A New Biginelli Reaction Procedure Using Potassium Hydrogen Sulfate as the Promoter for an Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-one

Article abstract of DOI:10.1055/s-2004-815419

Simple and improved conditions have been found to carry out the Biginelli reaction for the synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives. This synthesis was performed using potassium hydrogen sulfate as the promoter in glycol solution. Compared

Full text of DOI:10.1055/s-2004-815419

LETTER
537
A New Biginelli Reaction Procedure Using Potassium Hydrogen Sulfate as the
Promoter for an Efficient Synthesis of 3,4-Dihydropyrimidin-2(1H)-one
A
N
ewBigine
h
lli ReactionP
u
rocedure
U
j
i
tassium
a
H
ydroge
n
n
Sulfate g Tu,* Fang Fang, Songlei Zhu, Tuanjie Li, Xiaojing Zhang, Qiya Zhuang
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical Plant, Xuzhou; Jiangsu, 221009,
P. R. China
Fax +86(516)3403164; E-mail: laotu2001@263.net
Received 9 December 2003
dropyrimidinone derivatives, while the use of cyclic 1,3-
Abstract: Simple and improved conditions have been found to car-
dicarbonyl compounds has been seldom reported. Herein,
we would like to report a new economic approach to the
Beginelli reaction products using KHSO4 as the promoter
ry out the Biginelli reaction for the synthesis of 3,4-dihydropyrimi-
din-2(1H)-one derivatives. This synthesis was performed using
potassium hydrogen sulfate as the promoter in glycol solution.
Compared with the classical Biginelli reaction conditions, this new in glycol. This catalyst is efficient not only for open-
method has the advantage of excellent yields (85–99%) and short
reaction time (0.5–2 h).
chained 1,3-dicarbonyl compounds, but also for cyclic
1,3-dicarbonyl compounds. The synthesis can be finished
Key words: dihydropyrimidin-2(1H)-one, Biginelli reaction, po-
tassium hydrogen sulfate, cyclic 1,3-dicarbonyl compounds
within 2 hours at 100 °C to give very high yields
(Scheme 1, Scheme 2).
Ar
H
Ar
O
Dihydropyrimidinone derivatives have attracted consider-
able interest in recent years because these type of com-
pounds exhibits attractive pharmacological profiles as
calcium channel blockers, antihypertensive agents, alpha-
la-antagonists and neuropeptide Y (NPY) antagonists.1 In
addition, several marine alkaloids containing the dihydro-
pyrimidinone-5-carboxylate motifs also showed interest-
ing biological properties.2
O
O
2
R2
KHSO4
glycol
R2
NH
NH2
+
Me
O
N
H
Me
O
O
H2N
4
1
3
Scheme 1
Biginelli synthesis involves reaction of ethyl acetoacetate,
benzaldehyde and urea in alcohol solution in the presence
of a catalytic amount of hydrogen chloride to give 3,4-di-
hydropyrimidin-2(1H)-ones (Scheme 1).3 A major draw-
back of the classical Biginelli reaction is the poor to
moderate yields, particularly when substituted aromatic
aldehydes were employed. Therefore, several improved
procedures for the preparation of DHPMs (‘Biginelli
compounds’) have been reported during the last two de-
cades.4–11 Among the improved synthetic methods is to
use BF3·OEt2 as promoter as reported by Hu and Sidler.12
Later on, Kappe and co-workers further improved this
reaction by employing microwave irradiation in the
presence of PPE to give higher chemical yields of dihy-
dropyrimidinone products.13 Recently, the use of lan-
thanide compounds,14,15 Lewis acids,16–20 silica sulfuric
acid,21 and InBr322 also gave improved yield. In our previ-
ous communication,23 we reported that boric acid can cat-
alyze Beginelli reaction. All these improved procedures
can overcome the drawback of the classical Biginelli reac-
tion to some extent.
Ar
H
O
O
Ar
2
O
KHSO4
glycol
NH
NH2
+
O
N
H
6
H2N
O
O
5
3
Scheme 2
Furthermore, we have synthesized the bifunctional com-
pounds containing two dihydropyrimidinone units (8, 9),
using iso-phthalicaldehyde and tert-phthalicaldehyde as
precursor (Scheme 3).
The results (Table 1, Table 2) show that a wide range of
aldehydes can take part in this reaction to give excellent
yields (85–99%) of products. This new procedure is
O
O
N
N
HN
NH
O
O
Me
NH
NH
However, attention has so far been mainly paid to using
open-chained 1,3-dicarbonyl compounds to afford dihy-
HN
HN
OEt
O
O
Me
O
O
EtO
SYNLETT 2004, No. 3, pp 0537–0539
1
8.
0
2.
2
0
0
4
8
9
Advanced online publication: 12.01.2004
DOI: 10.1055/s-2004-815419; Art ID: U26703ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 3

538
S. Tu et al.
LETTER
Table 1 KHSO4 Catalyzed Open-Chained 1,3-Dicarbonyl Compounds
Entry
ArCHO
R2
Yield (%)
Aa
Mp (°C)
Found
Bb
94
–
Cc
78
51
49
58
–
Reported
4a
4b
4c
4d
4e
4f
C6H5CHO
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
95
91
90
92
86
86
91
93
87
91
91
93
90
95
87
90
89
85
86
85
96
99
202–203
215–217
186–187
207–208
257–258
202–203
248–250
214–215
228–230
227–229
165–168
237–238
193–196
206–208
193–195
280–282
290–292
152–153
172–174
205
202–20320
215–21813
187–18820
207–208.520
256–25720
201–20320
249–25020
213–21520
227–22920
23015
2-ClC6H4CHO
3,4-OCH2 °C6H3 CHO
4-NO2C6H4CHO
4-NMe2C6H4CHO
2-OHC6H4CHO
2,4-(Cl)2-C6H3CHO
4-ClC6H4CHO
–
91
–
–
19
69
56
67
–
4g
4h
4i
–
92
–
4-OHC6H4CHO
4-NO2C6H4CHO
4-OCH3C6H4CHO
4-NO2C6H4CHO
4-OCH3C6H4CHO
4-ClC6H4CHO
4j
–
4k
4l
Me
–
–
168–17015
235–23712
192–19412
204–20712
192–19415
280–28223
290–29223
152–15420
170–17220
203–20518
–
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
OEt
92
87
95
88
–
41
28
56
–
4m
4 n
4o
4p
4q
4r
4s
4-FC6H4CHO
2-NO2C6H4CHO
2-NO2-5-Cl-C6H3CHO
CH3CH2CH2CHO
(CH3)2CHCHO
Furfural
–
–
–
–
15
10
–
–
4t
–
8a
8b
1,3-CHOC6H4CHO
1,4-CHOC6H4CHO
–
–
>300
–
–
>300
–
a Method A: cat. KHSO4 in glycol at 100 °C for 0.5–2 h.25
b Method B: 1.3 equiv of BF3·OEt2, 10 mol% CuCl, 10 mol% HOAc, in THF, reflux for 18 h.12
c Method C: cat. HCl in EtOH, reflux for 18 h.14,24
simple and the work-up consists of simple filtration. All
the products were characterized by IR and 1H NMR anal-
ysis, and their melting points are identical to those of the
known compounds reported in the literature.
Table 2 KHSO4 Catalyzed Cyclic 1,3-Dicarbonyl Compounds
Entry
6a
ArCHO
Yield (%)
Mp (°C)
259.9–261.3
>300
4-ClC6H4CHO
93
91
95
95
92
92
95
According to the mechanism suggested by Folkers,
Johnson and Kappe, we think the reaction may proceed
through imine formation from the aldehyde and urea,
which is activated by protonation. Subsequent addition of
the carbanion derived from 1,3-diketone or b-keto ester to
the imine followed by cyclodehydration afford dihydro-
pyrimidin-2(1H)-one (Scheme 4).
During the reaction process, the hydrogen ion, H+, is do-
nated by the potassium hydrogen sulfate. The hydrogen
ion cannot only help the dehydration but also benefit the
enolization of 1,3-diketone or b-keto ester to form the
6b
6c
2-ClC6H4CHO
2,4-(Cl)2-C6H3CHO
3,4-(Cl)2-C6H3CHO
3-NO2C6H4CHO
1,3-CHOC6H4CHO
1,4-CHOC6H4CHO
226.8–227.7
>300
6d
6e
268.1–268.4
>300
9a
9b
>300
Synlett 2004, No. 3, 537–539 © Thieme Stuttgart · New York

LETTER
A New Biginelli Reaction Procedure Using Potassium Hydrogen Sulfate
539
(10) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem.
1997, 62, 2917.
(11) Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G.
Tetrahedron Lett. 1999, 40, 3465.
(12) Hu, E. H.; Silder, D. R.; Dolling, U. H. J. Org. Chem. 1998,
63, 3454.
(13) Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1799.
(14) Lu, J.; Bai, Y. J.; Wang, Z. J.; Yang, B. Q.; Ma, H. R.
Tetrahedron Lett. 2000, 41, 9075.
(15) Ma, Y.; Qian, C. T.; Wang, L. M.; Yang, M. J. Org. Chem.
2000, 65, 3864.
(16) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270.
(17) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B. Synlett
2001, 863.
+
OH
N
O
O
H+
H+
OH2
R1
+
R1
NH2
R1
H2N
NH2
H
NH2
N
O
H
O
H
H
O
O
H
H+
-H2O
R1
R2
H
Me
NH2
R1
NH2
N
+
N
O
H
O
R1
R1
O
R2OC
Me
Dehydration
NH
R2
NH
Promoted by
glycol
O
O
N
H
Me
H2N
O
(18) Reddy, C. V.; Mahesh, M.; Raju, P. V. K.; Bubu, R.; Reddy,
V. V. N. Tetrahedron Lett. 2002, 43, 2657.
(19) Maiti, G.; Kundu, P.; Guin, C. Tetrahedron Lett. 2003, 44,
2757.
Scheme 4
enolate intermediate. The solvent glycol can particularly
accelerate dehydration reaction of the last step.
(20) Lu, J.; Bai, Y. J. Synthesis 2002, 466.
(21) Fu, N. Y.; Yuan, Y. F.; Gao, Z.; Wang, S. W.; Wang, J. T.;
Peppe, C. Tetrahedron Lett. 2002, 58, 4801.
In conclusion, KHSO4 can be applied as an efficient cata-
lyst not only for the open-chained 1,3-dicarbonyl com-
pounds, but also for cyclic 1,3-dicarbonyl compounds. In
addition, the catalyst is suitable for the aromatic, aliphatic
and hetrocyclic aldehydes. The application of this novel
catalyst resulted in decreased reaction time and increased
yields of the potentially biologically active dihydropyri-
midinone derivatives. This method also has the advantage
of an easy work-up and being environmentally friendly
because of the atomic economy.
(22) Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Fard, M. A.
Tetrahedron Lett. 2003, 44, 2889.
(23) Tu, S. J.; Fang, F.; Miao, C. B.; Jiang, H.; Shi, D. Q.; Wang,
X. S. Tetrahedron Lett. 2003, 44, 6153.
(24) (a) Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem.
Soc. 1932, 54, 3751. (b) Folkers, K.; Johnson, T. B. J. Am.
Chem. Soc. 1933, 55, 3784.
(25) The general procedure is as follows: A solution of the
appropriate aldehyde (3 mmol) or dialdehyde (1.5 mmol),
1,3-dicarbonyl compound (3 mmol), urea (3.6 mmol), and
KHSO4 (0.75 mmol) in glycol (10 mL) was heated at 100 °C
with stirring for 0.5–2 h before cooled down to r.t. The
mixture was then poured into 50 mL of ice-water. The solid
product was filtered, washed with ice-water and EtOH
(95%), and subsequently dried and recrystallized from EtOH
to give pure product. All products (except 8a,b, 6a–e, 9a,b)
are known compounds, which were characterized by mp, IR
and 1H NMR spectral data. Compound 4p: mp 280–282 °C.
IR (KBr): 3539, 3232, 3108, 2954, 1702, 1644, 1530 cm–1.
1H NMR (DMSO-d6): d = 9.38 (s, 1 H, NH), 8.13–8.11 (m,
2 H, Ar-H), 7.91 (s, 1 H, NH), 7.66–7.61 (m, 2 H, Ar-H),
5.29 (d, J = 3.1 Hz, 1 H, CH), 3.53 (s, 3 H, OCH3), 2.26 (s,
3 H, CH3). Compound 4t: mp 205 °C. IR (KBr): 3413, 3239,
3119, 2984, 1702, 1644, 1457 cm–1. 1H NMR (DMSO-d6):
d = 9.22 (s, 1 H, NH), 7.74 (s, 1 H, NH), 7.53 (s, 1 H, furanH),
6.33 (d, J = 2.8 Hz, 1 H, furanH), 6.07 (d, J = 2.8 Hz, 1 H,
furanH), 5.20 (s, 1 H, CH), 3.98 (q, J = 7.2 Hz, 2 H, CH2),
2.22 (s, 3 H, CH3), 1.09 (t, J = 7.2 Hz, 3 H, CH3). Compound
6d: mp >300 °C. IR (KBr): 3283, 3258, 3065, 2962, 1706,
1676, 1617, 1442, 1371, 1243, 1189, 1132, 1021, 946, 758
cm–1. 1H NMR (DMSO-d6): d = 9.59 (s, 1 H, NH), 7.83 (s, 1
H, NH), 7.59 (d, J = 8.4 Hz, 1 H, Ar-H), 7.43 (s, 1 H, Ar-H),
7.21 (d, J = 8.4 Hz, 1 H, Ar-H), 5.19 (s, 1 H, CH), 1.82–2.45
(m, 6 H, CH2). Compound 8b: mp >300 °C. IR (KBr): 3231,
3112, 2973, 1700, 1458, 1374, 1321, 1227, 1171, 1094, 808,
663 cm–1. 1H NMR (DMSO-d6): d = 9.18 (s, 2 H, NH), 7.69
(s, 2 H, NH), 7.17 (s, 4 H, Ar-H), 5.09 (s, 2 H, CH), 3.97 (q,
J = 7.2 Hz, 4 H, OCH2), 2.22 (s, 6 H, CH3), 1.09 (t, J = 7.2
Hz, 6 H, CH3). Compound 9b: mp >300 °C. IR (KBr): 3241,
2948, 1699, 1672, 1613, 1369, 1240, 1181, 806, 764 cm–1.
1H NMR (DMSO-d6): d = 9.45 (s, 2 H, NH), 7.69 (s, 2 H,
NH), 7.01–7.19 (m, 4 H, Ar-H), 5.05–5.11 (m, 2 H, CH),
1.93–2.49 (m, 12 H, CH2).
Acknowledgment
We thank the National Natural Science Foundation of China (No.
20372057), the Natural Science Foundation of the Jiangsu Province
(No. BK2001142) and the Natural Science Foundation of Jiangsu
Education Department (No. 01KJB150008) and the Key Laboratory
of Chemical Engineering & Technology of the Jiangsu Province
Foundation (No. KJS02060) for financial support.
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Synlett 2004, No. 3, 537–539 © Thieme Stuttgart · New York