Bronsted acidic ionic liquid as an efficient and reusable catalyst for one-pot, three-component synthesis of pyrimidinone derivatives via biginelli-type reaction under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.501474

A mild and efficient method has been developed for the preparation of pyrimidinone derivatives from the reaction of aromatic aldehydes with cyclopentanone and urea or thiourea in the presence of N-(4-sulfonic acid) butyl triethyl ammonium hydrogen sulfate

Full text of DOI:10.1080/00397911.2010.501474

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Brønsted Acidic Ionic Liquid as an
Efficient and Reusable Catalyst for One-
Pot, Three-Component Synthesis of
Pyrimidinone Derivatives via Biginelli-
Type Reaction Under Solvent-Free
Conditions
Abdol R. Hajipour a b , Yosof Ghayeb b , Nafisehsadat Sheikhan b &
Arnold E. Ruoho a
a Department of Pharmacology, University of Wisconsin, Medical
School, Madison, Wisconsin, USA
b Pharmaceutical Research Laboratory, Department of Chemistry,
Isfahan University of Technology, Isfahan, Iran
Published online: 25 May 2011.
To cite this article: Abdol R. Hajipour , Yosof Ghayeb , Nafisehsadat Sheikhan & Arnold E. Ruoho
(2011): Brønsted Acidic Ionic Liquid as an Efficient and Reusable Catalyst for One-Pot, Three-
Component Synthesis of Pyrimidinone Derivatives via Biginelli-Type Reaction Under Solvent-Free
Conditions, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 41:15, 2226-2233
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Synthetic Communications1, 41: 2226–2233, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.501474
BRØNSTED ACIDIC IONIC LIQUID AS AN EFFICIENT
AND REUSABLE CATALYST FOR ONE-POT,
THREE-COMPONENT SYNTHESIS OF PYRIMIDINONE
DERIVATIVES VIA BIGINELLI-TYPE REACTION UNDER
SOLVENT-FREE CONDITIONS
Abdol R. Hajipour,1,2 Yosof Ghayeb,2 Nafisehsadat Sheikhan,2
and Arnold E. Ruoho1
1Department of Pharmacology, University of Wisconsin, Medical School,
Madison, Wisconsin, USA
2Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan
University of Technology, Isfahan, Iran
GRAPHICAL ABSTRACT
Abstract A mild and efficient method has been developed for the preparation of pyrimidi-
none derivatives from the reaction of aromatic aldehydes with cyclopentanone and urea
or thiourea in the presence of N-(4-sulfonic acid) butyl triethyl ammonium hydrogen sul-
fate ([TEBSA][HSO4]) as the Brønsted acidic ionic liquid and effective catalyst under
thermal and solvent-free conditions. Good yields, short reaction times, straightforward
workup, reusability of the catalyst, and green conditions are the most obvious advantages
of this procedure.
Keywords Biginelli-type reaction; Brønsted acidic ionic liquid; one-pot; pyrimidinone;
solvent-free
INTRODUCTION
One-pot multicomponent reactions have attracted significant attention in
organic and medicinal chemistry. In these reactions, highly diverse and complex
compounds are produced from easily available precursors in a single step by forma-
tion of multiple new bonds in one pot. Thus, multicomponent reactions are known
as important and environmentally benign processes in synthetic chemistry because
Received February 10, 2010.
Address correspondence to Abdol R. Hajipour, Pharmaceutical Research Laboratory, Department
of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran. E-mail: haji@cc.iut.ac.ir
2226

ACIDIC IONIC LIQUID
2227
they decrease the number of steps and reduce energy consumption and waste
production.[1–4]
Pyrimidinone and its derivatives constitute an important class of natural and
synthetic products that possess significant biological and pharmaceutical proper-
ties.[5,6] In particular, functionalized pyrimidinones such as fused pyrimidinones with
an arylidene part are essential heterocyclic motifs in antitumor agents.[7] These com-
pounds as important key intermediates are employed for preparation of many bio-
logically active products.[8–10] Because of the potential of arylidene heterobicyclic
pyrimidinones, numerous methods including the reaction of a,a0-bis (arylidene)cy-
cloalkanones with urea or thiourea catalyzed by strong bases such as sodium ethox-
ide[7] or strong acids such as HCl have been developed for their synthesis.[11] In
recent years, a Biginelli-type reaction involving one-pot, three-component conden-
sation of aromatic aldehydes, cyclopentanone, and urea or thiourea was also
reported as an efficient method for the synthesis of these compounds using TMSCl
as reagent in dimethylformamide (DMF)=CH3CN as solvent.[12] Also, ytterbium
chloride has effectively catalyzed this reaction under solvent-free conditions.[13]
However, these procedures suffered from long reaction times and used excess reagent
and mixed solvents. Regarding the importance of arylidene heterobicyclic pyrimidi-
nones and the great need for environmentally benign chemical productions, the
development of suitable green synthetic methods for these compounds has attracted
considerable interest.
Recently, ionic liquids as useful green solvents or catalysts have been applied in
many reactions[14,15] because of their specific properties such as undetectable vapor
pressure, resistance to combustion, wide liquid range, reusability, and high thermal
stability.[16,17] In particular, Brønsted acidic ionic liquids, containing useful charac-
teristics of solid acids and mineral liquid acids, are designed to replace traditional
mineral liquid acids such as sulfuric acid and hydrochloric acid in chemical proce-
dures.[18,19] N-(4-Sulfonic acid) butyl triethyl ammonium hydrogen sulfate ([TEB-
SA][HSO4]) has been synthesized and used as an efficient catalyst for nitration of
aromatic compounds,[20] esterification of various alcohols by different acids,[21]
and selective alkylation of m-cresol with tert-butanol.[22] Also, we applied this
Brønsted acidic ionic liquid as an efficient and reusable catalyst for synthesis of ami-
doalkyl naphthol derivatives.[23] In continuation of our investigations for developing
new synthetic methodologies,[24,25] herein we report a new, convenient, mild, and
efficient procedure for one-pot, three-component synthesis of pyrimidinone deriva-
tives from various aryl aldehydes, cyclopentanone, and urea or thiourea in the pres-
ence of [TEBSA][HSO4] as an effective and recoverable catalyst under solvent-free
conditions (Scheme 1). To the best of our knowledge, this is the first report using
a Brønsted acidic ionic liquid for synthesis of these pyrimidinone derivatives.
EXPERIMENTAL
General Remarks
All reagents were purchased from Merck and Aldrich and were used without
further purification. All yields refer to isolated products after purification. Products
1
were characterized by spectroscopy data [infrared (IR), H NMR, and 13C NMR

2228
A. R. HAJIPOUR ET AL.
Scheme 1. One-pot, three-component reaction of aryl aldehydes, cyclopentanone, and urea=thiourea.
1
spectra] and melting point. H NMR (400 and 500 MHz) and 13C NMR (100 and
125 MHz) spectra were run in dimethylsulfoxide (DMSO-d6) solvent relative to
tetramethylsilane (TMS). IR spectra were recorded on a Shimadzu 435 IR spectro-
photometer and performed using KBr pellets. All melting points were taken on a
Gallenkamp melting-point apparatus and are uncorrected.
General Procedure for the Preparation of Pyrimidinone Derivatives
A mixture of aldehyde (1 mmol), cyclopentanone (1 mmol, 0.084 g), urea
(1.2 mmol, 0.072 g) or thiourea (1.2 mmol, 0.091 g), and [TEBSA][HSO4] (synthesized
according to our previous work[23] (0.15 mmol, 0.050 g) was stirred at 100 ꢀC in oil
bath. The completion of the reaction was monitored with thin-layer chromatography
(TLC; ethyl acetate=cyclohexane, 1=1). After the completion of the reaction, water
(10 mL) was added, and the product was filtered. Then, it was recrystallized from
ethyl alcohol. The products were characterized by spectral data (IR, 1H NMR,
and 13C NMR) and comparison of their physical data with the literature data.
The spectral data of some synthesized compounds are given.
Compound 4a. 1H NMR (DMSO-d6, 400 MHz) d 1.94–2.05 (m, 1H),
2.31–2.41 (m, 1H), 2.78–2.90 (m, 2H), 5.15 (s, 1H), 6.62 (s, 1H), 7.14–7.40 (m,
11H), 8.76 (s, 1H); IR (KBr) cmꢁ1: 3410, 3215, 3118, 2922, 2848, 1672, 1467,
1444, 1353, 1071, 754.
Compound 4b. 1H NMR (DMSO-d6, 400 MHz) d 1.92–2.01 (m, 1H),
2.37–2.45 (m, 1H), 2.65–2.80 (m, 2H), 5.62 (s, 1H), 6.76 (s, 1H), 7.17–7.54 (m,
9H), 9.08 (s, 1H); IR (KBr) cmꢁ1: 3421, 3229, 3115, 2925, 2851, 1677, 1616, 1492,
1459, 1439, 1037, 867, 813, 754.
Compound 4h. 1H NMR (DMSO-d6, 400 MHz) d 1.95–2.05 (m, 1H),
2.38–2.45 (m, 1H), 2.76–2.94 (m, 2H), 3.83 (s, 6H), 5.29 (s, 1H), 6.72 (s, 1H), 7.33
(s, 1H), 7.43 (d, J ¼ 7.6 Hz, 4H), 7.91 (d, J ¼ 7.6 Hz, 2H), 7.98 (d, J ¼ 7.2 Hz, 2H),
8.91 (s, 1H); 13C NMR (100 MHz, DMSO-d6) d 28.76, 29.11, 52.43, 52.56, 57.66,
116.60, 120.15, 127.11, 127.29, 128.36, 129.31, 129.89, 130.09, 136.76, 142.52,
142.90, 148.72, 153.61, 166.45; IR (KBr) cmꢁ1: 3382, 3219, 3119, 2950, 2850,
1688, 1599, 1435, 1282, 1108, 898, 770. Anal. calcd. for C24H22N2O5: C, 68.89; H,
5.30; N, 6.69%; Found: C, 68.80; H, 5.44; N, 6.70%.
Compound 4i. 1H NMR (DMSO-d6, 500 MHz) d 1.95–2.02 (m, 1H),
2.33–2.40 (m, 1H), 2.71–2.85 (m, 2H), 5.17 (s, 1H), 6.62 (s, 1H), 7.13–7.22 (m, 5H),

ACIDIC IONIC LIQUID
2229
7.27–7.38 (m, 4H), 8.77 (s, 1H);13C NMR (125 MHz, DMSO-d6) d 29.00, 57.48,
116.11, 116.15, 116.28, 116.32, 116.51, 119.07, 129.32, 129.38, 130.48, 130.54,
135.10, 136.79, 139.64, 140.41, 153.95, 160.31, 163.30; IR (KBr) cmꢁ1: 3415, 3220,
3123, 2987, 2918, 1681, 1603, 1507, 1455, 1352, 1229, 1157, 1076, 886, 825, 755.
Compound 4l. 1H NMR (DMSO-d6, 500 MHz) d 1.65–2.02 (m, 1H),
2.32–2.38 (m, 1H), 2.68–2.83 (m, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 5.07 (s, 1H), 6.55
(s, 1H), 6.75–6.87 (m, 4H), 7.08 (s, 1H), 7.17 (d, J ¼ 8.5 Hz, 2H), 7.26 (d, J ¼ 8.7 Hz,
2H), 8.65 (s, 1H); IR (KBr) cmꢁ1: 3374, 3214, 3114, 2957, 2932, 2835, 1682, 1604,
1511, 1449, 1349, 1276, 1247, 1176, 1029, 890, 821, 755.
Compound 4m. 1H NMR (DMSO-d6, 500 MHz) d 1.94–2.02 (m, 1H), 2.27
(s, 6H), 2.31–2.39 (m, 1H), 2.73–2.82 (m, 2H), 5.08 (s, 1H), 6.57 (s, 1H), 7.11–7.25
(m, 9H), 8.70 (s, 1H); IR (KBr) cmꢁ1: 3445, 3217, 3119, 2917, 2847, 1687, 1512,
1458, 1348, 1081, 889, 808, 750.
Compound 4o. 1H NMR (DMSO-d6, 400 MHz) d 1.98–2.08 (m, 1H),
2.28–2.35 (m, 1H), 2.85–3.05 (m, 2H), 5.36 (s, 1H), 6.83 (s, 1H), 7.33 (s, 1H),
7.41–7.55 (m, 6H), 7.77–7.97 (m, 8H), 8.89 (s, 1H); 13C NMR (125 MHz, DMSO-d6)
d 29.25, 29.46, 58.60, 117.68, 119.64, 125.77, 125.82, 126.50, 126.87, 127.10, 127.23,
127.63, 128.26, 128.45, 128.71, 129.33, 132.33, 133.41, 133.73, 134.11, 136.25, 137.11,
140.72, 141.62, 154.10; IR (KBr) cmꢁ1: 3433, 3207, 3107, 2923, 2849, 1671, 1615,
1507, 1457, 1360, 1123, 901, 813, 745. Anal. calcd. for C28H22N2O: C, 83.56; H,
5.51; N, 6.96%; Found: C, 83.29; H, 5.68; N, 6.71%.
Compound 4q. 1H NMR (DMSO-d6, 500 MHz) d 1.95–2.02 (m, 1H),
2.34–2.42 (m, 1H), 2.71–2.87 (m, 2H), 5.18 (s, 1H), 6.62 (s, 1H), 7.23 (s, 1H),
7.27–7.34 (m, 4H), 7.41 (d, J ¼ 8.7 Hz, 2H), 7.45 (d, J ¼ 12.0 Hz, 2H), 8.80 (s, 1H);
IR (KBr) cmꢁ1: 3409, 3223, 3122, 2919, 2850, 1673, 1489, 1453, 1406, 1352, 1272,
1090, 1013, 887, 827, 815, 755.
Compound 4r. 1H NMR (DMSO-d6, 400 MHz) d 2.06–2.14 (m, 1H),
2.54–2.61 (m, 1H), 2.82–2.99 (m, 2H), 5.49 (s, 1H), 7.09 (s, 1H), 7.51–7.60 (m,
4H), 8.19 (d, J ¼ 8.4 Hz, 2H), 8.29 (d, J ¼ 7.6 Hz, 2H), 9.19 (s, 1H), 10.31 (s, 1H);
IR (KBr) cmꢁ1: 3387, 3202, 2923, 2848, 1667, 1587, 1518, 1475, 1340, 1181, 1110,
858, 750.
Compound 4s. 1H NMR (DMSO-d6, 400 MHz) d 2.01–2.11 (m, 1H),
2.33–2.42 (m, 1H), 2.62–2.73 (m, 2H), 3.79 (s, 6H), 5.48 (s, 1H), 6.87–7.04 (m,
5H), 7.12–7.21 (m, 2H), 7.25–7.33 (m, 2H), 8.67 (s, 1H), 10.18 (s, 1H); IR (KBr)
cmꢁ1: 3423, 3163, 2962, 2900, 2834, 1666, 1594, 1552, 1488, 1461, 1243, 1194,
1178, 1028, 873, 760.
RESULTS AND DISCUSSION
To obtain the best reaction conditions, the reaction of benzaldehyde (1 mmol,
0.106 g), cyclopentanone (1 mmol, 0.084 g), and urea (1.2 mmol, 0.072 g), was exam-
ined in the presence of 10 mol% of [TEBSA][HSO4] (0.1 mmol, 0.033 g) as catalyst in
refluxing acetonitrile. When the reaction mixture was refluxed for 3 h, undesired
products were observed. In view of the current interest in environmentally benign

2230
A. R. HAJIPOUR ET AL.
catalytic processes, a procedure performed under solvent-free conditions would be
more appreciated, and therefore we decided to carry out this reaction under
solvent-free conditions at 100 ꢀC and found the reaction to be completed after
10 min. Also, this reaction was checked under different temperatures including room
temperature and 80, 100, and 120 ꢀC. The greatest yield in the shortest reaction time
was obtained under solvent-free conditions at 100 ꢀC. The optimized amount of the
catalyst was determined using different molar amounts of [TEBSA][HSO4] such as
0.05, 0.10, 0.15, 0.30, 0.50, and 1 mmol under solvent-free conditions at 100 ꢀC. It
was observed that 15 mol% of [TEBSA][HSO4] was the best of amount of the catalyst
at 100 ꢀC. In addition, excess amounts of cyclopentanone and urea were necessary to
give the best yields. Accordingly, the best yield in the shortest reaction time was
obtained using the molar ratio of 1:1:1.2:0.15 of benzaldehyde, cyclopentanone,
urea, and acidic ionic liquid respectively.
Using these optimized conditions, various pyrimidinone derivatives were pre-
pared by the reaction of various aryl aldehydes with urea or thiourea and cyclopen-
tanone under solvent-free conditions at 100 ꢀC (Table 1, entries 1–20). As
demonstrated in Table 1, aromatic aldehydes were reacted with cyclopentanone
and urea or thiourea to produce the corresponding arylidene heterobicyclic pyrimi-
dinones in good to excellent yields in short reaction times. The aromatic aldehydes
with electron-withdrawing substituents (Table 1, entries 5–9) were converted to the
related pyrimidinone derivatives in shorter reaction times than aromatic aldehydes
Table 1. The one-pot three-component reaction of aryl aldehydes, cyclopentanone and urea=thiourea in
the presence of ionic liquid at 100 ꢀC under solvent-free conditionsa
Entry
Aldehyde (Ar)
X
Product
Time (min)
Yield (%)b
Mp[Ref.]
1
2
C6H5
2-ClC6H4
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
4a
4b
4c
4d
4e
4f
5
10
10
10
5
86
88
91
83
88
82
91
81
90
82
91
90
75
73
80
88
91
78
76
84
207–210[12]
219–222[12]
208–211[12]
217–220[13]
227–230[12]
217–220[12]
225–228[13]
218–222
214–217[12]
227–230[13]
180–183[13]
212–215[12]
210–213[12]
218–221[13]
207–211
3
4-ClC6H4
4-BrC6H4
4
5
3-O2NC6H4
4-O2NC6H4
4-NCC6H4
4-CH3OCOC6H4
4-FC6H4
6
5
7
4g
4h
4i
5
8
5
9
5
10
11
12
13
14
15
16
17
18
19
20
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-MeC6H4
1-Naphthyl
2-Naphthyl
C6H5
4j
10
10
10
10
25
15
10
10
15
5
4k
4l
4m
4n
4o
4p
4q
4r
225–227[12]
208–211[12]
202–206[12]
223–226[12]
208–211[13]
4-ClC6H4
S
4-O2NC6H4
2-MeOC6H4
4-MeC6H4
S
S
4s
S
4t
10
aAldehyde=cyclopentanone=urea or thiourea=IL ¼ 1:1:1.2:0.15.
bYields refer to isolated pure products and all synthesized pyrimidinone derivatives were characterized
by spectral data (IR, 1H and 13C NMR), melting points and comparison with authentic samples.

ACIDIC IONIC LIQUID
2231
Figure 1. Recycling of the Brønsted acidic ionic liquid catalyst.
with electron-donating substituents (Table 1, entries 10–13). It should be mentioned
that ortho-substituted benzaldehydes were converted to the corresponding arylidene
heterobicyclic pyrimidinones with good yields (Table 1, entries 2 and 10). When the
thiourea was used, the yields of the related products were high (Table 1, entries
16–20). It is noteworthy that the reaction times are very short and workup of
products is very convenient. All of the products were isolated by adding water to
the reaction mixture, and the solid compounds were filtered off as pure products.
Furthermore, this procedure is environmentally benign because it uses halogen-free
and recyclable acidic ionic liquid under solvent-free conditions without any organic
solvent.
To investigate the reusability of the [TEBSA][HSO4] catalyst, after each run,
the catalyst was extracted from the reaction mixture according to the previously
reported method[23] and reused for the reaction of benzaldehyde with cyclopenta-
none and urea under solvent-free conditions at 100 ꢀC (Fig. 1). The catalyst could
be employed four times, although the efficiency of the catalyst was gradually
Scheme 2. Mechanism of one-pot, three-component reaction of aryl aldehydes, cyclopentanone, and urea=
thiourea.

2232
A. R. HAJIPOUR ET AL.
decreased. This demonstrates that the acidic ionic liquid ([TEBSA][HSO4]) can
be used as an effective and reusable catalyst for the synthesis of pyrimidinone
derivatives.
As shown in Scheme 2, the reaction of cyclopentanone with aromatic aldehydes
in the presence of an acid catalyst is known to provide a,a0-bis (arylidene)
cyclopentanone (A).[13] Then compound A has reacted with urea or thiourea to
produce pyrimidinone derivatives (Scheme 2).
CONCLUSION
In conclusion, we have demonstrated that an acidic ionic liquid, N-(4-sulfonic
acid) butyl triethyl ammonium hydrogen sulfate ([TEBSA][HSO4]), can be used as a
highly efficient and recyclable catalyst for the one-pot synthesis of pyrimidinone
derivatives by coupling various aromatic aldehydes with cyclopentanone and urea
or thiourea under solvent-free conditions. Use of the relatively nontoxic
(halogen-free) and reusable acidic ionic liquid as an effective green catalyst, high
catalytic efficiency, good yields, short reaction times, and straightforward workup
under green conditions are advantages of this protocol.
ACKNOWLEDGMENTS
We gratefully acknowledge the funding support received for this project from
the Isfahan University of Technology (IUT), the government of Iran (A. R. H.), and
Grants GM 033138, MH 065503, NS 033650 (A. E. R.) from the National Institutes
of Health. Further financial support from the Center of Excellency in Sensor and
Green Chemistry Research (IUT) is gratefully acknowledged.
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