RETRACTED ARTICLE: Effective and Green One-Pot Multicomponent Synthesis of Novel Derivatives of 4H-Pyrans in the Presence of Hexamethylenetetramine as Catalyst in Water Medium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.2781

Hexamethylenetetramine (HMTA) catalyzes synthesis of new polyfunctionalized 4H-pyrans by 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 meth

Full text of DOI:10.1002/jhet.2781

Month 2016
Effective and Green One-Pot Multicomponent Synthesis of Novel Deriv-
atives 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, P. Code 15719-14911, Mofateh Avenue, Tehran, Iran
*E-mail: habibi@khu.ac.ir
Received July 15, 2016
DOI 10.1002/jhet.2781
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Hexamethylenetetramine (HMTA) catalyzes synthesis of new polyfunctionalized 4H-pyrans by reaction
of aromatic aldehyde, malononitrile, and β-keto esters via one-pot three-component procedure in water me-
dium. Addition of reactants was performed by two methods led to achieve similar results. Using HMTA 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 pro-
ductivity, convenient operation, and environmental friendliness. Structure of all products was proved by el-
1
emental analysis, IR, H-NMR, and 13C-NMR spectroscopy.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
diazabicyclo[5.4.0]undec-7-ene [11], triethylamine in
ethanol [12], hexadecyltrimethylammonium bromide [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 downsides, and the majority of them give humble
yields even after extended reaction time. This has
obviously exhibited that there is still extension to
improve an effective and impressive procedure for the
synthesis of 4H-pyrans.
During the last few years, hexamethylenetetramine
(HMTA) used as an alternative to antibiotics for the
prevention of urinary tract infection (UTI) [17].
Furthermore, protective effects of HMTA on sulfur
mustard are 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].
Today, considering the disadvantages of toxic and
expensive organic solvents, utilization of green and
environmentally 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
multicomponent reactions especially in water as solvent.
The capability of multicomponent reactions regarding
synthesis 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
biological and pharmaceutical characteristics are of
important structural units [2]. 4H-Pyrans are a major
component of some natural products [3], which have
revealed potent biological activities like antianaphylactic
[4], antiallergic [5], anti-bacterial [6], and antitumor [7].
As well, these compounds are employed in the treatment
of Alzheimer, schizophrenia, and mycolonous diseases
[8]. Some derivatives of 2-amino-4H-pyrans are the
valuable photoactive resources [9].
In consequence of the potential biological and
pharmacological
activities
of
2-amino-4H-pyran
derivatives, and based on our preceding studies and
interests in the synthesis of heterocyclic structures [20],
this letter is devoted to introduce a simple, eco-friendly,
green, and highly efficient method for the preparation of
privileged heterocyclic medicinal scaffolds involving 2-
amino-4H-pyran annulated frameworks. So we will
describe here HMTA-catalyzed three-component coupling
of aromatic aldehyde, malononitrile, and β-keto esters for
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-
© 2016 Wiley Periodicals, Inc.

M. Habibi, A. Habibi, S. Hakimi Nasab, H. Dolati, and S. M. Mahdavi
Vol 000
Table 1
the synthesis of 2-amino-4H-pyrans in water as a cheap,
Optimization of the reaction conditions for compound 4a (procedure A).
available, and eco-friendly solvent.
Entry
Solvent
Temperature (°C)
Time (h)
Yield (%)a
RESULTS AND DISCUSSION
1
2
3
4
5
6
7
8
9
10
EtOH
MeOH
CH2Cl2
CHCl3
THF
DMSO
H2O
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t
50
75
96
4
3
2
2
8
9
30
6
5
3
72
74
79
77
54
25
20
50
68
75
We commenced our investigation studies from three-
component
one-pot
nitrobenzaldehyde,
reaction
malononitrile,
involving
and
3-
methyl
isobutyrylacetate, in equimolar quantities in the presence
of 25 mol% of HMTA in water, as a model reaction
(Scheme 1).
H2O
H2O
After successful synthesis of compound 4a, in order to
optimize the reaction conditions, we carried out the
reaction in some other solvents by loading 25 mol% of
the catalyst (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 product in ethanol and methanol mediums, the yield
in the solvents 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 dichloromethane 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 eco-friendly
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.
aIsolated yield.
80
70
60
50
40
30
20
10
0
Solvents Applied
Series 2 Series 3
Series 1
Series 4
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 was excellent, but
by decreasing or increasing the catalyst loading,
qualitative parameters sank down progressively
(Table 2). Once the reaction performed at 35 mol% of
the catalyst, time increased and the yield declined
noticeably. Along with the increasing of the catalyst
amount, TLC analysis revealed some extra spots,
indicative of new adverse reactions.
Figure 1. The diagram of optimization of the reaction. [Color figure can
be viewed at wileyonlinelibrary.com]
with
electron-withdrawing
and
electron-releasing
functionalities (1) together with malononitrile (2) and β-
keto esters (3) were applied to preparation of a library of
2-amino-4H-pyran analogs (Scheme 2).
The reaction results are summarized in Table 3. It is
noteworthy to mention that generally aryl aldehydes with
electron-withdrawing groups took less time and gave
To generalize this methodology with the optimal
conditions in hand, a diverse set of aromatic aldehydes
Scheme 1. Synthesis of 4a in the presence of HMTA (25 mol%).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Novel Derivatives of 4H-Pyrans in the Presence of
Hexamethylenetetramine in Water
Table 2
HMTA as catalyst via a Knoevenagel condensation. In
next step, a Michael addition was performed by reacting
obtained intermediate 4 with the 1,3 dicarbonyl structures
(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 aldehydes were
reacted with the 1,3 dicarbonyls (Knoevenagel
condensation), and in the second step, the produced
Effect of the catalyst quantity on the reaction parameters for compound 4a
(procedure A).
Catalyst
Temperature
(°C)
Time
(h)
Yield
(%)a
loading
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
intermediate
5 was coupled with malononitrile to
generate the second intermediate 6, which could provide
the final product through steps. Take it into consideration
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 compared in
Table 3.
aIsolated yield.
higher yields comparing with the ones with electron-
releasing groups.
To do our best and to acquire the best yield out of the
reaction, as seen in Scheme 3, we performed the reaction
through two diverse methods, procedures A and B. In
procedure A, the carbonyl compounds (aromatic
aldehydes) were reacted with malononitrile utilizing
The products were collected by simple filtration, thus
resulting in a very efficient and easy-going procedure.
The structures of the synthesized compounds were
elucidated through IR, 1H-NMR, 13C-NMR, and
elemental analysis.
Scheme 2. Optimized synthesis of compounds 4a–n (HMTA 5 mol%).
Table 3
HMTA catalyzed synthesis of 4H-pyran derivatives 4(a–n).
Entry
Product
G
β-keto ester
Time (h)
Yield (method A), %
Yield (method B), %
M.p (°C)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
m-NO2
p-Cl
m-OMe
p-NO2
p-OMe
o-Cl
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
2
4
5
3
4
4
5
4
5
5
2:30
3
2:20
4
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
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
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Habibi, A. Habibi, S. Hakimi Nasab, H. Dolati, and S. M. Mahdavi
Vol 000
Scheme 3. The two paths implemented for synthesis of the adducts. [Color figure can be viewed at wileyonlinelibrary.com]
CONCLUSION
apparatus and were uncorrected. FTIR spectra were
taken on a Perkin-Elmer 843 spectrophotometer over
the range 400–4000 cmÀ1 using the KBr technique.
1H-NMR and 13C-NMR spectra were recorded on a
Bruker Avance-300 MHz employing tetramethylsilane
as an internal standard. Elemental analyses were carried
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 this methodology becomes a
utilized procedure in constructing 4H-pyrans analogs.
Exploring the potential bioactivity of the structures is in
progress in our laboratory.
out 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, 0.066 g), and
HMTA (0.05 mmol, 0.007g) in H2O (3 mL) in a
round-bottom flask after 30min stirring was obtained.
To this mixture, added β-keto ester 3a or 3b (1mmol).
The mixture was refluxed for the given time. Progress
of the reaction monitored by thin-layer chromatography
(TLC). After completion of the reaction (usually
changing of the color), the resulting mixture was
EXPERIMENTAL
All materials were purchased from Merck, Aldrich,
and Fulka and used as received. Melting points were
obtained in capillary tubes on Electrothermal 9100
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Novel Derivatives of 4H-Pyrans in the Presence of
Hexamethylenetetramine in Water
cooled to room temperature. The solid product was
collected by filtration and washed first with 20mL of
distilled water then with 5 mL of warm ethanol to give
the pure compound 4a–n.
Methyl 6-amino-5-cyano-2-isopropyl-4-(4-nitrophenyl)-4H-
pyran-3-carboxylate (4d).
Mp = 214–217°C; orange
powder; IR (KBr) (λmax, cmÀ1): 3407, 3319, 3200, 3076,
2963, 2206, 1676, 1607, 1521, 1408, 1345, 1266, 1093;
1H-NMR (300 MHz; CDCl3), δ, ppm: 8.19 (d, 2H,
J = 8.7Hz, Ar-H), 7.36 (d, 2H, J =9 Hz, 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 (300 MHz; CDCl3), δ, ppm: 165.72, 164.83,
157.92, 150.91, 147.00, 128.17, 124.14, 118.20, 105.22,
60.89, 51.97, 38.83, 29.25, 19.75, 19.16; 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.
Procedure B.
To a mixture of carbonyl compound
1a–n (1 mmol), β-keto ester 3a or 3b (1 mmol), and
HMTA (0.05 mmol, 0.007 g) in H2O (3mL) after
30min was placed malononitrile 2 (1 mmol, 0.066g).
Then the mixture heated at reflux temperature.
Following 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-(3-nitrophenyl)-4H-
Methyl 6-amino-5-cyano-2-isopropyl-4-(4-methoxyphenyl)-
pyran-3-carboxylate (4a).
Mp = 184–187°C; cream
4H-pyran-3-carboxylate (4e).
Mp = 174–176°C; cream
powder; IR (KBr) (λmax, cmÀ1): 3416, 3341, 3324, 3218,
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, 2H, J = 6
Hz, Ar-H), 6.8 (d, 2H, J= 6 Hz, 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= 6 Hz, 3H, CH3), 1.13 (d, J = 6
Hz, 3H, CH3); 13C-NMR (300 MHz; CDCl3), δ, ppm:
166.44, 162.98, 158.65, 157.58, 135.90, 128.35, 118.95,
118.75, 114.03, 106.57, 62.48, 55.20, 51.71, 38.01,
29.12, 19.78, 19.17; 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.
3074, 2971, 2196, 1672, 1603, 1531, 1408, 1347, 1247,
1
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 = 6 Hz, 3H, CH3), 1.17 (d,
J =6 Hz, 3H, CH3); 13C-NMR (300 MHz; CDCl3), δ,
ppm: 165.73, 164.82, 158.02, 148.60, 146.00, 133.65,
129.67, 122.44, 122.23, 118.25, 105.42, 61.08, 51.94,
38.78, 29.27, 19.78, 19.15; 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.
Methyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-isopropyl-4H-
Methyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-isopropyl-4H-
pyran-3-carboxylate (4f). Mp = 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 = 6 Hz, 3H, CH3); 13C-NMR (300 MHz;
CDCl3), δ, ppm: 166.03, 164.26, 157.90, 140.71, 133.14,
129.99, 129.78, 128.41, 127.30, 118.48, 105.22, 62.0,
51.71, 35.78, 29.02, 19.68, 19.14; Anal. Calcd for
C17H17ClN2O3 (332.78): C, 61.36; H, 5.15; N, 8.42;
found: 61.17; H, 5.11; N, 8.40.
pyran-3-carboxylate (4b).
Mp =138–141°C; orange
powder; IR (KBr) (λmax, cmÀ1): 3413, 3321, 3202, 2962,
2200, 1690, 1675, 1609, 1408, 1263, 1090; 1H-NMR
(300 MHz; 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), 1.2 (d, J = 6.9 Hz, 3H,
CH3), 1.1 (d, J = 6 Hz, 3H, CH3); 13C-NMR (300 MHz;
CDCl3), δ, ppm: 166.10, 163.74, 157.71, 142.22, 132.98,
128.87, 128.66, 118.62, 105.97, 62.10, 51.80, 38.31,
29.14, 19.76, 19.15; 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)-
Methyl 6-amino-5-cyano-2-isopropyl-4-(thiophen-2-yl)-4H-
4H-pyran-3-carboxylate (4c).
Mp = 129–132°C; cream
pyran-3-carboxylate (4g).
Mp =127–131°C; yellow
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 (300 MHz; CDCl3), δ, ppm: 166.29,
163.61, 159.75, 157.75, 145.25, 129.66, 119.58, 118.85,
113.07, 112.37, 106.17, 62.16, 55.11, 51.77, 38.70,
29.10, 19.79, 19.13; 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.
powder; IR (KBr) (λmax, cmÀ1): 3415, 3337, 3211,
2968, 2189, 1698, 1668, 1631, 1598, 1407, 1344, 1263,
1
1086, 696; H-NMR (300 MHz; CDCl3), δ, ppm: 7.16
(dd, 1H, J = 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 = 6 Hz, 3H, CH3), 1.12 (d,
J = 6 Hz, 3H, CH3); 13C-NMR (300 MHz; CDCl3), δ,
ppm: 166.04, 163.76, 158.28, 148.25, 126.91, 124.52,
124.24, 118.73, 106.58, 61.91, 51.87, 33.86, 29.10,
19.49, 19.09; 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.
Journal of Heterocyclic Chemistry
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M. Habibi, A. Habibi, S. Hakimi Nasab, H. Dolati, and S. M. Mahdavi
Vol 000
Methyl 6-amino-4-(3-chlorophenyl)-5-cyano-2-isopropyl-4H-
powder; IR (KBr) (λmax, cmÀ1): 3456, 3328, 3181, 2983,
pyran-3-carboxylate (4h).
Mp = 146–149°C; white
2196, 1711, 1673, 1596, 1468, 1341, 1257, 1088, 845,
704; H-NMR (300 MHz; DMSO-d6), δ, ppm: 7.59 (s,
1
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: 7.06–7.26 (m,
1H, Ar-H), 7.43 (m, 7H, Ar-H), 7.10 (s, 2H, NH2), 4.98
(s, 1H, CH), 3.73 (q, 2H, CH2), 0.72 (t, 3H, CH3); 13C-
NMR (300 MHz; DMSO-d6), δ, ppm: 164.95, 159.20,
159.16, 155.61, 140.47, 133.00, 132.27, 131.64, 129.98,
128.87, 128.49, 128.12, 128.05, 119.08, 107.14, 60.22,
55.20, 36.33, 13.17; 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
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 = 6 Hz, 3H, CH3); 13C-NMR (300 MHz;
CDCl3), δ, ppm: 166.01, 164.07, 157.87, 145.72, 134.49,
129.94, 127.49, 127.40, 125.60, 118.56, 105.82, 61.61,
51.80, 38.62, 29.14, 19.74, 19.17; 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).
Mp =164–166°C; cream
Ethyl 6-amino-5-cyano-4-(3-methoxyphenyl)-2-phenyl-4H-
powder; IR (KBr) (λmax, cmÀ1): 3455, 3327, 2982, 2196,
1711, 1673, 1595, 1468, 1366, 1257, 1088, 845, 704;
1H-NMR (300 MHz; CDCl3), δ, ppm: 7.40–7.49 (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, 2H, CH2), 0,84 (t, 3H, CH3); 13C-
NMR (300 MHz; CDCl3), δ, ppm: 165,24, 158,27,
155,89, 138,83, 133,99, 133,69, 132,82, 131,09, 130,23,
129,80, 128,39, 128,13, 127,71, 118,26, 107,85, 60,91,
60,57, 60,02, 36,52, 36,20, 13,35; 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.
Ethyl 6-amino-4-(3-chlorophenyl)-5-cyano-2-phenyl-4H-py-
ran-3-carboxylate (4n). Mp =179-182°C; cream powder;
IR (KBr) (λmax, cmÀ1): 3400, 3330, 2202, 2987, 2199,
1672, 1472, 1372, 1337, 1276, 1092, 698, 528; 1H-
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, 2H, CH2), 0.83 (t, 3H, CH3); 13C-
NMR (300 MHz; CDCl3), δ, ppm: 165.57, 158.18,
154.94, 144.99, 134.57, 132.89, 130.18, 129.99, 128.78,
128.47, 128.11, 127.83, 127.75, 126.07, 118.50, 109.07,
pyran-3-carboxylate (4i).
Mp = 172–175°C; cream
powder; IR (KBr) (λmax, cmÀ1): 3408, 3326, 3200, 2963,
2195, 1673, 1596, 1491, 1372, 1338, 1260, 1086, 700;
1H-NMR (300 MHz; DMSO-d6), δ, ppm: 7.43 (s, 5H,
Ar-H), 7.27 (t, 1H, Ar-H), 7.01 (s, 2H, NH2), 6.82 (d,
2H, J =6 Hz, Ar-H), 6.75 (s, 1H, Ar-H), 4.4 (s, 1H, CH),
3.77 (q, 2H, CH2), 3.73 (s, 3H, CH3), 0.73 (3, 3H, CH3);
13C-NMR (300 MHz; DMSO-d6), δ, ppm: 165.48,
159.31, 159.17, 154.19, 145.64, 133.07, 129.87, 129.77,
128.4, 128.06, 119.64, 119.47, 113.36, 111.96, 108.86,
60.17, 56.83, 54.97, 13.21; 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.
Ethyl 6-amino-5-cyano-2-phenyl-4-(thiophen-2-yl)-4H-py-
ran-3-carboxylate (4j).
Mp = 171–173°C; light yellow
powder; IR (KBr) (λmax, cmÀ1): 3395, 3330, 3201, 2987,
2194, 1669, 1609, 1597, 1472, 1370, 1337, 1247, 1088,
1
694; H-NMR (300 MHz; DMSO-d6), δ, ppm: 7.45 (m,
6H, Ar-H), 7.14 (s, 2H, NH2), 6.94 (m, 2H, Ar-H), 4.76
(s, 1H, CH), 3.84 (q, 2H, CH2), 0.80 (t, 3H, CH3); 13C-
NMR (300 MHz; DMSO-d6), δ, ppm: 165.25, 159.59,
154.54, 148.72, 132.89, 130.01, 128.50, 128.04, 127.01,
125.16, 124.34, 119.52, 109.10, 60.35, 56.97, 34.84,
13.27; 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.
Ethyl 6-amino-5-cyano-4-(2,6-dichlorophenyl)-2-phenyl-4H-
61.27,
60.88,
39.56,
13.37;
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.
REFERENCES AND NOTES
pyran-3-carboxylate (4k).
Mp = 216–218°C; white
powder; IR (KBr) (λmax, cmÀ1): 3459, 3286, 3164, 2973,
2195, 1711, 1670, 1591, 1367, 1330, 1254, 1094, 790;
1H-NMR (300 MHz; DMSO-d6), δ, ppm: 7.27–7.46
(m, 8H, Ar-H), 7.11 (s, 2H, NH2), 5.53 (s, 1H, CH), 3.72
(q, 2H, CH2), 0.68 (t, 3H, CH3); 13C-NMR (300 MHz;
DMSO-d6), δ, ppm: 164.90, 159.76, 155.71, 136.08,
135.49, 135.11, 133.33, 130.57, 129.84, 129.56, 129.11,
128.60, 128.14, 128.09, 119.00, 105.07, 60.13, 52.35,
36.02, 13.13; 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.
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