One-pot Synthesis of Novel 2,8-dithioxopyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione Catalyzed by p-Toluenesulfonic Acid

Article abstract of DOI:10.1002/jhet.2165

Novel 2,8-dithioxopyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione derivatives were synthesized by a clean and efficient methodologies involving one-pot regioselective and chemoselective reactions between two moles substituted thiobarbituric acid and 1 mol various aromatic aldehydes in the presence of p-toluenesulfonic acid as a catalyst in EtOH with good yields in compression with alternative conditions such as microwave and promoted ultrasound. All of the compounds have been characterized by IR,¹H NMR,¹³C NMR spectral data, and elemental analyses.

Full text of DOI:10.1002/jhet.2165

Month 2016 One-pot Synthesis of Novel 2,8-dithioxopyrano[2,3-d:6,5-d′]dipyrimidine-
,6(1H)-dione Catalyzed by p-Toluenesulfonic Acid
4
*
N. O. Mahmoodi, B. Sharifzadeh, M. Mamaghani, K. Tabatabaeian, and S. Shoja
Department of Organic Chemistry, University of Guilan, P.O. Box 1914, Rasht, Iran
*
E-mail: mahmoodi@guilan.ac.ir
Received September 11, 2013
DOI 10.1002/jhet.2165
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Novel 2,8-dithioxopyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione derivatives were synthesized by a
clean and efficient methodologies involving one-pot regioselective and chemoselective reactions between
two moles substituted thiobarbituric acid and 1 mol various aromatic aldehydes in the presence of
p-toluenesulfonic acid as a catalyst in EtOH with good yields in compression with alternative conditions
1
such as microwave and promoted ultrasound. All of the compounds have been characterized by IR, H
1
3
NMR, C NMR spectral data, and elemental analyses.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
hetero-Diels-Alder reactions in the presence of indium(III)
chloride [25].
Over the past years, the preparation of pyranopyrimidines
is of large interest in view of the pharmacological activities
associated with this system such as cardiotonic [1],
antibronchitic [2], antihypertensive [3], and antitumor [4,5]
activity. It can be assumed that pyranopyrimidines have dual
biological properties of both the pyran and the pyrimidine
rings. This is reported that pyran derivatives exhibit growth
stimulating effects [6], hypotensive effect [7], antifungal
and plant growth regulation effects [8], central nervous
system activity [9], antimicrobial activity [10], antitumor
activity [11], and as antiproliferation agents [12,13]. On the
other hand, pyrimidine has great biological and medicinal
The more complex model of their preparation from
malononitrile, aldehydes, and N,N′-dialkyl barbiturates is
also well-known, and synthesis of pyrano[2,3-d]pyrimidine
system is notable. However, as far as we look,
multicomponent coupling reactions (MCRs) methodology
especially based on the thiobarbituric acid was not still ex-
tended. In organic synthesis, MCRs have involved much con-
sideration [26]. In other words, MCRs constitute particularly
smart strategy in which several different starting materials re-
act to a target product in a one-pot process. In addition, they
are very useful tools in the current drug discovery procedure
and allow the quick, automatic, and high-power achievement
to organic complex constructions from simple precursors by
formation of various novel bonds in one pot [27].
[
[
14] applications including antiviral [15], antihypertensive
16], antibacterial [17], and antitumor activity [18].
The synthetic procedure of highly functional heterocyclic
Here in contribution to our previous synthetic efforts
rings has been extensively investigated [19,20]. Despite the
widespread developments in the synthesis of modified
pyrimidines, little consideration has been paid about the
chemistry of pyranopyrimidine [21]. The common proce-
dures for the synthesis of pyrano[2,3-d]pyrimidines usually
contain the reaction of benzylidenemalononitriles with
barbituric acids in the presence of base catalysts [22,23].
For example, it has been reported that pyrano[2,3-d]pyrimi-
dines synthesized subsequently via Knoevenagel, Micheal,
and heterocyclization reactions of aldehyde, malononitrile,
and barbituric acid/dimedone [24]. However, Prajapati and
Gohain reported the formation of pyrano[2,3-d]pyrimidines
and furopyrano[2,3-d]pyrimidines upon treating 1,3-dimethyl
barbituric acid with an aromatic aldehyde and ethyl vinyl
ether/2,3-dihydrofuran via a multicomponent Knoevenagel/
[
5
[
28–35], we describe one-pot three components synthesis of
-substituted-2,8-dithioxo-2,3,5,7,8,9-hexahydro-4H-pyrano
2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione derivatives via re-
action of various aldehydes and thiobarbituric acid deriva-
tives in the presence of p-toluenesulfonic acid (p-TSA) as
catalyst in EtOH under reflux condition. Recently, the appli-
cation of microwaves and ultrasound in synthesis is very pop-
ular because they frequently proceed greatly faster and carry
products in higher yield and ultrapurity.
RESULTS AND DISCUSSION
In this protocol, we explain an efficient one-pot method
for the regioselective synthesis of new pyranodipyrimidines
©
2016 Wiley Periodicals, Inc.

N. O. Mahmoodi, B. Sharifzadeh, M. Mamaghani, K. Tabatabaeian, and S. Shoja
Vol 000
Scheme 1. Reaction of synthesized 2,8-dithioxopyrano[2,3-d:6,5-d′]
dipyrimidine-4,6(1H)-dione derivatives 5a–e.
5
a–e via reaction of thiobarbituric acid as “active methylene”
groups 2a–b with different aromatic aldehydes 1a–d under
refluxing in EtOH containing p-TSA (Scheme 1).
The results are summarized in Table 1. The reaction is
compared with other conditions such as catalyst, solvents,
MW, and ultrasound.
The synthesis of 5a was considered as representative ex-
ample to determine the amount of p-TSA and effectiveness
of this catalyst comparative to the other ones (Table 2).
Table 1
3
-CR of synthesized 2,8-dithioxopyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione derivatives.
o
Entry
Structure of product
Melting point ( C)
Color
Reaction time (min)
Yield (%)
5a
320>
Orange
300
81
5b
305–307
Yellow
260
77
5
5
c
315>
Deep yellow
320
310
72
79
d
315>
Orange
5e
320>
Yellow
330
78
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Synthesis of Novel 2,8-dithioxopyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione
Table 2
The structure of the compounds was further confirmed by
H NMR and C NMR in DMSO-d . The H NMR
6
1
13
1
Catalytic activity for the synthesis of pyranodipyrimidine 5a.
spectrum of pyranodipyrimidines 5a–d exhibited two signals
at δ 9–11.5 ppm because of the NH protones. The H NMR
Entry
Catalyst
Yield (%)
Time (min)
1
1
2
3
4
5
6
7
(0.2 mmol) p-TSA
(0.3 mmol) p-TSA
(0.4 mmol) p-TSA
68
81
77
59
65
60
70
330
300
300
500
380
390
360
spectrum of pyranodipyrimidines 5a–e showed a sharp
singlet at δ 5–6 (in 5c appears in 8.6 ppm) because of CH
benzylic protons. Protons belonging to the aromatic ring
and substituted groups were observed within the expected
chemical shift regions along with their integral values.
The C NMR spectra of pyranodipyrimidines 5a–e
showed signals at 153.2–159.2 ppm assigned to carbonyl
of the pyrimidine ring. Thiocarboxamide carbons (C═S)
displayed a signal at 170.0–179.1 ppm for all of the com-
pounds. The signals due to the aromatic and other substituted
groups resonate at their usual positions (Experimental section).
Investigation in the mechanism shows that reaction may
continue at first via a Knoevenagel condensation of aldehyde
H
H
2
SO
SO
4
(0.3 mmol)
/SiO (0.3 mmol)
2
4
2
FeCl
FeCl
3
(0.3 mmol)
/KSF (0.3 mmol)
13
3
p-TSA, p-toluenesulfonic acid; KSF, Kilo-pound per square foot.
Table 2 demonstrates the amount of p-TSA in terms of
time and yields of product and suggests it as an efficient
catalyst relative to the other catalysts. Increasing the
amount of p-TSA from 0.2 to 0.3 mmol decreased the reac-
tion time from 330 to 300 min. In addition, the yield of the
product also increased from 68% to 81% (entry 2, Table 2).
The choice of an appropriate reaction media is of critical
importance for successful synthesis. Initially, the one-pot
reaction of 2-mmol thiobarbituric acid 2a, and 1-mmol
benzaldehyde 1a as a simple model substrate, was investigated
to ascertain the possibility of the strategy and optimize the
reaction conditions (Table 3). Different solvents in the
presence of p-TSA as an inexpensive and available catalyst
and various Lewis acids were screened in the model reaction.
In the presence of p-TSA, the desired product 5a that was
obtained in good yield EtOH was the solvent of choice entry 4,
Table 3. Synthesis of 5a base on the reaction time and yield
of the products under microwave and ultrasound conditions
entries 4 and 5 indicates significant improvement (Table 3).
The structures of the synthesized compounds were
1
with thiobarbituric acid 2 to afford the Michael acceptor 3.
The active methylenes of thiobarbituric acids 2′ reacted then
via its enol form with 3 to give the intermediate 4
tautomerized with 4′. Intramolecular cyclizative condensa-
tion of 4 or 4′ afforded the expected products 5. The products
precipitated from the reaction mixture as pure solids and
were easily recrystallized (Scheme 2).
In conclusion, this one-pot protocol provides
regioselective and chemoselective, fast, and practical method
for the preparation of novel pyranodipyrimidines from a
variety of thiobarbituric acid and aldehyde derivatives in
good yields. The best catalyst and solvent were p-TSA and
EtOH. Under microwave and ultrasound conditions, signifi-
cant improvements on the reaction time and yield of products
were observed. The simplicity, high atom economy, easy
execution, simple workup, and good yields, together with
the use of inexpensive starting materials and an environmen-
tally friendly process, are features of this procedure.
1
13
established by FTIR, H NMR, C NMR, and elemental
analyses. The IR spectrum of pyranodipyrimidines 5a–d
exhibited the characteristic band at 3100–3450 cm
À1
,
which indicates the presence of NH groups. The IR spectra
of pyranodipyrimidines 5a–e revealed the presence of
À1
EXPERIMENTAL
absorption bands at υ = 1600–1650 cm
C═O, absorption bands in the regions 1509–1610 cm
because of
À1
The IR absorption band maxima were measured with a
Shimadzu UV-2100 spectrophotometer (Shimadzu Corpo-
ration, Japan). Chemicals were purchased from Fluka,
Merck, and Aldrich. Melting points are uncorrected and
determined by Mettler Fp5 melting point apparatus. All
NMR data were recorded in DMSO using a BrukerAvance
corresponding to aromatic ring, and peaks in the regions
À1
1
355–1365 and 1055–1096 cm , which indicate the pres-
ence of C═S and C―N groups.
Table 3
4
00-MHz spectrometer (Billerica, MA). Chemical shifts
Solvent effect for synthesis of pyranodipyrimidines 5a.
are reported in ppm (δ) using deuterated solvents as
internal references. Elemental analyses were made by a
Carlo-Erba EA1110 CHNO-S analyzer and agreed with the
calculated values. For the microwave irradiation, a microwave
oven equipped with a turntable was used (LG Smart Chef
MS-255R operating at 2450 MHz having maximum output
of 800 W) for reaction. For the ultrasound reactions, ultra-
sound apparatus Astra 3D (4.25 L, 37 kHz frequency, with
heating power 200 W; Germany) from Elmasonic was used.
Entry Condition/solvent Yield (%) Time (min) T (°C)
1
2
3
4
5
6
Reflux/CH
Reflux/DMF
Reflux/H
Reflux/EtOH
MW
3
CN
45
45
Trace
81
84
83
380
480
600
300
12
85
155
100
80
—
30
2
O
Ultrasound
30
Bold values signifies the solvent of choice is EtOH.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. O. Mahmoodi, B. Sharifzadeh, M. Mamaghani, K. Tabatabaeian, and S. Shoja
Vol 000
Scheme 2. Proposed mechanism for pyranodipyrimidines synthesis.
2
,8-dithioxopyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione
5a–e) (typical procedure). A mixture of thiobarbituric acid
0.14 g, 1 mmol), 4-methoxybenzaldehyde (0.65 g, 0.5 mmol)
163.95 (C═O), 114.30–139.73 (Ar-C), 93.14 (C of benzyl).
Molecular weight: 403.39. Anal. Calcd. for C H N O S : C,
(
(
15 9 5 5 2
4
4.66; H, 2.25; N, 17.36. Found: C, 44.86; H, 2.24; N, 17.37.
and p-TSA (0.05 g, 0.3 mmol) in refluxing EtOH (5 mL) was
stirred for 5 h. Completion of the reaction confirmed by TLC
eluent: EtOAc/n-hexane, 1:3), the reaction mixture was
5
-(Thiophen-2-yl)-2,8-dithioxo-2,3,5,7,8,9-hexahydro-4H-
pyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione (5d). Orange
À1
(
solid; Yield 79%; Mp > 315 °C; IR (KBr) (ν max/cm ):
cooled to room temperature. Then, the precipitated product
was filtered and washed with water (10 mL) and EtOH
3410, 3120, 1753, 1603, 1467, 1389, 1257, 11368, 1149,
882, 773, 670. H NMR (400 MHz, DMSO): 12.41–12.38
1
(
5 mL) to afford the pure 5a as a yellow to orange powder.
(s, 4H, NH), 7.39–8.38 (d, 3H, J = 5.2 Hz, Ar-H), 8.60 (s,
1H, benzyl H). C NMR (100MHz, DMSO) (δ/ppm):
13
5
-(4-Methoxyphenyl)-2,8-dithioxo-2,3,5,7,8,9-hexahydro-4H-
pyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione (5a). Orange
solid; Yield 81%; Mp > 320 °C; IR (KBr) (ν max/cm ):
3
7
1
1
1
78.31 (C═S), 161.74 (C═O), 128.70–160.83 (Ar-C),
11.30 (C of benzyl(. Molecular weight: 364.41. Anal.
À1
410, 3120, 1753, 1603, 1467, 1389, 1257, 1149, 882,
Calcd. for C H N O S : C, 42.85; H, 2.21; N, 15.37.
13 8 4 3 3
1
73, 670. H NMR (400 MHz, DMSO): 12.31 (s, 2H, NH),
Found: C, 42.86; H, 2.22; N, 15.36.
1,3,7,9-Tetraethyl-5-(4-methoxyphenyl)-2,8-dithioxo-2,3,5,7,8,9-
hexahydro-4H-pyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione
2.4(s, 2H, NH), 6.74–7.90 (d, 4H, J = 6.8 Hz, Ar-H), 5.95
13
(
s, 1H, benzyl H), 3.86 (s, 3H, substituted-OCH3(.
NMR (100 MHz, DMSO) (δ/ppm): 178.25 (C═S), 163.95
C═O), 114.30–139.73 (Ar-C), 93.14 (C of benzyl),
5.37 (substituted-OCH ). Molecular weight: 388.42.
C
(5e).
Yellow solid; Yield 78%; Mp > 320 °C; IR
À1
(
KBr) (ν max/cm ): 3410, 3120, 1753, 1603, 1467,
(
5
1
1389, 1257, 11368, 1149, 882, 773, 670.H. HNMR
3
Anal. Calcd. for C H N O S : C, 49.48; H, 3.11; N,
(400MHz, DMSO): 6.74–7.90 (d, 4H, Ar-H), 6.21 (s, 1H,
1
6 12 4 4 2
benzyl H), 3.88 (s, 3H, substituted-OCH ), 4.35 (m, 8H,
NCH ), 1.18 (m, 12H, CH ). C NMR (100MHz,
2 3
1
4.42. Found: C, 49.46; H, 3.07; N, 14.44.
3
13
5
-(4-Chlorophenyl)-2,8-dithioxo-2,3,5,7,8,9-hexahydro-4H-
pyrano[2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione (5b).
solid; Yield 77%; Mp 305–307 °C; IR (KBr) (ν max/cm ):
Yellow
DMSO) (δ/ppm): 172.89 (C═S), 162.92 (C═O), 121.30–
141.73 (Ar-C), 95.49 (C of benzyl), 55.99 (substituted-
OCH ), 30.18 (CH ), 18.52 (CH ). Molecular weight:
À1
3410, 3120, 1753, 1603, 1467, 1389, 1257, 11368, 1149,
3
2
3
1
882, 773, 670. H NMR (400 MHz, DMSO): 12.31 (s, 2H,
5
00.63. Anal. Calcd. for C H N O S : C, 57.58; H, 5.64;
24 28 4 4 2
NH), 12.4(S, 2H, NH), 6.74–7.90 (d, 4H, J = 8.8 Hz, Ar-H),
N, 11.19. Found: C, 57.55; H, 5.65; N, 11.18.
13
5
.95 (s, 1H, benzyl H). C NMR (100 MHz, DMSO)
δ/ppm): 178.25 (C═S), 163.95 (C═O), 114.30–139.73
Ar-C), 93.14 (C of benzyl). Molecular weight: 392.83.
Anal. Calcd. for C H ClN O S : C, 45.86; H, 2.31; N,
(
(
Acknowledgment. Financial support from the Research Committee
of University of Guilan is gratefully appreciated.
15
9
4 3 2
1
4.26. Found: C, 45.85; H, 2.32; N, 14.25.
5-(4-Nitrophenyl)-2,8-dithioxo-2,3,5,7,8,9-hexahydro-4H-pyrano
REFERENCES AND NOTES
[
2,3-d:6,5-d′]dipyrimidine-4,6(1H)-dione (5c).
Deep yellow
À1
solid; Yield 72%; Mp > 315 °C; IR (KBr) (ν max/cm ):
3
8
NH), 6.74–7.90 (d, 4H,J= 8.8 Hz, Ar-H), 6.04 (s, 1H, benzyl
H(. C NMR (100 MHz, DMSO) (δ/ppm): 178.25 (C═S),
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet