Heteropoly acid supported on activated natural clay-catalyzed synthesis of 3,4-dihydropyrimidinones/thiones through Biginelli reaction under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2017.1396614

Dihydropyrimidinones/thiones (DHPM’s) have been prepared by one-pot condensation of methyl acetoacetate, aldehydes, urea/thiourea in the presence of heteropoly-11-tungsto-1-vanadophosphoric acid, H₄[PVW₁₁O₄₀] · 32H₂

Full text of DOI:10.1080/00397911.2017.1396614

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
Heteropoly acid supported on activated
natural clay-catalyzed synthesis of 3,4-
dihydropyrimidinones/thiones through Biginelli
reaction under solvent-free conditions
Karuppaiah Selvakumar, Thangamariyappan Shanmugaprabha, Murugan
Kumaresan & Ponnusamy Sami
To cite this article: Karuppaiah Selvakumar, Thangamariyappan Shanmugaprabha, Murugan
Kumaresan & Ponnusamy Sami (2017): Heteropoly acid supported on activated natural clay-
catalyzed synthesis of 3,4-dihydropyrimidinones/thiones through Biginelli reaction under solvent-
free conditions, Synthetic Communications, DOI: 10.1080/00397911.2017.1396614
To link to this article: https://doi.org/10.1080/00397911.2017.1396614
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Date: 01 January 2018, At: 05:24

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1396614
Heteropoly acid supported on activated natural clay-catalyzed
synthesis of 3,4-dihydropyrimidinones/thiones through
Biginelli reaction under solvent-free conditions
Karuppaiah Selvakumar, Thangamariyappan Shanmugaprabha, Murugan Kumaresan,
and Ponnusamy Sami
Department of Chemistry, V.H.N. Senthikumara Nadar College (Autonomous), Virudhunagar, India
ABSTRACT
ARTICLE HISTORY
Dihydropyrimidinones/thiones (DHPM’s) have been prepared by
one-pot condensation of methyl acetoacetate, aldehydes, urea/
thiourea in the presence of heteropoly-11-tungsto-1-vanadopho-
Received 24 August 2017
KEYWORDS
3
,4-Dihydropyrimidinones/
sphoric acid, H [PVW O ] · 32H O, (HPV) supported on activated
4
11 40
2
thiones; heteropoly acid;
multi-component synthesis;
natural clay
natural clay (HPVAC) under solvent-free reaction condition have been
proposed. The DHPM derivatives were identified through elemental
analysis and melting point measurements and characterized by FT-IR,
1
13
H-NMR, C-NMR spectroscopic methods.
GRAPHICAL ABSTRACT
Introduction
The Biginelli reaction is a one-pot three component reaction invented by Biginelli in
[
1]
1
893. This reaction involves the cyclocondensation of an aldehyde, β-ketoester, and
urea or thiourea using acidic catalysts to yield 3,4-dihydropyrimidin-2(1H)-ones/3,
-dihydropyrimidin-2(1H)-thiones (DHPMs). DHPMs are generally referred to as Biginelli
4
[
2]
compounds. Aryl substituted DHPMs and their derivatives have been receiving much
CONTACT Ponnusamy Sami
samirishi2614@gmail.com
Department of Chemistry, V.H.N. Senthikumara Nadar
College (Autonomous), Virudhunagar 626 001, 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
K. SELVAKUMAR ET AL.
attention in recent years due to their applications in the field of drugs and pharmaceuticals.
They exhibit a wide range of biological activities and are extensively used in pharmaceutical
as calcium channel blockers, antihypertensive, antibacterial, antitumor, anti-inflammatory,
and anti-cancer agents.[3,4]
In 1930, wool protection activity of Biginelli compounds was patented for the protection
[
2]
of wool against moths. Moreover, the dihydropyrimidine scaffold is a key component in
several alkaloids with marine sources, which also have interesting biological properties.
Most notably among these are the batzelladine alkaloids, which are inhibitors for the
[
5]
binding of HIV gp-120 to CD4 cells for the treatment of AIDS. These compounds have
[
6]
been becoming very interesting due to their wide spectrum of biological activities and
used as a starting point to prepare complex heterocyclic scaffolds with pharmacological
[
7]
properties.
Many synthetic methods for the synthesis of this heterocyclic scaffold are now
available. Recently, the synthesis of DHPM’s is the direct condensation reaction of
methyl acetoacetate, aldehydes, and urea/thiourea using catalysts such as PS-PEG-
SO H, AlKIT-5, ZnO, Al-M41, Sn(HPO ) · H O, Fe O @mesoporous SBA-15,
3
4 2
2
3
4
[
VSim][HSO ], pyridiniumtriflate, CuO-CeO , iodine, cellulose sulfuric acid, PPF-
4 2
SO H, PDAG-Co, citric acid, [PyPS] PW O , Fe O @SiO -imid-H [PMo O ],
3
3
12 40
3
4
2
3
12 40
Nafion-Ga, phytic acid, Cu@PMO-IL, zeolite-ZSM-5, Fe@SBIL-BPMO, NFS‐PRS,
[
Btto][p-TSA], aluminatesulfonic acid, SiO -BaCl , NH SCN, zirconia sulfuric acid,
2
2
4
[
8–36]
d-xylonic acid, and Ga(OTf)3.
Despite of the successful methods discussed above, unfortunately, many of these
catalysts suffer from one or more limitations, such as long reaction times, low yields,
occurrence of several side reactions, drastic reaction conditions and tedious workup
procedure. Some of the catalysts are expensive, complex or unavailable and in some of
the reaction organic solvents are also used. With the increase of environmental
consciousness in chemical research and industry, the solvent-free Biginelli reaction
has attracted much attention recently. These factors stimulate us to search for a better
catalyst, which has to show a higher activity for the synthesis of DHPMs under mild
reaction conditions. Recently the catalytic application of heteropoly-11-tungsto-
1
-vanadophosphoric acid, H [PVW O ].32H O, (HPV) supported on activated
4 11 40 2
0
natural clay (HPVAC) toward the synthesis of bis(indolyl)methanes, N,N -alkylidene
[
37,38]
bisamides and imidazoles have been reported.
In continuation of this work a
green route for the preparation of 3,4-dihydropyrimidin-2(1H)-ones and 3,4-dihydropyr-
imidin-2(1H)-thiones using HPVAC as a mild and reusable catalyst is reported in
this paper.
Results and discussion
Effect of catalysts
The condensation of methyl acetoacetate, benzaldehyde with thiourea in the presence of
catalysts was chosen as a model reaction to study the effectiveness of the catalysts chosen
for the present study. The effectiveness of the catalyst was evaluated with the aid of
percentage yield of the products. The results on the screening of catalysis are given in
Table 1. Among the different catalysts used, HPVAC produced high yield of 86%. This
optimization study tempted us to investigate on HPVAC with different loadings of HPV.

SYNTHETIC COMMUNICATIONS®
3
a
Table 1. Catalyst screening for the synthesis of 3,4-dihydropyrimidin-2(1H)-thione.
b
Run
Catalyst
Catalyst amount (g)
Yield (%)
1
2
3
4
5
6
7
Activated natural clay (AC)
0.05
0.03
0.03
0.03
0.05
0.05
0.05
48
60
63
66
75
86
87
H
H
H
3
4
5
[PW12
[PVW11
[PV
O
40
40
40
]
O
10
]
2
W
O
]
10% H
10% H
10% H
3
4
5
[PW12O
40]/AC
40]/AC
40]/AC
[PVW11
O
[PV
2
W
10
O
a
b
Reaction conditions: methyl acetoacetate (1 mmol), benzaldehyde (1 mmol), thiourea (1.25 mmol), solvent-free condition,
20 °C, 1.5 h.
Isolated yields.
1
Effect of HPV loadings
The dependency of amount of loading of HPV on the catalytic activity of HPVAC was also
investigated. The efficiency of the HPVAC-10, 20, and 30 was evaluated for the
condensation reaction of methyl acetoacetate, benzaldehyde with thiourea in terms of
the percentage yield of product. The HPVAC-20 showed higher efficiency compared to
that of HPVAC-10 and comparable efficiency with that of HPVAC-30. Hence HPVAC-20
has been optimized as the catalyst to perform the transformation (Table 2).
Effect of solvents
The title reaction was tried in several solvent media such as toluene, dichloromethane,
1
,2-dichloroethane, ethyleneglycol, dimethylsulfoxide, and dimethylforamide and the
results are given in Table 3. The results reveal that toluene is found to be the best solvent
among all the solvents. The yield of the reaction under solvent free condition is found to be
a
Table 2. Effect of catalyst loading in the synthesis of 3,4-dihydropyrimidin-2(1H)-thione.
b
Run
Catalyst
Catalyst amount (g)
Yield (%)
1
2
3
HPVAC-10
HPVAC-20
HPVAC-30
0.05
0.05
0.05
86
91
92
a
b
Reaction conditions: methyl acetoacetate (1 mmol), benzaldehyde (1 mmol), thiourea (1.25 mmol), solvent-free condition,
20 °C, 1.5 h.
Isolated yields.
1
Table 3. Effect of solvents on the reaction of methyl acetoacetate, benzaldehyde, thiourea catalyzed
a
by HPVAC-20.
b
Run
Solvent
Time (h)
Yield (%)
1
2
3
4
5
Dichloromethane
1,2-Dichloroethane
Toluene
Ethylene glycol
Dimethyl sulfoxide
Solvent free condition
5
5
60
68
75
62
61
91
5
5
5
1.5
c
c
6
a
Reaction conditions: methyl acetoacetate (1 mmol), benzaldehyde (1 mmol), thiourea (1.25 mmol), HPVAC-20 (0.05 g),
solvent (5 mL), reflux.
Isolated yield.
b
c
1
20 °C.

4
K. SELVAKUMAR ET AL.
a
Table 4. Effect of reusability of HPVAC-20 catalyst on the 3,4-dihydropyrimidin-2(1H)-thione yield.
b
Run
Cycle
Amount of catalyst (g)
Percentage of loss of catalyst (%)
Yield (%)
1
2
3
4
0
1
2
3
0.050
0.048
0.046
0.043
–
4
91
89
88
87
8
14
a
b
Reaction conditions: methyl acetoacetate (1 mmol), benzaldehyde (1 mmol), thiourea (1.25 mmol), HPVAC-20 (0.05 g),
solvent free, 120 °C, 1.5 h.
Isolated yield.
higher than all the other media. It is also interesting to note that the reaction time is
reduced from 5 to 1.5 h under solvent free condition.
Reusability of the catalyst
The reusability of the catalyst was evaluated for HPVAC-20 catalyst, by separating the solid
from the reaction mixture by simple filtration, washing with hot ethanol and drying in air
oven at 120 °C for 3 h prior to reuse in subsequent reactions. Each time a loss of 4% of the
catalyst has been found and the final loss of catalyst after its fourth consecutive usage was
found to be 14%. No significant loss in the product yield was observed for about four times
of its reuse (Table 4).
With the aid of the above experiments the best reaction condition for the title reaction is
achieved using HPVAC-20 as catalyst. Using this procedure, different kinds of aromatic
aldehydes were condensed with methyl acetoacetate and urea/thiourea to produce the
corresponding 3,4-dihydropyrimidin-2-(1H)-ones/thiones at 120 °C under solvent free
conditions (Scheme 1). Aromatic aldehyde with different functional groups was subjected
to the condensation reaction and the corresponding products were obtained in good
quantitative yields. In this manner 14 derivatives were prepared and the results in terms
of reaction time and percentage of yield are given in Table 5. The functional groups in
the aromatic ring of the aldehyde influence the yield of the reaction as well as the reaction
Scheme 1. Synthesis of 3,4-dihydropyrimidin-2(1H)-one/thione derivatives.

SYNTHETIC COMMUNICATIONS®
5
Table 5. The condensation reaction of methyl acetoacetate, aldehydes and urea/thiourea over HPVAC-
a
20 by conventional heating.
Substrates
Aldehyde
b
Entry
Benzil
Urea/thiourea
Product
Time (h) Yield (%)
4a
1.5
93
4
4
4
b
1
97
c
3
88
d
2
92
4
4
e
2
3
90
88
f
(Continued)

6
K. SELVAKUMAR ET AL.
Table 5. Continued.
Substrates
Aldehyde
b
Entry
Benzil
Urea/thiourea
Product
Time (h) Yield (%)
4g
1.5
91
4h
1
94
4i
3
87
4j
2
90
4
4
k
2
2
89
87
l
(Continued)

SYNTHETIC COMMUNICATIONS®
7
Table 5. Continued.
Substrates
Aldehyde
CH CH CHO
b
Entry
Benzil
Urea/thiourea
Product
Time (h) Yield (%)
4m
3
2
3
84
4n
3
86
a
b
Reaction conditions: methyl acetoacetate (1 mmol), aldehyde (1 mmol), and urea/thiourea (1.25 mmol), HPVAC-20 (0.05 g),
solvent free, 120 °C.
Isolated yields.
Scheme 2. A plausible reaction mechanism for the synthesis of 3,4-dihydropyrimidin-2(1H)-one/thione
using HPVAC catalyst.
Table 6. Comparative account of catalytic ability of HPVAC-20 with other catalysts toward the
synthesis of 3,4-dihydropyrimidin-2(1H)-thione.
S. no.
Catalysts
Amount (g)
Condition
Reaction time Yield (%) Reference
1
2
3
4
5
6
AlKIT-5
0.15
0.25
0.1
0.20
0.01
0.05
CH
3
CN solvent and reflux
4 h
82
75
95
94
85
91
[9]
[20]
PPF-SO
Iodine
3
H
Ethanol solvent and reflux
Microwave (600 W, 60 °C) solvent free
Microwave (120 °C) solvent free
Solvent free (100 °C)
8 h
15 min
10 min
30 min
1.5 h
[18]
[PyPS]
3
PW12
O
40
[23]
[26]
This work
Phytic acid
HPVAC-20
Solvent free (120 °C)

8
K. SELVAKUMAR ET AL.
time. The electron withdrawing groups in the aldehyde increase the product yield and
reduce the reaction time in comparison with electron donating functional groups.
The plausible mechanism for the title reaction has been proposed and is given in Scheme 2.
A comparative account of efficiency of HPVAC-20 with other reported catalysts for the
synthesis of 3,4-dihydropyrimidin-2(1H)-thione namely methyl 4-(phenyl)-6-methyl-2-
thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate was given in Table 6. The data clearly
ascertain the versatility of the present protocol using HPVAC-20 as catalyst over the other
catalysts.
Experimental
Materials and methods
All commercially available chemicals were obtained from Sigma Aldrich and used without
further purification. A series of HPV supported activated natural clay catalysts (HPVAC)
were prepared by varying the loading amount of HPV viz. 10, 20, and 30% (w/w) on to the
activated natural clay and characterized by the literature procedure recently published from
[
37]
this laboratory.
Melting points were measured on an electro-thermal melting point apparatus. FT-IR
spectra were recorded using Shimadzu IR Affinity-1 FT-IR spectrophotometer as KBr
1
13
discs. H and C-NMR spectra were recorded by Bruker 300 and 100 MHz NMR
instrument with DMSO-d as solvent and TMS as internal reference. Elemental analyses
6
were performed on Elementar Vario EL III equipment.
General method for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones
The catalytic activity of HPVAC toward the condensation reaction of methyl acetoacetate,
aldehyde and urea / thiourea to form the 3,4-dihydropyrimidin-2(1H)-ones/thiones was
established under solvent free condition. In a typical procedure methyl acetoacetate
(
1 mmol), aldehyde (1 mmol), urea/thiourea (1.25 mmol), and HPVAC-20 (0.05 g) were
mixed and the mixture was heated in an oil bath at 120 °C for appropriate time. Progress
of the reaction was monitored by TLC (ethylacetate/petroleum ether, 3:7). After
completion of the reaction, hot ethanol (15 mL) was added and the catalyst was separated
by filtration. The filtrate was poured into crushed ice with stirring. The crude product thus
obtained was filtered and washed with cold water (20 mL). The product was recrystallized
from 95% ethanol. Finally the pure products of 3,4-dihydropyrimidin-2(1H)-one/thione
derivatives (4a–n) were also identified by melting point measurement and elemental
1
13
analysis. Further the derivatives were characterized by FT-IR, H-NMR, and C-NMR
spectroscopic methods. The general pattern of the reaction is depicted in Scheme 1.
Conclusion
In conclusion, the efficient synthesis of 3,4-dihydropyrimidin-2(1H)-one/thione derivatives
was achieved by the condensation reaction of various aromatic aldehydes, methyl
acetoacetate and urea/thiourea using HPVAC-20 as a heterogeneous catalyst under solvent
free conditions at 120 °C for 1–3 h. This protocol can be considered as a green catalytic
system for the synthesis of 3,4-dihydropyrimidin-2(1H)-one/thione derivatives. On the
other hand, the catalyst can be reused for about four times without significant loss of its

SYNTHETIC COMMUNICATIONS®
9
catalytic activity. Organic derivatives were identified by melting point measurements
1
and through elemental (CHNS) analysis and characterized by FT-IR, H-NMR, and
1
3
C-NMR spectroscopic methods.
Funding
The authors Ponnusamy Sami and Karuppaiah Selvakumar thank University Grants Commission,
New Delhi, India, for the award of major research project (F. No. 42-349/2013(SR)) and financial
assistance. We also thank Managing Board, VHNSN College, Virudhunagar for infrastructural
facilities.
References
[
[
[
[
[
1] Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416.
2] Suresh, S.; Sandhu, J. S. Arkivoc 2012, 1, 66–133.
3] Ashok, M.; Holla, B. S.; Kumari, N. S. Eur. J. Med. Chem. 2007, 42, 380–385.
4] Nofal, Z. M.; Fahmy, H. H.; Zarea, E. S.; El-Eraky, W. Acta Pol. Pharm. 2011, 68, 507–517.
5] Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; Debrossi, C.; Mai, S.;
Truneh, A.; Faulkner, D. J.; Carte, B.; et al. J. Org. Chem. 1995, 60, 1182–1188.
6] Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.; O’Reilly,
B. C. J. Med. Chem. 1991, 34, 806–811.
[
[7] Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052.
[8] Quan, Z.-J.; Da, Y.-X.; Zhang, Z.; Wang, X.-C. Catal. Commun. 2009, 10, 1146–1148.
[9] Shobha, D.; Chari, M. A.; Mano, A.; Selvan, S. T.; Mukkanti, K.; Vinu, A. Tetrahedron 2009, 65,
1
0608–10611.
[
[
[
[
[
[
[
[
[
10] Bahrami, K.; Khodaei, M. M.; Farrokhi, A. Synth. Commun. 2009, 39, 1801–1808.
11] Murata, H.; Ishitani, H.; Iwamoto, M. Org. Biomol. Chem. 2010, 8, 1202–1211.
12] Hazarika, P.; Gogoi, P.; Hatibaruah, S.; Konwar, D. Green Chem. Lett. Rev. 2011, 4(4), 327–339.
13] Mondal, J.; Sen, T.; Bhaumik, A. Dalton Trans. 2012, 41, 6173–6181.
14] Pourjavadi, A.; Hosseini, S. H.; Soleyman, R. J. Mol. Catal. A Chem. 2012, 365, 55–59.
15] Raju, C.; Kalaipriya, M.; Uma, R.; Sridhar, R.; Ramakrishna, S. Curr. Chem. Lett. 2012, 1, 27–34.
16] Albadia, J.; Mansournezhad, A. Iran. J. Catal. 2013, 3(2), 73–79.
17] Liu, Q.; Pan, N.; Xu, J.; Zhang, W.; Kong, F. Synth. Commun. 2013, 43, 139–146.
18] Rajack, A.; Yuvaraju, K.; Praveen, C.; Murthy, Y. L. N. J. Mol. Catal. A Chem. 2013, 370,
1
97–204.
[
19] Shi, X.-L.; Yang, H.; Tao, M.; Zhang, W. RSC Adv. 2013, 3, 3939–3945.
[
20] Shockravi, A.; Kamali, M.; Sharifi, N.; Nategholeslam, M.; Moghanlo, S. P. Synth. Commun.
2
013, 43, 1477–1483.
[
[
21] Ghorbani-Choghamarani, A.; Taghipour, T.; Azadi, G. J. Chin. Chem. Soc. 2013, 60, 1202–1206.
22] Fu, R.; Yang, Y.; Lai, W.; Ma, Y.; Chen, Z.; Zhou, J.; Chai, W.; Wang, Q.; Yuan, R. Synth.
Commun. 2015, 45(4), 467–477.
[
[
23] Javidi, J.; Esmaeilpour, M.; Dodeji, F. N. RSC Adv. 2015, 5, 308–315.
24] Surya Prakash, G. K.; Lau, H.; Panja, C.; Bychinskaya, I.; Ganesh, S. K.; Zaro, B.; Mathew, T.;
Olah, G. A. Catal. Lett. 2014, 144(12), 2012–2020.
[
[
25] Zhang, Q.; Wang, X.; Li, Z.; Wu, W.; Liu, J.; Wu, H.; Cui, S.; Guo, K. RSC Adv. 2014,
4, 19710–19715.
26] Elhamifar, D.; Hosseinpoor, F.; Karimi, B.; Hajati, S. Micropor. Mesopor. Mat. 2015,
204, 269–275.
[
[
[
27] Bajaj, S. D.; Mahodaya, O. A.; Tekade, P. V. Pharm. Chem. J. 2015, 48(10), 681–684.
28] Elhamifar, D.; Nazari, E. Chem. Plus. Chem. 2015, 80(5), 820–826.
29] Eshghi, H.; Javid, A.; Khojastehnezhad, A.; Moeinpour, F.; Bamoharram, F. F.; Bakavoli, M.;
Mirzaei, M. Chinese J. Catal. 2015, 36, 299–307.
[
30] Zhang, Y.; Wang, B.; Zhang, X.; Huang, J.; Liu, C. Molecules 2015, 20, 3811–3820.

1
0
K. SELVAKUMAR ET AL.
[
[
[
[
31] Nasr-Esfahani, M.; Taei, M. RSC Adv. 2015, 5, 44978–44989.
32] Hatamjafari, F. J. Appl. Chem. Res., 2015, 9(1), 95–101.
33] Khatri, C. K.; Potadar, S. M.; Chaturbhuj, G. U. Tetrahedron Lett. 2017, 58(18), 1778–1780.
34] Hosseini, M. M.; Kolvari, E.; Koukabi, N.; Ziyaei, M.; Zolfigol, M. A. Catal. Lett. 2016, 146(6),
1
040–1049.
[
[
[
35] Ma, J.; Zhong, L.; Peng, X.; Sun, R. Green Chem. 2016, 18, 1738–1750.
36] Jingiing, X.; Kehua, Z. Heterocycles 2015, 91, 105–112.
37] Selvakumar, K.; Shanmugaprabha, T.; Annapoorani, R.; Sami, P. Synth. Commun. 2017, 47(9),
9
13–927.
[
38] Selvakumar, K.; Shanmugaprabha, T.; Kumaresan, M.; Sami, P. Synth. Commun. 2017,
47, 2115–2126. DOI: 10.1080/00397911.2017.1366524