Synthesis of 3,4-Dihydropyrimidin-2(1 H)-ones using Sodium Bisulfate as a Catalyst under Solvent-free Conditions

Full text of DOI:10.1080/00304948.2014.944407

This article was downloaded by: [Deakin University Library]
On: 15 September 2014, At: 16:01
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Organic Preparations and Procedures
International: The New Journal for
Organic Synthesis
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/uopp20
Synthesis of 3,4-Dihydropyrimidin-2(1H)-
ones using Sodium Bisulfate as a Catalyst
under Solvent-free Conditions
Min Wanga, Ji-Lei Songa, Shuang Zhaoa & Xin Wana
a College of Chemistry, Chemical Engineering and Food Safety, Bohai
University, Jinzhou 121013, P. R. China
Published online: 15 Sep 2014.
To cite this article: Min Wang, Ji-Lei Song, Shuang Zhao & Xin Wan (2014) Synthesis of 3,4-
Dihydropyrimidin-2(1H)-ones using Sodium Bisulfate as a Catalyst under Solvent-free Conditions,
Organic Preparations and Procedures International: The New Journal for Organic Synthesis, 46:5,
457-462, DOI: 10.1080/00304948.2014.944407
To link to this article: http://dx.doi.org/10.1080/00304948.2014.944407
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &
Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Organic Preparations and Procedures International, 46:457–462, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.944407
OPPI BRIEF
Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones using
Sodium Bisulfate as a Catalyst under Solvent-free
Conditions
Min Wang, Ji-Lei Song, Shuang Zhao, and Xin Wan
College of Chemistry, Chemical Engineering and Food Safety, Bohai University,
Jinzhou 121013, P. R. China
Pyrimidinones or dihydropyrimidinones (DHPMs) are important heterocycles that have
drawn much attention due to their biological1 and pharmacological2 action as well as their
potent calcium channel blocking activity.3–5 Thus, the synthesis of these compounds has
attracted considerable interest in recent years.6
Multicomponent reactions (MCRs) are highly flexible, chemo-selective, convergent
and atom-efficient processes. Over the past decade, a very efficient way to access heterocy-
cles has been the use of MCRs. In 2004, Wang et al. first reported MCR preparation methods
for the synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones from aromatic alde-
hydes, aromatic ketones and urea in the presence of FeCl3·6H2O/TMSCl in CH3CN.7 Later,
other catalysts such as NaI/TMSCl,8 Co(OAc)2/TMSCl,9 tBuONa/MWI,10 PTSA/MWI,11
AlCl3 or AlBr3 in CH3CN,12 I2,13 ZnI2/MWI,14 Fe(NO3)3·9H2O,15 and AlCl3/KI under N2
atmosphere16 etc. have been used as well. However, the majority of these methods suffer
from one or more disadvantages such as high toxicity of the solvent, high reaction tem-
perature (140◦C), the need for an additional promoter (TMSCl) or the use of microwave
irradiation. As part of our studies toward the green synthesis of heterocycles,17 we now
report an efficient procedure for the preparation of 5-unsubstituted 3,4-dihydropyrimidin-
2(1H)-ones via the one-pot condensation of aromatic aldehydes, acetophenones and urea
in the presence of NaHSO4 at 90◦C without solvent and promoter (Scheme 1).
We initiated our study with 2-nitrobenzaldehyde, acetophenone, and urea as a model
reaction to determine the best experimental conditions. Solvent, the amount of catalyst and
suitable reaction temperature were investigated. It was shown that 50% molar amount of
NaHSO4 under solvent-free conditions at 90◦C gave the best results.
Submitted by February 25, 2014.
Address correspondence to Min Wang, College of Chemistry, Chemical Engineering and Food
Safety, Bohai University, Jinzhou 121013, P. R. China. E-mail: minwangszg@hotmail.com
457

458
M. Wang et al.
On the basis of these results, various substituted aromatic aldehydes treated with
acetophenones and urea under these optimized reaction conditions to investigate the
scope of this Biginelli-type reaction. The results are summarized in Table 1. It could
be seen that all reactions proceed smoothly to afford the corresponding 5-unsubstituted
3,4-dihydropyri-midin-2(1H)-ones in short reaction times with excellent yields. Neither
electron-withdrawing nor electron-donating groups on the aromatic ring affected the re-
action significantly, either in the yield of product or the rate of the reaction. In addition,
one aliphatic aldehyde (propio-naldehyde), an unsaturated aldehyde (cinnamaldehyde) and
an aliphatic ketone (acetone) were also utilized in this reaction; unfortunately, after 3 h
only dark colored sticky materials were formed and none of the desired products could
be obtained. The condensation of benzaldehyde, acetophenone and thiourea under these
Table 1
Preparation of 5-Unsubstituted 3,4-dihydropyrimidin-2(1H)-ones Catalyzed by NaHSO4
Product
R1
R2
Time (min)
Yield (%)
mp (◦C)
Lit. (◦C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
H
2-Cl
H
H
H
H
H
H
H
H
20
13
8
10
17
7
30
30
40
45
15
60
10
10
20
12
45
15
40
84
92
89
82
91
90
75
76
85
86
74
89
95
88
73
94
92
87
90
217–219
209–211
213–215
225–226
201–202
197–198
230–232
211–212
209–210
261–262
213–215
198–200
191–193
219–220
202–203
195–197
193–194
216–217
193–195
218–2198
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
209–21111
263–26510
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
see Table 2
2,4-Cl2
2-NO2
3-NO2
4-NO2
2-CH3O
3-OH
H
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-CH3O
4-Cl
4-Cl
4-Cl
4-NO2
4-NO2
4-NO2
4-Cl
2-NO2
3-NO2
4-NO2
2-NO2
3-NO2
4-NO2
4-Cl
2-NO2
3-NO2
4s

Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
459
Table 2
Spectral Data of Compounds 4b-4h, 4k-4s
Elemental Analysis (Found)
IR
Cmpd mp (◦C)
C
H
N
(cm−1
)
1H NMR (δ)
4b
4c
4d
209–211 67.49
(67.65)
4.60
(4.54)
9.84
(9.73) 3308
1650
3340 10.36 (s, 1H, NH), 9.54 (s, 1H,
NH), 7.42-6.37 (m, 9H, ArH),
5.63 (s, 1H, CH), 5.45
(s, 1H, CH)
213–215 60.21
(60.06)
3.79
(3.85)
8.78
(8.70) 3293
1669
3428 10.28 (s, 1H, NH), 8.90 (s, 1H,
NH), 7.95-6.28 (m, 8H, ArH),
5.67 (s, 1H, CH), 5.45
(s, 1H, CH)
225–226 65.08
(65.22)
4.44
(4.36)
14.23 3480 10.25 (s, 1H, NH), 8.73 (s, 1H,
(14.35) 3301
1673
NH), 7.87-7.51 (m, 6H, ArH),
6.88 (d, 2H, J = 7.8 Hz,
ArH), 6.55 (t, 1H, J = 7.8 Hz,
ArH), 5.71 (s, 1H, CH),
5.45 (s, 1H, CH)
4e
4f
201–202 65.08
(64.89)
4.44
(4.53)
14.23 3440 10.15 (s, 1H, NH), 8.70 (s, 1H,
(14.31) 3297
1668
NH), 8.17-6.99 (m, 8H, ArH),
6.26-6.19 (m, 1H, ArH), 5.83
(s, 1H, CH), 5.45 (s, 1H,
CH)
197–198 65.08
(65.24)
4.44
(4.37)
14.23 3459 10.17 (s, 1H, NH), 8.70 (s, 1H,
(14.12) 3317
1662
NH), 8.43-7.30 (m, 6H, ArH),
7.04-6.98 (m, 2H, ArH),
6.25-6.17 (m, 1H, ArH), 5.82
(s, 1H, CH), 5.46 (s, 1H,
CH)
4g
4h
230–232 72.84
(73.00)
5.75
(5.64)
9.99
(10.12) 3321
1647
3441 10.01 (s, 1H, NH), 8.79 (s, 1H,
NH), 7.97-6.31 (m, 9H, ArH),
5.63 (s, 1H, CH), 5.43 (s,
1H, CH), 3.80 (s, 3H, OCH3)
211–212 72.16
(72.01)
5.30
(5.17)
10.52 3444 9.98 (s, 1H, NH), 9.40 (s, 1H,
(10.65) 3350
1652
NH), 7.12-6.03 (m, 10H, ArH
and -OH), 5.67 (s, 1H, CH),
5.45 (s, 1H, CH)
(Continued on next page)

460
M. Wang et al.
Table 2
Spectral Data of Compounds 4b-4h, 4k-4s (Continued)
Elemental Analysis (Found)
IR
Cmpd mp (◦C)
C
H
N
(cm−1
)
1H NMR (δ)
4k
213–215 62.76
(62.90)
4.65
(4.54)
12.92 3479 9.15 (s, 1H, NH), 8.73 (s, 1H,
(13.01) 3301
1672
NH), 7.87-7.51 (m, 5H, ArH),
6.88 (d, 2H, J = 7.4 Hz,
ArH), 6.56 (t, 1H, J = 7.4 Hz,
ArH), 5.71 (s, 1H, CH),
5.46 (s, 1H, CH), 3.84 (s, 3H,
OCH3)
4l
198–200 62.76
(62.61)
4.65
(4.72)
12.92 3438 10.15 (s, 1H, NH), 8.70 (s, 1H,
(12.84) 3300
1668
NH), 8.35-7.00 (m, 7H, ArH),
6.32-6.20 (m, 1H, ArH), 5.83
(s, 1H, CH), 5.45 (s, 1H,
CH), 3.84 (s, 3H, OCH3)
4m
4n
191–193 62.76
(62.58)
4.65
(4.73)
12.92 3447 10.17 (s, 1H, NH), 8.99 (s, 1H,
(13.01) 3313
1669
NH), 8.43-6.18 (m, 8H, ArH),
5.83 (s, 1H, CH), 5.46 (s,
1H, CH), 3.84 (s, 3H, OCH3)
219–220 58.28
(58.41)
3.67
(3.60)
12.74 3480 10.24 (s, 1H, NH), 8.73 (s, 1H,
(12.82) 3301
1673
NH), 8.14-7.51 (m, 5H, ArH),
6.88 (d, 2H, J = 7.5 Hz,
ArH), 6.55 (t, 1H, J = 7.5 Hz,
ArH), 5.71 (s, 1H, CH),
5.45 (s, 1H, CH)
4o
202–203 58.28
(58.16)
3.67
(3.57)
12.74 3440 10.15 (s, 1H, NH), 8.70 (s, 1H,
(12.85) 3298
1668
NH), 8.33-7.33 (m, 5H, ArH),
6.99 (d, 2H, J = 7.2 Hz,
ArH), 6.25-6.19 (m, 1H,
ArH), 5.82 (s, 1H, CH),
5.44 (s, 1H, CH)
4p
4q
195–197 58.28
(58.39)
3.67
(3.61)
12.74 3459 10.17 (s, 1H, NH), 8.87 (s, 1H,
(12.56) 3318
1662
NH), 8.43-6.19 (m, 8H, ArH),
5.83 (s, 1H, CH), 5.46 (s,
1H, CH)
193–194 58.28
(58.14)
3.67
(3.55)
12.74 3437 10.01 (s, 1H, NH), 8.87 (s, 1H,
(12.60) 3308
1654
NH), 8.36-6.15 (m, 8H, ArH),
5.71 (s, 1H, CH), 5.42 (s,
1H, CH)
(Continued on next page)

Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
461
Table 2
Spectral Data of Compounds 4b-4h, 4k-4s (Continued)
Elemental Analysis (Found)
IR
Cmpd mp (◦C)
C
H
N
(cm−1
)
1H NMR (δ)
4r
216–217 56.47
(56.32)
3.55
(3.61)
16.46 3440 10.25 (s, 1H, NH), 8.73 (s, 1H,
(16.37) 3301
1673
NH), 8.36-7.51 (m, 5H, ArH),
6.89 (d, 2H, J = 7.8 Hz,
ArH), 6.56 (t, 1H, J = 7.8 Hz,
ArH), 5.71 (s, 1H, CH),
5.46 (s, 1H, CH)
4s
193–195 56.47
(56.61)
3.55
(3.60)
16.46 3438 10.15 (s, 1H, NH), 8.84 (s, 1H,
(16.38) 3300
1668
NH), 8.36-8.13 (m, 2H, ArH),
7.78-7.33 (m, 3H, ArH), 7.00
(d, 2H, J = 7.7 Hz, ArH),
6.20 (t, 1H, J = 7.6 Hz, ArH),
5.83 (s, 1H, CH), 5.45
(s, 1H, CH)
optimized conditions was also examined and it afforded the corresponding 3,4-dihydro-
4,6-diphenyl-pyrimidin-2-(1H)-thione (mp. 249–251◦C11) albeit in only 28% yield after
1 h.
In conclusion, the mild and solvent-free conditions, short reaction times, excellent
yields, inexpensive, non-toxic, and commercially available catalyst, and broad substrate
range make this procedure a useful process for the synthesis of 5-unsubstituted 3,4-
dihydropyrimidin-2(1H)-ones.
Experimental Section
Mps were determined using an RY-1 micromelting point apparatus. Infrared spectra were
1
recorded on a Scimitar 2000 series Fourier Transform instrument of VARIAN. H NMR
spectra were obtained on an Agilent 400-MR spectrometer in DMSO-d6 using TMS as
an internal standard. Mass spectra were determined on an Agilent 1100 series LC/MSD
VL ESI instrument. Elemental analyses were carried out on EA 2400II elemental analyzer
(Perkin Elmer). All reagents were from commercial sources.
General Procedure
A mixture of an aromatic aldehyde (10 mmol), an aromatic ketone (10 mmol), urea (0.90 g,
15 mmol), NaHSO4 (5 mmol) was added into a 25 ml dried round-bottom flask. Then
the reaction mixture was stirred at 90◦C for an appropriate time. After completion of the
reaction (as indicated by TLC using ethyl acetate-n-hexane, 1:4), the mixture was cooled
to room temperature and the precipitated solid was collected and washed thoroughly with

462
M. Wang et al.
water. The product was purified by recrystallization from 95% ethanol. All products were
characterized by melting point, IR, 1H NMR, MS and elemental analysis.
References
1. C. O. Kappe, Eur. J. Med. Chem., 35, 1043 (2000).
2. S. Sasaki, N. Cho, Y. Nara, M. Harada, S. Endo, N. Suzuki, S. Furuya and M. Fujino, J. Med.
Chem., 46, 113 (2003).
3. K. S. Atwal, B. N. Swanson, S. E. Unger, D. M. Floyd, S. Moreland, A. Hedberg and B. C.
O’Reilly, J. Med. Chem., 34, 806 (1991).
4. G. C. Rovnyak, K. S. Atwal, A. Hedberg, S. D. Kimball, S. Moreland, J. Z. Gougoutas, B. C.
O’Reilly, J. Schwartz and M. F. Malley, J. Med. Chem., 35, 3254 (1992).
5. G. C. Rovnyak, S. D. Kimball, B. Beyer, G. Cucinotta, J. D. DiMarco, J. Gougoutas, A. Hedberg,
M. Malley, J. P. McCarthy, R. Zhang and S. Moreland, J. Med. Chem., 38, 119 (1995).
6. C. O. Kappe, D. Kumar and R. S. Varma, Synthesis, 1799 (1999).
7. Z. T. Wang, L. W. Xu, C. G. Xia and H. Q. Wang, Tetrahedron Lett., 45, 7951 (2004).
8. G. Sabitha, K. B. Reddy, R. Srinivas and J. S. Yadav, Helv. Chim. Acta, 88, 2996 (2005).
9. H. Kefayati, M. Fakhriyannejad and A. A. Mohammadi, Phosphorus, Sulfur 184, 1796 (2009).
10. I. T. Phucho, A. Nongpiur, R. Nongrum and R. L. Nongkhlaw, Indian J. Chem. B, 49, 346 (2010).
11. I. T. Phucho, S. Tumtin, A. Nongpiur, R. Nongrum and R. L. Nongkhlaw, J. Chem. Pharm. Res.,
2, 214 (2010).
12. A. Saini, S. Kumar and J. S. Sandhu, Indian J. Chem. B, 46, 1690 (2007).
13. Y. M. Ren and C. Cai, Monatsh. Chem., 140, 49 (2009).
14. B. Liang, X. Wang, J. X. Wang and Z. Du, Tetrahedron, 63, 1981 (2007).
15. M. Phukan, M. K. Kalita and R. Borah, Green Chem. Lett. Review, 3, 329 (2010).
16. A. Saini, S. Kumar and J. S. Sandhu, Indian J. Chem. B, 45, 684 (2006).
17. M. Wang, J. J. Gao, Z. G. Song and L. Wang, Org. Prep. Proced. Int., 44, 159 (2012).