Synthesis of Imidazole and Theophylline Derivatives Incorporating Pyrimidine-Fused Heterocycles Using Magnetic Nanoparticles-Supported Tungstic Acid (MNP-TA) Catalyst

Article abstract of DOI:10.1002/jhet.2639

In the current study, divers pyrimidine-fused heterocycles containing an imidazole, benzimidazole, or theophylline moieties were synthesized. For the synthesis of this category of compounds, first, some new bromo-substituted aldehydes (BSAs) were synthesi

Full text of DOI:10.1002/jhet.2639

Month 2016
Synthesis of Imidazole and Theophylline Derivatives Incorporating
Pyrimidine-Fused Heterocycles Using Magnetic Nanoparticles-Supported
Tungstic Acid (MNP-TA) Catalyst
*
Masoumeh Divar, Farhad Panahi, Sayedeh Rojin Shariatipour, and Ali Khalafi-Nezhad
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
*
E-mail: khalafi@chem.susc.ac.ir
Received October 16, 2015
DOI 10.1002/jhet.2639
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
In the current study, divers pyrimidine-fused heterocycles containing an imidazole, benzimidazole, or
theophylline moieties were synthesized. For the synthesis of this category of compounds, first, some
new bromo-substituted aldehydes (BSAs) were synthesized using reaction of 4-hydroxybenzaldehyde
and dibromides. Then, BSAs were reacted with imidazole, benzimidazole, and theophylline in order to
synthesize corresponding heterocyclic-substituted aldehydes (HSAs). Finally, the synthesized HSAs
underwent in a multi-components reaction with barbituric acids, amines, and dimedone in the presence
of magnetic nanoparticles-supported tungstic acid (MNP-TA) catalyst in order to synthesis target products
in good to excellent yields. The MNP-TA was reusable using an external magnetic field and providing a
clean and efficient reaction conditions for efficient synthesis of this class of compounds.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
PFH derivatives are used as anti-leukemic drugs, potas-
sium conserving diuretics, and anti-allergy drugs. Addi-
tional to inflammatory properties and antioxidant effects,
PFH compounds demonstrate further biological activities
such as anticancer, antimicrobial, and antiviral actions
[18–20].
In continuation of our previous studies on the synthesis
of benzimidazole- and theophylline-based analogues and
multicomponent reactions [21–35] herein we report an
efficient protocol for the synthesis of some novel
pyrimidine-fused heterocycles (PFH) incorporating im-
idazole, benzimidazole, and theophylline backbones
using a multicomponent reaction as final step.
Compounds with two or more heterocyclic moieties are
important in medicinal chemistry [1]. In most cases, the
heterocyclic moieties connected to each other via a spacer
which the type and length of spacer have significant effects
on biological activity of these compounds [2]. Imidazole
and benzimidazole heterocycles have been found in the
structure of many biological active compounds because
of their widespread biological activities [3–5]. When these
structures are jointed to other heterocycles a synergetic
effect or an improvement in their activity can be ob-
served. For example in the structure of compounds A
with change of type of heterocycle the JTK-109 inhibition
activity is significantly changed (Fig. 1) [6]. The chemical
structure of some of the biological active imidazole and
benzimidazoles incorporating other heterocycles is shown
in Figure 1 [7–11].
Theophylline has been used in therapeutic agents for the
treatment of diseases such as chronic obstructive pulmo-
nary disease and asthma [12,13]. Several important drugs
based on theophylline have been developed which contain
other heterocycles. The chemical structures of some of the
biologically active compounds based on theophylline are
shown in Figure 2 [14–17].
RESULTS AND DISCUSSION
One of the important classes of PFH can be synthesized
using a multicomponent reaction between aldehyde, amine
and barbituric acid or dimedone [36]. Synthesis of
pyrimidine-fused heterocycles frequently needs to an acid
catalyst system (Scheme 1).
In most cases, mineral and organic acids such as sulfuric
acid, p-toluene sulfonic acid, and heteropoly acids have
been used to synthesis this class of compounds [37–39].
The solvent for synthesis of this category of compounds
is ethanol because these compounds after formation precip-
itate and can be separated from the reaction mixture by
simple filtration and washing with ethanol. However, to
Pyrimidine fused heterocycles (PFH) ring is an impor-
tant chemical moiety which can be seen in the molecular
scaffold of a large number of alkaloids, drugs, antibiotics,
agrochemicals, and natural products. Also, some of the
© 2016 Wiley Periodicals, Inc.

M. Divar, F. Panahi, S. R. Shariatipour, and A. Khalafi-Nezhad
Vol 000
Figure 3. The chemical structure of MNP-TA. [Color figure can be viewed
in the online issue, which is available at wileyonlinelibrary.com.]
The acidic catalytic site of MNP-TA catalyst is tungstic
acid (TA) which has been previously used in many organic
reactions [40–42]. The immobilization of this acidic frag-
ment on different supports for synthesis of heterogeneous
catalyst systems has been considered and several acid cat-
alyst system based on TA has been prepared and applied
in organic transformations [43–45].
Figure 1. The chemical structure of some biologically active imidazole
and benzimidazoles incorporating other heterocycles.
In order to show the nanostructure and surface morphol-
ogy of this catalyst system the TEM and SEM images of it
are shown in Figures 4 and 5.
As shown in Figure 4, the catalyst particles are in spherical
morphology, and the core–shell structure of them is obviously
observable in TEM images. The average size of particles is es-
timated to be in range of 45nm which are suitable for catalysis
purposes.
Also, the SEM images of the MNP-TA catalyst (Fig. 5)
show that the catalyst particles possess near spherical
morphology with relatively good monodispersity. The
arrangement of particles provides high surface area which
is highly considered in catalysis.
remove the acid catalyst from the product we need to wash
it with a large amount of water and ethanol and in some
cases the catalyst remained in the structure of product. In
order to resolve this problem we decided to use a magnetic
reusable acidic catalyst to accomplish the reaction under
mild and heterogeneous conditions and after completion of re-
action it can be reusable using an external magnetic field. In
this way this problem associated to synthesis of this class of
compounds can be resolved to some extent. To aim this pur-
pose we used from our previously reported magnetic nanopar-
ticles catalyst system MNP-TA which is consisting of tungstic
acid supported on silica coated magnetic nanoparticles [26].
The chemical structure of the MNP-TA catalyst is
shown in Figure 3.
The catalyst loading of MNP-TA catalyst was estimated
to be 0.45mmol per gram [26].
Figure 2. The chemical structure of some theophylline-based biologically active compounds.
Scheme 1. Acid-catalyzed multicomponent reactions for synthesis of pyrimidine-fused heterocycles.
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Pyrimidine-Fused Heterocycles Incorporating Imidazole and Theophylline Moieties
Figure 4. The TEM image of MNP-TA catalyst.
theophylline fragments were synthesized and applied
in above multicomponent reactions for synthesis of tar-
get products.
Our study started with the synthesis of aldehydes 9a and
9b. As shown in Scheme 4, for the synthesis of these
compounds there is a two-step process. First, 4-hydroxy
benzaldehyde (1) was reacted with 1,3-dibromopropane
(7a) and 1,5-dibromopentane (7b) in order to produce
bromo-substituted aldehydes (BSAs) 8a and 8b. Reaction
of imidazole with 8a/8b resulted in the production of
imidazole-substituted aldehydes (ISAs) 9a and 9b.
Using reaction of benzimidazole with aldehydes 8a and
8b we synthesize benzimidazole-substituted aldehydes
(BISAs) 10a and 10b (Scheme 5).
A theophylline-based aldehyde was also synthesized using
the reaction of theophylline and aldehyde 8a (Scheme 6).
Another theophylline-based aldehyde (15) was syn-
thesized using reaction of theophylline with mixture
of 14a and 14b which previously generated via reac-
tion of 4-hydroxybenzaldehyde and epibromohydrin (13)
(Scheme 7).
Using abovementioned multicomponent reaction in-
volving synthetic aldehydes, barbituric acids and amine
in the presence of MNP-TA a range of pyrimidine-fused
heterocycles containing imidazole and theophylline frag-
ments were synthesized. Also, another class of PFH was
synthesized using a four-component reaction including
synthetic aldehydes, dimedone, barbituric acid, and amine
compounds (Scheme 8).
As shown in Scheme 8, it is possible to synthesize a
range of pyrimidine-fused heterocycles containing imid-
azole, benzimidazole, and theophiline moieties using
MNP-TA as a heterogeneous acidic catalyst in good to
excellent yields. In fact, be selection of different syn-
thetic aldehyde, amine, and dicarbonyl compound it is
Figure 5. The SEM image of MNP-TA.
The catalytic applicability of MNP-TA in synthesis of
pyrimidine-fused heterocycles was checked in the reaction
between 4-hydroxy benzaldehyde (1a), aniline (2a), and
barbituric acid (3a), and it was observed that the product
is obtained in 95% (Scheme 2). It should be mentioned that
after completion of the reaction the MNP-TA catalyst was
separated from the reaction mixture, and the pure product
was obtained with simple filtration and washing with EtOH
and water.
We also conducted a four-component coupling reaction
under above conditions using dimedone (5a) instead of
one equivalent of barbituric acid leading to the formation
of tetrahydropyrimido[4,5-b]quinoline-trione derivatives
[23] (Scheme 3).
The applicability of this method was investigated in
synthesis of diverse imidazole and theophylline deriva-
tives incorporating pyrimidine-fused heterocycles. For
this aim some of the aldehydes bearing imidazole and
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M. Divar, F. Panahi, S. R. Shariatipour, and A. Khalafi-Nezhad
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Scheme 2. MNP-TA-catalyzed multicomponent synthesis of 5-(4-hydroxyphenyl)-10-phenyl-5,10-dihydropyrido[2,3-d:6,5-d′]dipyrimidine-2,4,6,8
(1H,3H,7H,9H)-tetraone (4a) in reflux ethanol. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Scheme 3. MNP-TA-catalyzed multicomponent synthesis of 5-(4-hydroxyphenyl)-8,8-dimethyl-10-phenyl-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-
2,4,6(1H,3H,7H)-trione (6a). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
possible to synthesize a varity of these class of com-
pounds. The MNP-TA catalyst was easily speparated
from the reaction mixture using an external magnetic
field providing an easy handling workup process for
clean and efficient synthesis of this class of compounds.
This synthetic strategy opened up a new direction for
synthesis of PFH containing other heterocyclic moieties
starting from a hydroxy-aldehyde. Thus, this is a synthetic
strategy to connect a PFH with another heterocyclic moieties
togather to improve thire activitey using dual mode of activa-
tion strategy [46].
EXPERIMENTAL
All of the commercial
General experimental details.
reagents and solvents were used without further purification.
Melting points were determined in open capillary tubes.
FT-IR spectroscopy was employed for characterization
of the synthesized compounds using film KBr pellet
techniques. NMR spectra were acquired in CDCl3 with
tetramethylsilane (TMS) as the internal standard. The
sample was analyzed by GC/MS for mass spectrometry
and a microanalyzer for elemental analyses. Reaction
monitoring was accomplished by TLC on silica gel plates.
Column chromatography was carried out on columns of
silica gel 60 (70–230mesh).
CONCLUSIONS
Procedure for the synthesis of 8a and 8b. These aldehydes
were synthesized based on our previous work [21]. In a
double-necked round-bottomed flask (100mL), equipped
with a condenser, a mixture of the appropriate 4-
hydroxylbenzaldehyde (0.03 mol), K2CO3 (4.140 g,
0.03 mol), 1,n-dibromo alkanes [n = 3,5] (0.15 mol), and
catalytic amounts of tetra butyl ammonium bromide
(TBAB, 0.100g) were dissolved in MeCN (40mL). Then,
the mixture was heated to reflux for 10h (TLC control).
The solvent was evaporated at reduced pressure, and the
residue was dissolved in CHCl3 (150mL) and washed with
H2O (2×150mL). The organic layer was dried (Na2SO4,
10g) and concentrated to afford the crude products [4-((5-
bromopentyl)oxy)benzaldehyde or 4-((3-bromopentyl)oxy)
benzaldehyde]. The crudes were purified by column
In conclusion, we have synthesized a new class of
imidazole and theophylline derivatives incorporating
PFHs in a three-step process. The target molecules
were obtained using a multicomponent reaction involv-
ing a pre-prepared heterocycles-substituted aldehyde,
barbituric acids, dimedone, and amines in the presence
of MNP-TA as a magnetic reusable acidic catalyst. All
of the reactions were performed under mild conditions
and final products obtained in good yield. This study
opened up a new direction for the synthesis of divers
PFH compounds containing other heterocycles using a
MCR in a three-step process. The biological activity of
some of the synthesized compounds is under evaluation
and will be reported in due course.
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Scheme 4. Synthesis of aldehydes incorporating imidazole. i) K2CO3, TBAB, MeCN, reflux, 20 h; ii) K2CO3, TBAB, DMF, reflux 20 h;
Scheme 5. Synthesis of aldehyde derivatives containing benzimidazole. i) K2CO3, TBAB, MeCN, reflux, 20 h.
chromatography on silica gel eluting with proper solvent
(mixture of n-hexane-EtOAc) (1:2) Rf =0.6 the product was
obtained in 75%.
5-(4-(3-(1H-Imidazol-1-yl)propoxy)phenyl)-10-(4-methoxyphenyl)-
5,10-dihydropyrido[2,3-d:6,5-d′]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-
tetraone (16a). Yield: 90% (0.49g); white solid; mp: 230–
232°C. IR (KBr): 3412, 3108, 1689, 1490, 1235, 817cm–1.
1H NMR (250MHz, DMSO-d6): δ (ppm)=1.94–2.07 (m,
2H), 3.82–3.87 (m, 4H), 4.28 (s, 3H), 5.87 (s, 1H), 6.62–
7.65 (m, 9H), 8.75 (s, 1H) 9.96 (s, 4H). 13C NMR
(62.9MHz, DMSO-d6): δ (ppm)=29.0, 39.0, 47.4, 57.8,
63.5, 82.2, 114.4, 115.7, 117.5, 119.9, 122.7, 127.7,
130.9, 135.8, 137.6, 139.4, 150.6, 153.2, 156.6, 162.6,
165.5. Anal. Calcd for C28H25N7O6 (555.55): C, 60.54; H,
4.54; N, 17.65. Found: C, 60.59; H, 4.49; N, 17.80.
5-(4-((5-(1H-Imidazol-1-yl)pentyl)oxy)phenyl)-10-(4-methoxyphenyl)-
5,10-dihydropyrido[2,3-d:6,5-d′]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-
tetraone (16b). Yield: 86% (0.49g); yellow solid; mp: 186–
188°C. IR (KBr): 3420, 3118, 1679, 1495, 1238, 817cm–1.
1H NMR (250 MHz, DMSO-d6): δ (ppm) =1.43–1.49 (m,
2H) 1.75–1.84 (m, 4H) 3.43 (s, 3H) 3.93–3.99 (m, 4H) 5.97
(s, 1H) 6.88–7.29 (m, 10H) 8.32 (s, 1H) 10.27 (s, 4H). 13C
NMR (62.9MHz, DMSO-d6): δ (ppm)= 24.4, 29.5, 31.5,
41.4, 44.9, 51.5, 69.1, 102.3, 106.4, 117.3, 122.7, 127.7
129.8, 131.3, 134.9 135.8, 139.4, 144.0, 152.1, 153.6,
157.9, 161.0, 162.1, 164.2, 176.2. Anal. Calcd for
C30H25N7O6 (583.61): C, 61.74; H, 5.01; N, 16.80. Found:
C, 61.82; H, 4.98; N, 16.89.
Procedure for the synthesis of 9a and 9b. In double-necked
round bottom flask (100mL) equipped with a condenser was
added a mixture consisting of imidazole (0.01mol) K2CO3
(0.01 mol), 4-(3-bromopropoxy)benzaldehyde and 4-((5-
bromopentyl)oxy)benzaldehyde (3a and 3b) (0.015 mol),
and catalytic amount of TBAB (0.1g) in DMF (30mL). The
solution was refluxed until TLC monitoring indicated no
further improvement in the reaction (20 h). After cooling and
solvent evaporation the resulted foam was dissolved in CHCl3,
(150 mL) and washed with water (2 × 200 mL). The organic
layer was dried over anhydrous (Na2SO4) and evaporated.
The crude was purified by column chromatography on
silica gel eluting with proper solvent (mixture of n-hexane-
EtOAc) (1:2) Rf =0.5 the product was obtained.
4-(3-(1H-imidazol-1-yl)propoxy)benzaldehyde (9a). 1H NMR
(250MHz, DMSO-d6/TMS): δ (ppm)= 2.23–2.28 (m, 2H),
3.95–3.97 (m, 2H), 4.17–4.21 (m, 2H), 6.93–7.25 (m, 4H),
7.47 (s, 1H), 7.78–7.82 (m, 2H), 9.87 (s, 1H).
4-((5-(1H-imidazol-1-yl)pentyl)oxy)benzaldehyde (9b). 1H NMR
(250MHz, CDCl3/TMS): δ (ppm)=1.44–1.50 (m, 2H),
1.76–1.84 (m, 4H), 3.90–3.99 (m, 4H), 6.89–7.04 (m, 4H),
7.45 (s, 1H), 7.65–7.78 (m, 2H), 9.81 (s, 1H).
5-(4-((5-(1H-Imidazol-1-yl)pentyl)oxy)phenyl)-10-(4-methoxyphenyl)-
8-thioxo-5,8,9,10tetrahydropyrido[2,3-d:6,5-d′] dipyrimidine-2,4,6
(1H,3H,7H)-trione (16c). Yield: 80% (0.47 g); yellow solid;
mp: 200–202°C. IR (KBr): 3312, 3158, 1680, 1480, 1245,
General procedure for synthesis of 16a–d. A mixture of
barbituric acid or barbituric acid (2.0 mmol), 9a or 9b
(1.0 mmol), aniline or its derivatives (1.0 mmol), and
MNP-TA (0.1 g, 5.0 mol %) in refluxing ethanol (5 mL)
was stirred for 2–6 h. After completion of the reaction
confirmed by TLC (eluent EtOAc/MeOH), the reaction
mixture was cooled to room temperature. Then, the
precipitated product was filtered and washed with water
(2 × 10 mL) and ethanol (10 mL) to afford the pure product.
1
819 cm–1. H NMR (250 MHz, DMSO-d6): δ (ppm) =1.45–
1.49 (m, 2H), 1.75–1.84 (m, 4H), 3.93–3.99 (m, 4H), 4.22
(s, 3H), 5.91 (s, 1H), 6.41–7.28 (m, 10H), 8.49 (s, 1H),
10.75 (s, 4H). 13C NMR (62.9MHz, DMSO-d6): δ (ppm)
= 22.2, 29.4, 30.9, 42.3, 44.0, 51.5, 69.1, 102.3, 105.1,
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Scheme 6. Synthesis of an aldehyde containing theophylline moiety. i) K2CO3, TBAB, MeCN, reflux 20 h.
Scheme 7. Synthesis of theophylline-based aldehyde using reaction of epibromohydrin and theophylline. i) K2CO3, TBAB, DMF, reflux 10 h; ii) K2CO3,
TBAB, MeCN, reflux, theophylline 20 h.
117.3, 119.4, 127.7, 131.6, 134.9, 135.8, 139.4, 144.3, 150.6,
153.2, 159.1, 160.0, 162.6, 164.2, 176.2. Anal. Calcd for
C30H29N7O5S (599.67): C, 60.09; H, 4.87; N, 16.35.
Found: C, 60.13; H, 4.80; N, 16.53.
102.6, 113.9, 120.7, 127.7, 131.6, 133.0, 134.9, 137.2,
139.4, 143.9, 144.8, 150.6, 155.7, 157.9, 162.6, 198.1. Anal.
Calcd for C25H20N10O10 (567.65): C, 67.71; H, 5.86; N,
12.34. Found: C, 67.86; H, 35.79; N, 12.41.
5-(4-(3-(1H-Imidazol-1-yl)propoxy)phenyl)-10-(3-hydroxyphenyl)-
5,10-dihydropyrido[2,3-d:6,5-d′]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-
tetraone (16d). Yield: 90% (0.53g); white solid; mp: 270–
272°C. IR (KBr): 3482, 3108, 1682, 1494, 1232,
817 cm–1. 1H NMR (250 MHz, DMSO-d6): δ (ppm)
= 2.23–2.27 (m, 2H), 3.94–4.21 (m, 4H), 5.53 (s, 1H),
6.01 (s, 1H), 6.88–7.26 (m, 10H), 8.35 (s, 1H), 10.15 (s,
4H). 13C NMR (62.9 MHz, DMSO-d6): δ (ppm) = 30.6,
37.8, 47.1, 63.5, 80.8, 102.3, 108.6, 114.4, 115.7,
119.9, 128.1, 130.6, 131.6, 137.2, 139.4, 143.3, 152.1,
157.5, 159.1, 162.6, 163.9. Anal. Calcd for C27H23N7O6
(599.67): C, 58.16; H, 4.16; N, 17.58. Found: C, 58.24;
H, 4.09; N, 17.68.
5-(4-(3-(1H-imidazol-1-yl)propoxy)phenyl)-10-(3-hydroxyphenyl)-
8,8-dimethyl-2-thioxo-2,3,5,8,9,10-hexahydropyrimido[4,5-b]quinoline-
4,6(1H,7H)-dione (16f). Yield: 88% (0.50g); yellow solid;
mp: 215–217°C. IR (KBr): 3432, 3128, 1680, 1485, 1295,
1
873cm–1. H NMR (250MHz, DMSO-d6): δ (ppm)=1.07
(s, 6H), 1.94–2.07 (m, 6H), 3.82–3.87 (m, 4H), 4.22 (brs,
1H), 6.10, (s, 1H), 6.88–7.94 (m, 10H), 8.40 (s, 1H),
10.30 (s, 2H). 13C NMR (62.9MHz, DMSO-d6): δ (ppm)
=27.6, 27.9, 32.2, 37.9, 43.0, 47.6, 50.1, 52.4, 58.6, 71.3,
82.0, 101.6, 108.9, 111.8, 114.2, 115.9, 130.2, 132.0,
135.7, 143.1, 153.7, 156.5, 159.6, 163.1, 176.4, 195.3.
Anal. Calcd for C31H31N5O4S (569.68): C, 65.36; H, 5.49;
N, 12.29. Found: C, 65.40; H, 5.41; N, 12.32.
General procedure for synthesis of 16e and 16f. A mixture
of dimedone (0.14, 1.0mmol), barbituric acid or thiobarbituric
acid (1.0mmol), aldehyde 4a or 4b (1.0 mmol), aniline
derivatives (1.0 mmol), and MNP-TA (0.1g, 5.0 mol %) in
refluxing ethanol (5 mL) was stirred for 2–6h. After
completion of the reaction confirmed by TLC (eluent
EtOAc/MeOH), the reaction mixture was cooled to room
temperature. Then, the precipitated product was filtered and
washed with water (2 ×10 mL) and ethanol (10 mL) to
afford the pure product.
General procedure for synthesis of 10a and 10b. These
aldehydes were synthesized based on our previous work [21].
In double-necked round bottom flask (100mL) equipped with
a condenser was added a mixture consisting of benzimidazole
(1.180 g, 0.01 mol), K2CO3 (1.380 g, 0.01 mol), 4-(3-
bromopropoxy)benzaldehyde (8a) or 4-((5-bromopentyl)oxy)
benzaldehyde (8b) (0.015mol), and catalytic amount of
TBAB (0.100g) in MeCN (40mL). The solution was
refluxed until TLC monitoring indicated no further
improvement in the reaction (20h). After cooling and solvent
evaporation the resulted foam was dissolved in CHCl3
(150mL) and washed with water (2×200mL). The organic
layer was dried over anhydrous Na2SO4 and evaporated. The
crude was purified by column chromatography on silica gel
eluting with proper solvent (mixture of n-hexane-EtOAc)
(1:2) Rf = 0.4 and the product was obtained.
5-(4-(3-(1H-imidazol-1-yl)propoxy)phenyl)-10-(4-methoxyphenyl)-
8,8-dimethyl-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-2,4,6
(1H,3H,7H)-trione (16e).
Yield: 86% (0.48 g); yellow
solid; mp: 196–198°C. IR (KBr): 3392, 3118, 1690,
1
1490, 1230, 816 cm–1. H NMR (250 MHz, DMSO-d6):
δ (ppm) = 1.07 (s, 6H), 1.94–2.07 (m, 6H), 3.82–3.87(m,
4H), 4.28 (s, 3H), 5.10 (s, 1H), 6.88–8.07 (m, 10H),
8.46 (s, 1H) 11.8 (s, 2H). 13C NMR (62.9MHz, DMSO-d6):
δ (ppm)= 27.9, 30.9, 33.3, 42.1, 44.5, 47.1, 51.8, 55.1, 66.7
4-(3-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-
yl)-propoxy)benzaldehyde (10b).
1H NMR (250MHz,
DMSO-d6/TMS): δ (ppm) = 1.58–1.64 (m, 2H), 1.83–1.97
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Scheme 8. Synthesis of imidazole, benzimidazole, and theophylline derivatives incorporating containing pyrimidine-fused heterocycles. Reaction con-
ditions: MNP-TA (5.0 mol %), EtOH (5 mL), 80°C, barbituric acids (2 mmol in the absence of dimedone or 1 mmol with dimedone), dimedone (1 mmol),
aniline (1 mmol), 2–6 h. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
(m, 4H), 3.99 (t, J =5.0 Hz, 2H), 4.26 (t, J = 5.0 Hz, 2H),
6.93–7.45 (m, 4H), 8.27 (s, 1H) 9.87 (s, 1H).
5-(4-((5-(1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-10-(3-
hydroxyphenyl)-8,8-dimethyl-2-thioxo-2,3,5,8,9,10-hexahydropyrimido
[4,5-b]quinoline-4,6(1H,7H)-dione (16f). Yield: 82% (0.54 g);
yellow solid; mp: 270–272°C. IR (KBr): 3502, 3138, 1693,
General procedure for synthesis of 16g and 16h.
A
mixture of dimedone (0.14 g, 1.0 mmol), barbituric acid
or thiobarbituric acid (1.0 mmol), aldehyde 10a or 10b
(1.0 mmol), aniline or its derivatives (1.0mmol), and MNP-
TA (0.1g, 5.0mol %) in refluxing ethanol (5mL) was
stirred for 2–6h. After completion of the reaction confirmed
by TLC (eluent EtOAc/MeOH), the reaction mixture was
cooled to room temperature. Then, the precipitated product
was filtered and washed with water (2× 10mL) and ethanol
(10mL) to afford the pure product.
1
1495, 1239, 871 cm–1. H NMR (250 MHz, DMSO-d6): δ
(ppm)=0.95 (s, 3H), 1.07 (s, 3H) 1.43–1.49 (m, 2H), 2.75–
2.84 (m, 6H), 3.93–3.99 (m, 6H), 4.22 (brs, 1H), 5.88 (s,
1H) 6.61–7.79 (m, 12H), 8.30 (s, 1H), 10.06 (s, 2H). 13C
NMR (62.9MHz, DMSO-d6): δ (ppm)=22.2, 27.6, 29.4,
32.2, 37.9, 43.0, 51.1, 58.0, 69.0, 82.0, 102.0, 108.9, 109.6,
111.5, 112.3, 114.2, 119.8, 122.3, 130.4, 135.7, 138.1,
142.0, 144.1, 145.2, 153.7, 158.0, 158.5, 162.1, 175.7,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Divar, F. Panahi, S. R. Shariatipour, and A. Khalafi-Nezhad
Vol 000
193.3. Anal. Calcd for C37H37N5O4S (647.79): C, 68.60; H,
5.76; N, 10.81. Found: C, 68.65; H, 5.71; N, 10.94.
3.37 (s, 3H), 3.59 (s, 3H), 4.00 (t, J= 5.0Hz, 2H), 4.48 (t,
J=5.0Hz, 2H), 6.51–7.80 (m, 4H), 8.08 (s, 1H), 9.82 (s, 1H).
A procedure for synthesis of 5-(4-(3-(1,3-dimethyl-2,6-
dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propoxy)phenyl)-10-(3-
hydroxyphenyl)-5,10-dihydropyrido[2,3-d:6,5-d′]dipyrimidine-
5-(4-(3-(1H-benzo[d]imidazol-1-yl)propoxy)phenyl)-10-(4-
methoxyphenyl)-8,8-dimethyl-2-thioxo-2,3,5,8,9,10-hexahydropyrimido
[4,5-b]quinoline-4,6(1H,7H)-dione (16 h). Yield: 84% (0.53 g);
yellow solid; mp: 190–192°C. IR (KBr): 3392, 3118, 1697,
2,4,6,8(1H,3H,7H,9H)-tetraone (16j).
A mixture of
1
1498, 1265, 876 cm–1. H NMR (250MHz, DMSO-d6): δ
barbituric acid (0.26 g, 2.0 mmol), aldehyde 12 (0.342 g,
1.0 mmol), 3-hydroxyaniline (0.109 g, 1.0 mmol), and
MNP-TA (0.1 g, 5.0 mol %) in refluxing ethanol (5 mL)
was stirred for 3 h. After completion of the reaction
confirmed by TLC (eluent EtOAc/MeOH), the reaction
mixture was cooled to room temperature. Then, the
precipitated product was filtered and washed with water
(2×10mL) and ethanol (10mL) to afford the pure product.
Yield: 80% (0.52g); bright yellow solid; mp: 246–248°C.
(ppm) =1.07 (s, 6 H), 1.94–2.07 (m, 6H), 3.82–3.87 (m, 4H),
4.28 (s, 3H), 5.10 (s, 1H), 6.91–7.28 (m, 12H), 8.44 (s, 1H),
11.75 (s, 2H). 13C NMR (62.9MHz, DMSO-d6): δ (ppm)
= 24.5, 26.7, 28.1, 32.1, 41.3, 44.1, 51.0, 53.3, 55.4, 69.4,
103.0, 110.5, 112.9, 117.4, 118.0, 119.3, 121.7, 123.9, 127.4,
131.7, 134.1, 139.7, 141.6, 144.2, 152.1, 154.1, 156.1, 161.6,
191.6. Anal. Calcd for C36H35N5O4S (633.77): C, 68.23; H,
5.57; N, 11.05. Found: C, 68.30; H, 5.51; N, 11.12.
1
IR (KBr): 3402, 3128, 1669, 1492, 1235, 875cm–1. H
A procedure for synthesis of 5-(4-((5-(1H-benzo[d]imidazol-1-yl)
pentyl)oxy)phenyl)-10-(4-methoxyphenyl)-5,10-dihydropyrido[2,
NMR (250 MHz, DMSO-d6): δ (ppm)=2.34–2.44 (m, 2H),
3.34 (s, 3H), 3.53 (s, 3H), 4.00 (t, 2H, J=5.0 Hz), 4.48 (t,
2H, J=5.0Hz), 5.91 (s, 1H), 8.18 (s, 1H), 6.41–7.28 (m,
9H), 8.75 (s, 1H) 10.49 (s, 2H). 13C NMR (62.9 MHz,
DMSO-d6): δ (ppm)=29.6, 31.4, 41.1, 42.9, 49.4, 72.5,
102.5, 106.7, 114.8, 116.0, 123.5, 128.6, 129.1, 130.0,
134.3, 140.3, 141.0, 144.3, 149.4, 151.0, 152.9, 155.9,
158.8, 162.8.Anal. Calcd for C31H27N9O8 (653.61): C,
56.97; H, 4.16; N, 19.29 Found: C, 57.00; H, 4.11; N, 19.32.
A procedure for preparation of 4-(3-(1,3-dimethyl-2,6-dioxo-
1,2,3,6-tetrahydro-7H-purin-7-yl)-2hydroxypropoxy) benzaldehyde
(15). This aldehyde was synthesized based on our previous
work [21]. In a double-necked round-bottomed flask
(100mL), equipped with a condenser, a mixture of the
appropriate 4-hydroxylphenol (0.03mol), K2CO3 (4.14 g,
0.03 mol), epibromohydrin (4.92 g, 0.036mol), and
catalytic amounts of tetra butyl ammonium bromide TBAB
(0.1g) were dissolved in MeCN (40mL). Then, the mixture
was heated to reflux for 10h (TLC control). The solvent
was evaporated at reduced pressure, and the residue was
dissolved in CHCl3 (150mL) and washed with H2O
(2×150mL). The org. layer was dried (Na2SO4, 10g) and
concentrated to afford the crude product consisting of a
mixture of (14a) and (14b). The crude product was then
used without any further purification for the synthesis of
(15) according to the procedure described below.
In double-necked round bottom flask (100mL) equipped
with a condenser was added a mixture consisting of theophyl-
line (0.01mol, 1.8g) K2CO3 (1.38 g, 0.01mol), appropriate
bromo alcohol and another derivative with epoxide ring
(14b) and (14a) (0.015mol), and catalytic amount of TBAB
(0.1 g) in DMF (40 mL). The solution was refluxed until
TLC monitoring indicated no further improvement in the
reaction (8–10 h). After cooling and solvent evaporation
the resulted foam was dissolved in CHCl3, (150 mL) and
washed with water (2 × 200 mL). The organic layer was
dried over anhydrous (Na2SO4) and evaporated. The
crude was purified by column chromatography on silica
3-d:6,5-d′]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone (16i).
A
mixture of barbituric acid (0.26 g, 2.0 mmol), 10b
(1.0mmol),4-methoxyaniline (0.123g, 1.0mmol), and
MNP-TA (0.1g, 5.0mol %) in refluxing ethanol (5mL)
was stirred for 4h. After completion of the reaction
confirmed by TLC (eluent EtOAc/MeOH), the reaction
mixture was cooled to room temperature. Then, the
precipitated product was filtered and washed with water
(2×10mL) and ethanol (10mL) to afford the pure product.
Yield: 90% (0.57g); yellow solid; mp: 205–207°C. IR
(KBr): 3412, 3108, 1689, 1490, 1235cm–1. 1H NMR
(250MHz, DMSO-d6): δ (ppm)=1.01 (s, 6H), 1.94–2.07
(m, 6H), 3.96 (s, 3H), 4.26–4.46 (m, 4H), 6.10 (s, 1H),
6.88–7.94 (m, 12H), 8.35 (s, 1H), 10.44 (s, 4H). 13C NMR
(62.9MHz, DMSO-d6): δ (ppm)=25.0, 27.0, 41.0, 44.3,
52.6, 55.1, 69.1, 102.4, 110.5, 112.9, 120.5, 122.8, 130.4,
132.5, 135.2, 136.1, 143.0, 143.9, 149.9, 156.9, 159.5,
163.6.Anal.Calcd for C34H31N7O6 (633.66): C, 64.45; H,
4.93; N, 15.47. Found: C, 64.48; H, 4.89; N, 15.50.
A procedure for synthesis of 4-(3-(1,3-dimethyl-2,6-dioxo-
1,2,3,6-tetrahydro-7H-purin-7-yl)propoxy)benzaldehyde (12). This
aldehyde was synthesized based on our previous work [21]. In
a double-necked round-bottomed flask (100mL), equipped
with a condenser, a mixture of theophylline (0.03 mol,
5.4 g), K2CO3 (4.14 g, 0.03 mol), 4-(3-bromopropoxy)
benzaldehyde (8a) (0.15mol), and catalytic amounts of
tetra butyl ammonium bromide (TBAB, 0.1g) were
dissolved in MeCN (40mL). Then, the mixture was heated
to reflux for 10h (TLC control). The solvent was
evaporated at reduced pressure, and the residue was
dissolved in CHCl3 (150mL) and washed with H2O
(2×150 mL). The org. layer was dried (Na2SO4, 10g) and
concentrated to afford the crude products 12. The crudes
were purified by column chromatography on silica gel
eluting with proper solvent (mixture of n-hexane-EtOAc)
1
(1:2) Rf = 0.6 the product was obtained in 75%. H NMR
(250MHz, DMSO-d6/TMS): δ (ppm) 2.34–2.44 (m, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Pyrimidine-Fused Heterocycles Incorporating Imidazole and Theophylline Moieties
[6] Hirashima, S.; Suzuki, T.; Ishida, T.; Noji, S.; Yata, S.;
Ando, I.; Komatsu, M.; Ikeda, S.; Hashimoto, H. J Med Chem 2006,
49, 4721.
gel eluting with proper solvent (mixture of n-hexane-
EtOAc) (1:2) Rf = 0.5 the product was obtained in 70%. H
1
NMR (250MHz, DMSO-d6/TMS): δ (ppm)= 3.32 (s, 3H),
3.51 (s, 3H), 4.00–4.06 (m, 2H), 4.38–4.44 (m, 2H), 4.60–
4.65 (m, 1H), 6.93–7.79 (m, 5H), 8.06 (s, 1H), 9.80 (s, 1H).
A procedure for the synthesis of 10-(4-chlorophenyl)-5-(4-
(3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-2-
hydroxypropoxy)phenyl)-5,10-dihydropyrido[2,3-d:6,5-d′]dipyrimidine-
2,4,6,8(1H,3H,7H,9H)-tetraone (16k). A mixture of barbituric
acid (0.26 g, 2.0 mmol), aldehyde 15 (0.358g, 1.0mmol), 4-
chloroaniline (0.127g, 1.0 mmol), and MNP-TA (0.1 g,
5.0mol %) in refluxing ethanol (5mL) was stirred for 5 h.
After completion of the reaction confirmed by TLC (eluent
EtOAc/MeOH), the reaction mixture was cooled to room
temperature. Then, the precipitated product was filtered and
washed with water (2 ×10mL) and ethanol (10mL) to afford
the pure product. Yield: 85% (0.58g); yellow solid; mp:
260–262°C. IR (KBr): 3419, 3208, 1694, 1480, 1335,
873 cm–1. 1H NMR (250 MHz, DMSO-d6): δ (ppm)
= 3.38 (s, 3H), 3.53 (s, 3H), 4.01–4.06 (m, 4H), 4.38–
4.44 (m, 1H), 5.93 (brs, 1H), 6.08 (s, 1H) 7.42–8.56 (m,
9H), 10.26 (s, 4H). 13C NMR (62.9MHz, DMSO-d6): δ
(ppm)=29.4, 30.9, 40.0, 44.0, 49.2, 68.4, 71.9, 100.7,
105.4, 115.7, 128.5, 130.2, 133.2, 134.9, 135.3, 137.2,
140.5, 142.4 144.8, 150.1, 150.6, 154.2, 156.2, 157.5,
163.5. Anal. Calcd for C31H26Cl N9O8 (688.05): C, 54.12;
H, 3.81; N, 18.32. Found: C, 54.19; H, 3.78; N, 18.41.
5-(4-((5-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-
yl)pentyl)oxy)phenyl)-10-(3-hydroxyphenyl)-5,10-dihydropyrido
[2,3-d:6,5-d′]dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraone
(16l). Yield: 87% (0.59g); yellow solid; mp: 185–187°C.
[7] Li, H.-Y.; Wang, Y.; Heap, C. R.; King, C.-H. R.; Mundla, S. R.;
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Terranova, M. A.; Chang, R.; Donnelly-Roberts, D. L.; Namovic, M. T.;
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London, 2009.
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The Pyrimidines; Wiley-Interscience, 2009; Vol 52.
[21] Khalafi-Nezhad, A.; Divar, M.; Panahi, F. J Org Chem 2013,
78, 10902.
[22] Nourisefat, M.; Panahi, F.; Khalafi-Nezhad, A. Org Biomol
Chem 2014, 12, 9419.
[23] Khalafi-Nezhad, A.; Panahi, F. Synthesis 2011 984.
[24] Panahi, F.; Yousefi, R.; Mehraban, M. H.; Khalafi-Nezhad, A.
Carbohydrate Res 2013, 380, 81.
1
IR (KBr): 3382, 3109, 1679, 1490, 1235cm–1. H NMR
(250MHz, DMSO-d6): δ (ppm)=3.32 (s, 3H), 3.51 (s,
3H), 4.00–4.06 (m, 4H), 4.38–4.61 (m, 1H), 5.261 (brs,
2H), 6.09 (s, 1H), 6.88–7.32 (m, 8H), 8.18 (s, 1H), 8.35
(s, 1H), 10.18 (s, 4H). 13C NMR (62.9 MHz, DMSO-d6):
δ (ppm)=29.4, 30.9, 40.0, 44.0, 68.4, 71.9, 100.7, 105.4,
115.7, 128.5, 130.2, 133.2, 134.9, 135.3, 135.8, 137.2,
140.5, 142.4, 144.8, 150.1, 150.6, 154.2, 156.2, 157.5,
163.5. Anal. Calcd for C33H31N9O8 (681.67): C, 58.15; H,
4.58; N, 18.49. Found: C, 58.18; H, 4.50; N, 18.61.
Acknowledgments. The financial supports of research councils of
Shiraz University are gratefully acknowledged.
[25] Shahidpour, S.; Panahi, F.; Yousefi, R.; Nourisefat, M.;
Nabipoor, M.; Khalafi-Nezhad, A. Med Chem Res 2015, 24, 3086.
[26] Khalafi-Nezhad, A.; Divar, M.; Panahi, F. RSC Adv 2015,
5, 2223.
[27] Khalafi-Nezhad, A.; Nourisefat, M.; Panahi, F. Synthesis
2014, 46, 2071.
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DOI 10.1002/jhet

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