An efficient synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by thiamine hydrochloride in water under ultrasound irradiation

Article abstract of DOI:10.1016/j.tetlet.2010.04.037

An environmentally benign aqueous Biginelli protocol for the synthesis of substituted 3,4-dihydropyrimidin-2(1H)-ones using thiamine hydrochloride as a catalyst has been achieved. These ultrasound-assisted reactions proceed efficiently in water in the absence of organic solvent. Utilization of ultrasound irradiation, simple reaction conditions, isolation, and purification makes this manipulation very interesting from an economic and environmental perspective.

Full text of DOI:10.1016/j.tetlet.2010.04.037

Tetrahedron Letters 51 (2010) 3138–3140
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Tetrahedron Letters
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An efficient synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed
by thiamine hydrochloride in water under ultrasound irradiation
*
Priyanka G. Mandhane, Ratnadeep S. Joshi, Deepak R. Nagargoje, Charansingh H. Gill
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 February 2010
Revised 3 April 2010
Accepted 10 April 2010
Available online 14 April 2010
An environmentally benign aqueous Biginelli protocol for the synthesis of substituted 3,4-dihydropyrim-
idin-2(1H)-ones using thiamine hydrochloride as a catalyst has been achieved. These ultrasound-assisted
reactions proceed efficiently in water in the absence of organic solvent. Utilization of ultrasound irradi-
ation, simple reaction conditions, isolation, and purification makes this manipulation very interesting
from an economic and environmental perspective.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Biginelli reaction
Dihydropyrimidinones (DHPMs)
Thiamine hydrochloride
Multi-component reactions
Ultrasonication
1. Introduction
[bmim] [FeCl4].18 Recently, a base-catalyzed version of these reac-
tions was reported in EtOH at reflux.19 Modified syntheses of
Organic transformations in aqueous media without using haz-
ardous reagents or solvents are of interest.1 In the past decade,
dihydropyrimidinones (DHPMs) and their derivatives have at-
tracted considerable interest because they exhibit promising activ-
ities as calcium channel blockers, antihypertensive agents, and as
DHPMs have been advanced also in aqueous media.20 However,
more efficient syntheses of these biologically active compounds
in aqueous media are important. However, all the existing methods
displayed drawbacks, such as environmental pollution caused by
utilization of organic solvents, long reaction time, exotic reaction
conditions, unsatisfactory yields, and complicated operations.
Therefore, it is urgent to further develop an efficient and conve-
nient method to construct such significant scaffold.
a
-1a-antagonists and neuropeptide Y (NPY) antagonists.2 Further-
more, several isolated bioactive marine alkaloids were also found
to contain 2-amino-1,4-dihydropyrimidinone-5-carboxylate
a
core.3 Most notable among them are batzalladine alkaloids, which
have been found to be potent HIVgp-120-CD4 inhibitors.4 Their
derivatives exhibit a wide spectrum of biological effects including
antifungal, antiviral, anticancer, antibacterial, anti-inflammatory,
and antihypertensive effects.5 Thus, a synthesis of this heterocyclic
nucleus has been of much importance in current years.
Ultrasound-accelerated chemical reactions are well-known and
proceed via the formation and adiabatic collapse of transient cav-
itation bubbles. Ultrasound irradiation has been demonstrated as
an alternative energy source for organic reactions ordinarily
accomplished by heating. Many homogeneous and heterogeneous
reactions can be conducted smoothly by sonication to provide im-
proved yields and increased selectivities.21 Therefore, ultrasound
irradiation has been established as an important technique in or-
ganic synthesis.23
The use of solid acid catalysts has gained a vast importance in
organic synthesis due to their several advantages such as opera-
tionally simplicity, no toxicity, reusability, low cost, and ease of
isolation after completion of the reaction. It is well-known that thi-
amine hydrochloride (VB1) is a cheap and non-toxic reagent. The
structure of VB1 contains a pyrimidine ring and a thiazole ring
linked by a methylene bridge (Fig. 1). The use of VB1 analogs as
powerful catalysts for various organic transformations has been re-
ported.22 Herein, we report the thiamine hydrochloride-catalyzed
greener synthesis of 3,4-dihydropyrimidin-2-(1H)-ones in aqueous
A simple and direct method, originally reported by Biginelli,6 for
the synthesis of dihydropyrimidinones often suffers from low
yields of products in the case of substituted aromatic and aliphatic
aldehydes.7 This has led to the recent disclosure of several one-pot
methodologies for the synthesis of DHPM derivatives involving
classical conditions, with microwave and ultrasound irradiation
and by using Lewis acids as well as protic acid promoters such as
ZrCl4,8 CuCl2Á2H2O–HCl,9 LiBr,10 LaCl3–graphite,11 InBr3,12 GaX3,13
ZnBr2,14
1,1,3,3-tetramethylguanidinium
trifluoroacetate,15
Cu(OTf)2,16 [bmim] BF4-immobilized Cu(II) acetylacetonate,17 and
* Corresponding author. Tel.: +91 9822037127.
E-mail addresses: prof_gill@rediffmail.com, pgmandhane@gmail.com (C.H. Gill).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.037

P. G. Mandhane et al. / Tetrahedron Letters 51 (2010) 3138–3140
3139
Table 1
OH
NH2
N
Optimization of solvent effect on the model reactiona
Cl-
N+
Entry
Solvent
With USa yieldc (%)
Without USb yieldc (%)
N
S
1
2
3
4
5
6
7
Solvent free
Dimethylformide
Acetonitrile
Tetrahydrofuran
Methanol
25
34
65
67
72
78
94
29
54
56
65
70
86
Figure 1. Structure of thiamine hydrochloride (VB1).
Ethanol
Water
medium using ultrasound irradiation (Scheme 1). Compared with
those methods mentioned above, our reactions displayed their
advantages: (i) green synthesis without organic solvents is in-
volved; (ii) shortened time and improved yields; and (iii) mild con-
ditions and ready operations.
a
Reaction of benzaldehyde (2 mmol) with b-keto ester (2 mmol), urea (3 mmol),
and thiamine hydrochloride (5 mol %) under ultrasonic waves for 20 min.
b
Reaction of benzaldehyde with b-keto ester, urea, and thiamine hydrochloride
(5 mol %) under constant stirring for 60 min.
c
Isolated yield.
2. Results and discussion
Table 2
Effect of catalyst concentration on model reactiona
In the current study, the commercially available catalyst thia-
mine hydrochloride is used as a catalyst for Bigenelli reaction.
The use of VB1 catalyst under ultrasonic irradiation plays an
important role in the synthesis and hence the reaction rate was im-
proved and the reaction time was reduced. We have investigated
the effect of different solvents on the reaction rate as well as on
the yield of the products (Table 1). Initially, we have done this
experiment under solvent-free condition but reaction did not
proceed smoothly even after prolonged reaction time. The observa-
tions revealed that in aprotic solvents such as THF, DMF, and
acetonitrile the product yield was found to be very low, but in case
of protic solvent such as EtOH, MeOH, and water, the reaction rate
as well as the product yield was found to be improved compara-
tively. After screening for different solvents, water was found to
be the medium of choice, which afforded the products not only
in good yield but also with higher reaction rates (94% yield in
15 min). We have also studied the sonochemical effect on model
reaction by using diverse solvents. In all cases, the experimental re-
sults show that the reaction times are reduced and the yields of the
products are higher under sonication. Based on the results of this
study, it seems that the ultrasound irradiation improves the reac-
tion times and yields. The obtained results are summarized in (Ta-
ble 1, entries 1–7). Further we have studied the influence of
catalyst concentration on the reaction time and percentage yield.
As shown in Table 2, elevated amount of catalyst can improve
the reaction yields and shorten the reaction time. However, in
the absence of catalyst VB1, the reaction did not proceed even after
extending reaction time, the results of which are summarized in
(Table 2, entry 1). For example, when the catalyst concentration
was 1 mol %, the yield was found to be 68% within 50 min (Table 1,
entry 2), but when the catalyst concentration was increased to
5 mol %, the yield was found to be 94% within 15 min (Table 1, en-
try 6) under ultrasonic irradiation. Further increase in the concen-
tration of catalyst did not improve the yields. Therefore, the one-
pot condensation was carried out at 5 mol % of catalyst
concentration.
Entry
Catalyst (mol %)
Timeb (min)
Yieldc (%)
1
2
3
4
5
6
7
0
60
50
45
30
20
15
15
—
68
72
80
85
94
94
1.0
2.0
3.0
4.0
5.0
6.0
a
Reaction of benzaldehyde with b-keto ester, urea, and thiamine hydrochloride
(5 mol %) under ultrasonic irradiation.
b
Time required.
Isolated yield.
c
In conclusion, we have described a novel approach to explore
the use of ultrasound irradiation for the synthesis of 3,4-dihydro-
pyrimidin-2-(1H)-ones using thiamine hydrochloride (VB1) as a
catalyst under aqueous condition at ambient temperature within
15–25 min. In the given approach, 2 mmol of substituted alde-
hydes react with b-keto ester (2 mmol), urea (3 mmol), and thia-
mine hydrochloride (5 mol %), and the formation of 3,4-
dihydropyrimidin-2-(1H)-ones was observed in very high yield.
We believe that sonochemical synthesis of 3,4-dihydropyrimidin-
2-(1H)-ones using thiamine hydrochloride as a catalyst-promoted
methodology will be a valuable addition to the existing processes
in the field of 3,4-dihydropyrimidin-2-(1H)-ones (Table 3).
3. General procedure
A mixture of substituted aldehyde (1, 2 mmol), b-keto ester (2,
2 mmol), urea (3, 3 mmol), and thiamine hydrochloride (4,
5 mol %) was placed in a 50 ml round-bottomed flask. The mixture
was irradiated in the water bath of an ultrasonic cleaner for a per-
iod as indicated in (Table 3) (sonication was continued until the
aldehyde disappeared, as indicated by TLC). After completion of
the reaction, the resulting suspension was filtered. The collected
solid was filtered and recrystallized from ethanol to get the pure
product. The products 4(a–p) were confirmed by comparisons with
authentic samples, IR, 1H NMR, mass spectra, and melting point.
We also examined the reaction on the aliphatic aldehydes, it
gave the corresponding products in low yields after prolonged
reaction time (Table 3, entries 11 and 12).
O
R
O
O
O
VB1
R-CHO
+
R1O
H3C
NH
+
H3C
OR1
H2N
NH2
Water, )))))
N
H
4(a-p)
O
3
2
1(a-p)
Scheme 1. Synthesis of various 3,4-dihydropyrimidin-2-(1H)-ones using VB1 as a catalyst.

3140
P. G. Mandhane et al. / Tetrahedron Letters 51 (2010) 3138–3140
Table 3
Ultrasound-promoted synthesis of 3,4-dihydropyrimidin-2-(1H)-ones catalyzed by VB1a (4a–p)
Entry
Aldehyde
R1
Product
Timeb (min)
Yieldc (%)
1
2
3
4
5
6
7
8
Benzaldehyde
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
4a7b
4b25
4c26
4d24
4e7b
4f7b
4g7b
4h7b
4i7b
15
20
20
25
15
20
15
25
15
20
35
30
15
20
20
25
94
88
93
92
82
85
90
84
88
90
47
69
87
90
93
86
2-Chlorobenzaldehyde
3-Chlorobenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
2-Hydroxybenzaldehyde
4-Hydroxybenzaldehyde
3-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Hydroxy-3-methoxy benzaldehyde
Acetaldehyde
Butyraldehyde
Benzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
4-Nitrobenzaldehyde
9
10
11
12
13
14
15
16
4j7b
4k25
4l25
4m24
4n24
4o24
4p24
CH3
CH3
CH3
a
b
c
Reaction of aldehyde with b-keto esters and urea in the presence of thiamine hydrochloride (5 mol %) in water under ultrasonic irradiation.
Time required.
Isolated yield. All the compounds characterized by their spectroscopy method 1H NMR, mass, IR, and melting point from authentic sample.27
13. Saini, A.; Kumar, S.; Sandhu, J. S. Indian J. Chem., Sect. B 2007, 46, 1886–1889.
14. Yu, Y.; Liu, D.; Liu, C.; Jiang, H.; Luo, G. Prep. Biochem. Biotechnol. 2007, 37, 381–
387.
Acknowledgment
We are grateful to the Head, Department of Chemistry, Dr.
Babasaheb Ambedkar Marathwada University, Aurangabad-431
004 (MS), India for providing the laboratory facilities.
15. Shaabani, A.; Rahmati, A. Catal. Lett. 2005, 100, 177–179.
16. Paraskar, A. S.; Dewkar, G. K.; Sudalai, A. Tetrahedron Lett. 2003, 44, 3305–3308.
17. Jain, S. L.; Joseph, J. K.; Sain, B. Catal. Lett. 2007, 115, 52–55.
18. Chen, X.; Peng, Y. Catal. Lett. 2008, 122, 310–313.
19. (a) Suzuki, I.; Iwata, Y.; Takeda, K. Tetrahedron Lett. 2008, 49, 3238–3241; (b)
Chitra, S.; Pandiarajan, K. Tetrahedron Lett. 2009, 50, 2222; (c) Debache, A.;
Amimour, M.; Belfaitah, A.; Rhouati, S.; Carboni, B. Tetrahedron Lett. 2008, 49,
6119–6121; (d) Hida, T.; Nogusa, H. Tetrahedron 2009, 65, 270–274.
20. (a) Kumar, A.; Maurya, R. A. Synlett 2008, 883–885; (b) Polshettiwar, V.; Varma,
R. S. Tetrahedron Lett. 2007, 48, 7343–7346.
21. (a) Gaplovsky, A.; Gaplovsky, M.; Toma, S.; Luche, J. L. J. Org. Chem. 2000, 65,
8444–8447; (b) Suslick, K. S. Ultrasound, its Chemical, Physical and Biological
Effects; VCH: Weinheim, 1988; (c) Rajagopal, R.; Jarikote, D. V.; Srinivasan, K. V.
Chem. Commun. 2002, 616–617; (d) Deshmukh, R. R.; Rajagopal, R.; Srinivasan,
K. V. Chem. Commun. 2001, 1544–1545.
22. (a) Yasuhara, A.; Suzuki, N.; Sakamoto, T. Chem. Pharm. Bull. 2002, 50, 143–
145; (b) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org.
Chem. 2004, 69, 2896–2898; (c) Hiyama, T.; Hatanaka, Y. Pure App. Chem.
1994, 66, 1471–1478; (d) Sharma, R. K.; Fry, J. L. J. Org. Chem. 1983, 48,
2113–2117; (e) Sun, H.; Di Magno, S. G. J. Am. Chem. Soc. 2005, 127, 2050–
2051.
23. (a) Mandhane, P. G.; Joshi, R. S.; Nagargoje, D. R.; Gill, C. H. Tetrahedron Lett.
2010, 51, 1490–1492; (b) Joshi, R. S.; Mandhane, P. G.; Diwakar, S. D.; Gill, C. H.
Ultrason. Sonochem. 2009, 17, 298–300.
References and notes
1. (a) Li, C. J.; Chang, T. H. Organic Reactions in Aqueous Media; Wiley: New York,
1997; (b) Grieco, P. A. Organic Synthesis in Water; Blackie Academic and
Professional: London, 1998; (c) Lindstrom, U. M. Organic Reactions in Water;
Blackwell, 2007; (d) Ziyaei-Halimehjani, A.; Saidi, M. R. Tetrahedron Lett. 2008,
40, 1244–1248; (e) Jafari, A. A.; Moradgholi, F.; Tamaddon, F. Eur. J. Org. Chem.
2009, 1249–1255.
2. Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.; Dimarco, J. D.;
Gougoutas, J.; Hedberg, A.; Malley, M.; McCarthy, J. P.; Zhang, R.; Moreland,
S. J. Med. Chem. 1995, 38, 119–129.
3. Snider, B. B.; Shi, Z. J. Org. Chem. 1993, 58, 3828–3839.
4. (a) Patil, A. D.; Kumar, N. V.; Kokke, W. C.; Bean, M. F.; Freyer, A. J.; De Brosse,
C.; Mai, S.; Truneh, A.; Faulkner, D. J.; Carte, B.; Breen, A. L.; Hertzberg, R. P.;
Johnson, R. K.; Westley, J. W.; Potts, B. C. M. J. Org. Chem. 1995, 60, 1182–1188;
(b) Rama Rao, A. V.; Gurjar, M. K.; Vasudevan, J. J. Chem. Soc., Chem. Commun.
1995, 13, 1369–1370; (c) Snider, B. B.; Chen, J.; Patil, A. D.; Freyer, A.
Tetrahedron Lett. 1996, 37, 6977–6980.
5. (a) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052; (b) Ghorab, M. M.;
Abdel-Gawad, S. M.; El-Gaby, M. S. A. Farmaco 2000, 55, 249–255; (c)
Shivarama Holla, B.; Sooryanarayana Rao, B.; Sarojini, B. K.; Akberali, P. M.
Eur. J. Med. Chem. 2004, 39, 777–783.
24. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998, 63, 3454–3457.
25. Shaabani, A.; Bazgir, A.; Teimouri, F. Tetrahedron Lett. 2003, 44, 857–859.
26. Fu, N. Y.; Pang, M. L.; Yaun, Y. F.; Wang, J. T. Chin. Chem. Lett. 2002, 13, 921–922.
27. Spectral data of selected compounds
6. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–413.
Compound (4b): mp 252–254 °C; IR (KBr): 3215, 3080, 1687, 1641 cmÀ1 1H
;
7. (a) Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1934, 56, 1180–1185; (b) Folkers,
K.; Harwood, H. J.; Johnson, T. B. J. Am. Chem. Soc. 1932, 54, 3751–3758; (c)
Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819–7822.
8. Reddy, V.; Mahesh, M.; Raju, P. V. K.; Ramesh Babu, T.; Narayana Reddy, V. V.
Tetrahedron Lett. 2002, 43, 2657–2659.
9. Pathak, V. N.; Gupta, R.; Varshney, B. Indian J. Chem. 2008, 47B, 434–438.
10. Maiti, G.; Kundu, P.; Guin, C. Tetrahedron Lett. 2003, 44, 2757–2758.
11. Khabazzadeh, H.; Saidi, K.; Sheibani, H. Bioorg. Med. Chem. Lett. 2008, 18, 278–
280.
NMR (400 MHz, DMSO-d6): 2.31 (s, 3H, CH3), 3.47 (s, 3H, OCH3), 5.71 (s, 1H,
CH), 7.33–7.41 (m, 4H, Ar-H), 7.81 (s, 1H, NH), 9.15 (s, 1H, NH); MS: m/z: 281.3;
(4h): mp 279–281 °C; IR (KBr): 3333, 3215, 1710, 1645 cmÀ1 1H NMR (DMSO-
;
d6): 2.31 (s, 3H, CH3), 3.64 (s, 3H, OCH3), 5.31 (s, 1H, CH), 7.71–8.16 (m, 4H, Ar-
H), 7.85 (s, 1H, NH), 9.25 (s, 1H, NH); MS: m/z: 291.8; (4i): mp 205–207 °C; IR
(KBr): 3217, 1731, 1711, 1652 cmÀ1 1H NMR (DMSO-d6): 1.16 (t, 3H, J = 6.9 Hz,
;
CH3), 2.31 (s, 3H, CH3), 4.25 (q, 2H, OCH2), 5.16 (s, 1H, CH), 7.81 (d, 2H,
J = 7.5 Hz, Ar-H), 7.81 (s, 1H, NH), 8.25 (d, 2H, J = 7.2 Hz, Ar-H), 9.33 (s, 1H, NH);
MS: m/z: 291.8.
12. Fu, N. Y.; Yuan, Y. E.; Cao, Z.; Wang, S. W.; Wang, J. T.; Peppe, C. Tetrahedron
2002, 58, 4801–4807.