One-pot synthesis of 3,4-dihydropyrimidine-2-(1H)-ones using CsF-Celite as catalyst

Article abstract of DOI:10.1080/00397910802439175

A facile, efficient, and environmentally benign procedure for the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones via the cyclocondensation reaction of aromatic aldehyde, ethyl acetoaceate, and urea catalyzed by CsF-Celite was developed. This environmentall

Full text of DOI:10.1080/00397910802439175

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One-Pot Synthesis of 3,4-
Dihydropyrimidine-2-(1H)-ones
Using CsF–Celite as Catalyst
a
a
Sirirat Chancharunee , Pilaiwan Pinhom , Manat
b
c
Pohmakotr & Patrick Perlmutter
a
Chemistry Department , Faculty of Science,
Chiangmai University , Chiangmai, Thailand
b
Chemistry Department , Faculty of Science,
Mahidol University , Bangkok, Thailand
c
School of Chemistry and the Centre for Green
Chemistry , Monash University , Victoria, Australia
Published online: 29 Jan 2009.
To cite this article: Sirirat Chancharunee , Pilaiwan Pinhom , Manat Pohmakotr &
Patrick Perlmutter (2009) One-Pot Synthesis of 3,4-Dihydropyrimidine-2-(1H)-ones
Using CsF–Celite as Catalyst, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:5, 880-886, DOI:
10.1080/00397910802439175
To link to this article: http://dx.doi.org/10.1080/00397910802439175
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Synthetic Communications , 39: 880–886, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802439175
One-Pot Synthesis of 3,4-Dihydropyrimidine-
2
-(1H)-ones Using CsF–Celite as Catalyst
1
1
Sirirat Chancharunee, Pilaiwan Pinhom, Manat Pohmakotr,
2
3
and Patrick Perlmutter
Chemistry Department, Faculty of Science, Chiangmai University,
Chiangmai, Thailand
1
2
Chemistry Department, Faculty of Science, Mahidol University,
Bangkok, Thailand
School of Chemistry and the Centre for Green Chemistry, Monash
University, Victoria, Australia
3
Abstract: A facile, efficient, and environmentally benign procedure for the synth-
esis of 3,4-dihydropyrimidin-2-(1H)-ones via the cyclocondensation reaction of
aromatic aldehyde, ethyl acetoaceate, and urea catalyzed by CsF–Celite was
developed. This environmentally friendly method is superior to previous methods
with respect to reaction time, yield, and workup.
Keywords: Celite, cesium fluoride, dihydropyrimidinones, green chemistry,
multicomponent reaction
In recent years, dihydropyrimidinones (DHPMs, 4 and 5, Scheme 1) and
their derivatives have attracted considerable interest because of their
diverse therapeutic and pharmacological profiles, which include antihy-
[
1]
pertensive, antiviral, antifungal, antibacterial, and antitumor action.
4
4
-Aryl-3,4-dihydropyrimidinones, which have a structure similar to
-aryl-1,4-dihydropyridines, also exhibited calcium channel modulat-
[2]
ing activity. The structurally related marine alkaloids batzelladine
[
A and B have been found to be potent HIV gp-120CD4 inhibitors.
3]
Received April 29, 2008.
Address correspondence to Sirirat Chancharunee, Chemistry Department,
Faculty of Science, Chiangmai University, Chiangmai 50220, Thailand. E-mail:
siriratc@chiangmai.ac.th
8
80

Synthesis of 3,4-Dihydropyrimidine-2-(1H)-ones
881
Scheme 1. Preparation of compounds 4 and 5.
Additionally, monastrol (5g, X ¼ S, Ar ¼ 3-OHC H ) has been identified
6
5
[4]
as a novel anticancer drug. The classical synthesis of DHPMs, the
‘
[5]
‘Biginelli reaction,’’ involves the one-pot, multicomponent conden-
sation of a b-ketoester, an aldehyde, and urea under strongly acidic con-
ditions. In addition to strong acid, these reactions require long reaction
times, usually resulting in low yields. Several modified and improved pro-
cedures for the one-pot synthesis of dihydropyrimidinones have been
reported, employing a range of catalysts and promoters, including
[
6]
[7]
[8]
[9]
[10]
BF ꢀ OEt , polyphosphate ester (PPE), CeCl3, InCl3, FeCl3,
3
2
[11]
and montmorillonite–KSF clay.
However, many of these methods
have drawbacks such as long reaction times, harsh reaction conditions,
the use of stoichiometric reagents and toxic, flammable solvents, difficult
workups, or low yields of products.
Consequently, the search for new catalysts and cleaner methods
using less hazardous reagents and environmentally friendly conditions,
such as solvent-free conditions, is of considerable interest. In this report,
we disclose our preliminary results employing CsF–Celite–catalyzed
Biginelli synthesis of DHPMs under solvent-free conditions. The pre-
paration of the CsF–Celite was carried out in the same manner as
[12]
described by Hayat et al.
To establish the optimal conditions for our
new method, we carried out a set of experiments, varying the reaction
time, amount of catalyst, and the quantities of urea. The best conditions
to prepare the dihydropyrimidinone 4 were achieved when 10 mol% of
CsF–Celite, 1 equivalent of both aldehyde and ethyl acetoacetate, and
1
.3 equivalents of urea were mixed and heated together. Excellent yields,
after recrystallization from ethanol, were obtained (Table 1, entry 1).
Decreasing the catalyst concentration resulted in lower yields under the
same conditions (Table 1, entry 2). On the other hand, higher amounts
of catalyst did not improve the yield significantly (Table 1, entry 3). To
ascertain the generality of this procedure, several examples were studied,
and the results are summarized in Table 1. All synthesized compounds
were characterized by NMR spectroscopy and melting point.

8
82

Synthesis of 3,4-Dihydropyrimidine-2-(1H)-ones
883
þ
Scheme 2. Cs activation in three-component coupling for Biginelli reaction.
Aromatic aldehydes containing either electron-donating or electron-
withdrawing substituents reacted well under the reaction conditions to
give the corresponding DHPMs in high to quantitative yields. In all cases
examined, the condensation reactions were very clean, leading to DHPM
in short reaction times (1–3 h).
The feasibility of recovery and reuse of the catalyst in the present
methodology was also examined by using benzaldehyde as a model sub-
strate (Table 1, entry 1). The catalyst was recovered by filtration during
the recrystallization procedure, dried under reduced pressure, and then
reused for three cycles. It was found that catalyst activity remains almost
the same. This in turn makes the method more economical. This method
not only preserved the simplicity of Biginelli’s one-pot condensation but
also remarkably improved the yields (92–98%) of DHPMs in shorter
reaction times.
This reaction may proceed via imine intermediate 6, formed by the
þ
reaction of the aldehyde and urea and stabilized by Cs . Subsequent
nucleophilic addition of b-diketoeaster enolate to the imine, followed
by cyclization and dehydration, afford the corresponding 3,4-dihydro-
pyrimidin-2(1H)-ones 4 and 5 (Scheme 2).
In conclusion, we have demonstrated a new and efficient synthetic
methodology for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones and
their thio analogs under solvent-free conditions using a catalytic amount
of CsF–Celite. The procedure afforded 3,4-dihydro-pyrimidones within a
shorter period, in high purities, and with improved yields compared with
the classical solution-phase reaction. Moreover, the simplicity of the pro-
cedure, ease of separation=reuse of the catalyst because of its hetero-
geneous nature, and ease of workup make this method an attractive
synthetic tool for Biginelli condensation.
EXPERIMENTAL
Melting points were determined on a MelTemp melting-point apparatus
1 13
and are uncorrected. H and C NMR spectra were obtained on Bruker

884
S. Chancharunee et al.
1 13
Avance 400 (400 MHz, H; 100 MHz, C) spectrometers. All spectra
were taken in d -DMSO, and the chemical shifts are given in parts per
6
million (ppm) with respect to tetramethylsilane (TMS) used as internal
1
standard. Aldehyde, ethylacetoacetate, Celite 521, urea, and thiourea
were all commercial products and were purified before use.
Preparation of CsF–Celite
The CsF–Celite was prepared by stirring an aqueous solution of CsF
(15.2 g in 300 ml of distilled water) with 10 g of Celite 521 at room tem-
perature for 1 h, and water was removed under reduced pressure. The
remaining solid was shaken with 100 ml of acetonitrile, and the solid
was collected on a filter. The CsF–Celite was dried under vacuum and
kept in a desiccator.
General Procedure for the Synthesis of Compounds 4 and 5
Aldehydes (1 mmol), ethyl acetoacetate (1 mmol), urea (1.3 mmol), and
CsF–Celite (10 mol%) were mixed together in a 10-mL round-
ꢁ
bottomed flask and heated at 80–110 C for the appropriate time
(
(
Table 1). The reaction was monitored by thin-layer chromatography
TLC) until completion. The products were recrystallized from ethyl
alcohol.
All 3,4-dihydropyrimidin-2(1H)-one derivatives are known com-
1
pounds and were characterized by H NMR spectroscopy and their
melting points. Selected data for 5-ethoxycarbonyl-4-(3-hydroxyphenyl)-
6
Table 1, entry 15) are as follows: mp 182–184 C (lit. mp 182–
-methyl-3,4-dihydropyrimidin-2(1H)-thione (5g, X ¼ S, Ar¼ 3-OHC H ,
6
5
ꢁ
ꢁ
[13] 1
1
3
3
84 C).
H), 4.01 (q, J ¼ 7.1 Hz, 2H), 5.07 (d, J ¼ 3.5 Hz, 1H), 6.62–6.64 (m,
H NMR (DMSO-d ) d, 1.11 (t, J ¼ 7.1 Hz, 3H), 2.26 (s,
6
H), 7.09–7.12 (m, 1H), 9.44 (s, 1H, OH), 9.59 (br s, 1H, NH), 10.28
(br s, NH).
ACKNOWLEDGMENTS
We thank the Commission on Higher Education (CHE-RG) and Center
for Innovation in Chemistry: Postgraduate Education Program in Chem-
istry (PERCH-CIC) for financial support.

Synthesis of 3,4-Dihydropyrimidine-2-(1H)-ones
885
REFERENCES
1
. Kappe, C. O.; Stadler, A. The Biginelli dihydropyrimidinone synthesis. Org.
React. 2004, 63, 1–116, and references cited therein.
2
. (a) Grover, G. J.; Dzwonczyk, S.; McMullen, D. M.; Normandin, D. E.;
Parham, C. S.; Sleph, P. G.; Moreland, S. Pharmacologic profile of the dihy-
dropyrimidine calcium channel blockers SQ 32,547 and SQ 32,926. J. Cardi-
ovasc. Pharmacol. 1995, 26, 289–294; (b) 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. Calcium entry block-
ers and activators: Conformational and structural determinants of dihydro-
pyrimidine calcium channel modulators. J. Med. Chem. 1995, 38, 119–129.
. (a) Heys, L.; Moore, C. G.; Murphy, P. J. The guanidine metabolites of
Ptilocaulis spiculifer and related compounds: Isolation and synthesis. Chem.
Soc. Rev. 2000, 29, 57–67; (b) 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. Novel alkaloids from the sponge Batzella sp.: Inhibi-
tors of HIV gp120-human CD4 binding. J. Org. Chem. 1995, 60, 1182–1188.
. (a) Russowsky, D.; Canto, R. F. S.; Sanches, S. A. A.; D’ Oca, M. G. M.;
Fa’tima, A.; Pilli, R. A.; Kohn, L. K.; Antonio, M. A.; Carvalho, J. E.
Synthesis and differential antiproliferative activity of Biginelli compounds
against cancer cell lines: Monastrol, oxo-monastrol, and oxygenated analo-
gues. Bioorg. Chem. 2006, 34, 173–182; (b) Mayer, U. T.; Kapoor, M. T.;
Haggarty, J. S.; King, W. R.; Schreiber, I. S.; Mitchison, J. T. Science
3
4
1999, 268, 971–974.
5
6
. Biginelli, P. Aldureides of ethylic acetoacetate and ethylic oxalacetate. Gazz.
Chim. Ital. 1893, 23, 360–416.
. Hu, E. H.; Sidler, D. R.; Dolling, U.-H. Unprecedented catalytic three
component one-pot condensation reaction: An Efficient synthesis of 5-
alkoxycarbonyl-4-aryl-dihydropyrimidin-2(1H)-ones. J. Org. Chem. 1998, 63,
3454–3457.
7
. (a) Kappe, C. O.; Falsone, S. F. Synthesis and reactions of Biginelli
compounds, part 12: Polyphosphate ester–mediated synthesis of dihydropyr-
imidines: Improved conditions for the Biginelli reaction. Synlett 1998, 7,
718–720; (b) Kappe, C. O.; Kumar, D.; Varma, R. S. Microwave-assisted
high-speed parallel synthesis of 4-aryl-3,4-dihydropyrimidin-2(1H)-ones using
a solventless Biginelli condensation protocol. Synthesis 1999, 10, 1799–1803.
. Bose, D. S.; Fatima, L.; Mereyala, H. B. Green chemistry approaches to the
synthesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones by a
three-component coupling of one-pot condensation reaction: Comparison of
ethanol, water, and solvent-free conditions. J. Org. Chem. 2003, 68, 587–590.
. Ranu, B. C.; Hajra, A.; Jana, U. Indium(III) chloride–catalyzed one-pot
synthesis of dihydropyrimidinones by a three-component coupling of 1,3-
dicarbonyl compounds, aldehydes, and urea: An improved procedure for
the Biginelli reaction. J. Org. Chem. 2000, 65, 6270–6272.
8
9

886
S. Chancharunee et al.
1
0. Lu, J.; Ma, H. R. Iron(III)-catalyzed synthesis of dihydropyrimidinones:
Improved conditions for the Biginelli reaction. Synlett 2000, 1, 63–64.
1. Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. A revision of the
Biginelli reaction under solid acid catalysis: Solvent-free synthesis of
dihydropyrimidines over montmorillonite KSF. Tetrahedron Lett. 1999, 40,
1
3465–3468.
12. Hayat, S.; Atta-ur-Rahman Choudhary, M. I.; Khan, K. M.; Schumann, W.;
Bayer, E. N-Alkylation of anilines, carboxamides and several nitrogen
3
heterocycles using CsF–Celite=alkyl halides=CH CN combination. Tetrahe-
dron 2001, 57, 9951–9957.
1
1
1
3. Das Sharma, S.; Gogoi, P.; Konwar, D. A highly efficient and green method
for the synthesis of 3,4-dihydropyrimidin-2-ones and 1,5-benzodiazepines
catalyzed by dodecyl sulfonic acid in water. Green Chem. 2007, 9, 153–157.
4. Tu, S.; Fang, F.; Miao, C.; Jiang, H.; Feng, Y.; Shi, D.; Wang, X. One-pot
synthesis of 3,4-dihydropyrimidin-2(1H)-ones using boric acid as catalyst.
Tetrahedron Lett. 2003, 44, 6153–6155.
5. Fu, N.; Yuan, Y.; Cao, Z.; Wang, S.; Wang, J.; Peppe, C.; Nan-Yan, F.;
Yao-Feng, Y.; Zhong, C.; Shan-Wei, W.; Ji-Tao, W.; Clovis, P. Indium(III)
bromide–catalyzed preparation of dihydropyrimidinones: Improved protocol
conditions for the Biginelli reaction. Tetrahedron 2002, 58, 4801–4807.
6. Hegedues, A.; Hell, Z.; Vigh, I. Convenient one-pot heterogeneous catalytic
method for the preparation of 3,4-dihydropyrimidin-2(1H)-ones. Synth.
Commun. 2006, 36, 129–136.
1