (C–NH2), 159.6 (C]O), 167.3 (CONH2); MS (EI, 70 eV): m/z
2214, 1653, 1584, 1456, 1312, 1213, 1006, 800, 621; 1H NMR (300 (%) ¼ 350 (16) [M + 2]+, 349 (99) [M + 1]+, 348 (64) [M]+, 347 (100),
MHz, DMSO): d 0.55 (t, J ¼ 6.9 Hz, 3H, CH3), 3.73 (q, J ¼ 6.9 Hz, 346 (51), 332 (5), 301 (5), 275 (4), 251 (43), 237 (8), 205 (16), 194
2H, CH2), 5.69 (s, 2H, N–NH2), 7.24–7.52 (m, 4H, ArH), 8.47 (brs, (24), 180 (9), 152 (9), 140 (18), 113 (8), 100 (9), 88 (8), 63 (9), 44
1H, NH2), 9.00 (brs, 1H, NH2); 13C{1H} NMR (75.4 MHz, DMSO): (22); anal. calcd for C13H10BrN5O2: C, 44.85; H, 2.90; N, 20.12.
d 13.2 (CH3), 60.5 (O–CH2), 88.5 (C–CN), 91 (C–CO2Et), 116.4 Found: C, 41.97; H, 3.38; N, 17.42.
(CN), 127.4, 129, 129.3, 130.2, 130.7, 138.4 (Ar), 157 (C-4), 159.2
1,6-Diamino-4-(4-chlorophenyl)-3-cyano-2-oxo-1,2-dihydropyridine-5-
(C–NH2), 159.2 (C]O), 165.8 (CO2Et); MS (EI, 70 eV): m/z (%) ¼ carboxamide (6b). Pale brown solid; yield: 0.236 g (78%); mp: 280–
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282 ꢀC; IR (KBr) (nmax/cmꢁ1): 3386, 3301, 2208, 1635, 1574, 1461,
1398, 1268, 880, 585; 1H NMR (300 MHz, DMSO): d 5.67 (s, 2H,
N–NH2), 6.83 (brs, 1H, NH2), 7.21 (brs, 1H, NH2), 7.35 (d, J ¼
8.4 Hz, 2H, ArH), 7.51 (d, J ¼ 8.4 Hz, 2H, ArH), 7.78 (brs, 2H,
CONH2); 13C{1H} NMR (75.4 MHz, DMSO): d 83.8 (C–CN), 99.4
(C–CONH2), 118.1 (CN), 128.7, 130.5, 134.3, 135.7 (Ar), 153.8 (C-
4), 154 (C–NH2), 159.6 (C]O), 167.3 (CONH2); anal. calcd for
Acknowledgements
Financial support of this research from Imam Khomeini
International University, Iran is gratefully acknowledged.
Notes and references
C
13H10ClN5O2: C, 51.41; H, 3.32; N, 23.06. Found: C, 51.87; H,
3.54; N, 22.57.
1 S. C. Benson, J. L. Gross and J. K. Snyder, J. Org. Chem., 1990,
55, 3257–3269.
2 A. Thomass, M. Chakraborty and H. Junjappa, Tetrahedron,
1990, 46, 577–586.
3 J. Wolff and M. Taddei, Tetrahedron, 1986, 42, 4267–4272.
4 E. C. Taylor, J. Heterocycl. Chem., 1990, 27, 1–12.
5 Y. Tominaga, S. Kohra, H. Honkawa and A. Hosomi,
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6 Y. Tominaga, S. Mdokawa, Y. Shiroshita and A. Hosomi, J.
Heterocycl. Chem., 1987, 24, 1365.
1,6-Diamino-4-(3-chlorophenyl)-3-cyano-2-oxo-1,2-dihydropyridine-
5-carboxamide (6c). White solid; yield: 0.227 g (75%); mp: 322–
324 ꢀC; 1H NMR (300 MHz, DMSO): d 5.67 (s, 2H, N–NH2), 6.91
(brs, 1H, NH2), 7.26 (brs, 1H, NH2), 7.28–7.48 (m, 4H, ArH), 7.79
(s, 2H, CONH2); 13C{1H} NMR (75.4 MHz, DMSO): d 83.7 (C–CN),
99.5 (C–CONH2), 118 (CN), 127.4, 128.4, 129.4, 130.5, 133.1,
138.8 (Ar), 153.3 (C-4), 153.9 (C–NH2), 159.6 (C]O), 167.2
(CONH2); anal. calcd for C13H10ClN5O2: C, 51.41; H, 3.32; N,
23.06.
1,6-Diamino-4-(2-chlorophenyl)-3-cyano-2-oxo-1,2-dihydropyridine-
5-carboxamide (6d). Pale brown solid; yield: 0.212 g (70%); mp:
218–220 ꢀC; 1H NMR (300 MHz, DMSO): d 5.69 (s, 2H, N–NH2),
6.37 (br, 1H, NH2), 7.27 (br, 1H, NH2), 7.42–7.54 (m, 4H, ArH),
8.05 (s, 2H, CONH2); 13C{1H} NMR (75.4 MHz, DMSO): d 84.7 (C–
CN), 99.2 (C–CONH2), 117.4 (CN), 127.4, 130, 130.6, 131.1,
131.4, 135.8 (Ar), 152.4 (C-4), 154.6 (C–NH2), 159.4 (C]O), 166.8
7 C. J. Shishoo, M. B. Devani, V. S. Bhadti, S. Ananthan and
G. V. Ullas, Tetrahedron Lett., 1983, 24, 4611–4612.
8 Y. Tominaga, S. Kohra, H. Okuda, A. Ushirogouchi,
Y. Matsuda and G. kobayshi, Chem. Pharm. Bull., 1984, 32,
122.
9 E. Hahn, in Lectures in Heterocyclic Chemistry IX, ed. R. N.
Castle, Heterocorporation, Tampa, FL, 1990, p. 13.
(CONH2); anal. calcd for C13H10ClN5O2: C, 51.41; H, 3.32; N, 10 F. Sanger, S. Coulson and A. R. Coulson , Proc. Natl. Acad. Sci.
23.06.
U. S. A., 1977, 74, 5463.
1,6-Diamino-4-(4-uorophenyl)-3-cyano-2-oxo-1,2-dihydropyridine- 11 Y. Higashio and T. Shoji, Appl. Catal., A, 2004, 260, 251–259.
5-carboxamide (6e). Pale brown solid; yield: 0.186 g (65%); mp: 12 G. A. Youngdale, US Pat. 4288440, 1980Chem. Abstr., 1982,
237–239 ꢀC; 1H NMR (300 MHz, DMSO): d 5.66 (s, 2H, N–NH2),
96, 6596.
6.77 (brs, 1H, NH2), 7.21 (brs, 1H, NH2), 7.25–7.37 (m, 4H, ArH), 13 A. H. Todd, UK Pat. 1203,149, 1970Chem. Abstr., 1970, 73,
7.77 (s, 2H, CONH2); 13C{1H} NMR (75.4 MHz, DMSO): d 84.1 (C–
120509.
CN), 99.5 (C–CONH2), 118.1 (CN), 115.6, 130.9, 131, 133.2 (Ar), 14 G. Lohaus, W. Dittmar and S. Afric, IN Pat. 6906036, 1968,
154 (C-4), 154.1 (C–NH2), 159.7 (C]O), 167.4 (CONH2); MS (EI,
Chem. Abstr., 1970, 73, 120508.
70 eV): m/z (%) ¼ 288 (9) [M + 1]+, 287 (51) [M]+, 286 (21), 270 15 C. Gachet, M. Cattanea, P. Ohlmann, B. Lecchi, J. Cassel,
(17), 241 (10), 205 (26), 177 (12), 146 (18), 122 (100), 109 (24), 95
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Conclusion
We have reported a novel and green one-pot synthesis of three
classes of polysubstituted pyridine systems, 1,6-diamino-4-aryl-
3,5-dicyano-2-pyridone, ethyl 1,6-diamino-4-aryl-3-cyano-2-
pyridone-5-carboxylate
and
1,6-diamino-4-aryl-3-cyano-2-
pyridone-5-carboxamide derivatives, via a three-component
reaction between cyanoacetohydrazide, activated nitrile
compounds and aromatic aldehydes. The present process
includes some important advantages like easy operation mild
reaction conditions, facile accessibility of reactants, simple
workup procedure, the use of water or water/ethanol as green
reaction medium, high atom economy and good to high yields.
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Conflicts of interest
The authors declare no competing nancial interest.
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