One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using boric acid as catalyst

Article abstract of DOI:10.1016/S0040-4039(03)01466-7

A simple effective synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives, using boric acid as catalyst, from aromatic aldehydes, 1,3-dicarbonyl compounds and urea in glacial acetic acid is described. Compared with the classical Biginelli reaction condit

Full text of DOI:10.1016/S0040-4039(03)01466-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6153–6155
One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones using boric
acid as catalyst
Shujang Tu,* Fang Fang, Chunbao Miao, Hong Jiang, Youjian Feng, Daqing Shi and
Xiangshan Wang
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical Plant, Xuzhou,
Jiangsu 221009, PR China
Received 10 February 2003; revised 7 April 2003; accepted 4 June 2003
Abstract—A simple effective synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives, using boric acid as catalyst, from aromatic
aldehydes, 1,3-dicarbonyl compounds and urea in glacial acetic acid is described. Compared with the classical Biginelli reaction
conditions, this new method has the advantage of excellent yields (86–97%) and short reaction time (0.5–2 h).
© 2003 Elsevier Ltd. All rights reserved.
Biginelli reaction is a three-component condensation of
ethyl acetoacetate, benzaldehyde and urea for the synthe-
sis of 3,4-dihydropyrimidin-2(1H)-ones (Scheme 1).1 The
reaction can be carried out in a one-pot fashion in alcohol
solution in the presence of a catalytic amount of hydro-
gen chloride. A major drawback of the classical Biginelli
reaction is the poor to moderate yields, particularly when
substituted aromatic aldehydes are employed. This reac-
tion played an important role in organic and medicinal
chemistry due to the importance of the resulting dihy-
dropyrimidinone products. These compounds exhibit
attractive pharmacological properties by serving as the
integral backbones of several calcium channel blockers,
antihypertensive agents, alpha-la-antagonists and neu-
ropeptide Y (NPY) antagonists.2 In addition, several
marine alkaloids containing the dihydropyrimidinone-5-
carboxylate motifs also show interesting biological activ-
ities.3
tions has been actively pursued in several decades.4–11
Among such developments the report of Hu and Sidler12
using BF3·OEt2 as promoter, Kappe and co-workers
further improved this reaction by employing microwave
irradiation in the presence of PPE to give higher chemical
yields of dihydropyrimidinone products.13 Recently, sev-
eral other methods indicate the use of lanthanide
compounds14,15 and soluble polymer-supported16 and
several other Lewis acids17–20 can overcome the draw-
back of the classical Biginelli reaction.
Very recently, we found that the Biginelli reaction can
occur more smoothly under microwave irradiation in the
presence of ferric chloride or TsOH as the catalyst.21 In
this letter, we would like to report a simple effective
approach to the Biginelli reaction products by using boric
acid as the catalyst in glacial acetic acid. The synthesis
is usually complete within 0.5–2 h at 100°C to give very
high yields. The preferred ratio of aldehydes, 1,3-dicar-
bonyl compounds, urea and H3BO3 is 1:1:1.2:0.20
(Scheme 1).
Due to the importance of the Biginelli reaction products,
much work on improving the yield and reaction condi-
Scheme 1.
* Corresponding author. Tel.: 86-516-3403163; fax: 86-516-3403164; e-mail: laotu2001@263.net
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01466-7

6154
S. Tu et al. / Tetrahedron Letters 44 (2003) 6153–6155
Table 1. Boric acid catalyzed synthesis of dihydropyrimidinones
Entry
R1
R2
Yield(%)
Bb
Mp(°C)
Aa
Cc
Found
Reported
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
C6H5
2-ClC6H4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
97
93
90
89
86
86
94
93
89
92
93
92
94
98
89
95
90
94
–
–
91
–
–
–
92
–
–
–
92
87
95
88
–
78
51
49
58
–
19
69
56
67
–
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
202–20320
215–21813
187–18820
207–208.520
256–25720
201–20320
249–25020
213–21520
227–22920
23015
3,4-OCH2OC6H3
4-NO2C6H4
4-NMe2C6H4
2-OHC6H4
2,4-(Cl)2-C6H3
4-ClC6H4
4-OHC6H4
4-NO2C6H4
4-OCH3C6H4
4-NO2C6H4
4-OCH3C6H4
4-ClC6H4
Me
–
168–17015
235–23712
192–19412
204–20712
192–19415
–
OMe
OMe
OMe
OMe
OMe
OMe
41
28
56
–
–
–
4-FC6H4
2-NO2C6H4
2-NO2-5-Cl-C6H3
–
–
a Method A: cat. H3BO3 in glacial acetic acid at 100°C for 0.5–2 h.22
b Method B: 1.3 equiv. of BF3·OEt2, 10 mol% CuCl, 10 mol% AcOH, in THF, reflux for 18 h.12
c Method C: cat. HCl in EtOH, reflux for 18 h.14,24
Scheme 2.
The results (Table 1) show a series of aromatic alde-
hydes that undergo the cyclocondensation to give excel-
lent yields (86–97%) of the products.22 This new
procedure is also simple to operate. The work-up con-
sists of simple filtration. All the products were charac-
tautomer of the 1,3-diketone via complexing with the
two oxygen atoms. The catalytic role of boric acid is
especially evident for the aldehyde with electron donat-
ing substituents. Thus, reaction of 4-(N,N-dimethyl-
amino)benzaldehyde is complete within 1.7 h in the
presence of boric acid, but it did not reach a complete
conversion even after 5 h in its absence. These facts are
in agreement with mechanistic Scheme 2.
1
terized by IR and H NMR analysis. Meanwhile, the
structure of compounds 4b and 4n were further con-
firmed by X-ray diffraction study.23
The reaction may proceed through imine formation
from the aldehyde and urea, which is stabilized by boric
acid. Subsequent addition of the 1,3-diketone or b-keto
ester to the imine followed by cyclodehydration afford
dihydropyrimidin-2(1H)-one (Scheme 2).
In conclusion, a concise, high yielding and shortened
procedure for Biginelli reaction was found. The method
reported here is not only simple to operate but also
efficient.
Acknowledgements
Boric acid is supposed to increase the electrophilicity of
the imine by coordinating with the nitrogen and oxygen
lone pair and to promote the deprotonation of the enol
We thank Professor Kaibei Yu (Chengdu Center of
Analysis and Measurement, Chinese Academy of Sci-

S. Tu et al. / Tetrahedron Letters 44 (2003) 6153–6155
6155
ences) for X-ray structural analysis, and the Nature
Science Foundation of the Jiangsu Province (No.
BK2001142) and the Nature Science Foundation of
Jiangsu Education Department (No. 01KJB150008)
and the Key Laboratory of Chemical Engineering &
Technology of the Jiangsu Province Open Foundation
(No. KJS02060) for financial support.
Fang, F.; Miao, C. B.; Jiang, H.; Shi, D. Q. J. Chin.
Chem. 2003, 21, 706–709.
22. The general procedure is represented as follows: A solu-
tion of the appropriate aldehyde 1 (3 mmol), 1,3-dicar-
bonyl compound 2 (3 mmol), urea 3 (3.6 mmol), H3BO3
(0.6 mmol), in glacial acetic acid (10 mL) is heated at
100°C, while stirring for 0.5–2 h. Then it is cooled to
room temperature, and poured into 50 mL ice-water. The
solid products are filtered, washed with ice-water and
ethanol (95%), dried and recrystallized from ethanol to
give the pure product. All products (except 4p and 4q) are
known compounds, characterized by mp, IR and 1H
NMR spectral data. 4p: mp 280–282°C; wmax (KBr) 3359,
3232, 3108, 2954, 1702, 1644, 1530 cm−1; lH (400 MHz,
DMSO-d6) 9.38 (1H, br s, NH), 8.13–8.11 (2H, m,
aromH), 7.91 (1H, br s, NH), 7.66–7.61 (2H, m, aromH),
5.29 (1H, d, J=3.1 Hz, CH), 3.53 (3H, s, CH3OCO), 2.27
(3H, s, CH3). Anal. C13H13N3O5. Calcd: C, 53.61; H,
4.50; N, 14.43. Found: C, 53.56; H, 4.31; N, 14.40%. 4q:
mp 290–292°C; wmax (KBr) 3359, 3233, 3119, 2953, 1703,
1644, 1572, 1530 cm−1; lH (400 MHz, DMSO-d6): 9.45
(1H, br s, NH), 7.95 (1H, s, aromH), 7.92 (1H, br s, NH),
7.62–7.45 (2H, m, aromH), 5.80 (1H, d, J=2.7 Hz, CH),
3.39 (3H, s, OCOCH3), 2.26 (3H, s, CH3). Anal.
C13H12ClN3O5. Calcd: C, 47.94; H, 3.71; N, 12.90.
Found: C, 47.80; H, 3.52; N, 12.76%.
References
1. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416.
2. (a) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D.
M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med.
Chem. 1991, 34, 806–811; (b) Rovnyak, G. C.; Atwal, K.
S.; Hedberg, A.; Kimball, S. D.; Moreland, S.;
Gougoutas, J. Z.; O’Reilly, B. C.; Schwart, J.; Malley, M.
F. J. Med. Chem. 1992, 35, 3254–3263; (c) Grover, G. J.;
Dzwonczyk, S.; Mcmullen, D. M.; Normadinam, C. S.;
Slenph, P. G.; Moreland, S. J. J. Cardiovase Pharmacol
1995, 26, 289–294.
3. Snider, B. B.; Shi, Z. P. J. Org. Chem. 1993, 58, 3828–
3839 and references cited therein.
4. O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26,
1185–1188.
23. The single-crystal growth was carried out in an ethanol at
room temperature. X-Ray crystallographic analysis was
performed with a Siemens SMART CCD and a Siemens
P4 diffractometer (graphite monochromator, MoKa radi-
5. Atwal, K. S.; O’Reilly, B. C.; Gougoutas, J. Z.; Malley,
M. F. Heterocycles 1987, 26, 1189–1192.
6. Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz,
J. J. Org. Chem. 1989, 54, 5898–5907.
,
ation u=0.71073 A). Crystal data for 4b: C14H15ClN2O3,
7. Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P. L. Ind. J.
light yellow, crystal dimension 0.44×0.32×0.20 mm, tri-
Chem. 1995, 34B, 151–152.
clinic, space group P-1, a=7.688(1), b=9.106(2), c=
8. Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
7819–7822.
9. Studer, A.; Hadida, S.; Ferrito, R.; Kim, S. Y.; Jeger, P.;
Wipf, P.; Curran, D. P. Science 1997, 275, 823–826.
10. Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org.
Chem. 1997, 62, 2917–2924.
,
11.412(2)
A,
h=102.963(3),
i=105.957(2),
3
,
k=102.484(2)°, V=714.9(2) A , Mr=294.73, Z=2, Dc=
3
−1
,
1.369 g/cm , u=0.71073 A, v(MoKa)=0.276 mm
,
F(000)=308, S=1.084, R1=0.0845, wR2=0.2092. Crys-
tallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication No. CCDC 202250. Crystal data for
4n: C13H13ClN2O3, light yellow, crystal dimension 0.50×
11. Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G.
Tetrahedron Lett. 1999, 40, 3465–3470.
12. Hu, E. H.; Silder, D. R.; Dolling, U. H. J. Org. Chem.
1998, 63, 3454–3457.
0.32×0.28 mm, triclinic, space group P-1, a=5.4513(4),
13. Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999,
1799–1803.
14. Lu, J.; Bai, Y. J.; Wang, Z. J.; Yang, B. Q.; Ma, H. R.
Tetrahedron Lett. 2000, 41, 9075–9078.
3
,
,
b=7.619(1), c=16.118(4) A; V=646.19(19) A , h=
3
,
80.42(1), i=83.42(1), k=79.29(1)°, V=646.19(19) A ,
3
,
Mr=280.70, Z=2, Dc=1.443 g/cm , u=0.71073 A,
v(MoKa)=0.301 mm−1, F(000)=292, S=1.061, R1=
0.043, wR2=0.1167. Crystallographic data (excluding
structure factors) for the structure reported in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication No. CCDC
194807. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax: (+44) 1223-3366-033; e-mail:
deposit@ccdc.cam.ac.uk).
15. Ma, Y.; Qian, C. T.; Wang, L. M.; Yang, M. J. Org.
Chem. 2000, 65, 3864–3868.
16. Xia, M.; Wang, Y. G. Tetrahedron Lett. 2002, 43, 7703–
7705.
17. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270–6272.
18. Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
Synlett 2001, 863–865.
19. Lu, J.; Ma, H. R. Synlett 2000, 63–64.
20. Lu, J.; Bai, Y. J. Synthesis 2002, 4, 466–470.
21. (a) Tu, S. J.; Zhou, J. F.; Cai, P. J.; Wang, H.; Feng, J.
C. Synth. Commun. 2002, 32, 147–151; (b) Tu, S. J.;
24. (a) Folkers, K.; Harwood, H. J.; Johnson, T. B. J. Am.
Chem. Soc. 1932, 54, 3751–3758; (b) Folkers, K.; John-
son, T. B. J. Am. Chem. Soc. 1933, 55, 3784–3791.