Efficient biginelli reaction catalyzed by sulfamic acid or silica sulfuric acid under solvent-free conditions

Article abstract of DOI:10.1080/00397910600977632

Sulfamic acid efficiently catalyzes the three-component condensation reaction of aldehydes, 1,3-dicarbonyl compounds, and urea/thiourea under solvent-free conditions to afford the corresponding dihydropyrimidinones and thio-derivatives in high yields. Sil

Full text of DOI:10.1080/00397910600977632

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Efficient Biginelli Reaction Catalyzed by
Sulfamic Acid or Silica Sulfuric Acid under
Solvent‐Free Conditions
Wei‐Yi Chen a , Su‐Dong Qin b & Jian‐Rong Jin a
a College of Chemistry and Chemical Engineering of Suzhou University,
Suzhou, China
b Technical Department of JiangShan Pharmaceutical Corporation,
JingJiang, China
Published online: 25 Jul 2007.
To cite this article: Wei‐Yi Chen , Su‐Dong Qin & Jian‐Rong Jin (2007): Efficient Biginelli Reaction Catalyzed
by Sulfamic Acid or Silica Sulfuric Acid under Solvent‐Free Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:1, 47-52
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Synthetic Communicationsw, 37: 47–52, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600977632
Efficient Biginelli Reaction Catalyzed
by Sulfamic Acid or Silica Sulfuric Acid
under Solvent-Free Conditions
Wei-Yi Chen
College of Chemistry and Chemical Engineering of Suzhou University,
Suzhou, China
Su-Dong Qin
Technical Department of JiangShan Pharmaceutical Corporation,
JingJiang, China
Jian-Rong Jin
College of Chemistry and Chemical Engineering of Suzhou University,
Suzhou, China
Abstract: Sulfamic acid efficiently catalyzes the three-component condensation
reaction of aldehydes, 1,3-dicarbonyl compounds, and urea/thiourea under solvent-
free conditions to afford the corresponding dihydropyrimidinones and thio-derivatives
in high yields. Silica sulfuric acid is also found to be an efficient catalyst for the
Biginelli reaction under solvent-free conditions. Compared to the classical Biginelli
reaction conditions, this new method consistently has the advantage of giving good
yields and requiring short reaction times.
Keywords: aldehyde, Biginelli reaction, silica sulfuric acid, solvent-free, sulfamic
acid
3,4-Dihydropyrimidin-2(1H)-ones and related compounds have been found to
exhibit a wide spectrum of biological effects,[1,2] including antiviral,
Received in R.O.C. June 8, 2006
Address correspondence to Wei-Yi Chen, College of Chemistry and Chemical
Engineering of Suzhou University, Suzhou, China. E-mail: suzhoucwy@163.com
47

48
W.-Y. Chen, S.-D. Qin, and J.-R. Jin
antitumor, antibacterial, and anti-inflammatory activities. In addition, the
dihydropyrimidine-5-carboxylate core unit is found in many marine natural
products including batzelladine alkaloids, which are found to be potent
HIVgp-120-CD4 inbibitors.[3] So, the synthesis of this heterocyclic nucleus
is of importance.
The simple and direct method originally reported by Biginelli[4] for the
synthesis of dihydropyrimidinones involves three-component condensation
reactions (i.e., aldehydes, b-ketoester, and urea) under strong acidic
conditions with low yields (20–50%), and so it needs improving into an
efficient procedure. In recent years, interest in this reaction has increased
rapidly, and many synthetic methods for preparing these compounds have
been reported. For example, modifications and improvements using Lewis
acids as well as protic acid promoters such as Cu(OTf)2,[5] BF3 OEt2,
.
[6]
[9]
InX3 (X ¼ Cl, Br),[7] montmorillonite (KSF),[8] FeCl3 6H2O,
.
[10]
.
Mn(OAc)3 2H2O,
LiClO4,[11] H2SO4,[12] Zn(NH2SO3)2,[13] and ionic
liquid[14] have been reported. In addition, microwave irradiation is also
found to accelerate the reaction.[15] However, some of these one-pot
procedures generally require strong protic or Lewis acids, prolonged
reaction time, high temperature, stoichiometric amounts of catalysts, and
the use of toxic and inflammable solvents, and give unsatisfactory yields.
Therefore, the discovery of a milder and more efficient procedure for the
synthesis of dihydropyrimidinone is of prime importance. There is a need to
develop new methods using less hazardous solvents or, even better, those
that do not need solvents at all. More recently, some catalysts have been
used for this transformation under solvent-free conditions.[16] This prompted
us to seek an alternative and solvent-free method of synthesis of these
biologically significant compounds.
Recently, it was shown that sulfamic acid (SA) and silica sulfuric acid
(SSA) have potential to be used as substitutes for conventional acidic catalytic
materials. Sulfamic acid and silica sulfuric acid have been extensively used as
catalysts for many organic reactions by now,[17] and they also have been used
in the synthesis of 3,4-dihydropyrimidin-2(1H)-ones. In this article, we
describe an efficient and mild Biginelli reaction catalyzed by sulfamic acid or
silica sulfuric acid under solvent-free conditions in a short time.
To study the generality of this process, several examples were studied
(Table 1). The results showed that the efficiency and the yield of the
reaction in solution were less than those obtained under solvent-free con-
ditions. The use of 30 mol% of the catalyst was sufficient to promote the
reaction. Higher amounts of the catalyst did not improve the yields. When
the reaction was investigated at 1208C, the reaction was completed with
higher yield and in shorter reaction time (Table 1, entries 7, 10). Obviously,
the temperature and the catalyst have important effects on the reaction. The
best result was obtained when the reaction was carried out in the presence
of a catalytic amount of sulfamic acid or silica sulfuric acid at 1208C under
solvent-free conditions (Scheme 1).

Efficient Biginelli Reaction
49
Table 1. Reaction of benzaldehyde, ethyl acetoacetate, and urea under different
reaction conditions
Amount
of catalyst
(mol%)
Temp.
(8C)
Yield of
4a (%)
Entry
Catalyst
Solvent
Time
1
2
SA
20
—
10
20
30
40
30
30
30
30
EtOH
—
—
Reflux
100
100
8 h
80
70
86
88
89
92
94
90
92
95
—
20 min
20 min
15 min
15 min
10 min
8 min
6 h
3
SA
SA
4
—
—
100
100
5
SA
SA
6
—
—
100
120
7
SA
8
SSA
SSA
SSA
EtOH
—
—
Reflux
100
120
9
10
15 min
10 min
Having optimized the reaction conditions, we extended the three-
component condensation reaction to a wide variety of aldehydes. The
results obtained are shown in Table 2.
As can be seen from Table 2, aldehydes, 1,3-dicarbonyl compounds, and
urea or thiourea in the presence of a catalytic amount of sulfamic acid or silica
sulfuric acid gave the corresponding dihydropyrimidinones and thio-
derivatives in good yields under solvent-free conditions. In most cases, the
products were extracted from the reaction mixture with ethyl acetate. The
crude products were purified by recrystallization from ethanol. Meanwhile
the catalyst can be recovered by simple filtration and can be recycled in
subsequent reactions with comparable activity. An important feature of this
method is that aromatic aldehydes carrying either electron-donating or
electron-withdrawing groups afforded high yields of products in high purity.
In addition, cyclohexanecarboxaldehyde, which replaced the aromatic
aldehyde as one of the substrates, was tested, and the corresponding
products were produced in good yields under the same reaction conditions
Scheme 1.

50
W.-Y. Chen, S.-D. Qin, and J.-R. Jin
Table 2. SA/SSA-catalyzed Biginelli reaction under solvent-free conditionsa
Product
4
Time
Catalyst (min)
Yield
(%)b
R1
R2
X
Ref.
4a
4b
4c
4d
4e
4f
C6H5
4-CH3OC6H4
4-ClC6H4
OC2H5
OC2H5
OC2H5
O
O
O
O
O
O
S
SA
SA
8
10
10
10
8
94
86
91
84
92
80
91
93
95
96
81
91
92
80
95
94
94
93
95
91
92
89
94
88
81
[11]
[9]
SA
SA
[9]
[9]
4-(CH3)2NC6H4 OC2H5
4-O2NC6H4
c-C6H11
C6H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH3
SA
SA
[11]
[11]
[15]
[15]
[15]
[15]
[20]
[18]
[18]
[20]
[19]
[19]
[19]
[20]
[11]
[9]
12
8
4g
4h
4i
SA
SA
4-CH3OC6H4
4-O2NC6H4
4-ClC6H4
c-C6H11
S
8
S
SA
SA
8
4j
S
8
4k
4l
S
SA
SA
10
8
C6H5
O
O
O
S
4m
4n
4o
4p
4q
4r
4a
4b
4e
4g
4h
4i
3-O2NC6H4
c-C6H11
C6H5
CH3
CH3
SA
SA
8
10
8
CH3
CH3
SA
SA
4-CH3OC6H4
4-ClC6H4
4-O2NC6H4
C6H5
S
8
CH3
CH3
S
SA
SA
8
S
8
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
O
O
O
S
SSA
SSA
SSA
SSA
SSA
SSA
SSA
10
10
10
10
10
10
12
4-CH3OC6H4
4-O2NC6H4
C6H5
[11]
[15]
[15]
[15]
[20]
4-CH3OC6H4
4-O2NC6H4
c-C6H11
S
S
4k
S
aAll products were characterized by 1H NMR, IR, and mass spectroscopy.
bIsolated yields.
(4f, 4k, 4n). The structure of 4k was further confirmed by single-crystal X-ray
crystallography (Fig. 1). (Crystallographic data for the structural analysis have
been deposited with the Cambridge Crystallographic Data Centre, CCDC No.
219835 for compounds 4k. Copies of this information may be obtained free of
charge from the director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK
[E-mail: linstead@ccdc.cam.ac.uk or deposit@ccdc.cam.ac.uk; Fax: þ44
(1223)336033]. Structural parameters for 4k: data collection: Rigaku
˚
Mercury CCD area detector; radiation: MoK. Wavelength ¼ 0.71070 A;
crystal size: 0.4 ꢀ 0.3 ꢀ 0.12 mm3; crystal system: triclinic; space group:
˚
˚
˚
P-1 (#2); unit cell: a ¼ 8.5643(2) A, b ¼ 13.7994(2) A, c ¼ 14.4627 A,
a ¼ 98.74(2)8.)
In conclusion, we have demonstrated a very simple, efficient, and
practical method for the synthesis of dihydropyrimidinones and thio-
derivatives through a one-pot, three-component condensation of aldehydes,

Efficient Biginelli Reaction
51
Figure 1. X-ray structure of the title compound 4k.
1,3-dicarbonyl compounds, and urea or thiourea catalyzed by sulfamic acid or
silica sulfuric acid under solvent-free conditions. The main features of our
new reaction are as follows: (1) the procedure is operationally simple and
can furnish a wide variety of dihydropyrimidinones and thio-derivatives in
good yields; (2) the condensation reaction could be performed exclusively
using cheap, commercially available chemicals; (3) the catalyst could be
recycled with comparable activity; and (4) the method is cost-effective and
environmentally benign.
EXPERIMENTAL
Apparatus and Analysis
Melting points were recorded in open capillaries and are uncorrected. 1H NMR
(400 MHz) spectra were obtained for solution in DMSO-d6 with Me4Si as
internal standard on a Varian-Inova-400 spectrometer. IR spectra were
obtained on a Nicolet FT-IR500 spectrophotometer using KBr pellets. High-
resolution mass spectra were obtained using GCT-TOF instrument. The
X-ray diffraction was performed on a Rigaku Mercury CCD X-ray diffract-
ometer. Ethyl acetoacetate was purified by distillation prior to use.
General Procedure
A mixture of benzaldehyde (2 mmol), ethyl acetoacetate (2 mmol), urea
(3 mmol), and silica sulfuric acid (0.6 mmol) was stirred at 1208C under

52
W.-Y. Chen, S.-D. Qin, and J.-R. Jin
solvent-free conditions for 10 min. After completion of the reaction, the
mixture was extracted with ethyl acetate. The combined organic layers were
dried over anhydrous Na2SO4 and concentrated in vacuo, and the solid
1
product 4a was recrystallized from hot ethanol. Mp 204–2058C, H NMR
(DMSO-d6, 400 MHz) d: 1.08 (t, J ¼ 6.4 Hz, 3H, CH3), 2.31 (s, 3H, CH3),
4.02 (q, J ¼ 6.4 Hz, 2H, CH2), 5.10 (s, 1H, CH), 7.11–7.35 (m, 5H, ArH),
9.63 (s, 1H, NH), 10.38 (s, 1H, NH); IR (KBr) n: 3242, 3122, 2956, 1724,
1703, 1645 cm21; HRMS calcd. for C14H16N2O3: 260.1161, found: 260.1158.
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