Potassium phthalimide: An efficient and green organocatalyst for the synthesis of 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d] pyrimidin-2(5H)-ones/thiones under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2013.11.042

An efficient synthesis of Biginelli-type compounds using potassium phthalimide as a green, mild, and commercially available organocatalyst in a one-pot, multi-component cyclocondensation reaction of cyclopentanone, aldehydes, and urea/thiourea is reported

Full text of DOI:10.1016/j.cclet.2013.11.042

Chinese Chemical Letters 25 (2014) 313–316
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Chinese Chemical Letters
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Original article
Potassium phthalimide: An efficient and green organocatalyst for the
synthesis of 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-
cyclopenta[d]pyrimidin-2(5H)-ones/thiones under solvent-free
conditions
*
Hamzeh Kiyani , Maryam Ghiasi
School of Chemistry, Damghan University, Damghan 36715-365, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient synthesis of Biginelli-type compounds using potassium phthalimide as a green, mild, and
commercially available organocatalyst in a one-pot, multi-component cyclocondensation reaction of
cyclopentanone, aldehydes, and urea/thiourea is reported. The present methodology is a green approach
to access 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-ones/thiones.
It offers several merits such as simple operational procedures, no use of hazardous organic solvents, and
cheap and environmentally friendly solid basic catalyst.
Received 11 July 2013
Received in revised form 30 October 2013
Accepted 6 November 2013
Available online 28 November 2013
Keywords:
ß 2013 Hamzeh Kiyani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Organocatalyst
Potassium phthalimide
Biginelli reaction
Pyrimidinone
Solvent-free
1. Introduction
the synthesis of these compounds are catalyzed by different
catalysts. Some of these catalysts include rare earth metal
The Biginelli compounds or 3,4-dihydropyrimidin-2(1H)-ones
(DHMPs) and other compounds with the structural similarity
constitute an eye-catching class of heterocyclic organic com-
pounds, which exhibit significant biologic and pharmacologic
activities and have become the key structural units in many drugs
and drug candidates, such as monastrol, L-771688, SNAP-7941,
and SQ 32926 [1–11]. So far, a wide range of biologic effects,
including antiviral, antitumor, antifungal, anti-tubercular, anti-
bacterial, antihypertensive, and anti-inflammatory activities, have
been described for these compounds [12–15]. It was also reported
that some of the Biginelli-type analogs such as fused pyrimidi-
nones bearing an arylidene moiety have anticancer properties [16].
Consequently, the synthesis of this type of heterocycles is of much
current importance for both organic synthesis and medicinal
chemistry. These types of heterocyclic pyrimidinones are prepared
by the reaction of cycloalkanones with various aldehydes and urea/
thiourea [17–23]. In addition, these compounds can also be
bis(perfluorooctanesulfonyl)imide complexes [18], YbCl3 [20],
Brønsted acidic ionic liquid [21], as well as strong Brønsted acid
like HCl [25]. Strong Brønsted bases such as sodium ethoxide
[16,19], potassium hydroxide [26], sodium butoxide [27,28], and
potassium tert-butoxide [29] have also been used as the catalyst in
Biginelli-type reactions. Recently, base-catalyzed Biginelli reac-
tions have gained significance for the reason of the reasonable
yields compared to those of the acid-catalyzed reactions [29,30].
On the other hand, solvent-free organic processes have gained in
popularity in recent years from the viewpoint of green chemistry
and ecological importance. The benefits of reactions in the absence
of solvent are their simple workup procedures, high efficiency,
mild conditions, environmental friendliness, reduction of waste,
low cost, and handling [31–33].
In the 1950s when Pines and Eschinazi began studies of the
solid basic catalysts, the development of these kinds of catalytic
systems utilizing inexpensive, clean, environmentally benign, and
commercially available catalysts has been a challenge in organic
syntheses [34–36]. Potassium phthalimide (PPI) is a stable, mild,
green, inexpensive, commercially available, and efficient basic
recyclable catalyst. It has been utilized as a reagent in the synthesis
of primary amines by the Gabriel method [37,38], and the
synthesis of phthalimide derivatives [39–41]. Also, PPI showed
synthesized from the reaction of the
a,a’-bis(arylidene)cycloalk-
anones with urea/thiourea [24]. Typically, processes involved in
*
Corresponding author.
E-mail address: hkiyani@du.ac.ir (H. Kiyani).
1001-8417/$ – see front matter ß 2013 Hamzeh Kiyani. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.11.042

314
H. Kiyani, M. Ghiasi / Chinese Chemical Letters 25 (2014) 313–316
O
R
H
O
+
N: K
O
X
15 mol%
O
NH
+
2
+
H N
NH
2
2
eat
free, h
lvent-
So
R
N
H
X
X = O, S
R
1
2
3
4a-o
Scheme 1. Synthesis of 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-ones/thiones catalyzed by PPI.
high catalytic activity in the preparation of cyanohydrin tri-
methylsilyl ethers [42,43]. Literature survey shows that there are
no reports about the synthesis of pyrimidinone derivatives using
PPI as a catalyst. In the present work, we report a solvent-free and
solid base PPI-catalyzed synthesis of several derivatives of
Biginelli-like compounds via a one-pot, multi-component reaction
of aryl aldehydes, cyclopentanone, and urea/thiourea (Scheme 1).
o) were prepared by condensing cyclopentanone (1 mmol) with
aryl aldehydes (2 mmol) and urea/thiourea (1.3 mmol) under
conventional heating conditions using 15 mol% of PPI as a solid
basic catalyst without any solvent (Scheme 1).
At first, in order to optimize the amount of PPI, the
cyclocondensation reaction of benzaldehyde (1 mmol), cyclopen-
tanone (1 mmol), and thiourea (1.3 mmol) was carried out under
neat conditions at 120 8C in the presence of different quantities of
PPI as the catalyst (Table 1).
2. Experimental
As shown in Table 1, in the absence of the catalyst, the
formation of product 4l was not observed (Table 1, entry 1). By
adding catalyst (2.5 mol%) to the reaction mixture, the product was
formed with relatively low yield (Table 1, entry 2). The yield of
product 4l was improved as the amount of PPI increased from 2.5
to 5, 7.5, 10, and 15 mol% (Table 1, entries 2–6). A further increase
in mol% of PPI (20 mol%) did not have any significant effect on the
yield of the product or reaction time. It was observed that 15 mol%
loading of the catalyst provided the best yield. Therefore, 15 mol%
was chosen as the optimal quantity of PPI. Then, the same reaction
was tested under different temperatures including room temper-
ature, 50, 80, 100, and 120 8C. The maximum yield in shorter
reaction time was achieved under neat conditions at 120 8C.
Furthermore, the influence of solvent was also optimized; the
model reaction was conducted in various solvents under similar
reaction conditions. When the reaction was performed in EtOH,
CH2Cl2, and CH3CN, the product 4l was obtained in yields of 60%,
58%, and 50%, respectively.
To a mixture of aryl aldehyde 1 (2 mmol), cyclopentanone 2
(1 mmol), and urea or thiourea 3 (1.3 mmol) was added 15 mol% of
PPI. The reaction mixture was heated at 120 8C on a heating mantle
for 1.5–6 h. After the completion of the reaction (monitored by TLC
analysis), the system was cooled to room temperature. Water
(10 mL) was added to the reaction mixture, and the crude product
was obtained by filtration followed by washing with ethyl acetate
and ethanol. The solid thus obtained was further purified by
recrystallization using ethanol. The catalyst was recovered by
concentration of the filtrate, and was dried and reused for
subsequent reactions. Selected spectral data are listed below.
Compound 4a: IR (KBr, cmÀ1):
1670, 1468, 1445, 1355, 1070, 755; 1H NMR (400 MHz, DMSO-d6):
1.96–2.03 (m, 1H), 2.49 (m, 1H), 2.73–2.84 (m, 2H), 5.16 (s, 1H),
6.63 (s, 1H), 7.19–7.37 (m, 11H), 8.79 (s, 1H); 13C NMR (100 MHz,
DMSO-d6): 29.5, 29.8, 58.7, 117.8, 119.6, 127.2, 127.4, 128.6,
129.0, 129.5, 129.6, 137.1, 138.8, 140.3, 144.3, 154.4.
Compound 4c: IR (KBr, cmÀ1):
3385, 3215, 3115, 2955, 2850,
1684, 1600, 1440, 1285, 1110, 895, 768; 1H NMR (400 MHz, DMSO-
d6): 1.95–2.06 (m, 1H), 2.33–2.37 (m, 1H), 2.67–2.74 (m, 2H), 3.78
n 3410, 3218, 3120, 2920, 2850,
d
d
n
With the above-mentioned optimized conditions in hand, we
then proceeded to probe the substrate diversity of this multi-
component reaction by using readily available starting materials. It
was found that the reaction proceeded efficiently and afforded the
targeted products (4a–o) in good to high yields. The results are
offered in Table 2.
d
(s, 3H), 3.79 (s, 3H), 5.26 (s, 1H), 6.68 (s, 1H), 7.32 (s, 1H), 7.44 (d,
4H, J = 7.6 Hz), 7.89 (d, 2H, J = 7.6 Hz), 7.97 (d, 2H, J = 7.2 Hz), 8.89
(s, 1H); 13C NMR (100 MHz, DMSO-d6):
d 28.8, 29.1, 52.6, 57.7,
116.6, 120.2, 127.1, 127.3, 128.4, 129.3, 129.8, 130.0, 136.7, 142.5,
142.9, 148.7, 155.7, 157.9.
Based on the results presented in Table 2, it can be seen that the
reaction of aryl aldehydes bearing both electron-donating and
electron-withdrawing substituents with cyclopentanone and urea
or thiourea worked well, and the corresponding 4-aryl-7-
(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]-pyrimidin-
2(5H)-ones/thiones were obtained in reasonable yields. The
Compound 4n: IR (KBr, cmÀ1):
n
3388, 3205, 2923, 2850, 1668,
1586, 1520, 1476, 1341, 1182, 1109, 856, 752; 1H NMR (400 MHz,
DMSO-d6): 1.98–2.05 (m, 1H), 2.37–2.45 (m, 1H), 2.78–2.91 (m,
d
2H), 5.39 (s, 1H), 6.89 (s, 1H), 7.49–7.61 (m, 4H), 8.18 (d, 2H,
J = 8.4 Hz), 8.29 (d, 2H, J = 7.6 Hz), 8.80 (s, 1H), 10.26 (s, 1H).
Compound 4o: IR (KBr, cmÀ1):
n
3405, 3224, 3124, 2920, 2852,
1675, 1488, 1450, 1406, 1350, 1270, 1090, 1015, 889, 828, 814,
754; 1H NMR (400 MHz, DMSO-d6):
1.96–2.02 (m, 1H), 2.36–2.42
Table 1
Optimization of the amounts of catalyst PPI.a
d
Entry
Catalyst amount (mol%)
Time (h)
Yield (%)b
(m, 1H), 2.70–2.79 (m, 2H), 5.38 (s, 1H), 6.69 (s, 1H), 7.26 (s, 1H),
7.28-7.33 (m, 4H), 7.42 (d, 2H, J = 8.7 Hz), 7.46 (d, 2H, J = 12.0 Hz),
1
2
3
4
5
6
7
–
4
4
4
4
4
2
2
–
8.82 (s, 1H); 13C NMR (100 MHz, DMSO-d6):
d
28.6, 29.2, 57.8,
2.5
5.0
7.5
10.0
15.0
20.0
35
60
65
72
84
85
116.6, 121.1, 121.7, 121.9, 127.3, 128.4, 129.1, 129.8, 131.5, 134.9,
138.7, 156.5, 175.8
3. Results and discussion
a
Reaction conditions: benzaldehyde (2 mmol), cyclopentanone (1 mmol),
In the present study a series of 4-aryl-7-(arylmethylene)-3,4,6,7-
tetrahydro-1H-cyclopenta[d]-pyrimidin-2(5H)-ones/thiones (4a–
thiourea (1.3 mmol), 120 8C.
b
Isolated yields.

H. Kiyani, M. Ghiasi / Chinese Chemical Letters 25 (2014) 313–316
315
Table 2
Synthesis of 4-aryl-7-(arylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]-pyrimidin-2(5H)-ones/thiones (4a–o) catalyzed by PPI.a
Entry
R/Product
X
Time (h)
Yield (%)b
Mp (8C)
Observed
Reported [Ref.]
1
2
3
4
5
6
7
8
9
H/4a
O
O
O
O
O
O
O
O
O
O
O
S
1.5
2
88
90
90
89
86
92
94
90
90
88
90
84
80
93
93
242–246
239–241
253–254
225–227
249–251
224–226
233–235
257–259
253–256
233–236
275–277
225–227
224–227
204–207
228–230
236–239 [18]
238–241 [17]
250–252 [17]
226–227 [20]
250–251 [20]
225–228 [21]
232–234 [17]
252–255 [17]
252–255 [17]
235–239 [17]
280–283 [20]
219–223 [17]
223–226 [20]
203–207 [17]
226–228 [17]
4-CH3/4b
4-OCH3/4c
3-OCH3/4d
2-OCH3/4e
4-CN/4f
2-Cl/4g
6
3
4
3
2
4-Cl/4h
3
4-Br/4i
2.5
4
10
11
12
13
14
15
3-NO2/4j
4-NO2/4k
H/4l
3
2
2-OCH3/4m
4-NO2/4n
4-Cl/4o
S
2.5
4
S
S
4
a
Reaction conditions: aryl aldehyde (2 mmol), cyclopentanone (1 mmol), urea/thiourea (1.3 mmol), PPI (15 mol%), 120 8C.
Isolated yields.
b
Table 3
Comparison of the results of the reaction of benzaldehyde, cyclopentanone, and urea using PPI with those obtained by reported catalysts.
Catalyst/conditions
Catalyst amount (mol%)
Time (h)
Yield (%)
Ref.
YbCl3/90 8C, neat
Ytterbium bis(perfluorooctanesulfonyl)imide/C10F18/90 8C
AlCl3/PEG, 45 8C
3
3
79
91
94
93
86
88
[20]
[18]
[44]
[17]
[21]
–
1
2
30
10
15
15
2.5
2–3
0.083
1.5
TMSCl/DMF-CH3CN, r.t.
Ionic liquid/100 8C, neat
PPI/120 8C, neata
a
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After the completion of the reaction, the solid product was treated
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subsequent cycles. It showed nearly the same activity as a fresh
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