A convenient ferric chloride catalyzed synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones under microwave irradiation

Article abstract of DOI:10.1081/SCC-120001522

A series of ethyl 4-aryl-6-methyl-1,2,3,4-tetrahydropyrimidin-2-one-5-carboxylates 4 were synthesized by the condensation of aromatic aldehydes, ethyl acetoacetate and urea in the presence of ferric chloride hexahydrate under microwave irradiation. The reactions were completed in 4-6 min with 87-92% yield.

Full text of DOI:10.1081/SCC-120001522

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A CONVENIENT FERRIC CHLORIDE CATALYZED
SYNTHESIS OF 5-ALKOXYCARBONYL-4-ARYL-3,4-
DIHYDROPYRIMIDIN-2(1H)-ONES UNDER MICROWAVE
IRRADIATION
Shu-Jiang Tu a , Jian-Feng Zhou b , Pei-Jun Cai a , Hai Wang c & Jun-Cai Feng
a Department of Chemistry, Xuzhou Normal University , Xuzhou, 221009, P. R. China
b Department of Chemistry, Huaiyin, Teachers College , Huaiyin, 223001, P. R. China
c Department of Chemistry, Nanjing University , Nanjing, 210093, P. R. China
Published online: 21 Aug 2006.
To cite this article: Shu-Jiang Tu , Jian-Feng Zhou , Pei-Jun Cai , Hai Wang & Jun-Cai Feng (2002) A CONVENIENT FERRIC
CHLORIDE CATALYZED SYNTHESIS OF 5-ALKOXYCARBONYL-4-ARYL-3,4-DIHYDROPYRIMIDIN-2(1H)-ONES UNDER MICROWAVE
IRRADIATION, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:1, 147-151, DOI: 10.1081/SCC-120001522
To link to this article: http://dx.doi.org/10.1081/SCC-120001522
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SYNTHETIC COMMUNICATIONS, 32(1), 147–151 (2002)
A CONVENIENT FERRIC CHLORIDE
CATALYZED SYNTHESIS OF
5-ALKOXYCARBONYL-4-ARYL-3,4-
DIHYDROPYRIMIDIN-2(1H)-ONES
UNDER MICROWAVE IRRADIATION
Shu-Jiang Tu,1 Jian-Feng Zhou,2 Pei-Jun Cai,1
Hai Wang,3 and Jun-Cai Feng3,
*
1Department of Chemistry, Xuzhou Normal University,
Xuzhou, 221009, P. R. China
2Department of Chemistry, Huaiyin, Teachers College,
Huaiyin, 223001, P. R. China
3Department of Chemistry, Nanjing University,
Nanjing, 210093, P. R. China
ABSTRACT
A series of ethyl 4-aryl-6-methyl-1,2,3,4-tetrahydropyrimidin-
2-one-5-carboxylates 4 were synthesized by the condensation
of aromatic aldehydes, ethyl acetoacetate and urea in the
presence of ferric chloride hexahydrate under microwave
irradiation. The reactions were completed in 4–6 min with
87–92% yield.
*Corresponding author.
147
Copyright & 2002 by Marcel Dekker, Inc.
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TU ET AL.
Since Biginelli1 reported the synthesis of 3,4-dihydropyrimidin-
2(1H)-ones in 1893, scientists have found these compounds to be useful
as the calcium channel blockers, antihypertensive agents and a-1a-
antagonists.2 Consequently, the Biginelli reaction continues to attract the
attention of researchers for the discovery of a milder and more prac-
tical route for the synthesis of dihydropyrimidin-2(1H)-ones. Several
improved procedures for the preparation of DHPMs (Biginelli com-
pounds) have been reported,3–10 Hu11 and Kappe12 reported reagents
involving the use of BF3ꢀOEt2/CuCl and PPE (polyphosphate ester)-
mediated variation of the Biginelli reaction giving high yields of dihydro-
pyrimidinones of type (4). Then, Kappe13 improved this reaction by
employing microwave irradiation in the presence of PPE. Recently,
Stefani and Gatti14 have preparated Biginelli compounds (methyl ester)
using methyl acetoacetate under microwave irradiation without catalyst
and solvent free. However, in our laboratory, Hantzsch compounds
have obtained (not Biginelli compounds) using ethyl acetoacetate at the
same condition. But, Biginelli compounds (ethyl ester) have been success-
fully obtained when using ferric chloride hexahydrate as catalyst at above
condition.
In this paper, we would like to report the synthesis of ethyl 4-aryl-6-
methyl-1,2,3,4-tetrahydropyrimidin-2-one-5-carboxylates (4) by one-pot
condensation of aromatic aldehydes, ethyl acetoacetate and urea in the
presence of ferric chloride hexahydrate using silica gel as carrier under
microwave irradiation and solvent free. The reactions were completed in
4–6 min with 87–92% yields. All the products were confirmed by melting
points, elemental analysis and spectral data.
The results are shown in the Table 1.
In this reaction, the ferric chloride hexahydrate is necessary, because
diethyl 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (5) were
obtained without ferric chloride hexahydrate. The results are shown in the
Table 2.

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149
Table 1. Microwave-Induced and Iron (III)-Catalyzed Biginelli Condensations
Entry
Ar
Time (min)
M.P. (ꢁC)
Yield (%)
4a
4b
4c
4d
4e
4f
C6H5
6
5
5
4
5
4
6
5
202–4 (202.4)15
90
94
91
94
89
87
95
92
3,4-(OCH2O)C6H3
3,4-(CH3O)2C6H3
4-ClC6H4
3-O2NC6H4
4-HOC6H4
185–7 (187–8)15
175–7 (178–8.5)15
208–211 (213–5)11
224–6 (226–7.5)13
228–9 (227–9)15
199–200 (201–2)15
229–230 (232–3)15
4g
4h
4-CH3OC6H4
4-HO-3-CH3OC6H3
Table 2. The Reaction Results in Absence of Ferric Chloride Hexahydrate
Ar
M.P. (ꢁC)
Lit. M.P. (ꢁC)
Yield (%)
C6H5
4-HOC6H4
4-HO-3-CH3OC6H3
3,4-(CH3O)2C6H3
152–4
220–3
158–60
138–40
158–6016
227–817
163–417
142–517
68
70
75
77
The synthetic route is shown as following:
The structure of 5a is confirmed by X-ray diffraction studies on a mono-
crystal of 5a (Figure 1).18
EXPERIMENTAL
Melting points were determined in open capillaries and uncorrected.
1
IR spectra were recorded on a Nicolet FI-IR50DX instrument. HNMR
spectra were measured on a Bruker DPX 300 MHz spectrometer using
TMS as internal standard. Elemental analysis were determined by using

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TU ET AL.
Figure 1. X-ray crystal structure of 5a.
Perkin-Elmer 240 C elemental analyzer. X-ray diffraction were measured on
an Enraf-Nonius CCD4 diffractometer. Microwave irradiation was carried
out with a modified commercial microwave oven (2450 MHz, 650 W) under
atmospheric pressure.
General Procedure
Aromatic aldehyde (1, 10 mmol), ethyl acetoacetate (2, 1.43 g,
11 mmol), urea (3, 1.8 g, 30 mmol) and FeCl3ꢀ6H2O (1.35 g, 5 mmol) were
thoroughly mixed with silica gel (5.0 g, 70–230 mesh, 60 A) in an agate
mortar. The resulting fine powder was transferred to a flask (50 mL) con-
nected with refluxing equipment. After microwave irradiation of several
minutes, the reaction mixture was allowed to cool to room temperature.
The inorganic support was separated by filtration after extracting the
product with chloroform. The filtrate was evaporated to give the crude
product (4), which was purified by recrystallization from ethanol.
REFERENCES
1. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
2. 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. Rovnyak,
G.C.; Atwal, K.S.; Hedberg, A.; Kimball, S.D.; Moreland, S.;

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FERRIC CHLORIDE
151
Gougoutas, J.Z.;O’Reilly, B.C.; Schwartz, J.; Malley, M.F. J. Med.
Chem. 1992, 35, 3254. Grover, G.J.; Dzwonczyk, S.; McMullen, D.M.;
Normadinam, D.E.; Parham, C.S.; Seleph, P.G.; Moreland, S.
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Curran, D.P. Science 1997, 275, 823.
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10. Jun Lu, Huairang Ma. Synlett 2000, 1, 63.
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12. Kappe, C.O.; Falsone, S.F. Synlett 1998, 718.
13. Kappe, C.O.; Kumar, D.; Varma, R.S. Synthesis 1999, 10, 1799.
14. Stefani, H.A.; Gatti, P.M. Synth. Commun. 2000, 30, 2165.
15. Flokers, K.; Harwood, H.J.; Johnson, T.B. J. Am. Chem. Soc. 1932,
54, 3751.
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17. Tetsuji, K.; Kunio, O. Yakugaku Zasshi, 1966, 86, 815. (Chem. Abstr.
1966, 65, 20092h.)
18. X-ray analysis of 5a: Empirical formula C19H23NO4, monoclinic, space
group P21/c, a ¼ 9.745(2) A, b ¼ 7.388(2) A, c ¼ 24.354(5) A, ꢀ ¼ 90ꢁ,
ꢁ ¼ 92.60(3)ꢁ, ꢂ ¼ 90ꢁ, V ¼ 1751.6(6) A3, Z ¼ 4 Wr ¼ 329.38, Dc ¼
1.249 Mg/cm3, ꢃ(MoKa) ¼ 0,71073 A, ꢄ ¼ 0.087 mmꢂ1, F (000) ¼ 704,
1.67ꢁ < ꢅ < 24.97ꢁ, R ¼ 0.0416, Rw ¼ 0.1175.
Received in the USA February 22, 2001

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