Microwave-assisted bronsted acidic ionic liquid-promoted one-pot synthesis of heterobicyclic dihydropyrimidinones by a three-component coupling of cyclopentanone, aldehydes, and urea

Article abstract of DOI:10.1002/jhet.415

(Chemical Equation Presented) A simple and efficient method has been developed for the synthesis of heterobicyclic dihydropyrimidinone derivatives through a solvent-free one-pot three-component condensation of aromatic aldehydes, cyclopentanone, and urea or thiourea in the presence of Bronsted acidic ionic liquid under microwave irradiation. The catalyst can be reused at least six times without any noticeable decrease in catalytic activity.

Full text of DOI:10.1002/jhet.415

1230
Microwave-Assisted Brønsted Acidic Ionic Liquid-Promoted
One-Pot Synthesis of Heterobicyclic Dihydropyrimidinones by a
Three-Component Coupling of Cyclopentanone,
Aldehydes, and Urea
Vol 47
Matiur Rahman, Adinath Majee, and Alakananda Hajra*
Department of Chemistry, Visva-Bharati University, Santiniketan 731235, West Bengal, India
*E-mail: alakananda.hajra@visva-bharati.ac.in
Received September 25, 2009
DOI 10.1002/jhet.415
Published online 13 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient method has been developed for the synthesis of heterobicyclic dihydropyrimi-
dinone derivatives through a solvent-free one-pot three-component condensation of aromatic aldehydes,
cyclopentanone, and urea or thiourea in the presence of Brønsted acidic ionic liquid under microwave
irradiation. The catalyst can be reused at least six times without any noticeable decrease in catalytic
activity.
J. Heterocyclic Chem., 47, 1230 (2010).
INTRODUCTION
extended by variation of all three building blocks,
allowing access to a large number of structurally diver-
sified multifunctionalized dihydropyrimidinones [9]. The
use of the common open-chain b-dicarbonyl compounds
in Biginelli reactions has been extended to the use of
cyclic b-diketones, b-ketolactones, cyclic b-diesters or
b-diamides, benzocyclic ketones, and a-keto acids.
Microwave- (MW-) promoted reactions have been
attracting increasing research interest from chemists in
recent years, not only because these reactions exhibit
some particular or unexpected reactivities in some cases
but also because they are significantly useful for green
chemistry [10]. In our corresponding investigations, we
have reported few MW-promoted multicomponent cou-
pling reactions for various chemical transformation as
well as synthesis of useful heterocyclic compounds [11].
The application of Brønsted acidic task-specific ionic
liquids (TSILs) as catalytic materials is growing contin-
uously in the catalytic field. Combining the useful char-
acteristics of solid acids and mineral acids, TSILs have
been synthesized to replace traditional mineral liquid
acids, such as hydrochloric acid and sulfuric acid in
chemical reactions. In view of green chemistry, the
Dihydropyrimidinones and their derivatives are a very
important class of bioactive compounds because of their
pharmacological properties [1]. They are known to ex-
hibit a wide range of biological activities, such as cal-
cium channel blockers [2], antihypertensive agents [3],
a-adrenergic antagonists [4], and neuropeptide Y antag-
onists [5]. The biological activity of some recently iso-
lated alkaloids has also been attributed to the presence
of dihydropyrimidinone moiety in the molecules [6].
Most notable among these are the batzelladine alkaloids,
which have been found to be potent HIV gp-120-CD4
inhibitors [7]. Therefore, such a wide spectrum of bio-
logical activity allows consideration of the dihydropyri-
midinone structural unit as one of the most important
drug-like scaffolds.
The Biginelli reaction, which was discovered more
than a century ago is one of the most important reac-
tions in the synthesis of dihydropyrimidinones based on
acid-catalyzed three-component condensation of 1,3-
dicarbonyl compound, aldehyde, and urea [8]. The scope
of the original condensation reaction was gradually
C
V
2010 HeteroCorporation

September 2010
Microwave-Assisted Brønsted Acidic Ionic Liquid-Promoted One-Pot Synthesis of
1231
Heterobicyclic Dihydropyrimidinones by a Three-Component Coupling of Cyclopentanone, Aldehydes, and Urea
Scheme 1
obtained in 5 min. But, very low yield (10–15%) was
obtained after longer time irradiation (15–20 min).
Under these optimized conditions, the reaction between
various aromatic aldehydes and cyclopentatone in pres-
ence of urea was investigated (Table1). It was found that
all the reactions proceeded smoothly to give the corre-
sponding arylidene pyrimidinones in high yields. Both ar-
omatic aldehydes bearing electron-donating and electron-
withdrawing gave excellent yields. The mildness of the
procedure makes it very selective, as it tolerates a variety
of functionalities, including bromo, chloro, fluro,
methoxy, nitro, and methylenedioxy groups. The present
procedure was equally effective for thiourea also. The
results are summarized in Table 1, which clearly demon-
strates the generality and scope of the reaction with
respect to various aromatic aldehydes. No organic sol-
vents were required to isolate the product from the reac-
tion mixture. Only ethanol was used for recrystallization
to provide analytically pure samples. Use of just 5 mol %
IL is sufficient to push the reaction forward. Higher
amount of IL did not improve the reaction forward.
substitution of harmful liquid acids by reusable TSILs is
the most promising catalyst in chemistry [12].
Recently, it was found that some fused pyrimidinones
carrying an arylidene moiety are potential antitumor
agents [13]. In addition, some of these analogues also
showed a distinctive pattern of selectivity toward individ-
ual cell line, such as that of leukemia [14]. Because of
the various therapeutic utility of arylidene heterobicyclic
pyrimidinones, a number of synthetic procedures for this
type of derivatives were developed using different proto-
cols [15]. Pan and coworkers described an efficient alter-
native for the synthesis of these fused pyrimidinones by a
three-component condensation with aromatic aldehyde,
cyclopentanone, and urea or thiourea in presence of stoi-
chiometric amounts of TMSCl as additional reagent and
mixed DMF/CH3CN as reaction solvent appeared to be
necessary to obtain satisfactory results [16a]. Very
recently, Xu and Shen revealed that ytterbium chloride
could efficiently promote this one-pot three-component
condensation under solvent-free conditions without using
any additional reagents [16b]. In connection with our ear-
lier work on the synthesis of dihydropyrimidinones [17],
herein we report an efficient Brønsted acidic ionic liquid
catalyzed this Biginelli-type reaction of aromatic alde-
hyde, cyclopentanone, and urea or thiourea for the syn-
thesis of arylidene heterobicyclic pyrimidinones using
MW irradiation under solvent-free conditions (Scheme
1). To the best of our knowledge, this is the first report of
a functionalized ionic liquid-catalyzed synthesis of heter-
obicyclic dihydropyrimidinones.
Our interest in the preparation of novel scaffolds
prompted us to attempt the extension of this reaction to
condensations of cyclohexanone and /or aliphatic alde-
hydes in the Biginelli-type reaction. Unfortunately, the
Table 1
IL promoted microwave-assisted one-pot synthesis of pyrimidinone.
Entry
Ar
X
Time (min) Yielda (%) Ref.
1
2
3
4
5
6
7
8
9
Ph
O
O
O
O
O
O
O
O
O
5
5
5
5
5
5
5
5
5
82
73
64
77
79
91
68
83
67
16a
16a
16a
16b
16a
16a
16a
16a
16a
4-MeC6H4
4-MeO-C6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
RESULTS AND DISCUSSION
2-ClC6H4
4-NO2C6H4
3-NO2C6H4
The experimental procedure is very simple. To opti-
mize the reaction conditions, the reaction of benzalde-
hyde, cyclopentanone, and urea was selected as the
model in presence of catalytic amount of acidic ionic
liquid under MW irradiation. The best result was
obtained when the reaction of cyclopentanone, benzalde-
hyde, and urea was carried in a 2:2:1.2 mole ratio in
presence of acidic ionic liquid (5 mol %) under MW
irradiation (250 W, 90ꢀC) for 5 min. In a blank reaction,
without acidic ionic liquid, no desired product was
10
O
5
82
11
12
13
14
15
16
1-Naphthyl
Ph
O
S
S
S
S
S
6
10
12
10
8
84
82
64
78
73
75
16b
16a
16b
16a
16b
16a
4-MeC6H4
4-ClC6H4
4-FC6H4
4-NO2C6H4
18
a Yields refer to isolated pure product.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1232
M. Rahman, A. Majee, and A. Hajra
Vol 47
Table 2
Comparison of the present protocol with recently reported methods.
Reported method
[16b]
Reported method
[16a]
Present method
Yield (%)a
Entry
Product
Time
Time
3 h
Yield (%)b
79
Time
2–3 h
Yield (%)c
1
5 min
82
93
2
3
5 min
64
67
5 h
69
50
2–3 h
86
78
5 min
5 h
2–3 h
a Present reaction conditions: acidic ionic liquid (5 mol%) at 90ꢀC (250 W microwave).
b Reported reaction conditions: 3 mol% YbCl3 at 90ꢀC.
c Reported reaction conditions: stoichiometric amount of TMSCl in DMF/CH3CN solvent at rt.
reaction did not produce the corresponding benzylidene
pyrimidinones under the present reaction conditions,
instead leads to multiple products whose identities are
yet to be established.
produced by reaction of benzaldehyde with cyclopenta-
none in presence of acidic IL [16b].
The recovery and reusability of the ionic liquid were
investigated. After completion of the reaction, crushed ice
(20 g) was added to the reaction mixture and the solid prod-
uct was filtered. The aqueous layer consisting of the acidic
IL was extracted with diethyl ether (5 mL) to remove the
organic impurities. The catalyst was recovered after re-
moval of water under reduced pressure and reused for sub-
sequent reactions. It showed the same activity as a fresh
catalyst with out any loss of activity in terms of yield and
purity. After six recycles, the catalyst had a high activity
and gave the desired product in good yield (78%, entry 1).
The efficiency of the present protocol can be realized
by comparing some of the results presented here with
recently reported two methods as shown in the Table 2,
which compares reaction time, yields, and reaction con-
ditions. Thus, it is clear form the Table 2 that the pres-
ent protocol can act as an effective method with respect
to times and reaction conditions.
CONCLUSIONS
In conclusion, the present MW-assisted one-pot proce-
dure provides an efficient synthesis of heterobicyclic dihy-
dropyrimidinones by acidic IL-catalyzed condensation of
aldehyde, cyclopentanone, and urea or thiourea under sol-
vent-free conditions. We believe our procedure will find
important applications in the synthesis of biologically
active scaffolds to cater the needs of academia as well as
pharmaceutical industries. Further exploration of this
chemistry and biological evaluation of the synthesized scaf-
folds are in progress and will be reported in due course.
EXPERIMENTAL
Melting points were determined on a glass disk with an
electrical bath and are uncorrected. 1H NMR (400 MHz) and
13C NMR (100 MHz) spectra were run in DMSO-d6 solutions.
IR spectra were taken as KBr plates. Elemental analyses were
done by Perkin–Elmer autoanalyzer. The synthesis of the
Brønsted acidic ionic liquid, 1-butane sulfonic acid-3-methyli-
midazolium tosylate, [BSMIM]Ts was carried out using a
method similar to that reported [18].
The mechanism of this reaction is uncertain. The
reaction may proceed through the formation of acyl
imine intermediate, by the reaction of the aldehyde with
urea and activated acid [16a]. Another hypothesis is that
dibenzylidene cyclopentanone is the key intermediate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Microwave-Assisted Brønsted Acidic Ionic Liquid-Promoted One-Pot Synthesis of
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Heterobicyclic Dihydropyrimidinones by a Three-Component Coupling of Cyclopentanone, Aldehydes, and Urea
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Typical procedure for the synthesis of 4-benzo[1,3]-
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hydrocyclopentapyrimidin-2-one (entry 10, Table 1). To a
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lL, 168 mg, 2 mmol), and urea (72 mg, 1.2 mmol) acidic ionic
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1679, 1492, 1452, 1242 cmꢁ1 1H NMR (400 MHz, DMSO-
;
d6): d ¼ 8.61 (s, 1H), 7.07 (s, 1H), 6.87 (s, 3H), 6.79–6.71 (m,
3H), 6.52 (s, 1H), 5.98 (s, 4H), 5.04 (s, 1H), 2.76 (s, 2H), 2.76
(br, 1H), 2.48 (br, 1H); 13C NMR (100 MHz, DMSO-d6): d ¼
153.5, 147.9, 147.8, 146.9, 145.9, 137.9, 137.7, 136.3, 132.5,
122.6, 120.1, 118.1, 116.9, 108.9, 108.5, 107.8, 107.2, 101.4,
101.3, 57.4, 28.7, 28.6; Anal. Cald for C22H18N2O5: C, 67.69;
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The catalyst recovered for the aqueous layer was dried
under vacumn and reused for subsequent reactions.
Acknowledgments. A.H. is pleased to acknowledge the finan-
cial support from DST (Grant No. SR/FTP/CS-107/2006). A. M.
acknowledges financial support from CSIR (Grant No. 01(2251)/
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet