Cation exchange resin (Indion 130): An efficient, environment friendly and recyclable heterogeneous catalyst for the biginelli condensation

Article abstract of DOI:10.2174/157017809790442925

Ion exchange resin catalyzed multicomponent Biginelli reaction is studied for the synthesis of 3,4-dihydropyrimidin-2-ones. Among the various solid acid catalysts Indion-130 was found to be most efficient, recyclable and environmentally benign heterogeneo

Full text of DOI:10.2174/157017809790442925

Letters in Organic Chemistry, 2009, 6, 619-623
619
Cation Exchange Resin (Indion 130): An Efficient, Environment Friendly
and Recyclable Heterogeneous Catalyst for the Biginelli Condensation
Akshay M. Pansuriya, Mahesh M. Savant, Chirag V. Bhuva, Naval Kapuriya, Jyoti Singh and
Yogesh T. Naliapara*
Chemical Research Laboratory, Department of Chemistry, Saurashtra University, Rajkot, 360005, India
Received June 06, 2009: Revised October 20, 2009: Accepted October 20, 2009
Abstract: Ion exchange resin catalyzed multicomponent Biginelli reaction is studied for the synthesis of 3,4-
dihydropyrimidin-2-ones. Among the various solid acid catalysts Indion-130 was found to be most efficient, recyclable
and environmentally benign heterogeneous catalyst regarding reaction time, yield and ease of work up procedure.
Keywords: Biginelli reaction, 3,4-dihydropyrimidin-2-ones, Ion exchange resin, heterogeneous catalyst, Indion-130.
INTRODUCTION
conditions, longer reaction times, tedious workup,
environmental disposal problems and lower yields of the
products, leaving scope for further development of an
efficient and versatile method for Biginelli reaction.
Replacement of conventional, toxic and polluting
Bronsted and Lewis acid catalysts with eco-friendly reusable
solid acid heterogeneous catalysts like acidic zeolites, clays,
sulfated zirconia and ion exchange resins is an area of
current interest [1,2]. The use of solid acid catalyst instead of
liquids includes many advantages, such as reduced
equipment corrosion, ease of product separation, recycling of
the catalyst and environmental acceptability. In the recent
past ion exchange resins in general and styrene-DVB
mattrixed resin sulfonic acid (Indion-130) in particular,
which are strongly acidic and chemically as well as
thermally stable have been found to be excellent catalysts for
a variety of the major organic reactions like esterification,
alkylation, acetalisation, acylation and condensation [3-8].
Growing concern about environmental damage leads to
an urgent requirement for the development of eco-friendly
technology and economic processes. It is of great practical
importance to synthesize DHPM derivatives by the Biginelli
reaction by using a solid acid catalyst, because of the ability
to modify the acid strength, ease of handling, recycling of
the catalyst and environmental compatibility. In view of the
above requirement, and as a part of our program towards
green synthesis, we herein report a single-step and eco-
friendly protocol for the synthesis of DHPM derivatives by
the multicomponent reactions of ꢀ-dicarbonyl compound 1,
aldehydes 2 and urea 3 (Scheme 1) over Indion-130 with
good yields and selectivity.
3,4-Dihydropyrimidinones are well known heterocyclic
units in the realm of natural and synthetic organic chemistry
due to their therapeutic and pharmacological properties
including antiviral, antitumour, antibacterial and anti-
inflammatory activities [9-12]. Biginelli in 1893 reported for
the first time the synthesis of these compounds by the one-
pot cyclocondensation of ethyl acetoacetate, benzaldehyde
and urea in the presence of strong acid [13] however this
method suffers from the drawbacks, such as the lower yields
of the desired products (20-40%) particularly in case of
substituted aldehydes and loss of sensitive functional groups
during the reaction. Therefore, in the recent years several
improved methodologies mainly using lewis acids [14-17],
triflates [18,19], ionic liquids [20], natural HEU type zeolite
[21], polyaniline–bismoclite complex [22], heteropoly acid
[23-28], sulfated zirconia [29], L-proline [30], microwave
assisted methodologies [31,32], and ultrasonic mediated
methods [33] have been reported in the literature. However,
inspite of their potential utility many of the existing methods
suffers from the drawbacks, such as the use of strong acidic
RESULTS AND DISCUSSION
To evaluate the catalytic effect of various ion exchange
resins we started with the model reaction of ethyl
acetoacetate 1a (10 mmol) with benzaldehyde 2a (10 mmol)
and urea 3 (12 mmol) in refluxing ethanol without and with
use of various acidic ion exchange resins as catalysts to
afforded dihydropyrimidine 4a in various yields (Table 1). It
can be seen from Table 1 that Indion-130 was the most
efficient (Table 1, entries 2) among the three solid acidic ion
exchange resins studied. It was found that 0.5 g of Indion-
130 is sufficient to carry out the Biginelli reaction
successfully. An increase in the amount of Indion-130 to
more than 0.5 g showed no substantial improvement in the
yield, whereas the yield is reduced by decreasing the amount
of Indion-130.
Accordingly, a variety of reaction conditions were tried
using Indion-130 as the catalyst to minimize side reactions
and to improve the low yields that have been found even by
using conc. HCl as the catalyst. By adapting a 1:1:1.2 mole
ratio of ethyl acetoacetate, benzaldehyde and urea, the
selective formation of 4a can be achieved without the
*Address correspondence to the author at the Chemical Research
Laboratory, Department of Chemistry, Saurashtra University, Rajkot,
360005, India; Tel: +91 9428036310; Fax: +91 281 2576802;
E-mail: naliaparachem@yahoo.co.in
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

620 Letters in Organic Chemistry, 2009, Vol. 6, No. 8
Pansuriya et al.
R
X
O
R
X
O
O
Indion-130, EtOH
Reflux
R'
NH
+
+
H2N
NH2
R'
CHO
N
H
1
2
3
4
R = H, Me, OMe
R' = Me, OEt, t-OBu, n-OBu, Ph, 4-NO2 PhNH, 4-CF3 PhNH
X = O, S
Scheme 1. Indion-130 resin catalyzed synthesis of various DHPMs.
Table 1. Catalytic Activity of Different Acidic Ion Exchange Resins in Biginelli Condensationa
Entry
Ion Exchange Resin
Reaction Time (h)
Yieldb (%)
1
2
3
4
-
10
3
Trace
94
Indion-130
Amberlyst-15
Nafion-H
5.5
4.5
92.5
85
aReaction Conditions: ethyl acetoacetate (10 mmol), benzaldehyde (10 mmol) and urea (12 mmol) in dry ethanol (10 ml), ion exchange resin (0.5 g) at refluxing temperature.
bIsolated yields.
formation of side products. The effect of solvent on the
reaction was studied (Table 2, entries 1-5) and ethanol was
found to be the best solvent when considering the reaction
yields and environmental damage.
The mechanism of this multicomponent reaction is not
clear at this stage. Similar to the reports by Folkers and
Johnson [34], and Kappe [35] for the Biginelli reaction, the
formation of product 4 may involve an acyl imine
intermediate, the addition of ꢀ-diketone to the iminium ion,
and subsequent cyclodehydration (Scheme 2).
The catalyst could be recovered easily by washing with
ethyl acetate after filtration, and the remaining catalyst could
be used for further runs. No obvious decrease of the yield
was observed for four successive reactions (94, 93, 94 and
92%), demonstrating that the Indion-130 catalyst can be
recycled without significant loss of activity.
CONCLUSION
In conclusion, we have developed a simple, efficient,
environmentally benign and improved protocol for the
synthesis of 3,4-dihydropyrimidin-2-ones/thiones over
Indion-130 as the catalyst with excellent yields. The
simplicity of the system, ease of separation/reuse of the
catalyst due to its heterogeneous nature, excellent yields of
the products and ease of work-up fulfill the triple bottom line
philosophy of green chemistry and make the present
methodology environmentally benign.
Under this optimized reaction condition the scope of the
reaction was then explored. A broad range of structurally
diverse 1,3-dicarbonyl compounds, aldehydes and
urea/thiourea were subjected under this protocol to produce
the corresponding DHPMs (Table 3). A variety of dicarbonyl
compounds could be used successfully. Thiourea was also
used with similar success. The results are presented in Table
3. All the substrates were smoothly converted to their
corresponding DHPMs in excellent yields.
Table 2. Optimisation of the Reaction Conditions for the Synthesis of 4aa
Entry
Catalyst
Solvent
Time (h)
Yield (%)
1
2
3
4
5
Indion-130
Indion-130
Indion-130
Indion-130
Indion-130
EtOH
CH3CN
THF
3
4.5
6
94
85
87
Benzene
Toluene
10
10
Trace
Trace
aAll reactions were conducted at reflux temperature of the solvent used.

Cation Exchange Resin (Indion 130)
Letters in Organic Chemistry, 2009, Vol. 6, No. 8
621
Table 3. Indion-130 Catalyzed Synthesis of Dihydropyrimidin-2(1H)-ones and Thiones
Entry
R’
R
Product
X
Reaction Time (h)
Yielda (%)
1
OEt
Me
H
4a
4b
4c
4d
4e
4f
O
O
O
S
3.0
3.0
94
95
91
87
87
85
90
92
92
84
84
86
2
H
H
3
t-OBu
3.0
4
t-OBu
H
3.0
5
n-OBu
n-OBu
Ph
H
S
3.5
6
4-OMe
H
S
3.5
7
4g
4h
4i
O
O
O
O
O
O
3.25
3.25
3.25
3.75
3.75
3.5
8
Ph
4-Me
4-OMe
H
9
Ph
10
4-NO2 PhNH
4-NO2 PhNH
4-CF3 PhNH
4j
11
12
4-OCH3
H
4k
4l
aIsolated yields.
O
H
O
RCHO
+
H2N
NH2
R
N
NH2
-
SO3H
SO3
O
O
O
R
O
H
O
R'
H+
R'
N
NH2
R
N
H
NH2
H
O
H2O
O
R
R'
NH
= Styrene-DVB matrix
N
H
O
Scheme 2. The proposed mechanism for the formation of pyrimidine.
1
EXPERIMENTAL
8400 spectrophotometer using DRS prob. H NMR spectra
were recorded on a Bruker AVANCE II (400 MHz)
spectrometer in CDCl3. Chemical shifts are expressed in ꢀ
ppm downfield from TMS as an internal standard. Mass
spectra were determined by using direct inlet probe on a
GCMS-QP 2010 mass spectrometer (Shimadzu). Solvents
were evaporated with a BUCHI rotary evaporator.
All solvents and reagents were purchased from Aldrich
and Merck with high-grade quality, and used without any
purification. The Indion-130 was purchased from Ion
Exchange India Ltd. Nafion-H and Amberlyst-15 were
purchased from Aldrich. Melting points were determined on
electro thermal apparatus by using open capillaries and are
uncorrected. Thin-layer chromatography was accomplished
on 0.2-mm precoated plates of silica gel G60 F254 (Merck).
Visualization was made with UV light (254 and 365nm) or
with an iodine vapor. IR spectra were recorded on a FTIR-
General Experimental Procedure
A mixture of ꢁ-diketone (1, 10 mmol), aldehyde (2, 10
mmol), urea/thiourea (3, 12 mmol), and Indion-130 (500 mg)

622 Letters in Organic Chemistry, 2009, Vol. 6, No. 8
Pansuriya et al.
in anhydrous ethanol (10 mL) were refluxed for an
appropriate time as indicated by TLC. The catalyst was
filtered and washed with ethyl acetate until free from organic
material. The solvent was evaporated at reduced pressure and
obtained solid was crystallised from ethanol to afford pure
3,4-dihydropyrimidin-2-one/thione 4 in excellent yields.
(s, 1H, NH), 7.02-7.15 (m, 5H, Ar), 7.24-7.33 (m, 5H, Ar);
MS: m/z = 292.
5-Benzoyl-6-methyl-4-(4-methylphenyl)-3,4-dihydropyri-
midin-2(1H)-one (4h)
1
White; mp 211-213 ˚C; H NMR (400 MHz, CDCl3): ꢀ
2.16 (s, 3H, CH3), 2.32 (s, 3H, CH3) 5.02 (s, 1H, CH), 6.40
(s, 1H, NH), 6.71 (s, 1H, NH), 6.96-7.09 (m, 5H, Ar), 7.18-
7.46 (m, 4H, Ar); MS: m/z = 306.
Ethyl
1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenylpyri-
midine-5-carboxylate (4a)
White; mp 202–204 °C; IR (KBr, cm-1): 3245, 3120,
5-Benzoyl-4-(4-methoxyphenyl)-6-methyl-3,4-dihydropyri-
midin-2(1H)-one (4i)
1
3040, 1730, 1710; H NMR (400 MHz, CDCl3): ꢀ 1.17 (t,
3H, CH3), 2.33 (s, 3H, CH3), 4.04 (q, 2H, OCH2), 5.20 (s,
1H, CH), 7.41-7.54 (m, 5H, Ar), 7.79 (s, 1H, NH), 8.57 (s,
1H, NH); MS: m/z = 260 (M+).
1
White; mp 218-220 ˚C; H NMR (400 MHz, CDCl3): ꢀ
2.33 (s, 3H, CH3), 3.66 (s, 3H, OCH3) 5.01 (s, 1H, CH), 6.04
(s, 1H, NH), 6.47 (s, 1H, NH), 6.67-7.10 (m, 4H, Ar), 7.20-
7.47 (m, 5H, Ar); MS: m/z = 322.
5-Acetyl-3,4-dihydro-6-methyl-4-phenylpyrimidin-2(1H)-
one (4b)
6-Methyl-N-(4-nitrophenyl)-2-oxo-4-phenyl-1,2,3,4-tetra-
hydropyrimidine-5-carboxamide (4j)
White; mp 219–221 °C; IR (KBr, cm-1): 3256, 3056,
1701, 1664; H NMR (400 MHz, CDCl3): ꢀ 2.11 (s, 3H,
CH3), 2.36 (s, 3H, CH3), 5.19 (s, 1H, CH), 7.28-7.43 (m, 5H,
Ar), 7.90 (s, 1H, NH), 8.69 (s, 1H, NH); MS: m/z = 230
(M+).
1
1
White; mp 216-217 ˚C; H NMR (400 MHz, CDCl3): ꢀ
1.68 (s, 3H, CH3), 4.96 (s, 1H, CH), 6.96-7.24 (m, 4H, Ar),
7.33-7.89 (m, 5H, Ar), 8.16 (s, 1H, NH), 8.19 (s, 1H, NH),
9.97 (s, 1H, CONH); MS: m/z = 352.
tert-Butyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-phenylpyri-
midine-5-carboxylate (4c)
4-(4-Methoxyphenyl)-6-methyl-N-(4-nitrophenyl)-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (4k)
White; mp 215–216 °C; IR (KBr, cm-1): 3234, 3089,
1
1
White; mp 210-212 ˚C; H NMR (400 MHz, CDCl3): ꢀ
1707, 1694, 1645; H NMR (400 MHz, CDCl3): ꢀ 1.30 (s,
1.74 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 4.89 (s, 1H, CH),
6.85 (d, 2H, Ar), 7.19 (d, 2H, Ar), 7.87 (m, 2H, Ar), 8.17 (m,
2H, Ar), 8.54 (s, 1H, NH), 8.90 (s, 1H, NH), 10.21 (s, 1H,
CONH); MS: m/z = 382.
9H, t-Bu), 2.18 (s, 3H, CH3), 5.10 (s, 1H, CH), 6.87–7.21
(m, 5H, Ar), 7.74 (s, 1H, NH), 9.05 (s, 1H, NH); MS: m/z =
288 (M+).
tert-Butyl 1,2,3,4-tetrahydro-6-methyl-4-phenyl-2-thioxopy-
rimidine-5-carboxylate (4d)
6-Methyl-2-oxo-4-phenyl-N-[4-(trifluoromethyl)phenyl]-
1,2,3,4-tetrahydropyrimidine-5-carboxamide (4l)
Pale-Yellow; mp 206–207 °C; IR (KBr, cm-1); 3185,
1
1
White; mp 208-210 ˚C; H NMR (400 MHz, CDCl3): ꢀ
3050, 1710, 1554; H NMR (400 MHz, CDCl3): ꢀ 1.26 (s,
1.64 (s, 3H, CH3), 5.46 (s, 1H, CH), 7.22-7.50 (m, 4H, Ar),
7.67-8.09 (m, 5H, Ar), 8.45 (s, 1H, NH), 9.98 (s, 1H, NH),
10.14 (s, 1H, CONH); MS: m/z = 375.
9H, t-Bu), 2.22 (s, 3H, CH3), 5.09 (s, 1H, CH), 7.24-7.48
(m, 5H, Ar), 9.57 (s, 1H, NH), 10.19 (s, 1H, NH); MS: m/z =
304 (M+).
n-Butyl 1,2,3,4-tetrahydro-6-methyl-4-phenyl-2-thioxopyri-
midine-5-carboxylate (4e)
ACKNOWLEDGEMENTS
Pale-yellow; mp 206-208 ˚C; IR (KBr, cm-1): 1180,
Authors are thankful for the facilities & grants given
under UGC-SAP for the Department Research Support
(DRS) and the Department of Science & Technology (DST)
New Delhi for Fund for the Improvement of Science &
Technology (FIST) and the Department of Chemistry for
providing laboratory facilities.
1
1427,1456, 1707, 2868, 2976, 3215; H NMR (400 MHz,
CDCl3): ꢀ 0.84 (t, 3H, CH3), 1.20 (m, 2H, CH2), 1.47 (m,
2H, CH2), 2.34 (s, 3H CH3), 4.02 (m, 2H, CH2), 5.35 (s, 1H,
CH), 7.29 (m, 5H, Ph), 8.17 (s, 1H, NH), 8.76 (s, 1H, NH);
MS: m/z = 304 (M+).
n-Butyl 1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-6-methyl-
2-thioxopyrimidine-5-carboxylate (4f)
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Pale-yellow; mp 186-188 ˚C; IR (KBr, cm-1): 1462, 1560,
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1H, CH), 6.83 (d, 2H, Ph), 7.20 (d, 2H, Ph), 8.91 (s, 1H,
NH), 9.54 (s, 1H, NH); MS: m/z = 334.
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