Controllable selectivity in Biginelli and Hantzsch reactions using nanoZnO as a structure base catalyst

Article abstract of DOI:10.1016/j.molcata.2012.12.005

Preparative nanoZnO and ZnO have been found as reusable catalysts for either condensation or dissociation of urea to ammonia and controllable selectivity in the Biginelli and Hantzsch reactions. The feasibility of urea dissociation to ammonia and switchin

Full text of DOI:10.1016/j.molcata.2012.12.005

Journal of Molecular Catalysis A: Chemical 370 (2013) 117–122
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Controllable selectivity in Biginelli and Hantzsch reactions using nanoZnO as a
structure base catalyst
Fatemeh Tamaddon∗, Somayeh Moradi
Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-741, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2012
Received in revised form 5 December 2012
Accepted 9 December 2012
Available online 20 December 2012
Preparative nanoZnO and ZnO have been found as reusable catalysts for either condensation or dissocia-
tion of urea to ammonia and controllable selectivity in the Biginelli and Hantzsch reactions. The feasibility
of urea dissociation to ammonia and switching of the selectivity of heterocyclization for DHPMs to DHPs
over various metal oxides has been comparatively investigated. In the presence of nanoZnO and ZnO,
direction of the MCR reaction in either Biginelli or Hantzsch way is possible by choice of the reaction con-
ditions. Biginelli reaction occurs at 60 ◦C under solvent-free conditions, while Hantzsch reaction occurs
in water at ∼120–140 ◦C or under microwave irradiation using 5 mol% nanoZnO or 10 mol% ZnO.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Dissociation of urea
DHPMs
14-DHPs
NanoZnO
Biginelli
Hantzsch
1. Introduction
However, by proper choice of catalyst and conditions, dissociation
or condensation of urea and hence Biginelli or Hantzsch reaction
Multicomponent reactions (MCR) have performed quantitative
revolutions in molecular architecting, access to multifunctional
molecules, and combinatorial chemistry in recent years [1–3]. Big-
inelli and Hantzsch reactions are of great interest MCRs which
in a single step afford dihydropyrimidin-2(1H)-ones (DHPMs) and
1,4-dihydropyridines (DHPs) as essential pharmaceuticals for cal-
cium channel stimulating [4–8]. Although Biginelli and Hantzsch
reactions are familiar in two components and their products are
aza-analogous, they are varied in nitrogen sources. Urea, thiourea,
and guanidine are used in the Biginelli reaction, while ammonia,
ammonium salts, or atypically urea are nitrogen providers of DHPs
in the Hantzsch reaction [9–11]. To improve both reactions, var-
ious acidic or basic catalysts and energy sources have been well
documented [12–19,9,20–22].
In spite of the similarity in the starting materials and opportu-
nity of the competition between Biginelli and Hantzsch reactions
the feature of their borderlines is not clear [21]. According to the
proposed mechanisms for base- or acid-catalyzed Biginelli reac-
tion, urea, as a very cheap nitrogen source, condenses with other
components to produce the DHPM products. Urea can be also
dissociated to ammonium salts or ammonia at acidic or basic
conditions [23,24], and thus the opportunity of the competition
between Biginelli and Hantzsch reactins increases in these cases.
would be optioned. Where condensation of urea with aldehyde
and 1,3-dicarbonyl components occurs slower than dissociation
of urea, the Biginelli reaction turns to the Hantzsch reaction and
a divergent switching for Hantzsch/Biginelli is possible by utilize
of urea as nitrogen provider of the DHP ring in Hantzsch reac-
tion.
Metal oxide promoted organic transformations is a proficient
subdivision of heterogeneous reactions which were highlighted by
the use of nanosized metal oxide catalysts [25]. Stability under
reaction conditions, dual acid/base properties of metal oxides,
reusability, non toxicity, and non-hygroscopic properties make
metal oxides much favorite catalysts. Zinc oxide (ZnO) is a low-
priced metal oxide which professionally catalyzes various organic
transformations [26–32]. Due to the easiness of preparation, vari-
ous nanoZnO such as nanopowder, nanofluids and nanoparticles
have been artificially prepared and used as reaction promoters
[29–33]. Recently, we have prepared and used nanoZnO as efficient
catalysts in organic reactions which in adsorption of the start-
ing materials on the ZnO surface together with the coordination
of accessible zinc cation to functional groups led to the activa-
tion and enhancement of the reaction rates and yields [27–29,34].
The powerful interaction of urea with ZnO [23] and efficient
microwave-assisted dissociation of urea over ZnO [24] prompted
us to evaluate the catalyst-control dissociation/condensation of
urea and switching of the Biginelli/Hantzsch reactions. This can be
also helped to verify the borderlines of these well-known MCRs
(Scheme 1).
∗
Corresponding author. Tel.: +98 351 8122666; fax: +98 351 8210644.
E-mail address: ftamaddon@yazduni.ac.ir (F. Tamaddon).
1381-1169/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2012.12.005

118
F. Tamaddon, S. Moradi / Journal of Molecular Catalysis A: Chemical 370 (2013) 117–122
R1
2.3. General procedure for the nanoZnO-catalyzed Hantzsch
reaction
H
H3C
RO2C
H3C
O
O
Condensation with urea
NH
R1CHO
+
DHPM
ZnO or nanoZnO (5 mol%)
N
H
O
To a mixture of aldehyde (2 mmol), ethyl acetoacetate (4 mmol),
RO
and urea (1.2 mmol) in water (1 mL) was added nanoZnO
(0.5 mmol) or ZnO (1 mmol) and the mixture was irradiated by
microwave or stirred at 140 ◦C for the given times (Table 2). After
completion of the reaction (TLC monitoring), EtOAc (2× 10 mL) was
added and the precipitated catalyst was centrifuged and filtered off.
The resulting organic solution was washed with 10% NaHCO3 and
brine, dried over anhydrous Na2SO4, and evaporated to give the
desired DHP product. The structure of products was assigned by
analysis of their IR, 1H NMR, 13C NMR spectra and comparison to
authentic samples.
R = Me, Et R1=Ar, H, Alkyl
R1
X
CO2R
RO2C
H3C
Dissociation of urea and in situ generation of NH3
ZnO or nanoZnO (0.5 mmol), Water, >120 °c or MW
DHP
CH3
N
H
Scheme 1. Controllable Biginelli/Hantzsch reactions using nanoZnO catalyst.
2. Experimental
2.4. Reusability of catalyst
2.1. Preparation of nanoZnO
ZnO or nanoZnO was regenerated by washing with EtOAc and
drying at 300 ◦C or microwave irradiation and reused for three con-
secutive times in both Biginelli and Hantzsch reactions with no
significant decreasing in reaction yields (Table 3).
NanoZnO was prepared through the previously reported proce-
dures [28–30]. Zinc acetate dihydrate (5.5 g) was dissolved in 50 mL
of deionized water and then solid NaOH (16 g) was added slowly
into the solution under magnetic stirring at room temperature. A
transparent Zn(OH)4 solution was formed. Then 2 mL of ionic liquid
1-butyl-3-methylimidazolium bis (trifluoromethylsulfonyl) imide
([bmim][NTf2]) was added to 3 mL of the above solution. The sus-
pension was put into a domestic microwave oven (850 W) in air,
30% of the output power of the microwave was used to irradiate
the mixture for 5 min (on for 10 s and off for 5 s). The white precipi-
tate was collected by centrifugation, washed with deionized water
and ethanol several times, and dried in vacuum oven at 40 ◦C for
10 h.
2.5. Selected spectral data
2.5.1. Ethyl 6-methyl-2-oxo-4-p-tolyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (Table 1, entry
3)
White powder, mp = 209–210 ◦C. FT-IR: ꢀmax (KBr) 3231, 3094
(NH stretching), 1649, 1701 (C O) cm−1. 1H NMR (500 MHz, DMSO-
d6): ı = 1.1 (t, J = 7 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 2.26 (s, 3H, CH3),
3.98 (q, J = 7 Hz, 2H, CH2CH3), 5.11 (d, J = 3.5 Hz 1H, CH), 7.12 (s,
4H, Harom), 7.67 (s, 1H, NH), and 9.14 (s, 1H, NH) ppm. 13C NMR
(125 MHz, DMSO-d6): ı = 14.6, 18.2, 21.1, 54.2, 60.0, 100.0, 126.7,
129.4, 136.8, 142.5, 148.5, 152.5, and 166.2 ppm.
2.2. General procedure for the ZnO-catalyzed Biginelli reaction
To a mixture of aldehyde (2 mmol), ethyl acetoacetate (2 mmol),
and either urea, thiourea or guanidine (2.5 mmol) was added ZnO
(10 mol%) or nanoZnO (5 mol%) and the mixture was stirred at 60 ◦C
under solvent-free conditions for the given times (Table 1). After
the completion of the reaction (TLC monitoring), EtOAc (2× 10 mL)
was added and the precipitated ZnO was filtered off. The resulting
organic solution was washed with 10% NaHCO3 and brine, dried
over anhydrous Na2SO4, and evaporated to give the DHPM product.
The products were structurally assigned by their IR, 1H NMR, 13C
NMR spectra analysis and comparison to authentic samples.
2.5.2. Ethyl
6-methyl-2-oxo-4-phenyl-2-thioxopyrimidine-5-carboxylate
(Table 1, entry 12)
Pale yellow solid, mp = 203–205 ◦C. FT-IR (KBr): ꢀmax (KBr)
3328, 3186 (NH stretching), 1665 (C O), 1200 (C S) cm−1 1H NMR
.
(500 MHz, DMSO-d6,): ı = 1.15 (t, J = 7.0 Hz, 3H, CH3), 2.30 (s, 3H,
CH3), 4.00 (q, J = 7 Hz, 2H, CH2CH3), 5.21 (s, 1H, CH), 7.20–750 (m,
5H, Ph), 9.60 (br s, 1H, NH), and 10.14 (br s, 1H, NH) ppm. 13C NMR
Table 1
Zinc oxide-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones.
R1
H
H3C
EtOOC
O
O
H2N
+
NH2
NH
Solvent free, 60 °C
+
R1CHO
ZnO or nanoZnO (5 mol%)
X
H3C
N
H
X
EtO
Entry
R1
C6H5
X
Yield (%)a
Time (h)
Mp (◦C) Found (Reported)
1
2
3
4
5
6
7
8
O
O
O
S
O
S
O
O
O
S
95
95
94
93
95
89
67b
59b
68b
82
90
87
10
10
10
12
11
12
12
12
12
12
14
16
204–206 (200–203) [11]
209–210 (200–202) [11]
206–209 (215–216) [11]
209–211 (209–210) [35]
248–250 (228–230) [36]
206–209 (206–208) [35]
207–210 (208–211) [11]
209–212 (210–212) [11]
184–185 (186–188) [35]
212–215 (212–214) [35]
175–179 (176–178) [35]
203–206 (203–205) [37]
4-MeOC6H4
4-MeC6H4
4-N(Me)2C6H4
4-N(Me)2C6H4
2-OHC6H4
4-NO2C6H4
4-ClC6H4
4-FC6H4
3,4-(MeO)2C6H3
C6H5
9
10
11
12
NH
S
C6H5
a
Isolated yield.
b
As a part of the 3,4-dihydropyrimidin-2(1H)-one and 1,4-DHP mixture which was isolated by crystallization.

F. Tamaddon, S. Moradi / Journal of Molecular Catalysis A: Chemical 370 (2013) 117–122
119
Table 2
Switching of the Biginelli reaction to Hantzsch reaction under microwave irradiation.
Entry
X
Solvent (mL)
Catalyst (mmol)
Power (W)
Time (min)
Yield of DHP (%)a
1
2
3
4
5
6
7
8
9
O
O
O
O
O
O
S
H2O (1)
H2O (1)
H2O (1)
H2O (1)
H2O (1)
–
NanoZnO (0.05)
ZnO (0.1)
ZnO (0.5)
NanoZnO (0.5)
ZnO (1)
NanoZnO (0.05)
NanoZnO (0.5)
ZnO (1)
10
10
10
10
10
10
10
10
10
2
3
2
1.5
2
4
4
4
>4
70
63
85
96
95
61
45
35
52
–
–
S
O
H2O (1)
NanoMgO (1)
a
Isolated yield of DHP from the product mixture.
Table 3
Recyclability of ZnO and nanoZnO in the Biginelli and Hantzsch reactions.
Entry
Reaction
Catalyst
Run no.
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
Hantzsch
Hantzsch
Hantzsch
Hantzsch
Hantzsch
Hantzsch
Biginelli
Biginelli
Biginelli
Biginelli
NanoZnO
NanoZnO
NanoZnO
ZnO
ZnO
ZnO
NanoZnO
NanoZnO
NanoZnO
ZnO
1
2
3
1
2
3
1
2
3
2
2b
2b
96
95
96
95
95
94
95
94
95
91
2.5b
2.2b
2.5b
2.5b
10c
10c
10c
10
10.5c
a
Isolated yield.
b
c
Micriwave irradiation.
60 ◦C, h.
(125 MHz, DMSO-d6): ı = 12.5, 15.5, 52.6, 57.8, 99.5, 124.8, 125.7,
126.8, 143.2, 163.5, and 172.6 ppm.
As results show, among the verified metal oxides, 5 mol% of
nanoZnO and 10 mol% of ZnO were highly effective catalysts. The
oxophilicity of zinc cation, amphoteric nature of ZnO together with
the ability of the zinc cation for nearing of the activated starting
materials via an extra template affect supports the efficiency of
ZnO catalysts. However, higher surface area-to-volume ratio, high
diffusion, and better dispersion of ZnO nanoparticles in the reaction
mixture are accountable for the superiority of nanoZnO and higher
yield of product at 60 ◦C.
The scope of the nanoZnO-catalyzed Biginelli reaction was con-
firmed by condensation of various aromatic aldehydes with ethyl
acetoacetate and urea, thiourea, or guanidine under optimized
reaction conditions in good to excellent yields (Table 1).
Based on the illustrated results in Table 1, the yields of
DHPM products were lower for aldehydes bearing the electron-
withdrawing groups (entries 7–9). Fine analysis of the products of
these reactions showed that decreasing in the reaction yields is due
to the formation of DHP product via competitive Hantzsch reaction.
This means that electronic effect of substituent influences on the
2.5.3. Diethyl-2,6-dimethyl-4-(3-hydroxyphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate (Table 2, entry
7)
Pale yellow solid, mp = 180–182 ◦C, FT-IR: ꢁmax (KBr): 3349
(OH and NH stretching), 1648 (C O) cm−1 1H NMR (500 MHz,
.
CDCl3): ı = 1.26 (t, J = 7.1 Hz, 6H, 2 × CH3–CH2), 2.33 (s, 6H,
2 × CH3), 4.09–4.18 (m, 4H, O–CH2CH3), 5.00 (s, 1H, CH), 5.13
(br s, 1H, OH), 5.70 (br s, 1H, NH), 6.63 (dd, J = 7.95, 2.39 Hz,
1Harom), 6.80 (s, 1Harom), 6.89 (d, J = 7.69 Hz, 1Harom), and 7.09 (t,
J = 7.8 Hz, 1Harom) ppm. 13C NMR (125 MHz, CDCl3): ı = 14.62, 19.22,
39.44, 59.64, 103.22, 113.36, 115.39, 119.43, 149.97, 157.07, and
168.15 ppm. Anal. Calcd for C19H23NO5: C, 66.07; H, 6.71; and N,
4.06. Found: C, 66.04; H, 6.67; and N, 4.00.
2.5.4. Diethyl-2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine-
3,5-dicarboxylate (Table 2, entry
10)
Pale yellow solid, mp= 190–192 ◦C, FT-IR: ꢁmax (KBr): 3174 (NH
stretching), 1688 (C O) cm−1 1H NMR (500 MHz, CDCl3): ı = 1.24
.
95
100
80
60
40
20
0
91
(t, J = 7.13 Hz, 6H, 2 × CH3–CH2), 2.36 (s, 6H, 2 × CH3), 4.07–4.14 (m,
4H, O–CH2CH3), 5.01 (s, 1H, CH), 6.61 (s, 1H, NH), 7.19 (dd, J = 7.83,
4.98 Hz, 1H), 7.64–7.66 (m, 1H), 8.39 (dd, J = 4.79, 1.57 Hz, 1H), and
8.55 (d, J = 1.94 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): ı = 14.68,
19.75, 38.23, 60.27, 103.57, 123.55, 136.27, 144.00, 145.39, 147.40,
149.80, and 167.64 ppm. MS (EI): m/z: 330 (M+, 40), 301 (55), 285
(54), 252 (100), 224 (85), 196 (85), 150 (28), 106 (22), and 51 (18).
78
70
67
65
53
36
29
20
3. Results and discussion
Initially, condensation of ethyl acetoacetate and benzaldehyde
with urea as a Biginelli model reaction was examined compara-
tively in the presence of 10 mol% of various metal oxides and 5 mol%
of nanometal oxides at 60 ◦C under solvent-free conditions (Fig. 1).
Metal oxide catalysts
Fig. 1. Biginelli reaction in the presence of metal oxides.

120
F. Tamaddon, S. Moradi / Journal of Molecular Catalysis A: Chemical 370 (2013) 117–122
100
80
60
40
20
0
100
80
Optimized
60/35
60/35
temprature for
Biginelli reaction
53/42
50/45
a
38/57
60
40
20
0
a'
32/63
20/80
15/80
0/95
0/75 0/83
0
20
40
60
80
100
120
140
160
Temperature ( C)
Fig. 2. Shifting the Biginelli to Hantzsch reaction based on the temperature.
0
20
40
60
80
100
120
% NanoZnO loading (a) & % ZnO loading (a')
competitive formation of DHP product and percentage of DHPM
yields.
Fig. 3. Switching of the Biginelli to Hantzsch reaction based on catalyst loading.
In order to achieve the norm of ZnO-catalyzed Biginelli and
Hantzsch reactions, the reaction of ethyl acetoacetate, benzalde-
hyde, and urea was investigated from various aspects such
as reaction temperature, catalyst loading, solvent effect, and
microwave inducing effect. Therefore, in a first set of experiments,
the Biginelli model reaction was evaluated at various temperatures
in the presence of 5 mol% of nanoZnO (Fig. 2). The basis of determin-
ing of the yield in Table 2 is percentage ratio of undesired 1,4-DHP
to desired DHPM which were determined by isolation of 1,4-DHP
from DHPM component with cold ethanol. This was made by addi-
tion of cold ethanol, filtration of the remained DHPM, addition of
water to the ethanolic solution of 1,4-DHP product, and filtration
of the precipitated 1,4-DHP.
As Fig. 2 shows, the highest yield of desired DHPM and lowest
yield of undesired 1,4-DHP product is related to the reaction at 60 ◦C
(0:95 for 1,4-DHP:DHPM). Carrying out the reaction at higher tem-
peratures led to the obvious switching of the Biginelli to Hantzsch
reaction and formation of both desired DHPM and undesired 1,4-
DHP products. The percentage of 1,4-DHP and DHPM components
of product were determined by isolation of 1,4-DHP from DHPM
with cold ethanol. This was made by addition of cold ethanol, fil-
tration of the remained DHPM, addition of water to the ethanolic
solution of 1,4-DHP product, and filtration of the precipitated 1,4-
DHP. According to the Fig. 2, the maximum switching of the Biginelli
to Hantzsch reaction was observed for temperatures at 120–140 ◦C
(60:35 for 1,4-DHP:DHPM) and means maximum decomposition of
urea and liberation of ammonia in conjugation with the nanoZnO
and heating. The in situ generated ammonia subsequently con-
tributed in the formation of the corresponding 1,4-DHP via the
competitive Hantzsch reaction versus Biginelli reaction.
Due to the powerful interaction of urea with ZnO under
microwave irradiation [24] and maturity of water with MW-
assisted reactions, the Biginelli model reaction was evaluated in
water using ZnO or nanoZnO in an unmodified MW oven (Table 2).
We were surprised to find that complete Biginelli/Hantzsch
switching was occurred at 950 W for 120 s in water using 100 mol%
of ZnO or 50 mol% of nanoZnO (entries 4 and 5). This can be
explained as the result of complete dissociation of urea to ammo-
nia over ZnO under these conditions before its condensation with
other components. The maximum amount of microwave-assisted
switching of Biginelli to Hantzsch reaction was for nanoZnO, pre-
sumably due to the higher surface area of nanocatalyst, its excellent
diffusion to aqueous reaction mixture, and hence higher rate of
decomposition of urea to ammonia. The rate of decomposition of
thiourea over the surface of ZnO or nanoZnO was lower than urea,
so liberation of ammonia and hence %DHP product was lower than
urea (35–45%) (entries 7 and 8). The microwave-assisted nanoZnO-
catalyzed Hantzsch reaction is advantageous over conventional
methods due to the shorter reaction times, aqueous media, cleaner
reaction, reusability of catalyst, and the highest amount of in situ
generated ammonia via the urea decomposition.
Alternatively, switching of the modified Hantzsch to Biginelli
reaction was investigated by screening the four-component reac-
tion of 2 mmol ethyl acetoacetate, 1 mmol benzaldehyde, and
1 mmol of urea at various nanoZnO loading and temperatures.
Despite of the Hantzsch setting reaction, Biginelli product was
obtained in 97% yield with 5 mol% of catalyst loading at ∼60 ◦C,
whereas yield of Hantzsch DHP product was regularly increased
by increasing the temperature and catalyst loading. This is due to
A
NMR-based study was secondly made on the Biginelli
model reaction and its switching as function of catalyst
a
loading. The results showed an enhancement in the isolated
yield of diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate versus ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-
phenylpyrimidin-5-carboxylate by increasing the catalyst loading
(Fig. 3).
The maximum switching fitted in 1 mmol of ZnO catalyst or
0.5 mmol of nanoZnO, where decomposition of urea to ammonia
accelerates due to the higher surface area and better diffusion of
catalyst (Fig. 3).
Thirdly, solvent-effect was evaluated by screening the reac-
tion of ethyl acetoacetate, benzaldehyde, and urea in mixture of
EtOH:H2O, EtOH, H2O, and solvent-free conditions at 60 ◦C using
5 mol% of nanoZnO (Fig. 4).
100
80
60
40
20
0
0
20
40
60
80
100
120
The results showed that by increasing the amount of water the
liberation of ammonia and formation of the undesired DHP product
via a competitive Hantzsch reaction become a serious problem and
hence its% yield was increased versus DHPM (Fig. 4).
Amount of water
× 10 µl
Fig. 4. The effect of water on the ZnO-catalyzed Biginelli/Hantzsch reaction switch-
ing.

F. Tamaddon, S. Moradi / Journal of Molecular Catalysis A: Chemical 370 (2013) 117–122
121
45
40
35
30
25
20
15
10
5
Reusability of catalyst is an important factor for its upgrade
industrial uses. ZnO catalysts were recovered from the either
50 mmol scale of solvent-free Biginelli reaction of urea, ethyl ace-
toacetate, and benzaldehyde at 60 ◦C or microwave-assisted model
of Hantzsch reaction by washing with EtOAc and drying at 300 ◦C.
The regenerated ZnO or nanoZnO was then successfully reused for
three consecutive times in both Biginelli and Hantzsch reactions
with no significant decreasing in the reaction yields (Table 3).
4. Conclusion
In conclusion, nanoZnO and ZnO have been conveniently used
in the controllable synthesis of DHPMs/1,4-DHPs via the Biginelli
and Hantzsch reactions. Dissociation of urea to ammonia over ZnO
increases the possibility of switching of these reactions in each
direction. In the presence of reusable nanoZnO and ZnO, control
of the reaction progress in either direction is feasible by control-
ling the reaction conditions and catalyst loading. Thus, solvent-free
reaction of aldehydes, 1,3-dicarbonyls, and urea, thiourea or guani-
dine using 5 mol% of nanoZnO at ∼60 ◦C afforded the Biginelli DHPM
products, while nanoZnO-catalyzed four-component reaction of
aldehydes, 1,3-dicarbonyls, and urea in water under MW irradi-
ation (or at ∼120–140 ◦C) afforded the desired 1,4-DHP products in
high yields.
0
0
20
40
60
80
100
120
140
160
% NanoZnO loading
Fig. 5. The effect of nanoZnO loading on the Hantzsch/Biginelli switching.
the gradual decomposition of urea and increasing of the ammonia
liberation (Figs. 5 and 6).
Comparison between results in Figs. 1–6 show that the fea-
sibility of switching of the Biginelli to Hantzsch reaction is
more probable at higher temperatures and catalyst loading, while
complete switching occurs for performed reaction in water at
reaction temperatures >120 ◦C and ∼0.5 mmol nanoZnO loading.
Superior switching for Biginelli/Hantzsch reaction occurs under
similar conditions using MW irradiation, owing to the excellent
energy transfer for urea dissociation. A divergent switching for
Hantzsch/Biginelli takes place at lower temperature (∼60 ◦C) and
catalyst loading (∼0.05 mmol). Accordingly, it was confirmed that
by changing the conditions for either condensation or dissociation
of urea over ZnO or nanoZnO the Biginelli or Hantzsch product could
be obtained.
Acknowledgement
We acknowledge the Research Council of Yazd University.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2012.12.005.
We finally examined ammonium carbonate instead of urea as
nitrogen provider of 1,4-DHP in the nanoZnO-catalyzed Hantzsch
reaction of 2 mmol of ethyl acetoacetate and benzaldehyde in water
using 5 mol% of nanoZnO, thus the 1,4-DHP product was isolated
in 95% yield after 2 h at ∼60 ◦C. This confirmed the efficiency of
nanoZnO for the preparation of the 1,4-DHPs in water without shif-
ting the Hantzsch to Biginelli reaction in shorter times than that
previously report [11].
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