Room temperature synthesis of 3,4-dihydropyrimidin-2(1H)-one using apatite like oxyphosphate

Article abstract of DOI:10.1080/24701556.2017.1284088

An oxyphosphate of formula BiCa₄(PO₄)₃O was prepared and characterized by powder XRD, Fourier transform infrared spectroscopy (FTIR), and SEM-EDAX techniques. The catalytic activity of the synthesized compound was explored

Full text of DOI:10.1080/24701556.2017.1284088

Inorganic and Nano-Metal Chemistry
ISSN: 2470-1556 (Print) 2470-1564 (Online) Journal homepage: http://www.tandfonline.com/loi/lsrt21
Room temperature synthesis of 3, 4 –
Dihydropyrimidin-2(1H)-one using Apatite like
oxyphosphate
S. Sumathi & G. Buvaneswari
To cite this article: S. Sumathi & G. Buvaneswari (2017): Room temperature synthesis of 3, 4 –
Dihydropyrimidin-2(1H)-one using Apatite like oxyphosphate, Inorganic and Nano-Metal Chemistry,
DOI: 10.1080/24701556.2017.1284088
To link to this article: http://dx.doi.org/10.1080/24701556.2017.1284088
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Room temperature synthesis of 3, 4 - Dihydropyrimidin-2(1H)-one using Apatite like
oxyphosphate
S. Sumathi* and G. Buvaneswari
Department of Chemistry, School of Advanced Sciences
VIT University, Vellore-632014, Tamilnadu, India.
*Corresponding author: sumathishanmugam2003@gmail.com
Abstract
An oxyphosphate of formula BiCa4(PO4)3O was prepared and characterized by powder
XRD, FTIR, and SEM-EDAX techniques. The catalytic activity of the synthesized compound
was explored in the preparation of 3,4-dihydropyrimidin-2(1H)-one using Biginelli reaction.
Influence of parameters such as temperature and solvent on this reaction using this
heterogeneous catalyst was studied. A higher yield of 98% of the 3,4-dihydropyrimidin-2(1H)-
one was achieved within 120 min of duration at room temperature in the presence of acetic acid
(AcOH).
Keywords: Biginelli reaction, Phosphates, 3,4 dihydropyrimidin-2(1H)-one, Acetic acid,
oxyphosphate.
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Introduction
Multicomponent reactions are important with respect to synthetic organic chemistry,
because the desired product can be achieved in one pot using three or more components.
Biginelli[1] reported a multicomponent reaction in the year 1893 for the synthesis of 3,4-
dihydropyrimidin-2(1H)-one (DHPM) via the cyclic condensation of benzaldehyde, ethyl
acetoacetate, and urea under acidic conditions. 3,4- dihydropyrimidin-2(1H)-ones have attracted
the attention of the researchers because of its pharmacological activities such as antiviral,
antitumor, antibacterial, anti-inflammatory actions[2-5]. A bioactive alkaloid such as batzelladine
B containing this DHPM moiety isolated from marine source is found to inhibit the binding of
the HIV gp – 120 to CD4 cells, so it brings out a new field towards the development of AIDS
therapy[6]. Therefore this heterocyclic moiety has attracted the attention of many organic
chemists. It is observed that generally, the experimental procedure reported for the Biginelli
reaction involves the use of mineral acids, organic solvents and high temperature.
From the viewpoint of the potential applications of 3, 4-dihydropyrimidine-2(1H)-ones it
is necessary to find out a versatile, simple and eco-friendly process. In recent times, Biginelli
reaction with modified experimental conditions has been reported. Modifications have been
made with respect to catalysts, solvents and temperature. Several improved procedures have been
reported using Lewis acids and other heteropolyacids[7-13] as well as protic acids as promoters.
Many other methods including, microwave radiations, ultrasonic, clay, ionic liquids and catalyst
free procedures also reported[14, 15]. Recently kaolin[16], bronsted acidic ionic liquid based
magnetic nanoparticle[17] have been reported. However, some of the newer reported methods also
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suffer from drawbacks such as low yield, high temperature, cumbersome product isolation
procedures, expensive catalysts and environmental pollution. Among the phosphates, natural
phosphates[18], diammonium hydrogen phosphate[19], ammonium dihydrogen phosphate[20]
,
hydroxyapatite[21] and fluorapatite[22] alone or doped with metal halides reported as catalysts in
the Biginelli reaction. Modified apatite are found to be a better catalyst in this condensation
reaction than that of hydroxyapatite or fluorapatite.
Bismuth has an electronic configuration of [Xe]4f145d106s26p3, and due to the weak
shielding of the 4f electrons (Lanthanide contraction), bismuth(III) compounds exhibit Lewis
acidity[23]. Recently, bismuth compounds have emerged as efficient Lewis acids due to their
relatively low toxicity[24]. Some of the bismuth compounds such as bismuth triflate[25], bismuth
chloride[26], bismuth subnitrate[27] and bismuth nitrate[28] were reported in the Biginelli reaction.
Lewis acidic nature of the bismuth is utilized in many organic transformations. This kind of
bismuth substituted oxyphosphate is not studied for any kind of organic transformations. Acidic
nature of phosphate and bismuth drive us to for organic transformation. In view of the
importance of Biginelli reaction products, current study is attempted to investigate the catalytic
activity of hitherto unexplored apatite phosphates of the formula BiCa4(PO4)3O (BCPO) – an
oxyphosphate for the first time in the Biginelli condensation reaction.
Experimental
Preparation of the catalyst
Oxyapatite of the formula - BiCa4(PO4)3O, was prepared by high temperature solid state
method[29] using stoichiometric quantities of Bi2O3 (CDH, 99 %), CaCO3 (S.d fine. 99.9 %),
NH4H2PO4 (S.d. fine L.R). A thoroughly ground reactants were heated at 300o C for 6 h, 700o C
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for 12 h, 950o C for 24 h, 1050o C for 24 h with intermittent grinding. The compound was
characterized by powder X- ray diffraction (D8 Advance, Bruker) with CuKα radiation in the 2
range 10 -70o at room temperature, Fourier Transform Infrared spectroscopy (FT-IR)
(Thermonicolet Avator 330 USA model), Scanning Electron microscopy (F E I Quanta FEG
200).
General procedure for the preparation of 3,4-dihydropyrimidin-2(1H)-one
Biginelli reaction was carried out using a mixture of 10 mmol of ethyl acetoacetate, 10
mmol of benzaldehyde and 10 mmol of urea with 1.0 g of BCPO at room temperature (Acetic
acid solvent). After the completion of the reaction (monitored by Thin layer chromatography),
the catalyst was separated from the reaction mixture by filtration and the liquid part was poured
into water. The solid product obtained was filtered and dried. The crude product was purified by
recrystallization in ethanol. The products were characterized by melting point, FT-IR, Proton
nuclear magnetic resonance (1H NMR) and High resolution Mass spectroscopy (HR-Mass).
Results and Discussion
Catalyst Characterization
Powder X-ray diffraction analysis indicates the formation of highly crystalline and
completely pure (Fig. 1) phase without any impurities. XRD pattern indexed based on JCPDS
(52-1880). FT-IR confirms the formation of apatite phosphates[29, 31]. The peaks at 1042 and 971
3-
cm-1 are attributed to the asymmetric stretching vibrations for PO4 . The peaks ate 935 cm-1 and
3-
559-602 cm-1 corresponds to the symmetric stretching and bending vibrations of PO4
respectively (Fig. 2). SEM analysis exhibits the formation of homogeneous products. The
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morphology displays the formation of diffused particles. EDAX analysis confirms the presence
of bismuth, calcium, in the oxyapatite compound (Fig. 3).
Catalytic activity of BiCa4(PO4)3O
Best results are achieved with 1 g of the catalyst at room temperature (Scheme 1) and
0.25 g of the catalyst under reflux condition (Table 1) without any solvent. Larger amount of the
catalyst does not improve the yield. Effect of the solvents is studied both at room temperature
and reflux condition. Among the solvents studied, acetic acid results in high % yield both at
room temperature (98%) and under reflux condition (98%) (Table 2). The contribution of acetic
acid is checked by carrying out the reaction in the absence of the catalyst. The yield of the
product is found to be 69 % (at room temperature (2 h)). This confirms the catalytic efficiency of
BCPO toward this reaction. Acetic acid- a Bronsted acid reflects its efficiency as an additive in
the Biginelli reaction[32]
.
Oxyphosphate is noted to show a better activity. The derivatives of Biginelli products are
synthesized by varying the aldehydic part in benzaldehyde using the optimized reaction
condition (Catalyst –BCPO, amount - 1 g; Solvent – acetic acid; room temperature reaction).
Even though, the same percentage of yield is observed with acetic acid as solvent both at room
temperature and at reflux condition, room temperature condition is chosen for the derivatives
because of its operational simplicity and low energy consumption. Irrespective of the substituent
in aromatic aldehydes moderate to good yields are obtained (Table 3). The products are
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confirmed by FTIR, 1H NMR and HR mass spectroscopy and the spectral data of the derivatives
are given in Table 5.
The recovered catalyst was washed with ethanol and dried at 80oC. The reusability of the
recovered catalyst was checked for the model reaction with acetic acid at room temperature (upto
3 cycles) (Table 3). The yields of the product are comparable with the first cycle. It shows the
efficiency of the oxyapatite catalyst towards this reaction.
The activity of the current catalyst is compared with other catalysts where acetic acid and
toluene is used as solvent. The details are summarized in the table mentioned below (Table 4).
Considering the similar size of the ions Ca2+ and Bi3+ [39], replacement of Ca2+ by Bi3+ introduces
a highly charged ion into the lattice thus enhancing the acidic character [40]. The activity of this
catalyst could be due to the enhanced acidic nature of the compound by bismuth substitution
because the surface area of the synthesized compound is found to be meager (SA = 0.2381 m2 g-
1). Most of the heterogeneously catalyzed Biginelli condensation reactions are reported at higher
temperature [41, 42]. But the current system (BCPO) gives 98 % of the product within 120 min of
duration at room temperature
[43]
Ramalinga et al
proposed the mechanism for the bismuth type of compounds where
the formation of acyl imine intermediate is stabilized by bismuth. Acyl imine intermediate is the
rate determining step for the biginelli condensation. But still the mechanism for this type of
bismuth compound is underway. In the case of oxyapatite, an enhanced activity is observed
towards both the electron withdrawing and electron releasing substituents (Table 3). From the
results it is concluded that the substituted apatite like oxyphosphate compound is suitable
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catalyst for the preparation of 3, 4-dihydropyrimidin-2(1H)-one and its derivatives at room
temperature.
Conclusions
In conclusion, it is noted that Bi3+ ions substitution in hydroxyapatite and O in OH site
modifies the surface chemistry and thus enhances the catalytic activity. Bismuth substituted
oxyapatite BiCa4(PO4)3O has proved to be an effective catalyst. An excellent yield of 98 % is
obtained at room temperature within 120 min of duration with simple experimental procedure
compared with other phosphate catalysts.
Acknowledgement
1
The authors thank SAIF, Department of chemistry, IITM for SEM-EDAX, H NMR and
HR-Mass spectroscopy. We also thank TBI and Powder XRD lab VIT University, Vellore.
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Table 1 Optimization of experimental condition with respect to catalyst amount
Amount of the Catalyst
catalyst (g)
Room
temperature
%Yield Reflux condition %Yield (Time/min)
(Time/min)
2.0 (3 mmol)
25(85)
81(40)
78(45)
62(30)
83(75)
1.0 (1.5 mmol)
0.5 (0.75 mmol)
47(55)
34(60)
0.25 (0.37 mmol) 35(70)
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Table 2 Optimization of experimental condition with respect to solvent
Solvent
Catalyst
Room temperature
(Time/h)
%
Yield Reflux condition % Yield (Time/h)
Acetic acid
Acetonitrile
Ethanol
98(2)
98(0.45)
20(2)
42(2)
4(3)
81(6.5)
14(2.45)
22(12)
40(3)
n-hexane
Chloroform
Toluene
11(2)
11(14)
7(11)
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Table 3 BiCa4(PO4)3O catalyzed synthesis of different dihydropyrimidinones
Substituents attached to
benzaldehyde
Yield (%)
Time (h)
Melting point (Mp) (°C)
Found Reported
Nil (benzaldehyde) (4a)
3,4-dimethoxy (4b)
4- methoxy (4c)
4-methyl (4d)
98, 93a, 90b
2
202-204
176-178
202-204
216-218
212-214
182-184
172-174
198-200 [33]
175-177 [34]
201-202 [33]
213-216 [33]
209-212 [34]
182-184 [34]
174-176 [35]
87
80
86
69
52
56
7
7
6
4-chloro (4e)
18
6
4-fluoro (4g)
4-ethyl (4h)
9
Note: a, b – second and third runs
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Table 4 Comparison with other reported catalysts
Catalyst
NaH2PO4
KH2PO4
Time
Temperature Solvent
% yield
Acetic acid 66
Acetic acid 89
Ref
20-40 min
20-40 min
20-40 min
0.5 – 2 h
4 – 5 h
45-50oC
45-50oC
45-50oC
100oC
[32]
[32]
[32]
[36]
[37]
[18]
K2HPO4
Acetic acid 50
Acetic acid 97
Acetic acid 75
H3BO3
Heulandite
Natural
phosphate
doped
100oC
48 h
Reflux
Toluene
95
with
zinc chloride
ZrH2(PO4)2
1 h
Reflux
Toluene
Toluene
Toluene
88
20
18
[38]
Hydroxyapatite 72 h
Reflux
[21]
Fluorapatite
BiCa4(PO4)3O
72 h
2 h
Reflux
[22]
Room
Acetic acid 98
Present work
temperature
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Table 5 Spectral data for the derivatives (1H NMR, FT-IR and HR-Mass)
4a
1H NMR (500 MHz, DMSO-d6): 9.153 (s,1H, NH), 7.713 (s,1H, NH), 7.233
(m,5H, Ar-H), 5.126 (s,1H, CH), 3.959 (q, 2H, CH2,) 2.229 (s,3H, CH3) 1.053
(t,3H,CH3) IR (KBr): 3245, 3114, 1725, 1700, 1648 MS (m/z): 260.98
4b 1H NMR: 9.130 (s, 1H, NH), 7.598 (s,1H,NH), 6.903-6.719 (m,3H,Ar-H), 5.1
(d,1H,CH), 4.012 (q, 2H, OCH2CH3), 3.712 (s,6H,OCH3), 2.239 (s,3H,CH3),
1.124 (t,3H, CH3) IR (KBr): 3242, 3112, 1720, 1706, 1651 MS (m/z): 320.86
(M+)
4c
1H NMR: 9.129 (s,1H,NH), 7.650 (s,1H,NH), 7.169-6.869 (m,4H), 5.101
(d,1H,CH), 4.010 (q,2H,OCH2CH3), 3.724 (s,3H,OCH3), 2.238 (s,3H,
CH3),1.112 (t,3H, CH3) IR (KBr): 3247, 3113, 1722, 1708, 1654 MS (m/z):
290.34 (M+)
4d 1H NMR: 9.130 (s,1H,NH), 7.659 (s,1H,NH), 7.131 (s,4H), 5.102 (d,1H,CH),
4.008 (q,2H, OCH2CH3), 2.264 (s,6H,CH3), 1.114 (t,3H,CH3) IR (KBr): 3243,
3113, 1704, 1649 MS (m/z): 274.13 (M+)
4e
1H NMR: 9.219 (s,1H,NH), 7.752 (s,1H,NH), 7.405-7.244 (m,4H), 5.150
(d,1H,CH), 3.998 (q,2H, OCH2CH3), 2.244 (s,3H, CH3), 1.115 (t,3H,CH3) IR
(KBr): 3246, 3112, 1724, 1706, 1651 MS (m/z): 294.07 (M+)
4f
1H NMR: 9.200 (s,1H,NH), 7.729 (s,1H,NH), 7.281-7.130 (m,4H), 5.154
(d,1H,CH), 3.999 (q,2H, OCH2CH3), 2.246 (s,3H, CH3), 1.112 (t,3H,CH3) IR
(KBr): 3243, 3113, 1704, 1649 MS (m/z): 278.13 (M+)
4g 1H NMR: 9.137 (s,1H,NH), 7.669 (s,1H,NH), 7.150 (s,4H), 5.112 (d,1H,CH),
4.014 (q,2H,OCH2CH3), 2.557 (q,2H,CH2), 2.244 (s,3H,CH3), 1.139
(t,6H,CH3) IR (KBr): 3245, 3114, 1725, 1700, 1648 MS (m/z): 288.00 (M+)
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10
20
30
40
50
60
70
2 (degree)
Fig.1 Powder XRD pattern of BiCa4(PO4)3O
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Fig. 2 FT-IR Spectrum of BiCa4(PO4)3O
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Fig. 3 SEM-EDAX of BiCa4(PO4)3O
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R
O
O
O
BiCa4(PO4)3O
NH2
O
NH
C2H5O
+
OC2H5
CHO
H2N
3
+
H3C
RT, 1.0 g, AcOH
N
O
R
H
2
1
4
4a) R = H
4b) R= 3,4-OCH3
4c) R= 4-OCH3
4d) R= 4-CH3
4e) R= 4-Cl
4f) R= 4-F
4g) R= 4-C2H5
Scheme 1 Synthesis of 3, 4 – dihydropyrimidin-2(1H)-one catalyzed by oxyphosphate
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