One-pot three-component Biginelli-type reaction catalyzed by ionic liquids in aqueous media

Article abstract of DOI:10.1007/s00706-010-0271-y

For the first time, 3,4-dihydropyrimidin-2(1H)-one and 3,4- dihydropyrimidin-2(1H)-thione derivatives have been synthesized in good yields by a modified Biginelli-type reaction with dicationic acidic ionic liquids as catalysts. The products could be separ

Full text of DOI:10.1007/s00706-010-0271-y

Monatsh Chem (2010) 141:419–423
DOI 10.1007/s00706-010-0271-y
ORIGINAL PAPER
One-pot three-component Biginelli-type reaction catalyzed
by ionic liquids in aqueous media
•
Dong Fang Dai-zhen Zhang Zu-liang Liu
•
Received: 2 January 2010 / Accepted: 17 February 2010 / Published online: 11 March 2010
Ó Springer-Verlag 2010
Abstract For the first time, 3,4-dihydropyrimidin-2(1H)-
one and 3,4-dihydropyrimidin-2(1H)-thione derivatives
have been synthesized in good yields by a modified Bigi-
nelli-type reaction with dicationic acidic ionic liquids as
catalysts. The products could be separated simply from the
catalyst–water system, and the catalysts could be reused
at least six times without noticeably reducing catalytic
activity.
Recently, dihydropyrimidinones have been considered as
a new lead for the development of new anticancer drugs
[2, 3]. The simplest and the most straightforward approach
for DHPMs reported by Biginelli more than 100 years
ago involves a one-pot three-component acid-catalyzed
condensation, which is still one of the most often used
multi-component reactions (MCRs) [4], but this Biginelli-
type reaction suffers from harsh conditions, long reaction
times, and, frequently, low yields, and continues to attract
attention of researchers seeking a milder and more efficient
procedure and efficient catalysts for the synthesis of
DHPMs.
Keywords Biginelli-type reaction ꢀ Dicationic ionic
liquid ꢀ Catalyst ꢀ One-pot reaction
In recent years, several synthetic procedures for the
preparation of DHPMs have been made to improve and
modify this reaction. These include assistance of micro-
wave [5, 6] or ultrasound [7, 8] irradiation, and use of
Lewis and/or Brønsted acids as catalysts. Many catalysts,
for example FeCl3-supported nanopore silica [6], ferric
perchlorate [9], polyoxometalate [10], strontium(II) nitrate
[11], cerium(III) chloride [12], ytterbium chloride [13],
heteropoly acids [14], L-proline [15], silica sulfuric acid
[16], TMSCl [17], trifluoroacetic acid [18], and TBAB
[19], have been used, and the search for new, readily
available, and green catalysts is still being actively
pursued.
Introduction
3,4-Dihydropyrimidines (DHPMs) and their derivatives
are pharmacologically important compounds with broad
biological activity, including antiviral, antibacterial, anti-
tumor, and antihypertensive agents, a1a adrenergic anta-
gonists, and neuropeptide Y (NPY) antagonists. Furthermore,
these compounds have emerged as the integral backbones
of several calcium-channel blockers [1]. Some marine
alkaloids containing the dihydropyrimidine core unit have
interesting biological properties; batzelladine alkaloids
have been found to be potent HIV gp-120-CD4 inhibitors.
Nowadays ionic liquids attract much interest as envi-
ronmentally benign catalysts or excellent alternatives to
organic solvents, because of their favorable properties, for
example negligible volatility and high thermal stability.
Brønsted acidic or basic task-specific ionic liquids (TSILs)
are designed to replace traditional acids or bases as cata-
lysts in organic synthetic procedures. In view of the
advantages and disadvantages of homogeneous and heter-
ogeneous catalytic reactions, the use of TSILs as reaction
medium and/or catalytic system may be a convenient
D. Fang ꢀ D. Zhang
Jiangsu Provincial Key Laboratory of Coast Wetland
Bioresource and Environment Protection,
Yancheng 224002, People’s Republic of China
D. Fang (&) ꢀ Z. Liu
School of Chemical Engineering,
Nanjing University of Science and Technology,
Nanjing 210094, People’s Republic of China
e-mail: fang-njust@hotmail.com
123

420
D. Fang et al.
solution to the solvent-emission and catalyst-recycling
problems. TSILs have also been used as catalysts for the
Biginelli reaction [20–25]. Deng et al. [20, 21] synthesized
DHPMs in BMImBF4 or BMImPF6, Shaabani and Rahmati
[22] used the room-temperature ionic liquid 1,1,3,3-
tetramethylguanidinium trifluoroacetate as catalyst, Li
et al. [23] reported an ionic liquid (BMImSac) as catalyst,
Zheng et al. [24] used CMImHSO4 as catalyst for a Bigi-
nelli-type reaction, and Peng et al. [25] found the Lewis
acidic ionic liquid [bmim][FeCl4] to be an efficient catalyst
for synthesis of DHPMs. However, TSILs with imidazole
as the cation are relatively expensive, which hinders their
industrial application. Furthermore, typical ionic liquids
consist of halogen-containing anions (for example [PF6]-,
[BF4]-, [CF3SO3]-, or [(CF3SO2)2N]-) which to some
extent limits their ‘‘greenness’’ [26–29]. Therefore, it is
necessary to synthesize novel efficient and halogen-free
TSILs. In continuation of our study of ionic liquid-cata-
lyzed MCRs in aqueous media [30, 31], we synthesized
some dicationic acidic ionic liquids as halogen-free TSILs
that bear dialkane sulfonic acid groups in acyclic diamine
cations (Scheme 1), and subsequently used these as cata-
lysts in a one-pot, three-component Biginelli-type reaction
(Scheme 2). To the best of our knowledge of the open
literature, Biginelli-type reactions catalyzed by dicationic
ionic liquids have not been reported.
Results and discussion
The procedure for synthesis of catalyst TSILs was made up
of a two-step atom-economic reaction. The zwitterionic-
type precursors were prepared by a one-step direct sulfo-
nation reaction. Acidification of the zwitterions was
accomplished by mixing with twice the molar amount of
sulfuric acid (98%, aq.) to convert the pendant sulfonate
group into dicationic halogen-free acidic ionic liquids.
The chemical yields for both zwitterion formation and
acidification were essentially quantitative, because neither
reaction produced byproducts. The fresh new catalysts are
somewhat viscous pale yellow liquids at room temperature.
All the catalysts produced are entirely miscible with water
and soluble or partly soluble in organic solvents.
In the initial catalytic activity experiments, benzalde-
hyde, ethyl acetoacetate, and urea were employed as the
model reactants at 90 °C in TSILs for a length of time to
compare the catalytic performance of the TSILs (Table 1).
It was shown that no desirable product could be detected
when a mixture of benzaldehyde, ethyl acetoacetate, and
urea was heated at 90 °C for 60 min in the absence of
TSILs (entry 1), which indicated that the catalysts was
absolutely necessary for this three-component Biginelli-
type reaction. All TSILs proved to be very active. It is clear
that the yield was increased by addition of TSILs and the
optimum amount of TSILs was 2 mol% (entries 3, 7).
A larger amount of the catalysts could not improve the
yield. For the purpose of comparison, sulfuric acid as
catalyst was tested for this reaction under the same con-
ditions and a yield of 41% was obtained (entry 12).
Condensation reaction in TSILs–H2O gave the same yield
as in organic solvents. As a clean and inexpensive solvent,
it is important to carry out this reaction in water for envi-
ronmental and economic reasons.
O
O
S
N
(CH2)n
N
+
O
O3S
SO3
N
(CH2)n
N
1-3
HO3S
SO3H
H2SO4
N
(CH2)n
N
HSO4
HSO4
The recycling performance of the catalysts was also
investigated using the above model reaction. After sepa-
ration of the products, the filtrate containing the catalyst
was reused in the next run without further purification.
4-6
1, 4: n=2; 2, 5: n=3; 3, 6: n=6
Scheme 1
Scheme 2
R1
CHO
O
X
O
O
TSILs 4-6
R1
+
+
R3
NH
90 °C, 10-60min
R2
R3
H2N
NH2
R2
N
H
X
7
8
9
10
123

One-pot three-component Biginelli-type reaction
421
Table 1 Effect of the different catalysts on the Biginelli-type
reaction
Table 3 Three-component Biginelli-type reaction catalyzed by di-
cationic 4
Entry
Catalyst (mmol)
Isolated yield (%)
Entry R1
R2
R3
X
Time Yield Ref.
(min) (%)a
1
0
0
88
96
96
95
86
96
96
84
91
91
41
10a
10b
10c
10d
10e
10f
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OC2H5
OC2H5
OCH3
OCH3
CH3
O
S
10
30
10
30
10
10
30
10
30
30
45
15
60
15
45
10
30
15
96
84
92
80
93
95
91
90
86
87
76
92
83
90
88
85
81
90
[19]
[9]
2
4 (0.1)
4 (0.2)
4 (0.3)
4 (0.4)
5 (0.1)
5 (0.2)
5 (0.3)
6 (0.1)
6 (0.2)
6 (0.3)
H2SO4 (0.2)
H
3
H
O
S
[22]
[22]
[22]
[25]
[19]
[25]
[19]
[22]
[19]
[19]
[25]
[25]
[16]
[14]
[9]
4
H
5
H
O
O
S
6
4-CH3O
4-CH3O
4-CH3
4-NO2
4-NO2
3-NO2
4-Cl
2,4-Cl2
3-Br
OC2H5
OC2H5
OC2H5
OC2H5
OCH3
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH3
7
10g
10h
10i
8
O
O
O
O
O
O
O
O
O
O
O
9
10
11
12
10j
10k
10l
Reaction conditions: 10 mmol benzaldehyde, 10 mmol ethyl aceto-
acetate, 10 mmol urea, 0.2 mmol TSILs, 90 °C, 10 min
10m
10n
10o
10p
10q
10r
3,4-(CH3O)2 CH3
Table 2 Reuse of the dicationic ionic liquid catalysts
2-OH
2-Furyl
H
CH3
CH3
OC2H5
Run
Isolated yield (%)
C6H5 OC2H5
[16]
4
5
6
Reaction conditions: 10 mmol aldehyde, molar ratio of aldehyde,
acetoacetate, and urea (or thiourea) 1:1:1, 0.2 mmol 4, 90 °C
1
2
3
4
5
6
96
96
95
94
94
94
96
96
94
95
93
92
91
91
90
91
88
89
a
Isolated yield based on carbonyl compounds
Besides the b-ketoester, b-diketones can also be
employed without any decrease in yields (entries 5, 16).
Thiourea was used as one of the substrates to provide the
corresponding DHPMs in reasonable to good yields
(entries 2, 4, 7). It is of great importance that many of the
pharmacologically relevant substitution patterns on the
aromatic ring could be introduced without any interruption
in efficiency. Also important is the survival of a variety of
functional groups, for example as ethers, esters, nitro,
hydroxyl, and halides under these reaction conditions.
Aromatic aldehydes carrying either electron-donating or
electron-withdrawing substituents could afford good yields
of DHPMs in high purity.
Reaction conditions: 10 mmol benzaldehyde, 10 mmol ethyl aceto-
acetate, 10 mmol urea, 0.2 mmol TSILs, 90 °C, 10 min. After
separation of the product by filtration, the recovered solvent con-
taining the catalyst was reused directly
A mixture of benzaldehyde, ethyl acetoacetate, and urea in
stoichiometric ratio was added to the filtrate and stirred
under the same conditions. The data listed in Table 2 show
that the TSILs could be reused six times without a decrease
of catalytic activity. Compared with the traditional solvents
and catalysts, the easy recycling performance is also an
attractive property of the TSILs for environmental protec-
tion and economic reasons.
In summary, an efficient procedure for synthesis of
DHPMs via one-pot three-component Biginelli-type reaction
catalyzed by dicationic ionic liquids was developed. The
methodology has the advantages of short reaction time, lack
of organic solvent, recyclability of catalysts, and easy work-
up for isolation of the products in good yield with high purity.
This condensation reaction with various aldehydes, 1,3-
dicarbonyl compounds, and urea (or thiourea) in the pres-
ence of TSIL 1 as the catalyst was then explored under the
optimized reaction conditions described above; the results
are presented in Table 3. It can easily be seen that this
three-component Biginelli-type condensation was complete
within 10–60 min. Compared with the classical Biginelli
method, one additional important feature of the present
procedure is the ability to tolerate variations in all three
components simultaneously.
Experimental
Melting points were determined by use of an X6-Data
microscope apparatus. The IR spectra were run on a Bruker
Vectter 22 spectrometer and results are expressed in cm-1
123

422
D. Fang et al.
(KBr). 1H and 13C NMR spectra were recorded on a Bruker
DRX300 spectrometer at 300 and 75.5 MHz in D2O. Ele-
mental analyses were performed with a Perkin–Elmer C
elemental analyzer, and the results agreed favorably with
calculated values. Mass spectra were obtained with an
automated Finnigan TSQ Quantum Ultra AM (Thermal)
LC–MS spectrometer. All chemicals (AR grade) were
commercially available and used without further
purification.
then removed under vacuum at 100 °C and the product was
washed repeatedly with diethyl ether to remove unreacted
material and again dried under vacuum. TSIL 4 was
obtained quantitatively and in high purity as a colorless oil.
1H NMR (300 MHz): d = 1.85–1.95 (q, 29 2H, J =
7.65 Hz, N–C–CH2–C–SO3), 2.64 (t, 29 2H, J = 6.9 Hz,
N–C–C–CH2–SO3), 2.89 (s, 49 3H, N–CH3), 3.24 (t, 29
2H, J = 8.4 Hz, N–CH2–C–C–SO3), 3.60 (s, 4H, N–CH2–
CH2–N) ppm; 13C NMR (75.5 MHz): d = 18.71, 47.48,
51.72, 56.30, 64.18 ppm; MS: m/z = 556.89 (M?), 361.07
(M?- 2H2SO4, 100).
N,N,N0,N0-Tetramethylethylenediammonium-
bis(propanesulfonate) (1, C12H28N2O6S2)
N,N,N0,N0-Tetramethyl-N,N0-bis(3-sulfopropyl)-1,3-propa-
ndiyldiammonium bis(hydrogensulfate)
(5, C13H34N2O14S4)
To
a solution of 11.6 g tetramethylethylenediamine
(0.10 mol) in 20 cm3 1,2-dichloroethane was added
24.4 g 1,3-propanesulfone (0.20 mol), in portions, within
15 min. The mixture was then stirred under nitrogen for
2 h at 55–60 °C. The white precipitate thus formed was
cooled to room temperature, then isolated by filtration and
washed with petroleum ether. The product was recrystal-
lized from a mixture of water, ethanol, and diethyl ether to
give 98% yield of white solid product, m.p.: 298–300 °C
Synthesized by the same process as 4, quantitative yield of
1
pale yellow oily product. H NMR (300 MHz): d = 2.01–
2.11 (m, 4H?2H, N–C–CH2–C–SO3, N–C–CH2–C–N),
2.72–2.81 (m, 29 2H, N–C–C–CH2–SO3), 2.92 (s, 49 3H,
N–CH3), 3.21–3.32 (m, 4H?4H, N–CH2–C–C–SO3, N–
CH2–C–CH2–N) ppm; 13C NMR (75.5 MHz): d = 17.14,
19.09, 48.10, 52.33, 61.15, 63.77 ppm.
1
(dec). H NMR (300 MHz): d = 2.12–2.20 (m, 29 2H,
N–C–CH2–C–SO3), 2.88 (t, 29 2H, J = 6.9 Hz, N–C–C–
CH2–SO3), 3.14 (s, 49 3H, N–CH3), 3.49–3.52 (m, 29 2H,
N–CH2–C–C–SO3), 3.87 (s, 4H, N–CH2–CH2–N) ppm;
MS: m/z = 361.06 (M?).
N,N,N0,N0-Tetramethyl-N,N0-bis(3-sulfopropyl)-1,6-hexa-
ndiyldiammonium bis(hydrogensulfate)
(6, C16H40N2O14S4)
Synthesized by the same process as 4, quantitative yield of
1
pale yellow oily product. H NMR (300 MHz): d = 1.13
N,N,N0,N0-Tetramethyl-1,3-propandiyldiammonium-
bis(propanesulfonate) (2, C13H30N2O6S2)
Synthesized by the same process as 1 except that the reaction
(s, 4H, N–C–C–CH2–CH2–C–C–N), 1.49 (s, 4H, N–C–
CH2–C–C–CH2–C–N), 1.88–1.90 (m, 29 2H, N–C–CH2–
C–SO3), 2.64–2.68 (m, 29 2H, N–C–C–CH2–SO3), 2.79
(s, 49 3H, N–CH3), 3.00–3.02 (m, 29 2H, N–CH2–C–C–
SO3), 3.13–3.15 (m, 4H, N–CH2–C–C–C–C–CH2–N) ppm;
13C NMR (75.5 MHz): d = 17.92, 21.42, 24.74, 47.15,
50.40, 61.85, 63.84 ppm.
was carried out for 4 h at 35–40 °C. White solid, yield 96%,
1
m.p.: 292–294 °C (dec). H NMR (300 MHz): d = 2.06–
2.14 (m, 29 2H, N–C–CH2–C–SO3), 2.18–2.20 (m, 2H,
N–C–CH2–C–N), 2.85 (t, 29 2H, J = 6.8 Hz, N–C–C–
CH2–SO3), 3.03 (s, 49 3H, N–CH3), 3.30 (t, 29 2H,
J = 8.0 Hz, N–CH2–C–C–SO3), 3.41 (t, 4H, J = 8.3 Hz,
N–CH2–C–CH2–N) ppm; MS: m/z = 374.30 (M? -1).
General procedure for the three-component Bigineli-
type reaction catalyzed by 4
N,N,N0,N0-Tetramethyl-1,6-hexandiyldiammonium-
bis(propanesulfonate) (3, C16H36N2O6S2)
To a mixture of an aromatic aldehyde 7 (10 mmol), ace-
toacetate 8 (10 mmol), and urea 9 (thiourea or guanidine)
(10 mmol) in 10 cm3 H2O was added 0.2 mmol 4. The
mixture was stirred at 90 °C until TLC indicated the
starting materials had disappeared. The resulting mixture
was cooled and left to stand overnight. After filtration the
crude product was then purified by recrystallization from
alcohol to afford pure 3,4-dihydropyrimidines 10. All
Synthesized by the same process as 1 except that the
reaction was carried out for 2 h at 55–60 °C. White solid,
yield 95%, m.p.: 300–303 °C (dec). H NMR (300 MHz):
d = 1.30 (s, 4H, N–C–C–CH2–CH2–C–C–N), 1.66 (s, 4H,
N–C–CH2–C–C–CH2–C–N), 2.04–2.10 (m, 29 2H, N–C–
CH2–C–SO3), 2.84 (t, 29 2H, J = 7.1 Hz, N–C–C–CH2–
SO3), 2.96 (s, 49 3H, N–CH3), 3.20 (t, 29 2H, J = 8.4 Hz,
N–CH2–C–C–SO3), 3.33 (t, 4H, J = 8.5 Hz, N–CH2–C–
C–C–C–CH2–N) ppm; MS: m/z = 417.13 (M?).
1
1
products were characterized by IR and H NMR, and their
m.p.s were in agreement with reference values [9, 19, 25].
N,N,N0,N0-Tetramethyl-N,N0-bis(3-sulfopropyl)ethylenedi-
ammonium bis(hydrogensulfate) (4, C12H32N2O14S4)
To a solution of 36.1 g 1 (0.10 mol) in 10 cm3 water was
added 20.0 g sulfuric acid solution (98%, 0.20 mol). The
mixture was then stirred for 2 h at 80 °C. The water was
Acknowledgments We are grateful to the Education Commission
of Jiangsu Province (07KJD530238), Jiangsu Provincial Key Labo-
ratory of Coast Wetland Bioresource and Environment Protection
(JLCBE09023), and Professional Elite Foundation of Yancheng
Normal University for financial support.
123

One-pot three-component Biginelli-type reaction
423
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