The catalytic activity of an inorganic-organic complex with a vanadium-substituted polyoxometalate
1
, formulated as [Cu(2,2′-bipy)][Cu(2,2′-bipy)
2
]
2
[PMo
8
V
6
O
42
]·1.5H
2
O was studied in the Biginelli reactions. The obtained results showed that, in the one-pot synthesis of dihydropyrimidinones, the turnover frequencies (TOF) for the [Cu(2,2′-bipy)][Cu(2,2′-bipy)
2
]
2
[PMo
8
V
6
O
42
]·1.5H
2
O catalyst were higher than the H
3
PMo
12
O
40
catalyst.
INTRODUCTION
Recently, much work has been focused on the rational construction of new organic-inorganic complexes based on polyoxometalates (POMs) and transition metal complexes due to their intriguing structures and potential applications in many areas.
1
-
7
In these complexes, POMs can coordinate to “secondary” transition metal atoms with organic moieties using their terminal or bridging oxygen atoms to stabilize frameworks. Meanwhile, transition metal complexes with diverse structural arrangements not only serve as charge-compensating units but also modify the wide-ranging properties of POMs, such as magnetic and optical properties, electronic conductivities and electrocatalysis.
1
,
8
-
13
POM supported TMCs, [Cu(2,2′-bipy)][Cu(2,2′-bipy)
2
]
2
[PMo
8
V
6
O
42
]·1.5H
2
O, is constructed from bi-capped Keggin molybdenum-vanadium heteropolyoxoanions and copper complex fragments.
14
The molybdenum-vanadium cluster [PMo
8
V
6
O
42
]
6
- is based on the alpha-Keggin anion [PMo
8
V
4
O
40
]
10
- capped with two [VO]
2+
ions. In the α-Keggin anion, there exit four trimetallic groups, each of which is composed of one VO
5
square pyramid and two MoO
6
octahedra via edge-sharing mode. The molybdenum-vanadium cluster [PMo
8
V
6
O
42
]
6
- is based on the α- Keggin anion [PMo
8
V
4
O
40
]
10-
capped with two [VO]
2+
ions. In the α-Keggin anion, there exit four trimetallic groups, each of which is composed of one VO
5
square pyramid and two MoO
6
octahedra via edge-sharing mode (
. 1
). The bond valence sum calculations indicate that the polyoxoanion to be formulated as [PMoMo
8
IV
V
1
V
V
3
IV
O
40
(V
IV
O)
2
]
6-
, in agreement with the XPS spectrum analysis.
14
The bi-capped molybdenum-vanadium cluster tri-supported TMC in compound 1. All water molecules and hydrogen atoms are omitted for clarity.
Dihydropyrimidin-2(1
H
)-ones (DHPMs), “Biginelli compounds”, and their derivatives are known to exhibit therapeutic and pharmacological properties
15
including antiviral,
16
antitumor,
17
antibacterial,
18
anticancer,
19
antioxidant,
20
antihypertensive,
21
anti-inflammatory,
22
,
23
neuropeptide antagonists,
21
agents in treating anxiety
24
and optic nerve dysfunction.
25
Therefore, realizing the importance of 3,4-dihydropyrimidine-2-(1H)-ones in the synthesis of various drug sources many synthetic methods have been developed. These methods involve the use of catalysts like, [Al(H
2
O)
6
](BF
4
)
3
,
26
Y(OAc)
2
. xH
2
O,
27
Cu(NO
3
)
2
. 3H
2
O,
28
CdCl
2
29
and the use of microwave technique.
30
The development of efficient and versatile catalytic systems for Biginelli reaction is an active ongoing research area and thus, there is scope for further improvement toward milder reaction conditions, variations of substituents in all three components and better yields.
In continuation of our previously reported catalytic properties of heteropoly acids, (HPAs),
31
-
33
herein, we wish to report a suitable method for the Biginelli three-component one-pot synthesis in our laboratory (
1
).
RESULTS AND DISSCUSION
- Characterization of [Cu(2,2′-bipy)][Cu(2,2′-bipy)2]2[PMo8V6O42]·1.5H2O (1)
FTIR:
In the IR spectrum of
1
(
. 2
), the bands at 1051 and 1034 cm
-1
are ascribed to P-O stretching vibrations. The strong bands at 938 and 896 cm
-1
are associated with ν(M-O
t
) (M represents Mo or V), and those at 788 and 727 cm
-1
are due to ν(M-O
a
).
34
A series of bands in the range 1100-1600 cm
-1
are characteristic of 2,2′-bipy.
14
Besides, there are additional bands at 668 and 610 cm
-1
attributed to the asymmetry of Keggin anion affected by the covalent cation [Cu(2,2′-bipy)]
2+
and [Cu(2,2′-bipy)2]
2+
.
FTIR spectra of 1.
XRD:
X-ray powder analysis is widely used to study the structure of heteropoly complexes. The X-ray diffraction pattern of
1
is shown in
. 3.
XRD patterns of 1.
Uv-vis:
The UV-Vis spectrum of
1
is displayed in
. 4.
The two bands near 230 and 295 nm are attributed to the ligand-to-metal charge transfers of O
t
→M and μ
2
-O→M(M=V or W), respectively, where electrons are promoted from the low energy electronic states, mainly comprising of oxygen 2p orbitals, to the high-energy states, which mainly comprises of metal d orbitals.
35
The peak at 357 nm can be assigned to the d–d transition of WO
6
octahedra.
36
,
37
Uv-Vis spectra of 1.
TG:
The thermal stability of
1
was investigated on crystalline samples under air atmosphere from 50-350 ℃ (
. 5
). The TGA curve indicates the weight loss of [Cu(2,2′-bipy)][Cu(2,2′-bipy)
2
]
2
[PMo
8
V
6
O
42
]·1.5 H
2
O can be divided into two steps. The first weight loss of 0.96% from 65 to 120 ℃, may be assigned to the removal of all non-coordinated water molecules (1.5 H
2
O), which is in agreement with the calculated value 0.98 %. The second weight loss of 16.99% at 305-462 ℃ may be ascribed to decomposition of three molecule of 2,2′-bipy, which is in agreement with the calculated value 17.07%. The overall weight loss of 17.95% is accordant with the calculated value of 2,2′-bipy and water molecules of 18.5% in compound
1
.
TG analysis of 1.
- Synthesis of dihydropyrimidinones in the presence of catalytic amounts of 1
In choosing the reaction media, different solvents were investigated in the synthesis of dihydropyrimidinones with [Cu(2,2′-bipy)][Cu(2,2′-bipy)
2
]
2
[PMo
8
V
6
O
42
]·1.5H
2
O. Among the studied solvents, CH
3
CN was chosen as suitable solvent because higher dihydropyrimidinone derivatives (
1
). We also investigated the effect of reaction temperature on the synthesis of dihydropyrimidinones with
1
. It was observed that in the reaction of ethyl acetoacetone, 4-nitrobenzaldehyde and urea catalyzed by
1
, as a model reaction, only good yields of products were detected in the reaction mixture at room temperature. While, by increasing the reaction temperature (45 ℃) the conversion increased.
Various aromatic aldehydes reacted to give the corresponding dihydropyrimidinones in moderate to excellent yields (
2
). Many pharmacologically relevant substitution patterns could be introduced on the aromatic ring with high efficiency. Most importantly, aromatic aldehydes carrying either electron donating (
2
: 5i and 5j, 85-95%) or electron-withdrawing (
2
: 5b-5h, 86-98%) substituents all reacted very well, giving moderate to excellent yields. Even for aliphatic aldehydes, which normally show extremely poor yields in the Biginelli reaction, better yields of the corresponding dihydropyrimidin-2(1H)-ones (
2
: 5n, 5o, 88-90%) could be obtained.
Synthesis of dihydropyrimidinones using [Cu(2,2′-bipy)][Cu(2,2′-bipy)2]2[PMo8V6O42]·1.5H2O;1in different solvents under reflux conditions.a
aReaction conditions: ethyl acetoacetone (1 mmol), 4-nitrobenzaldehyde (1 mmol), urea (1.5 mmol), catalyst, 1 (3mol %) and solvent (5 mL). bIsolated yield.
Synthesis of DHPMs using [Cu(2,2′-bipy)][Cu(2,2′-bipy)2]2[PMo8V6O42]·1.5H2O;1as catalysts.a
aReaction conditions: [Cu(2,2′-bipy)][Cu(2,2′-bipy)2]2[PMo8V6O42]·1.5H2O (0.02 mmol), ethyl acetoacetate (1 mmol), aldehyde (1 mmol) and urea (1.5 mmol) were carried out in a one-pot condensation employing CH3CN (5 mL) as the solvent at 45℃. bIsolated yield. cIdentification of the products was ascertained by NMR and IR analysis.
In order to show the merit of the present work in comparison with recently reported protocols, we compared the results of the dihydropyrimidinones derivative synthesis from various aldehydes in the presence of H
3
PW
12
O
40
, [Al(H
2
O)
6
](BF
4
)
3
. xH
2
O, Cu(NO
3
)
2
. 3H
2
O and CdCl
2
with respect to the amounts of the catalysts used, reaction times and yields of the products (
3
). Comparison of compound
1
with these catalysts for this reaction show that activity of
1
seems to be higher than or equal with other known catalysts (
3
).
Comparision of compound1with several catalysts for synthesis of dihydropyrimidinone derivatives with aromatic aldehydes, urea and ethyl acetoacetate.
Comparision of compound 1 with several catalysts for synthesis of dihydropyrimidinone derivatives with aromatic aldehydes, urea and ethyl acetoacetate.
In order to show the effect of hybridization on the catalytic activity of H
3
PMo
12
O
40
in the Biginelli reactions, all reactions were repeated with the same reaction conditions in the presence of H
3
PMo
12
O
40
as the catalyst. It was found that the hybrid catalyst gave higher conversions (TOFs) than unhybridized H
3
PMo
12
O
40
complex.
EXPERIMENTAL
- Materials and measurements
All materials were commercial reagent grade. H
3
PW
12
O
40
(HPW) was purchased from Aldrich chemical company. FT-IR spectra were obtained as potassium bromide pellets in the range 400-4000 cm
-1
with Nicolet
Impact 400 D
.
1
H NMR spectra were recorded with a Bruker-Avance AQS 300 MHZ. The melting points were determined using an electrothermal digital melting point apparatus and are uncorrected. Reaction courses and product mixtures were monitored by thin layer chromatography. The X-ray powdered diffraction patterns were taken on a Bruker-D8 advance with automatic control. The patterns were run with monochromatic Cu Kα (1.5406 Å) radiation with a scan rate of 2° min
-1
.
- Preparation of [Cu(2,2′-bipy)][Cu(2,2′-bipy)2]2[PMo8V6O42]·1.5H2O, 1
Compound
1
was hydrothermally synthesized in 60% yield (based on Mo). A mixture of Na
2
MoO
4
·2H
2
O (0.73 g, 3.0 mmol), NH
4
VO
3
(0.35 g, 3.0 mmol), CuSO
4
·5H
2
O (0.75 g, 3.0 mmol), 2,2′-bipy (0.117 g, 0.75 mmol), H
2
C
2
O·2H
2
O (0.38 g, 3.0 mmol) and distilled water (13.5 mL, 750 mmol) in a molar ratio of 4:4:4:1:4:1000 was stirred for 120 min. The pH of the mixture was adjusted to 4 with dilute H
3
PO
4
solution. The resultant mixture was sealed in a 20 mL Teflon-lined autoclave and heated at 170 ℃ for 96 h. The autoclave was then cooled to room temperature. The crystalline product was filtered, washed with distilled water and dried at ambient temperature to give 0.73 g solids.
14
- General procedure for the synthesis of dihydropyrimidinones, 5
In the presence of
1
(0.02 mmol), the reaction of ethyl acetoacetate
3
(1 mmol), aldehyde
2
(1 mmol) and urea
4
(1.5 mmol) were carried out in a one-pot condensation employing refluxing CH
3
CN (5 mL) as the solvent (
1
) for the appropriate time (
2
). After the reaction was completed, as indicated by TLC analysis, the solvent was evaporated, the residue was dried and washed with water and the resulting solid was treated with hot EtOH and filtered again. The filtrate was concentrated to afford the recrystallized product. The products were characterized by IR and
1
HNMR spectral data and by comparison with melting points of the reported compounds.
- Spectroscopic data of some 3,4-dihydropyrimidin-2(1H)-ones
Ethyl-6-methyl-4-(4-methylphenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5a):
mp 213-215 ℃; IR (KBr): ν [cm
-1
] 3326, 3152, 1691, 1562, 1232, 1051, 783;
1
H NMR (DMSO-d
6
) δ (ppm): 1.12 (t,
J
= 7.5 Hz, 3H), 2.28, 2.30 (s, 3H), 4.00 (q,
J
= 7.5 Hz, 2H), 5.11 (d,
J
= 3.0 Hz, 1H), 7.25 (m, 4H), 7.70 (br s, 1H, NH), 9.19 (br s, 1H, NH).
Ethyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5b):
mp 208-210 ℃; IR (KBr): ν [cm
-1
] 3230, 3120, 1730, 1710, 1650;
1
H NMR (DMSO-d
6
) d (ppm): 1.11 (t,
J
= 7.5 Hz, 3H), 2.29 (s, 3H), 4.00 (q,
J
= 7.5 Hz, 2H), 5.29 (d,
J
= 3.0 Hz, 1H), 7.51 (d,
J
= 10Hz, 2H), 7.91 (br s, 1H), 8.23 (d,
J
= 8.76 Hz, 2H, arom CH), 9.37 (s, 1H, NH).
Ethyl-6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5c):
mp 2178-220 ℃; IR (KBr): ν [cm
-1
] 3300, 3120, 1710, 1690, 1630;
1
H NMR (DMSO-d
6
) d (ppm): 1.11 (t,
J
= 7.5 Hz, 3H), 2.29(s, 3H), 4.02 (q,
J
= 7.5 Hz, 2H), 5.31 (d,
J
= 3.0 Hz, 1H), 7.65-7.75 (m, 2H), 7.95 (br s, 1H), 8.09-8.20 (m, 2H), 9.34 (br s, 1H).
Ethyl-6-methyl-4-(2-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5d):
mp 220-222 ℃; IR (KBr): ν [cm
-1
] 3240, 3100, 1710, 1650;
1
H NMR (DMSO-d
6
) d (ppm): 0.94 (t,
J
= 7.5 Hz, 3H), 2.30 (s, 1H), 3.88 (q,
J
= 7.5 Hz, 2H), 5.81 (d,
J
= 3.0 Hz, 1H), 7.49-7.98 (m, 5H), 9.39 (br s, 1H).
Ethyl-6-methyl-4-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5e):
mp 219-221 ℃; IR (KBr): ν [cm
-1
] 3220, 3100, 1720, 1700;
1
H NMR (DMSO-d
6
) d (ppm): 1.10 (t,
J
= 7.2, 3H), 22 (s, 3H), 3.96 (q,
J
= 7.2, 2H), 5.02 (s,
J
= 3.2, 1H), 6.64 (d,
J
= 8.4, 2H), 7.02 (d,
J
= 8.4, 2H), 7.57 (s, 1H), 9.07 (s, 1H).
Ethyl-6-methyl-4-(2-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5f):
mp 214-216 ℃; IR (KBr): ν [cm
-1
] 3360, 3220, 1690, 1640;
1
H NMR (DMSO-d
6
) d (ppm): 1.08 (t,
J
= 7.5 Hz, 3H, CH
3
), 2.32 (s, 3H, CH
3
) 3.91 (q,
J
= 7.5 Hz, 2H, OCH2), 5.67 (d,
J
= 2.5 Hz, 1H), 7.22-7.46 (m, 4H, arom H), 7.72 (br s, 1H, NH), 9.30 (br s, 1H, NH).
CONCLUSIONS
In conclusion, we have developed an economical and simple procedure for the synthesis of dihydropyrimidinones/thiones with high yields and short reaction times using [Cu(2,2′-bipy)][Cu(2,2′-bipy)
2
]
2
[PMo
8
V
6
O
42
]·1.5H
2
O as the catalyst in acetonitrile at 45 ℃. Besides its simplicity, neutral reaction conditions and use of commercial solvents without previous purifications or drying, this method was effective with a variety of substituted aromatic aldehydes independently of the nature of the constituents in the aromatic ring, representing an improvement to the classical Biginelli’s methodology.
Acknowledgements
We gratefully thank Islamic Azad University, Shahreza Branch for financial support.
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