Facile Biginelli-type reactions catalysed by super acidic ionic liquid under solvent-free conditions

Article abstract of DOI:10.3184/174751912X13518654161237

[MeC(OH)₂]⁺ClO₄^-?as a super acidic ionic liquid is an extremely active catalyst for Biginelli-type reactions. The present method is especially effective for the inactive aliphatic aldehydes. The solvent-free conditions, high catalytic activity, wide substrates tolerance and convenient product isolation make the protocol more advantageous.

Full text of DOI:10.3184/174751912X13518654161237

712 RESEARCH PAPER
DECEMBER, 712–714
JOURNAL OF CHEMICAL RESEARCH 2012
Facile Biginelli-type reactions catalysed by super acidic ionic liquid under
solvent-free conditions
Liang Wang*, Min Zhou, Qun Chen and Ming-Yang He
Jiangsu Province Key Laboratory of Fine Petro-ChemicalTechnology, Changzhou University, Changzhou 213164, P. R. China
[MeC(OH)2]+ClO4− as a super acidic ionic liquid is an extremely active catalyst for Biginelli-type reactions. The present
method is especially effective for the inactive aliphatic aldehydes. The solvent-free conditions, high catalytic activity,
wide substrates tolerance and convenient product isolation make the protocol more advantageous.
Keywords: Biginelli-type reactions, super acid, multi-component reaction, dihydropyrimidinones
Dihydropyrimidinones (DHPMs) and their derivatives have
attracted much attention in recent years due to the broad bio-
logically activities. Many synthetic samples have been studied
as antibacterial, antiviral, antihypertensive and anticancer
agents.1 Also, the natural products containing these heterocy-
clic moieties have been studied as possibilities for AIDS thera-
pies.2 Generally, the simple and straightforward procedure
for the synthesis of dihydropyrimidinones involves one-pot
condensation of ethyl acetoacetate, aldehyde, and urea under
strong acid conditions, which was first reported by Biginelli
in 1893.3 However, the major drawback associated with this
protocol is the low yield and long reaction time.
Recently, several synthetic procedures for the preparation of
DHPMs have been made to improve and modify this reaction.
These include assistance of microwave4,5 or ultrasound6,7
irradiation, and utilisation of various Lewis acids, Brønsted
acids and organocatalysts. Many catalysts, for example ferric
perchlorate,8 strontium(II) nitrate,9 ytterbium chloride,10
heteropoly acids,11 trifluoroacetic acid,12 silica sulfuric acid,13
L-proline,14 TBAB15 and ionic liquid,16 have been used, and the
search for new, efficient and readily available catalysts is still
being pursued. Although remarkable advances have been
achieved in this field, more effort is required in order to make
the reaction efficient, substrate compatible and environmen-
tally friendly. There are two main issues that need to be
addressed: (1) most of the reported methods for Biginelli
reactions are focused on the aromatic aldehydes. The yields of
Biginelli condensation products from aliphatic aldehydes are
much lower than those from aromatic aldehydes; (2) the
reported methods are always conducted in organic solvents or
using metal-based catalysts, which can cause environmental
and product pollution. Consequently, there is room for further
improvement toward milder reaction conditions for the
Biginelli-type condensation.
(Scheme 2). The reaction conditions could also be utilised in
other Biginelli-type reactions.
Initially, reaction of butyraldehyde, ethyl acetoacetate and
urea was performed to find the optimal reaction conditions. As
shown in Table 1, the best result was obtained in the presence
of 1 mol% [MeC(OH)2]+ClO4− under solvent-free conditions at
90 °C (Table 1, entry 4). In all cases, the reaction products
precipitated as the reaction progressed. Comparative studies
using a large excess of AcOH or HClO4 under the same
conditions showed that much lower yields were obtained
together with a prolonged time. The catalyst, however, showed
extremely high activity for the reaction. Only 0.5 mol% of
catalyst could afford the product in 83% yield within 30 min-
utes, and 1 mol% of catalyst was the best choice. In addition,
the reactions were obviously affected by the temperature. The
studies showed that 90 °C was the optimal and the lower the
temperature, the lower the yield. Finally, different solvents
were evaluated (Table 1, entries 10–12). Generally, polar
solvents were more effective than the non-polar ones, while
the solvent-free system afford the best yield.
With these results, several aliphatic and aromatic aldehydes
were examined under the optimised conditions. The results
were summarised in Table 2. It was obvious that the Biginelli
condensation of aliphatic aldehydes proceeded smoothly to
give the corresponding 3,4-dihydropyrimidin-2-(1H)-ones in
good to excellent yields within 60 minutes. Using methyl ace-
toacetate and acetylacetone instead of ethyl acetoacetate, the
desired products were also obtained in high yields (Table 2,
entries 7–10). Thiourea was also used in the similar way to
produce the corresponding thio derivatives of dihydropyrim-
idinones which are also of interest with respect to their
biological activities. In addition, aromatic aldehydes with
different functional groups showed excellent activities towards
the reaction, providing better yields in less reaction time.
Moreover, this procedure not only preserves the simplicity of
the Biginelli reaction, but also produces good yields of the
products with high purity.
Next, we extended this protocol to the preparation of
5-unsubstituted 3,4-dihydropyrimidinones via Biginelli-type
condensation (Table 3). Under the above optimised conditions,
various functional groups showed good compatibilities, and
the reaction of aldehydes, acetophenone and urea (or thiourea)
proceeded rapidly within 20 minutes, giving the products in
good to excellent yields.
Finally, due to the biological activity of 5-carboxamide sub-
stituted 3,4-dihydropyrimidine-2(1H)one derivatives, we tried
a four-component Biginelli-type reaction of amine, diketene,
aromatic aldehyde and urea (or thiourea) in the presence of
catalytic [MeC(OH)2]+ClO4− (Scheme 3). The results clearly
showed that the four-component Biginelli-type reaction pro-
ceeded well and good yields were obtained. As for the possible
mechanism, it is reasonable to assume that addition of an
amine to diketene results in the N-alkyl-3-oxobutanamide,
which undergoes the Biginelli condensation as a β-dicarbonyl
synthon (Scheme 4).32
Recently, Tamaddon et al. reported an efficient protocol for
the preparation of 1-amido- and 1-carbamato-alkyl naphthols
by employing a super acidic ionic liquid [MeC(OH)2]+ClO4−.17
The superacid was readily prepared by mixing acetic acid
and perchloric acid at room temperature, while showing a
strong protonation ability even for very weak organic bases
(pH = –4.4) (Scheme 1).18,19 We envisioned that this acidic
room-temperature ionic liquid should be a good catalyst for
Biginelli-type reactions. We now report an improved method
for the synthesis of DHPMs using super acidic ionic liquid as
catalyst under solvent-free conditions in short reaction time
Scheme 1 Preparation of super acidic ionic liquid.
* Correspondent. E-mail: lwcczu@126.com

JOURNAL OF CHEMICAL RESEARCH 2012 713
Scheme 2 Super acidic ionic liquid catalysed the Biginelli-type reactions under solvent-free conditions.
Table 1 Optimisation of reaction conditionsa
Table 3 Synthesis of 5-unsubstituted 3, 4-dihydropyrimidin-
one using [MeC(OH)2]+ClO4−a
Entry Catalyst/mol%
Solvent Temp Time Yield
/°C
/min /%b
Entry
R3
X
Time/
min
Yield
/%b
M.p. /°C(lit.)
1
2
AcOH (10)
–
90
90
120 Trace
HClO4 (10)
–
120
30
30
30
30
30
30
60
60
60
60
66
83
95
92
90
81
55
24
89
70
39
1
2
H
O
O
O
O
O
O
O
S
10
15
15
15
15
15
20
10
15
15
20
92
95
87
85
88
92
84
91
83
90
81
228–230(229–230)26
266(265–266)26
3
[MeC(OH)2]+ClO4− (0.5)
[MeC(OH)2]+ClO4− (1)
[MeC(OH)2]+ClO4− (5)
[MeC(OH)2]+ClO4− (10)
[MeC(OH)2]+ClO4− (1)
[MeC(OH)2]+ClO4− (1)
[MeC(OH)2]+ClO4− (1)
[MeC(OH)2]+ClO4− (1)
[MeC(OH)2]+ClO4− (1)
[MeC(OH)2]+ClO4− (1)
–
90
4-Cl
4
–
90
3
2-Cl
3-Br
4-Me
4-MeO
3-NO2
H
4-MeO
4-Cl
3-NO2
262–263(264–265)26
256–258(258–259)26
246–248(248–250)27
259–260(259–261)27
201–202(196–197)28
250–252(251–253)29
223–225(227–229)29
224–228(220–230)30
182–183(185)31
5
–
90
4
6
–
90
5
7
–
70
6
8
–
–
50
7
9
rt
8
10
11
12
EtOH
CH3CN Reflux
Toluene Reflux
Reflux
9
S
10
11
S
S
a Reaction conditions: butyraldehyde (10 mmol), ethyl acetoac-
etate (10 mmol), urea (15 mmol).
a Reaction conditions: aldehyde (10 mmol), acetophenone
(10 mmol), urea or thiourea (15 mmol), catalyst (1 mol%), 90 °C.
b Isolated yield.
bIsolated yield.
Table 2 Substrates evaluation using various aldehydesa
Experimental
All reagents were obtained from local commercial suppliers and used
1
without further purification. H and 13C NMR spectra were recorded
on a Bruker Advance III 500 analyser. All the products are known
compounds and were identified by comparing their physical and
spectra data with those reported in the literature.
Entry
R1
Hc
R2
X
Time Yield
/min /%b
M.p./°C (lit.)
1
2
OC2H5
O
O
O
O
O
O
O
O
O
O
S
60
30
30
30
30
30
30
30
30
30
45
45
15
15
15
73 244–246(242–244)20
89 179–180(179–181)21
95 150–152(153–155)22
90 194–196(195–197)21
87 153–155(154–155)21
83 233–235(235–236)23
93 173–174(174–175)21
85 215–216(216–218)21
85 131–132(128–130)21
91 150–152(151–152)21
93 148–149(148–151)24
88 138–139(138–142)25
95 203–204(202–204)20
97 201–203(202–204)20
92 213–215(212–214)20
Synthesis of compounds in Table 2; general procedure
CH3CH2 OC2H5
CH3(CH2)2 OC2H5
(CH3)2CH OC2H5
CH3(CH2)5 OC2H5
Cyclohexyl OC2H5
CH3(CH2)2 OCH3
(CH3)2CH OCH3
CH3(CH2)6 OCH3
CH3(CH2)2
CH3(CH2)2 OC2H5
CH3(CH2)2
C6H5
4-MeOC6H4 OC2H5
4-ClC6H4 OC2H5
A mixture of aldehyde (10 mmol), 1,3-dicarbonyl compound (10 mmol),
urea (15 mmol) and [MeC(OH)2]+ClO4− (1 mol%) were added succes-
sively to a sealed flask, followed by stirring at 90 °C under solvent-
free conditions for 15–60 min. After completion of the reaction, a
solid precipitated and was filtered off, and then washed with cold
water and ethanol, dried in vacuo to give the product. In some cases
the products were recrystallised from ethanol.
Ethyl 6-methyl-2-oxo-4-propyl-1,2,3,4-tetrahydropyrimidine-5-carb-
oxylate (Table 2, entry 3): M.p. 150–152 °C; IR (KBr): ν 3250, 3120,
2958, 1720, 1646 cm−1; 1H NMR (500 M, DMSO-d6) δ (ppm): 0.87 (t,
3H, CH2CH2CH3), 1.21 (t, J = 4.7 Hz, 3H, OCH2CH3), 1.40 (m, 4H,
CH2CH2CH3), 2.16 (s, 3H, CH3), 4.10 (q, J = 4.7 Hz, 3H, H-4 and
OCH2CH3), 7.33 (brs, 1H, NH), 8.93 (brs, 1H, NH); MS (MALDI)
m/z 227.2 (M+H+).
3
4
5
6
7
8
9
10
11
12
13
14
15
CH3
CH3
OC2H5
S
O
O
O
a Reaction conditions: aldehyde (10 mmol), β-dicarbonyl
compound (10 mmol), urea or thiourea (15 mmol), catalyst
(1 mol%), 90 °C.
Synthesis of 5-unsubstituted 3,4-dihydropyrimidinones; general
procedure
b Isolated yield.
A mixture of aldehyde (10 mmol), acetophenone (10 mmol), urea
(15 mmol) and [MeC(OH)2]+ClO4− (1 mol%) were added successively
to a sealed flask, followed by stirring at 90 °C under solvent-free con-
ditions for 10–20 min. After completion of the reaction, a solid pre-
cipitated and was filtered off, and then washed with cold water and
ethanol, dried in vacuo to give the product. In some cases the products
were recrystallised from ethanol.
c Paraformaldehyde.
In summary, the present procedure described a facile and
efficient protocol for the Biginelli-type condensation of ali-
phaticaldehydesinthepresenceof1mol%of[MeC(OH)2]+ClO4−
. This protocol were also effective for the three-component and
four-component Biginelli-type reactions, affording the 5-
unsubstituted 3,4-dihydropyrimidinones and 5-carboxamide
substituted 3,4-dihydropyrimidinones in good to excellent
yields. Short reaction times, high yields, purity of products and
simple workup are features of this procedure.
4-(4-Chlorophenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-one
(Table 3, entry 2): M.p. 266 °C; IR (KBr) ν 3230, 2934, 1682, 1575,
1
1467 cm−1; H NMR (500 M, DMSO-d6) δ (ppm): 5.16 (d, 1H, J =
3.5 Hz, CH), 5.46(d, J = 3.5 Hz, 1H, CH), 7.30–7.52 (m, 9H, ArH),
8.10 (s, 1H, NH), 8.67 (s, 1H, NH); MS (MALDI) m/z 285.7
(M+H+).

714 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 3 Synthesis of dihydropyrimidine-5-carboxamides via four-component reaction.
Scheme 4 Possible mechanism.
7
8
9
J.T. Li, J.F. Han, J.H. Yang and T.S. Li, Ultrason. Sonochem., 2003, 10,
119.
M.M. Heravi, F.K. Behbahani and H.A. Oskooie, Chin. J. Chem., 2008, 26,
2203.
C. Liu, J. Wang and Y. Li, J. Mol. Catal. A: Chem., 2006, 258, 367.
Synthesis of 5-carboxamide substituted 3,4-dihydropyrimidinone;
general procedure
A solution of benzylamine (1.07 g, 10 mmol) and diketene (0.84 g, 10
mmol) was magnetically stirred for 10 min. Then, 4-chlorobenzalde-
hyde (1.40 g, 10 mmol), urea (0.90 g, 15 mmol) and [MeC(OH)2]+ClO4−
(1 mol%) were added. The reaction mixture was stirred at 90 °C under
solvent-free conditions for 25 min. After completion of the reaction,
the reaction mixture was filtered and the residue was washed with
cold water and ethanol, dried in vacuo to give the pure product.
N-benzyl-4-(4-chlorophenyl)-1,2,3,4-tetrahydro-6-methyl-2-oxo-
pyrimidine-5-carboxamide (Scheme 3): M.p. 234–236 °C. IR (KBr)
10 H. Zhang, Z. Zhou, Z. Xiao, F. Xu and Q. Shen, Tetrahedron Lett., 2009,
50, 1622.
11 E. Rafiee and F. Shahbazi, J. Mol. Catal. A: Chem., 2006, 250, 57.
12 D. Shobha, M.A. Chari and K.H. Ahn, Chin. Chem. Lett., 2009, 20, 1059.
13 P. Salehi, M. Dabiri, M.A. Zolfigol and M.A.B. Fard, Tetrahedron Lett.,
2003, 44, 2889.
14 M. Gohain, D. Prajapati and J.S. Sandhu, Synlett, 2004, 235.
15 B. Ahmed, R.A. Khan and K.M. Habibullah, Tetrahedron Lett., 2009, 50,
2889.
16 D. Fang, D.Z. Zhang and Z.L. Liu, Monatsh Chem., 2010, 141, 419.
17 F. Tamaddon and J.M. Bistgani, Synlett, 2011, 2947.
18 N.F. Hall and J.B. Conant, J. Am. Chem. Soc., 1927, 49, 3047.
19 J.B. Conant and N.F. Hall, J. Am. Chem. Soc., 1927, 49, 3062.
20 N.Y. Fu, Y.F. Yuan, Z. Cao, S.W. Wang, J.T. Wang and C. Peppe,
Tetrahedron, 2002, 58, 4801.
21 M. Wang, H. Jiang and Z. Wang, J. Chem. Res., 2005, 691.
22 J.J.V. Eynde, N. Audiart, V. Canonne, S. Michel, Y.V. Haverbeke and C.
Kappe, Heterocycles 1997, 45, 1967.
1
ν 3437, 3397, 3105, 2929, 1673, 1619, 1536, 1457, 1454 cm−1; H
NMR (500 M, DMSO-d6) δ (ppm): 2.01 (3H, s, CH3), 4.14–4.32 (2H,
m, CH2), 5.44 (1H, brs, CH), 6.92–7.40 (9H, m, ArH), 7.54 (1H, brs,
NH), 8.12 (1H, brs, NH), 8.64 (1H, brs, NH); MS (MALDI) m/z 356.8
(M+H+).
This project was funded by the Priority Academic Program
Development (PAPD) of Jiangsu Higher Education Institutions
which is fully acknowledged.
23 J.S.Yadav, B.V.S. Reddy, P. Sridhar, J.S.S. Reddy, K. Nagaiah, N. Lingaiah
Received 13 September 2012; accepted 14 October 2012
Paper 1201515 doi: 10.3184/174751912X13518654161237
Published online: 5 December 2012
and P.S. Saiprasad, Eur. J. Org. Chem., 2004, 552.
24 D.L. da Silva, F.S. Reis, D.R. Muniz, A.L.T.G. Ruiz, J.E. de Carvalho,
A.A. Sabino, L.V. Modolo and A. de Fátima, Bioorg. Med. Chem., 2012,
20, 2645.
25 Y.X. Li and W.L. Bao, Chin. Chem. Lett., 2003, 14, 993.
26 Y.M. Ren and C. Cai, Monatsh. Chem., 2009, 140, 49.
27 B. Liang, X. Wang, J.X. Wang and Z. Du, Tetrahedron, 2007, 63, 1981.
28 S. Pandit, R. Shivaji and V. Pandit; Rasayan J. Chem., 2009, 2, 907.
29 I.T. Phucho, S. Tumtin, A. Nongpiur, R. Nongrum and R.L. Nongkhlaw,
J. Chem. Pharm. Res., 2010, 2, 214.
30 S.R. Mistry and K.C. Maheria, J. Mol. Catal. A: Chem., 2012, 355, 210.
31 M.A. Salama and S.A. El-Essa, Indian J. Chem. B, 42B, 173.
32 A. Shaabani, M. Seyyedhamzeh, A. Maleki and F. Hajishaabanha,
Tetrahedron, 2010, 66, 4040.
References
1
C.O. Kappe, O.V. Shishkin, G. Uray and P. Verdino, Tetrahedron, 2000, 56,
1859.
2
3
4
5
C.O. Kappe, J. Med. Chem., 2000, 35, 1043.
P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360.
A. Shaabani and A. Bazgir, Tetrahedron Lett., 2004, 45, 2575.
B.J. Ahn, M.S. Gang, K. Chae, Y. Oh, J. Shin and W. Chang, J. Ind. Eng.
Chem., 2008, 14, 401.
6
X.L. Zhang,Y.P. Li, C.J. Liu and J.D. Wang, J. Mol. Catal. A: Chem., 2006,
253, 207.