Efficient sonochemical protocol for the facile synthesis of dipyrimido-dihydropyridine and pyrimido[4,5-d]pyrimidines in aqueous β-cyclodextrin

Article abstract of DOI:10.1080/00397911.2017.1390685

An economical and efficient synthesis of dipyrimido-dihydropyridines and pyrimido[4,5-d]pyrimidines is described using greener and recyclable β-cyclodextrin as a supramolecular catalyst in aqueous medium. The remarkable features of this method are mild reaction conditions, short reaction times, easy workup procedure, recyclability of the catalyst, and excellent yields of the products. The highly functional group tolerance and shorter reaction times make this method suitable for the synthesis of dihydropyridine and pyrimido[4,5-d]pyrimidine derivatives with a wide substitution pattern.

Full text of DOI:10.1080/00397911.2017.1390685

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient sonochemical protocol for the facile
synthesis of dipyrimido-dihydropyridine and
pyrimido[4,5-d]pyrimidines in aqueous β-
cyclodextrin
Chandrakant Jadhav, Lalit D. Khillare & Manisha R. Bhosle
To cite this article: Chandrakant Jadhav, Lalit D. Khillare & Manisha R. Bhosle (2017):
Efficient sonochemical protocol for the facile synthesis of dipyrimido-dihydropyridine and
pyrimido[4,5-d]pyrimidines in aqueous β-cyclodextrin, Synthetic Communications, DOI:
10.1080/00397911.2017.1390685
To link to this article: https://doi.org/10.1080/00397911.2017.1390685
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Date: 27 December 2017, At: 00:51

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1390685
Efficient sonochemical protocol for the facile synthesis of
dipyrimido-dihydropyridine and pyrimido[4,5-d]pyrimidines
in aqueous β-cyclodextrin
Chandrakant Jadhav, Lalit D. Khillare, and Manisha R. Bhosle
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad, Maharashtra, India
ABSTRACT
ARTICLE HISTORY
Received 22 September
2017
An economical and efficient synthesis of dipyrimido-dihydropyridines
and pyrimido[4,5-d]pyrimidines is described using greener and
recyclable β-cyclodextrin as a supramolecular catalyst in aqueous
medium. The remarkable features of this method are mild reaction
conditions, short reaction times, easy workup procedure, recyclability
of the catalyst, and excellent yields of the products. The highly
functional group tolerance and shorter reaction times make this
method suitable for the synthesis of dihydropyridine and pyrimido
[4,5-d]pyrimidine derivatives with a wide substitution pattern.
KEYWORDS
β-cyclodextrin;
dihydropyridines;
dipyrimido-dihydropyridines;
pyrimido[4,5-d]pyrimidines;
ultrasonication
GRAPHICAL ABSTRACT
Introduction
1,4-Dihydropyridine (DHP) scaffold represents the heterocyclic unit of remarkable
pharmacological efficiency.[1] Dipyrimido-dihydropyridines having DHPs as privileged
pharmacophore provide important ligands for biological receptors.[2] These compounds,
although described for the first time more than a century ago, have recently been
recognized as vital drugs, e.g., amlodipine and felodipine (Figure 1) as antihypertensive
and calcium channel blockers. Moreover, DHPs also act as nicotinamide adenine
dinucleotide (NADH) mimics for the reduction of carbonyl compounds and their
derivatives.[3] In human body, the main metabolic route of dihydropyridine drugs involve
their oxidation to pyridines catalyzed by cytochrome P450 in liver.[4] Pyrimido[4,5-d]
CONTACT Manisha R. Bhosle
d.manisha11@gmail.com
Department of Chemistry, Dr. Babasaheb Ambedkar
Marathwada University, Aurangabad 431004, Maharashtra, India.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2017 Taylor & Francis

2
C. JADHAV ET AL.
Figure 1. Biologically active molecules.
pyrimidine derivatives are also important heterocycles well recognized as bronchodilators,
vasodilators, antiallergic, antihypertensive, and anticancer agents.[5]
Barbituric acid is one of the most important nitrogen-containing heterocyclic systems; it
is found in various natural and synthesized compounds of anesthetics, anti-inflammatory
drugs, analgesics, anxiolytics, anticancer drugs, HIV/AIDS protease inhibitors, and
others.[6] Riboflavin (vitamin B2) and Phenobarbital (to treat epilepsy) are vital molecules
in the market having barbituric acid as one of the pharmacophores (Figure 1).[6e]
Therefore, lot of efforts have been made toward the synthetic manipulation of uracil
for the preparation of dipyrimido-dihydropyridines and pyrimido[4,5-d]pyrimidine
derivatives, using Zn2þ@KSF,[7a] Fe3O4@SiO2,[7b] In-SiO2 composite,[8] l-proline[9] as
catalysts and MW assisted reaction[10] which usually requires forcing conditions, long
reaction times and complex synthetic pathways. Therefore, there is a need to develop more
efficient and sustainable chemical process for the synthesis of pyrimido[4,5-d]pyrimidines.
The development of green alternatives to multicomponent reactions (MCRs) has
attracted much attention as these reactions produced important biological scaffolds and
marketed drugs in an environment-friendly pathway.[11] The reaction parameters, such
as solvent, catalyst of an MCR determine the selectivity, versatility, and environmental
acceptability. Water is the greenest solvent among all and consequently it has been
widely used as the reaction medium for elementary organic transformations as well as in
MCRs.[12] It has also been reported that water accelerates the rate of reaction due to its high
polarity, hydrogen bonding in the transition state, and hydrophobic effect.[13] Thus, the
synthesis of bioactive scaffolds through MCR using a mild and inexpensive catalyst in a
green solvent like water is valued.
Catalysis is also a keystone in chemical sciences supported by the improvement
of known industrial reactions, the development of new reaction pathways, and the
exponential burgeoning of organocatalysis.[14] Cyclodextrins are promising supramolecular
catalysts in aqueous medium because they are nontoxic, biodegradable and, in many
instances, they are recyclable.[15] β-Cyclodextrin (β-CD) is a cyclic oligosaccharide
composed of seven α-1, 4-linked glucopyranosyl units. Cyclodextrins contain hydrophobic
cavities inside and hydrophilic hydroxyl groups outside (Figure 2). The most prominent
feature of cyclodextrins is their capability to form inclusion complexes (host–guest
complexes) with different classes of compounds by noncovalent bonding interactions.[16,17]
The internal cavity of the cyclodextrin molecule is strongly hydrophobic in nature, and this
particular characteristic of the cyclodextrin molecule enables it to bind with a wide range of
guest molecules.[18] Cyclodextrin binds with the substrate in its hydrophobic cavity and
catalyzes reactions in a selective manner.

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Figure 2. Chemical structure of β-cyclodextrin.
Ultrasound irradiation is a vital tool in heterocyclic chemistry, which allows reactions
under mild conditions and is known to enhance yields and reduce reaction times.[19]
Ultrasound also offers advantages such as minimal waste production and energy savings
among others, consequently it is expedient green chemistry approach.[20] Thus, researchers
attempted to use ultrasonication for improving the recognized MCRs.
In continuation of our work on β-CD,[21] we now disclose a newer methodology for the
synthesis of known dipyrimido-dihydropyridines and pyrimido[4,5-d]pyrimidines as
one-pot synthesis involving three-component annulation of substituted aldehydes,
barbituric acid, and ammonium acetate/urea in the presence of β-CD as a recyclable
catalyst in aqueous media at 60–65 °C.
Results and discussion
Optimization of reaction conditions and scope of the reaction
To find out the best experimental conditions for the preparation of dipyrimido-
dihydropyridines, a model reaction, involving the three-component annulation between
benzaldehyde (1a), barbituric acid (2a), and ammonium acetate was selected.
In this study, a model reaction was conducted by the addition of benzaldehyde (1a),
barbituric acid (2), and ammonium acetate at room temperature in the presence of catalyst,
p-toluenesulfonic acid, cetyltrimethylammonium bromide, tetradecyltrimethylammonium
bromide, β-CD to obtain the corresponding dihydropyridines (3a) in aqueous medium.
Among all these catalysts, β-CD gives product in good yield (Table 1). This might be
due to the most notable feature of cyclodextrins, i.e., their ability to form solid inclusion
complexes (host–guest complexes) with a very wide range of compounds by a molecular
complexation. This will result in solubility enhancement of highly insoluble guests.
Temperature has more than one effect upon cyclodextrin complexes. Heating can
increase the solubility of the complex but at the same time also destabilizes the complex.
These effects often need to be balanced. Therefore to check the effect of temperature on
reaction rate, the model reaction was performed at different temperatures, 40, 50, 60,
70 °C. The reaction was found to be sluggish at 40 °C; however, by increasing the

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C. JADHAV ET AL.
Table 1. Optimization of reaction condition using different catalysts for the synthesis of 5-(phenyl)-
1,3,5,7,9,10-hexahydropyrimido[50,40-5,6]pyridine[2,3-d]pyrimidine-2,4,6,8-tetraone (3a).a
Entry
Catalyst
Solvent
Time (h)
Concentration (mol%)
Temperature (°C)
Yield (%)b
1
2
—
Water
Water
Water
Water
Water
Water
Water
Water
EtOH
27
6
—
40/stir
No condensation
p-TSA
CTAB
TTAB
β-CD
β-CD
α-CD
γ-CD
β-CD
β-CD
β-CD
20
40/stir
69
3
6
20
40/stir
40/stir
75
71
4
6
20
5
1
20
40, 50, 60, 70/stir
60/US
71, 79, 85, and 86
71, 86, 90, and 91
45
39
84
79
82
6
1
10, 15, 20, 25
7
10
8
20
20
20
20
20
40/US
8
60/US
9
1
60/US
10
11
MeOH
DCM
1
60/US
1
60/US
Bold values for selected catalyst concentration and its respective yield.
CTAB, cetyltrimethylammonium bromide; p-TSA, p-toluenesulfonic acid; TTAB, tetradecyltrimethylammonium bromide; US,
ultrasonication.
aReaction conditions: Benzaldehyde (1a) (1 mmol), barbituric acid (2) (2 mmol), ammonium acetate (3 mmol).
bIsolated yield.
temperature to 60 °C, the corresponding product (3a) was obtained in 85% yield within 7 h
(Scheme 1).
Considering the significance of ultrasonication as it offers an alternative energy source
for reactions that ordinarily require longer reaction time, we performed the model reaction
using β-CD under ultrasonication, it was observed that the corresponding product was
obtained in 90% yield within 1 h at 60 °C. Here, ultrasonication reduces the reaction time
from 7 to 1 h. Ultrasound accelerates reaction rates by facilitating mass transfer in the
microenvironment, through the process of acoustic cavitation. Cavitation occurs in an
irradiated liquid, involving bubble formation, growth, and impulsive collapse. The
collapsing bubbles induce high temperature and pressure, in the form of hot spots with
sufficient energy to facilitate chemical reactions.[22] Therefore, all the reactions are carried
under ultrasonication.
Furthermore, effort was made to perform the cyclocondensation using different
cyclodextrins in water under ultrasound irradiation. Based on the screening results in
Table 1, β-CD is the best catalyst among others. Low conversions were observed with either
α- and γ-cyclodextrin. It is clear that α-CD was not a good catalyst because the cavity of
α-CD might be too small and the cavity of γ-CD was too big compared to β-CD. β-CD
has usually one order of degree, higher affinity for the benzene derivatives as compared
to α- and γ-CD. No product formation was detected in the absence of cyclodextrin, which
Scheme 1. Synthesis of 5-(benzyl)-1,3,5,7,9,10-hexahydropyrimido[50,40-5,6]pyridine[2,3-d]pyrimidine-
2,4,6,8-tetraone (3a).

SYNTHETIC COMMUNICATIONS®
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clearly demonstrates the catalytic role of cyclodextrin. Therefore, β-CD was preferred as a
catalyst for this reaction.
To optimize the catalyst, the model reaction was performed at different concentration of
β-CD in water. As catalyst concentration is important factor that exclusively affects the
reaction rate and product yield. To study this, the reaction was performed at different
concentrations of β-CD, i.e., 10, 15, 20, and 25 mol%, and gave the product in 71, 86,
90, and 91% yield, respectively (Table 1). Thus, it is clear that reaction rate was positively
influenced by increasing catalyst concentration up to 10 mol% and then became static
on further increasing the catalyst concentration. It means that the presence of 10 mol%
of β-CD was sufficient for catalyzing the reaction effectively in the forward direction.
Recycling of β-CD
The catalyst recyclability was studied thrice including the use of fresh catalyst for the
synthesis of dipyrimido-dihydropyridine (3a). The catalyst was almost quantitatively recov-
ered and no significant loss in yield was observed (Figure 3). The FTIR spectra of fresh and
recovered β-CD were also measured (Figure 4), and no change was found in the functional
groups as well as the fingerprint region, indicating that no reaction occurs with β-CD.
With this optimized result in hand, we next explored the scope of this reaction. The
efficiency of the catalyst:β-CD was also checked for the coupling of diversely substituted
aryl aldehydes, barbituric acid, and ammonium acetate (Scheme 2). The results (Table 2)
showed that substituted aryl aldehydes containing either electron-donating or electron-
withdrawing groups gave the analogous products in good yields (Table 2).
Having established by these results, we extended this process to other substrates. The
scope of the reactions is illustrated with respect to urea for synthesizing pyrimido[4,5-d]
pyrimidines (4a–g) by using number of aldehydes (1a–g), barbituric acid (2), and urea
(Scheme 3). Under the optimized reaction conditions, we used various aromatic
aldehydes to react with barbituric acid and urea and a series of functionalized pyrimido
[4,5-d]pyrimidine derivatives were synthesized with excellent yields. The results of
reactions are summarized in Table 2. As shown in Table 2, we found that all the reactions
were performed smoothly, and the aromatic aldehydes, with either electron-withdrawing
groups or electron-donating groups, could all be used for the synthesis of functionalized
pyrimido[4,5-d]pyrimidine derivatives with excellent yields.
Figure 3. Reuse and recovery of β-CD and its effect on yield.

6
C. JADHAV ET AL.
Figure 4. FTIR spectra of β-CD before reaction (upper red curve) and third run (lower pink curve).
Plausible reaction mechanism for the synthesis of dipyrimido-dihydropyridines
The process represents a typical cascade of Knoevenagel condensation followed by Michael
addition and cyclization in the cavity of β-CD.[23] Subsequent Michael addition takes
place by sequential addition of ammonium acetate on benzylidine barbiturate resulting
into intermediate, which is also stabilized by H-bonding with the secondary hydroxyl
groups of β-CD.
The rate acceleration of this condensation can be attributed to (1) aqueous β-CD which
provides a unique hydrophobic truncated cone-shaped cavity and hydrophilic outwardly
hydroxyl groups.[23] The aldehydes and barbituric acid might be forming noncovalent revers-
ible supramolecular complexes with β-CD in the cavity, enhancing the localized concentration
of the aldehydes and barbituric acid resulting in the dissolution in aqueous medium. Because
of this, aldehydes become readily available to interact with barbituric acid and (2) the electro-
philic behavior of carbonyl carbon of the aldehydes would have been enhanced because of
intermolecular hydrogen bonding between outwardly hydroxyl groups of β-CD and carbonyl
oxygen of the aldehydes and resulting into benzylidine barbiturate. Then followed by
Scheme 2. General scheme of the synthesis of dihydropyridines (3a–j).

SYNTHETIC COMMUNICATIONS®
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Table 2. Synthesis of 5-(substituted)-1,3,5,7,9,10-hexahydropyrimido[50,40-5,6]pyridine[2,3-d]pyrimidine-2,
4,6,8-tetraones (3a–k) and 5,6-dihydro-5-(substituted phenyl)pyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-
triones (4a–g).a
Melting point (°C)c
Structure of
products
Yieldb
S. no.
1
Substrates
CH3COONH4
(%)
Found
Reported
295–297
90
294–296
2
CH3COONH4
87
>300
>300
3
CH3COONH4
79
>300
>300
4
CH3COONH4
81
300–302
300–301
5
CH3COONH4
80
>300
>300
(Continued)

8
C. JADHAV ET AL.
Table 2. Continued.
Melting point (°C)c
Structure of
products
Yieldb
(%)
S. no.
6
Substrates
CH3COONH4
Found
>300
Reported
>300
84
7
CH3COONH4
72
260–262
261–263
8
CH3COONH4
78
257–258
255–257
9
CH3COONH4
73
287–289
287–288
10
CH3COONH4
84
295–297
293–295
11
CH3COONH4
72
230–232
233–234
(Continued)

SYNTHETIC COMMUNICATIONS®
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Table 2. Continued.
Melting point (°C)c
Structure of
products
Yieldb
(%)
S. no.
12
Substrates
Found
Reported
244–246
89
243–245
13
14
15
16
86
285–286
210–211
276–278
212–214
284–286
210–212
275–277
210–212
81
77
76
(Continued)

10
C. JADHAV ET AL.
Table 2. Continued.
Melting point (°C)c
Structure of
products
Yieldb
(%)
S. no.
17
Substrates
Found
Reported
256–257
82
255–257
18
75
272–274
273–275
aReaction conditions: Substituted aldehydes (1a–k) (1 mmol), (2) barbituric acid (2 mmol), ammonium acetate (2 mmol), or
urea (1 mmol), β-cyclodextrin (20 mol%), at 60–65 °C.
bIsolated yield.
cMelting points, IR, 1H NMR and 13C NMR are in good agreement with those reported in the literature.[10,24]
Scheme 3. Synthesis of pyrimido[4,5-d]pyrimidines (4a–g).
intramolecular cyclization, loss of CO2 molecule and hydrolysis, there is formation of desired
product. After the formation of the product, the escape from the CD cavity occurs readily
(Scheme 4).
Experimental
General
All the chemicals used were of laboratory grade. Melting points of all the synthesized
1
compounds were determined in open capillary tubes and are uncorrected. H NMR and
13C NMR spectra were recorded with a Bruker Avance 400 spectrometer operating at
400 and 100 MHz using DMSO-d6 solvent and tetramethylsilane as the internal standard
and chemical shift in δ ppm. Mass spectra were recorded on a Sciex, Model; API
3000 LC–MS/MS Instrument. The progress of reaction was checked by TLC using
silica gel, 60F254 aluminum sheets as adsorbent and visualization was accomplished by

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Scheme 4. Plausible mechanism for the synthesis of dihydropyridine.
iodine/ultraviolet light. The ultrasonic-assisted reactions were performed in Bandelin
Sonorex (with a frequency of 35 kHz and a nominal power 200 W) ultrasonic bath built
in heating, 30–80 °C thermostatically adjustable. The reaction flask was located in the
cleaner, where the surface of reactants is slightly lower than the level of the water.
All compounds were known and IR, 1H, 13C NMR spectra were found to be identical to
the ones described in the literature.[10,24]
General procedure for the synthesis of 5-(substituted phenyl)-1,3,5,7,9,
10-hexahydropyrimido[50,40-5,6]pyridine[2,3-d]pyrimidine-2,4,6,8-tetraones (3a–k)
A mixture of substituted aldehydes (1a–k) (1 mmol), barbituric acid (2a) (2 mmol), and
ammonium acetate (2 mmol) was added in β-CD (20 mol%) solution containing water.
The resulting mixture was stirred under ultrasonication at 60–65 °C. The progress of the
reaction was monitored by thin-layer chromatography. After 1 h of ultrasound irradiation,
the reaction mixture was cooled to room temperature, filtered, and washed with hot water
to remove β-CD. Dried product was crystalized from ethanol to afford the purified desired
1
product. All synthesized compounds were characterized by IR, H, 13C NMR spectra and
were found to be identical to the ones described in the literature.[10,24]

12
C. JADHAV ET AL.
Spectral data of selected compound
5-(Benzyl)-1,3,5,7,9,10-hexahydropyrimido[50,40-5,6]pyridine[2,3-d]pyrimidine-2,4,6,
8-tetraone (3a)
White solid, yield 90%; mp 294–296 °C; IR (ATR, υ cm−1): 3551 (CONH stretching), 3478
=
(CONH stretching) 3196 (N–H stretching), 2820 (C–H stretching), 1676, 1611 (C O
1
stretching), 1442, 1288, 1031, 861, 799. H NMR (400 MHz, DMSO-d6, ppm): 11.39 (s,
2H, NH), 11.23 (s, 2H, NH), 10.59 (s, 1H, NH), 7.08–7.54 (m, 5H, Ar–H), 5.21 (s, 1H,
pyrimidine).[10,24] 13C NMR (100 MHz, DMSO-d6, ppm): 162.41 (2C), 157.78 (2C),
152.50, 151.51, 149.46, 146.32, 128.67, 123.37 (2C), 118.74 (2C), 87.43, 40.09. Mass (LC–
MS): m/z 326 [MþH]þ. Anal. calcd. for C15H11N5O4: N, 21.53; C, 55.39; H, 3.41. Found:
N, 21.49; C, 55.40; H, 3.47%.
General procedure for the synthesis of pyrimido[4,5-d]pyrimidine (4a–g)
A mixture of aldehyde (1a) (1 mol), barbituric acid (2a) (1 mol), and urea (1 mol) was
added in β-CD (20 mol%) solution containing water. The resulting mixture was stirred
under ultrasonication at 60–65 °C. The progress of the reaction was monitored by
thin-layer chromatography. After 1 h of ultrasound irradiation, the reaction mixture was
cooled to room temperature, filtered, and washed with hot water to remove β-CD. Dried
product was crystallized from ethanol to afford the purified desired product. The rest of the
substrates (4b–g) were prepared by a procedure similar to that for 4a. The known com-
1
pounds (4a–g) were characterized by IR, H, 13C NMR spectra and showed satisfactory
spectroscopic data in agreement with those reported in the literature.[10,24]
Spectral data of selected compound
5,6-Dihydro-5-(benzyl)pyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,8H)-trione (4a)
Off-white solid, yield 89%; mp 243–245 °C; IR (ATR, υ cm−1): 3525 (CONH stretching),
2372 (C–H stretching), 1672, 1623 (C O stretching), 1453, 1227, 1063, 827, 793. 1H
=
NMR (400 MHz, DMSO-d6, ppm): 11.28 (s, 1H, NH), 11.25 (s, 1H, NH), 8.39 (s, 1H,
NH), 7.23–7.35 (m, 5H, A-H), 5.47 (s, 1H).[10,24] 13C NMR (100 MHz, DMSO-d6, ppm):
163.69, 157.24, 154.57, 143.35, 138.75, 128.23 (2C), 127.41 (2C), 124.13, 90.71, 47.28. Mass
(LC–MS): m/z 259 [MþH]þ. Anal. calcd. for C12H10N4O3: N: 21.70; C: 55.81; H: 3.90.
Found: N, 21.69; C, 55.85, H: 3.90%.
Conclusion
In conclusion, an efficient method has been developed for the synthesis of biologically
relevant dipyrimido-dihydropyridines (3a–k) and pyrimido[4,5-d]pyrimidine (4a–g)
derivatives using β-CD as a catalyst in aqueous medium. The operational simplicity,
mild reaction conditions, short reaction time, high yields (72–90%), and environmental
friendliness are the notable features of this procedure. Indeed, a wide range of aldehydes
were converted to the corresponding known dipyrimido-dihydropyridines (3a–k) and
pyrimido[4,5-d]pyrimidine (4a–g) in aqueous β-CD.
Acknowledgments
The authors are thankful to Professor Ramrao A. Mane for his invaluable discussions and guidance.
The authors are also thankful to the Department of Chemistry, Dr. Babasaheb Ambedkar

SYNTHETIC COMMUNICATIONS®
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Marathwada University, Aurangabad and Central Drug Research Institute (CDRI), Lucknow for
providing necessary facilities and spectral analysis, respectively.
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