P-Sulfonic acid calixarenes as efficient and reusable organocatalysts for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones

Article abstract of DOI:10.1016/j.tetlet.2011.08.175

A new and efficient methodology is proposed for obtaining 3,4-dihydropyrimidin-2(1H)-ones/-thiones through Biginelli reactions. It is based on the use of less than the stoichiometric amount ofp-sulfonic acid calixarenes as organocatalysts. A number of aro

Full text of DOI:10.1016/j.tetlet.2011.08.175

Tetrahedron Letters 52 (2011) 6328–6330
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
p-Sulfonic acid calixarenes as efficient and reusable organocatalysts
for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/-thiones
Daniel L. da Silva a, Sergio A. Fernandes b, Adão A. Sabino a, Ângelo de Fátima a,
⇑
a Departamento de Química, Universidade Federal de Minas Gerais, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil
b Departamento de Química, Universidade Federal de Viçosa, Av. Peter Henry Rolfs, 36570-000 Viçosa, MG, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient methodology is proposed for obtaining 3,4-dihydropyrimidin-2(1H)-ones/-thiones
through Biginelli reactions. It is based on the use of less than the stoichiometric amount of p-sulfonic acid
calixarenes as organocatalysts. A number of aromatic aldehydes as well as urea or thiourea can be
employed for successfully synthesizing the corresponding Biginelli adducts. The described methodology
is devoid of metal-containing catalysts, which in turn is very attractive for safely producing 3,4-dihydro-
pyrimidin-2-(1H)-ones/-thiones of pharmacological interest. In addition, the catalyst efficiency is not
compromised after its successive use in reactions. This is the first report about the application of calixa-
renes as catalysts in the multicomponent Biginelli reaction.
Received 21 April 2011
Revised 13 August 2011
Accepted 16 August 2011
Available online 19 September 2011
Keywords:
Calixarene
p-Sulfonic acid calix[4]arene
Organocatalysis
Ó 2011 Elsevier Ltd. All rights reserved.
Biginelli reaction
3,4-Dihydropyrimidin-2(1H)-one
3,4-Dihydropyrimidin-2(1H)-thione
Organocatalysis is the acceleration of chemical reactions with a
substoichiometric amount of a metal-free organic compound.1 In-
creased interest in organocatalysis is due to its operational simplic-
ity, low toxicity and cost, and also high tolerance to molecular
oxygen and traces of water. In addition, products from reactions
catalyzed by non-metallic organic compounds are desirable to
food, pharmaceutical, and cosmetic industries.2
Multicomponent reactions (MCRs) are very attractive tools to
obtain complex molecules from one-pot procedures. In 1893, the
Italian chemist Pietro Biginelli reported the cyclocondensation of
ethyl acetoacetate, urea, and an aryl aldehyde in the presence of
an acid, furnishing 3,4-dihydropyrimidin-2(1H)-ones (DHPMs or
Biginelli adducts) as products.3 This approach is known as Biginelli
reaction or Biginelli condensation.4 Compounds bearing a DHPM
moiety have shown promising biological activities, making Biginel-
li reaction an interesting approach for the synthesis of such com-
Calixarenes, macrocycles formed from the condensation of p-
substituted phenols with formaldehyde in basic medium, have
been widely used as ligands in organometallic catalysis.15 Never-
theless, their roles as organocatalysts are still poorly investi-
gated.16 The p-sulfonic acid calixarenes 7 and 10 (Table 1) have
been reported as catalysts in Mannich-type reactions,17 while com-
pound 10 was also successfully employed as a catalyst in allylic
alkylation reactions.18
Herein we describe an efficient and simple method for the syn-
thesis of 3,4-dihydropyrimidin-2(1H)-ones through Biginelli reac-
tions by using calixarenes19 (Table 1) as organocatalysts.
Preliminary studies focused on the screening of calixarenes 5–
10 as catalysts in Biginelli reactions containing ethyl acetoacetate
(1), 4-hydroxybenzaldehyde (2a), and urea (3a).20 The yield of cal-
ixarene-free reactions was lower than 12% (Table 1, entry 1). The
use of tert-butyl-calixarenes 5 or 8 has raised the yields by 4.7-fold
(Table 1, entries 2 and 3). Similar results were obtained by using
calixarenes 6 or 9 (Table 1, entries 4 and 5). These results suggest
that neither tert-butyl group nor calixarene cavity size is critical for
catalytic efficiency. On the other hand, substitution of tert-butyl for
a sulfonyl group (calixarenes 7 and 10) allowed obtaining Biginelli
adducts in yields higher than 70% (Table 1, entries 6 and 7). Fur-
thermore, the reaction time was considerably reduced, without
affecting the yield, when calixarenes 7 or 10 were used at
0.5 mol % (Table 1, entries 8 and 9). The improvement of reaction
yield from the use of sulfonated calixarenes is likely due to their
increased acidity.18,19,21 To explore the role of calixarenes spatial
pounds. Several studies have shown
a variety of inorganic
Brønsted–Lowry acids as catalysts in Biginelli reaction and more
recently, Lewis acids have gained special attention for this pur-
pose.5 The use of ionic liquids,6 microwave irradiation,7 solid-
phase reagents,8 baker’s yeast9 or polymer-supported catalysts,10
zelolite,11 dodecyl sulfonic acid12, and PEG13 has also been re-
ported. Only a few examples of organocatalysts have been de-
scribed for Biginelli reaction.14
⇑
Corresponding author. Tel.: +55 31 3409 6373; fax: +55 31 3409 5700.
E-mail address: adefatima@qui.ufmg.br (Â. de Fátima).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.175

D. L. da Silva et al. / Tetrahedron Letters 52 (2011) 6328–6330
6329
Table 1
Table 3
Screening of calixarenes as organocatalysts for Biginelli reactionsa
Use of different aldehydes in calixarene 7-catalyzed Biginelli reactionsa
O
R
O
OH
NH2
X
7 (0.5 mol%)
EtOH
EtO
NH
+
+
RCHO
EtO
Me
(1)
H2N
CHO
O
N
H
X
O
NH2
Catalyst
(2a-2s)
O
Reflux (8h)
+
EtO
Me
(1)
X = O (3a)
X = S (3b)
+
H2N
O
EtOH, Reflux
(4a-4s)
EtO
NH
O
(3a)
OH
N
H
O
(2a)
Product
Aldehydes (2a–s)
X
O
Yield (%)
81
(4a)
CHO
n = 1 and R = tBu (5)
n = 1 and R = H (6)
R
R
R
R
4a
n = 1 and R = SO3H (7)
n = 3 and R = tBu (8)
n = 3 and R = H (9)
Catalysts =
OH
CHO
n
HO
OH
OH
OH
n = 3 and R = SO3H (10)
4b
4c
O
O
79
69
Entry
Catalyst (mol %)
Time (h)
Yield (%)
OH
1
2
3
4
5
6
7
8
9
—
24
24
24
24
24
24
24
8
8
8
8
8
12
56
51
54
53
77
72
81
75
69
74
68
CHO
5 (0.15)
8 (0.15)
6 (0.15)
9 (0.15)
7 (0.15)
10 (0.15)
7 (0.50)
10 (0.50)
PHSA (0.50)
PHSA (2.0)
PHSA (3.0)
CHO
4d
4e
O
O
76
56
OCH3
OH
10
11
12
CHO
a
Reagents and conditions20
: 4-hydroxybenzaldehyde/ethyl acetoacetate/urea
OH
OH
CHO
(molar ratio = 1:1.5:1.5). PHSA, p-hydroxybenzenesulfonic acid.
4f
O
O
O
O
91
62
68
78
Table 2
Effect of solvents on the yield of calixarene 7-catalyzed Biginelli reactionsa
F
CHO
OH
4g
4h
4i
CHO
O
7 (0.5 mol%)
NH2
NO2
O
+
EtO
Me
(1)
+
CHO
H2N
O
Solvent
EtO
NH
O
(3a)
Reflux (8h)
OH
N
H
O
(2a)
Br
(4a)
OCH3
CHO
Entry
Solvent
Ethanol
Tetrahydrofuran
1,4-Dioxane
Acetonitrile
Methanol
Yield (%)
1
2
3
4
5
6
81
NP
18
31
52
NP
OCH3
CHO
4j
O
O
89
92
Hexane
OCH3
CHO
a
Reagents and conditions20
: 4-hydroxybenzaldehyde/ethyl acetoacetate/urea
(molar ratio = 1:1.5:1.5). NP, no product detected under the tested experimental
conditions.
4k
SCH3
CHO
arrangement on the catalysis efficiency, we used p-hydroxyben-
zenesulfonic acid (PHSA) as a catalyst. PHSA (Table 1, entries 10–
12) was less efficient than calixarenes 7 and 10. This indicates that
the sulfonyl and phenolic groups in calixarene structures are not
solely responsible for the achievement of good reaction yields.
Overall, calixarene 7 was an organocatalyst slightly more efficient
than 10 (Table 1, entries 8 and 9). Large scale reactions carried out
with aldehydes, urea, and ethylacetoacetate at 30, 45, and
45 mmol, respectively, provided similar good yields of Biginelli
adducts.
4l
O
O
O
71
34
38
O
O
4m
4n
CH3CH2CH2CHO
CHO
CHO
The promising results obtained with calixarene 7 prompted us
to further investigate the effect of solvents on Biginelli reactions
catalyzed by this macrocyclic compound. Ethanol (Table 2, entry
1) was the best solvent, followed by methanol, acetonitrile, and
4o
S
78
OCH3
(continued on next page)

6330
D. L. da Silva et al. / Tetrahedron Letters 52 (2011) 6328–6330
the use of p-sulfonic acid calix[4]arene 7 as an organocatalyst. A
Table 3 (continued)
broad variety of aromatic aldehydes can be employed. The meth-
odology here is environmentally friendly since it does not employ
metal-based catalyst. This is, in turn, very attractive for safely
obtaining 3,4-dihydropyrimidin-2-(1H)-ones/-thiones of pharma-
cological interest. To the best of our knowledge, this is the first
report on the application of calixarenes as catalysts in multicom-
ponent Biginelli reactions.
Product
Aldehydes (2a–s)
X
S
Yield (%)
72
CHO
4p
4q
4r
OCH3
OH
CHO
S
S
74
78
Acknowledgments
OCH3
CHO
The authors are grateful to Dr. Luzia V. Modolo for critical read-
ing of this manuscript. This work was funded by FAPEMIG, CAPES,
and CNPq. D.L.S. and A.D.F. are supported by CNPq scholarship and
research fellowship, respectively.
SCH3
CHO
Supplementary data
4s
S
64
O
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.175.
Reagents and conditions20: aldehyde/ethyl acetoacetate/urea/thiourea (molar
a
ratio = 1:1.5:1.5).
References and notes
1. Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
2. Amarante, G. W.; Coelho, F. Quim. Nova 2009, 32, 469.
3. Biginelli, P. Grazz. Chim. Ital. 1893, 23, 360.
100
80
60
40
20
0
4. Kappe, C. O. QSAR Comb. Sci. 2003, 22, 630.
5. (a) Kolosov, M. A.; Orlov, V. D.; Beloborodov, D. A.; Dotsenko, V. V. Mol. Divers.
2009, 13, 5; (b) Lu, J.; Bai, Y. Synthesis 2002, 466; (c) Varala, R.; Mujahid, A. M.;
Adapa, S. P. Synlett 2003, 67; (d) Russowsky, D.; Lopes, F. A.; da Silva, V. S. S.;
Canto, K. F. S.; Montes D’Oca, G. V.; Godói, M. N. J. Braz. Chem. Soc. 2004, 15, 165;
(e) Ranu, B. C.; Hajra, A.; Jana, U. J. J. Org. Chem. 2000, 65, 6270; (f) Kumar, K. A.;
Kasthuraiah, M.; Reddy, C. S.; Reddy, C. D. Tetrahedron Lett. 2001, 42, 7873; (g)
Paraskar, A. S.; Dewkar, G. K.; Sudalai, A. Tetrahedron Lett. 2003, 44, 3305; (h)
Pandiarajan, S. C. K. Tetrahedron Lett. 2009, 50, 2222.
6. (a) Li, M.; Guo, W. S.; Wen, L. R.; Li, Y. F.; Yang, H. Z. J. Mol. Catal. A: Chem. 2006,
258, 133; (b) Gholap, A. R.; Venkatesan, K.; Lahoti, T. D. R. J.; Srinivasan, K. V.
Green Chem. 2004, 6, 147.
7. Mirza-Aghayan, M.; Bolourtchian, M.; Hosseini, M. Synth. Commun. 2004, 34,
3335.
8. Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10, 49.
9. Kumar, A.; Maurya, R. A. Tetrahedron Lett. 2007, 48, 4569.
10. Dondoni, A.; Massi, A. Tetrahedron Lett. 2001, 42, 7975.
11. Rani, V. R.; Srinivas, N.; Kishan, M. R.; Kulkarni, S. J.; Raghavan, K. V. Green
Chem. 2001, 3, 305.
12. Sharma, S. D.; Gogoi, P.; Konwar, D. Green Chem. 2007, 9, 153.
13. (a) Jain, S. L.; Singhal, S.; Sain, B. Green Chem. 2007, 9, 740; (b) Verma, S.; Jain, S.
L.; Sain, B. Tetrahedron Lett. 2010, 51, 6897.
First
Second
Third
Run
Fourth
Fifth
Figure 1. Reuse capacity of calixarene 7 in Biginelli reactions.
14. (a) Jin, T.; Zhang, S.; Li, T. Synth. Commun. 2002, 32, 1847; (b) Wang, Y.; Yang,
H.; Yu, J.; Miao, Z.; Chen, R. Adv. Synth. Catal. 2009, 351, 3057; (c) Xin, J.; Chang,
L.; Hou, Z.; Shang, D.; Liu, X.; Feng, X. Chem. Eur. J. 2008, 14, 3177; (d) Chen, X.
H.; Xu, X. Y.; Liu, H.; Cun, L. F.; Gong, L. Z. J. Am. Chem. Soc. 2006, 128, 14802; (e)
Yu, Y.; Liu, D.; Liu, C.; Luo, G. Bioorg. Med. Chem. Lett. 2007, 17, 3508.
15. Homden, D. M.; Redshaw, C. Chem. Rev. 2008, 108, 5086.
16. (a) Bozkurt, S.; Durmaz, M.; Yilmaz, M.; Sirit, A. Tetrahedron: Asymmetry 2008,
19, 618; (b) Xu, Z. X.; Li, G. K.; Chen, C. F.; Huang, Z. T. Tetrahedron 2008, 64,
8668; (c) Shimizu, S.; Shirakawa, S.; Susuki, T.; Sasaki, Y. Tetrahedron 2001, 57,
6169; (d) Shimizu, S.; Kito, K.; Sasaki, Y.; Hirai, C. Chem. Commun. 1997, 1629.
17. Shimizu, S.; Shimada, N.; Sasaki, Y. Green Chem. 2006, 8, 608.
18. Liu, Y. L.; Liu, L.; Lin, Y. W.; Han, Y. C.; Wang, D.; Chen, Y. J. Green Chem. 2008,
10, 635.
19. The calixarenes 5–10 were synthesized by following classical procedures
described in: (a) Gutsche, C. D.; Iqbal, M. Org. Synth. 1989, 68, 234; (b) Casnati,
A.; Ca, N. D.; Sansone, F.; Ugozzoli, F.; Ungaro, R. Tetrahedron 2004, 60, 7869; (c)
Shinkai, S.; Araki, K.; Tsubaki, T.; Some, T.; Manabe, O. J. Chem. Soc., Perkin
Trans. 1987, 2297.
20. General procedure for the synthesis of DHPMs: Aldehydes (3 mmol),
ethylacetoacetate (4.5 mmol), and urea or thiourea (4.5 mmol) were
dissolved in 3 mL of ethanol containing a calixarene (0.15–0.5 mol %). The
mixture was heated under reflux and stirred for 8 h. Reactions were monitored
by TLC. The mixtures were concentrated under vacuum, following the addition
of few drops of cold water to precipitate the product. All products were
characterized by NMR (1H, 13C), melting point and elemental analyses
(Supplementary data).
1,4-dioxane. Surprisingly, acetonitrile, a solvent commonly used in
Biginelli reactions, provided poor yields (Table 2, entry 4). Tetrahy-
drofuran and hexane were not suitable solvents (Table 2).
After pursuing the best solvent, we evaluated the scope of
calixarene 7-catalyzed Biginelli reaction by using a variety of alde-
hydes. Aromatic aldehydes bearing electron-donating or electron-
withdrawing groups were employed in Biginelli reactions and the
expected products were obtained in good yields (Table 3). Non-
aromatic aldehydes, however, were less reactive, affording moder-
ate yields (Table 3, products 4m and 4n). Both urea and thiourea
were suitable substrates as attested by the yields of corresponding
formed DHPMs (Table 3).
We also checked whether or not calixarene 7 could be reused in
such reactions (Fig. 1). Calixarene 7 was then recovered from the
reaction medium through liquid–liquid extraction with water.
After drying, the residue was used in successive reactions. Calixa-
rene 7 was found to be efficient in reactions containing ethyl ace-
toacetate (1), 4-hydroxybenzaldehyde (2a), and urea (3a) even
after five cycles of use (Fig. 1).
21. (a) Scharff, J. P.; Mahjouli, M.; Perrin, R. New J. Chem. 1991, 15, 883; (b)
Matsumiya, H.; Terazono, Y.; Iki, N.; Miyano, S. J. Chem. Soc., Perkin Trans. 2
2002, 1166.
In conclusion, an efficient procedure for the synthesis of 3,4-
dihydropyrimidin-2(1H)-ones/-thiones was developed based on