Phthalimide-N-sulfonic acid: a new and efficient organocatalyst for the Biginelli reaction under solvent-free conditions

Article abstract of DOI:10.1007/s11164-014-1766-7

Abstract Phthalimide-N-sulfonic acid (PISA) was straightforwardly synthesized via addition of chlorosulfonic acid to a solution of potassium phthalimide in dry dichloromethane. This reagent is found to be an efficient solid acidic catalyst in the Biginell

Full text of DOI:10.1007/s11164-014-1766-7

Res Chem Intermed
DOI 10.1007/s11164-014-1766-7
Phthalimide-N-sulfonic acid: a new and efficient
organocatalyst for the Biginelli reaction under
solvent-free conditions
•
Hamzeh Kiyani Maryam Ghiasi
Received: 30 May 2014 / Accepted: 7 July 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Phthalimide-N-sulfonic acid (PISA) was straightforwardly synthesized
via addition of chlorosulfonic acid to a solution of potassium phthalimide in dry
dichloromethane. This reagent is found to be an efficient solid acidic catalyst in the
Biginelli reaction. The three-component reaction of aryl aldehydes, urea/thiourea,
and ethyl acetoacetate or acetylacetone occurs by means of 10 mol % of PISA in
solvent-free reaction conditions (SFRCs) at 120 °C. The present methodology is a
green approach to access a series of 3,4-dihydropyrimidin-2(1H)-ones/thiones in
high yields. In addition, the use of PISA as the catalyst offers several notable
features such as simple operational procedure, no use of hazardous organic solvents,
and recyclability of catalyst.
Keywords Phthalimide-N-sulfonic acid Á Organocatalyst Á Biginelli-3CR Á 3,4-
Dihydropyrimidin-2(1H)-ones/thiones Á Solvent-free conditions
Introduction
The one-pot multicomponent reaction (MCR) was an attractive broad area of
research in the synthesis of N-containing heterocyclic scaffolds such as the 3,4-
dihydropyridin-2-1H-(ones)/3,4-dihydropyridin-2-1H-(thiones) (DHPMs) and their
heterocyclic derivatives [1–19]. A one-pot process in organic synthetic chemistry
that generates DHPMs via MCR in a single operation is called the Biginelli
3-component reaction (Biginelli-3CR). Since the 3CR synthesis of ethyl-6-methyl-
Electronic supplementary material The online version of this article (doi:10.1007/s11164-014-1766-7)
contains supplementary material, which is available to authorized users.
H. Kiyani (&) Á M. Ghiasi
School of Chemistry, Damghan University, 36715-364 Damghan, Iran
e-mail: hkiyani@du.ac.ir
123

H. Kiyani, M. Ghiasi
2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate by Italian chemist Pie-
tro Biginelli in 1893 [20], synthesis and biological evaluation of different classes of
these heterocyclic rings have been widely and extensively studied. DHPMs and
associated heterocyclic molecules have attracted a lot of attention due to their
unique characteristics. Some examples of heterocyclic structures with a dihydro-
pyrimidine (DHPM) core have been established a wide scope of important
applications in biological and pharmacological fields [21–27]. A large number of
various heterocyclic compounds containing DHMP exhibit broad ranges of
medicinal properties, including antibacterial, antihypertensive, calcium channel
modulation, antiviral, antitumor, antifungal, anti-tubercular, mitotic kinesin Eg5
inhibition, anti-HIV, anti-HSV, and anti-inflammatory [28–32]. Moreover, some
DHPMs and their derivatives can be found as the structural motif in a wide range of
natural marine alkaloids such as batzelladine A and B as well as drug candidates.
Among the best-known examples of DHMP-containing heterocycles, which are
considered as drug candidates, include monastrol, enanstrone, piperastrol, dime-
thylenastron, fluorastrol, L-771688, SNAP-7941, SQ 32926, SQ32547, mon 97, and
SWO2. Taking into consideration the importance of 3,4-dihydropyrimidin-contain-
ing heterocycles, many researchers in the synthetic organic chemistry and
pharmaceutical research institutions were interested in developing newer
approaches for the synthesis of these types of eye-catching heterocyclic compounds.
A literature survey indicates that novel protocols to perform the Biginelli reaction
using various catalysts, reagents, reaction conditions, and nonconventional
techniques, such as microwave, ultrasound, high-pressure, and grindstone chemis-
try, have been developed by different research groups. To date, a huge number of
important reviews about the different synthetic methods towards of 3,4-
dihydropyrimidin-containing heterocycles have been presented [32–39]. A large
part of the catalysts, reagents, and conditions/techniques for the Biginelli-3CR has
also been reported elsewhere in the literature [40–42]. Also, metal-free organocat-
alytic multicomponent reactions (OMCRs) are one of the effective green catalytic
synthetic approaches to preparation of Biginelli adducts [43]. In the last few years,
newer metal-free organocatalytic versions of Biginelli-3CR have also been
described. Some of these metal-free catalysts are listed as follows: N,O-
bis(trimethylsilyl)acetamide (BSA) and dicyclohexyl carbodimide (DCC) [44],
ethylene glycol [45], triphenylphosphine (PPh3) [46], choline-based ionic liquids
(CIL) [47], oxalic acid [48], N-sulfonic acid poly(4-vinylpyridinium) chloride
(NSPVPC) [49], PEG1000-DAIL/toluene [50], b-cyclodextrin [51], poly(SIL) [52],
bovine serum albumin (BSA) [53], pentafluorophenyl-ammonium triflate (PFPAT)
[54], bioglycerol-based sulfonic acid functionalized carbon [55], nitrite ionic liquid
[56], trifluoroethanol [57], sulfonated carbon [58], tartaric acid [59], citric acid [59,
60], Me3SiCl [61], xanthan sulfuric acid [62], acidic ionic liquids [63–67], 1,3,5-
triazine-2,4,6-triyltrisulfamic acid (TTSA) [68], deep eutectic solvent [69], chiral
bisphosphorylimides [70], 3-[(3-(trimethoxysilyl)propyl)thio]propane-1-oxy-sul-
fonic acid [71], amino acid functionalized ionic liquid [72], phase transfer catalysis
[73], trimethylsilyl chloride (TMSCl) in ethyl lactate (EL) [74], iodine under
microwave irradiation [75], sulfonic acid-functionalized polypropylene fiber [76],
and phytic acid [77].
123

Phthalimide-N-sulfonic acid: a new and efficient organocatalyst
Organocatalysts, on the other hand, are classically small organic molecules that
are able to facilitate chemical transformations with a substoichiometric amount of
an organic compound. Organocatalytic strategies have attracted attention for their
application in organic synthesis due to their efficiency and selectivity. Compared
with metallic catalysts, the preparation and handling of most organocatalysts is
easier, cheaper, and relatively stable [78–81]. Organocatalysts possess other
advantages, for example, cost-effectiveness, ready availability, a metal-free
environment, relatively low toxicity, simple functionality, non-sensitivity to air
and moisture, promotion of a variety of chemical transformations via various
activation modes, mildness of the reaction conditions required, huge potential for
the development of large-scale production [82–84]. Alternatively, implementation
of organic transformations under solvent-free reaction conditions (SFRCs) have
gained in popularity in recent years because of their simple workup procedure, high
efficiency, mild conditions, environmental friendliness, cleanliness, low cost,
handling, and economical friendliness [85, 86]. Recently, we have explored the
Biginelli-type cyclocondensation of substituted benzaldehydes with cyclopentanone
and urea/thiourea [87] and Biginelli compounds [88]. Followed by our research
work, this article describes preparation of phthalimide-N-sulfonic acid (PISA)
(Scheme 1) as well as a solvent-free and solid PISA-catalyzed synthesis of several
derivatives of Biginelli compounds via a simple one-vessel 3-CR condensation
between substituted benzaldehydes (4), b-dicarbonyl compounds (5a,b), and urea/
thiourea (6a,b) (Scheme 2). Phthalimide-N-sulfonic acid (PISA) acts as highly
O
O
OH
S
CH2Cl2
0 0C-r.t., 2.5 h
- KCl
N:K+
N
O
+
ClSO3H
O
O
O
1
2
PISA, 3
Scheme 1 The synthesis of phthalimide-N-sulfonic acid (PISA) (3)
R1
R1
O
O
N
H
SO3
R2
H
NH
10 mol%
H
O
PISA, 3
O
O
4
0C
120
Solvent-free,
R2
H
N
X
3C
NH2
X
+
H
3C
O
H N
2
7a-t
2
=
=
5a:
5b:
=
R
R
OEt
6a: X
6b: X = S
O
2
H
C
3
Scheme 2 Biginelle-3C synthesis of 3,4-dihydropyrimidin-5(1H)-ones/thiones (7a–t) catalyzed by PISA
(3)
123

H. Kiyani, M. Ghiasi
efficient solid acidic organocatalyst for the synthesis of the Biginelli products under
SFRCs.
Experimental
General
All chemicals were purchased from Alfa Aesar and Aldrich and were used without
further purification, with the exception of 4-methylbenzaldehyde, 4-methoxylbenz-
aldehyde, and benzaldehyde, which were distilled before using. All solvents were
distilled before using. The products were characterized by comparison of their
physical data with those of known samples or by their spectral data. Melting points
were measured on a Buchi 510 melting point apparatus and are uncorrected. NMR
spectra were recorded at ambient temperature on a BRUKER AVANCE DRX-500
and 400 MHz using CDCl3 or DMSO-d6 as the solvent. FT-IR spectra were
recorded on a Perkin-Elmer RXI spectrometer. Elemental microanalyses were
performed on an Elementar Vario EL III analyzer. The development of reactions
was monitored by thin-layer chromatography (TLC) analysis on Merck pre-coated
silica gel 60 F254 aluminum sheets, visualized by UV light.
Preparation of the phthalimide-N-sulfonic acid (PISA)
In a fume hood, a clean and oven-dried 50-mL suction flask was cooled at 0 °C in an
ice bath. This flask charged with a solution of potassium phthalimide (3.704 g,
20 mmol) in anhydrous dichloromethane (15 mL) was equipped with a constant
pressure-dropping funnel containing chlorosulfonic acid (2.33 g, 20 mmol). Chlo-
rosulfonic acid was added dropwise over a period of 20 min with slow stirring at the
same temperature. After addition was complete, the reaction mixture was heated to
room temperature and stirred for a further 2.5 h. The reaction mixture was filtered
off and the solid residue was washed with water (4 mL) as well as diethyl ether
(3 9 6 mL) and dried under vacuum. PISA was achieved as a cream-colored solid.
Yield: 92 %, 4.18 g; M.p. 156–157 °C; IR (KBr, cm-1): m 3,500–2,500 (O–H),
1
1,706 (C=O), 1,298 and 1,128 (S=O), 718 (S–O); H NMR (400 MHz, DMSO-d6):
d 7.85 (m, 4H, Ar–H), 11.35 (s, 1H, SO3H); 13C NMR (100 MHz, DMSO-d6): d
123.4, 133.0, 134.8, 169.6, 169.7. Anal. Calcd. For. C8H5NO5S (%): C, 42.29; H,
2.22; N, 6.17; S, 14.11. Found: C, 42.28; H, 2.20; N, 6.20; S, 14.05.
Typical procedure for the preparation of 3,4-dihydropyrimidin-2(1H)-ones and–
thiones (7a–t)
To a mixture of aryl aldehyde 4 (1 mmol), b-dicarbonyl 5 (1 mmol), and urea or
thiourea 6 (1.2 mmol) was added 10 mol % of phthalimide-N-sulfonic acid (PISA).
The reaction mixture was heated to 120 °C on a heating mantle for the appropriate
time. After completion of the reaction, as indicated by TLC analysis, the system was
cooled to room temperature. Ethanol (5 mL) was added to the reaction mixture, and
123

Phthalimide-N-sulfonic acid: a new and efficient organocatalyst
the mixture was heated until a homogeneous solution was obtained. Next, ethyl
acetate was added to the resulting mixture and then cooled to RT, and the catalyst
was recovered by filtration and washed thoroughly with ethyl acetate and then
diethyl ether. The recovered catalyst was then reused under the same conditions as
above for at least five reactions. After this, the organic phase was concentrated by
evaporation, distilled water was added to the residue, and the solid thus obtained.
The resulting solid product was filtered off, washed with cold water, and then the
reaction mixture was subjected to isolation with preparative TLC using a mixture of
ethyl acetate and n-hexane (3:10) as eluent. Selected spectral data are listed below.
Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (7c)
IR (KBr, cm-1): m 3,220 (N–H), 3,102 (N–H), 2,980 (CH), 2,931 (CH), 1,724
1
(C=O); H NMR (500 MHz, DMSO-d6): d 1.20 (t, 3H, J = 7.1 Hz, CH3), 2.35 (s,
3H, CH3), 3.80 (s, 3H, OCH3), 4.08–413 (m, 2H, CH2), 5.37 (s, 1H, CH), 5.92 (s,
1H, NH), 6.84–6.87 (m, 2H, Ar–H), 7.25–7.30 (m, 2H, Ar–H), 8.41 (s, 1H, NH); 13
C
NMR (100 MHz, DMSO-d6): d 14.3, 18.7, 50.7, 53.6, 98.7, 128.0, 128.5, 131.7,
143.5, 148.9, 151.9, 165.6.
Ethyl 6-methyl-4-(3-nitrophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (7i)
IR (KBr, cm-1): m 3,330 (N–H), 3110 (N–H), 1,706 (C=O), 1,550 (NO2), 1,345
1
(NO2); H NMR (400 MHz, DMSO-d6): d 1.10 (t, 3H, J = 7.0 Hz, CH3), 2.25 (s,
3H, CH3), 3.90 (q, 2H, J = 7.0 Hz, CH2), 5.57 (s, 1H, CH), 7.45–7.88 (m, 4H, Ar–
H), 7.05 (s, 1H, NH), 8.42 (s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): d 13.9,
17.7, 53.3, 59.4, 99.4, 115.1, 118.7, 120.1, 129.3, 146.9, 147.5, 150.2, 155.7, 163.5.
Ethyl 1,2,3,4-tetrahydro-6-methyl-4-(4-nitrophenyl)-2-thioxopyrimidine-5-
carboxylate (7o)
IR (KBr, cm-1): m 3,234 (N–H), 3,110 (N–H), 2,942 (CH), 1,670 (C = O), 1,580
1
(NO2), 1,340 (NO2); H NMR (400 MHz, DMSO-d6): d 1.48 (t, 3H, J = 7.2 Hz,
CH3), 2.24 (s, 3H, CH3), 4.23 (q, 2H, J = 7.2 Hz, CH2), 5.74 (s, 1H, CH), 7.12 (s,
1H, NH), 7.48–8.35 (m, 4H, Ar–H), 8.41 (s, 1H, NH); 13C NMR (100 MHz, DMSO-
d6): d 14.5, 15.7, 54.7, 62.3, 105.8, 123.5, 126.1, 144.2, 150.1, 161.2, 167.3, 175.3.
Results and discussion
In the present investigation, as shown in Scheme 1, phthalimid-N-sulfonic acid (PISA)
was synthesized as a solid acidic organocatalyst and applied to preparation of a series
of 3,4-dihydropyrimidin-5(1H)-ones/thiones (7a–t) by condensing aryl aldehydes (4),
b-dicarbonyls (ethyl acetoacetate, 5a, or pentane-2,4-dione, 5b) and urea (6a)/
thiourea (6b) under conventional heating conditions without any solvent (Scheme 2).
123

H. Kiyani, M. Ghiasi
The structure of PISA is supported by spectral data. In the IR spectrum of PISA, the
absorption bands characteristic for C=O, S=O, and S–O are visible at 1,706, 1,298,
1,128, and 718 cm-1, respectively. The appearance of a broad band between 3,500 and
2,500 cm-1 is attributed to the hydroxyl group (–OH) of sulfunic acid fragment. In 1H
NMR spectrum, the resonance of the proton belongs to—SO3H appeared at
d = 11.35 ppm as a singlet. The multiplet signal appeared at d = 7.85 ppm integrating
for four protons confirms the aromatic protons. The 13C NMR spectrum of synthesized
catalyst showed three signals at d = 123.4, 133.0, and 134.8 ppm attributable to the
aromatic carbons. The data revealed the presence of the C = O group at d = 169.6 and
169.7 ppm. Given the 13C NMR spectrum of the catalyst, it seems that the structure of
PISA is not symmetric. Appearance of two peaks at d = 169.6 and 169.7 ppm support
the asymmetric structure of the catalyst. The reaction of the PISA formation is easy and
clean as well as needs no special workup and purification methods.
In order to find the most appropriate reaction conditions, 3CR cyclocondensation
reaction of 4-methoxybenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), and
Table 1 Effect of the amounts of the PISA (3) and temperature on the synthesis of ethyl-4-(4-
methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (7c) in the absence of
solventa
OCH3
OCH3
O
N
SO3H
O
O
H
O
PISA
4c
3
O
H3C
O
NH
H3C
O
NH2
O
+
Conditions
H3C
N
O
H3C
5a
O H2N
H
7c
6a
Entry
Catalyst (mol %)
Temperature (°C)
Time (h)b
Yield (%)c
1
–
120
120
120
120
120
120
Ambient
50
10
5
20
55
82
94
95
94
0
2
2.5
5
3
4d
3
10
15
20
10
10
10
10
10
2
5
2
6
2
7
10
10
10
10
2
8
40
54
70
95
9
80
10
11
a
100
130
Reaction conditions: 4-methoxybenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (1.2 mmol)
Reaction progress monitored by TLC analysis
Isolated yields
b
c
d
Optimized conditions shown in bold
123

Phthalimide-N-sulfonic acid: a new and efficient organocatalyst
urea (1.2 mmol) was selected as the model reaction. The mentioned reaction was
implemented under neat conditions at 120 °C using 2.5, 5, 10, 15, and 20 mol % of
PISA as the solid acid organocatalyst (Table 1).
Table 1 shows the results of the optimization. When the reaction was carried out
in the absence of the catalyst, the product 7c was only formed in 20 % of the
reaction yield for 10 h. Implementation of the reaction using 2.5 % of PISA catalyst
at 120 °C led to the enhancement of the reaction yield to 55 % and shortening
reaction time from 10 h into 5 h (Table 1, entry 2). As a result, the rise in the
reaction yield as well as shortening of the reaction time means that the catalytic
amount of the PISA for performing this reaction is mandatory. When the amount of
the catalyst was increased from 2.5 to 10 mol %, the yield of the formation of
compound 7c was improved from 55 to 94 % and the reaction time was further
reduced to 2 h (Table 1, entries 2–4). Hence, the 2-h period was enough time for the
conducting of the model reaction. Otherwise, increasing the catalyst loading from
10 to 15 and 20 mol % does not significantly change the yield (Table 1, entries
5–6). Consequently, the amount of 10 mol % of PISA was chosen as the catalyst for
conduction the other reactions. The temperature dependence study was also
investigated (Table 1, entries 7–11). When the reaction was carried out at ambient
temperature, formation of the product was not observed. Increasing of the
temperature from ambient temperature to 50, 80, and 100 °C, the yield of the
product 7c was improved. Increasing the temperature from 100 to 130 °C does not
significantly effect the yield of the reaction. It was found that the reaction
temperature should be 120 °C in the presence of 10 mol % of PISA. In the next
section of this exploration, the solvent effect was investigated by means of the
Table 2 The synthesis of ethyl-4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (7c) using PISA (10 mol %) in various solvents under reflux conditionsa
OCH3
OCH3
O
N
SO3H
O
O
PISA (10 mol%)
3
H
O
O
4c
+
H3C
O
NH
Solvent, reflux
H3C
O
NH2
H3C
N
O
H
H3C
5a
OH2N
O
7c
6a
Entry
Solvent
Time (h)b
Isolated Yield (%)
1
2
3
4
5
a
CH3CN
EtOH
22
22
72
22
22
80
78
76
55
65
CH2Cl2
H2O
CHCl3
Reaction conditions: 4-methoxybenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (1.2 mmol)
Reaction progress monitored by TLC analysis
b
123

H. Kiyani, M. Ghiasi
model reaction in various solvents using 10 mol % of PISA in reflux conditions
(Table 2).
As can be seen in Table 2, both the yields and the reaction times suggested that
solution conditions were not efficient. In addition, increasing the reaction times did
not have a significant effect on the yields. As a consequence, based on the results of
the screening study of the temperature, the amount of PISA (Table 1), and the
solvent effect (Table 2) showed that 10 mol % of PISA was sufficient. Also, 120 °C
as well as solvent-free were the optimal reaction temperature and conditions for
completion of the reaction. Therefore, all further reactions were carried out using
Table 3 The synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones (7a–t) catalyzed by PISA (3) under
SFRCs
R1
O
H
O
O
X
N
SO3H
O
R2
+
+
H2N
NH2
10 mol%
R2
H3C
NH
3
O
H3C
O
R1
Solvent-free, 120 °C
N
H
X
6 (1.2 mmol)
4 (1 mmol)
5 (1 mmol)
7a-t
Entry
R1
R2
X
Product
7a–t
Time
(h)
Isolated
yield (%)
Mp (°C)
Observed
Reported [ref.]
1
H
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
CH3
O
O
O
O
O
O
O
O
O
O
S
7a
7b
7c
7d
7e
7f
1.25
1.5
2
85
92
94
98
90
92
88
92
90
88
89
92
90
90
91
79
88
90
94
93
204–207
214–215
200–202
258–260
210–211
165–166
214–215
206–208
225–226
209–211
211–214
154–155
194–196
185–186
110–112
195–197
230–233
200–202
167–168
228–230
200–201 [59]
215–216 [91]
201–202 [59]
262–263 [90]
200–201 [89]
163–164 [89]
215–217 [58]
207–208 [59]
225–226 [89]
207–210 [59]
205–208 [59]
153–154 [59]
200–202 [58]
184–187 [89]
108–110 [89]
196–198 [92]
230–231 [89]
203–205 [93]
168–170 [89]
220–224 [89]
2
4-CH3
4-OCH3
2-OCH3
4-OH
3-OH
4-Cl
3
4
2
5
2.5
2.5
3
6
7
7g
7h
7i
8
4-NO2
3-NO2
2-NO2
H
3
9
3.2
3
10
11
12
13
14
15
16
17
18
19
20
7j
7k
7l
2
4-OCH3
4-OH
3-OH
4-NO2
2-NO2
H
S
3
S
7m
7n
7o
7p
7q
7r
7s
3.2
3
S
S
3.5
4
S
O
O
O
O
1
4-CH3
4-OCH3
4-OH
CH3
1
CH3
1
CH3
7t
3
123

Phthalimide-N-sulfonic acid: a new and efficient organocatalyst
O
X
H
X
O
O
S
-
H
2O
H
3C
R2
N
O
r
A
r
A
N
NH2
N
NH2
H
O
H
O
O
H
O
O
X
O
A
B
3
O
S
H
r
A
H
H2N
NH2
N
O
4
6
O
r
r
O
A
A
O
O
r
A
O
H
O
R2
H
NH
R2
H
NH
-
H
2O
R2
NH
HN
X
N
H
X
N
H
X
3C
H
3C
O
O
H
O
H
D
7a-t
C
N
S
O
O
O
Scheme 3 The proposed mechanism for the formation of 3,4-dihydropyrimidin-5(1H)-ones/thiones (7a–
t)
Table 4 Reusability of PISA in the synthesis of 7ca
Catalyst recycle
Time (h)b
Yield (%)c
Fresh
2
94
92
92
90
88
86
1
2
3
4
5
a
2
2
2.5
2.5
3.5
Reaction conditions: 4-methoxybenzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), urea (1.2 mmol)
b
c
Reaction progress monitored by TLC analysis
Isolated yields
10 mol % of the catalyst in solid state at 120 °C. The activity and reusability of the
catalyst were found to be excellent.
In the direction of exhibition the scope of these optimal conditions (10 mol % of
PISA, 120 °C, and the absence of solvent), this three-component reaction was well
evaluated by applying different substituted benzaldehydes bearing electron-donat-
ing and electron-withdrawing groups, ethyl acetoacetate or acetylacetone, and urea
or thiourea. The results are presented in Table 3. Based on the results indicated in
Table 3, it can be seen that the reaction of aryl aldehydes bearing both electron-
donating and electron-withdrawing substituents with 1,3-dicarbonyl compounds and
urea or thiourea worked well and afforded the corresponding products (7a–t) in
reasonable yields.
The mechanism of the reaction is not clear. However, based on the literature [49,
66], the imaginable reaction mechanism for the green formation of products (7a–
t) can be presented in Scheme 3. Probably, aldehyde 4 was activated by PISA
catalyst and condensation of activated aldehyde 4 with urea or thiourea (6) lead to
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H. Kiyani, M. Ghiasi
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Phthalimide-N-sulfonic acid: a new and efficient organocatalyst
formation of A. This intermediate was dehydrated to generate imine intermediate
B. Next, compound C is formed via addition of enol-form of b-dicarbonyl 5 to
imine B in the presence of a catalytic amount of PISA. Then, intermediate
C undergoes an intramolecular cyclization reaction afford the cyclic intermediate D,
which subsequently undertakes dehydration to form targeted compounds 7a–t.
The reusability of the PISA for the preparation of 7c was also studied. The
catalyst was recovered after each run, washed with ether, dried, and reused for
subsequent cycles (Table 4). It showed nearly the same activity as a catalyst along
but with a slight decrease of yield. The decrease of the yield of the product is
probably related to a slight decrease in the catalytic activity of the catalyst or could
be attributed to the loss of catalyst recovery in the course of the reaction.
With the aim of showing the benefit of the catalyst and comparison of the efficiency
of the PISA catalyst with other catalysts in the synthesis of 3,4-dihydropyrimidin-
4(1H)-ones/thiones, results of the reaction of 4-methoxybenzaldehyde (4c), ethyl
acetoacetate (5a), and urea (6a) are shown in Table 5. As presented in Table 5, PISA is
comparable to the formerly reported approaches in terms of reaction times and yields.
Contrasting some of the pervious reported methods, this procedure does not require
any additives or anhydrous conditions. Besides these features, this process also does
not use hazardous solvents such as acetonitrile.
Conclusions
In summary, a simple, efficient, and environmentally benign method using the PISA
for the preparation of 3,4-dihydropyrimidin-2(1H)-ones/thiones by coupling b-
ketoesters, aldehydes, and urea or thiourea was developed. The reactions are
conducted under thermal SFRCs within 1-4 h yielding the corresponding Biginelli
adducts with good to high yields. The use of this catalyst in the synthesis of DHMPs
includes benefits such as clean reaction profiles, a simple operational procedure,
green, minimization of waste, and recyclability of the new organocatalyst. This
work will be valuable for the synthesis of potentially therapeutic agents.
Acknowledgments The authors are thankful to Damghan University Research Council for partial
support of this work.
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