An efficient synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydro-pyrimidin- 2(1H)-ones catalyzed by KSF montmorillonite

Article abstract of DOI:10.3390/51201240

A mild and efficient catalytic method for synthesis of 5-alkoxycarbonyl-4- aryl-3, 4-dihydropyrimidin-2(1H)-ones using KSF montmorillonite as catalyst is described.

Full text of DOI:10.3390/51201240

Molecules 2000, 5, 1240-1243
molecules
ISSN 1420-3049
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An Efficient Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4-dihydro-
pyrimidin-2(1H)-ones Catalyzed by KSF Montmorillonite
Haixia Lin1,*, Jinchang Ding1, Xianten Chen1 and Ziyi Zhang2
1Department of Chemistry, Wenzhou Normal College, Wenzhou 325003, China.
2Department of Chemistry, Lanzhou University, Lanzhou 730000, China
*Author to whom correspondence should be addressed; e-mail xlh@mail.wzptt.zj.cn
Received: 21 September 2000; in revised form 27 October 2000/ Accepted: 8 November 2000 /
Published: 18 December 2000
Abstract: A mild and efficient catalytic method for synthesis of 5-alkoxycarbonyl-4-aryl-3,
4- dihydropyrimidin-2(1H)-ones using KSF montmorillonite as catalyst is described.
Keywords: Biginelli reaction, dihydropyrimidinones, Montmorillonite
Introduction
4-Aryl-3,4-dihydropyrimidin-2(1H)-ones 4 (“Biginelli compounds”, DHPMs) have been reported to
possess diverse biological activities such as antiviral, antibacterial, antihypertensive and anti-tumor
effects [1-3]. More recently, DHPMs have emerged as the integral backbones of several calcium
channel blockers [4]. Furthermore, several marine alkaloids with interesting biological activities
containing the dihydropyrimidine-5-carboxylate core have been isolated [5]. Consequently a great need
still exists for versatile and simple processes whereby compounds 4 may be formed under very mild
conditions. However, Biginelli’s initial one-pot method of refluxing a ꢀ-keto ester 1, aryl aldehyde 2
and urea 3 with a catalytic amount of acid frequently afforded low (20-60%) yields of the desired target
molecules 4 [6]. This has led to the recent disclosure of several improved reaction protocols for the
synthesis of DHPMs, either by modification of the classical one-pot Biginelli approach itself [7-10], or
by the development of novel, but more complex multistep strategies [11,12]. In addition, several
combinatorial approaches towards DHPMs 4 have been reported [13,14].
Montomorillonite clays have been widely used in organic synthesis due to their ready availability,
ease of set up and of work up, mild experimental condition and high yield and selectivity. Recently,
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Molecules 2000, 5
1241
Bigi [15] reported that the Biginelli reaction could be performed under solventless conditions using
KSF montmorillonite, although the procedures described suffer limitations such as long reaction times
and moderate yields. Our group has exploited the catalytic potential of montomorillonite for various
synthetic organic transformations [16]. While optimizing the reaction conditions of the Biginelli
reaction, we found that treatment of ꢀ-keto ester, aryl aldehyde and urea with KSF montmorillonite in
methanol afforded DHPMs in good to excellent yields (Table 1).
R
3
O
C
R
3
O
C
O
C
R
R O
1
Mont
H
CH
C
2
N
+
+
H N
2
NH
2
O
R
1
N
2
O
CHO
O
R
H
2
2
3
1
4
Results and Discussion
Our results show that it is necessary to control the molar ratio of the reactant. When the molar ratio
of ꢀ-keto ester (1): aryl aldehyde (2): urea (3) is 1:1:1.2, our method produced higher yields. The same
reaction when run in methanol gave better yields than in tetrahydrofuran. A variety of
montomorillonites, including montomorillonite K 10 and montomorillonite KSF showed catalytic
activity for Biginelli reaction, although montomorillonite KSF reagent proved superior to
montomorillonite K 10.
Table 1. Experimental results and physical data of dihydropyrimidinones 4.
Yield(%)
m.p. ( C)
entry
R1
R2
R3
Aa
88
93
89
82
92
80
90
Bb
Cc
Dd
(literature) [7]
1
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Ph
Me
Cl
213-4
2
3
4
5
6
7
56
54
37
71
10
42
92
91
85
94
70
88
76
214-5(213-5)
209-11(208-11)
200-2(201-3)
205-6(202-4)
158-9(157-9)
211-3(209-12)
NO2
OMe
H
79
82
75
H
Me
H
a Method A: New reaction conditions(montomorillonite KSF in methanol, reflux 8-10h).
b Method B: Classical Biginelli conditions (cat.H2SO4 in EtOH, reflux 18h)[6]
c Method C: Hu improved conditions (BF3·OEt2/CuCl in THF, reflux 18h)[7]
d Method D: Bigi improved conditions (montmorillonite KSF without solvent at 130

Molecules 2000, 5
1242
Our approach not only preserved the simplicity of Biginelli’s one-pot reaction, but also consistently
provided excellent yields of dihydropyrimidinones 4, regardless of the keto ester or aldehyde
substituents tested. Montmorillonite KSF has many advantages over catalysts like BF3•OEt2/CuCl such
as ease of handling, low cost and elimination of metal wastes (use of an environmentally-friendly
catalyst). When compared to Bigi’s conditions (Table 1), our method consistently produced higher
yields and required shorter reaction times. Detailed work on the mechanism of the transformation is
still in progress.
Conclusions
We have presented a mild and effecient catalytic method for synthesis of 5-alkoxycarbonyl-4-aryl-3,
4- dihydropyrimidin-2(1H)-ones using KSF montmorillonite as catalyst.
Experimental
General
Melting points were determined using a XT 4A melting point apparatus and were uncorrected. The
1H- and 13C-NMR spectra were acquired on a Bruker Avance 300 spectrometer in DMSO with TMS as
internal standard. IR spectra were recorded on a Nicolet Axatar IR 360 spectrometer. Elemental
analysis data were taken on a Perkin-Elmer 240C elemental analytical instrument.
Syntheses
A mixture of ꢀ-keto ester (20mmol), aryl aldehyde (20mmol), urea (24mmol) and montmorillonite
KSF (0.6g) was refluxed in dry methanol (15mL), The completion of the reaction was monitored vide
tlc. Montomorillonite KSF filtered off and methanol was removed under reduced pressure. The product
was crystallised from ethanol. The results were summarized in Table 1. All the products except entry 1
1
13
are known compounds, which were satisfactorily characterised by melting point, H-NMR, C-NMR
and IR spectra.
1
Entry 1 ( 88% yield) mp 213-4 , IR(KBr) 3245, 3114, 2981, 2942, 1725, 1706, 1650 cm-1; H-NMR
(DMSO-d6) /9.13 ( s,1H ), 7.66 ( d, J=3.11Hz, 1H ), 7.09 ( m, 4H ), 5.08 (d, J=3.11Hz, 1H ), 3.95 ( q,
13
J=7.03Hz, 2H ), 2.23 ( s, 3H ), 2.21 ( s, 3H ), 1.08 ( t, J=7.03Hz, 3H); C-NMR (DMSO-d6) /165.5,
152.3, 148.2, 142.1, 136.4, 129.0, 126.3, 99.6, 59.3, 53.8, 20.8, 17.9, 14.2. Anal. Calcd for
C15H18N2O3: C, 65.67; H, 6.61; N, 10.21. Found: C, 65.42; H, 6.65; N, 10.16.

Molecules 2000, 5
1243
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Samples Availability: Samples are available from the authors.
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