Efficient Synthesis of 4-Phenyl-4H-pyran Derivatives via a DIPEA-catalyzed One-Pot Three-Component Reaction

Article abstract of DOI:10.1134/S107042801911023X

A novel one-pot approach has been developed for a high-yield synthesis of 4-phenyl-4H-pyran derivatives by the three-component condensation of dimethyl 3-oxopentanedioate or 3-oxo-3-arylpropanoic acid esters, aldehydes, with malononitrile in the presence

Full text of DOI:10.1134/S107042801911023X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 11, pp. 1791–1799. © Pleiades Publishing, Ltd., 2019.
Efficient Synthesis of 4-Phenyl-4H-pyran Derivatives
via a DIPEA-catalyzed One-Pot Three-Component Reaction
Jun Lia, Jie Lia, Shi-yu Hua, Ye Chena,*, and Ju Liua,**
a College of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning
Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, P.R. China
e-mail: *sy-chenye@163.com; **e-mail: liuju1216@126.com
Received June 20, 2019; revised July 24, 2019; accepted September 3, 2019
Abstract—A novel one-pot approach has been developed for a high-yield synthesis of 4-phenyl-4H-pyran
derivatives by the three-component condensation of dimethyl 3-oxopentanedioate or 3-oxo-3-arylpropanoic
acid esters, aldehydes, with malononitrile in the presence of a DIPEA catalyst in ethanol at room temperature.
The significant features of the present strategy include efficiency, high yield, inexpensive catalyst, mild
reaction conditions, and simple purification procedure.
Keywords: 4H-pyran, multicomponent reactions, synthetic methods
DOI: 10.1134/S107042801911023X
Multicomponent reactions (MCRs) have been widely
used in organic synthesis for the generation of complex
products. They provide an efficient and a powerful tool
for the production of a great diversity of molecules
without isolation of intermediates, which features high
atom-economy and excellent yields [1, 2]. A lot of
heterocycles have been prepared by one-pot MCRs as
the most efficient route to achieving structural
diversity [3, 4].
low yields, expensive catalysts, and long reactions
times. To the best of our knowledge, some basic
catalysts, too, have been involved in MCRs [20–23],
but the use of a DIPEA catalyst has never been
reported.
In view of the aforesaid and preliminary results of
our research on 4H-pyran derivatives, we designed a
series of novel 4-phenyl-4H-pyran derivatives and set
ourselves the goal was to develop a new methodology
for their synthesis via one-pot condensation of 3-oxo-
pentanedioates, malononitrile, and various aldehydes
[24, 25], using DIPEA as a catalyst. We started with
the condensation of 4-methoxybenzaldehyde (1a),
malononitrile (2), and dimethyl 3-oxopentanedioate (3)
at a molar ratio of 1 : 1 : 1 in ethanol as a solvent. To
evaluate the catalytic performance of the catalyst,
several basic catalysts were tested. As shown in Table 1,
DIPEA proved to be an optimal catalyst (yield 71%).
Further on the reaction conditions were optimized
using DIPEA. Varying the solvents (ethanol, methanol,
ethyl acetate, acetonitrile, DMF, and THF) showed that
no other tested solvent could provide product 4a in a
yield higher than ethanol (71%; Table 2, entry 1).
Derivatives of 4H-pyran were found to possess
anticancer, antiinflammatory, antimicrobial [5],
anticoagulant, and antianaphylactic activity [6–8]. On
the other hand, a fused pyran ring is a well-known
heterocycle and an important structural unit both in
natural compounds and synthetic heterocyclic
molecules. Many types of bioactive molecules with
broad medical and agrochemical applications contain a
fused pyran ring, 4-phenylpyran among them [9]. In
recent years, fused 4H-pyran and its derivatives have
attracted high interest of researchers focusing on the
development of efficient synthetic approaches and
identification of novel biologically active compounds
[10]. A lot of methods including various catalysts, such
as Triton B [11], Mg/La mixed oxide [12], L-proline
[13], Ni–Al2O3 [14], decaniobate ions [15], potassium
phthalimide–N-oxyl [16], SnCl2/nano SiO2 [17], silica
nanoparticles [18], and silica-bonded N-propyl-
piperazine sodium n-propionate [19], have been
developed. However, some of the mentioned methods
suffer from at least one of the following drawbacks:
The effect of the catalyst concentration was then
investigated. Catalyst loadings from 0.5–3 equiv were
tested (Table 3, entries 1–6). The reaction was carried
out with 0.5 equiv of DIPEA in EtOH at room tem-
perature (Table 3, entry 1), and the desired product was
obtained in 66% yield. Similar reactions were per-
1791

JUN LI et al.
Table 1. Effect of the catalyst on the synthesis of 4H-pyran 4a in ethanola
1792
Entry
Catalyst
Et3N
Yield, %
61
1
2
Pyridine
55
3
Piperidine
DIPEA
63
4
71
5
CH3COONH4
CH3COONa
DMAP
58
6
67
7
54
8
NaOH
21
9
N-Methylmorpholine
67
a
Catalyst 1 equiv, ethanol 20 mL, reaction time 4 h.
formed using 1 and 1.5 equivs of DIPEA (Table 3,
entries 2 and 3). The desired product was obtained in
71% and 73% yields, respectively. When the catalyst
concentration was increased further to 2, 2.5, and 3
equivs, the yields gradually decreased (Table 3, entries
4, 5 and 6).
dology with different aldehydes. Table 4 indicates that
all the reactions proceeded smoothly, and the desired
products were obtained in yields of 73–95%. In order
to further explore the versatility of the developed
protocol, a wide variety of reactions were investigated
with aromatic aldehydes 5 and 3-oxo-3-arylpropanoic
acid esters 6 containing electron-acceptor and electron-
donor substituents, as well as halogens in different
positions of the aromatic rings to obtain 4-aryl-4H-
pyran derivatives 7 in high yields (Table 5). The
resulting data suggested that the reactions can tolerate
a wide variety of differently substituted aldehydes and
3-oxo-3-arylpropanoic acid esters.
After the optimal solvent and catalyst had been
determined, the temperature effect on the reaction was
examined (Table 3, entries 3, 7, and 8). The product
was obtained in a yield of 73% at room temperature,
while the yields at 40 and under reflux were lower.
The obtained evidence allowed us to conclude that
the reaction was the most efficient when conducted with
1.5 equiv of DIPEA in EtOH at room temperature.
All the synthesized compounds were previously
unknown. and were characterized by the CHN analyses
and 1H and 13C NMR and ESI–MS spectra.
With the optimal reaction conditions, we
investigated the scope and limitations of the metho-
Table 2. Effect of the solvent on the synthesis of 4H-pyran 4a in the presence DIPEAa
Entry
Solvent
Yield, %
1
2
3
4
5
6
EtOH
MeOH
71
64
53
59
54
39
Ethyl acetate
Acetonitrile
DMF
THF
a
DIPEA 1 equiv, solvent 20 mL, reaction time 4 h (2h in THF).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 11 2019

EFFICIENT SYNTHESIS OF 4-PHENYL-4H-PYRAN DERIVATIVES
1793
Table 3. Effect of the DIPEA concentration and temperature on the synthesis of 4H-pyran 4a in ethanola
Entry
DIPEA concentration, equiv
T, °C
Yield, %
1
0.5
1
rt
66
71
73
71
68
65
63
28
2
rt
3
1.5
2
rt
rt
4
5
2.5
3
rt
6
rt
7
8
1.5
1.5
40
Reflux
a
Ethanol, 20 mL.
In conclusion, we have developed a simple, fast,
tallization, rather than column chromatography, which
facilitates the work-up procedure. The mentioned advan-
tages make the described protocol an attraction option
for the synthesis of 4-phenyl-4H-pyran derivatives.
and high-yield synthesis of 4-phenyl-4H-pyran deri-
vatives 4a–4i and 7a–7k via a DIPEA-catalyzed one-
pot three-component reaction of aryl aldehydes, malo-
nonitrile, and 3-oxopropanoic acid esters. The use of
inexpensive starting materials, mild reaction conditions,
and high yields are some notable characteristics of the
developed strategy. The reaction products are
easily separated by filtration and purified by recrys-
EXPERIMENTAL
All reagents were obtained commercially and used
without further purification unless otherwise specified.
Table 4. Synthesis of 4-aryl-4H-pyran derivatives 4a–4i
R
O
O
O
O
R
CN
CN
CN
DIPEA (1.5 equiv)
H3CO
+
+
H3CO
OCH3
EtOH, rt, 4 h
CHO
O
NH2
H3CO
O
1a_1i
2
3
4a_4i
Product no.
R
Yield, %
4a
4b
4c
4d
4e
4f
4-OCH3
73
76
80
84
95
79
76
78
78
2,3,4-(OCH3)3
4-CF3
4-Ph
3-NO2
2,4-Cl2
2-Cl
4g
4h
4i
4-F
4-Cl
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 11 2019

JUN LI et al.
1794
Table 5. Synthesis of 4-aryl-4H-pyran derivatives 7a–7k
R
O
O
O
CN
R1
CN
DIPEA (1.5 equiv)
EtOH, rt, 4 h
R1
O
R
O
+
+
CN
X
O
NH2
CHO
R2
X
R2
5a_5k
2
6a_6k
7a_7k
Product no.
X
C
N
C
C
C
C
C
N
N
N
C
R1
Et
R2
R
Yield, %
91
7a
7b
7c
7d
7e
7f
4-COOEt
2-Cl
CH3
Et
H
4-COOEt
4-COOEt
2,4-Cl2
4-OCH3
4-F
2,3,4-(OCH3)3
2,4-Cl2
91
85
Et
4-OCH3
82
CH3
Et
4-F
89
2,3,4-(OCH3)3
4-OCH3
79
7g
7h
7i
Et
80
CH3
CH3
CH3
Et
4-OCH3
H
3-Br-4,5-(OCH3)2
3-NO2
87
89
7j
H
4-OCH3
78
7k
4-F
3-Br-4,5-(OCH3)2
81
The melting points were taken on a Beijing Taike X-4
microscopy melting point apparatus and were
uncorrected. The 1H and 13C NMR spectra were
recorded on a Bruker Biospin 600 MHz instrument in
CDCl3 with TMS as internal standard. All chemical
shifts are reported in ppm. The IR spectra were
recorded on a PerkinElmer Spectrum One FTIR
spectrometer in KBr pellets. The mass spectra were
measured on an Agilent 6460 QQQ LC/MS system
(ESI, direct injection). The elemental analyses were
obtained on a Carlo Erba 1108 analyzer.
recrystallized from EtOH to obtain the desired
product.
Methyl 6-amino-5-cyano-2-(2-methoxy-2-oxo-
ethyl)-4-(4-methoxyphenyl)-4H-pyran-3-carboxy-
late (4a). Yield 73%, mp 154–156°C (157–159°C
[26]). IR spectrum, ν, cm–1: 3415 (NH2), 3326 (NH2),
2187 (CN), 1757 (C=O), 1699 (C=O), 1676 (C=Carom),
1641, 1603, 1439, 1415, 1362, 1329, 1275, 1167,
1
1120, 1068, 861 (δC–Harom), 773. H NMR spectrum
(CDCl3), δ, ppm: 7.20 d (2Harom, J 8.4 Hz), 6.87 d
(2Harom, J 8.4 Hz), 4.52 s (2H, NH2), 4.45 s (1H, CH),
3.94 d (1H, CH2, J 16.8 Hz), 3.80 s (3H, CH3),
3.77 br.s (4H, CH3, CH2), 3.61 s (3H, CH3). 13C NMR
spectrum (CDCl3), δ, ppm: 168.87 (CO), 165.83
(CH2CO), 158.82, 157.15, 152.74, 135.60, 128.54,
118.64, 114.13, 110.55, 63.02, 55.25 (OCH3), 52.50
(COOCH3), 52.00 (CH2COOCH3), 37.84 (CH), 37.82
(CH2). Mass spectrum: m/z 381.2 [M + Na]+. Found, %:
C 60.38; H 5.02; N 7.85. C18H18N2O6. Calculated, %:
C 60.33; H 5.06; N 7.82.
Synthesis of 4-phenyl-4H-pyran derivatives 4a–4i
and 7a–7k (general procedure). A mixture of aldehyde
1a–1i or 5a–5k (4 mmol), malononitrile (4 mmol),
dimethyl 3-oxo-1,5-pentanedioate or methyl/ethyl
3-oxo-3-arylpropanoate (4 mmol), respectively, and
DIPEA (6 mmol) in EtOH (20 mL) was stirred at room
temperature. The reaction progress was monitored by
TLC. After completion of the reaction, the solid
material that formed was collected by filtration and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 11 2019

EFFICIENT SYNTHESIS OF 4-PHENYL-4H-PYRAN DERIVATIVES
1795
Methyl 6-amino-5-cyano-2-(2-methoxy-2-oxo-
ethyl)-4-(2,3,4-trimethoxyphenyl)-4H-pyran-3-car-
boxylate (4b). Yield 76%, mp 158–160°C. IR spec-
trum, ν, cm–1: 3476 (NH2), 3340 (NH2), 3000, 2952,
2835, 2188(CN), 1747 (C=O), 1703 (C=O), 1682
(C=Carom), 1640, 1598, 1493, 1465, 1399, 1354, 1280,
128.75, 127.83, 127.56, 127.26, 127.08, 118.62,
110.27, 62.62, 52.54 (COOCH3), 52.09 (CH2CO·
OCH3), 38.28 (CH), 37.89 (CH2). Mass spectrum: m/z
427.7 [M + Na]+. Found, %: C 68.33; H 4.94; N 6.96.
C23H20N2O5. Calculated, %: C 68.31; H 4.98; N 6.93.
1
Methyl 6-amino-5-cyano-2-(2-methoxy-2-oxo-
ethyl)-4-(3-nitrophenyl)-4H-pyran-3-carboxylate
(4e). Yield 95%, mp 155–156°C (135–136°C [26]). IR
spectrum, ν, cm–1: 3390 (NH2), 3197 (NH2), 2950,
2923, 2197(CN), 1754 (C=O), 1680 (C=O), 1637
1174, 1094, 1070, 1039, 811 (δC–Harom). H NMR
spectrum (CDCl3), δ, ppm: 6.90 d (2Harom, J 8.4 Hz),
6.65 d (2Harom, J 8.4 Hz), 4.84 s (1H, CH), 4.50 s (2H,
NH2), 3.97 s (3H, CH3), 3.92 d (1H, CH2, J 16.8 Hz),
3.88 s (3H, CH3), 3.85 s (3H, CH3), 3.79 br.s (4H,
CH2, CH3), 3.59 s (3H, CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 168.94 (CO), 165.93 (CH2CO),
157.46, 153.18, 152.92, 151.41, 141.89, 129.17,
123.28, 118.87, 110.13, 107.45, 62.61 (3-OCH3), 61.27
(2-OCH3), 60.66, 55.91 (4-OCH3), 52.45 (COOCH3),
51.88 (CH2COOCH3), 37.83 (CH), 32.24 (CH2). Mass
spectrum: m/z 441.5 [M + Na]+. Found, %: C 57.35; H
5.31; N 6.73. C20H22N2O8. Calculated, %: C 57.41; H
5.30; N 6.70.
1
(C=Carom), 1535 (NO2), 1384, 1354, 1273, 1070. H
NMR spectrum (CDCl3), δ, ppm: 8.12 br.s (2Harom),
7.65 d (1Harom, J 7.8 Hz), 7.52 t (1Harom, J 7.8 Hz),
4.77 s (2H, NH2), 4.61 s (1H, CH), 4.07 d (1H, CH2, J
16.8 Hz), 3.79 s (3H, CH3), 3.71 d (1H, CH2, J
16.8 Hz), 3.60 s (3H, CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 168.53 (CO), 165.16 (CH2CO),
157.66, 154.37, 148.70, 145.71, 133.83, 129.79, 122.60,
122.35, 118.10, 109.14, 61.17, 52.75 (COOCH3),
52.24 (CH2COOCH3), 38.57 (CH), 38.10 (CH2). Mass
spectrum: m/z 395.9 [M + Na]+. Found, %: C 54.65; H
4.03; N 11.29. C17H15N3O7. Calculated, %: C 54.69; H
4.05; N 11.26.
Methyl 6-amino-5-cyano-2-(2-methoxy-2-oxo-
ethyl)-4-[4-(trifluoromethyl)phenyl]-4H-pyran-3-
carboxylate (4c). Yield 80%, mp 156–158°C. IR
spectrum, ν, cm–1: 3415 (NH2), 3326 (NH2), 3005,
2956, 2187 (CN), 1757 (C=O), 1699 (C=O), 1676
(C=Carom), 1642, 1603, 1439, 1415, 1362, 1329, 1275,
1167, 1120, 1068, 861 (δC–Harom), 773 (CF3). 1H NMR
spectrum (CDCl3), δ, ppm: 7.61 d (2Harom, J 8.4 Hz),
7.42 d (2Harom, J 8.4 Hz), 4.62 s (2H, NH2), 4.56 s (1H,
CH), 4.04 d (1H, CH2, J 16.8 Hz), 3.79 s (3H, CH3),
3.74 d (1H, CH2, J 16.8 Hz), 3.61 s (3H, CH3). 13C
NMR spectrum (CDCl3), δ, ppm: 168.69 (CO), 165.34
(CH2CO), 157.44, 153.89, 147.22, 129.60, 129.51,
127.77, 125.85, 125.00, 123.20, 118.19, 109.62, 61.91,
52.57 (COOCH3), 52.14 (CH2COOCH3), 38.53 (CH),
37.90 (CH2). Mass spectrum: m/z 419.7 [M + Na]+.
Found, %: C 54.51; H 3.84; N 7.10. C18H15F3N2O5.
Calculated, %: C 54.55; H 3.82; N7.07.
Methyl 6-amino-5-cyano-4-(2,4-dichlorophenyl)-
2-(2-methoxy-2-oxoethyl)-4H-pyran-3-carboxylate
(4f). Yield 79%, mp 152–155°C (142–143°C [26]). IR
spectrum, ν, cm–1: 3468 (NH2), 3344 (NH2), 2955,
2196 (CN), 1737 (C=O), 1695 (C=O), 1678 (C=Carom),
1637, 1384, 1363, 1277, 1188, 1168, 1124, 1069, 842
(δC–Harom). 1H NMR spectrum (CDCl3), δ, ppm: 7.37 d
(1Harom, J 1.8 Hz), 7.23 m (2Harom), 5.08 s (1H, CH),
4.63 s (2H, NH2), 4.04 d (1Harom, CH2, J 16.8 Hz), 3.76 s
(3H, CH3), 3.69 d (1Harom, CH2, J 16.8 Hz), 3.57 s (3H,
CH3). 13C NMR spectrum (CDCl3), δ, ppm: 168.72
(CO), 165.30 (CH2CO), 157.61, 154.20, 139.57,
133.56, 130.81, 129.49, 127.99, 118.00, 109.13, 60.94,
52.57 (COOCH3), 52.13 (CH2COOCH3), 37.80 (CH),
34.73 (CH2). Mass spectrum: m/z 419.6 [M + Na]+.
Found, %: C 51.45; H 3.53; N 7.08. C17H14Cl2N2O5.
Calculated, %: C 51.41; H 3.55; N 7.05.
Methyl 4-([1,1'-biphenyl]-4-yl)-6-amino-5-cyano-
2-(2-methoxy-2-oxoethyl)-4H-pyran-3-carboxylate
(4d). Yield 84%, mp 180–186°C. IR spectrum, ν, cm–1:
3412 (NH2), 3324 (NH2), 3027 (C–Harom), 2950, 2183
(CN), 1738 (C=O), 1707 (C=O), 1669 (C=Carom), 1637
(C=Carom), 1438, 1384, 1157, 1068, 747 (δC–Harom),
Methyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-
(2-methoxy-2-oxoethyl)-4H-pyran-3-carboxylate
1
(4g). Yield 76%, mp 161–164°C. H NMR spectrum
1
(CDCl3), δ, ppm: 7.34 m (1Harom), 7.29 m (1Harom),
7.24 m (1Harom), 7.15 m (1Harom), 5.12 s (1H, CH),
4.66 s (2H, NH2), 3.99 d (1H, CH2, J 16.8 Hz), 3.75 m
(4H, CH3, CH2), 3.56 s (3H, CH3). 13C NMR spectrum
(CDCl3), δ, ppm: 168.81 (CO), 165.55 (CH2CO),
157.67, 153.92, 140.84, 132.89, 129.87, 129.77,
697. H NMR spectrum (CDCl3), δ, ppm: 7.58 m
(4Harom), 7.45 m (2Harom), 7.35 m (3Harom), 4.57 s (2H,
NH2), 4.55 s (1H, CH), 3.99 d (1H, CH2, J 16.8 Hz),
3.80 t (4H, CH3, CH2), 3.63 s (3H, CH3). 13C NMR
spectrum (CDCl3), δ, ppm: 168.85 (CO), 165.76
(CH2CO), 157.39, 153.25, 142.35, 140.78, 140.24,
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JUN LI et al.
1796
128.52, 127.57, 118.29, 109.48, 61.16, 52.54 (CO·
OCH3), 52.03 (CH2COOCH3), 37.79 (CH), 35.04
(CH2). Mass spectrum: m/z 385.7 [M + Na]+. Found, %:
C 56.24; H 4.15; N 7.76. C17H15ClN2O5. Calculated, %:
C 56.29; H 4.17; N 7.72.
CH), 4.67 br.s (2H, NH2), 4.40 q (2H, OCH2, J 7.2 Hz),
3.84 q (2H, OCH2, J 7.2 Hz), 1.40 t (3H, CH3, J 7.2 Hz),
0.84 t (3H, CH3, J 7.2 Hz). 13C NMR spectrum (CDCl3),
δ, ppm: 165.88 (PhCO), 165.04 (CO), 158.17, 154.54,
139.82, 137.21, 133.43, 131.83, 130.33, 130.21,
129.33, 128.84, 128.57, 127.44, 118.33, 109.22, 61.34
(COOCH2CH3), 61.04 (PhCOOCH2CH3), 60.58, 36.96
(CH), 14.32 (COOCH2CH3), 13.43 (PhCOOCH2CH3).
Mass spectrum: m/z 453.4 [M + H]+. Found, %: C
63.62; H 4.63; N 6.15. C24H21ClN2O5. Calculated, %:
C 63.65; H 4.67; N 6.19.
Methyl 6-amino-5-cyano-4-(4-fluorophenyl)-2-
(2-methoxy-2-oxoethyl)-4H-pyran-3-carboxylate
(4h). Yield 78%, mp 154–155°C. IR spectrum, ν, cm–1:
3418 (NH2), 3835 (NH2), 2956, 2912, 2192 (CN), 1740
(C=O), 1683 (C=O), 1645 (C=Carom), 1609, 1510, 1439,
1407, 1347, 1269, 1228, 1144, 1067, 851 (δC–Harom),
1
Methyl 6-amino-5-cyano-2-(pyridin-4-yl)-4-
(2,3,4-trimethoxyphenyl)-4H-pyran-3-carboxylate
(7b). Yield 91%, mp 178–181°C. IR spectrum, ν, cm–1:
3461 (NH2), 3415 (NH2), 3005, 2950, 2191 (CN),
1706 (C=O), 1675, 1617 (C=Carom), 1596, 1495, 1406,
764. H NMR spectrum (CDCl3), δ, ppm: 7.24 m
(2Harom), 7.00 m (2Harom), 4.61 s (2H, NH2), 4.46 s
(1H, CH), 3.96 d (1H, CH2, J 16.8 Hz), 3.76 s (3H,
CH3), 3.72 d (1H, CH2, J 16.8 Hz), 3.58 s (3H, CH3).
13C NMR spectrum (CDCl3), δ, ppm: 168.81 (CO),
165.62 (CH2CO), 162.84, 161.22, 157.32, 153.20,
139.23, 129.05, 118.49, 115.70, 115.56, 110.18, 62.34,
52.54 (COOCH3), 52.05 (CH2COOCH3), 37.98 (CH),
37.87 (CH2). Mass spectrum: m/z 369.8 [M + Na]+.
Found, %: C 58.98; H 4.33; N 8.12. C17H15FN2O5.
Calculated, %: C 58.96; H 4.37; N 8.09.
1
1344, 1294, 1254, 1156, 1102. H NMR spectrum
(CDCl3), δ, ppm: 8.72 br.s (2Harom), 7.39 br.s (2Harom),
6.90 d (1Harom, J 8.4 Hz), 6.66 d (1Harom, J 8.4 Hz),
4.84 s (1H, CH), 4.62 br.s (2H, NH2), 3.98 s (3H,
OCH3), 3.89 s (3H, OCH3), 3.87 s (3H, OCH3), 3.45 s
(3H, OCH3). 13C NMR spectrum (CDCl3), δ, ppm:
165.69 (CO), 157.86, 153.54, 152.12, 151.33, 148.98,
142.21, 141.87, 127.45, 123.73, 123.01, 118.63,
111.27, 107.24, 61.77 (3-OCH3), 61.24 (2-OCH3),
60.70, 55.94 (4-OCH3), 51.98 (COOCH3), 34.86 (CH).
Mass spectrum: m/z 423.8 [M + H]+. Found, %: C
62.46; H 5.04; N 9.90. C22H21N3O6. Calculated, %: C
62.41; H 5.00; N 9.92.
Methyl 6-amino-4-(4-chlorophenyl)-5-cyano-2-
(2-methoxy-2-oxoethyl)-4H-pyran-3-carboxylate
(4i). Yield 78%, mp 148–152°C (142–143°C [26]). IR
spectrum, ν, cm–1: 3410 (NH2), 3329 (NH2), 2956,
2923, 2196 (CN), 1739 (C=O), 1682 (C=O), 1640
(C=Carom), 1610, 1438, 1384, 1349, 1269, 1149, 1065,
1
840 (δC–Harom). H NMR spectrum (CDCl3), δ, ppm:
Ethyl 6-amino-5-cyano-4-(2,4-dichlorophenyl)-2-
[4-(ethoxycarbonyl)phenyl]-4H-pyran-3-carboxy-
late (7c). Yield 85%, mp 170–172°C. IR spectrum, ν,
cm–1: 3430 (NH2), 3308 (NH2), 2988, 2923, 2188
(CN), 1714 (C=O), 1699 (C=O), 1601 (C=Carom),
1514, 1468, 1384, 1329, 1290, 1253, 1154, 1091, 1021,
7.32 d (2Harom, J 8.4 Hz), 7.24 d (2Harom, J 8.4 Hz),
4.67 s (2H, NH2), 4.49 s (1H, CH), 4.00 d (1H, CH2, J
16.8 Hz), 3.79 s (3H, CH3), 3.75 d (2H, CH2, J
16.8 Hz), 3.61 s (3H, CH3). 13C NMR spectrum (CDCl3),
δ, ppm: 168.77 (CO), 165.52 (CH2CO), 157.38, 153.44,
141.95, 133.17, 128.96, 128.82, 118.41, 109.90, 62.05,
52.56 (COOCH3), 52.09 (CH2COOCH3), 38.13 (CH),
37.89 (CH2). Mass spectrum: m/z 384.6 [M + Na]+.
Found, %: C 56.26; H 4.13; N 7.75. C17H15ClN2O5.
Calculated, %: C 56.29; H 4.17; N 7.73.
1
858 (δC–Harom). H NMR spectrum (CDCl3), δ, ppm:
8.08 d (2Harom, J 8.4 Hz), 7.49 d (2Harom, J 8.4 Hz),
7.40 d (1Harom, J 1.2 Hz), 7.26 br.s (2Harom), 5.13 s
(1H, CH), 4.69 s (2H, NH2), 3.99 s (3H, Ar-OCH3),
4.40 q (2H, COCH2, J 7.2 Hz), 3.85 q (2H, COCH2, J
7.2 Hz), 1.40 t (3H, CH3, J 7.2 Hz), 0.86 t (3H, CH3, J
7.2 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 165.82
(PhCO), 164.89 (CO), 158.20, 154.86, 138.54, 137.03,
134.12, 133.94, 131.96, 131.22, 129.97, 129.35,
128.55, 127.81, 118.10, 108.77, 61.37 (COOCH2CH3),
61.16 (PhCOOCH2CH3), 60.17, 36.70 (CH), 14.32
(COOCH2CH3), 13.47 (PhCOOCH2CH3). Mass spec-
trum: m/z 487.5 [M + H]+. Found, %: C 59.13; H 4.11;
N 5.78. C24H20Cl2N2O5. Calculated, %: C 59.15; H
4.14; N 5.75.
Ehyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-(4-
(ethoxycarbonyl)phenyl)-4H-pyran-3-carboxylate
(7a). Yield 91%, mp 230–232°C. IR spectrum, ν, cm–1:
3416 (NH2), 3335 (NH2), 3030, 3005, 2951, 2202
(CN), 1742 (C=O), 1685 (C=O), 1647 (C=Carom),
1609, 1438, 1403, 1355, 1336, 1271, 1239, 1155,
1063, 830 (δC–Harom), 755. 1H NMR spectrum (CDCl3),
δ, ppm: 8.08 d (2Harom, J 7.8 Hz), 7.50 d (2Harom, J
7.8 Hz), 7.37 d (1Harom, J 8.4 Hz), 7.33 d (1Harom, J
7.8 Hz), 7.27 m (1Harom), 7.20 m (1Harom), 5.18 s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 11 2019

EFFICIENT SYNTHESIS OF 4-PHENYL-4H-PYRAN DERIVATIVES
1797
Ethyl 6-amino-5-cyano-2-(4-(ethoxycarbonyl)-
phenyl)-4-(4-methoxyphenyl)-4H-pyran-3-carboxy-
late (7d). Yield 82%, mp 181–184°C. IR spectrum, ν,
cm–1: 3416 (NH2), 3316 (NH2), 3195, 2979, 2938,
2189 (CN), 1715 (C=O), 1674 (C=O), 1605 (C=Carom),
1510, 1464, 1406, 1367, 1328, 1314, 1291, 1174,
1154, 1127, 1093, 1032, 1021, 859 (δC–Harom), 778. 1H
NMR spectrum (CDCl3), δ, ppm: 8.09 d (2Harom, J
8.4 Hz), 7.51 d (2Harom, J 8.4 Hz), 7.26 d (2Harom, J
8.4 Hz), 6.90 d (2Harom, J 8.4 Hz), 4.60 br.s (2H, NH2),
4.56 s (1H, CH), 4.42 q (2H, COCH2, J 7.2 Hz), 3.87 q
(2H, COCH2, J 7.2 Hz), 3.82 s (3H, Ar-OCH3), 1.43 t
(3H, CH3, J 7.2 Hz), 0.86 t (3H, CH3, J 7.2 Hz). 13C
NMR spectrum (CDCl3), δ, ppm: 165.88 (PhCO),
165.57 (CO), 159.01, 157.75, 152.91, 137.31, 134.84,
131.75, 129.28, 128.86, 128.58, 118.67, 114.20,
110.92, 62.39 (COOCH2CH3), 61.33 (PhCOOCH2·
CH3), 60.98, 55.28 (OCH3), 39.04 (CH), 14.31 (CO·
OCH2CH3), 13.50 (PhCOOCH2CH3). Mass spectrum:
m/z 449.1 [M + H]+. Found, %: C 66.92; H 5.35; N
6.29. C25H24N2O6. Calculated, %: C 66.95; H 5.39; N
6.25.
(CO), 160.92, 158.29, 154.31, 153.13, 152.02, 142.10,
130.05, 128.67, 125.52, 123.71, 119.29, 113.47,
108.58, 107.19, 61.82 (CH2CH3), 61.25 (3-OCH3),
60.65 (2-OCH3), 60.63, 55.94 (4-OCH3), 55.38
(PhOCH3), 34.56 (CH), 13.64 (CH2CH3). Mass spec-
trum: m/z 467.3 [M + H]+. Found, %: C 64.32; H 5.60;
N 6.03. C25H26N2O7. Calculated, %: C 64.37; H 5.62;
N 6.01.
Ethyl 6-amino-5-cyano-2-(4-fluorophenyl)-4-(4-
methoxyphenyl)-4H-pyran-3-carboxylate (7g). Yield
80%, mp 156–159°C. IR spectrum, ν, cm–1: 3386
(NH2), 3326 (NH2), 3204, 2981, 2937, 2194 (CN),
1715 (C=O), 1681 (C=O), 1605 (C=Carom), 1510, 1464,
1409, 1368, 1335, 1253, 1175, 1154, 1083, 1032, 838
1
(δC–Harom), 817. H NMR spectrum (CDCl3), δ, ppm:
7.43 m (2Harom), 7.24 d (2Harom, J 8.4 Hz), 7.11 t
(2Harom, J 8.4 Hz), 6.90 d (2Harom, J 8.4 Hz), 4.60 br.s
(3H, NH2, CH), 4.42 q (2H, CH2, J 7.2 Hz), 3.88 q
(2H, CH2, J 7.2 Hz), 3.81 s (3H, OCH3), 0.89 t (3H,
CH3, J 7.2 Hz). 13C NMR spectrum (CDCl3), δ, ppm:
165.79, 164.44, 162.78, 158.96, 157.82, 153.10,
135.09, 130.74, 130.69, 129.22, 129.20, 128.82,
118.79, 115.33, 115.19, 114.17, 110.19, 62.31
(CH2CH3), 60.88 (4-OCH3), 55.28, 39.06 (CH), 13.55
(CH2CH3). Mass spectrum: m/z 395.4 [M + H]+.
Found, %: C 67.04; H 4.89; N 7.09. C22H19FN2O4.
Calculated, %: C 67.00; H 4.86; N 7.10.
Methyl 6-amino-5-cyano-2-(2,4-dichlorophenyl)-
4-(4-fluorophenyl)-4H-pyran-3-carboxylate (7e).
Yield 89%, mp 149–152°C. IR spectrum, ν, cm–1: 3412
(NH2), 2950, 2923, 2198 (CN), 1680 (C=O), 1637
(C=Carom), 1583, 1507, 1384, 1350, 1263, 1155, 1091,
1
847 (δC–Harom). H NMR spectrum (CDCl3), δ, ppm:
Methyl 6-amino-4-(3-bromo-4,5-dimethoxyphe-
nyl)-5-cyano-2-(6-methoxypyridin-3-yl)-4H-pyran-
3-carboxylate (7h). Yield 87%, mp 178–181°C. IR
spectrum, ν, cm–1: 3414 (NH2), 3323 (NH2), 2954,
2193 (CN), 1700 (C=O), 1671 (C=O), 1601 (C=Carom),
1567, 1493, 1377, 1356, 1287, 1248, 1154, 1131, 1089,
1044, 1016, 1004, 830 (δC–Harom), 764. 1H NMR
spectrum (CDCl3), δ, ppm: 8.24 d (1Harom, J 2.4 Hz),
7.63 d.d (1Harom, J 2.4, 9.0 Hz), 7.01 d (1Harom, J
1.8 Hz), 6.80 m (2Harom), 4.67 br.s (2H, NH2), 4.54 s
(1H, CH), 3.98 s (3H, OCH3), 3.87 s (3H, OCH3), 3.84 s
(3H, OCH3), 3.49 s (3H, OCH3). 13C NMR spectrum
(CDCl3), δ, ppm: 165.90 (CO), 165.11, 158.00, 153.74,
153.16, 147.40, 145.79, 40.03, 138.75, 123.36, 121.96,
118.45, 118.11, 111.38, 110.30, 109.12, 61.67 (4-
OCH3), 60.57, 56.16 (5-OCH3), 53.88 (Ar-OCH3),
52.04 (COOCH3), 39.36 (CH). Mass spectrum: m/z
502.1 [M + H]+. Found, %: C 52.64; H 4.03; N 8.337.
С22H20BrN3O6C. Calculated, %: C 52.60; H 4.01; N
8.37.
7.51 s (1Harom), 7.33 m (4Harom), 7.06 t (2Harom, J
8.4 Hz), 4.64 s (1H, CH), 4.59 s (2H, NH2), 3.44 s (3H,
CH3). 13C NMR spectrum (CDCl3), δ, ppm: 164.73
(CO), 162.99, 161.36, 157.81, 152.38, 138.70, 136.59,
131.18, 129.62, 129.34, 129.29, 127.19, 118.33,
115.83, 115.69, 111.82, 62.28, 52.02 (COOCH3), 38.61
(CH). Mass spectrum: m/z 419.2 [M + H]+. Found, %:
C 57.32; H 3.16; N 6.64. C20H13Cl2FN2O3. Calculated, %:
C 57.30; H 3.13; N 6.68.
Ethyl 6-amino-5-cyano-2-(4-methoxyphenyl)-4-
(2,3,4-trimethoxyphenyl)-4H-pyran-3-carboxylate
(7f). Yield 79%, mp 142–145°C. IR spectrum, ν, cm–1:
3459 (NH2), 3326 (NH2), 2938, 2837, 2193 (CN),
1697 (C=O), 1677 (C=O), 1603 (C=Carom), 1514, 1491,
1465, 1418, 1340, 1277, 1253, 1176, 1095, 1042, 838
1
(δC–Harom),791. H NMR spectrum (CDCl3), δ, ppm:
7.39 d (2Harom, J 8.4 Hz), 6.92 m (3Harom), 6.65 d
(1Harom, J 8.4 Hz), 4.85 s (1H, CH), 4.51 s (2H, NH2),
3.99 s (3H, Ar-OCH3), 3.99 m (5H, Ar-OCH3,
COCH2), 3.86 s (6H, Ar-OCH3), 0.92 t (3H, CH3, J
7.2 Hz). 13C NMR spectrum (CDCl3), δ, ppm: 166.33
Methyl 6-amino-5-cyano-4-(3-nitrophenyl)-2-
(pyridin-4-yl)-4H-pyran-3-carboxylate (7i). Yield
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 11 2019

JUN LI et al.
1798
1
FUNDING
89%, mp 177–180°C. H NMR spectrum (CDCl3), δ,
ppm: 8.73 d (2Harom, J 6.0 Hz), 8.17 d (2Harom, J 1.8 Hz),
7.68 d (1Harom, J 7.7 Hz), 7.57 d (1Harom, J 8.4 Hz),
7.34 q (2Harom), 4.7 d (2H, NH2, J 12.6 Hz), 3.41 s (3H,
OCH3). 13C NMR spectrum (CDCl3), δ, ppm: 165.03
(CO), 158.01, 153.09, 150.02, 148.80, 144.56, 140.27,
134.08, 129.96, 123.02, 122.60, 117.74, 110.05, 110.00,
60.95, 62.17 (COOCH3), 39.55 (CH). Mass spectrum:
m/z 379.6 [M + H]+. Found, %: C 60.30; H 3.71; N 14.86.
C19H14N4O5. Calculated, %: C 60.32; H 3.73; N 14.81.
This study was financially supported by the Shenyang
Science & Technology project (project no. 18-013-0-03) and
Natural Science Funds for Young Scholar of Liaoning
University (project no. LDQN201436).
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
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78%, mp 178–180°C. H NMR spectrum (CDCl3), δ,
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1.8 Hz), 6.83 br.s (1Harom), 4.65 s (2H, NH2), 4.56 s
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153.86, 153.69, 145.79, 140.00, 130.75, 128.96,
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