Lewis acid-doped natural phosphate: New catalysts for the one-pot synthesis of 3,4-dihydropyrimdin-2(1H)-one

Article abstract of DOI:10.1080/00397910500213963

Inexpensive and readily available natural phosphate doped with metal halides is used to efficiently catalyze the three-component condensation reaction of an aldehyde, a beta-keto ester, and urea to afford the corresponding dihydropyrimidin-2(1H)-ones in h

Full text of DOI:10.1080/00397910500213963

Synthetic Communicationsw, 35: 2561–2568, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500213963
Lewis Acid–Doped Natural Phosphate:
New Catalysts for the One-Pot Synthesis
of 3,4-Dihydropyrimdin-2(1H)-one
Hanane El Badaoui, Fathallaah Bazi, Soumia Tamani, and
Sa¨ıd Boulaajaj
Laboratoire de Chimie Organique Catalyse et Environnement, Universite
´
´
Hassan II, Faculte des Sciences Ben M’Sik, Casablanca, Morocco
Mohamed Zahouily
`
Laboratoire de Catalyse, Synthese et Environnement, UFR de Chimie
´
´ ´
Appliquee, Universite Hassan II, Faculte des Sciences et Techniques,
Mohammedia, Morocco
Hassan B. Lazrek
Laboratoire de Chimie Bio-organique, Universite Cadi Ayyad, Faculte
des Sciences Semlalia, Marrakech, Morocco
´
´
Sa¨ıd Sebti
Laboratoire de Chimie Organique Catalyse et Environnement, Universite
´
Hassan II, Faculte des Sciences Ben M’Sik, Casablanca, Morocco
´
Abstract: Inexpensive and readily available natural phosphate doped with metal
halides is used to efficiently catalyze the three-component condensation reaction of
an aldehyde, a beta-keto ester, and urea to afford the corresponding dihydropyrimi-
din-2(1H)-ones in high yields.
Keywords: Biginelli reaction, catalysis, condensation, pyrimidinones
Received in Poland May 1, 2005
¨
Address correspondence to Saıd Sebti, Laboratoire de Chimie Organique Catalyse
´
´
et Environnement, Universite Hassan II, Faculte des Sciences Ben M’Sik, B.P. 7955,
20702, Casablanca, Morocco. Tel.: þ212 61 46 48 19; Fax: þ212 22 24 96 72;
E-mail: saidsebti@yahoo.fr; s.sebti@univh2m.ac.ma
2561

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H. El Badaoui et al.
3,4-Dihydropyrimidin-2(1H)-ones and related compounds exhibit a wide
range of pharmacological activities[1] such as antiviral, antibacterial, and anti-
flammatory properties. The biologically active dihydropyrimidinones have
been recently reviewed.[2] The simple and direct method for the synthesis of
dihydropyrimidin-2-ones, reported first by Biginelli in 1893, involves the
one-pot condensation of an aldehyde, a beta-keto ester, and urea under
strongly acidic conditions.[3] Recently, several improved procedures have
been reported using a variety of catalysts such as manganese acetate,[4]
ytterbium/resin,[5] clay,[6] and zirconium chloride.[7] More recently, other
processes in this area have been developed using zinc chloride,[8] heteropoly-
acid Ag3PW12O40,[9] cadmium chloride,[10] SnCl2, 2H2O/LiCl,[11] potassium
hydrogen sulfate,[12,13] ionic liquid/ultrasound irradiation,[14] and Cu/
microwave.[15] A recent review has been also published.[16]
However, we have used the natural phosphate (NP) alone or doped as the
heterogenous catalyst for several reactions such as Claisen–Schmidt con-
densation,[17] nitrile hydratation,[18] a-hydroxyphosphonates synthesis,[19]
Knoevenagel condensation,[20] alkene epoxidation,[21] flavonones synthesis,[22]
and Michael addition.[23] NP has been used also as a Lewis acid catalyst or
as support in Friedel–Crafts alkylation,[24] 1,3-dipolar cycloaddition,[25]
nucleoside synthesis,[26] and building blocks for polyamide nucleic acids
synthesis.[27] In this work, we report a convenient and efficient one-pot
synthesis of dihydropyrimidin-2-ones by condensation of tree components
aldehydes, beta-keto esters, and urea (Scheme 1), catalysed for the first time
by natural phosphate doped with ZnCl2, CuCl2, NiCl2, and CoCl2.
First of all, we tested the activity of NP alone in the Biginelli reaction. The
yields of dihydropyrimidin-2-ones obtained after 48h of reaction time are poor
(10–20%). Thereafter, the use of NP doped with metal halides as catalysts for
this reaction was investigated. Reactions were carried out under a variety of con-
ditions that were designed to optimize the system in a general way. For an initial
evaluation of activity of ZnCl2/NP, we studied the influence of amount of the
catalyst in the condensation of benzaldehyde, ethyl acetocetate, and urea. The
yield of dihydropyrimidinone 4a increased as the weight of catalyst increased.
This result indicate that ZnCl2/NP is effectively a good catalyst for this
reaction (Table 1). Although the increase is not dramatic from 0.2 g of the
catalyst to 1 g, we decided to continue optimization with 0.2 g of catalyst.
Scheme 1.

Lewis Acid–Doped Natural Phosphate
2563
Table 1. Effect of the weight of ZnCl2/NP
in the synthesis of product 4a (24 h)
Yield (%)
Weight of ZnCl2/NP (g)
62
80
95
98
0.2
0.3
0.5
1
Furthermore, the metal halide effect was also examined. Thus, we have
tested CuCl2/NP, NiCl2/NP, and CoCl2/NP in this reaction. To evaluate
the catalytic activity of these materials in comparison with ZnCl2/NP and
NP alone, we carried out the condensation of benzaldehyde, ethyl acetoace-
tate, and urea to afford the product 4a. The kinetic curves of these
reactions, as shown in Figure 1, indicate clearly the promoting effect of
metal halides. For example the yields obtained after 24 h of reaction time
are 13, 37, 48, 52, and 62% using NP, NiCl2/NP, CuCl2/NP, CoCl2/NP,
and ZnCl2/NP, respectively. It appears that ZnCl2/NP is the most active
catalyst.
As a result of the optimization of the reaction conditions, we found that
increased yields were observed when the reaction was conducted in 5 ml of
toluene using 1 mmol of aldehyde and ethyl acetoacetate, 3 mmol of urea,
and 0.2 g of catalyst. To determine the scope and limitation of the reaction,
the optimum conditions were applied to other substrates as shown in
1
Table 2. All products were isolated and analysed by H and 13C NMR. It
Figure 1. Kinetic curves of product 4a synthesis using NP alone or doped with
ZnCl2, CuCl2, NiCl2, and ZnCl2.

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H. El Badaoui et al.
Table 2. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by NP and
MCl2/NP
Catalyst
Yield (%)a [Time (h)]
Product
R
NP
ZnCl2/NP CuCl2/NP NiCl2/NP CoCl2/NP
4a
4b
4c
4d
4e
Ph-
4-Cl-C6H4-
20 (48)
15 (48)
95 (48)
84 (48)
90 (48)
94 (48)
90 (48)
79 (48)
89 (72)
87 (48)
78 (48)
80 (48)
76 (48)
70 (48)
53 (48)
79 (72)
88 (48)
76 (48)
83 (48)
81 (48)
74 (48)
50 (48)
76 (72)
73 (48)
80 (48)
78 (48)
79 (48)
87 (48)
64 (48)
80 (72)
4-MeO-C6H4- 13 (48)
3-MeO-C6H4- 10 (48)
3-O2N-C6H4- 10 (48)
11 (48)
4f
29 (72)
aYields of isolated products.
can be seen that for all substrates the yields obtained are good. The only
example where yield is low is for the synthesis of product 4f. In this case,
the electronic effect of the furanyl group probably made the reaction less
favorable. However, the yields obtained using different doped materials are
in the range of 50–79% after 48 h, which can be increased to 76–89% with
longer reaction times (72 h). More interestingly, for the other products
aromatic aldehydes carrying either electron-donating or electron-withdrawing
substituents all reacted very well, giving good yields. However, it can be seen
that for all cases (Table 2) ZnCl2/NP is the most active catalyst for the
Biginelli reaction.
In summary, we have reported an efficient and convenient route to the het-
erogeneous one-pot synthesis of 3,4-dihydropyrimidin-2-ones using metal
halide–doped natural phosphate. The yields of products obtained are very
good for a range of substrates and demonstrate that these doped materials
are both highly active and versatile.
EXPERIMENTAL
Preparation of the Catalysts
Natural phosphate comes from an extracted ore in the region of Khouribga
(Morocco). A portion of 100–400-mm grain size was isolated, washed with
water, calcined at 9008C for 2 h, washed again, calcined at 9008C for 0.5 h,
and ground (63–125 mm) to give the NP catalyst. The structure of calcined
phosphate NP is similar to that of fluorapatite Ca10(PO4)6F2, as shown by the
X-ray diffraction pattern and IR spectroscopy. The chemical composition was
determined to be Ca (54.12%), P (34.24%), F (3.37%), Si (2.42%), S (2.21%),

Lewis Acid–Doped Natural Phosphate
2565
C (1.13%), Na (0.92%), Mg (0.68%), Al (0.46%), Fe (0.36%), K (0.04%), and
other metals less than 6 ppm. The specific surface area of NP was determined
by the BET method from the adsorption–desorption isotherm of nitrogen at
its liquid temperature (77 K). The total pore volume was calculated by the
BJH method at P/P0 ¼ 0.98. The NP shows a very low surface area
(1–2 m2 g21) together with a low total pore volume (VT ¼ 0.007 cm3/g21).
The preparation of MCl2/NP [M ¼ Zn, Ni, Cu or Co] was as follows:
10mmol of MCl2 and 10g of NP were mixed in 100 ml of water and then evap-
orated to dryness under vacuum and dried for 2 h at 1508C before use.
Typical Procedure for 3,4-Dihydropyrimidin-2(1H)-ones Synthesis
A mixture of aldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (3 mmol),
and catalyst (0.2 g) was stirred in refluxing toluene (5 mL). After the appropri-
ate time, the solid catalyst was removed by filtration and washed with
methanol. The solution was evaporated under vacuum and the crude product
was purified by recrystallization in ethanol and identified by 1H and 13C NMR.
5-Ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one,
1
4a: Mp 209–2108C; H NMR (DMSO-d6, 300 MHz) d 1.12 (t, J ¼ 7.2 Hz,
3H), 2.29 (s, 3H), 4.02 (q, J ¼ 7.2 Hz, 2H), 5.19 (d, J ¼ 2.7 Hz), 7.27–7.42
(m, 5H), 7.76 (s, 1H), 9.21 (s, 1H). 13C NMR (DMSO-d6, 75 MHz) d 14.1,
17.9, 54.2, 59.3, 99.5, 126.4, 127.4, 128.5, 145.0, 148.5, 152.3, 165.5. HR-
FAB-MS: calc. for C14H17O3N2 (261.30): 261.1239 ([M þ H]þ, 100%);
found: 261.1233.
4-(4-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-
2(1H)-one, 4b: Mp 213–2148C; 1H NMR (DMSO-d6, 300 MHz) d 1.09
(t, J ¼ 6.7 Hz, 3H), 2.24 (s, 3H), 3.97 (q, J ¼ 6.7 Hz, 2H), 5.14
(d, J ¼ 3.1 Hz), 7.23 (d, J ¼ 7.3 Hz), 7.38 (d, J ¼ 7.3 Hz), 7.76 (s, 1H), 9.23
(s, 1H). 13C NMR (DMSO-d6, 75 MHz) d 14.9, 18.7, 54.3, 60.1, 99.7, 129.0,
129.2, 132.7, 144.6, 149.6, 152.8, 166.2. HR-FAB-MS: calc. for
C14H16O3N2Cl (295.75): 295.0849 ([M þ H]þ, 100%); found: 295.0840.
5-Ethoxycarbonyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one, 4c: Mp 202–2038C; 1H NMR (DMSO-d6, 300 MHz) d 1.09
(t, J ¼ 7 Hz, 3H), 2.23 (s, 3H), 3.70 (s, 3H), 3.97 (q, J ¼ 7 Hz, 2H), 5.09
(d, J ¼ 3.1 Hz), 6.87 (d, J ¼ 8.6 Hz), 7.15 (d, J ¼ 8.6 Hz), 7.65 (s, 1H), 9.13
(s, 1H). 13C NMR (DMSO-d6, 75 MHz) d 15.0, 18.6, 54.3, 55.9, 60.1,
100.5, 114.6, 128.3, 138.0, 148.9, 153.1, 159.4, 166.3. HR-FAB-MS: calc.
for C15H19O4N2 (291.33): 291.1345 ([M þ H]þ, 29.8%); found: 291.1351.
5-Ethoxycarbonyl-4-(3-methoxyphenyl)-6-methyl-3,4-dihydropyrimidin-
2(1H)-one, 4d: Mp 223–2248C; 1H NMR (DMSO-d6, 300 MHz) d 1.09

2566
H. El Badaoui et al.
(t, J ¼ 6.9 Hz, 3H), 2.23 (s, 3H), 3.70 (s, 3H), 3.98 (q, J ¼ 6.9 Hz, 2H), 5.12
(d, J ¼ 3.1 Hz), 6.78–7.24 (m, 4H), 7.67 (s, 1H), 9.13 (s, 1H). 13C NMR
(DMSO-d6, 75 MHz) d 15.0, 18.7, 54.7, 55.9, 60.1, 100.2, 113,1, 113.3,
119.2, 130.4, 147.3, 149.3, 153.2, 160.2, 166.3. HR-FAB-MS: calc. for
C15H19O4N2 (291.33): 291.1345 ([M þ H]þ, 100%); found: 291.1342.
5-Ethoxycarbonyl-6-methyl-4-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-
one, 4e: Mp 223–2248C; 1H NMR (DMSO-d6, 300 MHz) d 1.08 (t, J ¼ 7 Hz,
3H), 2.28 (s, 3H), 4.02 (q, J ¼ 7 Hz, 2H), 5.32 (d, J ¼ 2.8 Hz), 7.63–8.15
(m, 4H), 7.89 (s, 1H), 9.36 (s, 1H). 13C NMR (DMSO-d6, 75 MHz) d 14.0,
17.9, 53.6, 59.4, 98.4, 121.1, 122.4, 130.2, 133.0, 147.0, 147.8, 149.4,
151.8, 165.1. HR-FAB-MS: calc. for C14H16O5N3 (306.30): 306.1090
([M þ H]þ, 45.3%); found: 306.1082.
5-Ethoxycarbonyl-4-(2-furfuryl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one,
1
4f: Mp 209–2108C; H NMR (DMSO-d6, 300 MHz) d 1.12 (t, J ¼ 6.9 Hz,
3H), 2.22 (s, 3H), 3.99 (q, J ¼ 6.9 Hz, 2H), 5.20 (d, J ¼ 2.7 Hz), 6.08
(s, 1H), 6.33 (s, 1H), 7.52 (s, 1H), 7.71 (s, NH), 9.20 (s, NH). 13C NMR
(DMSO-d6, 75 MHz) d 14.1, 17.7, 47.8, 59.2, 96.8, 105.3, 110.3, 142.1,
149.3, 152.4, 155.9, 165.0. HR-FAB-MS: calc. for C12H15O4N2 (251.26):
251.1032 ([M þ H]þ, 100%); found: 251.1025.
ACKNOWLEDGMENTS
Financial assistance from the National Center for the Scientific and technical
Research, Government of Morocco (PROTARS, P2T3/59) and the Research
Center for Studies on Mineral Phosphates (CERPHOS), OCP Group, is grate-
fully acknowledged.
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