Solvent-free synthesis of 6-unsubstituted dihydropyrimidinones using 2-pyrrolidonium bisulphate as efficient catalyst

Article abstract of DOI:10.1515/chempap-2016-0048

A one-pot three-component Biginelli-like reaction of enaminones, aldehydes with urea/thiourea in the presence of 2-pyrrolidonium bisulphate as an acidic ionic liquid catalyst for the preparation of 6-unsubstituted dihydropyrimidinones is described. The ex

Full text of DOI:10.1515/chempap-2016-0048

Chemical Papers 70 (8) 1126–1130 (2016)
DOI: 10.1515/chempap-2016-0048
SHORT COMMUNICATION
Solvent-free synthesis of 6-unsubstituted dihydropyrimidinones
using 2-pyrrolidonium bisulphate as efficient catalyst
a
b
aHeshmatollah Alinezhad*, Mahmood Tajbakhsh, Mahboobeh Zare,
aMahbooeh Mousavi
aFaculty of Chemistry, University of Mazandaran, University Street, 47416-95447 Babolsar, Iran
bFaculty of Science and Herbs, Amol University of Special Modern Technologies, Taleghani Street, 16846-13114 Amol, Iran
Received 5 August 2015; Revised 25 December 2015; Accepted 13 January 2016
A one-pot three-component Biginelli-like reaction of enaminones, aldehydes with urea/thiourea in
the presence of 2-pyrrolidonium bisulphate as an acidic ionic liquid catalyst for the preparation of
6-unsubstituted dihydropyrimidinones is described. The excellent yield, short reaction time, simple
procedure and avoidance of the use of organic solvents are some advantages of this method.
c
ꢀ 2016 Institute of Chemistry, Slovak Academy of Sciences
Keywords: 6-unsubstituted dihydropyrimidinone, 2-pyrrolidonium bisulphate, enaminone, alde-
hyde, urea/thiourea
Dihydropyrimidinones (DHPMs) have a wide spec-
trum of bio-therapeutic activities (Rovnyak et al.,
1995; Nagarathnam et al., 1999), exhibiting an-
tiviral (Patil et al., 1995), antibacterial (Kappe,
1993) and antihypertensive (Atwal et al., 1991)
properties. The first synthesis of functionalised 3,4-
dihydropyrimidinones by treating aromatic aldehydes
and β-keto esters with urea was reported by Big-
inelli in 1893 (Dallinger & Kappe, 2005). Recently,
the Biginelli-like reaction has been employed to syn-
thesise DHPM using active methylene building blocks
including ketone (Safari & Gandomi-Ravandi, 2014),
alkyl acetoacetate (Kappe, 2000), acetoxy acetalde-
hyde (Kolosov & Orlov, 2005), aldehyde (Bailey et
al., 2007) and enaminone (Wan & Pan, 2009) in the
place of β-ketoester.
Although these methods significantly extended the
Biginelli reaction, they suffered from limitations such
as low yield, long reaction time, high temperature,use
of organic solvent and they require stoichiometric
quantities of catalyst. In addition, a few systematic
methods have been established to synthesise DHPMs
using enaminones (Wan & Pan, 2009; Darwish et al.,
2010; Al-Mousawi et al., 2010; Wan et al., 2011; Hassa-
neen & Abdelhamid, 2013). This could be an effective
extension of the Biginelli-like reaction, affording syn-
thesis of a large number of multifunctionalised pyrim-
idinones.
On the other hand, ionic liquids have gained at-
tention in electrochemistry (Hagiwara & Ito, 2000),
the synthesis of nano-structured materials (Antonietti
et al., 2014), reaction media and catalysis (Gordon,
2001; Roy et al., 2011). Acidic ionic liquids as “green”
media are regarded as promising catalysts replacing
cation-exchange resins or solid acids in organic reac-
tions (Tao et al., 2011). Pyrrolidonium acidic ionic liq-
uids have been synthesised in simple procedures and
showed excellent conversion and selectivity in different
reactions such as the esterification of acetic acid and
butanol, synthesis of benzoxanthene derivatives and
the preparation of azides and 3,4-dihydropyrimidine-
2-(1H)-ones (Huang et al., 2008; Hajipour et al., 2009;
Shaterian et al., 2011; Shaterian & Aghakhanizadeh,
2013).
In the present study, an efficient Biginelli-like re-
action for preparing 6-unsubstituted dihydropyrim-
idinones via the condensation of aldehydes, enam-
inones and urea or thiourea in the presence of
*Corresponding author, e-mail: heshmat@umz.ac.ir
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H. Alinezhad et al./Chemical Papers 70 (8) 1126–1130 (2016)
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Fig. 1. Synthesis of 6-unsubstituted DHPMs under solvent-free conditions.
Table 1. Synthesis of 6-unsubstituted DHPMs in the presence of 2-pyrrolidonium bisulphate as catalysta
Entry
R1
R2
X
Product
Time/min
Yield/%
M.p./◦C
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
4-Me
4-OMe
3-OMe
4-NO2
4-CN
4-Cl
4-Br
2-I
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
S
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
IVj
IVk
IVl
IVm
IVn
IVo
IVp
IVq
IVr
120
120
150
135
110
120
120
120
120
150
120
120
135
150
120
120
135
120
92 (65)b
90 (86)c
87 (85)c
88
282–284b
231–234c
229–231c
175–177
251–253c
264–265
257–260
255–257
202–205
201–202
238–240
166–168
278–280c
279–281c
266–268c
269–271c
283–285c
235–238
95 (92)c
94
93
91
88
92
92
93
2-Cl, 5-NO2
3-OMe
4-CN
H
4-NO2
4-NO2
H
H
H
H
H
H
H
4-Me
4-NO2
4-Cl
4-Br
90 (95)c
89 (91)c
93 (93)c
91 (95)c
89 (89)c
91
S
S
S
S
2-Cl, 5-NO2
S
a) Reactions were performed at 80◦C using benzaldehyde (1 mmol), enaminone (1 mmol), urea/thiourea (1.2 mmol) and
[Hnhp][HSO4] (10 mole %) under solvent-free conditions; b) reported by Darwish et al. (2010); c) reported by Wan and Pan
(2009).
2-pyrrolidonium bisulphate ([Hnhp][HSO4]) as an
acidic ionic liquid catalyst under solvent-free condi-
tions (Fig. 1) is reported.
trometer operating at an ionisation potential of 70 eV.
General procedure for the synthesis of 6-unsubsti-
tuted DHPMs: a stirred mixture of aldehyde (1 mmol),
enaminone (1 mmol), urea or thiourea (1.2 mmol) and
10 mole % of 2-pyrrolidonium bisulphate (0.0183 g)
was allowed to react in an oil bath at 80◦C for the ap-
propriate time (Table 1). The progress of the reaction
was monitored by TLC. After the reaction was com-
plete, the mixture was cooled to ambient temperature
and water (5 mL) was added. The catalyst was dis-
solved in water and filtered for separation of the crude
product. The residue was washed twice with 5 mL of
water. Then the product was purified by recrystalli-
sation in EtOH/H2O (1 : 1, vol.). All the products
were characterised by their spectral data (1H NMR,
13C NMR, IR and MS).
Materials were purchased from Merck (Germany)
and Aldrich (USA) chemical companies and used with-
out further purification. 2-Pyrrolidonium bisulphate
(Shaterian et al., 2011) and enaminones (Sun et al.,
2006) were prepared following the reported proce-
dures. The samples were analysed using an FT-IR
vector 22 spectrometer (Bruker Vector in KBr ma-
trix (Germany)). NMR spectra were recorded using
a Bruker DRX 400 AVANCE instrument (Germany)
1
(400.1 MHz for H, 100.6 MHz for 13C) with DMSO
as the solvent. Chemical shifts (δ) are given in parts
per million (ppm) relative to TMS and coupling con-
stants (J) are reported in hertz (Hz). Mass spectra
were recorded on a Agilent 5975C (USA) mass spec-
Initially, to optimise the reaction conditions, the
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H. Alinezhad et al./Chemical Papers 70 (8) 1126–1130 (2016)
Table 2. Optimisation of type of solvent for synthesis of 5-benzoyl-4-(4-nitro-phenyl)-3,4-dihydro-1H-pyrimidin-2-onea
Entry
Solvent
Temperature/◦C
Time/h
Yield/%b
1
2
3
4
5
6
–
80
2
5
5
5
5
5
95
20
30
25
Trace
Trace
Acetonitrile
Ethanol
Methanol
Water
Reflux
Reflux
Reflux
Reflux
Reflux
Hexane
a) Reactions were performed using 4- nitrobenzaldehyde (1 mmol), phenyl enaminone (1 mmol), urea (1.2 mmol) and [Hnhp][HSO4]
(10 mole %); b) yields refer to isolated products.
Table 3. Effect of [Hnhp][HSO4] catalyst-loading on model
reacting with urea or thiourea in the presence of
[Hnhp][HSO4] at 80◦C under solvent-free conditions
(Table 1).
reactiona
Entry Amount of catalyst/mole % Time/h Yield/%b
As indicated in Table 1, aromatic aldehydes with
both electron-withdrawing and electron-donating sub-
stituents performed well with phenyl enaminone and
urea in the presence of 2-pyrrolidonium bisulphate un-
der solvent-free conditions at 80◦C in affording the de-
sired products with excellent yields (Table 1, entries 1–
10). 4-Nitrophenyl enaminone reacted smoothly with
various aromatic aldehydes and urea under the same
reaction conditions to afford excellent yields of the cor-
responding DHPMs (Table 1, entries 11–12).
1
2
3
4
–
5
10
20
5
5
2
5
20
60
95
75
a) Reactions were performed using 4-nitrobenzaldehyde
(1 mmol), phenyl enaminone (1 mmol), urea (1.2 mmol) and
[Hnhp][HSO4] at 80◦C; b) yields refer to isolated recrystallised
products.
Similarly, a reaction of different aromatic alde-
hydes with phenyl enaminone and thiourea un-
der the optimal reaction conditions afforded 3,4-
dihydropyrimidin-2(1H)-thiones with excellent yields
(Table 1, entries 13–18). In general, electron-with-
drawing groups were observed to accelerate the reac-
tion in comparison with electron-donating groups.
Mechanistically (Maheswara et al., 2008; Darwish
et al., 2010), the reaction may proceed via imine for-
mation from aldehyde and urea and the subsequent
addition of the enaminone to the imine followed by
intramolecular condensation removing dimethylamine
to afford 6-unsubstituted DHPM (Fig. 2).
To display the merit of the present procedure for 6-
unsubstituted DHPM synthesis via the one-pot three-
component reaction between aldehydes, enaminones
and urea, the results obtained with [Hnhp][HSO4] were
compared with some of those reported in the literature
(Table 4). Although all the methods are effective, the
present method affords a comparatively high yield of
the product in a short time using only 10 mole % of
catalyst.
effects of the catalyst and solvent were investigated us-
ing 4-nitrobenzaldehyde, phenyl enaminone and urea
as a model (Tables 2 and 3). This reaction was ob-
served to perform well under solvent-free conditions
in comparison with commonly used organic solvents
such as acetonitrile, ethanol, methanol, water and hex-
ane (Table 2, entries 1–6). To verify the efficiency
of the catalyst, the amount of [Hnhp][HSO4] on the
reaction was investigated. At a mild temperature, a
low yield of the product was achieved in the absence
of [Hnhp][HSO4]. To evaluate the quantity of cata-
lyst required, 5–20 mole % of [Hnhp][HSO4] was used
and the products were obtained with 60–95 % yields.
In addition, decreasing the amount of catalyst from
10 mole % to 5 mole % reduced the yield significantly
from 95 % to 60 %. However, increasing the quantity
of catalyst from 10 mole % to 20 mole % reduced the
yield from 95 % to 75 % (Table 3, entries 1–4). Ac-
cordingly, 10 mole % of catalyst was selected as the
optimal amount of catalyst for this reaction.
In order to evaluate the general character of this
method, different 6-unsubstituted DHPMs were syn-
thesised using a variety of aldehydes and enaminones
In summary, a simple, convenient and eco-friendly
approach is described for the synthesis of 6-unsubsti-
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H. Alinezhad et al./Chemical Papers 70 (8) 1126–1130 (2016)
1129
Table 4. Evaluation of present method in comparison with some other reported methodsa
Entry
Catalyst, amount/mole %
Conditions
Yieldb/%
Time/h
Reference
1
2
3
TMSCl, 150
AcOH or HCl, few drops
[Hnhp][HSO4], 10
DMF, 85◦C
Dioxane, reflux
Solvent free, 80◦C
89
65
92
10
–
2
Wan and Pan (2009)
Darwish et al. (2010)
This work
a) Reaction between benzaldehyde, phenyl enaminone and urea; b) yields refer to isolated recrystallised products.
Fig. 2. Plausible mechanism for synthesis of 6-unsubstituted DHPM derivatives.
tuted DHPMs by a one-pot three-component Biginelli-
like reaction of various aldehydes, enaminones and
urea/thiourea in the presence of 2-pyrrolidonium
bisulphate as an ionic liquid catalyst. This method
affords excellent yields, short reaction time, simple
work-up procedure and solvent-free conditions.
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financial support received from the University of Mazandaran
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The supplementary data associated with this ar-
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