Effective and Green One-Pot Multicomponent Synthesis of Novel Derivatives of 4H-Pyrans in the Presence of Hexamethylenetetramine as Catalyst in Water Medium

Article abstract of DOI:10.1002/jhet.2748

Hexamethylenetetramine catalyzes synthesis of new polyfunctionalized 4H-pyrans by the reaction of aromatic aldehyde, malononitrile, and β-keto esters via one-pot three-component procedure in water medium. Addition of reactants was performed by two methods

Full text of DOI:10.1002/jhet.2748

Month 2016
Effective and Green One-Pot Multicomponent Synthesis of Novel
Derivatives of 4H-Pyrans in the Presence of Hexamethylenetetramine
as Catalyst in Water Medium
*
Maysam Habibi, Azizollah Habibi, Saber Hakimi Nasab, Hadi Dolati, and Seyedeh Mahbobeh Mahdavi
Faculty of Chemistry, Kharazmi University, No. 43, Mofateh Avenue, 15719-14911, Tehran, Iran
*
Email: habibi@khu.ac.ir
Received April 2, 2016
DOI 10.1002/jhet.2748
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Hexamethylenetetramine catalyzes synthesis of new polyfunctionalized 4H-pyrans by the reaction of ar-
omatic aldehyde, malononitrile, and β-keto esters via one-pot three-component procedure in water medium.
Addition of reactants was performed by two methods led to achieve similar results. Using hexamethylenetet-
ramine in catalytic amount not only represents the economic face of the reaction but also due to the use of
water, a green and safe reaction condition is organized. Thus, the current strategy provides the benefits of
high productivity, convenient operation, and environmental friendliness. The structure of all products were
1
proved by elemental analysis, IR, H NMR, and 13C NMR spectroscopy.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
[5.4.0]undec-7-ene [11], triethylamine in ethanol [12],
hexadecyltrimethylammoniumbromide [13], 1-deoxy-1-
methylamino-D-glucitol [14], some other organic bases
[15], and ionic liquids [16]. However, these methodologies
regularly persevere from one or the other kind of down-
sides, and the majority of them give humble yields even af-
ter extended reaction time. This has obviously exhibited
that there is still extension to improve an effective and im-
pressive procedure for the synthesis of 4H-pyrans.
During the last few years, hexamethylenetetramine
(HMTA) used as an alternative to antibiotics for the pre-
vention of urinary tract infection [17]. Furthermore, protec-
tive effects of HMTA on sulfur mustard is demonstrated
[18]. That has additionally been proved to be powerful
and favorable catalyst because of being affordable, easily
accessibility, nontoxicity, and its steadiness. HMTA is a
base catalysis, and many medicinal functions are reported
for it thus far [19].
In consequence of the potential biological and pharmaco-
logical activities of 2-amino-4H-pyran derivatives, and based
on our preceding studies and interests in the synthesis of het-
erocyclic structures [20], this letter is devoted to introduce a
simple, ecofriendly, green, and highly efficient method for
the preparation of privileged heterocyclic medicinal scaf-
folds involving 2-amino-4H-pyran annulated frameworks.
So we will describe here HMTA-catalyzed three-component
coupling of aromatic aldehyde, malononitrile, and β-keto es-
ters for the synthesis of 2-amino-4H-pyrans in water as a
cheap, available, and ecofriendly solvent.
Today, considering the disadvantages of toxic and ex-
pensive organic solvents, utilization of green and environ-
mentally benign solvents such as water has enormously
increased. Within the last decade, green chemistry has
grown to be an effective tool in organic chemistry and
has stimulated interests in the generation of complex
molecular system through solvent-free synthesis multi-
component reactions especially in water as solvent. The
capability of multicomponent reactions regarding synthe-
sis of desired products in a single procedure from three
or more reactant molecules devoid of spreading poisonous
intermediate has been recognized doubtlessly [1].
Polyfunctionalized 4H-pyrans due to their broad biologi-
cal and pharmaceutical characteristics are of important
structural units [2]. 4H-pyrans are a major component of
some natural products [3], which have revealed potent bi-
ological activities like antianaphylactic [4], antiallergic
[5], antibacterial [6], and antitumor [7]. As well, these
compounds are employed in the treatment of Alzheimer’s,
schizophrenia, and mycolonous diseases [8]. Some deriv-
atives of 2-amino-4H-pyrans are the valuable photoactive
resources [9].
Also, regarding the vast ranging of biological activities
of 4H-pyrans, synthetic chemists have designed several
methodologies for their syntheses comprising two-step as
well as one-pot three-component synthesis, catalyzed by
2-hydroxyethylammonium acetate [10], 1,8-diazabicyclo
© 2016 Wiley Periodicals, Inc.

M. Habibi, A. Habibi, S. Hakimi Nasab, H. Dolati, and S. M. Mahdavi
Vol 000
Table 1
RESULTS AND DISCUSSION
Optimization of the reaction conditions for compound 4a (Procedure A).
We commenced our investigation studies from three-
componentone-potreactioninvolving3-nitrobenzaldehyde,
malononitrile, and methyl isobutyrylacetate, in equimolar
quantities in the presence of 25 mol% of HMTA in water,
as a model reaction (Scheme 1).
Entry
Solvent
Temperature (°C)
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
9
10
EtOH
MeOH
CH2Cl2
CHCl3
THF
DMSO
H2O
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
RT
50
75
96
4
3
2
2
8
9
30
6
5
3
72
74
79
77
54
25
20
50
68
75
After a successful synthesis of compound 4a, in order to
optimize the reaction conditions, we carried out the reac-
tion in some other solvents by loading 25 mol% of the cat-
alyst (Procedure A). As demonstrated in Table 1, the
reaction yield in EtOH and MeOH was good (Table 1,
Entries 1 and 2). In contrast to the good yield of the prod-
uct in ethanol and methanol mediums, the yield in the sol-
vents like DMSO and H2O (at room temperature) seemed
to be poor (Table 1, Entries 6 and 7). As seen, comparing
the reaction results in H2O, chloroform and dichlorometh-
ane at reflux exposed that the reaction yield in CH2Cl2
and CHCl3 was the most effective (Table 1, Entries 3 and
4). Nevertheless, considering the cheapness, availability,
and ecofriendly characteristics of water, we preferred this
solvent, and the other optimization tests were performed
in it (Table 1, Entry 10). It is also remarkable to note that
the reaction without using any amount of the catalyst was
set up, but no prominent result screened. These data are
presented as a diagram in Figure 1.
H2O
H2O
aIsolated yield.
In continuation of optimizing conditions, we centered on
the amount of the catalyst. When the reaction run at the
5 mol%, the yield and the time were excellent, but by de-
creasing or increasing the catalyst loading, qualitative pa-
rameters sank down progressively (Table 2). Once the
reaction performed at 35 mol% of the catalyst, time in-
creased and the yield declined noticeably. Along with the
increasing of the catalyst amount, TLC analysis revealed
some extra spots, indicative of new adverse reactions.
To generalize this methodology with the optimal condi-
tions in hand, a diverse set of aromatic aldehydes with elec-
tron withdrawing and electron releasing functionalities 1
together with malononitrile 2 and β-keto esters 3 were ap-
plied to preparation of a library of 2-amino-4H-pyran ana-
logues (Scheme 2).
Figure 1. The diagram of optimization of the reaction. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 2
Effect of the catalyst quantity on the reaction parameters for compound 4a
(Procedure A).
Catalyst
Temperature
(°C)
loading
Time
(h)
Yield
(%)a
Entry Solvent
(%)a
1
2
3
4
5
H2O
H2O
H2O
H2O
H2O
96
96
96
96
96
3
5
15
25
35
3
2
4
5
6
91
95
90
82
73
The reaction results are summarized in Table 3. It is note-
worthy to mention that generally, aryl aldehydes with
electron-withdrawing groups took less time and gave higher
yields comparing to the ones with electron-releasing groups.
aIsolated yield.
Scheme 1. Synthesis of 4a in the presence of HMTA (25 mol%).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Green Synthesis of 4H-Pyrans in the Presence of Hexamethylenetetramine
in Water
Scheme 2. Optimized synthesis of compounds 4a–n (HMTA, 5 mol%).
Table 3
HMTA catalyzed synthesis of 4H-pyran derivatives 4a–n.
Entry
Product
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
G
β-keto ester
3a
Time (h)
Yield (Method A) %
Yield (Method B) %
mp (°C)
1
2
3
4
5
6
7
8
m-NO2
p-Cl
m-OMe
p-NO2
p-OMe
o-Cl
2
4
5
3
4
4
5
4
5
95
91
87
94
88
84
82
90
81
87
82
93
83
90
73
57
55
61
52
51
48
61
45
42
67
61
65
59
181–183
135–137
126–128
211–213
171–173
141–143
124–126
143–145
169–171
169–171
213–215
159–161
161–163
176–178
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
2-Thionyl
m-Cl
9
m-OMe
2-Thionyl
2,6-Cl
2,4-Cl
2,5-Cl
m-Cl
10
11
12
13
14
5
2:30
3
2:20
4
4m
4n
Scheme 3. The two paths implemented for synthesis of the adducts. [Color figure
can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
To do our best and to acquire the best yield out of
the reaction, as seen in Scheme 3, we performed the re-
action through two diverse methods, Procedures A and
B. In Procedure A, the carbonyl compounds (aromatic
aldehydes) were reacted with malononitrile utilizing
HMTA as catalyst via a Knoevenagel condensation. In
next step, a Michael addition was performed by reacting
obtained intermediate 4 with the 1,3dicarbonylstructures
(β-keto esters) to produce the second intermediate 6.
The second one, following some steps gives the final
product. While in Procedure B, at first, aromatic alde-
hydes were reacted with the 1,3 dicarbonyls
(Knoevenagel condensation) and in the second step, the
produced intermediate 5 was coupled with malononitrile
to generate the second intermediate 6, which could pro-
vide the final product through steps. Take it into consid-
eration that the second intermediate in each procedure is
the same, and also, the final product is identical. The
yield results of the reactions by two procedures are com-
pared in Table 3.
The products were collected by simple filtration, thus
resulting in a very efficient and easy-going procedure.
The structures of the synthesized compounds were eluci-
dated through IR, 1HNMR, 13CNMR, and elemental
analysis.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Habibi, A. Habibi, S. Hakimi Nasab, H. Dolati, and S. M. Mahdavi
Vol 000
CONCLUSION
CH3), 1.17 (d, J =6 Hz, 3H, CH3); 13C-NMR (75 MHz;
CDCl3), δ, ppm: 165.7, 164.8, 158.0, 148.6, 146.0,
133.6, 129.6, 122.4, 122.2, 118.2, 105.4, 61.0, 51.9,
38.7, 29.2, 19.7, 19.1. Anal. calcd. For C17H17N3O5
(343.33): C, 59.47; H, 4.99; N, 12.24. Found: C, 59.37;
H, 4.89; N, 12.21.
Concisely, we have developed the synthetic route for the
synthesis of new derivatives of 4H-pyran structures. These
molecular building blocks are well known for biological
activity and are synthesized by a very efficient, cheap,
and environment-friendly protocol. On account of these
unique features, we suppose that this methodology be-
comes a utilized procedure in constructing 4H-pyrans ana-
logues. Exploring the potential bioactivity of the structures
is in progress in our laboratory.
Methyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-isopropyl-4H-
pyran-3-carboxylate (4b).
Melting point = 138–141°C;
Orange powder; IR (KBr) (λmax, cmÀ1): 3413, 3321, 3202,
2962, 2200, 1690, 1675, 1609, 1408, 1263, 1090; 1H
NMR (300MHz; CDCl3), δ, ppm: 7.28 (m, 2H, Ar–H),
7.12 (m, 2H, Ar–H), 4.52 (s, 2H, NH2), 4.43 (s, 1H, CH),
3.82 (m, 1H, CH), 3.59 (s, 3H, CH3), 1.20 (d, J=6.9Hz,
3H, CH3), 1.10 (d, J=6Hz, 3H, CH3); 13C-NMR
(75MHz; CDCl3), δ, ppm: 166.1, 163.7, 157.7, 142.2,
132.9, 128.8, 128.6, 118.6, 105.9, 62.1, 51.8, 38.3, 29.1,
19.7, 19.1. Anal. calcd. For C17H17ClN2O3 (332.78): C,
61.36; H, 5.15; N, 8.42. Found: C, 61.40; H, 5.02; N, 8.74.
Methyl 6-amino-5-cyano-2-isopropyl-4-(3-methoxyphenyl)-
4H-pyran-3-carboxylate (4c). Melting point = 129–132°C;
Cream powder; IR (KBr) (λmax, cmÀ1): 3397, 3320,
3190, 2965, 2196, 1721, 1673, 1605, 1407, 1259, 1081;
1H NMR (300 MHz; CDCl3), δ, ppm: 7.23 (t, 1H, Ar–H),
6.72–6.79 (m, 3H, Ar–H), 4.50 (s, 2H, NH2), 4.42 (s, 1H,
CH), 3.85 (m, 1H, CH), 3.79 (s, 3H, CH3), 3.60 (s, 3H,
CH3),1.24 (d, J= 6 Hz, 3H, CH3), 1.14 (d, J = 6 Hz, 3H,
CH3); 13C-NMR (75 MHz; CDCl3), δ, ppm: 166.2, 163.6,
159.7, 157.7, 145.2, 129.6, 119.5, 118.8, 113.0, 112.3,
106.1, 62.1, 55.1, 51.7, 38.7, 29.1, 19.7, 19.1. Anal. calcd.
For C18H20N2O4 (328.36): C, 65.84; H, 6.14; N, 8.53.
Found: C, 66.12; H, 6.15; N, 8.85.
EXPERIMENTAL
All materials were purchased from Merck, Aldrich, and
Fulka and used as received. Melting points were obtained
in capillary tubes on Electrothermal 9100 apparatus and
were uncorrected. FTIR spectra were taken on a Perkin-
Elmer 843 Spectrophotometer over the range of 400–
4000 cmÀ1 by using the KBr technique. 1H and 13C
NMR spectra were recorded on a BrukerAvanceemploying
tetramethylsilane as an internal standard. Elemental analy-
ses were carried out by using a Perkin-Elemer 2004 series
[II] CHN elemental analyzer.
General procedure for Preparation of 4H-Pyrans 4a–n
Procedure A. A mixture of aromatic aldehyde 1a–n
(1 mmol), malononitrile 2 (1 mmol, 0.066g), and HMTA
(0.05mmol, 0.007 g) in H2O (3mL) in a round-bottom
flask after 30-min stirring was obtained. To this mixture,
β-keto ester 3a or 3b (1 mmol) was added. The mixture
was refluxed for the given time. The progress of the reac-
tion was monitored by thin-layer chromatography (TLC).
After the completion of the reaction (usually changing of
the color), the resulting mixture was cooled to room tem-
perature. The solid product was collected by filtration and
washed first with 20 mm of distilled water then with
5 mm of warm ethanol to give the pure compound 4a–n.
Procedure B. A mixture of carbonyl compound 1a–n
(1 mmol), malononitrile 2 (1 mmol, 0.066g), and HMTA
(0.05mmol, 0.007 g) in H2O (3 mL) after 30 min was ob-
tained, and β-keto ester 3a or 3b (1mmol) was added.
Then the mixture was heated at reflux temperature. Follow-
ing the completion of the reaction, the resulting precipitates
of 4a–n were treated as mentioned in Procedure A. The
precipitates were recrystallized from ethanol.
Methyl 6-amino-5-cyano-2-isopropyl-4-(4-nitrophenyl)-4H-
pyran-3-carboxylate (4d).
Melting point = 214–217°C;
Orange powder; IR (KBr) (λmax, cmÀ1): 3407, 3319,
3200, 3076, 2963, 2206, 1676, 1607, 1521, 1408, 1345,
1
1266, 1093; H NMR (300 MHz; CDCl3), δ, ppm: 8.19
(d, J = 8.7 Hz, 2H, Ar–H), 7.36 (d, J= 9 Hz, 2H, Ar–H),
4.61 (s, 2H, NH2), 4.57 (s, 1H, CH), 3.88 (m, 1H, CH),
3.60 (s, 3H, CH3),1.26 (d, 3H, CH3), 1.17 (d, 3H, CH3);
13C-NMR (75 MHz; CDCl3), δ, ppm: 165.7, 164.8,
157.9, 150.9, 147.0, 128.1, 124.1, 118.2, 105.2, 60.8,
51.9, 38.8, 29.2, 19.7, 19.1. Anal. calcd. For C17H17N3O5
(343.33): C, 59.47; H, 4.99; N, 12.24. Found: C, 59.35;
H, 4.94; N, 12.15.
Methyl 6-amino-5-cyano-2-isopropyl-4-(4-methoxyphenyl)-
4H-pyran-3-carboxylate (4e). Melting point = 174–176°C;
Cream powder; IR (KBr) (λmax, cmÀ1): 3401, 3324,
3197, 2956, 2198, 1715, 1679, 1604, 1508, 1408, 1254,
1089; 1H NMR (300 MHz; CDCl3), δ, ppm: 7.09 (d,
J = 6Hz, 2H, Ar–H), 6.8 (d, J =6 Hz, 2H Ar–H), 4.47 (s,
2H, NH2), 4.39 (s, 1H, CH), 3.77 (m, 4H, CH, CH3),
3.59 (s, 3H, CH3),1.23 (d, J = 6Hz, 3H, CH3), 1.13 (d,
J = 6Hz, 3H, CH3); 13C-NMR (75 MHz; CDCl3), δ, ppm:
166.4, 162.9, 158.6, 157.5, 135.9, 128.3, 118.9, 118.7,
Methyl 6-amino-5-cyano-2-isopropyl-4-(3-nitrophenyl)-4H-
pyran-3-carboxylate (4a).
Melting point =184–187°C;
Cream powder; IR (KBr) (λmax, cmÀ1): 3416, 3341,
3324, 3218, 3074, 2971, 2196, 1672, 1603, 1531, 1408,
1
1347, 1247, 1222, 1089; H NMR (300 MHz; CDCl3), δ,
ppm: 8.11 (m, 1H, Ar–H), 8.04 (t, 1H, Ar–H), 7.53 (m,
2H, Ar–H), 4.62 (s, 2H, NH2), 4.58 (s, 1H, CH), 3.88
(m, 1H, CH), 3.61 (s, 3H, CH3), 1.27 (d, J = 6Hz, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Green Synthesis of 4H-Pyrans in the Presence of Hexamethylenetetramine
in Water
114.0, 106.5, 62.4, 55.2, 51.7, 38.0, 29.1, 19.7, 19.1. Anal.
calcd. For C18H20N2O4 (328.36): C, 65.84; H, 6.14; N,
8.53. Found: C, 65.73; H, 6.10; N, 8.42.
113.3, 111.9, 108.8, 60.1, 56.8, 54.9, 13.2. Anal. calcd.
For C22H20N2O4 (376.41): C, 70.20; H, 5.36; N, 7.44.
Found: C, 70.12; H, 5.29; N, 7.41.
Methyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-isopropyl-4H-
Ethyl 6-amino-5-cyano-2-phenyl-4-(thiophen-2-yl)-4H-py-
ran-3-carboxylate (4j). Melting point = 171–173°C; Light
yellow powder; IR (KBr) (λmax, cmÀ1): 3395, 3330,
3201, 2987, 2194, 1669, 1609, 1597, 1472, 1370, 1337,
1247, 1088, 694; 1H NMR (300 MHz; DMSO-d6), δ,
ppm:7.41–7.49 (m, 6H, Ar–H), 7.14 (s, 2H, NH2), 6.93–
6.97 (m, 2H, Ar–H), 4.76 (s, 1H, CH), 3.84 (q,
J = 7.2 Hz, 2H, CH2), 0.80 (t, J =6.9 Hz, 3H, CH3); 13C-
NMR (75 MHz; DMSO-d6), δ, ppm: 165.2, 159.5, 154.5,
148.7, 132.8, 130.0, 128.5, 128.0, 127.0, 125.1, 124.3,
119.5, 109.1, 60.3, 56.9, 34.8, 13.2. Anal. calcd. For
C19H16N2O3S (352.41): C, 64.76; H, 4.58; N, 7.95. Found:
C, 64.58; H, 4.47; N, 7.93.
pyran-3-carboxylate (4f).
Melting point= 144–147°C;
White powder; IR (KBr) (λmax, cmÀ1): 3460, 3319, 3187,
2963, 2201, 1716, 1674, 1601, 1404, 1232, 1094; 1H
NMR (300 MHz; CDCl3), δ, ppm: 7.32 (m, 1H, Ar–H),
7.13–7.25 (m, 3H, Ar–H), 5.05 (s, 1H, CH), 4.48 (s, 2H,
NH2), 3.88 (m, 1H, CH), 3.57 (s, 3H, CH3), 1.24 (d,
J =6 Hz, 3H, CH3), 1.14 (d, J = 6Hz, 3H, CH3); 13C-
NMR (75 MHz; CDCl3), δ, ppm: 166.0, 164.2, 157.9,
140.7, 133.1, 129.9, 129.7, 128.4, 127.3, 118.4, 105.2,
62.0, 51.7, 35.7, 29.0, 19.6, 19.1. Anal. calcd. For
C17H17ClN2O3 (332.78): C, 61.36; H, 5.15; N, 8.42.
Found: 61.17; H, 5.11; N, 8.40.
Methyl 6-amino-5-cyano-2-isopropyl-4-(thiophen-2-yl)-4H-
Ethyl 6-amino-5-cyano-4-(2,6-dichlorophenyl)-2-phenyl-4H-
pyran-3-carboxylate (4g).
Melting point =127–131°C;
pyran-3-carboxylate (4k).
Melting point =216–218°C;
Yellow powder; IR (KBr) (λmax, cmÀ1): 3415, 3337,
White powder; IR (KBr) (λmax, cmÀ1): 3459, 3286, 3164,
3211, 2968, 2189, 1698, 1668, 1631, 1598, 1407,
1344, 1263, 1086, 696; H NMR (300 MHz; CDCl3), δ,
2973, 2195, 1711, 1670, 1591, 1367, 1330, 1254, 1094,
790; H NMR (300MHz; DMSO-d6), δ, ppm:7.46–7.27
1
1
ppm: 7.16 (dd, 1H, J1 = 1.2 Hz, J2 = 1.2 Hz, Ar–H),
6.86–6.92 (m, 2H, Ar–H), 4.86 (s, 1H, CH), 4.60 (s,
2H, NH2), 3.82 (m, 1H, CH), 3.68 (s, 3H, CH3), 1.20
(d, J = 6Hz, 3H, CH3), 1.12 (d, J =6 Hz, 3H, CH3);
13C-NMR (75 MHz; CDCl3), δ, ppm: 166.0, 163.7,
158.2, 148.2, 126.9, 124.5, 124.2, 118.7, 106.5, 61.9,
51.8, 33.8, 29.1, 19.4, 19.0. Anal. calcd. For
C15H16N2O3S (304.36): C, 59.19; H, 5.30; N, 9.20.
Found: C, 59.21; H, 5.23; N, 9.09.
(m, 8H, Ar–H), 7.11 (s, 2H, NH2), 5.53 (s, 1H, CH), 3.72
(q, J =7.2 Hz,, 2H, CH2), 0.68 (t, J= 7.2 Hz, 3H, CH3);
13C-NMR (75 MHz; DMSO-d6), δ, ppm: 164.9, 159.7,
155.7, 136.0, 135.4, 135.1, 133.3, 130.5, 129.8, 129.5,
129.1, 128.6, 128.1, 128.0, 119.0, 105.0, 60.1, 52.3, 36.0,
13.1; Anal. calcd. For C21H16Cl2N2O3 (415.27): C, 60.74;
H, 3.88; N, 6.75; Found: C, 60.41; H, 3.73; N, 6.56.
Ethyl 6-amino-5-cyano-4-(2,4-dichlorophenyl)-2-phenyl-4H-
pyran-3-carboxylate (4l).
Melting point = 162–164°C;
Methyl 6-amino-4-(3-chlorophenyl)-5-cyano-2-isopropyl-4H-
Light yellow powder; IR (KBr) (λmax, cmÀ1): 3456,
pyran-3-carboxylate (4h).
Melting point =146–149°C;
3328, 3181, 2983, 2196, 1711, 1673, 1596, 1468, 1341,
1257, 1088, 845, 704; H NMR (300MHz; DMSO-d6),
1
White powder; IR (KBr) (λmax, cmÀ1): 3419, 3322, 3217,
2959, 2198, 1696, 1673, 1592, 1409, 1339, 1265, 1084,
703, 465; H NMR (300 MHz; CDCl3), δ, ppm: 7.06–
δ, ppm:7.59 (s, 1H, Ar–H), 7.48–7.38 (m, 7H, Ar–H),
7.10 (s, 2H, NH2), 4.98 (s, 1H, CH), 3.73 (q, J= 5.7Hz,
2H, CH2), 0.72 (t, J =5.7 Hz, 3H, CH3); 13C-NMR
(75 MHz; DMSO-d6), δ, ppm: 164.9, 159.2, 159.1, 155.6,
140.4, 133.0, 132.2, 131.6, 129.9, 128.8, 128.4, 128.1,
128.0, 119.0, 107.1, 60.2, 55.2, 36.3, 13.1. Anal. calcd.
For C21H16Cl2N2O3 (415.27): C, 60.74; H, 3.88; N, 6.75.
Found: C, 60.66; H, 3.79; N, 6.65.
1
7.26 (m, 4H, Ar–H), 4.55 (s, 2H, NH2), 4.42 (s, 1H,
CH), 3.84 (m, 1H, CH), 3.60 (s, 3H, CH3), 1.24 (d,
J =6 Hz, 3H, CH3), 1.14 (d, J = 6Hz, 3H, CH3); 13C-
NMR (75 MHz; CDCl3), δ, ppm: 166.0, 164.0, 157.8,
145.7, 134.4, 129.9, 127.4, 127.4, 125.6, 118.5, 105.8,
61.6, 51.8, 38.6, 29.1, 19.7, 19.1. Anal. calcd. For
C17H17ClN2O3 (332.78): C, 61.36; H, 5.15; N, 8.42.
Found: C, 61.29; H, 5.05; N, 8.25.
Ethyl 6-amino-5-cyano-4-(2,5-dichlorophenyl)-2-phenyl-4H-
pyran-3-carboxylate (4m).
Melting point =164–166°C;
Ethyl 6-amino-5-cyano-4-(3-methoxyphenyl)-2-phenyl-4H-
Cream powder; IR (KBr) (λmax, cmÀ1): 3455, 3327,
pyran-3-carboxylate (4i).
Melting point =172–175°C;
2982, 2196, 1711, 1673, 1595, 1468, 1366, 1257, 1088,
845, 704; H NMR (300MHz; CDCl3), δ, ppm: 7.40–
1
Cream powder; IR (KBr) (λmax, cmÀ1): 3408, 3326,
3200, 2963, 2195, 1673, 1596, 1491, 1372, 1338, 1260,
1086, 700; H NMR (300 MHz; DMSO-d6), δ, ppm: 7.43
7.49 (m, 6H, Ar–H), 7.23–7.25 (m, 2H, Ar–H), 5.14 (s,
1H, CH), 4.65 (s, 2H, NH2), 3.84 (q, J= 7.2Hz, 2H,
CH2), 0.84 (t, J =7.2 Hz, 3H CH3); 13C-NMR (75 MHz;
CDCl3), δ, ppm: 165.2, 158.2, 155.8, 138.8, 133.9,
133.6, 132.8, 131.0, 130.2, 129.8, 128.3, 128.1, 127.7,
118.2, 107.8, 60.9, 60.5, 60.0, 36.5, 36.2, 13.3. Anal.
calcd. For C21H16Cl2N2O3 (415.27): C, 60.74; H, 3.88;
N, 6.75. Found: C, 60.82; H, 3.79; N, 6.67.
1
(s, 5H, Ar–H), 7.27 (t, J= 7.5 Hz, 1H, Ar–H), 7.01 (s,
2H, NH2), 6.82 (d, J = 6Hz, 2H, Ar–H), 6.75 (s, 1H, Ar–
H), 4.4 (s, 1H, CH), 3.77 (q, J =7.5 Hz, 2H, CH2), 3.73
(s, 3H, CH3), 0.73 (t, J= 6.9 Hz, 3H, CH3); 13C-NMR
(75 MHz; DMSO-d6), δ, ppm: 165.4, 159.3, 159.1, 154.1,
145.6, 133.0, 129.8, 129.7, 128.4, 128.0, 119.6, 119.4,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Habibi, A. Habibi, S. Hakimi Nasab, H. Dolati, and S. M. Mahdavi
Vol 000
Ethyl 6-amino-4-(3-chlorophenyl)-5-cyano-2-phenyl-4H-py-
J Med Chem 2009, 44, 3805; (c) Lazzeri Adreani, L.; Lapi, E. Boll Chim
Farm 1960, 99, 583.
[5] Witte, E. C.; Neubert, P.; Roesch, A.; Offen, G. DE3427985
Chemical Abstracts 1986, 104.
[6] El-Saghier, A. M. M.; Naili, M. B.; Rammash, B. K.; Saleh,
N. A.; Kreddan, K. M. ARKIVOC 2007, 2007, 83.
[7] Wang, J. L.; Liu, D.; Zhang, Z. J.; Shan, S.; Han, X.;
Srinivasula, S. M.; Croce, C. M.; Alnemri, E. S.; Huang, Z. Proc Natl
Acad Sci U S A 2000, 97, 7124.
[8] Konkoy, C. S.; Fick, D. B.; Cai, S. X.; Lan, N. C.; Keana, J. F.
W. Chemical Abstracts 2001, 134.
[9] O’Callaghan, C. N.; McMurry, T. B. H. J Chem Res, Synop
1999 457.
[10] Jin, S.-S.; Ding, M.-H.; Guo, H.-Y. Heterocycl Commun 2013,
19, 139.
[11] Saluja, P.; Aggarwal, K.; Khurana, J. M. Synth Commun
2013, 43, 3239.
ran-3-carboxylate (4n).
Melting point =179–182°C;
Cream powder; IR (KBr) (λmax, cmÀ1): 3400, 3330,
2202, 2987, 2199, 1672, 1472, 1372, 1337, 1276, 1092,
1
698, 528; H NMR (300 MHz; CDCl3), δ, ppm: 7.43 (s,
5H, Ar–H), 7.21–7.30 (m, 4H, Ar–H), 4.63 (s, 2H, NH2),
4.59 (s, 1H, CH), 3.86 (q, J = 7.2 Hz, 2H, CH2), 0.83 (t,
J =7.2 Hz, 3H, CH3); 13C-NMR (75 MHz; CDCl3), δ,
ppm: 165.5, 158.1, 154.9, 144.9, 134.5, 132.8, 130.1,
129.9, 128.7, 128.4, 128.1, 127.8, 127.7, 126.0, 118.5,
109.0, 61.2, 60.8, 39.5, 13.3. Anal. calcd. For
C21H17ClN2O3 (380.82): C, 66.23; H, 4.50; N, 7.36.
Found: C, 66.24; H, 4.35; N, 7.15.
[12] Saeedi, M.; Heravi, M. M.; Beheshtiha, Y. S.; Oskooie, H. A.
Tetrahedron 2010, 66, 5345.
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35, 1859.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet