ZrOCl2·8H2O as an efficient reagent for the solvent-free synthesis of 3,4-dihydropyrimidin-2-(1H)-ones

Article abstract of DOI:10.1080/00397910600639828

ZrOCl₂·8H₂O, a commercially available reagent, can be used for the promotion of the synthesis of 3,4-dihydropyrimidin-2(1H)- ones under solvent-free reaction conditions. All reactions were performed at 90°C in good to high yields. Co

Full text of DOI:10.1080/00397910600639828

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ZrOCl2 · 8H2O as an Efficient Reagent
for the Solvent‐Free Synthesis of
3,4‐Dihydropyrimidin‐2‐(1H)‐ones
Farhad Shirini a , Mohammad Ali Zolfigol b & Esmail Mollarazi a
a Department of Chemistry, College of Science, Guilan University, Rasht,
Iran
b Department of Chemistry, College of Science, Bu‐Ali Sina University,
Hamadan, Iran
Published online: 22 Sep 2006.
To cite this article: Farhad Shirini , Mohammad Ali Zolfigol & Esmail Mollarazi (2006) ZrOCl2 · 8H2O
as an Efficient Reagent for the Solvent‐Free Synthesis of 3,4‐Dihydropyrimidin‐2‐(1H)‐ones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:16,
2307-2310, DOI: 10.1080/00397910600639828
To link to this article: http://dx.doi.org/10.1080/00397910600639828
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Synthetic Communicationsw, 36: 2307–2310, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600639828
.
ZrOCl2 8H2O as an Efficient Reagent
for the Solvent-Free Synthesis of
3,4-Dihydropyrimidin-2-(1H)-ones
Farhad Shirini
Department of Chemistry, College of Science, Guilan University,
Rasht, Iran
Mohammad Ali Zolfigol
Department of Chemistry, College of Science, Bu-Ali Sina University,
Hamadan, Iran
Esmail Mollarazi
Department of Chemistry, College of Science, Guilan University,
Rasht, Iran
.
Abstract: ZrOCl2 8H2O, a commercially available reagent, can be used for the
promotion of the synthesis of 3,4-dihydropyrimidin-2(1H)-ones under solvent-free
reaction conditions. All reactions were performed at 908C in good to high yields.
Keywords: Aldehydes, Biginelli condensation, 3,4-dihydropyrimidin-2(1H)-ones,
.
solvent-free reactions, ZrOCl2 8H2O
Because of their therapeutic and pharmacological properties and also because
of the presence in their structures of several biologically active marine
alkaloids,[1–4] synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones
(DHPMs) has attracted considerable attention in recent years. The classical
method for the synthesis of these types of compounds involves a one-pot,
three-component condensation of b-dicarbonyl compounds with aldehydes
Received in the U.K. June 14, 2005
Address correspondence to Farhad Shirini, Department of Chemistry, College of
Science, Guilan University, Rasht, Iran. E-mail: shirini@guilan.ac.ir or fshirini@
yahoo.com
2307

2308
F. Shirini, M. A. Zolfigol, and E. Mollarazi
and urea or thiourea in ethanol under strongly acidic conditions.[5] This
method suffers from long reaction times, acidic reaction conditions, and unsat-
isfactorily low yields in cases of aliphatic and some substituted aromatic
aldehydes. Therefore, several improved procedures for the preparation of
DHPMs, by modification of the classical one-pot approach and complex
multistep strategies, have been reported during the past years.[6–16]
However, the practical application of these methods suffers from disadvan-
tages such as the use of expensive or less easily available reagents, vigorous
reaction conditions, prolonged standing, and tedious manipulations to
isolate the products. Therefore, a need still exists for efficient and simple
protocols whereby DHPMs may be obtained under milder conditions.
In recent years, organic reactions under solvent-free conditions have
attracted attention because of their enhanced selectivity, milder reaction con-
ditions, much improved reaction rates, formation of cleaner products, and
associated ease of manipulation.[17] In continuation of our ongoing research
program on organic solvent-free reactions,[18–20] we have found that
.
ZrOCl2 8H2O, a stable and commercially available reagent, has received
little attention in organic chemistry.[21,22] Herein, we report that
.
ZrOCl2 8H2O is able to improve the Biginelli condensation reaction under
solvent-free conditions (Scheme 1).
Optimization of the reaction conditions is carried out by the condensation
of benzaldehyde, ethyl acetoacetate, and urea under solvent-free conditions. The
best result was achieved by carring out the reaction of benzaldehyde, ethyl acet-
oacetate, and urea (with 1 : 1 : 1.5 mol ratio) in the presence of 0.1 mol of
.
ZrOCl2 8H2O at 908C for 2 h under solvent-free conditions (Table 1, entry 1).
Aliphatic and other substituted aldehydes were also reacted under the
same reaction conditions to produce the corresponding DHPMs in good to
high yields (Table 1). Methyl acetoacetate and thiourea were also used with
similar success to provide the corresponding 3,4-dihydropyrimidin-2(1H)-
thiones.[23]
.
In conclusion, ZrOCl2 8H2O can be applied as an efficient reagent for
the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones. The main
advantages of this methodology are high yields, easy synthetic procedure,
and mild and solvent-free reaction conditions. We believe that this method
can be a useful addition to the present methodologies for the synthesis of
3,4-dihydropyrimidin-2(1H)-ones and -thiones.
Scheme 1.

.
ZrOCl2 8H2 as Reagent
2309
Table 1. Solvent-free synthesis of 3,4-dihydropyrimidin-2(1H)-ones and -thiones in
a
.
the presence of ZrOCl2 8H2O
Entry
R1
R2
X
Yield (%)b
Mp (8C)
Lit. mp (8C)
1
2
C6H5
Et
Et
O
O
O
O
O
O
O
O
O
O
S
95
92
85
70
82
70
80
70
95
85
95
85
87
70
85
85
70
95
204–206
208–210
229–230
205–207
198–200
260–262
257–258
231–232
207–209
156–158
208–209
191–192
153–156
203–205
229–231
203–205
189–192
208–209
202–204[13]
213–215[13]
226–227[13]
206–208[13]
201–203[13]c
262[13]d
256–257[24]
232–235[13]
209–211[25]
157–158[26]
208–210[13]
192–195[24]
150–152[13]
206–207[13]
233–236[13]
204–207[13]
192–194[13]
210–212[27]
4-ClC6H4
3-NO2C6H4
2-NO2C6H4
4-MeOC6H4
2-MeOC6H4
4-NMe2C6H4
C6H5CH55CH
2-Furyl
3
Et
Et
4
5
Et
Et
6
7
Et
Et
8
9
Et
Et
10
11
12
13
14
15
16
17
18
n-Bu
C6H5
Et
Et
4-Cl C6H4
4-MeOC6H4
3-NO2C6H4
C6H5
S
Et
Et
S
S
Me
Me
Me
Me
O
O
O
O
4-Cl C6H4
4-MeOC6H4
2-Furyl
aProducts were characterized by their physical constants, comparison with authentic
samples, and IR and NMR spectroscopy.
bIsolated yield.
cReaction is performed at 1108C.
dReaction is performed at 1008C.
EXPERIMENTAL
Chemicals were purchased from Fluka, Merck, and Aldrich chemical
companies. Yields refer to isolated products. Products were characterized by
their physical constants, comparison with authentic samples, and IR and NMR
spectroscopy. The purity determination of the substrates and reaction monitoring
were accompanied by TLC on silica-gel polygram SILG/UV 254 plates.
General Procedure
A mixture of b-dicarbonyl compound (1 mmol), aldehyde (1 mmol), urea or
.
thiourea (1.5 mmol), and ZrOCl2 8H2O (0.1 mmol) was heated in an oil
bath (908C) for 2 h. After completion (monitored by TLC), the reaction
mixture was poured into water (5 mL). The precipitate was filtered and succes-
sively washed with water (5 mL) and petroleum ether–EtOAc (5 : 1, 5 mL).
The crude product was purified by recrystallization to give the pure
products in good to high yields.

2310
F. Shirini, M. A. Zolfigol, and E. Mollarazi
ACKNOWLEDGMENT
We are thankful to the Guilan University Research Council for partial support
of this work.
REFERENCES
1. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
2. Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.;
Hedberg, A.; O’Rielly, B. C. J. Med. Chem. 1991, 34, 806.
3. Rovynak, G. C.; Kimball, S. C.; 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.
4. Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.; Moreland, S.;
Swanson, B. N.; Gougoutas, J. Z.; Schwarts, J.; Smillie, K. M.; Malley, M. F.
J. Med. Chem. 1990, 33, 2629.
5. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
6. Reddy, C. V.; Mahesh, M.; Raju, P. V. K.; Babu, T. R.; Reddy, V. V. N. Tetrahe-
dron Lett. 2002, 43, 2657.
7. Fu, N. Y.; Yuan, Y. F.; Cao, Z.; Wang, S. W.; Wang, J. T.; Peppe, C. Tetrahedron
2002, 58, 4801.
8. Dondoni, A.; Massi, A. Tetrahedron Lett. 2001, 42, 7975.
9. Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Raj, K. S.; Prasad, A. R. J. Chem. Soc.,
Perkin Trans. 1 2001, 1939.
10. Lu, J.; Bai, Y.; Wang, Z.; Yang, B.; Ma, H. Tetrahedron Lett. 2000, 41, 9075.
11. Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.; Wang, X. Tetrahedron Lett.
2003, 44, 6153.
12. Maiti, G.; Kundu, P.; Guin, C. Tetrahedron Lett. 2003, 44, 2757.
13. Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Bodaghi Fard, M. A. Tetrahedron Lett.
2003, 44, 2889.
14. Ghosh, R.; Maiti, S.; Chakraborty, A. J. Mol. Cat. 2004, A217, 47.
15. Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999, 1799.
16. Yarapathi, R. V.; Kurva, S.; Tammishetti, S. Cat. Commun. 2004, 5, 511.
17. Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
18. Shirini, F.; Zolfigol, M. A.; Khaleghi, M. Phosphorous, Sulfur Silicon Relat. Elem.
2003, 178, 2107.
19. Shirini, F.; Zolfigol, M. A.; Abadini, M.; Salehi, P. Mendeleev Commun. 2003,
265.
20. Shirini, F.; Zolfigol, M. A.; Mallakpour, B.; Mohammadpoor-Baltork, I.;
Mallakpour, S. E.; Hajipour, A. R. J. Chem. Res. Synop. 2003, 28.
21. Firouzabadi, H.; Fakoorpour, M.; Hazarkhani, H. Synth. Commun. 2001, 31, 3859.
22. Shirini, F.; Zolfigol, M. A.; Mollarazi, E. Synth. Commun. 2005, 35, 1541.
23. Dondoni, A.; Massi, A.; Sabbatini, S. Tetrahedron Lett. 2002, 43, 5913.
24. Lu, J.; Bai, Y. J. Synthesis 2002, 466.
25. Paraskar, A. S.; DewKar, G. K.; Sudalai, A. Tetrahedron Lett. 2003, 44, 3305.
26. Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864.
27. Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270.