An Efficient Synthesis of Tetracyclic Pyrano[2,3-d]pyrimidines

Article abstract of DOI:10.1002/jhet.2630

A series of pyrano[2,3-d]pyrimidine derivatives have been synthesized by the reaction of 2-amino-3-cyano-4H-pyrans and acetic anhydride with acid catalyst. This method is very efficient because of short reaction times and easy work-up, and it provides an

Full text of DOI:10.1002/jhet.2630

Month 2016
An Efficient Synthesis of Tetracyclic Pyrano[2,3-d]pyrimidines
*
Zhi-Lan Lin, Jun-Min Zhang, and Yuan Gao
College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, Guangdong 518060
People’s Republic of China
*
E-mail: szgaoy311@163.com
Received December 4, 2015
DOI 10.1002/jhet.2630
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A series of pyrano[2,3-d]pyrimidine derivatives have been synthesized by the reaction of 2-amino-3-
cyano-4H-pyrans and acetic anhydride with acid catalyst . This method is very efficient because of short
reaction times and easy work-up, and it provides an efficient and promising synthetic strategy for the
construction of the tetracyclic pyrano[2,3-d]pyrimidine skeleton. The X-ray crystal structures of products
are confirmed, and the possible mechanism is provided in this paper.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
RESULTS AND DISCUSSION
Pyran scaffolds are an important class of heterocycles
widely distributed in nature, including iridoids, polyether
antibiotics, carbohydrates, pheromones, and alkaloids
[1,2]. Moreover, pyran derivatives are well known for
pharmacological and biological properties. They can be an-
titumor [3], antiallergic [4], antiviral [5], estrogenic [6], an-
tibacterial [7], spasmolytic [8], and antifungal [9], as well
as inhibit calcium signaling [10]. Fused pyrimidines, such
as pyrano[2,3-d]pyrimidines, pyrido[2,3-d]pyrimidines, or
pyrazo[3,4-d]pyrimidines, are also reported to have a wide
range of biological activities [11–15]. The synthesis of
compounds containing a pyran and a pyrimidine ring show
significant synthetic challenges.
Of the many methods available for the synthesis of pyrano
[2,3-d]pyrimidines, the most widely used is the one-pot reac-
tion of aromatic aldehydes, compounds with active α-hydro-
gen (Meldrum’s acid or Malononitrile), and compounds with
the pyrimidinone skeleton (barbituric acid or 2-amino-4,6-
dihydroxypyrimidine) [16–19]. However, less previous works
have employed the tricyclic pyrans to build pyrano[2,3-d]py-
rimidines skeleton directly. In recent work, we have studied
the reaction of the 2-amino-3-cyano-4H-pyran derivatives
with acetic anhydride in the presence of various catalysts
[20]. Herein, we report a facile and rapid route for the syn-
thesis of tetracyclic pyrano[2,3-d]pyrimidine derivatives
with acid catalyst. As far as we know, there are no similar
reports in the literature on the X-ray crystal structure of
the corresponding products and the possible mechanism.
In initial experiments, the mixtures of 2-amino-4-(2-nitrophe-
nyl)-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-
carbonitrile 1a and acetic anhydride were heated at the
temperature in the range of 60–120°C for 30 min (Ta-
ble 1, entry 1). Only trace amount of product 4a was
formed even extending the reaction time to 14 h (Table 1,
entries 1 and 2). Referring to the literature [21], we next
investigated the above reaction in the presence of
20 mol% of various acid catalysts in heated acetic anhy-
dride. The results showed that the sulfuric acid-catalyzed
reaction gave the highest yields, as illustrated in Table 1.
To further optimize the reaction conditions, the identical
reaction was carried out at different temperatures ranging
from 70°C to 110°C in the presence of 20mol% of sulfuric
acid. We found that the yield of product 4a was improved
and the reaction time was shortened as the reaction temper-
ature was increased to 90°C from 70°C (Table 1, entries 6
and 7). Further increasing the temperature to 110°C could
not improve the reaction outcome (Table 1, entry 8). So
sulfuric acid as the catalyst in acetic anhydride at 90°C
was identified as the optimal reaction conditions for the
synthesis of product 4a.
We then investigated the substrate scope of this synthe-
sis by subjecting a series of aryl (R group) substituted com-
pounds 1, 2, and 3 to the reactions with acetic anhydride
under the optimal condition. As shown in Table 2, various
aryl groups (R) bearing either electron-withdrawing or
electron-donating functional groups on benzene ring, such
© 2016 Wiley Periodicals, Inc.

Z.-L. Lin, J.-M. Zhang, and Y. Gao
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Table 1
Initial experiments and optimizations of reaction conditionsa for the synthesis of 4a.
Entry
Catalyst
None
T (°C)
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
60–120
60–120
95
90
95
70
90
110
30
14 h
30
35
45
15
15
15
Trace
Trace
39
21
18
56
69
69
None
Phosphorus pentoxide
Hydrochloric acid
Silica sulfuric acid
Sulfuric acid
Sulfuric acid
Sulfuric acid
aThe mixture of 1a (1 mmol), acetic anhydride (1 mL), and 0.2 equiv of catalyst was stirred at different temperatures.
bIsolated yield.
as nitro, chloro, bromo, or methyl, were all found to be
suitable for the reaction (Table 2, entries 1–8).
compound A is acetylated to generate intermediate C.
Then, cyan-hydrolysis of the intermediate C yields inter-
mediate F, which undergoes keto-enol tautomerism to give
the amide intermediate G. The intermediate G undergoes
intramolecular dehydration–cyclization to afford the inter-
mediate H, which is converted into the final product I.
In conclusion, we have developed an efficient acid-
catalyzed heterocyclization reaction, which allows us to build
blocks of potentially bioactive tetracyclic pyrano[2,3-d]pyrim-
idines with a range of substituents. This method is very effi-
cient because of the short reaction time and easy work-up.
To further expand the scope of the methodology, 2-
amino-4-aryl-4H-benzo[h]chromene-3-carbonitrile 2 and
2-amino-5-oxo-4-aryl-4,5-dihydropyrano[3,2-c]chromene-
3-carbonitrile 3 were employed instead of compound 1
to react with acetic anhydride, respectively. These reac-
tions occurred rapidly to give the desired products
5a–5g, and 6a–6g in 66–75%, and 67–78% yields, respec-
tively (Table entries 9–15 and 16–22). The structures of all
products have been confirmed by infrared (IR), 1H nuclear
magnetic resonance (NMR) spectroscopy, and elemental
analysis. Additionally, the structure of products 4g, 5a,
and 6b were also determined by single crystal X-ray diffrac-
tion (Figs. 1–3).
EXPERIMENTAL
The IR spectrum of compounds showed strong absorption
peaks at 1684–1653 and 1395–1360cmÀ1, which attested to
the presence of carbonyl and methyl groups, respectively.
The cyano group, which would show absorption peak at
All reagents purchased from commercial sources were
used as received. 2-Amino-4-aryl-5,10-dioxo-5,10-dihydro-
4H-benzo[g]chromene-3-carbonitrile 1, 2-amino-4-aryl-4H-
benzo[h]chromene-3-carbonitrile 2, and 2-amino-5-oxo-
1
2260–2220cmÀ1, was disappeared. The H NMR spectrum
4-aryl-4,5-dihydropyrano[3,2-c]chromene-3-carbonitrile
3
of compounds exhibited the singlet at δ 12.82–12.45 and
2.43–2.22, which are the characteristic representation of the
secondary amino group and the methyl group protons,
respectively.
As Figures 1–3 showed, we found that four contiguous
heterocycles in the molecule structures of compounds were
nearly coplanar. The dihedral angles between the plane of
aryl ring and the plane of pyran ring in the molecules of
compounds 4g, 5a, and 6b were 82.94°, 77.18°, and 73.95°, re-
spectively. The crystal data and structure refinement for 4g,
5a, and 6b were given in Table 3.
were prepared according to literature procedures [22,23].
Melting points were determined with an X-4 apparatus
and were uncorrected. IR spectra were recorded on a
PerkinElmer Spectrum One Version B (PerkinElmer Inc.,
1
Waltham, MA) spectrometer with KBr pellets. H NMR
spectrum was obtained on a Varian Inova-400 MHz spec-
trometer with trimethylsilyl (TMS) as internal standard
and DMSO-d6 as solvent. Elemental analysis was deter-
mined by using an Elementar-vario EL cube elemental
analysis instrument (Elementar Inc., Hanau, Germany).
The reflection data of 4g, 5a, and 6b were collected on a
Rigaku Saturn724+ (Rigaku Corp., Tokyo, Japan) charge
coupling device (CCD) diffractometer with an area detec-
tor at 173(2) K.
Although the detailed mechanism of the previously
mentioned reaction remains to be unclear, a possible mech-
anism was proposed in Scheme 1. Initially, the amino of
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An Efficient Synthesis of Tetracyclic Pyrano[2,3-d]pyrimidines
Table 2
Synthesis of compounds 4, 5, and 6 under the optimized conditionsa.
Entry
Product
R
Time (min)
Yield (%)b
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
6d
6e
6f
2,6-Cl2C6H3
3,4-(CH3)2C6H3
4-CH3C6H4
4-ClC6H4
15
10
13
13
15
13
10
13
10
12
10
15
14
13
10
10
10
12
15
14
12
11
76
68
69
70
71
65
64
71
67
75
72
71
66
70
73
67
72
78
68
72
74
69
4-BrC6H4
3-CH3C6H4
3-NO2C6H4
2-NO2C6H4
C6H5
3-NO2C6H4
4-ClC6H3
3-(OCH3)C6H4
3,4-(OCH3)2C6H4
2,6-Cl2C6H4
4-NO2C6H4
C6H5
4-MeC6H4
4-ClC6H4
3-OCH3C6H3
2,6-Cl2C6H4
4-BrC6H3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
6g
4-NO2C6H4
aThe mixture of 1, 2, or 3 (1 mmol), acetic anhydride (1 mL), and 0.2 equiv of sulfuric acid was stirred at 90°C.
bIsolated yield.
Figure 1. X-ray crystal structure of compound 4g (CCDC: 1435232).
Figure 2. X-ray crystal structure of compound 5a (CCDC: 1435230).
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Z.-L. Lin, J.-M. Zhang, and Y. Gao
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into 250mL water. The solid product was filtrated and pu-
rified by recrystallization from 95% ethanol to afford the
pure product.
5-(2,6-Dichlorophenyl)-2-methyl-3H-benzo[6,7]chromeno[2,3-d]
pyrimidine-4,6,11(5H)-trione (4a).
Brown crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1666, 1596, 1392.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.60 (s, 1H,
NH), 8.09–8.06 (m, 1H, ArH), 7.91–7.85 (m, 3H, ArH),
7.51-7.48 (m, 1H, ArH), 7.26–7.22 (m, 2H, ArH), 5.93
(s, 1H, CH), 2.31 (s, 3H, CH3).
Anal. calcd for C22H12Cl2N2O4: C 60.16, H 2.75, N
6.38; found: C 60.17, H 2.73, N 6.39.
5-(3,4-Dimethylphenyl)-2-methyl-3H-benzo[6,7]chromeno
[2,3-d]pyrimidine-4,6,11(5H)-trione (4b).
Yellow solid, mp >300°C
IR (KBr, ν, cmÀ1): 1670, 1594, 1394.
Figure 3. X-ray crystal structure of compound 6b (CCDC:1435231).
1H NMR (400MHz, DMSO-d6) (δ, ppm): 12.66 (s, 1H,
NH), 8.10–8.06 (m, 1H, ArH), 7.88–7.85 (m, 3H, ArH),
6.96 (s, 1H, ArH), 6.81–6.80 (m, 2H, ArH), 5.01 (s, 1H,
CH), 2.89 (s, 3H, CH3), 2.73 (s, 3H, CH3), 2.30 (s, 3H, CH3).
Anal. calcd for C24H18N2O4: C 72.35, H 4.55, N 7.03;
found: C 72.37, H 4.58, N 7.05.
Sample experimental.
General procedure for the
synthesis of 4, 5, or 6:
In an oven-dried 25-mL flask, compounds 1, 2 or 3
(1 mmol), acetic anhydride (1mL), and sulfuric acid
(0.2 mmol) were mixed and magnetically stirred at 90°C
until thin-layer chromatography indicated total consump-
tion of the starting material. Upon completion, the reaction
mixture was cooled to room temperature and then poured
2-Methyl-5-(p-tolyl)-3H-benzo[6,7]chromeno[2,3-d]pyrimidine-
4,6,11(5H)-trione (4c).
Yellow crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1670, 1593, 1395.
Table 3
Crystal data and structure refinement for 4g, 5a, and 6b.
Identification code
4g
5a
6b
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
C
22H13N3O6
415.35
173 (2)
C22H16N2O2
340.37
173 (2)
0.71073
Monoclinic
C22H16N2O4
372.37
173 (2)
0.71073
Monoclinic
0.71073
Monoclinic
C2/c
Space group
P2(1)/n
P2(1)/c
Unit cell dimensions
a = 15.519 (3) Å α = 90.00°
b = 12.716 (3) Å β = 111.03 (3)°
c = 19.369 (4) Å γ = 90.00°
3567.7 (13) Å3
a = 8.948 (4) Å α = 90.00°
b = 11.278 (5) Å β = 98.982 (7)°
c = 16.323 (7)Å γ = 90.00°
1627.0 (12) Å3
4
a = 13.764(3) Å α = 90.00°
b = 8.8079 (18) Å β = 114.28 (3)°
c = 16.517 (3) Å γ = 90.00°
1825.4 (6) Å3
Volume
Z
8
4
Density (calculated) (mg/m3)
Absorption coefficient (mmÀ1)
F(000)
1.547
0.115
1712
1.390
0.090
712
1.355
0.095
776
Crystal size (mm)
Theta range for data collection
Index ranges
0.24 × 0.21 × 0.13
2.71° to 27.47°
0.53 × 0.11 × 0.10
2.80° to 27.46°
À11 ≤ h ≤ 11, À14 ≤ k ≤ 14,
-12 ≤ l ≤ 21
0.61 × 0.33 × 0.01
2.83° to 27.49°
À17 ≤ h ≤ 14, À11 ≤ k ≤ 11,
-13 ≤ l ≤ 21
À19 ≤ h ≤ 19, À14 ≤ k ≤ 16,
-17 ≤ l ≤ 25
Absorption correction
Reflections collected
Semi-empirical from equivalents
7719
Semi-empirical from equivalents
12816
Semi-empirical from equivalents
12485
Independent reflections
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma (I)]
R indices (all data)
3995 [R(int) = 0.0343]
1.0000 and 0.7239
Full-matrix least-squares on F2
3995/0/281
3710 [R(int) = 0.0508]
1.0000 and 0.5910
Full-matrix least-squares on F2
3710/0/236
4163 [R(int) = 0.0630]
0.9993 and 0.9445
Full-matrix least-squares on F2
4163/0/255
1.149
1.211
1.234
R1 = 0.0685, wR2 = 0.1349
R1 = 0.0813, wR2 = 0.1422
R1 = 0.0682, wR2 = 0.1341
R1 = 0.0778, wR2 = 0.1388
R1 = 0.0841, wR2 = 0.1563
R1 = 0.1025, wR2 = 0.1656
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An Efficient Synthesis of Tetracyclic Pyrano[2,3-d]pyrimidines
Scheme 1. Possible reaction mechanism of the reaction.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.66 (s, 1H,
NH), 8.09–8.06 (m, 1H, ArH), 7.93–7.90 (m, 1H, ArH),
7.87–7.84 (m, 2H, ArH), 7.23 (d, J = 8.02Hz, 2H, ArH),
7.04 (d, J= 8.02Hz, 2H, ArH), 5.03 (s, 1H, CH), 2.30 (s,
3H, CH3), 2.20 (s, 3H, CH3).
Anal. calcd for C23H16N2O4: C 71.87, H 4.20, N 7.29;
found: C 71.89, H 4.23, N 7.31.
5-(4-Chlorophenyl)-2-methyl-3H-benzo[6,7]chromeno[2,3-d]
pyrimidine-4,6,11(5H)-trione (4d).
2-Methyl-5-(3-nitrophenyl)-3H-benzo[6,7]chromeno[2,3-d]
pyrimidine-4,6,11(5H)-trione (4g).
Green crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1671, 1593, 1393.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.73 (s, 1H,
NH), 8.23 (t, 1H, ArH), 8.01–8.04 (m, 2H, ArH), 7.92–
7.84 (m, 5H, ArH), 5.20 (s, 1H, CH), 2.32 (s, 3H, CH3).
Anal. calcd for C22H13N3O6: C 63.62, H 3.15, N 10.12;
found: C 63.64, H 3.17, N 10.16.
Yellow solid, mp >300°C
2-Methyl-5-(2-nitrophenyl)-3H-benzo[6,7]chromeno[2,3-d]
pyrimidine-4,6,11(5H)-trione (4h).
IR (KBr, ν, cmÀ1): 1681, 1593, 1394.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.71 (s, 1H,
NH), 8.09–8.07 (m, 1H, ArH), 7.93–7.84 (m, 3H, ArH),
7.41 (d, J = 8.61Hz, 2H, ArH), 7.30 (d, J = 8.61Hz, 2H,
ArH), 5.06 (s, 1H, CH), 2.31 (s, 3H, CH3).
Anal. calcd for C22H13ClN2O4: C 65.28, H 3.24, N 6.92;
found: C 65.30, H 3.27, N 6.90.
Brown crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1670, 1597, 1387.
1H NMR (400MHz, DMSO-d6) (δ, ppm): 12.62 (s, 1H,
NH), 8.10–8.07 (m, 1H, ArH), 7.93 (dd, J =8.22 Hz, 1H,
ArH), 7.89–7.85 (m, 3H, ArH), 7.59–7.52 (m, 2H, ArH),
7.43–7.39 (m, 1H, ArH), 6.13 (s, 1H, CH), 2.30 (s, 3H,
CH3).
5-(4-Bromophenyl)-2-methyl-3H-benzo[6,7]chromeno[2,3-d]
pyrimidine-4,6,11(5H)-trione (4e).
Anal. calcd for C22H13N3O6: C 63.62, H 3.15, N 10.12;
found: C 63.61, H 3.13, N 10.14.
Brown solid, mp >300°C
IR (KBr, ν, cmÀ1): 1681, 1594, 1393.
10-Methyl-7-phenyl-7H-benzo[7,8]chromeno[2,3-d]pyrimidin-8
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.71 (s, 1H,
NH), 8.09–8.07 (m, 1H, ArH), 7.92–7.84 (m, 3H, ArH),
7.44 (d, J = 8.61Hz, 2H, ArH), 7.34 (d, J = 8.61Hz, 2H,
ArH), 5.04 (s, 1H, CH), 2.31 (s, 3H, CH3).
Anal. calcd for C22H13BrN2O4: C 58.82, H 2.92, N 6.24;
found: C 58.87, H 2.97, N 6.26.
(9H)-one (5a).
Colorless crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1654, 1572, 1374.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.61 (s, 1H,
NH), 8.34 (d, J = 7.98Hz, 1H, ArH), 7.99 (d, J= 7.04 Hz,
1H, ArH), 7.74–7.67 (m, 3H, ArH), 7.41–7.23 (m, 6H,
ArH), 5.35 (s, 1H, CH), 2.43 (s, 3H, CH3).
Anal. calcd for C22H16N2O2: C 77.63, H 4.74, N 8.23;
found: C 77.65, H 4.72, N 8.26.
2-Methyl-5-(m-tolyl)-3H-benzo[6,7]chromeno[2,3-d]pyrimidine-
4,6,11(5H)-trione (4f).
Red brown solid, mp >300°C
IR (KBr, ν, cmÀ1): 1670, 1595, 1392.
10-Methyl-7-(3-nitrophenyl)-7H-benzo[7,8]chromeno[2,3-d]
pyrimidin-8(9H)-one (5b).
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.66 (s, 1H,
NH), 8.09–8.07 (m, 1H, ArH), 7.93–7.84 (m, 3H, ArH),
7.16–7.13 (m, 3H, ArH), 6.99–6.96 (m, 1H, ArH), 5.03
(s, 1H, CH), 2.31 (s, 3H, CH3), 2.23 (s, 3H, CH3).
Anal. calcd for C23H16N2O4: C 71.87, H 4.20, N 7.29;
found: C 71.86, H 4.22, N 7.30.
White solid, mp >300°C
IR (KBr, ν, cmÀ1): 1660, 1572, 1374.
1H NMR (400MHz, DMSO-d6) (δ, ppm): 12.59 (s, 1H,
NH), 8.29 (d, J = 8.25Hz, 1H, ArH), 8.19 (t, 1H, ArH),
7.92 (d, J = 7.43Hz, 1H, ArH), 7.73–7.53 (m, 5H, ArH),
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7.33 (d, J = 8.59Hz, 1H, ArH), 5.53 (s, 1H, CH), 2.35 (s,
3H, CH3).
Anal. calcd for C22H15N3O4: C 68.57, H 3.92, N 10.90;
found: C 68.60, H 3.89, N 10.92.
7-(4-Chlorophenyl)-10-methyl-7H-benzo[7,8]chromeno[2,3-d]
pyrimidin-8(9H)-one (5c).
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.60 (s, 1H,
NH), 8.28 (d, J = 8.26Hz, 1H, ArH), 8.12 (d, J = 8.82Hz,
2H, ArH), 7.92 (d, J = 7.87Hz, 2H, ArH), 7.66–7.57 (m,
5H, ArH), 7.29 (d, J = 7.43Hz, 2H, ArH), 5.48 (s, 1H,
CH), 2.35(s, 3H, CH3).
Anal. calcd for C22H15N3O4: C 68.57, H 3.92, N 10.90;
found: C 68.60, H 3.95, N 10.89.
10-Methyl-7-phenylchromeno[3’,4’:5,6]pyrano[2,3-d]pyrimidine-
6,8(7H,9H)-dione (6a).
White solid, mp >300°C
IR (KBr, ν, cmÀ1): 1655, 1566, 1375.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.55 (s, 1H,
NH), 8.26 (d, J = 8.22Hz, 1H, ArH), 7.92 (d, J = 8.41Hz,
1H, ArH), 7.68–7.58 (m, 4H, ArH), 7.30–7.28 (m, 4H,
ArH), 5.30 (s, 1H, CH), 2.34 (s, 3H, CH3).
Anal. calcd for C22H15N2O2Cl: C 70.50, H 4.03, N 7.47;
found: C 70.54, H 3.89, N 7.49.
Colorless crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1663, 1597, 1372.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.74 (s, 1H,
NH), 7.98–7.96 (m, 1H, ArH), 7.74–7.70 (m, 1H, ArH),
7.51–7.46 (m, 2H, ArH), 7.32–7.16 (m, 5H, ArH), 4.87
(s, 1H, CH), 2.33 (s, 3H, CH3).
7-(3-Methoxyphenyl)-10-methyl-7H-benzo[7,8]chromeno[2,3-d]
pyrimidin-8(9H)-one (5d).
Anal. calcd for C21H14N2O4: C 70.39, H 3.94, N 7.82;
found: C 70.43, H 3.97, N 7.79.
10-Methyl-7-(p-tolyl)chromeno[3’,4’:5,6]pyrano[2,3-d]pyr
imidine-6,8(7H,9H)-dione (6b).
White solid, mp >300°C
IR (KBr, ν, cmÀ1): 1654, 1570, 1374.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.53 (s, 1H,
NH), 8.25 (d, J = 7.81Hz, 1H, ArH), 7.91 (d, J = 6.93Hz,
1H, ArH), 7.67–7.58 (m, 3H, ArH), 7.38–7.34 (m, 1H,
ArH), 7.16–7.12 (m, 1H, ArH), 6.89–6.88 (m, 1H, ArH),
6.77–6.75 (m, 2H, ArH), 5.23 (s, 1H, CH), 3.69 (s, 3H,
CH3), 2.35 (s, 3H, CH3).
Colorless crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1665, 1596, 1371.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.73 (s, 1H,
NH), 7.96–7.94 (m, 1H, ArH), 7.74–7.69 (m, 1H, ArH),
7.50–7.46 (m, 2H, ArH), 7.17 (d, J= 8.41 Hz, 2H, ArH),
7.05 (d, J= 8.41Hz, 2H, ArH), 4.82 (s, 1H, CH), 2.33 (s,
3H, CH3), 2.22 (s, 3H, CH3).
Anal. calcd for C23H18N2O3: C 74.58, H 4.90, N 7.56;
found: C 74.59, H 4.91, N 7.58.
7-(3,4-Dimethoxyphenyl)-10-methyl-7H-benzo[7,8]chromeno
[2,3-d]pyrimidin-8(9H)-one (5e).
Anal. calcd for C22H16N2O4: C 70.39, H 4.33, N 7.52;
found: C 70.41, H 4.32, N 7.57.
White solid, mp >300°C
7-(4-Chlorophenyl)-10-methylchromeno[3’,4’:5,6]pyrano[2,3-
d]pyrimidine-6,8(7H,9H)-dione (6c).
IR (KBr, ν, cmÀ1): 1658, 1571, 1373.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.59 (s, 1H,
NH), 8.33 (d, J = 8.10Hz, 1H, ArH), 7.99 (d, J = 8.05Hz,
1H, ArH), 7.75–7.67 (m, 3H, ArH), 7.45 (d, J = 8.58Hz,
1H, ArH), 7.09 (d, J= 2.02 Hz, 1H, ArH), 6.87 (d,
J =8.32 Hz, 1H, ArH), 6.71–6.69 (m, 1H, ArH), 5.29 (s,
1H, CH), 3.78 (s, 3H, CH3), 3.73 (s, 3H, CH3), 2.43 (s,
3H, CH3).
White solid, mp >300°C
IR (KBr, ν, cmÀ1): 1664, 1599, 1373.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.77 (s, 1H,
NH), 7.97–7.95 (m, 1H, ArH), 7.75–7.71 (m, 1H, ArH),
7.49 (t, 2H, ArH), 7.36–7.30 (m, 4H, ArH), 4.85 (s, 1H,
CH), 2.33 (s, 3H, CH3).
Anal. calcd for C21H13N2O4Cl: C 64.21, H 3.34, N 7.13;
found: C 64.91, H 3.37, N 7.15.
Anal. calcd for C24H20N2O4: C 70.50, H 4.03, N 7.47;
found: C 70.53, H 4.99, N 7.50.
7-(3-Methoxyphenyl)-10-methylchromeno[3’,4’:5,6]pyrano
[2,3-d]pyrimidine-6,8(7H,9H)-dione (6d).
7-(2,6-Dichlorophenyl)-10-methyl-7H-benzo[7,8]chromeno
[2,3-d]pyrimidin-8(9H)-one (5f).
White solid, mp >300°C
IR (KBr, ν, cmÀ1): 1678, 1586, 1370.
White solid, mp >300°C
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.74 (s, 1H,
NH), 7.96 (d, J= 7.87 Hz 1H, ArH), 7.72 (t, 1H, ArH), 7.49
(t, 2H, ArH), 7.17 (t, 1H, ArH), 6.87–6.76 (m, 3H, ArH),
4.85 (s, 1H, CH), 3.69 (s, 3H, CH), 2.33 (s, 3H, CH3).
Anal. calcd for C22H16N2O5: C 68.04, H 4.15, N 7.21;
found: C 68.07, H 4.18, N 7.17.
IR (KBr, ν, cmÀ1): 1655, 1566, 1375.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.45 (s, 1H,
NH), 8.24 (d, J = 7.73Hz, 1H, ArH), 7.90 (d, J = 7.87Hz,
1H, ArH), 7.67–7.58 (m, 4H, ArH), 7.31–7.24 (m, 2H,
ArH), 6.99(d, J = 8.60Hz, 1H, ArH), 6.23 (s, 1H, CH),
2.34 (s, 3H, CH3).
7-(2,6-Dichlorophenyl)-10-methylchromeno[3’,4’:5,6]
pyrano[2,3-d]pyrimidine-6,8(7H,9H)-dione (6e).
White solid, mp >300°C
Anal. calcd for C22H14Cl2N2O2: C 64.56, H 3.45, N
6.84; found: C 64.51, H 3.47, N 6.86.
10-Methyl-7-(4-nitrophenyl)-7H-benzo[7,8]chromeno[2,3-d]
pyrimidin-8(9H)-one (5g).
IR (KBr, ν, cmÀ1): 1664, 1598, 1369.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.67 (s, 1H,
NH), 7.95 (d, J= 8.81Hz 1H, ArH), 7.73 (t, 1H, ArH), 7.48
White solid, mp >300°C
IR (KBr, ν, cmÀ1): 1660, 1572, 1374.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
An Efficient Synthesis of Tetracyclic Pyrano[2,3-d]pyrimidines
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(t, 4H, ArH), 7.26 (t, 1H, ArH), 5.79 (s, 1H, CH), 2.34 (s,
3H, CH3).
Anal. calcd for C21H12N2O4Cl2: C 59.04, H 2.83, N
6.56; found: C 59.09, H 2.81, N 6.58.
7-(4-Bromophenyl)-10-methylchromeno[3’,4’:5,6]pyrano[2,3-d]
[6] Akhmed Khodzhaeva, Kh. S.; Bessonova, I. A. Dokl. Akad.
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pyrimidine-6,8(7H,9H)-dione (6f).
Colorless crystal, mp >300°C
IR (KBr, ν, cmÀ1): 1664, 1597, 1371.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.77 (s, 1H,
NH), 7.97–7.95 (m, 1H, ArH), 7.75–7.70 (m, 1H, ArH),
7.51–7.43 (m, 4H, ArH), 7.29–7.27 (m, 2H, ArH), 4.84
(s, 1H, CH), 2.33 (s, 3H, CH3).
Anal. calcd for C21H13N2O4Br: C 57.69, H 3.00, N 6.41;
found: C 57.69, H2.99, N 6.43.
10-Methyl-7-(4-nitrophenyl)chromeno[3’,4’:5,6]pyrano[2,3-d]
pyrimidine-6,8(7H,9H)-dione (6g).
White solid, mp >300°C
IR (KBr, ν, cmÀ1): 1664, 1599, 1360.
1H NMR (400 MHz, DMSO-d6) (δ, ppm): 12.82 (s, 1H,
NH), 8.12 (d, J =8.81 Hz, 2H, ArH), 8.00–7.98 (m, 1H,
ArH), 7.77–7.72 (m, 1H, ArH), 7.63 (d, J =8.82Hz, 2H,
ArH), 7.53–7.48 (m, 2H, ArH), 5.00 (s, 1H, CH), 2.34 (s,
3H, CH3).
Anal. calcd for C21H13N3O6: C 62.53, H 3.25, N 10.42;
found: C 62.50, H 3.22, N 10.40.
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Acknowledgments. We are grateful for financial support from
the National Natural Science Foundation of China (21402124).
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REFERENCES AND NOTES
[1] Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder Methodo-
logy in Organic Synthesis; Academic Press: San Diego, 1987.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet