Facile synthesis of pyridopyrimidine and coumarin fused pyridine libraries over a Lewis base-surfactant-combined catalyst TEOA in aqueous medium

Article abstract of DOI:10.1039/c3ra23254a

A highly convergent and efficient protocol, for the facile synthesis of a library of coumarin fused pyridine and pyridopyrimidine derivatives, has been developed by applying a Lewis base-surfactant-combined catalyst (LBSC) triethanolamine (TEOA). The method described has the benefits of operational simplicity and excellent yields of the targeted molecule. The LBSCs were found to form stable colloidal dispersions rapidly in the presence of reaction substrates in water, even when the substrates are solid. In light of the increased demand for reduction of organic solvents in industry, the surfactant aided Lewis base catalysis described here may have immense practical consequences in organic synthesis. This work may not only lead to environmentally benign systems but also will provide a newer aspect of organic chemistry in water.

Full text of DOI:10.1039/c3ra23254a

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Facile synthesis of pyridopyrimidine and coumarin
fused pyridine libraries over a Lewis base-surfactant-
combined catalyst TEOA in aqueous medium3
Cite this: RSC Advances, 2013, 3, 3203
Received 10th December 2012,
Accepted 13th January 2013
Pranabes Bhattacharyya, Sanjay Paul and Asish R. Das*
DOI: 10.1039/c3ra23254a
www.rsc.org/advances
A highly convergent and efficient protocol, for the facile synthesis
of a library of coumarin fused pyridine and pyridopyrimidine
derivatives, has been developed by applying a Lewis base-
surfactant-combined catalyst (LBSC) triethanolamine (TEOA). The
method described has the benefits of operational simplicity and
excellent yields of the targeted molecule. The LBSCs were found
to form stable colloidal dispersions rapidly in the presence of
reaction substrates in water, even when the substrates are solid.
In light of the increased demand for reduction of organic solvents
in industry, the surfactant aided Lewis base catalysis described
here may have immense practical consequences in organic
synthesis. This work may not only lead to environmentally benign
systems but also will provide a newer aspect of organic chemistry
in water.
Pyridopyrimidines represent an important class of compounds
being the main components of any naturally occurring products,
and have been of interest in recent years due to their useful
biological and pharmacological aspects. The potential utilities of
these heterocyclic scaffolds have been identified in virtually all of
the major therapeutic areas, as many of them are found to exhibit
antitumor,3 antiallergic,4 antifolate,3 tyrosine kinase, antimicro-
bial,5 calcium channel antagonist,6 antibacterial,7 anti-inflamma-
tory,
analgesic,8
antihypertensive,9
antileishmanial,10
tuberculostatic,11 anticonvulsant,12 diuretic, potassium sparing,13
and antiaggressive activities.14 Furthermore, the pyridopyrimi-
dines are an important class of annelated uracils with biological
significance because of their connection with the purine pyridine
system.15 Compounds A and B (Fig. 1) have been found to show
adenosine kinase and human neutrophil elastase (HNE) inhibitory
activities, respectively.16 On the other hand coumarin fused
heterocycles are one of the most active classes of compounds
possessing a wide spectrum of biological activities.17 Many of the
coumarin fused heterocycles show antitumor,18 antibacterial,19
antifungal,20 anticoagulant,21 anti-inflammatory,22 and antiviral23
activities. It was thought that molecules containing two active
pharmacophores, coumarin and pyridine would produce novel
molecular templates which are likely to exhibit interesting
biological properties.
Introduction
From the green chemistry point of view, water is considered to be
the perfect solvent to carry out chemical operations since it is safe,
non-toxic, inexpensive and poses no threat to the environment.
However, water is rarely used or hardly considered as a solvent for
organic reactions. One of the principal reasons is undoubtedly the
limited solubility of most organic compounds in pure water. Our
goal is to develop a novel catalytic system which enables the use of
water as a solvent for a wide range of organic reactions. The
drawback in the use of water (the solubility problem) may be
overcome by using surfactants or surfactant-like ligands1 which
solubilize organic materials or form colloidal dispersions with
them in water. Triethanolamine (TEOA) has been used as a
surfactant-like ligand for the synthesis of metal or metal oxide
nanoparticles.2 We have applied TEOA as a Lewis base-surfactant-
combined catalyst which serves a dual role: as a base to activate
the substrate molecules and as a surfactant to solubilise organic
reactants in aqueous medium.
There is a maiden report on the synthesis of coumarin fused
pyridine derivatives but there are a handful of reports regarding
the synthesis of pyridopyrimidines.24a–e Although there are a
certain number of methods available for the synthesis of
University of Calcutta, Kolkata, India. E-mail: ardchem@caluniv.ac.in;
ardas66@rediffmail.com; Fax: +913323519754; Tel: +913323501014
Tel: +919433120265
Fig. 1 Biologically active pyridopyrimidine derivatives.
Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra23254a
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Table 1 Catalyst optimization for the synthesis of pyridopyrimidinesa
pyridopyrimidine derivatives, the reported methods have their
demerits and limitations such as multi-step synthesis, use of
expensive harmful reagents, application of toxic solvents like DMF
and DMSO, complicated work up procedure and low yields. Based
on their extensive application, it is necessary to further develop
more efficient and convenient methods to construct such
significant heterocyclic compounds. In this communication we
wish to uncover a green one pot three-component protocol for the
synthesis of pyridopyrimidines and coumarin fused pyridines
derivatives from the reaction of aldehyde, 6-aminouracil/4-
aminocoumarin and malononitrile/1,3-dimethylbarbituric acid
under thermal conditions in the presence of an efficient, green
and inexpensive catalyst triethanolamine (TEOA) in aqueous
media.
Entry
Catalyst
Time (hr)
Yieldb (%)
1
2
3
4
—
24
6
6
Trace
15
21
Nano Al2O3
Nano SiO2
L-Proline
6
43
5
6
7
8
9
10
11
12
Nano ZnO
p-toluene sulphonic acid
Acetic acid
DBU
TUD
Triethylamine
Triethylamine/SDS
Triethanolamine (TEOA)
6
6
4
4
4
4
3
2
32
44
50
42
33
58
70
85
a
3-nitrobenzaldehyde (1a) (1 mmol), malononitrile (2a) (1 mmol),
and 6-aminouracil (3a) (1 mmol) were stirred at 80 uC in 5 ml water
b
in the presence of 15 mol% of the catalyst. Isolated yield of the
pure product.
Results and discussion
During initial exploratory reactions, we studied the synthesis of
pyridopyrimidine derivative 4a from the condensation of an
equimolar amount of 3-nitrobenzaldehyde (1a), malononitrile (2a),
and 6-aminouracil (3a) in the presence of a variety of catalysts to
optimize the reaction conditions (Scheme 1). It was found that,
when the reaction was carried out without any catalyst no product
was observed even after 24 h (Table 1, entry 1). As shown in
Table 1, low yields of the target product 4a (15–50%) were
obtained when we tested the reaction using some different
Brønsted and Lewis acids like nano Al2O3, nano SiO2, L-proline,
nano ZnO, p-toluene sulphonic acid, acetic acid (Table 1, entry 2–
7). The reaction using Lewis base, triethylamine, as the catalyst
gave the corresponding product 4a in moderate yield (Table 1,
entry 10). The yield of the desired product 4a was improved when
the reaction was performed using a triethylamine/SDS catalyst
combination (Table 1, entry 11). The above results (Table 1, entry
10, 11) encouraged us to think about a catalyst having both
surfactant properties and strong Lewis basicity to promote the
three-component reaction. For the ‘‘Lewis base-surfactant-com-
bined catalyst (LBSC)’’ we have advocated triethanolamine (TEOA)
as the catalyst for MCR and to our delight, TEOA provided
satisfactory results (Table 1, entry 12).
(4a) was 94% when the reaction was performed in water (Table 2,
entry 10).
Catalyst concentration is a significant factor that exclusively
affects the reaction rate and product yield. To study this, the
reaction was performed at different concentrations of TEOA, i.e.,
10, 15, 20 and 25 mol%, and gave the product in 78%, 85%, 94%
and 95% yield, respectively (Table 2). Thus, it is clear that reaction
rate was positively influenced by increasing catalyst concentration
up to 20 mol% and then became static on further increasing the
catalyst concentration. It means that the presence of 20 mol% of
TEOA was sufficient for catalyzing the reaction effectively in the
forward direction.
The above observations indicate that the reaction proceeds well
in the presence of 20 mol% of TEOA in aqueous media. The mild
reaction conditions and clean TLC pattern are the main
advantages of the reaction in water. With these optimal
conditions, we next embarked on an investigation of the substrate
scope of this new multicomponent domino process (Table 3) for
the synthesis of pyridopyrimidine derivatives with aldehydes, two
Afterward, various solvents were also screened to test their
efficiency in the reaction at 80 uC, and the results are summarized
in Table 2. When the reaction media was changed from methanol
to ethanol, DMSO or DMF, the compound 4a was produced in
moderate yields (Table 2, entries 1–4). When CHCl3, acetone, and
toluene were used as the solvent, the product was formed in poor
yields (Table 2, entries 5–7). It was evident that water showed
superiority over other solvents and the yield of the desired product
Table 2 Solvent screening and optimization of catalyst load for the model
reactiona
Entry
TEOA (mol%)
Solvent
T/uC
Yieldb (%)
1
2
3
4
5
6
7
8
9
15
15
15
15
15
15
15
15
10
20
25
Methanol
Ethanol
DMSO
DMF
CHCl3
Acetone
Toluene
H2O
65
80
80
80
80
60
80
80
80
80
80
44
56
46
44
43
26
28
85
78
94
95
H2O
H2O
H2O
10
11
a
3-nitrobenzaldehyde (1a) (1 mmol), malononitrile (2a) (1 mmol),
and 6-aminouracil (3a) (1 mmol) were stirred in 5 ml solvent in
b
presence of mentioned catalytic load of TEOA. Isolated yield of the
pure product.
Scheme 1 Synthesis of pyridopyrimidines.
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Table 3 Substrate scope for the synthesis of pyridopyrimidines and coumarin fused pyridinesa
Entry
Active methylene
Ar
Heteroamine
Reaction time (h)
Product
Yieldb,c (%)
1
2
3
4
5
6
7
8
9
3-NO2-C6H4
4-Cl-C6H4
4-F-C6H4
4-NO2-C6H4
Ph
4-OCH3-C6H4
2-Fur
2
2
2
2
2.5
2.5
2.5
3
2.5
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
94
91
88
90
87
83
79
86
89
82
Ph
3-NO2-C6H4
4-OCH3-C6H4
10
4j
11
12
13
14
15
16
17
18
19
3-NO2-C6H4
4-Cl-C6H4
4-F-C6H4
1.5
2
2
2.5
2.5
3
2.5
2
4k
4l
96
92
90
89
87
84
83
88
81
4m
4n
4o
4p
4q
4r
Ph
4-OCH3-C6H4
3-OH 4-OCH3-C6H4
Ph
3-NO2-C6H4
4-OCH3-C6H4
3
4s
20
21
22
23
Ph
4.5
3.5
4
4t
87
92
91
83
3-NO2-C6H4
4-Cl-C6H4
4-OCH3-C6H4
4u
4v
4w
5.5
a
Aldehyde (1 mmol), active methylene (2a) (1 mmol), and amine (3a) (1 mmol) were stirred in 5 ml water in the presence of 20 mol% TEOA
at 80 uC for the stipulated time. Isolated yield of the pure product. The products were characterized by 1H NMR, 13C NMR, IR, HRMS and
b
c
elemental analysis.25
heteroamines and two active methylene substances (malononitrile
and 1,3-dimethylbarbituric acid). Variation of the electronic
environment of the substituents at the aromatic ring of the
aldehydes was quite tolerable with high yields ranging from 79%
to 96%. To further widen the potential of this approach as a tool
for the construction of coumarin fused pyridine derivatives, we
focused our attention on the investigation of the reaction of
4-aminocoumarin, malononitrile, and aldehydes (Table 3). A
library of pyridopyrimidine and coumarin fused pyridine deriva-
tives was synthesized by applying this green synthetic protocol
(Table 3). In all the cases, the reaction was completed within 1.5–
5.5 h and the products could be isolated by simple filtration of the
precipitated mass formed. The progress of the reaction was
monitored by TLC. It can be observed that the process results in a
wide variety of aldehydes and three hetero amine derivatives,
providing a variety of substituted pyridine derivatives with high
purity. The structures of the desired products were well
1
characterized by IR, H, 13C NMR spectral data, and HRMS, as
well as by elemental analysis.
TEOA is a sterically hindered neutral organic base and is
especially useful for inhibition of the formation of unwanted side
products. This new type of catalyst, ‘‘Lewis base-surfactant-
combined catalyst (LBSC)’’ would act both as a catalyst to activate
the substrate molecules and as a surfactant to form colloidal
particles. It is pertinent to mention that the addition of TEOA in
the reaction flask converted the initially floating reaction mass
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Fig. 2 (a) DLS study of the reaction media showing formation of aggregates. (b) Optical microscopic image showing nano-vesicles in the reaction media.
into a homogeneous mixture, which on stirring became a white
turbid emulsion. This observation implies that there was
formation of micelles or micelle-like colloidal aggregates. The
average sizes of the colloidal particles formed from LBSC and the
reaction mixture in water were measured by dynamic light
scattering, and appeared to be about 100 nm in diameter
(Fig. 2a). Formation of emulsion droplets in the present reaction
system was also confirmed by optical microscopy (Fig. 2b). The
emulsion formation is attributed to the property of triethanola-
mine as a surfactant, and this property should be important to
accelerate the rate of the reaction. That is, these colloidal vesicles
would function as an effective reaction domain in water. The
driving force of the reaction in the presence of micelles may be
related to the hydrophobic force which compresses the reactants
together in a highly compact arrangement of complexes together
within a restricted hydrophobic domain. Although TEOA has a
very short carbon chain, the aggregation of TEOA takes place
through the formation of intermolecular H-bonding and following
this type of polymerization, the TEOA generates micelle-like
colloidal aggregates.
With these excellent results in hand, we are now in a position
to propose the mechanism of the reaction which involves,
Knoevenagel condensation, Michael addition, and then intramo-
lecular cyclization catalyzed by TEOA and finally aerial oxidation
for the formation of a pyridine ring as presented in Scheme 2. The
catalytic effect of micellar TEOA in this reaction can be explained
as follows. In the micellar solution, heteroamine, active methylene
compound and aryl aldehyde, which are hydrophobic, are forced
to enter inside the hydrophobic core of the micelles, thus allowing
the reaction to take place more easily (Scheme 2).
In addition, the development of a protocol for recovery and
reuse of the catalysts is indispensable to apply the LBSC system to
large-scale synthesis. Therefore, it is worth mentioning that the
product was collected only by filtration of the reaction mixture.
The filtrate that is the LBSC–water mixture was reused for the new
set of reactions.
Scheme 2 Plausible mechanism for the formation of pyridopyrimidines and coumarin fused pyridines.
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Conclusion
Notes and references
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In summary, an efficient multicomponent domino approach to
pyridopyrimidines and coumarin fused pyridine derivatives with
formations of up to four s bonds including two C–N bonds has
been established by performing the reaction in a one-pot
operation in water under thermal conditions, applying a dual
responsive catalyst (LBSC) TEOA. The reactions showed a broad
substrate scope and readily available, inexpensive commercial
starting materials such as aldehydes, 6-aminouracil/4-aminocou-
marin and malononitrile/1,3-dimethylbarbituric acid could be
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the environmentally friendly reaction can occur in water; (2) fast
reaction rates which enable the reaction to be completed within
1.5–5.5 h, (3) the convenient work-up which only needs simple
filtration since the products directly precipitated out after the
reaction is finished.
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reactions. All the solvents used in the reaction were distilled and
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General procedure for the preparation of pyridopyrimidine/
coumarin fused pyridine
A mixture of an aldehyde (1 mmol), active methylene compound (1
mmol), 6-aminouracil derivative/4-aminocoumarin (1 mmol) and
TEOA (20 mol%) was stirred at 80 uC temperature in 5 ml water.
The progress of the reaction was monitored by TLC
(MeOH : EtOAc = 1 : 9). After completion of the reaction the
reaction mixture was cooled to room temperature and filtered to
obtain the product. The crude product was washed thoroughly
with water and finally with methanol to obtain the pure product.
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We thank University of Calcutta and UGC for financial and
technical support. PB thanks CSIR for his Senior Research
Fellowship (09/028/(0768)/2010-EMR-I). SP thanks UGC, India
for his Senior Research Fellowship. We are thankful to Prof.
Ajay Ghosh of Applied Photonics Department of C.U. for
providing optical microscope. We are also thankful to Dr. Dilip
K. Maiti, Chemistry Department of C.U. for providing
‘‘Dynamic Light Scattering’’ facilities.
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NMR (300 MHz, DMSO-d6): d 7.63-7.71(2H, m), 7.81–7.89 (2H,
m), 8.09 (2H, s), 11.37 (1H, s), 11.89 (1H, s); 13C NMR (75 MHz,
DMSO-d6): d 88.9, 115.8, 128.2, 130.0, 133.5, 136.1, 150.7, 156.0,
158.1, 160.6, 161.3; Anal. Calcd for C14H8ClN5O2: C 53.60, H
2.57, N 22.33%. Found: C 53.62, H 2.55, N 22.38%; HRMS of
[C14H8ClN5O2 + H+]: Calcd: 314.0439 found: 314.0436; 1,3,7,9-
tetramethyl-5-phenylpyrido[2,3-d:6,5-d9]dipyrimidine-
2,4,6,8(1H,3H,7H,9H)-tetraone (4q): White crystalline solid; Mp:
1
228 uC; IR (KBr): 3311, 1711, 1672 cm21; H NMR (300 MHz,
DMSO-d6): d 3.26 (6H, s), 3.55 (6H, s), 6.95–7.25 (5H, m); 13C
NMR (75 MHz, DMSO-d6): d 28.7, 30.6112.1, 114.7, 123.3, 124.2,
126.4, 126.5, 136.2, 149.4, 157.3, 160.6, 166.9; Anal. Calcd for
C19H17N5O4: C 60.15, H 4.52, N 18.46%. Found: C 60.19, H 4.49,
N 18.48%; HRMS of [C19H17N5O4 + H+]: Calcd: 380.1353 found:
380.1355, 2-amino-4-(3-nitrophenyl)-5-oxo-5H-chromeno[4,3-
b]pyridine-3-carbonitrile (4u): White crystalline solid; Mp:
1
>300 uC; IR (KBr): 3314, 2217, 1722, 1682 cm21; H NMR (300
MHz, DMSO-d6): d 7.36–7.47 (2H, m), 7.67–7.89 (4H, m), 8.33–
8.40 (4H, m); 13C NMR (75 MHz, DMSO-d6): d 89.1, 114.6, 119.3,
126.1, 126.7, 126.8, 128.7, 129.0, 129.3, 136.2, 140.5, 154.3,
157.7; Anal. Calcd for C19H10N4O4: C 63.69, H 2.81, N 15.64%.
Found: C 63.71, H 2.78, N 15.68%; HRMS of [C19H10N4O4 + H+]:
Calcd: 359.0775 found: 359.0771.
25 Representative physical data of the synthesized compounds:
7-amino-5-(4-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyr-
ido[2,3-d]pyrimidine-6-carbonitrile (4b): White crystalline solid;
1
Mp: >300 uC; IR (KBr): 3400, 3330, 2224, 1695, 1644 cm21; H
3208 | RSC Adv., 2013, 3, 3203–3208
This journal is ß The Royal Society of Chemistry 2013