Silica-supported ZnCl2 - A highly active and reusable heterogeneous catalyst for the one-pot synthesis of dihydropyrimidinones-thiones

Article abstract of DOI:10.1139/V07-018

A novel silica-supported zinc chloride catalyst was prepared and investigated for the Biginelli reaction. The key features of the catalyst include rapid reaction with 100% conversion of aldehyde, good catalyst recyclability, and high stability under the r

Full text of DOI:10.1139/V07-018

197
Silica-supported ZnCl2 — A highly active and
reusable heterogeneous catalyst for the one-pot
synthesis of dihydropyrimidinones–thiones
Raman Gupta, Monika Gupta, Satya Paul, and Rajive Gupta
Abstract: A novel silica-supported zinc chloride catalyst was prepared and investigated for the Biginelli reaction. The
key features of the catalyst include rapid reaction with 100% conversion of aldehyde, good catalyst recyclability, and
high stability under the reaction conditions (passes hot filtration test successfully). A low catalyst loading (12 mol% of
ZnCl2) was required to achieve a quantitative reaction. Other catalysts such as SiO2–AlCl2, SiO2–AlCl2–ZnCl2 were
also prepared and their activity was compared with SiO2–ZnCl2 for the Biginelli reaction.
Key words: silica gel, zinc chloride, Biginelli compounds, heterogeneous catalysis, reusability.
Résumé : On a préparé un nouveau catalyseur de chlorure de zinc supporté par du gel de silice et on a étudié son uti-
lité dans la réaction de Biginelli. Le catalyseur est caractérisé par une vitesse de réaction rapide avec une conversion
de l’aldéhyde à 100%, une bonne facilité de récupération du catalyseur et une grande stabilité dans les conditions de la
réaction puisqu’il passe avec succès le test de la filtration à chaud. La charge de catalyseur nécessaire pour obtenir
une réaction quantitative est faible (12 moles% de ZnCl2) est faible. On a aussi préparé d’autres catalyseurs, tel le
SiO2–AlCl2, SiO2–AlCl2–ZnCl2 et on a comparé leur activité avec celle du SiO2–ZnCl2 pour la réaction de Biginelli.
Mots-clés : gel de silice, chlorure de zinc, composés de Biginelli, catalyse hétérogène, possibilité de réutilisation.
[Traduit par la Rédaction] Gupta et al. 201
Introduction
Zinc chloride, an inexpensive and easily available Lewis
acid catalyst, has been widely used in organic synthesis.
However, it suffers from the serious drawback of being
highly hygroscopic in nature so that it always needs to be
fused prior to use and requires highly anhydrous conditions;
it also produces exogenous wastes. These issues make the
work-up process cumbersome.
Pyrimidinones and their derivatives are medicinally im-
portant as calcium channel blockers and also are antiviral,
antibacterial, antihypertensive, and α-1a-antagonists (6). The
betzelladine alkaloids containing the dihydropyrimidine core
unit are particularly notable, as they were recently found to
be potent HIV gp-120-CD4 inhibitors (7).
The Biginelli reaction, which was discovered more than a
century ago (8), is one of the most important reactions in the
synthesis of dihydropyrimidinones (DHPMs). The classical
Biginelli reaction of an aldehyde, β-ketoester, and urea or
thiourea requires strongly acidic conditions. Low to moder-
ate yields are usually obtained, in particular when substi-
tuted aromatic or aliphatic aldehydes are employed.
Recently, many methods for preparing DHPMs have been
developed, and the Biginelli reaction has gained particular
importance for ongoing research programs (9). However,
many of these methods have drawbacks such as long reac-
tion times, low product yields, harsh reaction conditions, the
use of stiochiometric reagents, difficulties in work-up, the
use of toxic and inflammable solvents, and incompatibility
with other functional groups in the molecules. Therefore,
there is a need to develop a heterogeneous catalyst for the
synthesis of Biginelli compounds that is mild, reusable, eas-
Green chemistry, the design of chemical products and pro-
cesses that reduce or eliminate the use and generation of
hazardous substances (1), is an overreaching approach that is
applicable to all aspects of chemistry. From feedstock to sol-
vents, synthesis, and processing, green chemistry actively
seeks ways to produce materials in a way that is more be-
nign to human health and the environment (2). The area of
catalysis is sometimes referred to as a “fundamental pillar”
of green chemistry (3).
The development of heterogeneous catalysts for fine
chemical synthesis has become a major area of research
recently, as the potential advantages of these materials (sim-
plified recovery and reusability and the potential for incor-
poration in continuous reactors and microreactors) over
homogeneous systems can make a major impact on the envi-
ronmental performance of a synthesis (3, 4). The majority of
these novel catalysts are based on silicas, primarily since sil-
ica displays many advantageous properties such as excellent
stability (chemical and thermal), high surface area, good ac-
cessibility, and catalytic materials can be robustly anchored
onto its surface to provide catalytic centres (5).
Received 13 October 2006. Accepted 23 February 2007.
Published on the NRC Research Press Web site at
http://canjchem.nrc.ca on 21 March 2007.
R. Gupta, M. Gupta, S. Paul,1 R. Gupta. Department of
Chemistry, University of Jammu, Jammu 180 006, India.
1Corresponding author (e-mail: paul7@rediffmail.com).
Can. J. Chem. 85: 197–201 (2007)
doi:10.1139/V07-018
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198
Can. J. Chem. Vol. 85, 2007
Figure 1. Probable structure of covalently anchored silica-
supported zinc chloride.
ily separable, compatible with acid sensitive functional
groups, and cost-effective.
Keeping in view the biological importance of Biginelli
compounds and that of heterogeneous catalysis in academia
and industry, we wish to report here the application of heter-
ogeneous catalysis to the synthesis of Biginelli compounds
using reusable silica-supported zinc chloride (12 mol% of
Zn as determined by atomic absorption spectrophotometer).
Recently, ZnCl2 has been reported for the synthesis of
Biginelli compounds (10).
Results and discussion
Silica-supported zinc chloride was prepared by refluxing
ZnCl2 (3 g) with activated K100 silica gel (10 g) in sodium
dried toluene for 10 h; at this temperature, some of the
ZnCl2 may react with the surface hydroxyl groups to create
highly acidic species chemically bonded to the support. Af-
ter separation of the catalyst by filtration under reduced
pressure, it was dried at 110 °C for 12 h and stored in a des-
iccator. It could be used for several months. The proposed
structure of the catalyst in which ZnCl2 reacted with the sur-
face hydroxyl groups of the silica gel is shown in Fig. 1. The
other catalysts, SiO2–AlCl2 (11) (anhydr. AlCl3 3 g,
SiO2 10 g) and SiO2–AlCl2–ZnCl2 (AlCl3 1.5 g, ZnCl2 1.5 g,
SiO2 10 g) were prepared by a similar procedure and stored
in a desiccator. The stability of these catalysts was deter-
mined by thermogravimetric analysis (TGA). For SiO2–
ZnCl2, the initial weight loss at 80 °C followed by 95-
150 °C and 285-310 °C may be due to the loss of residual
solvent and HCl, which may have formed during the reac-
tion of ZnCl2 with silica gel. Up to 310 °C, there is no possi-
bility of loss of physiosorbed and chemisorbed ZnCl2 from
the surface of silica gel, so it is safe to carry out the reaction
at 80 °C.
To optimize the reaction conditions, the reaction of 4-
methoxybenzaldehyde, ethyl acetoacetate, and urea was se-
lected as the model to examine the effects of catalyst (5–20
mol%), different solvents (methylene chloride, toluene, and
acetonitrile), and reagents at different temperatures (RT, 50,
80, and 100 °C). The reactions were monitored by TLC and
all yields reported in Tables 1 and 2 are isolated yields. The
best conditions employ 0.12:1:1:1 mole ratios of catalyst
(12 mol% of Zn, 0.2 g), 4-methoxybenzaldehyde, ethyl
acetoacetate, and urea at 80 °C for 7 h using acetonitrile as
the solvent.
Using optimized conditions, the reactions of various aro-
matic–heterocyclic aldehydes, ethyl acetoacetate, and urea or
thiourea were investigated (Scheme 1). It was found that all
the reactions proceeded smoothly to give the corresponding
3,4-dihydropyrimidin-2-(1H)-ones–thiones in high yields
(Table 1). Cinnamaldehyde, which showed poor yield in the
absence of catalyst and 81% yield in the presence of very
expensive lanthanide triflate (12), gave the corresponding
pyrimidinones–thiones 4g and 4p in 85% and 87% isolated
yields. Both aromatic aldehydes bearing electron-donating
groups such as 4-OMe (4b, 92%) and electron-withdrawing
groups such as 4-NO2 (4d, 91%) gave excellent yields. More
importantly, 2-furfuraldehyde, which normally gives low
yield of products (9c, 13) afforded the desired products in
86% (4f) and 82% (4o) yields in 8.5 and 8 h, respectively. 2-
Scheme 1.
Chloro-3-formylquinolines gave low yield of products (4i
20%, 4r 32%). The mildness of the procedure makes this
procedure very selective as the chlorine atoms in 4h, 4i, 4q,
and 4r remain unaffected under the reaction conditions. The
results are summarized in Table 1, which clearly indicates
the generality and scope of the reaction with respect to vari-
ous aromatic, heterocyclic, and unsaturated aldehydes.
The activity of the catalyst SiO2–ZnCl2 was also com-
pared with unsupported anhydr. ZnCl2 (0.0408 g, 12 mol%),
AlCl3 (0.0399 g, 12 mol%), and other silica supported cata-
lysts SiO2–AlCl2 (0.185 g, 12 mol% of Al) and SiO2–AlCl2–
ZnCl2 (0.2 g, 5.5 mol% of Zn, 7.5 mol% of Al) taking 4-
methoxybenzaldehyde, ethyl acetoacetate, and urea to give
3,4-dihydropyrimidinone 4b as the model reaction, using
acetonitrile as solvent and 80 °C as the reaction temperature.
The results are summarized in Table 2. Among all catalysts,
SiO2–ZnCl2 was found to be the most active, stable, and re-
usable catalyst.
To verify whether the reaction was catalyzed by SiO2-
ZnCl2 or by the silica gel used for preparing the catalyst, we
carried out the reaction (in the case of product 4b) using ac-
tivated silica gel (0.2 g) under similar conditions as with
SiO2-ZnCl2. It was found that 4b was formed in 23% yield
(based on 1H NMR) in 7 h. This clearly indicates that the re-
action was catalyzed by SiO2-ZnCl2.
When using a supported metal catalyst, two important is-
sues need to be addressed to qualify this to be a purely het-
erogeneous catalyst. One is the possibility that some active
metal migrates from the solid to the liquid phase and that
this leached metal salt would become responsible for a sig-
nificant part of the catalytic activity. To rule out the contri-
bution of the homogeneous catalysis in the results shown in
Table 1, the reaction of 4-methoxybenzaldehyde, ethyl
acetoacetate, and urea was carried out in the presence of
SiO2–ZnCl2 until the conversion was 30% (1H NMR yield,
after 1 h), and at that point the solid was filtered off at the
© 2007 NRC Canada

Gupta et al.
199
Table 1. Silica-supported zinc chloride catalyzed synthesis of 3,4-dihydropyrimidinones–thiones (4a–4r) at 80 °C using acetonitrile as
solvent.
Compound
R
X
Time (h)
Yield (%)
mp, lit. mp
4a
4b
4c
4d
4e
4f
C6H5
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
4-HO-3-MeOC6H3
2-Furfuryl
Ph-CH=CH
O
O
O
O
O
O
O
O
8.5
7
7
7.5
9
8.5
9
90
92
87
91
92
86
85
70
207 to 208, 209 to 210 (10)
203 to 204, 201 to 202 (14)
215 to 216, 216 to 217 (10)
208 to 209, 211–213 (10)
232 to 233, 231 to 232 (14)
205 to 206, 208–210 (10)
241 to 242, 245 to 246 (10)
159–161
4g
4ha
8.5
4ia
O
10
20
>230, >265 (15)
4j
4k
4l
4m
4n
4o
4p
4qa
C6H5
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
4-HO-3-MeOC6H3
2-Furfuryl
Ph-CH=CH
S
S
S
S
S
S
S
S
8
83
88
87
88
83
82
87
72
193 to 194, 191–193 (16)
151 to 152, 150–153 (16)
213 to 214, 207 to 208 (17)
205–207
149–151, 147–149 (18)
186–188, 183 (dec, 18)
242 to 243, 243–245 (18)
165–167
8.5
8.5
8
10
8
10.5
9.2
4ra
S
10
32
217–219
aIn case of compounds 4h, 4i, 4q, and 4r catalysts, 16 mol% was used.
bYield refers to the isolated yield from three experimental runs.
Table 2. Effect of various catalysts in the synthesis of 3,4-
dihydropyrimidinone (4b) from 4-methoxybenzaldehyde, ethyl
acetoacetate, and urea at 80 °C using acetonitrile as solvent.
sulting from complexation with both starting materials and
products or microscopic changes in the structure of the cata-
lyst. However, AAS analysis after the 4th use indicates that
there is no change in the amount of Zn from the fresh to the
4th use of the catalyst.
Catalyst
Time (h)
Yield (%)a
No catalyst
ZnCl2
AlCl3
SiO2–ZnCl2
SiO2–AlCl2
7
7
7
7
7
7
No reaction
55
20
92
35
65
Experimental
General
b
Silica gel (K100, 0.063–0.200 mm) was purchased from
Merck (Germany) and anhydrous zinc chloride was pur-
chased from Merck (India) and fused prior to use. All melt-
ing points were determined on a Perfit melting point
b
SiO2–ZnCl2–AlCl2
aIsolated yield of the purified products based on separation by column
chromatography.
bCatalysts SiO2–AlCl2 and SiO2–ZnCl2–AlCl2 were prepared by the sim-
ilar procedure given in the experimental section for SiO2–ZnCl2.
1
apparatus and are uncorrected. H NMR spectra were regis-
tered on a Bruker DPX-200 NMR spectrometer (200 MHz)
in CDCl3 – CDCl3 + DMSO-d6 using tetramethylsilane as
internal standard. The IR spectra were recorded using KBr
disc on PerkinElmer FTIR spectrophotometer. Mass spectral
data were recorded on Jeol JMS D-300 mass spectrometer at
70 ev. Thermal analysis was carried out on DTG-60
Shimadzu thermal analyzer with heating rate of 10 °C/sec
and the amount of metal content was determined on a double
beam atomic absorption spectrophotometer GBC 932 AB
(manufactured in Australia). The catalyst was stirred in dil.
HCl for 10 h and the resulting filtrate was subjected to
atomic absorption spectrophotometric analysis. Elemental
analysis was carried out on Leco-CHNS-932 elemental ana-
lyzer manufactured by Leco corporation (USA).
reaction temperature. The liquid was then transferred to an-
other flask and the reaction was continued for the remaining
time, but no further significant formation of product was ob-
served. This indicates that no active species was present in
the supernatant and that the observed catalysis is purely het-
erogeneous. The second important point concerning hetero-
geneous catalysis is the deactivation and reusability of the
catalyst. To test this, a series of 4 consecutive runs of the re-
action of 4-methoxybenzaldehyde, ethyl acetoacetate, and
urea with SiO2–ZnCl2 was carried out (1st use: 92% isolated
yield after 7 h; 2nd use: 85% isolated yield after 8.5 h; 3rd
use: 78% isolated yield after 12 h; 4th use: 67% isolated
yield after 16 h). These results demonstrate that there is a
decrease in the activity of the catalyst after every use. This
may be due to either the deactivation of active centres re-
Preparation of activated silica
K100 silica gel (10 g) was added to a round-bottomed
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200
Can. J. Chem. Vol. 85, 2007
flask (250 mL) containing a 1:1 mixture of conc. HCl and
distilled water (100 mL). The reaction mixture was refluxed
in an oil bath for 24 h. On cooling, silica gel was filtered off
and washed with excess distilled water until the washings
were neutral. It was dried in an oven at 110 °C for 15 h.
CH2CH3), 2.34 (s, 3H, CH3), 4.10–4.23 (q, 2H, J = 7.1 Hz,
CH2CH3), 5.43 (d, 1H, C4-H), 6.15 (d, 1H, CH=), 7.47 (d,
2H, ArH), 7.95 (d, 2H, ArH), 8.02 (bs, 1H, NH), 9.42 (bs,
1H, NH). m/z: 355 (M+), 358 (M+2). Anal. calcd. for
C16H16Cl2N2O3: C 54.10, H 4.54, N 7.88; found: C 54.07, H
4.51, N 7.86.
General procedure for the preparation of silica-
supported zinc chloride
To a mixture of anhydrous zinc chloride (3 g) and acti-
Ethyl 4-(2-chloro-3-quinolinyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-one-5-carboxylate (4i)
IR (KBr, cm–1) νmax: 3438, 3312, 3227, 2973, 1704, 1648,
vated silica (10g, K100) in
a round-bottomed flask
1
1562, 1446. H NMR (DMSO-d6) δ: 0.95–1.15 (t, 3H, J =
(100 mL), sodium dried toluene (60 mL) was added and the
reaction mixture was refluxed for 10 h. SiO2–ZnCl2 was ob-
tained as a free-flowing powder after filteration under re-
duced pressure and dried at 110 °C for 12 h. It was stored in
a desiccator and could be used for several months without
loss of activity.
7.2 Hz, CH2CH3), 2.36 (s, 3H, CH3), 3.95–4.15 (q, 2H, J =
7.2 Hz, CH2CH3), 5.70 (s, 1H, C4-H), 7.60–7.90 (m, 4H,
ArH), 8.04 (s, 1H, ArH), 8.30 (bs, 1H, NH), 9.35 (bs, 1H,
NH). m/z: 344 (M+).
Ethyl 6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-
thione-5-carboxylate (4j)
General procedure for the preparation of 3,4-
dihydropyrimidinones–thiones
IR (KBr, cm–1) νmax: 3412, 3312, 3174, 3096, 2967, 1667,
1
1610, 1575. H NMR (DMSO-d6) δ: 1.02–1.18 (t, 3H, J =
To a mixture of aldehyde 1 (2.5 mmol), ethyl acetoacetate
2 (2.5 mmol), and urea or thiourea 3 (2.5 mmol) in a round-
bottomed flask (100 mL), acetonitrile (15 mL) was added.
The reaction mixture was stirred at RT for 5 min and then
the catalyst SiO2–ZnCl2 (200 mg, 12 mol% of Zn) was
added and the stirring was continued at 80 °C in an oil bath
for an appropriate time (Table 1). After completion of the re-
action (monitored by TLC), the reaction mixture was filtered
off. The product was obtained after removal of the solvent
under reduced pressure and crystallization from EtOAc –
petroleum ether. The residue was washed with acetonitrile
followed by methylene chloride and dried at 110 °C for 5 h.
It could be used further for carrying out the reaction.
7.1 Hz, CH2CH3), 2.32 (s, 3H, CH3), 4.02–4.21 (q, 2H, J =
7.1 Hz, CH2CH3), 5.50 (s, 1H, C4-H), 7.15–7.35 (m, 5H,
ArH), 8.90 (bs, 1H, NH), 9.95 (bs, 1H, NH). m/z: 276 (M+).
Ethyl 6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-thione-5-carboxylate (4m)
IR (KBr, cm-1) νmax: 3429, 3218, 3142, 3018, 1693, 1558.
1H NMR (DMSO-d6) δ: 1.10–1.22 (t, 3H, J = 7.2 Hz,
CH2CH3), 2.38 (s, 3H, CH3), 4.07–4.23 (q, 2H, J = 7.1 Hz,
CH2CH3), 5.61 (s, 1H, C4-H), 7.43–7.64 (d, 2H, ArH),
8.14–8.30 (d, 2H, ArH), 8.3 (bs, 1H, NH), 9.63 (bs, 1H,
NH). m/z: 321 (M+). Anal. calcd. for C14H15N3O4S: C 52.32,
H 4.70, N 13.07, S 9.97; found: C 52.29, H 4.68, N 13.05, S
9.94.
1
The structures of the products were confirmed by IR, H
NMR, and mass spectral data, and comparison with authen-
tic samples prepared according to the literature methods.
Ethyl 4-[2-chloro-2-(4-chlorophenyl)vinyl]-6-methyl-3,4-
dihydropyrimidin-2(1H)-thione-5-carboxylate (4q)
IR (KBr, cm–1) νmax: 3422, 3311, 3218, 2996, 1658, 1556,
Spectral data of selected compounds
1
1445. H NMR (CDCl3) δ: 1.08–1.17 (t, 3H, J = 7.1 Hz,
Ethyl 6-methyl-4-(4-methoxyphenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (4b)
CH2CH3), 2.39 (s, 3H, CH3), 4.07–4.18 (q, 2H, J = 7.2 Hz,
CH2CH3), 5.52 (d, 1H, C4-H), 6.21 (d, 1H, CH=), 7.54 (d,
2H, ArH), 8.04 (d, 2H, ArH), 8.22 (bs, 1H, NH), 9.53 (bs,
1H, NH). m/z: 371 (M+), 374 (M + 2). Anal. calcd. for
C16H16Cl2N2O2S: C 51.76, H 4.34, N 7.54, S 8.63; found: C
51.73, H 4.31, N 7.52, S 8.59.
IR (KBr, cm–1) νmax: 3390, 3243, 3106, 2958, 1706, 1651,
1
1278, 1088. H NMR (DMSO-d6) δ: 1.01–1.20 (t, 3H, J =
7 Hz, CH2CH3), 2.30 (s, 3H, CH3), 3.80 (s, 3H, OCH3),
3.90–4.20 (q, 2H, J = 7 Hz, CH2CH3), 5.60 (s, 1H, C4-H),
6.80–6.90 (d, 2H, J = 7.2 Hz, ArH), 7.15–7.25 (d, 2H, J =
7.2 Hz, ArH), 7.65 (bs, 1H, NH), 9.17 (bs, 1H, NH). m/z:
290 (M+).
Ethyl 4-(2-chloro-3-quinolinyl)-6-methyl-3,4-
dihydropyrimidin-2(1H)-thione-5-carboxylate (4r)
IR (KBr, cm–1) νmax: 3423, 3343, 3232, 2978, 1678, 1560,
1
Ethyl 6-methyl-4-(4-nitrophenyl)-3,4-dihydropyrimidin-
2(1H)-one-5-carboxylate (4d)
1460. H NMR (DMSO-d6) δ: 1.05–1.23 (t, 3H, J = 7.2 Hz,
CH2CH3), 2.41 (s, 3H, CH3), 3.98–4.21 (q, 2H, J = 7.0 Hz,
CH2CH3), 5.73 (s, 1H, C4-H), 7.63–7.90 (m, 4H, ArH), 8.08
(s, 1H, ArH), 8.43 (bs, 1H, NH), 9.55 (bs, 1H, NH). m/z:
361 (M+), 363 (M + 2). Anal. calcd. for C17H16ClN3O2S: C
56.42, H 4.45, N 11.61, S 8.86; found: C 56.39, H 4.41, N
11.60, S 8.84.
IR (KBr, cm–1) νmax: 3449, 3258, 3184, 3015, 1686, 1648,
1
1582. H NMR (DMSO-d6) δ: 1.05–1.20 (t, 3H, J = 7 Hz,
CH2CH3), 2.35 (s, 3H, CH3), 4.00– 4.20 (q, 2H, J = 7 Hz,
CH2CH3), 5.45 (s, 1H, C4-H), 7.40– 7.60 (d, 2H, J = 7.2 Hz,
ArH), 8.10– 8.25 (d, 2H, J = 7.2 Hz, ArH), 7.69 (bs, 1H,
NH), 9.27 (bs, 1H, NH). m/z: 305 (M+).
Conclusion
Ethyl 4-[2-chloro-2-(4-chlorophenyl)vinyl]-6-methyl-3,4-
dihydropyrimidin-2(1H)-one-5-carboxylate (4h)
In conclusion, we have developed a mild, simple, cost-
effective, and green procedure for the synthesis of
dihydropyrimidinones using reusable SiO2–ZnCl2 under het-
IR (KBr, cm–1) νmax: 3408, 3318, 3232, 2986, 1702, 1652,
1
1560, 1453. H NMR (CDCl3) δ: 1.12–1.22 (t, 3H, J = 7 Hz,
© 2007 NRC Canada

Gupta et al.
201
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Acknowledgement
One of the authors (MG) thanks the Council of Scientific
and Industrial Research (CSIR), New Delhi, for awarding
Senior Research Fellowship (SRF).
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