1-Methylimidazolium hydrogen sulfate/chlorotrimethylsilane: An effective catalytic system for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and hydroquinazoline-2,5-diones

Article abstract of DOI:10.1016/j.molliq.2012.01.019

Bronsted acidic ionic liquid, 1-methylimidazolium hydrogen sulfate, in the presence of catalytic amount of chlorotrimethylsilane has been used as an efficient and reusable catalyst for the one-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones and hydroquin

Full text of DOI:10.1016/j.molliq.2012.01.019

Journal of Molecular Liquids 172 (2012) 147–151
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Short Communication
1-Methylimidazolium hydrogen sulfate/chlorotrimethylsilane: An effective catalytic
system for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and
hydroquinazoline-2,5-diones
b
b
Hassan Kefayati a, , Fatereh Asghari , Raheleh Khanjanian
⁎
a
Department of Chemistry, Science and Research Branch, Islamic Azad University, Guilan, Iran
Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 August 2011
Received in revised form 3 November 2011
Accepted 23 January 2012
Available online 4 February 2012
Brønsted acidic ionic liquid, 1-methylimidazolium hydrogen sulfate, in the presence of catalytic amount of
chlorotrimethylsilane has been used as an efficient and reusable catalyst for the one-pot synthesis of 3,4-
dihydropyrimidin-2(1H)-ones and hydroquinazoline-2,5-diones under thermal and solvent-free conditions.
High yields of the products were obtained in a few minutes by using this new catalysis system.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Biginelli reaction
Dihydropyrimidinone
Hydroquinazoline-2,5-dione
Chlorotrimethylsilane
1-methylimidazolium hydrogen sulfate
1. Introduction
Ionic liquids posses the advantages like negligible vapor pressure, rea-
sonable thermal stability and recyclability. They dissolve many organic
Biginelli reaction is ranked as one of the most powerful routs for
the synthesis of complex heterocyclic scaffolds for therapeutic and
pharmacological properties [1–3]. Classical Biginelli reaction involves
one-pot condensation of an aldehyde, a β-ketoester, and urea under
strongly acidic conditions [4].
In recent decades, the scope of the original Biginelli reaction was
extended by variation of the 1,3-dicarbonyl compound building blocks.
Many groups have elegantly demonstrated the synthetic versatility of
numerous 1,3-dicarbonyl compounds, including β-ketoester and cyclic
β-diketones [5–34]. However, in spite of their potential utility, all of
the reported synthetic methods suffer from limitations such as the use
of expensive reagents, strong acidic conditions, low yields and long
reaction times. Also, the requirement for the use of stoichiometric
amount of catalyst and un-recoverability of strong acids or solvents as
well as harsh reaction conditions are of the other limitations of these
reports. Therefore, to avoid these limitations, introducing milder and
more efficient methods are needed.
and inorganic substrates and are tunable to specific chemical tasks [37].
Recently, ionic liquids have been successfully employed as solvents
with catalytic activity for a variety of reactions [38].
In this study, in continuation of our effort to develop applicability of
Biginelli reaction [39,40], an efficient, facile and solvent-free procedure
was introduced for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones
(Table 1) and hydroquinazoline-2,5-diones/thiones (Table 2). For this
purpose, the reaction of aromatic aldehydes, cyclic or acyclic ketones
and urea/thiourea using Brønsted acidic ionic liquid (1-methylimidazo-
lium hydrogen sulfate, [Hmim]HSO4), in the presence of catalytic
amount of chlorotrimethylsilane (TMSCl) (Schemes 1, 2) as an effective
catalytic system was investigated for the first time. The procedure pre-
sented here not only gives the desired products in good yields, but also
avoids the problems associated with conventional solvents such as cost,
handling, safety and pollution, and moreover the reaction times are
reduced to a few minutes.
Due to environmental concerns, the use of benign solvents as alter-
natives to volatile organic solvents is of much interest to organic chem-
ists. The use of ionic liquids as reaction media and catalyst can offer a
solution to solvent emission and catalyst recycle problems [35,36].
2. Experimental
All reagents were purchased from Merck and Fluka and used with-
out further purification. Melting points were obtained in open capil-
lary tubes and were measured on an Electro-thermal IA 9100
apparatus. IR spectra were recorded on KBr pellets on a Shimadzu
FT-IR 8600 spectrophotometer. 1H and 13C NMR spectra were deter-
mined on a Bruker 500 DRX Avance instrument at 500 and 125 MHz.
⁎
Corresponding author at: P. O. Box: 41335-3516. Tel.: +98 131 7222822; fax: +98
131 7229629.
E-mail address: kefayati@iaurasht.ac.ir (H. Kefayati).
0167-7322/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.molliq.2012.01.019

148
H. Kefayati et al. / Journal of Molecular Liquids 172 (2012) 147–151
Table 1
Synthesis of 3,4-dihydropyrimidin-2(1H)-ones and comparison of efficiency 1-methylimidazolium hydrogen sulfate/chlorotrimethylsilane catalytic system with other catalysts and
methodsa.
Products
R1
R2
R3
X
Found
Reported
m.p.
(°C)
Time
(min)
Yield
(%)
m.p.
(°C)
Time
(min)
Yield
(%)
Ref.
4a
4b
4c
4d
4e
4f
4g
4h
4k
4l
4m
4n
4o
4p
4q
4r
3-NO2
4-NO2
3-OMe
3-Br
4-Me
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
S
S
S
S
O
O
O
O
O
S
221–223
256–258
191–193
201–203
236–238
260–261
263–264
284–286
276–277
253–255
204-205
230–232
210–211
260–261
205–206
193–195
205–207
40
25
35
50
60
45
50
35
35
25
30
20
25
35
30
25
25
96(95,92,90)b
222–224
–
7
–
96
–
[39]c
–
[39]c
–
96
87
88
80
94
92
89
96
91
92
96
91
86
90
92
94
191–193
–
7
–
91
–
–
–
–
–
259–261
263–265
5
5
97
95
–
[39]c
[39]c
–
3-Cl
4-Cl
–
–
4-NO2
2,4-diCl
H
3-NO2
3-OMe
2-OMe
H
Ph
Ph
–
–
–
–
Me
Me
Me
Me
Me
Me
Me
Me
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
–
–
–
–
206–208
230–232
206–208
–
240
240
240
–
97
94
94
–
[27]
[27]
[27]
–
207–208
–
240
–
92
–
[27]
–
2-OMe
3-NO2
S
S
4s
206–207
240
92
[27]
a
Reaction condition: aromatic aldehyde (1 mmol), ketone or β-ketoester (1 mmol), urea (2 mmol) or thiourea (2 mmol), [Hmim]HSO4 (0.5 mmol), TMSCl (0.5 mmol) in an oil
bath at 80 °C.
b
c
The yields of reaction with recycled ionic liquid after three successive runs.
Reaction carried out under microwave irradiation.
to Tables 1, 2. After completion of reaction, as indicated by TLC, the re-
action mixture was allowed to cool to room temperature. Then, 5 mL
distilled water was added into the beaker and stirred. The obtained
precipitate was filtered off. The crude product was recrystallized
from ethanol and dried to afford powder compounds of 4a-s, 7a-p.
The filtrate was concentrated under reduced pressure and washed
with diethyl ether. Then, it was dried in a vacuum evaporator to
recover the ionic liquid for subsequent use.
2.1. Preparations of 1-methylimidazolium hydrogen sulfate,
[Hmim]HSO4, as Brønsted acidic ionic liquid
The ionic liquid of [Hmim]HSO4 was prepared by reported proce-
dure [41]. 1-Methylimidazole (1.59 mL, 20 mmol) and acetonitrile
(5 mL) were charged into a 25 mL round-bottom flask. Then, the
mixture was stirred at 0 °C for 1 min. Stoichiometric amount of
concentrated sulfuric acid (97%, 1.03 g/mL) was added dropwise
and the mixture stirred for 1 h at 0 °C and then stirred for 2 h at
room temperature. The [Hmim]HSO4 was washed repeatedly with
diethyl ether (2.5 mL) to remove non-ionic residues and then it was
dried in a vacuum evaporator.
3,4-Dihydro-4-(4-NO2-phenyl)-5,6-diphenylpyrimidine-2(1H)-one
(4b). White powder; mp: 256–258 °C; IR (KBr) νmax: 3232, 3097, 2928,
;
1702, 1651, 1530 cm−1 1H NMR (500 MHz, DMSO-d6) δH: 5.35
(d, J=4.2 Hz, 1H), 6.80–7.26 (m, 10H), 7.61 (d, J=8.6 Hz, 2H), 8.25
(d, J=8.6 Hz, 2H), 8.58 (s, 1H, NH), 9.46 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) δc: 58.1, 110.2, 124.9, 127.3, 128.7, 128.8, 129.2,
129.4, 129.9, 130.5, 134.3, 134.7, 137.4, 147.9, 150.2, 153.4.
2.2. General procedure for preparation of 4a-s and 7a-p
A mixture of aldehyde (1 mmol), cyclic or acyclic ketone (1 mmol),
urea or thiourea (2 mmol), [Hmim]HSO4 (0.5 mmol) and TMSCl
(0.5 mmol) was heated at 80 °C for the appropriate time according
3,4-Dihydro-4-(3-Br-phenyl)-5,6-diphenylpyrimidine-2(1H)-one
(4d). White powder; mp: 201–203 °C; IR (KBr) νmax: 3220, 3091,
2918, 1689, 1595, 1471 cm−1 1H NMR (500 MHz, DMSO-d6) δH:
;
Table 2
Synthesis of hydroquinazoline-2,5-diones/thiones and comparison of efficiency 1-methylimidazolium hydrogen sulfate/chlorotrimethylsilane catalytic system with other catalysts.
Products
R1
R2
R3
X
Found
Reported
Time (h)a
Time (min)
Yield (%)
m.p.(°C)
Yield (%)b
m.p.(°C)
Ref.
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
3-NO2
2- NO2
2-Cl
3,5-Cl
4-Br
H
2-Br
3-Br
4-NO2
4-Cl
4-OMe
4-Cl
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
O
O
O
O
S
O
O
O
O
O
O
O
O
O
S
15
15
15
15
15
15
15
15
15
15
15
10
10
10
10
10
94
85
84
82
78
86
88
95
82
93
68
91
87
89
86
82
308–310
271–273
299–301
324–326
306–308
307–308
289–290
302–303
299–300
285–287
277–278
296–297
276–288
286–288
271–274
251–253
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
10, 6.5
10
10
10, 6.5
10, 6
10
2, 10
0.42
1.5, 2.5, 0.33
0.5
70, 94
66
68
67, 81
76, 88
74
94, 72
75
308–309
291–292
304–305
302–303
287–288
279–280
296–297
277–279
287–290
271–274
250–252
[23,34]
[23]
[23]
[23,34]
[23,34]
[23]
[33,23]
[24]
[33,34,24]
[24]
[24]
2-Cl
H
4-Cl
3-NO2
95, 92, 73
52
46
S
0.58
a
Numbers of this column refer to reported time (h) in literatures that are shown in the reference column, respectively.
Numbers of this column refer to reported yield in literatures that are shown in the reference column, respectively.
b

H. Kefayati et al. / Journal of Molecular Liquids 172 (2012) 147–151
149
(s, 1H, NH), 8.08 (s, 1H), 8.10 (d, J=6.8 Hz, 1H), 9.6 (s, 1H, NH); 13C
NMR (125 MHz, DMSO-d6) δc: 21.5, 26.7, 37.0, 52.3, 108.3, 121.8,
123.1, 130.9, 133.8, 147.5, 148.6, 152.3, 156.0, 194.2.
4-(2-NO2-Phenyl)-3,4,7,8-tetrahydro-1H,6H-quinazolin-2,5-dione
(7b). Yellow powder; mp: 271–273 °C; IR (KBr) νmax: 3429, 3211, 3120,
2966, 1699, 1645, 1604, 1519 cm−1; 1H NMR (500 MHz, DMSO-d6) δH:
1.82 (m, 1H), 1.90 (m, 1H), 2.08 (m, 1H), 2.16 (m, 1H), 2.46 (m, 1H),
2.49 (m, 1H), 5.85 (s, 1H), 7.47 (t, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.68 (t,
1H), 7.74 (s, 1H, NH), 7.84 (d, J=8.0 Hz, 1H), 9.60 (s, 1H, NH); 13C
NMR (125 MHz, DMSO-d6) δc: 21.5, 26.6, 36.8, 48.8, 108.2, 124.7,
129.3, 130.1, 134.6, 139.5, 148.6, 151.7, 155.8, 193.9.
R1
R3
R2
O
X
R1
R3
[Hmim]HSO4
TMSCl
R2
NH
+
+
H2N
NH2
N
H
4
X
CHO
X=O, S
1
2
3
Scheme 1. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones.
5.19 (d, J=2.7 Hz, 1H), 6.78–7.24 (m, 10H), 7.30 (s, 1H), 7.31–7.38
(m, 3H), 7.53 (s, 1H, NH), 8.66 (s, 1H, NH); 13C NMR (125 MHz,
DMSO-d6) δc: 58.7, 108.9, 125.5, 125.9, 126.8, 127.4, 127.8, 127.9,
128.1, 129.2, 129.3, 130.5, 133.0, 134.7, 153.0, 137.6, 146.2, 152.8.
3,4-Dihydro-4-(4-Me-phenyl)-5,6-diphenylpyrimidine-2(1H)-one
(4e). White powder; mp: 236–238 °C; IR (KBr) νmax: 3209, 3018, 2943,
4-(2-Cl-Phenyl)-3,4,7,8-tetrahydro-1H,6H-quinazolin-2,5-dione (7c).
Yellow powder; mp: 299–301 °C; IR (KBr) νmax: 3382, 3222, 3120,
2958, 1701, 1645, 1604, 1494 cm−1 1H NMR (500 MHz, DMSO-d6) δH:
;
1.88 (m, 1H), 1.92 (m, 1H), 2.14 (m, 1H), 2.21 (m, 1H), 3.32 (m, 1H),
3.43 (m, 1H), 5.56 (s, 1H), 7.22 (m, 1H), 7.24 (m, 1H), 7.26 (m, 1H),
7.38 (d, J=7.43 Hz, 1H), 7.62 (s, 1H, NH), 9.50 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) δc: 21.7, 26.8, 37.1, 51.1, 107.7, 128.3, 129.8,
130.0, 130.3, 132.8, 141.8, 151.8, 156.0, 193.8.
1649, 1569, 1479 cm−1
;
1H NMR (500 MHz, DMSO-d6) δH: 2.28
(s, 3H), 5.07 (d, J=2.8 Hz, 1H), 6.79 (m, 2H), 7.00–7.28 (m, 12H),
8.87 (s, 1H, NH), 9.28 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6) δc:
20.6, 58.6, 111.2, 126.3, 127.0, 127.8, 128.0, 129.2, 128.4, 129.2, 133.3,
133.8, 137.1, 137.3, 139.5, 153.0.
4-(3,5-Dichlorophenyl)-3,4,7,8-tetrahydro-1H,6H-quinazolin-2,5-
dione (7d). Yellow powder; mp: 324–326 °C; IR (KBr) νmax: 3228,
3,4-Dihydro-4-(4-Cl-phenyl)-5,6-diphenylpyrimidine-2(1H)-thione
(4h). White powder; mp: 284–286 °C; IR (KBr) νmax: 3211, 3060, 2906,
3116, 2956, 1701, 1614, 1581, 1465 cm−1 1H NMR (500 MHz, DMSO-
;
d6) δH: 1.81 (m, 1H), 1.90 (m, 1H), 2.22 (m, 2H), 2.45 (t, 1H), 2.49
(t, 1H), 5.20 (s, 1H), 7.21 (s, 1H), 7.22 (s, 1H), 7.46 (t, 1H), 7.82 (s, 1H,
NH), 9.60 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6) δc: 21.5, 26.7,
37.0, 52.1, 107.9, 125.9, 127.7, 134.8, 149.4, 152.2, 156.2, 194.2.
4-(4-Br-Phenyl)-3,4,7,8-tetrahydro-1H,6H-2-thioxoquinazolin-5-one
(7e). Yellow powder; mp: 306–307 °C; IR (KBr) νmax: 3242, 3184, 2991,
1658, 1596, 1490 cm−1
;
1H NMR (500 MHz, DMSO-d6) δH: 5.20
(d, J=3.4 Hz, 1H), 6.79–7.24 (m, 10H), 7.37 (d, J=8.38 Hz, 2H), 7.42
(d, J=8.38 Hz, 2H), 8.72 (s, 1H, NH), 9.35 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) δc: 59.5, 110.0, 126.8, 126.8, 128.7, 128.9, 129.0,
129.5, 129.8, 130.2, 132.8, 135.7, 135.8, 138.7, 143.7, 172.5.
3,4-Dihydro-4-(4-NO2-phenyl)-5,6-diphenylpyrimidine-2(1H)-
thione (4k). White powder; mp: 276–277 °C; IR (KBr) νmax: 3228, 3089,
1623, 1566, 1460 cm−1 1H NMR (500 MHz, DMSO-d6) δH: 1.80
;
(m, 1H), 1.91 (m, 1H), 2.22 (m, 1H), 2.27 (m, 1H), 2.48 (m, 1H), 2.51
(m, 1H), 5.17 (s, 1H), 7.15 (d, J=8.55 Hz, 2H), 7.51 (d, J=8.55 Hz, 2H),
9.60 (s, 1H, NH), 10.6 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6) δc:
21.3, 26.1, 37.1, 52.3, 109.5, 121.5, 129.5, 132.2, 143.4, 151.7, 175.3, 194.8.
2926, 1685, 1649, 1531 cm−1 1H NMR (500 MHz, DMSO-d6) δH: 5.36
;
(d, J=3.4 Hz, 1H), 6.81–7.05 (m, 10H), 7.60 (d, J=8.6 Hz, 2H), 8.25
(d, J=8.6 Hz, 2H), 9.46 (s, 1H, NH), 10.12 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6) δc: 59.1, 111.3, 124.9, 127.4, 128.8, 128.9, 129.4,
129.5, 129.9, 130.6, 134.4, 134.8, 137.6, 147.9, 150.3, 174.8.
3,4-Dihydro-5-etoxycarbonyl-4-(2,4-dichlorophenyl)-6-methyl-
pyrimidine-2(1H)-one (4l). White powder; mp: 253–255 °C; IR (KBr)
3. Results and discussion
ν
max: 3244, 3216, 2977, 1724, 1702, 1647, 1463 cm−1
;
1H NMR
Recently, chlorotrimethylsilane has been used as a mild and effi-
cient promoter for various organic reactions [28–32]. It has been
reported as a useful and inexpensive Lewis acid catalyst for the syn-
thesis of octahydroquinazolinones. In 2006, reaction of dimedone,
aromatic aldehydes and urea in the presence of TMSCl was carried
out by Kantevari, in the MeCN/DMF at 80 °C. There are disadvantages
for this report due to long reaction time (1.5–3 h), use of stoichiomet-
ric amount of TMSCl and unrecoverable solvent [33]. In 2010, the syn-
thesis of octahydroquinazolinones using cyclohexadione instead of
dimedone in the presence of TMSCl in [Bmim]BF4 was reported by
refluxing for 6.5–8 h [34], yet the reaction time was very high.
In our previous work [39], the condensation reaction of aromatic
aldehyde, deoxybenzoin, and urea in the presence of TMSCl/
Co(OAc)2·4H2O under microwave irradiation was studied. Herein,
to introduce a milder method, our initial attempts were directed
toward the synthesis of 3,4-dihydro-4-aryl-5,6-diphenylpyrimidin-
2(1H)-ones. In order to find the optimum conditions, for the forma-
tion of 4a, reaction of 3-nitrobenzaldehyde (1 mmol) 1a, deoxyben-
zoin (1 mmol) 2a, and urea (2 mmol) 3 was performed in the
presence of various ionic liquids such as [Hmim]HSO4, 1-buthyl-3-
methyimidazolium bromide ([Bmim]Br), 1-methyl-2-pyrolidonium
hydrogen sulfate ([NMP]HSO4). We found that, all of the above ionic
liquids could promote the reaction, but the yields were not so high
(Table 3, entries 1–3).
(500 MHz, DMSO-d6) δH: 1.00 (t, 3H), 2.28 (s, 3H), 3.89 (q, 2H), 5.59
(d, J=1.5 Hz, 1H), 7.30–7.55 (m, 3H), 7.73 (s, 1H, NH), 9.30 (s, 1H,
NH); 13C NMR (125 MHz, DMSO-d6) δc: 14.7, 18.5, 52.0, 60.0, 98.3,
128.8, 129.5, 130.1, 133.4, 133.5, 141.8, 150.4, 152.0, 165.7, 187.0.
3,4-Dihydro-5-etoxycarbonyl-4-(2-OMe-phenyl)-6-methylpyr-
imidine-2(1H)-thione (4r). White powder; mp: 193–195 °C; IR (KBr)
ν
max: 3176, 3132, 2985, 1703, 1645, 1583, 1479 cm−1 1H NMR
;
(500 MHz, DMSO-d6) δH: 1.00 (t, 3H), 2.28 (s, 3H), 3.78 (s, 3H), 3.90
(m, 2H), 5.50 (d, J=3.2 Hz, 1H), 6.87–7.27 (m, 4H), 9.21 (s, 1H, NH),
10.20 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6) δc: 14.8, 17.8, 50.3,
56.3, 60.2, 100.2, 112.1, 121.0, 128.6, 129.9, 131.4, 145.9, 157.5, 166.0,
175.0.
4-(3-NO2-phenyl)-3,4,7,8-tetrahydro-1H,6H-quinazolin-2,5-dione
(7a). Yellow powder; mp: 308–310 °C; IR (KBr) νmax: 3338, 3209, 3091,
2952, 1706, 1622, 1527, 1446 cm−1; 1H NMR (500 MHz, DMSO-d6) δH:
1.82 (m, 1H), 1.92 (m, 1H), 2.23 (m, 1H), 2.25 (m, 1H), 2.43 (m, 1H),
2.52 (m, 1H), 5.33 (s, 1H), 7.62 (t, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.9
R1
O
O
CHO
X
[Hmim]HSO4
NH
+
+
However, satisfactory results were obtained when the reactions
were carried out in the presence of TMSCl. The amount of ionic liquid
and TMSCl was examined, and the results are summarized in Table 3.
It could be seen that 0.5 mmol [Hmim]HSO4 and 0.5 mmol TMSCl
gave the best yield (96%) at 80 °C (entry 4, Table 3).
H2N
NH2
TMSCl
R2
R3
R2
O
N
X
R3
H
R1
5
6
7
Scheme 2. Synthesis of hydroquinazoline-2,5-diones/thiones.

150
H. Kefayati et al. / Journal of Molecular Liquids 172 (2012) 147–151
Table 3
Brønsted acidic ionic liquid ([Hmim]HSO4) can activate the car-
bonyl groups of aldehyde via hydrogen bonding between the carbonyl
group and the cationic (N+–H) or anionic component (HSO4−) of ionic
liquid to decrease the energy of transition state. The TMSCl effects may
be explained in terms of hard–soft reagent, which activates the
carbonyl group of deoxybenzoin and considerably accelerates the
reaction.
After reaction, the ionic liquid is easily separated from the reaction
medium by washing with distilled water (IL is soluble in water). The
washed ionic liquid is distilled under vacuum to recover solvent for
reuse in subsequent reactions. After three successive runs, recycled
ionic liquid showed no loss of efficiency with regard to reaction time
and yield (Table 1).
Effects of the type and amount of ionic liquid and TMSCl on the formation of 4a.
Entry
Ionic liquid (mmol)
TMSCl (mmol)
t (min)
Yield (%)
1
2
3
4
5
6
7
8
[Hmim]HSO4(0.5)
[Bmim]Br(0.5)
[NMP]HSO4(0.5)
[Hmim]HSO4(0.5)
[Bmim]Br(0.5)
[NMP]HSO4(0.5)
[Hmim]HSO4 (0.5)
[Hmim]HSO4 (0.5)
[Hmim]HSO4 (0.5)
[Hmim]HSO4 (0.25)
[Hmim]HSO4 (0.75)
[Hmim]HSO4 (1)
–
40
60
90
40
40
90
45
50
60
60
40
60
72
60
22
96
82
35
81
84
78
75
85
77
–
–
0.5
0.5
0.5
0.25
0.75
1
0.5
0.5
0.5
9
10
11
12
Reaction condition: 3-Nitrobenzaldehyde (1 mmol), deoxybenzoin (1 mmol), urea
(2 mmol), 80 °C.
4. Conclusion
The ionic liquid, [Hmim]HSO4, in the presence of TMSCl can effi-
ciently catalyze the condensation of an aromatic aldehyde, cyclic or
acyclic ketones or β-ketoester and urea (or thiourea) that affords
the corresponding 3,4-dihydropyrimidin-2(1H)-ones/thiones and
hydroquinazoline-2,5-diones/thiones. A simple procedure for product
isolation, lack of problems connected with conventional solvent use,
descend reaction time with improved yield and use of catalytic
amount of TMSCl as compared to other reported methods are advan-
tages of the proposed procedure.
In order to examine the substrate scope of Biginelli reaction, the
reaction of various aromatic aldehydes and urea (or thiourea) with
deoxybenzoin (or ethyl acetoacetate) under the optimized reaction
conditions was examined (Scheme 1). The results are shown in
Table 1. According to the table, we could see that all the reactions
afforded the corresponding DHPMs 4a-s in good to high yields.
Prompted by this success and in order to explore the generality of
the method, we extended the reaction of various aldehydes and urea
(or thiourea) with cyclic diketones such as dimedone and cyclohexane-
dione under similar conditions and as the results hydroquinazoline-2,5-
diones/thiones 7a-p were obtained as products (Table 2, Scheme 2).
A brief comparison of the present method with those previously
reported in literature in terms of reaction times and yields reveals
the merit of this method for the synthesis of the desired products. As
shown in Tables 1 and 2, reaction times were considerably decreased
and yield of reaction increased. Thus, the [Hmim]HSO4 and TMSCl
act as a suitable catalytic medium with respect to reaction times and
yields of the products.
Acknowledgment
We are grateful to the Islamic Azad University, Rasht Branch for
financial support of this work.
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H2N NH2
TMSHN NH2
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R2
R3
R3
R2
NH
NH
X
NH -TMSOH
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