Effect of Liquid Glass Composition on the Catalytic Preparation of Pyrano[2,3-d]pyrimidine Derivatives

Full text of DOI:10.1080/00304948.2019.1600124

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
Effect of Liquid Glass Composition on the Catalytic
Preparation of Pyrano[2,3-d]pyrimidine Derivatives
Mehdi Abaszadeh, Seyyed Jalal Roudbaraki & Majid Ghashang
To cite this article: Mehdi Abaszadeh, Seyyed Jalal Roudbaraki & Majid Ghashang (2019): Effect
of Liquid Glass Composition on the Catalytic Preparation of Pyrano[2,3-d]pyrimidine Derivatives,
Organic Preparations and Procedures International, DOI: 10.1080/00304948.2019.1600124
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Organic Preparations and Procedures International, 0:1–15, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1600124
Effect of Liquid Glass Composition on the
Catalytic Preparation of Pyrano[2,3-d]pyrimidine
Derivatives
Mehdi Abaszadeh,1 Seyyed Jalal Roudbaraki,2 and
Majid Ghashang3
1Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman
University of Medical Sciences, Kerman 76175493, Iran
2Department of Chemistry, Lahijan Branch, Islamic Azad University,
Lahijan, Iran
3Department of Chemistry, Najafabad Branch, Islamic Azad University,
Najafabad, Iran
The main objective of this study was the catalytic preparation 5-aryl-1,3,4,5-tetrahydro-
2H-pyrano[2,3-d]pyrimidine-6-carbonitrile derivatives using liquid glass as a catalyst.
All reactions were performed in water under reflux conditions. As a further objective,
the procedure was investigated using high-speed ball milling (HSBM) techniques. The
effects of liquid glass composition and addition of metal oxide impurities were
investigated.
Recently, compounds containing at least one core moiety of pyrano[2,3-d]pyrimi-
dine have received considerable attention in synthetic organic chemistry because of
their potential as drugs and bioactive compounds.1–5 Pyrano[2,3-d]pyrimidines have
attracted interest in medicine as antitumor,2 anti-hypertensive,3 antibacterial4 and anti-
leishmanial5 drugs. Pyrano[2,3-d]pyrimidines have been produced by a number of
methods. A complete review of the synthetic procedures and discussion about these
compounds is available.6
Liquid glass with the formula of Na2(SiO2)nO is an aqueous solution of sodium
silicate which can be easily prepared from the reaction of NaOH (25%) with SiO2 or by
melting sodium carbonate with silicon dioxide. Liquid glass has been used as a binding
and coating agent for decades. Liquid glass is a non-toxic, heat durable, stable, low-cost
and environmentally friendly material with a strong basic nature. Moreover, liquid
glasses show unique chemical properties because their surface charge can be modified
and their viscosity can be regulated.7 Unfortunately their application in organic synthe-
sis has been neglected.8,9
This has encouraged us to continue our investigations10–23 on the catalytic activity
of liquid glass for the synthesis of a variety of pyrano[2,3-d]pyrimidine derivatives via
Received May 26, 2017; in final form November 3, 2018.
Address correspondence to Majid Ghashang, Department of Chemistry, Najafabad Branch,
Islamic Azad University, P.O. Box 517, Najafabad, Iran. E-mail: ghashangmajid@gmail.com
1

2
Ghashang et al.
Table 1
Solvent Screening (Scheme 1)
Entry
Solvent (5 mL)
Temperature (ꢀC)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
Hexane
EtOAc
EtOH
H2O
Et2O
CH2Cl2
–
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
80
120
120
60
35
69
80
93
–
60
120
120
60
–
68
aIsolated yield.
Scheme 1. Preparation of pyrano[2,3-d]pyrimidine derivatives.
a three-component reaction of malononitrile, aromatic aldehydes and barbituric acid
(Scheme 1).
Initially, the liquid glass catalytic potential was investigated for the preparation of 7-
amino-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile
(1C) through the cyclocondensation reaction of benzaldehyde (1 mmol), malononitrile,
(1 mmol) and barbituric acid (1 mmol) in different solvents. The results are summarized
in Table 1. In solvents with boiling points less than 50 ꢀC, e. g., Et2O and CH2Cl2, no
product was formed. Solvent screening with non-protic solvents such as CH3CN and

Pyrano[2,3-d]pyrimidines
3
Table 2
Preparation of Compounds 1C-38C using Liquid Glass as Catalyst (Scheme 1)
Method A:
Time (min)/
Yield (%)a
Method B:
Time (min)/
Entry
Ar
R
Compound
Yield (%)a
1
2
3
4
5
Ph
Ph
4-CH3Ph
4-CH3Ph
H
CH3
H
CH3
H
1C
2C
3C
4C
5C
60/93
60/90
80/86
80/88
70/79
20/89
20/93
30/89
30/94
30/83
6
CH3
6C
70/75
30/80
7
8
9
4-ClPh
4-ClPh
H
CH3
H
CH3
H
CH3
H
CH3
H
7C
8C
9C
45/91
45/95
45/88
45/90
60/71
60/68
45/86
45/82
45/94
45/96
45/87
15/94
15/93
15/94
15/97
25/79
25/83
15/86
15/90
15/92
15/89
15/93
4-NO2Ph
4-NO2Ph
2-NO2Ph
2-NO2Ph
3-NO2Ph
3-NO2Ph
4-NCPh
4-NCPh
10
11
12
13
14
15
16
17
10C
11C
12C
13C
14C
15C
16C
17C
CH3
H
18
19
CH3
H
18C
19C
45/86
45/81
15/91
15/92
20
21
CH3
H
20C
21C
45/87
45/86
15/98
15/86
(Continued)

4
Ghashang et al.
Table 2
(Continued)
22
CH3
22C
45/90
15/89
23
24
H
23C
24C
45/91
45/83
15/87
15/82
CH3
25
26
27
28
29
30
31
32
33
34
35
36
37
38
4-MeOPh
4-MeOPh
3,4-(MeO)2Ph
3,4-(MeO)2Ph
3,4,5-(MeO)3Ph
3,4,5-(MeO)3Ph
2,4-Cl2Ph
2,4-Cl2Ph
2-ClPh
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
CH3
H
25C
26C
27C
28C
29C
30C
31C
32C
33C
34C
35C
36C
37C
38C
80/80
80/85
90/87
90/83
90/80
90/79
60/89
60/87
60/79
60/78
45/96
45/97
60/81
60/82
30/91
30/89
35/89
35/84
30/88
30/87
30/79
30/82
20/87
20/84
15/93
15/95
25/84
25/80
2-ClPh
4-BrPh
4-BrPh
4-FPh
4-FPh
CH3
aIsolated yield; All products were characterized on the basis of NMR analysis. Method A:
Water, Reflux; Method B: Solvent-free, 50ꢀC, HSBM technique.
EtOAc showed lower product yields. It was demonstrated that water as solvent gave a
higher yield (Table 1, entry 4). The stabilization of ionic intermediates in water is higher
than other solvents which makes water a suitable medium for the reaction of organic sub-
stances catalyzed by liquid glass.
After solvent screening, the substrate scope was investigated (Table 2, Method A).
Aromatic aldehydes containing electron-withdrawing groups as well as electron-donat-
ing groups were well tolerated in the reaction, producing the desired pyrano[2,3-d]pyri-
midines in high yields (Table 2). In general, the electronic nature of the substituents
had little influence on the product yields, but it did have considerable influence on the
reaction times. Aromatic aldehydes substituted at para and meta positions with elec-
tron-withdrawing groups (e. g., NO2, CN, Cl, Br) showed more reactivity compared to
those of electron-donating groups (e. g., CH3, OCH3). ortho-Substituted aldehydes
showed longer reaction times than their para-counterparts. Furfural could also achieve
a high yield in a reasonably short time. Aldehydes substituted with benzenesulfonate, 4-
methyl benzenesulfonate and tosylamide gave the desired product in high yields in

Pyrano[2,3-d]pyrimidines
5
Figure 1. Preparation of 7-Amino-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyr-
imidine-6-carbonitrile: Effect of liquid glass composition (37% solution in water, MOH bases; sil-
ica (TLC and column grade)). 1a: Si/M ratio: 1.5; 1b: Si/M ratio: 1.
shorter reaction times compared with benzaldehyde. In summary, all of the reactions
took place in good to excellent yields.
Next, we were interested to explore the substrate scope of the liquid glass catalyzed
methodology using high speed ball milling (HSBM) techniques (Method B).
Implementing HSBM can be useful because it can promote the reaction under milder
conditions. The results are summarized in Table 2. In all cases, aldehydes with elec-
tron-withdrawing substituents had slower reaction times than those with electron-donat-
ing substituents. Compared with solvent media (Method A), the solvent-free conditions
(Method B) have shorter reaction times, but no considerable effect was observed on the
product yields.
Additionally, we investigated the large-scale synthesis of 7-amino-2,4-dioxo-5-phe-
nyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile (1C) through cyclo-
condensation of benzaldehyde (50 mmol), malononitrile, (50 mmol) and barbituric acid
(50 mmol) under solvent-free conditions using HSBM. Our result (86% yield, see
Experimental Section) shows that the synthetic methodology can be applied for the
large-scale synthesis of pyrano[2,3-d]pyrimidines.
The key parameters that determine the properties of liquid glasses are the weight
ratio of Si to Na, the kind of bases used and the amount and kind of impurities. Thus
we continued our investigations using liquid glasses with different weight ratios of Si/
Na. Two different kinds of silica were used, including TLC grade and column grade.
All experiments were done in aqueous media at reflux. The results show that silica
sources have no significant effect on the product yield and reaction time. However, the
kind of base can influence the reaction rate significantly (Figure 1). Three different
bases, including NaOH, KOH and LiOH, were used (Figure 1). Under the same

6
Ghashang et al.
Figure 2. Effect of different metal oxide impurities on the liquid glasses (NaOH; silica TLC
grade; 37% solution in water, Si/Na ratio: 1.5) catalyzed preparation of 7-amino-2,4-dioxo-5-phe-
nyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile.
Figure 3. Effect of MgO (3a) ZnO (3b) and impurity on the liquid glasses (NaOH; silica TLC
grade; 37% solution in water, Si/Na ratio: 1.5) catalyzed preparation of 7-amino-2,4-dioxo-5-phe-
nyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile.

Pyrano[2,3-d]pyrimidines
7
Table 3
Comparison Results
Time (min)/
Entry
Catalyst
Condition [Ref.]
Yield (%)a
1
2
3
4
5
6
7
8
Iron ore pellet
Dibutylamine (20 mol%)
L-proline (25 mol)
EtOH: H2O (1:1), reflux [24]
EtOH: H2O (1:1), reflux [25]
8/73
58/94
130/76
120/74
90/35
90/58
90/45
90/-
ꢂ
EtOH: H2O (1:1), r.t. [26]
ꢂ
(NH4)2HPO4 (10 mol%)
EtOH: H2O (1:1), reflux [27]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
H2O, reflux [-]
.
FeCl3 6H2O (25 mol%)
Dibutylamine (25 mol%)
Pyridine (25 mol%)
Triethyl amine (25 mol%)
Morpholine (25 mol%)
Diethyl amine (25 mol%)
L-proline (25 mol%)
(NH4)2HPO4 (25 mol%)
Ca(OH)2 (25 mol%)
Mg(OH)2 (25 mol%)
SiO2-SO3H (25 mol%)
Al2O3 (25 mol%)
9
90/35
90/-
10
11
12
13
14
15
16
17
90/69
90/51
90/35
90/48
90/64
90/-
SiO2/NaOH
90/55
(1g/0.25 g) (25 mol%)
SiO2 (25 mol%)
Liquid glass (25 mol%)
18
19
H2O, reflux [-]
H2O, reflux [-]
90/-
60/93
aꢂIsolated yield; based on the synthesis of 1C.
This reference does not report product 1C per se, so we prepared it using the
reported conditions.
conditions, the liquid glasses prepared from NaOH have higher activity than those of
KOH and LiOH sources. This may be due to the stronger basicity of NaOH than KOH
and LiOH.
The variation of the silica composition with the addition of impurities can strongly
affect the reaction rate. Such impurities as Lewis acids or Lewis bases increase the reac-
tion rate. Different metal oxides including MgO, ZnO, CaO, NiO, TiO2, Al2O3, BaO
and CeO2 were investigated. The results are summarized in Figure 2. From Figure 2,
the reaction rate can be categorized as follows: Pure silica ꢁ ZnO < MgO ꢁ CaO ꢁ
NiO ꢁ TiO2 ꢁ Al2O3<BaO ꢁ CeO2.
However, the role of impurities is not clear. While some of them increased the
yield, most impurities actually decreased the yield of the reaction (Figure 2). Figure 3
shows the effect of different concentration of MgO and ZnO impurities respectively.
When the impurity percentage increased, the rate of the reaction increased (Figure 3).
Comparing the results of the catalytic activity of liquid glass in the synthesis of 1C
with literature reports (such as iron ore pellets [ref.24], dibutylamine [ref. 25], L-proline
[ref. 26], (NH4)2HPO4 [ref. 27]) has shown that the liquid glass exhibits a significant
catalytic potential compared to the other catalysts with regard to reaction time and yield
of desired product. The comparison results are shown in Table 3. In order to perform a

8
Ghashang et al.
reasonable and realistic comparison, we performed the reactions using the specified
catalytic systems (both reported and unreported) under our optimized conditions. Non-
volatile secondary and tertiary amines such as dibutyl amine, pyridine and morpholine
gave low to moderate yields, while such volatile amines as triethylamine and diethyl-
amine do not form any product. This is likely due to the simple evaporative removal of
the volatile amines from the reaction media. Compared to Lewis and Bronsted acids—
.
such as FeCl3 6H2O, L-proline, (NH4)2HPO4 and SiO2-SO3H—liquid glass shows better
reaction time and yield. Some basic catalytic systems—such as Ca(OH)2, Mg(OH)2 and
mechanically mixed SiO2/NaOH (1g/0.25 g)—have shown moderate yields, while
Al2O3 and SiO2 do not give product. Generally, liquid glass showed better results.
In summary, we developed practical methods for the facile liquid glass catalyzed syn-
thesis of 7-amino-2,4-dioxo-5-aryl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-car-
bonitriles via a solvent-free one-pot reaction of aromatic aldehydes, malononitrile and
barbituric acids. In our investigations, we explored the bases, sources of silica and impur-
ities. The compounds may be obtained in high yields. The products could be isolated from
the reaction mixture with exceptional ease. No by-product was formed during the reaction.
This methodology is applicable to both laboratory scale and large scale. Compared to other
methods for the preparation of these compounds, ours offers simplicity of operation, con-
venience and the avoidance of reaction solvents. Our results indicate that liquid glass is a
promising catalyst for applications in synthetic organic chemistry.
Experimental Section
All reagents were purchased from Merck and Aldrich and used without further purification.
The NMR spectra were recorded on a Bruker Avance DPX 400 MHz instrument. The spec-
tra were measured in DMSO-d6 relative to TMS (0.00 ppm). Melting points were deter-
mined in open capillaries with a BUCHI 510 melting point apparatus. TLC was performed
on silica gel Polygram SIL G/UV 254 plates. Elemental analysis was performed on a
Heraeus CHNS-O-Rapid analyzer. All compounds gave 1H and 13C-NMR data compatible
with the proposed structures and with literature values. Representative characterization
data, including satisfactory elemental analyses, are shown below for compounds 1C-23C.
General Procedure (Method A)
To a mixture of barbituric acid or 1,3-dimethylbarbituric acid (1mmol), malononitrile
(1mmol) and aryl aldehyde (1mmol) in 5 mL water, liquid glass (three drops, 25 mol%)
was added and the mixture was refluxed until TLC showed complete disappearance of
starting material (Table 2). After completion of the reaction, the mixture was cooled to
25 ꢀC and the solid product was filtered off and purified by recrystallization from ethanol.
General Procedure (Method B)
A mixture of barbituric acid or 1,3-dimethylbarbituric acid (1 mmol), malononitrile
(1 mmol), aryl aldehyde (1 mmol) and liquid glass (three drops, 25 mol%) was milled in
a stainless steel grinding vial (10 mL volume) equipped with a stainless steel ball (diam-
eter: 6 mm; mass: 1.04 g) for 20-30 min at 25 Hz and 60 ꢀC. After completion of the
reaction, which was confirmed by TLC (eluent: n-hexane/ethyl acetate, 4/1), the

Pyrano[2,3-d]pyrimidines
9
resulting crude product mixture was mixed with CHCl3, and the catalyst was filtered.
The solvent was evaporated. Then the solid product was purified by recrystallization
from aqueous EtOH.
Large-scale Procedure
A mixture of barbituric acid (50 mmol), malononitrile (50 mmol), benzaldehyde
(50 mmol) and liquid glass (25 mol%) was milled in a stainless steel grinding vial
(65 mL volume) equipped with four stainless steel balls (diameter 6.35 mm) for 30 min
at 25 Hz and 60 ꢀC. The remainder of the procedure was similar to Method B (86%).
7-Amino-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
carbonitrile (1C)
1
mp 219-221 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 4.28 (s, 1H, CH), 7.04 (s, 2H,
NH2), 7.15 (t, J ¼ 7.8 Hz, 1H), 7.24 (d, J ¼ 7.8 Hz, 2H), 7.32 (t, J ¼ 7.8 Hz, 2H), 11.34
(s, 1H, NH), 12.03 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): d ¼ 38.6, 61.9,
118.8, 127.1, 128.4, 128.3, 129.3, 145.0, 152.4, 159.0, 161.7, 162.8.
Anal. Calcd for C14H10N4O3: C, 59.57; H, 3.57; N, 19.85. Found: C, 59.48; H,
3.46; N, 19.80.
7-Amino-1,3-dimethyl-2,4-dioxo-5-phenyl-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (2C)
1
mp 217-219ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.11 (s, 3H, NCH3), 3.42 (s, 3H,
NCH3), 4.32 (s, 1H, CH), 6.99 (s, 2H, NH2), 7.15 (t, J ¼ 7.8 Hz, 1H), 7.23 (d,
J ¼ 7.8 Hz, 2H), 7.31 (t, J ¼ 7.8 Hz, 2H); 13C-NMR (100 MHz, DMSO-d6): d ¼ 29.4,
31.1, 38.9, 62.1, 118.9, 127.1, 128.4, 128.3, 129.3, 145.0, 152.4, 159.0, 161.9, 163.0.
Anal. Calcd for C16H14N4O3: C, 61.93; H, 4.55; N, 18.06. Found: C, 61.87; H,
4.48; N, 18.00.
7-Amino-2,4-dioxo-5-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
carbonitrile (3C)
1
mp 214-216 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 2.26 (s, 3H, CH3), 4.21 (s, 1H,
CH), 6.99 (s, 2H, NH2), 7.06 (d, J ¼ 7.7 Hz, 2H), 7.18 (d, J ¼ 7.8 Hz, 2H), 11.09 (s, 1H,
NH), 11.98 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): d ¼ 21.4, 38.7, 61.8, 119.2,
126.1, 129.2, 129.5, 139.1, 149.9, 152.4, 158.9, 161.7, 162.7.
Anal. Calcd for C15H12N4O3: C, 60.81; H, 4.08; N, 18.91. Found: C, 60.67; H,
3.89; N, 18.78.
7-Amino-1,3-dimethyl-2,4-dioxo-5-(p-tolyl)-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (4C)
1
mp 207-209 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 2.27 (s, 3H, CH3), 3.10 (s, 3H,
NCH3), 3.42 (s, 3H, NCH3), 4.29 (s, 1H, CH), 6.91 (s, 2H, NH2), 7.06 (d, J ¼ 7.6 Hz,

10
Ghashang et al.
2H), 7.17 (d, J ¼ 7.6 Hz, 2H); 13C-NMR (100 MHz, DMSO-d6): d ¼ 21.3, 29.4, 31.2,
39.4, 62.2, 119.3, 126.8, 127.4, 129.3, 138.3, 145.1, 152.4, 159.0, 161.9, 162.9.
Anal. Calcd for C17H16N4O3: C, 62.95; H, 4.97; N, 17.27. Found: C, 62.87; H,
4.93; N, 17.24.
7-Amino-5-(furan-2-yl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-
carbonitrile (5C)
mp 278-28 ꢀC; 1H-NMR (400 MHz, DMSO-d6): d ¼ 4.38 (s, 1H, CH), 6.48 (d,
J ¼ 8.4 Hz, 1H), 6.59 (d, J ¼ 8.5 Hz, 1H), 7.23 (s, 2H, NH2), 7.26 (d, J ¼ 8.6 Hz, 1H),
11.97 (s, 1H, NH), 12.19 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): d ¼ 37.9,
62.3, 106.9, 111.5, 120.3, 129.5, 143.8, 152.4, 155.9, 161.3, 161.7, 162.7.
Anal. Calcd for C12H8N4O4: C, 52.95; H, 2.96; N, 20.58. Found: C, 53.14; H, 3.12;
N, 20.49.
7-Amino-5-(furan-2-yl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (6C)
1
mp 265-267 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.12 (s, 3H, NCH3), 3.43 (s, 3H,
NCH3), 4.41 (s, 1H, CH), 6.48 (d, J ¼ 8.4 Hz, 1H), 6.58 (d, J ¼ 8.5 Hz, 1H), 7.17 (s,
2H, NH2), 7.24 (d, J ¼ 8.6 Hz, 1H); 13C-NMR (100 MHz, DMSO-d6): d ¼ 29.3, 31.3,
39.8, 62.3, 107.7, 111.3, 120.3, 129.2, 142.7, 152.0, 154.3, 155.8, 160.8, 162.9.
Anal. Calcd for C14H12N4O4: C, 56.00; H, 4.03; N, 18.66. Found: C, 56.14; H,
4.12; N, 18.55.
7-Amino-5-(4-chlorophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (7C)
1
mp 239-241 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 4.43 (s, 1H, CH), 7.19 (s, 2H,
NH2), 7.24 (d, J ¼ 7.9 Hz, 2H), 7.36 (d, J ¼ 7.9 Hz, 2H), 11.23 (s, 1H, NH), 12.56
(s, 1H, NH).
Anal. Calcd for C14H9ClN4O3: C, 53.10; H, 2.86; N, 17.69. Found: C, 53.21; H,
2.99; N, 17.77.
7-Amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (8C)
1
mp 210-212 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.10 (s, 3H, NCH3), 3.42 (s, 3H,
NCH3), 4.44 (s, 1H, CH), 7.22 (s, 2H, NH2), 7.24 (d, J ¼ 7.8 Hz, 2H), 7.36 (d,
J ¼ 7.8 Hz, 2H); 13C-NMR (100 MHz, DMSO-d6): d ¼ 29.5, 31.4, 39.8, 62.4, 120.1,
128.3, 128.8, 129.3, 136.1, 145.1, 152.0, 154.4, 161.6, 162.9.
Anal. Calcd for C16H13ClN4O3: C, 55.74; H, 3.80; N, 16.25. Found: C, 55.85; H,
3.75; N, 16.33.

Pyrano[2,3-d]pyrimidines
11
7-Amino-5-(4-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-
6-carbonitrile (9C)
1
mp 242-244 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 5.07 (s, 1H, CH), 7.14 (s, 2H,
NH2), 7.47 (d, J ¼ 7.8 Hz, 2H), 8.22 (d, J ¼ 7.8 Hz, 2H), 11.31 (s, 1H, NH), 12.76 (s,
1H, NH).
Anal. Calcd for C14H9N5O5: C, 51.38; H, 2.77; N, 21.40. Found: C, 51.46; H, 2.90;
N, 21.33.
7-Amino-1,3-dimethyl-5-(4-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (10C)
1
mp 213-215 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.11 (s, 3H, NCH3), 3.43 (s, 3H,
NCH3), 5.08 (s, 1H, CH), 7.11 (s, 2H, NH2), 7.47 (d, J ¼ 7.8 Hz, 2H), 8.22 (d,
J ¼ 7.8 Hz, 2H).
Anal. Calcd for C16H13N5O5: C, 54.09; H, 3.69; N, 19.71. Found: C, 54.15; H,
3.77; N, 19.65.
7-Amino-5-(2-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-
6-carbonitrile (11C)
mp 235-237 ꢀC; 1H-NMR (400 MHz, DMSO-d6): d ¼ 5.11 (s, 1H, CH), 7.44 (t,
J ¼ 7.6 Hz, 1H), 7.46 (s, 2H, NH2), 7.53 (d, J ¼ 7.6 Hz, 2H), 7.67 (t, J ¼ 7.6 Hz, 1H),
7.86 (d, J ¼ 7.6 Hz, 2H), 11.02 (s, 1H, NH), 12.22 (s, 1H, NH).
Anal. Calcd for C14H9N5O5: C, 51.38; H, 2.77; N, 21.40. Found: C, 51.46; H, 2.74;
N, 21.32.
7-Amino-1,3-dimethyl-5-(2-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (12C)
1
mp 211-213 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.08 (s, 3H, NCH3), 3.39 (s, 3H,
NCH3), 5.10 (s, 1H, CH), 7.44 (t, J ¼ 7.6 Hz, 1H), 7.49 (s, 2H, NH2), 7.53 (d,
J ¼ 7.6 Hz, 2H), 7.67 (t, J ¼ 7.6 Hz, 1H), 7.86 (d, J ¼ 7.6 Hz, 2H).
Anal. Calcd for C16H13N5O5: C, 54.09; H, 3.69; N, 19.71. Found: C, 54.22; H,
3.84; N, 19.60.
7-Amino-5-(3-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-
6-carbonitrile (13C)
1
mp 256-258 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 5.04 (s, 1H, CH), 7.39 (s, 2H,
NH2), 7.64-7.67 (m, 2H), 7.97 (s, 1H), 8.10 (d, J ¼ 7.5 Hz, 1H), 11.18 (s, 1H, NH),
12.29 (s, 1H, NH).
Anal. Calcd for C14H9N5O5: C, 51.38; H, 2.77; N, 21.40. Found: C, 51.43; H, 2.77;
N, 21.35.

12
Ghashang et al.
7-Amino-1,3-dimethyl-5-(3-nitrophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (14C)
1
mp 210-212 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.09 (s, 3H, NCH3), 3.41 (s, 3H,
NCH3), 5.03 (s, 1H, CH), 7.44 (s, 2H, NH2), 7.64-7.67 (m, 2H), 7.98 (s, 1H), 8.12 (d,
J ¼ 7.5 Hz, 1H).
Anal. Calcd for C16H13N5O5: C, 54.09; H, 3.69; N, 19.71. Found: C, 54.17; H,
3.88; N, 19.64.
7-Amino-5-(4-cyanophenyl)-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidine-
6-carbonitrile (15C)
1
mp 253-255 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 5.03 (s, 1H, CH), 7.34 (s, 2H,
NH2), 7.42 (d, J ¼ 7.9 Hz, 2H), 7.74 (d, J ¼ 7.9 Hz, 2H), 11.64 (s, 1H, NH), 12.87 (s,
1H, NH).
Anal. Calcd for C15H9N5O3: C, 58.63; H, 2.95; N, 22.79. Found: C, 58.56; H, 2.94;
N, 22.65.
7-Amino-5-(4-cyanophenyl)-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidine-6-carbonitrile (16C)
1
mp 236-238 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.11 (s, 3H, NCH3), 3.43 (s, 3H,
NCH3), 5.07 (s, 1H, CH), 7.37 (s, 2H, NH2), 7.42 (d, J ¼ 7.9 Hz, 2H), 7.74 (d,
J ¼ 7.9 Hz, 2H).
Anal. Calcd for C17H13N5O3: C, 60.89; H, 3.91; N, 20.89. Found: C, 60.97; H,
4.03; N, 20.85.
4-(7-Amino-6-cyano-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidin-5-
yl)phenyl benzenesulfonate (17C)
1
mp 267-269 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 4.97 (s, 1H, CH), 7.18 (s, 2H,
NH2), 7.17 (d, J ¼ 8.0 Hz, 2H), 7.24 (d, J ¼ 8.0 Hz, 2H), 7.58 (t, J ¼ 8.3 Hz, 2H), 7.70
(t, J ¼ 8.3 Hz, 1H), 7.81 (d, J ¼ 8.3 Hz, 2H), 11.54 (s, 1H, NH), 12.34 (s, 1H, NH); 13C-
NMR (100 MHz, DMSO-d6): d ¼ 38.7, 64.7, 119.2, 121.7, 126.8, 128.1, 129.5, 129.9,
131.8, 135.3, 145.1, 149.4, 152.3, 161.1, 161.9, 163.0.
Anal. Calcd for C20H14N4O6S: C, 54.79; H, 3.22; N, 12.78; S, 7.31. Found: C,
54.88; H, 3.31; N, 12.69; S, 7.23.
4-(7-Amino-6-cyano-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidin-5-yl)phenyl benzenesulfonate (18C)
1
mp 251-253 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 3.09 (s, 3H, NCH3), 3.41 (s, 3H,
NCH3), 4.99 (s, 1H, CH), 7.13 (s, 2H, NH2), 7.17 (d, J ¼ 8.0 Hz, 2H), 7.24 (d,
J ¼ 8.0 Hz, 2H), 7.57 (t, J ¼ 8.3 Hz, 2H), 7.69 (t, J ¼ 8.3 Hz, 1H), 7.80 (d, J ¼ 8.3 Hz,
2H); 13C-NMR (100 MHz, DMSO-d6): d ¼ 29.5, 31.2, 38.7, 64.7, 119.2, 121.7, 126.8,
128.1, 129.5, 129.9, 131.8, 135.3, 145.1, 149.4, 152.3, 161.1, 161.9, 163.0.

Pyrano[2,3-d]pyrimidines
13
Anal. Calcd for C22H18N4O6S: C, 56.65; H, 3.89; N, 12.01; S, 6.87. Found: C,
56.74; H, 3.88; N, 12.12; S, 6.79.
4-(7-Amino-6-cyano-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidin-5-
yl)phenyl 4-methylbenzenesulfonate (19C)
1
mp 274-276 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 2.39 (s, 3H, CH3), 4.95 (s, 1H,
CH), 7.12 (s, 2H, NH2), 7.17 (d, J ¼ 8.0 Hz, 2H), 7.24 (d, J ¼ 8.0 Hz, 2H), 7.41 (d,
J ¼ 8.4 Hz, 2H), 7.82 (d, J ¼ 8.4 Hz, 2H), 11.48 (s, 1H, NH), 12.26 (s, 1H, NH); 13C-
NMR (100 MHz, DMSO-d6): d ¼ 21.0, 38.7, 64.7, 119.2, 121.7, 126.9, 128.0, 129.6,
130.2, 131.8, 144.7, 145.1, 149.9, 152.4, 161.3, 161.8, 162.8.
Anal. Calcd for C21H16N4O6S: C, 55.75; H, 3.56; N, 12.38; S, 7.09. Found: C,
55.82; H, 3.66; N, 12.29; S, 7.03.
4-(7-Amino-6-cyano-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidin-5-yl)phenyl 4-methylbenzenesulfonate (20C)
1
mp 259-261 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 2.39 (s, 3H, CH3), 3.09 (s, 3H,
NCH3), 3.41 (s, 3H, NCH3), 4.96 (s, 1H, CH), 7.07 (s, 2H, NH2), 7.18 (d, J ¼ 7.9 Hz,
2H), 7.24 (d, J ¼ 7.9 Hz, 2H), 7.41 (d, J ¼ 8.4 Hz, 2H), 7.82 (d, J ¼ 8.4 Hz, 2H); 13C-
NMR (100 MHz, DMSO-d6): d ¼ 21.0, 29.4, 31.2, 38.9, 64.8, 119.4, 121.6, 127.0,
128.1, 129.5, 130.1, 131.8, 144.6, 145.1, 149.9, 152.3, 161.4, 161.7, 162.9.
Anal. Calcd for C23H20N4O6S: C, 57.49; H, 4.20; N, 11.66; S, 6.67. Found: C,
57.61; H, 4.32; N, 11.58; S, 6.59.
N-(4-(7-Amino-6-cyano-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidin-5-
yl)phenyl)-4-methylbenzenesulfonamide (21C)
1
mp >300 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 2.36 (s, 3H, CH3), 4.81 (s, 1H,
CH), 7.06 (s, 2H, NH2), 7.12 (d, J ¼ 7.8 Hz, 2H), 7.29 (d, J ¼ 7.9 Hz, 2H), 7.34 (d,
J ¼ 8.6 Hz, 2H), 7.73 (d, J ¼ 8.6 Hz, 2H), 9.51 (s, 1H, NH), 11.19 (s, 1H, NH), 12.03
(s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): d ¼ 20.8, 38.6, 64.5, 114.6, 119.4,
127.8, 128.9, 129.5, 129.9, 136.3, 136.8, 144.6, 145.1, 152.3, 161.2, 161.8, 162.9.
Anal. Calcd for C21H17N5O5S: C, 55.87; H, 3.80; N, 15.51; S, 7.10. Found: C,
56.01; H, 3.93; N, 15.44; S, 7.06.
N-(4-(7-Amino-6-cyano-1,3-dimethyl-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-
d]pyrimidin-5-yl)phenyl)-4-methylbenzenesulfonamide (22C)
1
mp 291-293 ꢀC; H-NMR (400 MHz, DMSO-d6): d ¼ 2.38 (s, 3H, CH3), 3.10 (s, 3H,
NCH3), 3.42 (s, 3H, NCH3), 4.82 (s, 1H, CH), 7.06 (s, 2H, NH2), 7.12 (d, J ¼ 7.9 Hz,
2H), 7.29 (d, J ¼ 7.9 Hz, 2H), 7.34 (d, J ¼ 8.5 Hz, 2H), 7.72 (d, J ¼ 8.5 Hz, 2H), 9.49 (s,
1H, NH); 13C-NMR (100 MHz, DMSO-d6): d ¼ 20.9, 29.3, 31.2, 38.8, 64.3, 114.6,
120.7, 127.1, 128.3, 129.1, 129.7, 136.3, 136.7, 144.1, 145.2, 151.4, 153.8,
160.6, 162.5.

14
Ghashang et al.
Anal. Calcd for C23H21N5O5S: C, 57.61; H, 4.41; N, 14.61; S, 6.69. Found: C,
57.52; H, 4.35; N, 14.49; S, 6.58.
3-(7-Amino-6-cyano-2,4-dioxo-1,3,4,5-tetrahydro-2H-pyrano[2,3-d]pyrimidin-5-
yl)phenyl benzenesulfonate (23C)
mp 266-268 ꢀC;1H-NMR (400 MHz, DMSO-d6): d ¼ 4.77 (s, 1H, CH), 6.99-7.34 (m,
6H), 7.56 (t, J ¼ 8.4 Hz, 2H), 7.68 (t, J ¼ 8.4 Hz, 1H), 7.80 (d, J ¼ 8.6 Hz, 2H), 11.11 (s,
1H, NH), 12.02 (s, 1H, NH); 13C-NMR (100 MHz, DMSO-d6): d ¼ 38.6, 64.6, 111.2,
119.9, 120.4, 121.5, 127.8, 128.6, 129.1, 129.2, 131.4, 134.4, 142.6, 151.4, 152.6,
160.7, 161.3, 162.9.
Anal. Calcd for C20H14N4O6S: C, 54.79; H, 3.22; N, 12.78; S, 7.31. Found: C,
54.70; H, 3.16; N, 12.70; S, 7.26.
Acknowledgment
The authors are indebted to the Islamic Azad University, Najafabad Branch, for finan-
cial support of this research.
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