Efficient and expeditious synthesis of pyrano-pyrimidines, multi-substituted γ-pyrans, and their antioxidant activity

Article abstract of DOI:10.1002/jhet.2019

An efficient, expeditious catalytic route for the synthesis of ethyl 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylates 2 was achieved via a three-component, one-pot reaction of malononitrile, ethyl acetoacetate, and various aromatic aldehydes in wat

Full text of DOI:10.1002/jhet.2019

Month 2013 Efficient and Expeditious Synthesis of Pyrano-pyrimidines, Multi-substituted
g-Pyrans, and Their Antioxidant Activity
a
a
a
b
c
*
Khairy A. M. El-Bayouki, Wahid M. Basyouni, Tamer K. Khatab, Fakhry A. El-Basyoni, Ahmed R. Hamed,
and Eslam A. Mostafaa
aOrganometallic and Organometalloid Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
bChemistry Department, Faculty of Science, Ain Shams University, Cairo 12752, Egypt
cPharmaceutical Research Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki,
Cairo 11111, Egypt
*
E-mail: khelbayouki@yahoo.com
Received January 9, 2013
DOI 10.1002/jhet.2019
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
An efficient, expeditious catalytic route for the synthesis of ethyl 6-amino-5-cyano-2-methyl-4-aryl-4H-
pyran-3-carboxylates 2 was achieved via a three-component, one-pot reaction of malononitrile, ethyl
acetoacetate, and various aromatic aldehydes in water as a solvent at room temperature. The key advantages
are excellent yield, reaction time, and inexpensive catalyst. Also, cyclization of 4H-pyrans 2 to the corre-
sponding 4H-pyrano[2,3-d]pyrimidines 3 using silica sulfuric acid in the presence of acetic anhydride was
described. Some synthesized compounds exhibited promising antioxidant activities.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
dihydro-3H-pyrano[2,3-d]pyrimidine-6-carboxylate using
silica sulfuric acid (SSA) in the presence of acetic anhy-
dride in an excellent yield, short reaction time, and inex-
pensive catalyst advantages.
Multi-component reactions are processes in which three
or more reactants combined in a single chemical step to
produce products incorporating substantial portions of all
the reactants. These reactions are known to be effective
in building highly functionalized small organic molecules
from readily available starting materials in a single step
with inherent flexibility for creating molecular complexity
and diversity coupled with minimization of time, labor,
cost, and waste production [1].
Polyfunctionalized 4H-pyrans and their fused deriva-
tives have received considerable attention over the past
years because of their wide range of biological activity.
Compounds with these ring systems have diverse pharma-
cological activity, such as antitumor [2], cardiotonic [3],
hepatoprotective [4], antihypertensive, antibronchitic [5],
as well antifungal activity [6].
Heterogeneous catalysts are advantageous over conven-
tional homogeneous catalysts as they can easily recovered
from the reaction mixture by simple filtration and can be
reused after activation, thereby making the process eco-
nomically viable. Catalysts based on silica are considered
as one of the most significant types of heterogeneous cata-
lysts because of their high surface areas and porosities,
excellent stabilities (chemical and thermal), and facile
functionalization with organic groups that can be robustly
anchored to the surface [7–9].
RESULTS AND DISCUSSION
In continuation to our investigations for the synthesis of
novel alicyclic and heterocyclic compounds for designing
novel procedures in multi-component reactions, one-pot
synthesis using tetrachlorosilane (TCS)/ZnCl2 [10], we
have developed in the present work an efficient and
a rapid reaction for the synthesis of ethyl 6-amino-
4-phenyl-5-cyano-2-methyl-4H-pyran-3-carboxylate 2a
in an excellent yield. This reaction was accomplished
through three-component one-pot reaction of benzaldehyde
1a, ethylacetoacetate, and malononitrile in the presence of
piperidine, using deionized water as a solvent at room
temperature (Scheme 1).
For optimization, some preliminary trials were investi-
gated for the reaction conditions with regard to some
catalysts (e.g., piperidine, SSA, ZnCl2, TCS) and solvents.
The reaction was carried out under various conditions in
order to find out the best catalyst, solvent, time, and yield
(Table 1).
From the primary optimization, the best reaction results
were 1:1:1 ratio of aldehyde, malononitrile, and ethyl
acetoacetate, respectively, in the presence of few drops of
piperidine (0.5 mL) and deionized water (as a solvent) at
room temperature (entry 1). These initial results prompted
So, the present work aimed to explore cyclization of
some prepared ethyl 6-amino-5-cyano-2-methyl-4-aryl-
4H-pyran-3-carboxylates to the related 5-substited-4,5-
© 2013 HeteroCorporation

K. A. M. El-Bayouki, W. M. Basyouni, T. K. Khatab, F. A. El-Basyoni,
A, R, Hamed, and E. A. Mostafa
Vol 000
Scheme 1. Synthesis of ethyl 6-amino-4-phenyl-5-cyano-2-methyl-4H-pyran-3-carboxylates 2a.
us to explore the potential synthesis of functionalized 4H-
pyrans (2a–k). Thus, when several examples of the
aromatic aldehydes (1a–k), ethyl acetoacetate and
malononitrile were left to react at room temperature in ace-
tonitrile in the presence of few drops of piperidine, the
pyran-3-carboxylates (2a–k) were afforded in good yield
(Table 2). The obtained results are presented in Scheme 2.
The IR spectra of the 4H-pyran-3-carboxylates 2 showed
the characteristic bands for NH2, CO, and CꢀN. The
NMR spectra revealed signals for three CH3 proton signals
at (d: ppm) [1.20 (t, CO2CH2CH3), 2.46 (s, CH3) and 4.00
(q, CO2CH2CH3)], for CH at 4.48 (s, CH) and for
NH2 at 4.62 (b, NH2) together with the aromatic pro-
tons in 7.25–7.79 region (m, ArH). The mass spectra
of 2i, k revealed molecular ion peaks at m/z = 288 (12.12%)
and 334.92 (24.12%), respectively.
Numerous pyrano [2,3-d]pyrimidines are considered as
one of the most important derivatives of 4H-pyrans and
well known to have diverse pharmacological activity.
Several derivatives with such annulated uracils have
antitumor [3], antibacterial [11], (antihypertensive,
hepatoprotective, and cardiotonic) [4], vasodilator [12],
bronchodilators [3], and antiallergic activities [13]. Some
of these uracils exhibited antimalarial [14], antifungal [6],
analgesics [15], and herbicidal [16] properties. As a contin-
uation of the present investigation, a trial was attempted
to synthesize pyrano[2,3-d]pyrimidine derivatives 3.
Thus, when selected examples of the pyran-3-carboxylates
Table 1
Effect of catalysts and solvent on the yield and time of the one-pot synthesis of ethyl 6-amino-4-phenyl-5-cyano-2-methyl-4H-pyran-3-carboxylate 2a.
Entry
Catalyst
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
Piperidine
Piperidine
Piperidine
Silica sulfuric acid
ZnCl2
CH3CN
Deionized water
CH2Cl2
CH3CN
CH3CN
10
5
20
30
30
30
98
87
65
50
25
20
Tetrachloro silane
CH3CN
Table 2
Multi-component synthesis of ethyl 6-amino-4-aryl-5-cyano-2-methyl-4H-pyran-3-carboxylate 2a–k.
1,2
Ar
Reaction time (min)
2: yield (%)
1,2
Ar
Reaction time (min)
2: yield (%)
(a)
(b)
(c)
(d)
(e)
(f)
C6H5
5
5
20
15
20
15
98
95
90
90
88
94
(g)
(h)
(i)
(j)
(k)
4-NO2C6H5
2-Furyl
5-Mefuryl
2-Thienyl
2-Naphthyl
25
20
10
15
20
80
85
90
85
82
4-F-C6H4
2-Cl-C6H4
3-Br-C6H4
4-CN-C6H4
4-MeOC6H5
Scheme 2. Multi-component synthesis of ethyl 6-amino-4-aryl-5-cyano-2-methyl-4H-pyran-3-carboxylates 2a–k.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Efficient and Expeditious Synthesis of Pyrano-pyrimidines, Multi-substituted g-Pyrans,
and Their Antioxidant Activity
(2a–d, h) were stirred at room temperature for 3 h, or heated
in the presence of piperidine, a mixture of SSA and acetic
anhydride (1:1 ratio: 0.5 mmol) for a short time (2–20min)
afforded smoothly the corresponding pyrano[2,3-d]pyrimi-
dine derivative in a relatively high yield.
Upon heating 2-amino-pyran 2a under reflux in excess
acetic anhydride (excess) without any catalyst for 5–6 h,
ethyl 2,7-dimethyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrano
[2,3-d]pyrimidine-6-carboxylate 3a was formed in low yield
(25%). This reaction step can recommend the role of SSA
presence in the reaction medium for obtaining products of
type 3 in a relative good yield (62–85%) and in short reaction
time (2–20 min). Presumably, this may be due to the presence
of hetero-aryl moiety in their structure (Scheme 3 and
Table 3).
Structure of the obtained pyrano[2,3-d]pyrimidines (3a–h)
was confirmed by careful inspections of their spectroscopic
data. The IR spectra of 3a and c showed bands at υ = 3471,
1714, 1665, 1599 cmꢁ1 corresponding to NH, carbonyl of
(C2H5OCO), carbonyl of (NHCO) and CN functional
groups, respectively. The PMR spectra of 3a, c displayed
signals at (d: ppm, 500 MHz, CDCl3) 1.15 (CH3), 2.33
(CH3), 2.46 (CH3), 4.05 (CO2CH2CH3), 4.90–4.35 (CH),
13.30–13.21 (NH, D2O-exchangeable).
The 13C NMR of (3c) showed characteristic signals for
(CH3CH2), (C7CH3), (C2CH3), (CH2O), (C-7), (NHCO),
and (CO-carboxylate) at (d: ppm) 14.4, 18.90, 21.28,
61.60, 158.61, 160.6, and 166, respectively. Mass spectra
of the pyrano[2,3-d]pyrimidines (3a and d) revealed molec-
ular ion peaks at: m/z = 326 (43.46%) and 406 (15.55%),
respectively (Experimental Part). Moreover, the reactivity
of 4H-pyrans of type 2, to our knowledge, is unknown
towards TCS/ZnCl2 as a binary catalytic reagent. Therefore,
when 4H-pyrans (2a–e as selected examples) reacted with
acetic anhydride and this binary catalytic reagent (1:3:3 ratio)
for 30–45 min, hydrolysis of the CN to CONH2 function
occurred with simultaneous acetylating of NH2 at 6 position;
the corresponding 4-aryl-4H-pyran-3-carboxylates (4a–e)
were afforded in good yield (62–83%), and no traces of the
expected pyrano [2,3-d]pyrimidines of type (3) were detected.
The IR spectra of products (4) showed characteristic
bands for NH2 and NH, and CO at 3470–320 and
1710–1705, and 1670–1650 cmꢁ1 regions, respectively.
The proton NMR spectra of these products revealed
signals for CH3, CH, (NH2 and NH D2O exchangeable)
beside the aromatic proton signals. Also, 13C NMR spec-
trum of product 4c confirmed its proposed structure
(Scheme 4 and Table 4).
Scheme 3. Synthesis of ethyl 5-aryl-2,7-dimethyl-4-oxo-4,5-dihydro-4Hpyrano[2,3-d]pyrimidine-6-carboxylates.
Table 3
Silica sulfuric acid/acetic anhydride catalyzed synthesis of ethyl 5-aryl-2,7-dimethyl-4-oxo-4,5-dihydro-4H-pyrano[2,3-d]pyrimidine-6-carboxylates 3a–h.
3
Ar
Reaction time (min)
Yield (%)
3
Ar
Reaction time (min)
Yield (%)
(a)
(b)
(c)
(d)
C6H5
2
2
12
12
85
82
78
78
(e)
(f)
(g)
(h)
4-OMeC6H4
4-NO2C6H4
5-Me-Furyl
2-Naphtyl
15
20
10
15
84
62
75
65
4-F-C6H4
2-Cl-C4H4
3-Br-C6H4
Scheme 4. Synthesis of ethyl 6-acetamido-5-carbamoyl-2-methyl-4-aryl-4H-pyran-3-carboxylates 4a–e.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. A. M. El-Bayouki, W. M. Basyouni, T. K. Khatab, F. A. El-Basyoni,
A, R, Hamed, and E. A. Mostafa
Vol 000
Table 4
produced ethyl 2,7-dimethyl-5-phenyl-4-(propylthio)-5H-
pyrano[2,3-d]pyrimidine-6-carboxylate (8). Synthesis of
such latter products can consider as another confirmation
for the structures of the synthesized pyrano[2,3-d]pyrimi-
dines of type (3). IR, NMR, and mass spectral determina-
tions confirmed well the structures of the latter
compounds. The IR spectrum of the thione product (7)
showed characteristic bands due to CO (carboxylate) and
CS vibrations at 174 and 1239 cmꢁ1, respectively. Mass
spectrum revealed molecular ion peak at m/z = 342 (as base
peak, 100%). PMR spectrum displayed signals (d: ppm)
for NH (broad band-D2O exchangeable) together with
other signals for CH3, CH2 CH, and aromatic protons.
The 13C NMR spectrum (500 MHz, DMSO; d: ppm) of
product 8 displayed signals for SCH2 (31.71) with other
signals for CH3, CH2, C2 (CH3), C5, C6, CS, C8a, and
CO (carboxylate). Its mass spectrum showed molecular
ion peak at m/z = 384 (49.78%) (Scheme 5 and Experimen-
tal part).
Synthesis of ethyl 6-acetamido-5-carbamoyl-2-methyl-4-aryl-4H-pyran-3-
carboxylates 4a–d.
Yield (%)
Reaction time (min)
Ar
4
83
82
75
71
80
30
30
45
45
60
C6H5
(a)
(b)
(c)
(d)
(e)
4-F-C6H4
2-Cl-C6H4
3-Br-C6H4
4-NO2C6H4
The present work was continued for exploring other
related derivatives of 4H-pyrano[2,3-d] pyrimidines. Thus,
when pyrano[2,3-d]pyrimidine-6-carboxylate (3a) was
heated under reflux with POCl3/PCl5 in ethanol for ~10 h,
it gave ethyl 4-chloro-2,7-dimethyl-5-phenyl-5H-pyrano
[2,3-d]pyrimidine-6-carboxylate (5) in 81% yield. IR spec-
trum of the chloro compound (5) showed only one band
due to CO (carboxylate) at 1714 cmꢁ1. Its mass spectrum
revealed molecular ion peak m/z = 344 (4.3%). The latter
chloro derivative afforded ethyl 2,7-dimethyl-5-phenyl-4-
(propylamino)-5H-pyrano[2,3-d]pyrimidine-6-carboxylate
(6) when reacted with propane-1-amine in absolute ethanol
in the presence of Et3N (few drops). Also, the chloro
pyrano[2,3-d]pyrimidine-6-carboxylate (5) on reaction with
thiourea gave ethyl 2,7-dimethyl-5-phenyl-4-thioxo-4,5-
dihydro-3H-pyrano[2,3-d]pyrimidine-6-carboxylate (7).
Previously, some thiopurine and pyrrolo[2,3-d]pyrimi-
dine derivatives were obtained by treating chloro-purines
with thiourea [17]. The thioxo-pyrano[2,3-d] pyrimidines
(7) when left to react with iodopropane in ethanol in the
presence of Et3N while stirring at room temperature
EXPERIMENTAL
Melting points are uncorrected. Microanalyses were carried out
by the Micro analytical Laboratory, National Research Center,
Cairo, Egypt. Infrared spectra (KBr) were recorded using a Jasco
FT/IR-300E spectrophotometer. 1H and 13C NMR spectra were
measured in CDCl3 using Varian Mercury 500MHz spectrometers
with chemical shifts using TMS as internal standard. Mass spectra
were recorded on a GC/MS Finnigan SSQ 7000 spectrophotometer.
All reactions were carried out under atmospheric conditions at room
temperature. TCS, SSA, and anhydrous zinc chloride were obtained
from commercial sources. Analytical TLC was performed with
silica-gel GF254 plates [petroleum ether/ethyl acetate (4:1 by
volume)], and the products were visualized by UV detection. The
Scheme 5. Synthesis of 5-aryl-4H-pyrano[2,3-d]pyrimidines 5–8.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Efficient and Expeditious Synthesis of Pyrano-pyrimidines, Multi-substituted g-Pyrans,
and Their Antioxidant Activity
antioxidant activity of the selected compound was assessed by mea-
suring the ability of each compound to scavenge the free radical of
1,1-diphenyl-2-picrylhydrazyl (DPPH) using previously published
methods [18,19] and modified one [20]. Test compounds were
prepared in DMSO as 10ꢂ stocks from each test concentration
(0.1–2.0 mM). The compounds were then tested to determine the
EC50 (effective concentration of the compound producing 50%
scavenging of the stable free radical DPPH). Some known radical
scavengers, quercetin, t-butyl hydroquinone, and gallic acid, were
tested in the assay as positive controls. Briefly, each of compound
stock solutions (15 mL/well) was pipetted onto 96-well plate. The
assay was started with the addition of DPPH reagent (0.004% w/v
in methanol, 135 mL/well). Appropriate negative controls were
simultaneously run using methanol to serve as a correction for the
optical density of colored compounds at 540nm. The plate was
immediately shaken for 30s and incubated in the dark for 30 min
at room temperature. The remaining DPPH was measured in a
micro-plate reader (BMG Fluostar Optima, Germany) at 540nm.
The percentage of antioxidant activity (AA) was calculated
using the following equation:
Ethyl 6-amino-4-(3-bromophenyl)-5-cyano-2-methyl-4H-pyran-
3-carboxylate (2d). Yellow crystals, yield: 90%, mp 156–158ꢃC
(EtOH). Rf = 0.35. IR (potassium bromide): υ: cmꢁ1 = 3396, 3329
(NH2), 2191 (CN), 1685 (CO) cmꢁ1. MS (m/z: %): 362 (11.73%),
364 (10.50%). Anal. Calcd for C16H15BrN2O3; MW= (363.21): C,
52.91; H, 4.16; N, 7.71. Found: C, 53.09; H, 4.19; N, 7.80%.
Ethyl 6-amino-5-cyano-4-(4-cyanophenyl)-2-methyl-4H-pyran-
3-carboxylate (2e). Brown crystals, yield: 88% mp 156–158ꢃC
(EtOH). Rf = 0.27. IR (potassium bromide): (υ: cmꢁ1); 3403.74,
3330.46 (NH2), 2231.24, 2198.45 (CN), 1719.23 (CO), 1679.69
(C), 1602, 56 (CC). MS (m/z: %): 309.10 (9.73%). Anal. Calcd for
C17H15N3O3; MW = (309.32): C, 66.01; H, 4.89; N, 13.58. Found:
C, 65.98; H, 4.87; N, 13.56%.
Ethyl 6-amino-5-cyano-4-(4-methoxyphenyl)-2-methyl-4H-pyran-
3-carboxylate (2f). White crystals yield 94%, mp 138–140ꢃC
(Ref. [15]); (EtOH). Rf = 0.30. IR (potassium bromide): υ:
cmꢁ1 = 3401, 3330 (NH2), 2190 (CN), 1686 (CO) cmꢁ1. MS
(m/z: %): 314 (12.75%). Anal. Calcd for C17H18N2O4;
MW= (314.34): C, 64.96; H, 5.77; N, 8.91. Found: C, 64.87; H,
5.76; N, 8.89%.
Ethyl 6-amino-5-cyano-2-methyl-4-(4-nitrophenyl)-4H-pyran-
3-carboxylate (2g). Brown crystals, yield: 80%, mp 176–178ꢃC
(EtOH). Rf = 0.25. IR (potassium bromide): (υ: cmꢁ1); 3402.78,
3332.39 (NH2), 2197.49 (CN), 1688.37 (CO), 1603, 52 (CC). MS
(m/z: %): 329.05 (28.49%). Anal. Calcd for C16H15N3O5; MW
(329.31): C, 58.36; H, 4.59; N, 12.76. Found: C, 58.40; H, 4.44;
N, 12.78%.
Ethyl 6-amino-5-cyano-4-(furan-2-yl)-2-methyl-4H-pyran-3-
carboxylate (2h). Violet crystals yield 85%, mp 216–118ꢃC
(Ref. [23]); (EtOH). Rf = 0.28. IR (potassium bromide): υ:
cmꢁ1 = 3399, 3325 (NH2), 2195 (CN), 1683 (CO) cmꢁ1. MS
(m/z: %): 274 (6.12%). Anal. Calcd for C14H14N2O4; MW
(274.27): C, 61.31; H, 5.41; N, 10.21%, Found: C, 61.26; H,
5.39; N; 10.17%.
Ethyl 6-amino-5-cyano-2-methyl-4-(5-methylfuryl)-4H-pyran-
3-carboxylate (2i). White crystals yield 90%, mp 196–198ꢃC
(EtOH). Rf = 0.50. IR (potassium bromide): υ: cmꢁ1 = 3401, 3332
(NH2), 2191 (CN), 1688 (CO) cmꢁ1. MS (m/z: %): 288
(12.12%).1H NMR (500 MHz, CDCl3): d = 1.20 (t, J = 7.2 Hz, 3H,
CO2CH2CH3), 2.16 (3H,s, CH3), 2.33 (3H,s, CH3), 4.12
% Antioxidant activity ðAAÞ 100
¼
ꢀ
OD540 nm ðblankÞ ꢁ OD540 nm ðsampleÞ
ꢂ
(1)
OD540nm ðblankÞ
Regression analysis was used to determine the EC50 values
for each compound using the concentration–% AA relationship.
All data were represented as the mean value of duplicate absor-
bance measurement.
Synthesis of compounds 2a–k. General procedure: To an
aqueous mixture of aldehyde 1 (2 mmol), malononitrile (2mmol),
and ethylacetoacetate (2 mmol) was added piperidine (0.5mL).
The reaction mixture was stirred at room temperature for the
specified time (Table 2). The precipitated product was filtered,
washed with water, and then with a mixture of ethyl acetate/
cyclohexane (20:80 v: v). The obtained solid product was
crystallized from ethanol to give products 2a–k.
Ethyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-
carboxylate (2a). Yellow crystals, yield 98%, mp: 192–194ꢃC
(Ref. [21]); (EtOH). Rf = 0.35. IR (potassium bromide): υ:
cmꢁ1 = 3401, 3330 (NH2), 2188 (Cꢀ N), 1688 (CO) cmꢁ1. MS
(EI) (m/z: %): 284 (68.24%). Anal. Calcd for C16H16N2O3;
MW= (284.31): C, 67.59; H, 5.67; N, 9.85. Found: C, 67.56; H,
5.54; N, 9. 83%
Ethyl 6-amino-5-cyano-4-(4-fluorophenyl)-2-methyl-4H-pyran-
3-carboxylate (2b). Yellow crystals, yield: 95%, mp 158–160ꢃC
(Ref. [22]); (EtOH). Rf = 0.33. IR (potassium bromide): (υ: cmꢁ1);
3406.64, 3333.36 (NH2), 2193.63 (CN), 1688.37 (CO), 1610.27
(CC). 1H NMR (500 MHz, CDCl3) d = 1.09 (t, J = 7.2Hz, 3H,
CO2CH2CH3), 2.35 (3H, s, CH3), 4.02 (q, J = 7.2Hz,
2H, CO2CH2CH3), 4.24 (1H, s, CH), 4.51 (2H, s, NH2,
D2O-exchangeable), 6.97–7.16 (4H, m, Ar-H). Anal. Calcd for
C16H15FN2O3; MW= (302.30): C, 63.57; H, 5.00; N, 9.27.
Found: C, 63.66; H, 4.98; N, 9.19%.
(q, J = 7.2Hz, 2H, CO2CH2CH3), 4.51 (1H, s, CH), 4.54 (2H, b,
13
NH2), 5.82 (1H, s, ArH), 5.94 (1H, s, ArH) ppm.
C NMR
(500MHz, DMSO-d6): d = 13.84 (Me-furyl), 14.32 (CH3CH2),
18.63 (CH3-C2), 33.03 (C4), 54.75 (C5), 60.81 (CH2O), 105.75,
106.64, 151.14, 154.72 (4 furyl carbon atoms), 106.94 (C3),
120.18 (CN), 160.03 (C6), 157.87 (C2), 165.09 (CO, carboxylate)
ppm. Anal. Calcd for C15H16N2O4; MW (288.30): C, 62.49; H,
5.59; N, 9.72. Found: C, 62.42; H, 6.04; N, 9.80%.
Ethyl 6-amino-5-cyano-2-methyl-4-(thiophen-2-yl)-4H-pyran-
3-carboxylate (2j). Brown crystals yield 85%, mp 175–177ꢃC
(EtOH). Rf = 0.33. IR (KBr): υ: cmꢁ1 = 3396, 3328 (NH2), 2192
(CN), 1692 (CO) cmꢁ1. MS (m/z: %): 290 (12.12%). Anal. Calcd
for C14H14N2O3S; MW= (290.34): C, 57.92; H, 4.86; N, 9.65; S,
11.04. Found: C, 57.87; H, 4.86; N, 9.58; S, 10.98%.
Ethyl 6-amino-5-cyano-2-methyl-4-(naphthalen-2-yl)-4H-pyran-
3-carboxylate (2k). White crystals yield 82%, mp 150–152ꢃC
(EtOH). Rf = 0.63. IR (potassium bromide): υ: cmꢁ1 = 3402, 3331
(NH2), 2192 (CN), 1691 (CO) cmꢁ1. MS (m/z: %): 288.95
(24.12%).1H NMR (500 MHz, CDCl3): d = 1.05 (t, J = 7.0 Hz, 3H,
CO2CH2CH3), 2.46 (3H, s, CH3), 4.00 (q, J = 7.0 Hz, 2H,
CO2CH2CH3), 4.48 (1H, s, CH), 4,62 (2H, b, NH2), 7.25–7.79
Ethyl 6-amino-5-cyano-4-(4-chlorophenyl)-2-methyl-4H-pyran-
3-carboxylate (2c). Yellow crystals, yield: 90%, mp 170–172ꢃC
(EtOH). Rf = 0.33 IR (potassium bromide): (υ: cmꢁ1); 3408.64,
3333.36 (NH2), 2193.63 (CN), 1688.37 (CO), 1610, 27 (CC). MS
(m/z: %): 318.10 (19.30%). Anal. Calcd for C16H15ClN2O3;
MW= (318.75): C, 60.29; H, 4.74; N, 8.79. Found: C, 60.27; H,
4.70; N, 8.76%.
13
(7H, m, ArH) ppm. C NMR (500 MHz, DMSO-d6): d = 14.26
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. A. M. El-Bayouki, W. M. Basyouni, T. K. Khatab, F. A. El-Basyoni,
A, R, Hamed, and E. A. Mostafa
Vol 000
(CH3-CH2), 18.76 (CH3-C2), 39.89 (C4), 57.64(C5) 60.70 (CH2O),
107.62 (C3), 126.22, 126.77, 128.03, 128.22, 128.81, 132.64,
133.41, 142.74 (10 aromatic carbon atoms), 120.28 (CN), 159.05
(C6), 157.21 (C2), 166.01 (CO, carboxylate) ppm. Anal. Calcd for
C20H18N2O3; MW= (334.37): C, 71.84; H, 5.43; N, 8.38. Found:
C, 71.90; H, 5.40; N, 8.50%.
CO2CH2CH3), 4.35 (1H, s, CH), 7.19–7.25 (4H, m, ArH), 13.3
(1H, b, NH) ppm. 13C NMR (500MHz, DMSO-d6): d = 14.46
(CH3CH2), 18.95 (C7-CH3), 21.28 (C2-CH3), 34.46 (C5), 61.60
(CH2O), 100.10 (C4a), 107.15 (C6), 128.00–141.43 (6 aromatic
carbon atoms),158.61 (C7), 160.59 (CO), 159.40 (C8a),
162.00 (C2), 166.09 (CO, carboxylate) ppm Anal. Calcd for
C18H17ClN2O4; MW = (360.79): C, 59.92; H, 4.75; N, 7.76.
Found: C, 59.90; H, 4.73; N, 7.75%.
Ethyl 5-(3-bromophenyl)-2,7-dimethyl-4-oxo-3,5-dihydro-4H-
pyrano[2,3-d]pyri-midine-6-carboxylate (3d). White crystals;
yield 78%, mp 220–222ꢃC (EtOH). Rf = 0.12. IR (potassium
bromide): υ: cmꢁ1 = 3399 (NH), 1712 (CO), 1668 (CO), 1605
(CN) cmꢁ1. MS (m/z: %): 406 (15.55%), 404 (14.95%). 1H NMR
(500MHz, CDCl3): d = 1.14 (t, J = 7.2 Hz, 3H, CO2CH2CH3),
2.38 (3H, s, CH3), 2.50 (3H, s, CH3), 4.06 (q, J = 7.2 Hz, 2H,
Synthesis of compounds (3a–h).
General method A: A
mixture of pyran 2 (2.5 mmol), acetic anhydride (5 mL), and
SSA (0.5 mmol) was stirred at room temperature for 3 h. The
reaction mixture was poured on ice. The obtained solid was
filtered off. To recover the catalyst; the crystalline residue was
dissolved in dichloromethane (10 mL) and filtered. Evaporation
of the filtrate gave products 3 as solid products.
Method B: A mixture of pyran 2a (2.5 mmol) and acetic anhy-
dride (5mL) was heated under reflux for the specified time
(Table 3). The reaction was monitored by TLC. After completion of
the reaction, the mass was cooled. The reaction mixture was filtered
and the obtained residue was washed with water (10mL). To
recover the catalyst; the crystalline residue was dissolved in
dichloromethane (10 mL) and filtered. Evaporation of the filtrate
gave products 3 as solid products. The products were further puri-
fied by crystallization from ethanol.
Ethyl 2,7-dimethyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrano
[2,3-d]pyrimidine-6-carboxylate (3a). White crystals; yield 85%,
mp 256–258ꢃC (Ref. [24]); (EtOH). Rf = 0.08. IR (potassium
bromide): υ: cmꢁ1 = 3417 (NH), 1714 (CO), 1665 (CO), 1599
(CN) cmꢁ1. MS (m/z: %): 326 (43.46%). 1H NMR (500 MHz,
CDCl3): d = 1.13 (t, J = 7.2Hz, 3H, CO2CH2CH3), 2.30 (3H, s,
CH3), 2.49 (3H, s, CH3), 4.04 (q, J = 7.2 Hz, 2H, CO2CH2CH3),
4.91 (1H, s, CH), 7.18–7.29 (5H, m, ArH), 13.21 (1H, b, NH)
ppm. Anal. Calcd for C18H18N2O4; MW = (326.35): C, 66.25; H,
5.56; N, 8.58. Found: C, 66.23; H, 5.54; N, 8.54%.
Method B: Reaction of 5- amino-pyran (2a) with acetic
anhydride without SSA catalyst. A mixture of pyran 2a
(2.5 mmol) and acetic anhydride (5 mL) was heated under refluxed
for 5–6 h; the reaction was monitored by TLC. After completion
of the reaction, the mixture was poured on ice water. The obtained
solid was filtered off and crystallized from ethanol to give 3a,
yield 25%, (mp and mixed mp undepressed).
CO2CH2CH3), 4.87 (1H, s, CH), 7.1–7.47 (4H, m, ArH), 13.27
13
(1H, b, NH) ppm.
C NMR (500MHz, DMSO-d6): d = 14.27
(CH3CH2), 18.98 (C7-CH3), 21.44 (C2-CH3), 39.80 (C5), 60.78
(CH2O), 100.49 (C4a), 107.63 (C6), 121.72, 127.62, 130.00,
130.78, 131.51, 147.29 (6 aromatic carbon atoms),159.33
(C7), 160.39 (CO), 159.52 (C8a), 162.44 (C2), 165.87
(CO, carboxylate) ppm. Anal. Calcd for C18H17BrN2O4;
MW= (405.24): C, 53.35; H, 4.23; N, 6.91. Found: C, 53.31; H,
4.20; N, 6.88%.
Ethyl 5-(4-methoxyphenyl)-2,7-dimethyl-4-oxo-3,5-dihydro-
4H-pyrano[2,3d]-pyrimidine-6-carboxylate (3e). White crystals;
yield 84%, mp 240–242ꢃC (EtOH). Rf = 0.08. IR (potassium
bromide): υ: cmꢁ1 = 3412 (NH), 1713 (CO), 1668 (CO), 1602
(CN) cmꢁ1. MS (m/z: %): 356 (100%). 1H NMR (500 MHz,
CDCl3): d = 1.15 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.36 (3H, s,
CH3), 2.48 (3H, s, CH3), 3.72 (3H, s, OCH3), 4.06
(q, J = 7.2 Hz, 2H, CO2CH2CH3), 4.89 (1H, s, CH), 6.72–7.20
(4H, m, ArH), 13.19 (1H, b, NH) ppm. Anal. Calcd for
C19H20N2O5; MW = (356.37): C, 64.04; H, 5.66; N, 7.86.
Found: C, 64.01; H, 5.61; N, 7.82%.
Ethyl 5-(4-nitrophenyl)-2,7-dimethyl-4-oxo-3,5-dihydro-4H-
pyrano[2,3-d]pyri-midine-6-carboxylate (3f). White crystals;
yield 62%, mp 264–266ꢃC (EtOH). Rf = 0.05. IR (potassium
bromide): υ: cmꢁ1 = 3296 (NH), 1723 (CO), 1672 (CO), 1604
1
Ethyl 5-(4-fluorophenyl)-2,7-dimethyl-4-oxo-3,5-dihydro-4H-
pyrano[2,3d]pyri-midine-6-carboxylate (3b). White crystals,
yield: 82%, mp 240–242ꢃC (EtOH). Rf =0.10. IR (potassium
bromide): (υ: cmꢁ1); 3414.35 (NH), 1715.37 (CO), 1666.2 (CO),
(CN) cmꢁ1. MS (m/z: %): 371 (44.52%). H NMR (500 MHz,
CDCl3): d = 1.14 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.38 (3H, s,
CH3), 2.49 (3H, s, CH3), 4.05 (q, J = 7.2 Hz, 2H, CO2CH2CH3),
5.03 (1H, s, CH), 7.46–7.47(d, 2H, J = 8.5 Hz, ArH), 8.07–8.09
(d, 2H, J = 8.5 Hz, ArH), 12.98 (1H, b, NH) ppm. Anal. Calcd
for C18H17N3O6; MW = (371.34): C, 58.22; H, 4.61; N, 11.32.
Found: C, 58.18; H, 4.56; N, 11.28%.
1
1599.7 (CN). MS (m/z%): 344.00 (63.39%) 344.95 (15.23%). H
NMR (500 MHz, CDCl3) d = 1.20 (t, J = 7.2Hz, 3H,
CO2CH2CH3), 2.37 (3H, s, CH3), 2.52 (3H, s, CH3), 4.07
(q, J =7.2 Hz, 2H, CO2CH2CH3), 4.91 (1H, s, CH), 6.88–7.29
(4H, m, Ar-H), 12.99 (1H, b, NH, D2O-exchangeable). 13 C NMR
(500 MHz, DMSO-d6): d = 14.33 (CH3CH2), 18.91 (C7-CH3),
21.42 (C2-CH3), 39.71 (C5), 60.72 (CH2O), 100.96 (C4a), 108.19
(C6), 115.17,115.34, 130.40, 140.80, 159.27 (6 aromatic carbon
atoms), 158.85 (C7), 160.33 (CO), 159.27 (C8a), 162.44 (C2),
166.04 (CO, carboxylate) ppm. Anal. Calcd for C18H17FN2O4;
MW= (344.34): C, 62.79; H, 4.98; N, 8.14. Found: C, 63.33; H,
5.02; N, 8.08%.
Ethyl 5-(5-methylfuryl)-2,7-dimethyl-4-oxo-3,5-dihydro-4H-
pyrano[2,3-d]pyri-midine-6-carboxylate (3g). White crystals;
yield: 65%, mp 260–262ꢃC (EtOH). Rf = 0.08. IR (potassium
bromide) (υ: cmꢁ1); 3424.96 (NH), 1720.19 (CO), 1639.2
(CO), 1565.92 (CN). MS (m/z%): 330.12 (44.52%). 1H NMR
(500 MHz, CDCl3) : d = 1.19 (t, J = 7.2 Hz, 3H, CO2CH2CH3),
2.19 (3H,s, CH3), 2.23 (3H,s, CH3), 2.31 (3H,s, CH3), 4.12
(q, J = 7.2 Hz, 2H, CO2CH2CH3), 4.51 (1H, s, CH), 5.82 (1H, s,
13
CH), 5.94 (1H, s, CH), 12,60 (H, b, NH, D2O-exchangeable).
Ethyl 5-(2-chlorophenyl)-2,7-dimethyl-4-oxo-3,5-dihydro-4H-
pyrano[2,3-d]pyri-midine-6-carboxylate (3c). White crystals yield
78%, mp 240–242ꢃC (Ref. [24]); (EtOH). 0.07. IR (potassium
bromide): υ: cmꢁ1 = 3417 (NH), 1714 (CO), 1665 (CO), 1599
(CN) cmꢁ1. MS (m/z: %): 360 (5.29%) 360.95. 1H NMR
(500 MHz, CDCl3): d = 1.13 (t, J = 7.2 Hz, 3H, CO2CH2CH3),
2.33 (3H,s,CH3), 2.46 (3H, s, CH3), 4.06 (q, J =7.2 Hz, 2H,
C NMR (500 MHz, DMSO-d6): d = 12.85 (CH3-furyl), 14.50
(CH3CH2), 18.95 (C7-CH3), 21.49 (C2-CH3), 29.84 (C5), 60.94
(CH2O), 98.07.96 (C4a), 108.19 (C6), 106.01, 107.02, 148.19,
152.16 (4 furyl carbon atoms),158.85 (C7), 161.20 (CO),
159.56 (C8a), 162.41 (C2), 166.01 (CO, carboxylate) ppm.
Anal. Calcd for C17H18N2O5; MW = (330.34): C, 61.81; H,
5.49; N, 8.48. Found: C, 61.10; H, 5.02; N, 8.45%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Efficient and Expeditious Synthesis of Pyrano-pyrimidines, Multi-substituted g-Pyrans,
and Their Antioxidant Activity
Ethyl 2,7-dimethyl-5-(naphthalen-2-yl)-4-oxo-3,5-dihydro-
4H-pyrano[2,3-d]py-rimidine-6-carboxylate (3 h). White crystals;
yield 65%, mp 222–224ꢃC (EtOH). Rf = 0.07. IR (potassium
bromide): υ: cmꢁ1 = 3333, 3331 (NH), 1722 (CO), 1681 (CO),
1563 (CN) cmꢁ1. MS: (m/z: %)= 376.34 (24.12%). 1H NMR
(500 MHz, DMSO): d = 1.05 (t, J = 7.0 Hz, 3H, CO2CH2CH3),
2.29 (3H, s, CH3), 2.49 (3H, s, CH3), 4.02 (q, J = 7.2Hz, 2H,
CO2CH2CH3), 5.08 (1H, s, CH), 7.25–7.72 (7H, m, ArH), 12.45
(1H, b, NH) ppm. 13C NMR (500 MHz, DMSO-d6): d = 14.49
(CH3CH2), 18.90 (C7-CH3), 21.28 (C2-CH2), 37.46 (C5), 60.73
(CH2O), 101.02 (C4a), 108.32 (C6), 126.20, 126.76,126.88,
127.19, 127.55, 128.03, 128.30, 132.47, 133.26, 142.15
(10 aromatic carbon atoms), 159.32 (C7), 162.50 (CO), 160.40
(C8a), 166.17 (C2), 167.70 (CO, carboxylate) ppm. Anal. Calcd
for C22H20N2O4; MW= (376.41): C, 70.20; H, 5.36; N, 7.44.
Found: C, 70.17; H, 5.33; N, 7.41%.
NH) ppm. 13C NMR (500 MHz, DMSO-d6): d = 14.46 (CH3CH2),
18.38 (C7-CH3), 23.28 (C2-CH3), 37.10 (C5), 60.58 (CH2O),
100.11 (C3-CONH2), 107.12 (C5), 128.35-141.70 (6 aromatic
carbon atoms), 158.86 (C6), 166.10 (C3-CONH2) 162.20(C2),
167.46 (COCH3), 166.79 (CO, carboxylate) ppm. Anal. Calcd for
C18H19ClN2O5; MW = (378.81): C, 57.07; H, 5.06; N, 7.40.
Found: C, 57.02; H, 5.01; N, 7.35%.
Ethyl 6-acetamido-5-carbamoyl-4-(3-bromophenyl)-2-methyl-
4H-pyran-3-carboxylate (4d). White crystals; yield 71%, mp
144–146ꢃC. Rf = 0.08. IR (potassium bromide): υ: cmꢁ1 = 3415,
3338 (NH2, NH), 1699 (CO), 1660 (CO) cmꢁ1. MS (m/z: %): 422
(6.91%) 424 (6.75%). 1H NMR (500 MHz, CDCl3): d = 1.27
(t, J =7.2 Hz, 3H, CO2CH2CH3), 2.39 (3H, s, CH3), 2.28 (3H,s,
CH3), 4.14 (q, J = 7.2Hz, 2H, CO2CH2CH3), 4.54 (1H, s, CH),
5.54 (2H, b, NH2), 7.16–7.43 (4H, m, ArH), 11.80 (1H, b, NH)
ppm. 13C NMR (500 MHz, DMSO-d6): d = 14.42 (CH3CH2),
18.61 (C7-CH3), 24.33 (C2-CH3), 39.88 (C5), 60.82 (CH2O),
91.46 (C3-CONH2), 108.12 (C5), 127.40, 130.16,131.07,
131.21, 139.34, 147.50 (6 aromatic carbon atoms), 158.86 (C6),
166.01 (C3-CONH2) 162.20 (C2), 169.45 (COCH3), 167.74
(CO, carboxylate) ppm. Anal. Calcd for C18H19BrN2O5;
MW= (423.26): C, 51.08; H, 4.52; N, 6.62. Found: C, 51.02; H,
4.50; N, 6.58%.
Synthesis of ethyl 6-acetamido-5-carbamoyl-2-methyl-4-aryl-
4H-pyran-3-carboxylates (4a–e). General Method: A mixture of
pyran derivative
2 (5 mmol), acetic anhydride (5 mmol),
anhydrous ZnCl2 (15 mmol) in CH2Cl2 (20 mL) was stirred with
exclusion of moisture on an ice path for the specified time
(Table 4). TCS (15 mmol) was then added, and the reaction
mixture was stirred again for the specified time. The reaction
mixture was then poured onto ice-cold water (~100 mL),
neutralized by Na2CO3 and extracted with CHCl3 (3 ꢂ 30 mL).
The organic liquid was dried over anhydrous Na2SO4. Excess
solvent was removed under reduced pressure, and the obtained
residue was triturated with ethanol to give solid products 4a–e,
which were re-crystallized in ethanol for purification.
Ethyl 6-acetamido-5-carbamoyl-2-methyl-4-(4-nitrophenyl)-
4H-pyran-3-carboxylate (4e). White crystals; yield 80%, mp
150–152ꢃC. Rf = 0.08. IR (potassium bromide): υ: cmꢁ1 = 3474,
3383 (NH2, NH), 1722 (CO), 1667 (CO) cmꢁ1. MS (m/z: %): 389
1
(1.29%). H NMR (500MHz, CDCl3): d = 1.26 (t, J = 7.2 Hz, 3H,
CO2CH2CH3), 2.25 (3H,s, CH3), 2.24(3H,s, CH3), 4.16
(q, J = 7.2Hz, 2H, CO2CH2CH3), 4.56 (1H, s, CH), 5.44 (2H, b,
NH2), 7.25–7.52 (two d, 2H, J = 7.5 Hz, ArH), 11.77 (1H, b, NH)
ppm. 13C NMR (500MHz, DMSO-d6): d = 14. 34 (CH3CH2),
19.04 (C7-CH3), 21.44 (C2-CH3), 39.60 (C5), 60.89 (CH2O),
100.06 (C3-CONH2), 107.09 (C5), 123.75,124.11. 129.68,
130.00,130.68, 146.82 (6 aromatic carbon atoms), 159.84 (C6),
165.10 (C3-CONH2) 162.40(C2), 169.46 (COCH3), 165.73 (CO,
carboxylate) ppm. Anal. Calcd for C18H19N3O7; MW =(389.36):
C, 55.53; H, 4.92; N, 10.79. Found: C, 55.51; H, 4.88; N, 10.76%.
Synthesis of ethyl 4-chloro-2,7-dimethyl-5-phenyl-5H-pyrano
[2,3-d]pyrimidine-6-carboxylate (5). A mixture of the pyrano
[2,3-d]pyrimidin-4(5H)-one (3a) (0.005 mol), POCl3 (30 mL),
and PCl5 (0.5 g) was heated under reflux for 10 h. After cooling,
the reaction mixture was poured onto crushed ice. The obtained
crystal product was filtered off, washed with water several
times, dried, and crystallized from petroleum ether (50–60) to
give 5; as white crystals, mp 108–110ꢃC, yield: (1.3 g, 81.25%).
Rf = 0.92. IR (potassium bromide): υ: cmꢁ1 = 1714 (CO), 1649
(CN), 1594 (CC) cmꢁ1. MS (m/z: %): 344 (4.3%), 346
(6.61%).1H NMR (500 MHz, CDCl3): d = 1.14 (t, J = 7.2 Hz,
3H, CO2CH2CH3), 2.40 (3H, s, CH3), 2.49 (3H,s, CH3), 4.o6
(q, J = 7.2 Hz, 2H, CO2CH2CH3), 4.98 (1H, s, CH), 7.16–7.26
(5H, m, ArH) ppm. Anal. Calcd for C18H17ClN2O3;
MW = (344.79): C, 62.70; H, 4.97; N, 8.12. Found: C, 62.68; H,
4.94; N, 8.10%.
Ethyl 6-acetamido-5-carbamoyl-2-methyl-4-phenyl-4H-pyran-
3-carboxylate (4a). White crystals yield 83%, mp 138–140ꢃC.
Rf = 0.13. IR (potassium bromide): υ: cmꢁ1 = 3411, 3273 (NH2,
1
NH), 1709 (CO), 1659 (CO). MS (m/z: %): 344.15 (13.30%). H
NMR (500MHz, CDCl3): d = 1.25 (t, J = 7.2Hz, 3H,
CO2CH2CH3), 2.19 (3H,s, CH3), 2.16 (3H,s, CH3), 4.14
(q, J = 7.2 Hz, 2H, CO2CH2CH3), 4.56 (1H, s, CH), 5.60 (2H, b,
NH2), 7.22–7.30 (5H, m, ArH), 11.76 (1H, b, NH) ppm. Anal.
Calcd for C18H20N2O5; MW= (344.36): C, 62.78; H, 5.85; N,
8.13. Found: C, 62.76; H, 5.82; N, 8.10%.
Ethyl 6-acetamido-5-carbamoyl-4-(4-fluorophenyl)-2-methyl-
4H-pyran-3-carb-oxylate (4b). White crystals; yield: 82%, mp
160–162ꢃC. Rf = 0.10. IR (potassium bromide): (υ: cmꢁ1); 3421.1,
3335.28, 353.32 (NH2, NH), 1704.76 (CO), 1652.7 (CO), 1604,
48 (CC). MS (m/z: %): 362.15(13.30%). 1H NMR (500 MHz,
CDCl3): d = 1.26 (t, J = 7.2 Hz, 3H, CO2CH2CH3), 2.25(3H,s,
CH3), 2.24(3H,s, CH3), 4.16 (q, J = 7.2Hz, 2H, CO2CH2CH3),
4.56 (1H, s, CH), 5.44 (2H, b, NH2), 6.97–7.29 (4H, m, Ar-H),
11.77 (1H, b, NH, D2O-exchangeable). 13C NMR (500 MHz,
DMSO-d6): d = 14.41 (CH3CH2), 18.54 (C7-CH3), 24.17 (C2-
CH3), 39.61 (C5), 60.79 (CH2O), 97.15 (C3-CONH2), 108.33
(C5), 115.55–144.74 (6 aromatic carbon atoms), 158.22 (C6),
166.20 (C3-CONH2) 160.55 (C2), 169.79 (COCH3), 167.89 (CO,
carboxylate) ppm. Anal. Calcd for C18H19FN2O5; MW= (362.35):
C, 59.66; H, 5.29; N, 7.73. Found: C, 59.03; H, 5.02; N, 7.72%.
Ethyl 6-acetamido-5-carbamoyl-4-(2-chlorophenyl)-2-methyl-
Synthesis of ethyl 2,7-dimethyl-5-phenyl-4-(propylamino)-
5H-pyrano[2,3-d]pyrimidine-6-carboxylate (6). A mixture of
5 (0.005 mol), propane-1-amine (0.01 mol), triethyl amine (few
drops) in absolute ethyl alcohol was heated on boiling water-
bath for ~5 h. The reaction mixture was then left to cool. The
obtained solid product was filtered off, washed with 5 mL cold
ethanol, dried and crystallized from methanol to give 6 as
colorless crystals; mp 170–172, yield: (1.25 g, 73%). Rf = 0.85.
4H-pyran-3-carboxylate (4c).
White crystals; yield 75%, mp
144–146ꢃC. Rf = 0.08. IR (potassium bromide): υ: cmꢁ1 = 3383,
3223 (NH2, NH), 1707 (CO), 1669 (CO) cmꢁ1. MS: (m/z: %) =378
(11.90%), 380 (3.22%). 1H NMR (500MHz, CDCl3): d = 1.22
(t, J = 7.3Hz, 3H, CO2CH2CH3), 2.46(3H,s, CH3), 2.33(3H,s,
CH3), 4.13 (q, J =7.3 Hz, 2H, CO2CH2CH3), 4.56 (1H, s, CH),
5.44 (2H, b, NH2), 7.25–7.29 (4H, m, ArH), 12.0 (1H, b,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

K. A. M. El-Bayouki, W. M. Basyouni, T. K. Khatab, F. A. El-Basyoni,
A, R, Hamed, and E. A. Mostafa
Vol 000
IR (potassium bromide): υ max = 3420 (NH), 1706 (CO), 1570
(CC) cmꢁ1. MS (m/z %): 367.19 (95%), 368 (17%), 369(2.00%).
1H NMR (500 MHz, CDCl3): d =0.92 (NHCH2CH2CH3), 1.20
(CO)OCH2CH3), 2.25 (OCH3CC), 2.13 (NCCH3N), 3.20 (NHCH2),
4.31 (OCH2CH3), 7.42 (NH-D2O-exchangeable), 7.40–7.23 (5H, m,
Ar-H). Anal. Calcd for C21H25N3O3; MW = (367.44): C, 68.64;
H, 6.86; N, 11.44. Found: C, 68.62; H, 6.77; N, 11.42%.
(C8a), 165.83 (C2), 169.54 (CO, carboxylate) ppm. Anal. Calcd
for C21H24N2O3S; MW= (384.49): C, 65.60; H, 6.29; N, 7.29;
S, 8.34. Found: C, 65.55; H, 6.24; N, 7.25; S, 8.30%.
CONCLUSION
The present work was directed to carry out an efficient and
Synthesis of ethyl 2,7-dimethyl-5-phenyl-4-thioxo-4,5-dihydro-
3H-pyrano[2,3-d]pyrimidine-6-carboxylate (7). A mixture of 5
(0.005mol) and thiourea (0.01 mol) in absolute ethanol (30mL)
was heated under reflux for 2 h and left to cool. The obtained
product was filtered off and crystallized from ethanol to give the
thione 7 as yellowish crystals; mp 156–160ꢃC, yield: (1.2g,
71.4%). Rf = 0.43. IR (potassium bromide): υ: cmꢁ1 = 3407 (NH),
a
rapid catalytic reaction for the synthesis of
polyfunctionalized 4H-pyrans and fused 4H-pyrans. Thus,
upon stirring the selected aldehydes, malononitrile, ethyl
acetoacetate, and piperidine (few drops) in deionized water
at room temperature 4H-pyrans were obtained in good yield,
in short reaction time. Also, when the obtained 4H-pyrans
reacted with acetic anhydride and SSA, 4H-pyrano[2,3-d]py-
rimidines were readily afforded in a short time and excellent
yield. Moreover, upon using TCS/ZnCl2 as a catalyst ethyl 6-
acetamido-5-carbamoyl-2-methyl-4-aryl-4H-pyran-3-car-
boxylates were readily afforded instead of the expected 4H-
pyrano[2,3-d]pyrimidines. Furthermore, when ethyl 2,7-
dimethyl-4-oxo-5-phenyl-4,5-dihydro-3H-pyrano[2,3-d]py-
rimidine-6-carboxylate (3a) reacted with POCl3/PCl5
yielded its corresponding chloro derivative, which in turn
reacted with propane-1-amine and thiourea to afford the
respective propylamino- and thione- derivatives. The latter
thione gave the corresponding 4-propyl thio derivative upon
reaction with iodopropane.
1714 (CO), 1655 (CN), 1576 (CC), 1430, 1370, 1239 (CS) cmꢁ1
.
MS (m/z:%): 342 (100%), 344 (33.18%).1H NMR (500 MHz,
CDCl3): d = 1.22 (t, J = 7.2Hz, 3H, CO2CH2CH3), 2.38 (3H, s,
CH3), 2.48 (3H,s, CH3), 4.11 (q, J = 7.2 Hz, 2H, CO2CH2CH3),
4.24 (1H, s, CH), 6.97–7.29 (4H, m, ArH), 12.70 (1H, b, NH)
13
ppm.
C NMR (500MHz, DMSO-d6): d = 14.45 (CH3CH2),
18.78 (C7-CH3), 21.27 (C2-CH3), 39.87 (C5), 60.94 (CH2O),
109.76 (C4a), 113.98 (C6), 127.13, 128.32, 129.31, 143.43
(6 aromatic carbon atoms),158.08 (C7), 158.83 (C8a), 160.05
(C2), 165.89 (CO, carboxylate), 183.22 (CS) ppm. Anal. Calcd for
C18H18N2O3S; MW= (342.41): C, 63.14; H, 5.30; N, 8.18; S,
9.36. Found: C, 63.11; H, 5.28; N, 8.15; S, 9.32%.
Synthesis of ethyl 2,7-dimethyl-5-phenyl-4-(propylthio)-5H-
pyrano[2,3-d]pyrimidine-6-carboxylate (8). To a solution of
7 (0.85 g, 0.0025 mol) in ethanol (25 mL) and triethylamine
(1/2 mL), the appropriate iodopropane (0.0025 mol) was added.
The reaction mixture was stirred at room temperature for 10h.
Excess solvent was then concentrated under reduced pressure and
left to cool. The solid product obtained was filtered and
crystallized from petroleum ether (60–70) to give 8 as white
crystals. White crystals, mp 78–80ꢃC, yield: (67.16%). Rf = 1.0. IR
(potassium bromide): υ: cmꢁ1 = 1714 (CO), 1649 (CN) cmꢁ1. MS
(m/z: %): 384 (49.78%). 1H NMR (500 MHz, CDCl3): d = 0.95
(t, J = 7.2 Hz, 3H, CH2CH3), 1.24 (t, J = 7.2 Hz, 3H,
CO2CH2CH3), 1.64 (m, J = 7.2Hz, 2H, CH2CH3), 2.47 (3H, s,
CH3), 2.55 (3H,s,CH3),3.26 (t, J = 7.2 Hz, 2H, CH2CH2S), 4.13
(q, J =7.2 Hz, 2H, CO2CH2CH3), 4.90 (1H, s, CH), 7.22–7.25
(4H, m, ArH) ppm. 13C NMR (500 MHz, DMSO-d6):
d = 13.66 (CH2CH2CH3), 14.39 (CH3CH2), 19.05 (C7-CH3),
22.56 (C2-CH3), 25.83 (CH2CH2CH3), 31.71(SCH2), 32.67 (C5),
60.99 (CH2O), 109.18 (C4a), 110.26 (C6), 128.20–142.75
(6 aromatic carbon atoms), 158.54 (C7), 165.69(CS), 160.84
ANTIOXIDANT ACTIVITY
There is an increasing interest in antioxidants, particu-
larly in those intended to prevent the presumed deleterious
effects of free radicals in the human body and to prevent
the deterioration of fats and other constituents of food-
stuffs. Antioxidants are defined as substances that when
present at low concentrations compared with those of an
oxidizable substrate significantly delay or prevent oxida-
tion of that substrate. DPPH is a stable free radical often
used as a substance to evaluate the antioxidant capacity
of an oxidant [25,26].
Results of antioxidant screening by DPPH assay. The
preliminary screening for antioxidant activity of some
Table 5
DPPH radical scavenging activity (cell-free system) of compounds represented as EC50 values.
Compound
EC50 (mM)
Compound
EC50 (mM)
Compound
EC50 (mM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
>2
>2
>2
>2
>2
1.15
>2
>2
>2
2j
2k
3a
3b
3c
3d
3e
3f
>2
>2
>2
>2
>2
>2
>2
>2
1.71
3h
4a
4b
4c
4d
4e
7
>2
>2
>2
>2
>2
>2
0.22
>2
8
3g
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Efficient and Expeditious Synthesis of Pyrano-pyrimidines, Multi-substituted g-Pyrans,
and Their Antioxidant Activity
Figure 1. Concentration–response relation of the DPPH radical scavenging activity of compounds 2f, 3g, and 7 (left panel) and their corresponding
nonlinear regression curves (right panel).
high concentration of 2 mM (i.e., EC50 >2 mM (Table 5).
The concentration–response curve fits for the most active
compounds 7, 2f, and 3g are shown in Figures 1 and 2.
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