PEG-embedded thiourea dioxide (PEG.TUD) as a novel organocatalyst for the highly efficient synthesis of 3,4-dihydropyrimidinones

Article abstract of DOI:10.1016/j.tetlet.2010.10.124

The host-guest complex between polyethylene glycol and thiourea dioxide (PEG.TUD) was prepared via different approaches involving co-crystallization method and by a chemical reaction. The resulting PEG.TUD complex was found to be very active and recyclabl

Full text of DOI:10.1016/j.tetlet.2010.10.124

Tetrahedron Letters 51 (2010) 6897–6900
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PEG-embedded thiourea dioxide (PEG.TUD) as a novel organocatalyst
for the highly efficient synthesis of 3,4-dihydropyrimidinones
⇑
Sanny Verma, Suman L. Jain , Bir Sain
Chemical Sciences Division, Indian Institute of Petroleum (Council of Industrial & Scientific Research), Dehradun 248005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The host–guest complex between polyethylene glycol and thiourea dioxide (PEG.TUD) was prepared
via different approaches involving co-crystallization method and by a chemical reaction. The resulting
PEG.TUD complex was found to be very active and recyclable catalyst for the direct synthesis of 3,4-dihy-
dropyrimidinones via Biginelli condensation and provided high product yields. Interestingly, the corre-
sponding poly(ethylene glycol)–thiourea complexes, PEG.TU, were found to be unreactive and no
reaction occurred under similar reaction conditions.
Received 6 August 2010
Revised 18 October 2010
Accepted 24 October 2010
Available online 30 October 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Host–guest complex
Organocatalyst
Thiourea
Biginelli
Green method
Multi-component coupling reactions (MCR’s), involving the
inherent formation of several bonds in one step, have proven to
be efficient and powerful tool for the rapid formation of complex
heterocyclic compounds in recent years.1 The unique features of
these reactions are their operational simplicity, structural diver-
sity, versatility, high synthetic efficiency, atom-economy, and sin-
gle step synthesis without isolating the intermediates. The
synthesis of 3,4-dihydropyrimidinones via one-pot condensation
of aldehyde, b-dicarbonyl compound, and urea/thiourea known
backs, such as the use of toxic metals, volatile organic solvents,
high cost, low yields, longer reaction times, and harsh reaction con-
ditions. Therefore, it is still needed to develop an efficient and cost-
effective method for the synthesis of these valuable compounds.
Development of organocatalytic processes in which the reactions
are catalyzed by small organic molecules has become an area of
tremendous importance in current organic synthesis particularly
from the green chemistry point of view. Unlike the conventional
catalysis, these organocatalysts are advantageous in many ways
like high stability, availability of the catalyst, metal free nature, re-
duced toxicity, and simple reaction conditions and can promote a
chemical reaction through different activation modes. Small organ-
ic molecules, such as urea and thiourea derivatives due to their
strong hydrogen bonding ability have been distinguished as effi-
cient organocatalysts and their versatility as a general acid catalyst
has been successfully demonstrated by several groups.11 Neverthe-
less a number of reports related to the organocatalytic multi-com-
ponent reactions have been reported in the literature.12 However,
1
0
2
as Biginelli reaction is one of the most recognized and often used
MCR’s for the synthesis of these valuable heterocyclic compounds.
3
,4-Dihydropyrimidinones are remarkably important heterocy-
clic units that possess a wide spectrum of therapeutic and pharma-
cological applications including antiviral, antitumor, antibacterial,
3
and anti-inflammatory activities. They also have emerged as cal-
cium channel blockers, antihypertensive agents, and a-1a-adrener-
gic antagonists. Furthermore, several alkaloids containing the
dihydropyrimidine nucleus obtained form marine sources are well
4
known to show interesting biological activities. Owing to the wide
among the known organocatalysts,
L-proline and its derivatives
13
synthetic utility and potential applications, the synthesis of this
heterocyclic nucleus is of much importance. A number of improved
methods involving the use of transition-metal-based catalysts/re-
have been widely used in various MCR’s such as aldol reaction,
1
4
15
16
Robinson annulation, Mannich reactions, Michael reactions,
1
7
18
Diels–Alder reactions, Baylis–Hillman reactions, and aza-Mori-
5
6
7
19
20
agents, ionic liquids, polymer immobilized reagents, micro-
wave, and ultrasound irradiation9 have been recently reported
for their synthesis. However, most of them suffer from the draw-
ta–Baylis–Hillman reactions. Recently, Yadav et al. reported the
application of -proline as catalyst in Biginelli reaction for the syn-
thesis of dihydropyrimidin-2-ones (thiones). Feng and co-work-
8
L
2
1
ers reported an enantioselective Biginelli reaction by using a
simple chiral secondary amine and achiral Brønsted acid via a
2
2
⇑
Corresponding author. Tel.: +91 135 2525901; fax: +91 135 2660202.
E-mail addresses: suman@iip.res.in (S.L. Jain), birsain@iip.res.in (B. Sain).
dual-activation route. Suzuki et al. reported the hydrazine type
organocatalysts for Biginelli condensation. However, to the best
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.124

6
898
S. Verma et al. / Tetrahedron Letters 51 (2010) 6897–6900
of our knowledge there is no literature report on the use of host–
guest complex type organocatalysts for organic transformation.
In the present Letter, we wish to report a first successful devel-
opment of the PEG-embedded thiourea dioxide (PEG.TUD) host–
guest complex as a highly efficient, cost effective and recyclable
the end of the reaction; whereas, PEG–thiourea dioxide complexes
(PEG.TUD I–II) showed excellent catalytic efficiency and provided
corresponding 3,4-dihydropyrimidinone in almost quantitative
yield within shorter reaction times. The results of these experi-
ments are presented in Table 1 (entry 1). Next, we carried out
the recycling experiments of the PEG.TUD complexes I–II by using
the 4-chlorobenzaldehyde, ethyl acetoacetate, and urea as a repre-
sentative example. After completion of the reaction, the catalyst
could readily be recovered by precipitation with diethyl ether
and reused for subsequent experiments (5 runs). However, the fil-
trates so obtained were concentrated and subjected to usual work-
up to obtain the pure product. During the course of this study, the
PEG.TUD II complex did not show any significant decrease in the
catalytic activity; whereas PEG.TUD I, showed slight decrease in
catalytic activity with each passing run and after 8 runs, it showed
very poor catalytic activity and provided poor yield of the desired
product. This is probably due to the leaching of the thiourea diox-
ide from the support in PEG.TUD I, in which thiourea is bonded to
the support via physical attraction forces. On the other hand, in
PEG.TUD II, thiourea is attached to the support by covalent bond-
ing, preventing the leaching of thiourea dioxide from the PEG sup-
port during the reaction. Further, the leaching of the organic
molecule TUD from the support in PEG.TUD I was established by
heating the catalyst in ethanol at 50 °C for 3 h. After cooling the
reaction mixture at room temperature, the catalyst was separated
by precipitation with diethyl ether and the resulting filtrate was
concentrated and charged with chlorobenzaldehyde, ethyl acetoac-
etate, and urea. The reaction was continued under optimized reac-
tion conditions without adding further amount of the catalyst. The
reaction was found to progress well and afforded corresponding
3,4-dihydropyrimidinone in almost similar yield, confirming the
leaching of TUD from catalyst I. These facts established that the
PEG.TUD complex II was a truly heterogeneous catalyst which
could be reused with consistent catalytic efficiency for several
runs. Further, we used only PEG.TUD II to extend the reaction with
a variety of aromatic, aliphatic, heterocyclic aldehydes, dicarbonyl
catalyst for the synthesis of 3,4-dihydropyrimidinones by
a
three-component condensation, that is, Biginelli reaction. The
required PEG.TUD complex could readily be prepared from
23
poly(ethylene)glycol and thiourea dioxide (TUD) either by co-
crystallization or via a chemical approach as shown in Scheme 1.
For the comparison purpose we also prepared the corresponding
polyethylene glycol–thiourea (PEG.TU) complexes in a similar
manner (Scheme 1). In the co-crystallization method, PEG400 was
dissolved in a methanol solution saturated with thiourea dioxide
(
TUD) and the resulting solution was stirred until a white precipi-
tate appeared. The resulting precipitate was separated by filtration,
washed with diethylether, and dried under vacuum to give white
solid, PEG.TUD I. Following the chemical approach,24 the reaction
of TUD and MeOPEG400 in a fixed molar ratio (1:2) in dry DMF at
8
0 °C for 5–6 h followed by usual work-up could easily give a white
powdered PEG.TUD II in high yields. Similarly, the corresponding
PEG–thiourea complexes, that is, PEG.TU I and PEG.TU II were pre-
pared as shown in Scheme 1. The thermal stability of the com-
plexes (PEG.TUD I–II
& PEG.TU I–II) was determined by
thermogravimetric analysis (TGA), the complexes were found to
be quite stable up to 170–180 °C and could be completely decom-
posed around 300–350 °C.
At first we studied the reaction between 4-chlorobenzaldehyde,
ethyl acetoacetate, and urea by using the catalytic amount of syn-
thesized complexes (PEG.TUD I–II and PEG.TU I–II) in order to
evaluate their catalytic potential. The reaction was continued at
5
0 °C under stirring until the mixture became solidified. Surpris-
ingly, the PEG–thiourea (PEG.TUD I–II) complexes did not show
any catalytic activity and starting materials could be recovered at
H
C
compounds, and urea/thiourea under similar reaction conditions
O
O
O
25
O
P
R
E
C
I
(Scheme 2).
O
O
O
H2N
H2N
PEG400
C S
The results of these experiments are summarized in Table 1. All
the aldehydes either containing electron donating or withdrawing
O
O
H2N
H2N
C
S
O
O
H
H
O
OH
OH
P
A
T
I
O
N
O
TUD-I
Table 1
PEG400
O
O
a
H2N
PEG.TUD II catalyzed synthesis of 3,4-dihydropyrimidinones
O
C S
O
H2N
H N
2
PEG400
C
S
0
R
Yieldb (%)
O
Entry
Product
R
X
H2N
O
c
d
e
f
g
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
4-ClC
6
H
4
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
O
O
O
O
O
O
O
O
O
O
O
O
O
S
97, 95 , — , — , — , 85
O
M
E
T
H
O
D
O
H
C
H
6 5
98
96
96
95
94
92
90
96
92
90
92
89
98
96
94
4-CH
4-CH
3
C
6
H
4
3
OC
6
H
4
TU-I
2 6 4
4-NO C H
2-ClC H4
6
3 2 2
n-CH CH CH
2-Furyl
C H
6 5
O
MeO
H
O
C
H
E
M
I
C
A
L
10
4-NO
4-CH
4-ClC
2-Furyl
2
C
6
H
4
PEG400
11
12
13
14
15
3
OC
6
H
4
O
O
H2N
NH2
6
H
4
C
S
N
O
O
H2N
C
S
O
O
MeO
OMs
TUD-II
6 5
C H
3 6
4-CH C H
O
O
S
S
4
PEG400
16
4-NO
2
C
6
H
4
O
O
MeO
M
E
T
H
O
D
a
O
H2N
H2N
O
Reaction condition: aldehyde (2 mmol), urea/thiourea (2 mmol), b-dicarbonyl
C
S
compound (2 mmol), PEG.TUD II (10 mol %) at 50 °C.
PEG400
b
Isolated yields.
By using PEG.TUD I as catalyst.
By using PEG.TU I as catalyst.
By using PEG.TU II as catalyst.
Blank experiment in the absence of catalyst.
By using thiourea dioxide as catalyst.
O
H
c
N
NH2
O
d
e
f
C
S
TU-II
g
Scheme 1. Synthesis of PEG.TUD and PEG.TU complexes.

S. Verma et al. / Tetrahedron Letters 51 (2010) 6897–6900
6899
R
able substances like PEG, and recycling without loss in activity
make this method more efficient and open an avenue to explore
the potential of this cost-effective catalyst for developing many
other synthetic methodologies.
R'OC
X
O
O
PEG.TUDII (10 mol %)
0 0
NH
+
RCHO
+
H3C
R'H2N NH2
5
C
3
H C
N
H
2a-n
X
1
a-n
R'=OEt, OMe
X=O,S
Acknowledgments
2
2
2
2
2
2
2
a, R=4-ClC6H4, R'=OEt; X=O
b, R=Ph, R'=OEt; X=O
2
2
2
2
2
2
2
2
2
h, R=2-Furyl, R'=OEt; X=O
i, R=C6H5, R'=OMe; X=O
We are thankful to the Director, IIP for his kind permission to
publish these results. S.V. acknowledges the CSIR, New Delhi for
the award of his Research Fellowship. We acknowledge Dr. J. K.
Gupta for providing the TGA analysis of our samples.
c, R=4-CH3C6H4, R'=OEt; X=O
d, R=4-CH3OC6H4, R'=OEt; X=O
e, R=4-NO2C6H4, R'=OEt; X=O
f, R=2-ClC6H4, R'=OEt; X=O
g, R=CH3(CH2)2; X=O
j=R=4-NO2C6H4, R'=OMe; X=O
k, R=4-CH3OC6H4,R'=OMe; X=O
l, R=4-ClC6H4,R'=OMe; X=O
m, R=2-Furyl, R'=OMe; X=O
n, R=Ph, R'=OEt; X=S
o, R=4-CH3C6H4, R'=OEt; X=S
p, R=4-NO2C6H4, R'=OEt; X=S
References and notes
1.
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Scheme 2. Biginelli condensation by using PEG.TUD II.
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groups were smoothly converted into their corresponding 3,4-
dihydropyrimidinones in excellent yields. Similarly, b-ketoesters,
such as ethyl acetoacetate and methyl acetoacetate smoothly re-
acted under these reaction conditions. Further, the use of thiourea
in place of urea afforded corresponding 3,4-dihydropyrimidinones-
2. (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360; Synthesis and Reactions of Biginelli
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2
(1H)-thiones, which also exhibit a number of interesting biologi-
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cal activities. Use of organic solvents, such as acetonitrile and
ethanol did not enhance the reaction rates to any significant extent
and, therefore, all the experiments were carried out under solvent-
free conditions. It is worthy to mention that the reaction between
4
-chlorobenzadehyde, ethyl acetoacetate, and urea did not proceed
2
399.
5. (a) Khabazzadeh, H.; Saidi, K.; Sheibani, H. Bioorg. Med. Chem. Lett. 2008, 18,
78; (b) Jain, S. L.; Prasad, V. V. D. N.; Sain, B. Catal. Commun. 2008, 9, 499; (c)
even after 24 h in the absence of catalyst under otherwise similar
reaction conditions (Table 1, entry 1). Similarly, the use of thiourea
dioxide alone as a catalyst showed poor catalytic efficiency than
PEG.TUD II, indicating the important role of PEG support in making
the reactions faster. The reaction was found to be very slow at
room temperature, whereas, 50 °C was found to be optimum for
this reaction. Further increase in reaction temperature did not
affect the rate of the reaction to any considerable extend.
The exact mechanism of the reaction is not clear; the probable
mechanism of the reaction may involve the activation via the
strong hydrogen bonding ability of the PEG.TUD II with oxygen
of the carbonyl group as shown in Scheme 3. This activation will
be promoting the formation of acylimine intermediate by the reac-
tion of aldehyde with urea/thiourea. In analogy to the well estab-
2
Lannou, M. I.; Helion, F.; Namy, J. L. Synlett 2008, 105; (d) Suzuki, I.; Wata, Y.;
Takeda, K. Tetrahedron Lett. 2008, 49, 3238; (e) Chen, X. F.; Peng, Y. Q. Catal. Lett.
2008, 122, 310; (f) Bailey, C. D.; Houlden, C. E.; Bar, G. L. J.; Lloyd-jones, G. C.;
Booker-Milburn, K. I. Chem. Commun. 2007, 2932. and references cited therein.
. (a) Shaabani, A.; Sarvary, A.; Rahmati, A.; Rezayan, A. H. Lett. Org. Chem. 2007, 4,
6
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7. Leia, M.; Wua, D.-D.; Weib, H.-G.; Wanga, Y.-G. Synth. Commun. 2009, 39, 475.
and references therein.
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(a) Stadler, A.; Kappe, C. O. J. Comb. Chem. 2001, 3, 624; (b) Li, Y. X.; Bao, W. L.
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S.; Fedorova, O. V.; Rusinov, G. L.; Ovchinnikova, I. G. Russ. Chem. Bull. Int. Ed.
2003, 52, 2527.
1
0. (a) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (b) Palomo, C.;
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Chem. 2007, 119, 1590; Angew. Chem., Int. Ed. 2007, 46, 1570; (e) Dalko, P. I.
Enantioselective Organocatalysis; Wiley-VCH: Weinheim, Germany, 2007; (f)
Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem. 2008, 120,
2
6
lished mechanism, the generation of acylimine intermediate is
the key step, which subsequently reacts with b-dicarbonyl
compound followed by cyclodehydration to give corresponding
6232; Angew. Chem. Int. Ed. 2008, 47, 6138.
3
,4-dihydropyrimidinones. Further studies to establish the
1
1. (a) Connon, S. J. Chem. Eur. J. 2006, 12, 5418; (b) Sohtome, Y.; Tanatani, A.;
Hashimoto, Y.; Nagasaw, K. Tetrahedron Lett. 2004, 45, 5589; (c) Takemoto, Y.
Org. Biomol. Chem. 2005, 3, 4299; (d) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520; (e) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett.
mechanistic pathway for the present reaction are currently under
progress.
In summary, we have developed for the first time a novel
and recyclable host–guest type PEG-embedded thiourea dioxide
2006, 8, 2901.
1
2. (a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570;
(b) Pellissier, H. Tetrahedron 2006, 62, 2143; (c) Guillena, G.; Ramón, D. J.; Yus,
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Chem., Int. Ed. 2006, 45, 354; (e) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1; (f)
Gerencser, J.; Dorman, G.; Darvas, F. QSAR Comb. Sci. 2006, 25, 439; (g) Erkkila,
A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416.
(
PEG.TUD) organocatalysts for the efficient synthesis of 3,4-dihy-
dropyrimidinones. The key advantages, such as ease of synthesis,
fast reaction rates, use of cost effective, environmentally accept-
1
3. (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395; (b)
Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III J. Org.
Chem. 2006, 71, 3822; (c) Suri, J. T.; Ramachary, D. B.; Barbas, C. F., III Org. Lett.
H2N
O
H2N
2
005, 7, 1383; (d) Storer, R. I.; MacMillan, D. W. C. Tetrahedron 2004, 60, 7705;
(
e) Casas, J.; Sundén, H.; Córdova, A. Tetrahedron Lett. 2004, 45, 6117; (f)
Northrup, A. B.; Mangion, I. K.; Hettche, F.; MacMillan, D. W. C. Angew. Chem.,
Int. Ed. 2004, 43, 2152; (g) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P.
H.-Y.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558.
R
O
R
O
H2N
O
O
PEG
O
MeO
H
R'
NH
14. (a) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481; (b) Bui, T.; Barbas, F., III
Tetrahedron Lett. 2000, 41, 6951.
15. (a) Córdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C. F., III J. Am.
Chem. Soc. 2002, 124, 1842; (b) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N.
S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III J. Org. Chem. 2003, 68, 9624;
H
N
S
NH PEG
N
R'
1
-
H2O
Me
N
H
O
-
H2O
O
O
R
H
TUD-II
Scheme 3. Plausible mechanistic pathway.
2
(
c) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K.
Angew. Chem., Int. Ed. 2003, 42, 3677.

6
1
900
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6. (a) Gryko, D. Tetrahedron: Asymmetry 2005, 16, 1377; (b) Mangion, I. K.; Mac-
Millan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3696; (c) List, B.; Pojarliev, P.;
Martin, H. J. Org. Lett. 2001, 3, 2423; (d) Betancort, J. M.; Barbas, C. F., III Org.
Lett. 2001, 3, 3737.
24. Synthesis of PEG.TUD II: A mixture containing thiourea dioxide (2 mmol, 0.2 g)
and MeOPEG400 (4 mmol, 2.0 g) in dry DMF (15 ml) was heated at 80 °C over
night. After being cooled to room temperature, the reaction mixture was
concentrated under reduced pressure and the residue obtained was treated
with diethyl ether. The white precipitate thus obtained was isolated by
filtration, washed thoroughly with 2-propanol and diethyl ether, and dried
under vacuum to yield PEG.TUD II, yield (1.8 g, 82%). PEG.TU I & PEG.TU II were
prepared exactly as PEG.TUD I and PEG.TUD II, respectively.
1
7. (a) Sabitha, G.; Fatima, N.; Reddy, E. V.; Yadav, J. S. Adv. Synth. Catal. 2005, 347,
1
353; (b) Thayumanavan, R.; Dhevalapally, B.; Sakthivel, K.; Tanaka, F.; Barbas,
C. F., III Tetrahedron Lett. 2002, 43, 3817.
1
8. (a) Chen, S. H.; Hong, B. C.; Su, C. F.; Sarshar, S. Tetrahedron Lett. 2005, 46, 8899;
(
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25. General experimental procedure: A stirred mixture containing the aldehyde
(2 mmol), urea/thiourea (2 mmol), b-dicarbonyl compound (2 mmol), and TUD
II (10 mol %) was heated at 50 °C until the mixture became solidified. After
completion, resulting solid was separated and washed with hot ethanol. The
catalyst could readily be recovered from the filtrate by the precipitation using
diethylether. The crude product was purified by recyrstallization with ethanol
to afford the pure 3,4-dihydropyirimidinones. All the products were
M.; Jiang, J. K.; Li, C. Q. Tetrahedron Lett. 2002, 43, 127.
1
2
2
9. Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III Angew. Chem., Int. Ed. 2007,
4
6, 1878.
0. Yadav, J. S.; Kumar, S. P.; Kondaji, G.; Rao, R. S.; Nagaiah, K. Chem. Lett. 2004, 33,
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1
3
characterized by comparing their physical (mps) and spectral data (IR & 1
NMR) with the authentic compounds.
H
2
2. Suzuki, I.; Iwata, Y.; Takeda, K. Tetrahedron Lett. 2008, 49, 3238.
2
3. Ohura, O.; Fujimoto, O. U.S. Patent 4,233,238, 1980.
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