P-dodecylbenzenesulfonic acid (DBSA), a Br?nsted acid-surfactant catalyst for Biginelli reaction in water and under solvent free conditions

Article abstract of DOI:10.1016/j.cclet.2010.12.030

We report herein the use of p-dodecylbenzenesulfonic acid (DBSA) as a catalyst for a one-pot Biginelli reaction to afford 3,4-dihydropyrimidinone derivatives in good to excellent yields. This reaction proceeds efficiently in water and under solvent free conditions. Comparisons of results indicate that although the yields are high and comparable for both methods, the reaction times are considerably shorter under solvent free conditions.

Full text of DOI:10.1016/j.cclet.2010.12.030

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 903–906
www.elsevier.com/locate/cclet
P-Dodecylbenzenesulfonic acid (DBSA), a Brønsted
acid-surfactant catalyst for Biginelli reaction in water and under
solvent free conditions
*
Mohammad Ali Bigdeli , Ghazaleh Gholami, Enayatollah Sheikhhosseini
Faculty of Chemistry, Tarbiat Moallem University, 49 Mofateh, Tehran, Iran
Received 3 November 2010
Available online 19 May 2011
Abstract
We report herein the use of p-dodecylbenzenesulfonic acid (DBSA) as a catalyst for a one-pot Biginelli reaction to afford 3,4-
dihydropyrimidinone derivatives in good to excellent yields. This reaction proceeds efficiently in water and under solvent free
conditions. Comparisons of results indicate that although the yields are high and comparable for both methods, the reaction times
are considerably shorter under solvent free conditions.
# 2010 Mohammad Ali Bigdeli. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Biginelli reaction; Dihydropyrimidinone; P-Dodecylbenzenesulfonic acid (DBSA)
In 1893, Pietro Biginelli reported the first synthesis of 3,4-dihydropyrimidin-2(1H)-one (DHPM) by a one pot
condensation reaction of aromatic aldehydes and ethylacetoacetate urea under a strongly acidic condition [1].
Dihydropyrimidinones (DHPMs) exhibit a wide range of biological activities such as antiviral, antitumor, antibacterial
and anti-inflammatory actions [2]. Some marine natural products containing the dihydropyrimidinone-5-carboxylate
units such as batzelladine alkaloids have been found to be potent HIV (gp-120-CD4) inhibitors [3]. Thus the synthesis
of these heterocyclic compounds is of current interest. Recently, numerous improved procedures using FeCl3/HCl [4],
LaCl3-graphite [5], PPh3 [6], SbCl3 [7], PhB(OH)2 [8], InBr3 [9], Dowex [10], baker’s yeast [11], heteropoly acids
[12], CuCl2Á2H2O [13], NBS [14], I2 [15], covalently anchored sulfonic acid on silica [16] and TCCA [17] are
reported. Many of these protocols suffer from the use of expensive catalysts, prolonged reaction times and low yields.
Thus search for newer and more efficient methods are needed. Recently, organic reactions in water without the use of
harmful organic solvents have attracted much attention. p-Dodecylbenzenesulfonic acid (DBSA) is a Brønsted acid-
surfactant-combined catalyst, composed of an acidic group and a hydrophobic moiety that has been studied as a
catalyst in organic chemistry [18]. The behavior of DBSA as a catalyst has been studied in Mannich type reactions [19]
and also in esterification of various carboxylic acids and alcohols [20]. In this study, we report our results for the
synthesis of DHPMs using DBSA in environmentally benign conditions.
* Corresponding author.
E-mail address: mabig397@yahoo.com (M.A. Bigdeli).
1001-8417/$ – see front matter # 2010 Mohammad Ali Bigdeli. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.12.030

904
M.A. Bigdeli et al. / Chinese Chemical Letters 22 (2011) 903–906
1. Experimental
1
IR spectra were recorded on a Perkin-Elmer FT-IR 240-C spectrophotometer (KBr). H NMR spectra were
recorded on a varian 300 MHZ spectrometer. Melting points were determined using an Electrotermal 9100 and are
uncorrected. Reactions were monitored by thin layer chromatography and products were identified fully or by
comparison of melting points and spectroscopic data with those previously reported.
1.1. General procedure for synthesis of DHPM using DBSA (in water)
A mixture of urea (0.168 g, 2.8 mmol), benzaldehyde or substituted benzaldehydes (2 mmol), b-ketoester (2 mmol)
and DBSA (0.4 mmol) in water (5 mL) was heated at 54 8C for 7 h. Upon cooling, solid material precipitated from the
solution (Table 2). The precipitates were filtered off, washed with water and were recrystalized from EtOH to afford
pure DHPMs as yellow-white solids.
1.2. General procedure for synthesis of DHPM using DBSA (solvent free)
A mixture of urea (0.168 g, 2.8 mmol), benzaldehyde or substituted benzaldehyde (2 mmol), b-ketoesters (2 mmol)
and DBSA (0.4 mmol) was heated at 100 8C, while stirring for 30 min. The solid material which precipitated upon
cooling was recrystalized from EtOH to afford pure DHPMs (Table 2).
Compound 4e (0.54 g, 81%) mp 231–233 8C (found: C, 49.55; H, 4.43; N, 8.22. C14H15BrN2O3 requires C, 49.57;
H, 4.46; N, 8.26%); nmax/cmÀ1 3353 and 3222 (NH), 1694 and 1646 (C O); 1H NMR (300 MHz; DMSO-d6; Me4Si): d
1.05 (t, 3H, CH3CH2), 2.23 (s, 3H, Me), 3.9(q, 2H, CH2), 5.1 (d, 1H, 4-H), 7.1–7.5 (m, 4H, Ph), 7.7(s, 1H, 3-H), 9.23(s,
1H, 1-H); 13C NMR (75 MHz; DMSO-d6; Me4Si): d 14.05, 17.79, 53.47(C-4), 59.25(CH2), 98.74(C-5), 120.29,
128.53, 131.3, 144.18, 148.72(C-6), 151.91, 165.18.
Compound 4h (0.51 g, 81%) mp 167–170 8C (found: C, 70.75; H, 5.61; N, 8.67. C19H18N2O3 requires: C, 70.79; H,
5.63; N, 8.69%); nmax/cmÀ13356 and 3219 (NH), 1704 and 1687 (C O); 1H NMR (300 MHz; DMSO-d6; Me4Si): d
2.25(s, 3H, CH3), 4.96 (q, 2H, CH2), 5.15 (d, 1H, 4-H), 7.11–7.31(m, 10H, 2Ph), 7.74 (s, 1H, 3-H), 9.25 (s, 1H, 1-H);
13C NMR (75 MHz; DMSO-d6; Me4Si): d 17.84(CH3), 53.91(C-4), 64.78(CH2), 98.70(C-5), 126.27, 127.29, 127.52,
127.68, 128.25, 128.41, 136.50, 144.63, 149.26(C-6), 151.96, 165.04.
Compound 7a (0.16 g, 23%) mp 198–201 8C (found: C, 48.22; H, 4.35; N, 8.15. C14H15F3N2O5: C, 48.28; H, 4.34;
1
N, 8.04%); nmax/cmÀ13598(OH), 3343 and 3320 (NH), 1703 and 1623 (C O); H NMR (300 MHz; DMSO-d6;
Me4Si): d 1.87(s, 3H, CH3), 3.72(s, 3H, CH3), 3.02(d, 1H, 5-H), 4.76(d, 1H, 4-H), 7.13(s, 1H, OH), 7.55(s, 1H, 3-H),
7.67 (s, 1H, 1-H); 6.86-7.28(m, 4H, Ph); 13C NMR (75 MHz; DMSO-d6; Me4Si): d 30.47, 52.45, 55.09, 57.42, 80.40,
80.82, 113.85, 129.24, 153.55, 159.19, 204.15.
Compound 7b (0.33 g, 45%) mp 215–217 8C (found: C, 42.87; H, 3.21; N, 11.48. C13H12F3N3O6: C, 42.98; H,
3.33; N, 11.57%); nmax/cmÀ1 3588(OH), 3354 and 3316 (NH), 1726 and 1675 (C O); 1H NMR (300 MHz; acetone-
d6; Me4Si): d 1.88(s, 3H, CH3), 3.66(d, 1H, 5-H), 5.13 (d, 1H, 4-H), 6.39(s, 1H, 3-H), 6.75(s, 1H, 1-H), 7.16(s, 1H,
OH), 7.69–8.39(m, 4H, Ph); 13C NMR (75 MHz; acetone-d6; Me4Si): d 32.37, 55.10, 82.22, 122.38, 123.85, 124.62,
126.98, 131.09, 135.42, 141.15, 149.44, 154.62, 205.89.
2. Results and discussion
We wish to report the use of DBSA as a catalyst in Biginelli’s reaction (Scheme 1). A summary of the optimized
experiments is listed in Table 1. Our results show that the best yields are obtained in water at 54 8C (entry 5) and the
optimum amount of DBSA is found to be 20 mol% (entry 5).
In order to investigate the scope of these reactions, various types of substituted benzaldehydes and different b-
ketoesters were studied in water and under solvent free conditions. Comparison of the results obtained under the two
conditions is reported in Table 2.
b-Ketoesters containing CF3 groups, however, did not behave similarly. More careful analysis of spectroscopic data
revealed that the products obtained from these starting materials were in fact the non dehydrated precursors of
expected DHPMs (7a, 7b). The mechanism of the reaction is depicted in Scheme 2. We later found evidence of similar

[()TD$FIG]
M.A. Bigdeli et al. / Chinese Chemical Letters 22 (2011) 903–906
905
R3
O
O
O
O
R2
NH
DBSA (20mol%)
R3CHO
+
H2N
R1
R2
+
NH2
O
R1
N
H
1
2
3
(4a-4k)
Scheme 1. Synthesis of DHPMs catalyzed by DBSA in H2O.
Table 1
Reaction of benzaldehyde, methyl acetoacetate and urea in watera.
Entry
DBSA%
Time (h)
Temperature (8C)
Yield%
1
2
0
5
7
7
7
7
7
7
7
9
8
7
54
54
54
54
54
54
54
18
34
68
0
38.6
44.7
61.3
90
3
10
15
20
25
30
20
20
20
4
5
6
81
7
70
8
0
9
65.4
90
10
a
benzaldehyde/methyl acetoacetate/urea, 1:1:1.4.
Table 2
DBSA catalyzed synthesis of dihydropyrimidinones in water or solvent free.
Compound
R1
R2
R3
In water
Time (h)
Solvent free
Time (min)
mp (8C)
Lit. mp (8C)
Yield (%)
Yield (%)
4a
4b
4c
4d
4e
4f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CF3
CF3
OMe
C6H5
7
7
8
8
7
9
7
8
8
9
8
7
9
90
89
78
76
81
83
69
81
80
80
75
23
45
30
30
20
15
15
15
20
10
15
10
10
–
96
92
80
81
88
88
72
89
87
92
88
–
212–214
204–207
213–218
208–211
231–233
194–197
279–281
167–170
190–193
213–215
217–219
198–201
215–217
209–212 [21]
OEt
C6H5
202–205 [17]
OEt
4-MeOC6H4
4-NO2C6H4
4-BrC6H4
3-ClC6H4
2-Naphthyl
C6H5
215–216 [9]
OEt
208–211 [21]
OEt
–
OEt
193–195 [9]
4g
4h
4i
OEt
–
OCH2Ph
OCH2Ph
OCH2Ph
OCH2Ph
OMe
–
–
–
–
–
–
4-MeOC6H4
2-ClC6H4
3-NO2C6H4
4-MeOC6H4
3-NO2C6H4
4j
4k
7a
7b
OMe
–
–
behavior in previous reports [22]. It appears that the presence of CF3 groups has two effects on the faith of this reaction.
It slows down the overall rate of reaction (hence the low yields) and it also prohibits the dehydration step.
The reaction times are shorter under solvent free conditions than when water is used as solvent. Biginelli reaction
requires strong acidic conditions. It is possible that water hinders the reaction to some extend by lowering the acidity
and hence longer reaction times.

9[()TD$FIG] 06
M.A. Bigdeli et al. / Chinese Chemical Letters 22 (2011) 903–906
R3
O
O
O
O
N
C
acid
+
H2N
+
R1
R2
R3
H
NH2
- H2O
3
1
2
O
NH2
5
R3
R3
R3
O
O
O
R2
R2
R2
NH
NH
NH
C
OH2N
O
HO
O
R1
O
R1
N
H
N
H
R1
6
7
4
7b R1 =CF3
7a R1 = CF3
R2 =OMe
R2 = OMe
R3 =3-NO2Ph
R3 = 4-OMePh
Scheme 2. Possible mechanism of the reaction.
3. Conclusion
In conclusion, we report the development of a one pot, simple, inexpensive, ecofriendly (non-toxic solvents and
catalyst), benign and efficient method for Biginelli reaction. High yields and short reaction times are further positive
features of this work.
Acknowledgment
We wish to thank the faculty of chemistry of Tarbiat Moallem University for supporting this work.
References
[1] P. Biginelli, Gazz. Chim. Ital. 23 (1893) 360.
[2] C.O. Kappe, Eur. J. Med. Chem. 35 (2000) 1043.
[3] B.B. Snider, Z. Shi, J. Org. Chem. 58 (1993) 3828.
[4] I.S. Zorkun, S. Sarac¸, S. C¸ elebi, K. Erol, Bioorg. Med. Chem. Lett. 14 (2006) 8582.
[5] H. Khabazzadeh, K. Saidi, H. Sheibani, Bioorg. Med. Chem. Lett. 18 (2008) 278.
[6] A. Debache, M. Amimour, A. Belfaitah, et al. Tetrahedron Lett. 49 (2008) 6119.
´
´
[7] I. Cepanec, M. Litvic, M. FIlipan-Litvic, I. Gru¨ngold, Tetrahedron 63 (2007) 11822.
[8] A. Debache, B. Boumoud, M. Amimour, et al. Tetrahedron Lett. 47 (2006) 5697.
[9] N.Y. Fu, Y.F. Yuan, Z. Cao, et al. Tetrahedron 58 (2002) 4801.
[10] K. Singh, D. Arora, S. Singh, Tetrahedron Lett. 47 (2006) 4205.
[11] A. Kumar, R.A. Maurya, Tetrahedron Lett. 48 (2007) 4569.
[12] B.G. Mishra, D. Kumar, V.S. Rao, Catal. Commun. 7 (2006) 457.
[13] O.M. Singh, S.J. Singh, M.B. Devi, et al. Bioorg. Med. Chem. Lett. 18 (2008) 6462.
[14] H. Hazarkhani, B. Karimi, Synlett (2004) 1239.
[15] K.V.N. Srivas, B. Das, Synthesis (2004) 2091.
[16] R. Gupta, S. Paul, R. Gupta, J. Mol. Catal. A 266 (2007) 50.
[17] M.A. Bigdeli, S. Jafari, G.H. Mahdavinia, et al. Catal. Commun. 8 (2007) 1641.
[18] K. Manabe, Y. Mori, S. Kobayashi, Tetrahedron 57 (2001) 2537.
[19] M. Shiri, M.A. Zolfigol, Tetrahedron 65 (2009) 587.
[20] Y. Han, Y. Chu, J. Mol. Catal. A: Chem. 237 (2005) 232.
[21] E.H. Hu, D.R. Sidler, U.U.K. Dolling, J. Org. Chem. 63 (1998) 3454.
[22] Y. Ma, C. Qian, L. Wang, M. Yang, J. Org. Chem. 65 (2000) 3864.