Mg-Al hydrotalcite as an efficient catalyst for microwave assisted regioselective 1,3-dipolar cycloaddition of nitrilimines with the enaminone derivatives: A green protocol

Article abstract of DOI:10.1016/j.molcata.2012.11.009

Microwave assisted generation of in situ nitrilimines and their regioselective 1,3-dipolar cycloaddition reaction with enaminones to produce pyrazole derivatives by Mg-Al hydrotalcite (Mg-Al HT) catalyst is introduced. Short reaction times with high yields (90-94%), the absence of an organic solvent and reuse of the catalyst for at least five times without loss of activity could regard as cost effective, environmentally friendly and greener process. The fresh and used catalysts were characterized by X-ray diffraction (XRD), Fourier transform infrared (FTIR), Raman spectroscopy, N₂ physisorption and temperature programmed desorption by CO₂ (CO ₂-TPD) to understand the role of hydrotalcite in the reaction mechanism and the robust nature of the catalyst. It appears that better microwave absorptivity of the catalyst with Mg-Al HT structure might be responsible for shorter reaction times with high yields. A plausible mechanism for 1,3-dipolar cycloaddition over the Mg-Al HT is proposed.

Full text of DOI:10.1016/j.molcata.2012.11.009

Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Mg–Al hydrotalcite as an efficient catalyst for microwave assisted regioselective
1,3-dipolar cycloaddition of nitrilimines with the enaminone derivatives:
A green protocol
Tamer S. Saleh, Katabathini Narasimharao, Nesreen S. Ahmed, Sulaiman N. Basahel,
Shaeel A. Al-Thabaiti, Mohamed Mokhtar∗
Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave assisted generation of in situ nitrilimines and their regioselective 1,3-dipolar cycloaddition
reaction with enaminones to produce pyrazole derivatives by Mg–Al hydrotalcite (Mg–Al HT) catalyst is
introduced. Short reaction times with high yields (90–94%), the absence of an organic solvent and reuse of
the catalyst for at least five times without loss of activity could regard as cost effective, environmentally
friendly and greener process. The fresh and used catalysts were characterized by X-ray diffraction (XRD),
Fourier transform infrared (FTIR), Raman spectroscopy, N2 physisorption and temperature programmed
desorption by CO2 (CO2-TPD) to understand the role of hydrotalcite in the reaction mechanism and the
robust nature of the catalyst. It appears that better microwave absorptivity of the catalyst with Mg–Al
HT structure might be responsible for shorter reaction times with high yields. A plausible mechanism for
1,3-dipolar cycloaddition over the Mg–Al HT is proposed.
Received 5 October 2012
Received in revised form
11 November 2012
Accepted 13 November 2012
Available online 22 November 2012
Keywords:
1,3-Dipolar cycloaddition
Regioselectivity
Enaminones
© 2012 Elsevier B.V. All rights reserved.
Nitrilimines
Microwave irradiation
Mg–Al hydrotalcite
1. Introduction
synthesize 1,3-di-substituted nitrilimines. Later on, many research
groups [15] used different homogeneous and heterogeneous cata-
Synthesis of pyrazole derivatives has still been an active area
of research due its prominent structure motif found in numerous
pharmaceutically active compounds [1]. Pyrazole framework plays
an essential role in biologically active compounds and therefore
represents an interesting template for combinatorial as well as
medicinal chemistry [2–5]. The pyrazole nucleus is a ubiquitous
feature of fertile source of medicinal agents such as antimicro-
bial [6], antiviral [7,8] and anticancer [9,10] agents specially after
the discovery of the natural pyrazole C-glycoside pyrazofurin; 4-
hydroxy-3-ˇ-d-ribofuranosyl-1H-pyrazole-5-carboxamide (Fig. 1)
[11].
One of the most important method used for synthesis of
pyrazole derivatives is 1,3-dipolar cycloaddition (1,3-DC) utiliz-
ing nitrilimine (generated in situ by the action of base on the
hydrazonoyl halide) and ˛,ˇ-unsaturated carbonyl compounds
(Scheme 1) [12,13]. Huisgen [14] first reported the dehydrohalo-
genation of hydrazidic halides under mild conditions (benzene
solution with triethylamine as catalyst) is a convenient route to
lysts for 1,3-DC of 1,3-dipoles with ␲-electronic deficient moieties
to synthesize five or six membered heterocyclic compounds.
Recently, Tseng et al. [16] have developed new method for one-
pot 1,3-DC to prepare a series of 3,5-disubstituted 1,2,4-triazole
compounds by reacting various aldehydes with hydrazonoyl
hydrochlorides in the presence of hydroxylamine hydrochloride as
a functionality transferring reagent, triethylamine as a basic cata-
lyst and toluene as solvent.
However, these homogeneous methodologies are suffering from
disadvantages mainly, use of homogeneous base such as tri-
ethylamine and non-polar solvent such as benzene, which are
undesirable from an environmental point of view and also these
reactions generate considerable amounts of wasteful salts. In recent
years, researchers are dedicating their efforts to find alternative
methodologies for waste minimization in fine chemicals and drugs
manufacturing processes by replacing the stoichiometric organic
synthesis methodologies, which uses large amounts of inorganic
and organic reagents with cleaner, catalytic methodologies [17].
A deep search in the literature revealed a lack of general investi-
gation on utilization of heterogeneous catalysts for 1,3-DC reaction.
For the first time, Broggini et al. [18] reported the application of
Ag2CO3 as a promoter in heterogeneous reaction conditions for
∗
Corresponding author. Tel.: +966 500558045; fax: +966 26952292.
E-mail address: mmokhtar2000@yahoo.com (M. Mokhtar).
1381-1169/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2012.11.009

T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
13
HO
induced Organic Reaction Enhancement” (MORE) chemistry has
been utilized for rapid and sustainable regioselective synthesis of
some pyrazole derivatives. Here we are reporting a green protocol,
which does not generate any harmful and/or wasteful co-products
via using recyclable solid Mg–Al HT catalyst for in situ generation
of nitrilimine and subsequent 1,3-DC with enaminone derivatives.
To best of our knowledge, the application of Mg–Al HT catalysts
for the aforementioned reaction has not previously been reported.
A detailed characterization of fresh and spent catalysts has been
carried out to understand the role and stability of HT structure.
O
OH
N
OH
H2N
OH
O
HN
Fig. 1. Structure of pyrazofurin.
in situ generation of nitrile iminies from hydrazononyl halides.
They observed that the reaction between hydrazononyl chlorides
and allylic alcohols in the presence of Ag2CO3 exhibits differ-
ent features than in the presence of conventional bases such
as tertiary amines. Later, Bonini et al. [19] used Ag2CO3 as a
base along with Sc(OTf)3 for the 1,3-DC of nitrile imines with
functionalized acetylenes. The same group extended the applica-
tion of the same methodology to the regiocontrolled synthesis of
thieno[2,3-c]-pyrazoles through 1,3-DC of nitrile imines and sub-
stituted acetylenes bearing thiol or sulfone groups [19]. 1,3-Dipolar
ions have been shown to undergo a wide variety of cycloadditions
usually in situ, but the mechanism of this process remains contro-
versial [20].
In recent years, hydrotalcites (HTs) have found applications
in various base catalyzed reactions including [3 + 2] cycloaddition
reactions that are used for the synthesis of isoxazoles and tetrazoles
[21]. Due to its ability of altering the nature of the basic sites by the
preparation conditions, HTs showed great potential in the reactions
that required Lewis basic sites, Brönsted basic sites or even pairs
of acid–base sites [22]. The use of microwave irradiation in organic
synthesis has become increasingly popular within the pharmaceu-
tical and academic arenas, because it is a new enabling technology
for drug discovery and development [23]. Taking the advantage of
this efficient source of energy (enhances reaction rates, high yields,
improved purity, ease of work up after the reaction and eco-friendly
reaction conditions compared to the conventional methods), com-
pound libraries for lead generation and optimization can be
assembled in a fraction of the time required by classical thermal
methods. Kaddar et al. [24] studied the 1,3-DC activity of hydra-
zonoyl chlorides over Al2O3 with various alkenes and alkynes under
microwave irradiation. They observed that the microwave heating
accelerates the cycloaddition process when the reaction performed
in non-polar solvent, but the yields are relatively low for the investi-
gated substrates (maximum 50%). The lower yields of the products
could be related to the lower basic strength of the Al2O3 catalyst.
Motivated by the aforementioned findings, and in a continuation of
our interest in synthesis of a wide range of heterocyclic systems for
biological screening program in our laboratory [25], also, as a part of
our program toward the non-conventional approach to the experi-
mental set up of organic reactions [26], the concept of “Microwave
2. Experimental
2.1. Preparation of catalysts
Mg–Al (3:1) HT catalyst was prepared by following the proce-
dure reported in our previous publication [27]. Synthetic HT was
prepared by co-precipitation using two solutions (A) and (B). Solu-
tion (A) contained the desired amount of Mg and Al nitrates and
solution (B) consisted of the precipitating agents NaOH and Na2CO3.
Within 5 min the two solutions were added simultaneously into the
reaction vessel while the pH was maintained at ca. 10 under vigor-
ous stirring at 30 ◦C for 17 h by ultrasound. Finally, the sample was
washed by dispersion in distilled water under gentle stirring fol-
lowed by filtration. This washing/filtration step was repeated five
times till the precipitate was free from sodium ions as confirmed
from ICP analyses. The precipitate was dried at 80 ◦C for 12 h. For
calcination the as-synthesized HT sample was heated under the
flow of air for 3 h at 450 ◦C in a muffle furnace.
2.2. Characterization of catalysts
X-ray powder diffraction (XRD) studies were performed for all
the prepared solid samples using a Bruker diffractometer (Bruker
D8 advance target). The patterns were run with Cu K˛ with
˚
secondly monochromator (ꢀ = 1.5405 A) at 40 kV and 40 mA. The
identification of different crystalline phases in the samples was
performed by comparing the data with the Joint Committee for
Powder Diffraction Standard (JCPDS) files. FTIR spectra of catalysts
were recorded using Shimadzu FT-IR 8101 PC infrared spectropho-
tometer. The Raman spectra of samples were measured with a
Bruker Equinox 55 FT-IR spectrometer equipped with a FRA106/S
FT-Raman module and a liquid N2 cooled Ge detector, using the
1064 nm line of an Nd:YAG laser with an output laser power
of 200 mW. Textural properties of the prepared samples were
determined from nitrogen adsorption/desorption isotherms mea-
surements at −196 ◦C using Autosorb iQ automated gas sorption
system 70 (Quantachrome, USA). The specific surface area, SBET, was
Scheme 1. 1,3-Dipolar cycloaddation protocol via nitrilimines and ˛,ˇ-unsaturated carbonyl compounds.

14
T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
calculated by applying the Brunauer–Emmett–Teller (BET) equa-
tion. Pore size distribution over the mesopore range was generated
by the Barrett–Joyner–Halenda (BJH) analysis of the desorption
branches, and values of the average pore size were calculated. CO2-
TPD patterns were recorded using Chembet-3000 (Quantachrome,
USA).
Anal. Calcd for C18H13FN2O2 (308.31): C, 70.12; H, 4.25; N, 9.09%.
Found: C, 70.28; H, 4.19; N, 8.99%.
2.3.2.4. 3-Acetyl-4-(4-flurobenzoyl)-1-(4-flurophenyl)pyrazole (5d).
mp. 162–164 ◦C, IR (KBr) ꢁmax/cm−1: 1686, 1654 (2C O), 1592
(C N), 1H NMR (CDCl3): ı 2.66 (s, 3H, CH3), 7.25–7.87 (m, 8H, ArH’s),
8.45 (s, 1H, pyrazole-5-CH), 13C NMR (CDCl3): ı 26.95, 111.84,
113.12, 113.13, 116.21, 116.22, 119.44, 128.00, 1287.79, 133.06,
133.07, 144.62, 159.98, 161.11, 191.54, 193.90. MS (m/z): 326 (M+),
Anal. Calcd for C18H12F2N2O2 (326.30): C, 66.26; H, 3.71; N, 8.59%.
Found: C, 66.51; H, 3.61; N, 8.44%.
2.3. Synthesis of pyrazole derivatives, 5a–f
2.3.1. Microwave irradiation method
Mg–Al HT (0.5 g) was added to an enaminone derivative
3
(10 mmol) and the appropriate hydrazonyl chloride 1a–c
2.3.2.5. 3-Acetyl-4-benzoyl-1-(4-trifluromethylphenyl)pyrazole (5e).
mp. 177 ◦C, IR (KBr) ꢁmax/cm−1: 1692, 1658 (2C O), 1599 (C N),
1H NMR (CDCl3): ı 2.59 (s, 3H, CH3), 7.15–7.76 (m, 9H, ArH’s), 8.36
(s, 1H, pyrazole-5-CH), 13C NMR (CDCl3): ı 26.25, 111.02, 119.54,
119.55, 122.00, 126.55, 127.84, 127.85, 128.56, 130.02, 133.46,
134.75, 146.33, 147.18, 192.56, 195.07. MS (m/z): 358 (M+). Anal.
Calcd for C19H13F3N2O2 (358.31): C, 63.69; H, 3.66; N, 7.28%. Found:
C, 63.96; H, 3.53; N, 7.14%.
(10 mmol) in a mortar, and the mixture was grounded thoroughly
with a pestle at room temperature. The total mixture was placed in a
Teflon process vial and it was irradiated by microwaves with power
of 330 W to reach a reaction temperature of 120 ◦C under auto gen-
erated pressure. The vial was exposed to microwaves for a required
time to complete the reaction. The progress of the reaction was
monitored by TLC for every 1 min (eluent; petroleum ether: chlo-
roform). Upon completion of the reaction, the mixture was cooled
and the product was extracted by dissolution in ethanol. The cata-
lyst was removed by filtration and washed with hot ethanol and the
solvent was evaporated under reduced pressure to obtain the solid
product. The obtained solid product was purified by crystallization
using ethanol/dimethyl formamide solvent mixture to afford the
pure pyrazole derivatives 5a–f in excellent yields. Compound 5a
was obtained by using various heterogeneous catalysts (basic alu-
mina, KF/basic alumina, K2CO3, MgO, Mg: Al-HT and also in neat
conditions (without catalyst) under microwave irradiation.
2.3.2.6. 3-Acetyl-4-(4-flurobenzoyl)-1-(4-
trifluromethylphenyl)pyrazole (5f). mp. 158 ◦C, IR (KBr) ꢁmax/cm−1
:
1698, 1659 (2C O), 1592 (C N), 1H NMR (CDCl3): ı 2.63 (s, 3H,
CH3), 7.09–7.84 (m, 8H, ArH’s), 8.52 (s, 1H, pyrazole-5-CH), 13C
NMR (CDCl3): ı 26.45, 112.23, 116.02, 119.54, 122.62, 126.33,
126.34, 128.04, 128.98, 130.38, 130.39, 139.45, 144.08, 161.21,
191.27, 194.06. MS (m/z): 376 (M+). Anal. Calcd for C19H12F4N2O2
(376.30): C, 60.64; H, 3.21; N, 7.44%. Found: C, 60.93; H, 3.06; N,
7.30%.
2.3.2. Conventional electrical heating method
2.4. Synthesis of pyrazolo[3,4-d]pyridazine derivatives, 8a–f
The reactions were performed on the same scale as described
above. The reactants and catalyst were put in a flask then sealed
with a rubber septum. The reaction mixture was heated at 120 ◦C
on a thermostatic oil-bath for required time to complete the reac-
tion as monitored by TLC. After the completion of the reaction, the
reaction mixture was cooled to room temperature and the products
were obtained and purified as described in the previous method.
Physical and spectral data of the compounds 5a–f are listed
below.
2.4.1. Microwave irradiation method
To a solution of appropriate pyrazole derivatives 5a–f (1 mmol)
in ethanol (2 mL), hydrazine hydrate (98%), (2 mL, 10 mmol) was
added in a process vial. The vial was capped properly and irra-
diated by microwaves with a power of 330 W to reach reaction
temperature, 120 ◦C. The progress of the reaction was moni-
tored by TLC for every 1 min. The solid reaction product was
removed from vial and washed with ethanol and recrystallized
using dimethyl formamide (DMF) solvent to afford the correspond-
ing pyrazolo[3,4-d]pyridazine derivatives 8a–f.
2.3.2.1. 3-Acetyl-4-benzoyl-1-phenylpyrazole
(5a). mp.
141–143 ◦C, IR (KBr) ꢁmax/cm−1
:
1695, 1652 (2C O), 1602
(C N), 1H NMR (CDCl3): ı 2.69 (s, 3H, CH3), 7.23–7.92 (m, 10H,
ArH’s), 8.11 (s, 1H, pyrazole-5-CH), 13C NMR (CDCl3): ı 26.11,
110.55, 121.22, 127.54, 128.08, 128.09, 129.68, 129.69, 130.65,
132.87, 138.54, 146.32, 189.94, 195.75, MS (m/z): 290 (M+), Anal.
Calcd for C18H14N2O2 (290.31): C, 74.47; H, 4.86; N, 9.65%. Found:
C, 74.61; H, 4.81; N, 9.56%.
2.4.2. Conventional electrical heating method
A
mixture of the pyrazole derivative 5a–f (1 mmol) and
hydrazine hydrate (98%), (2 mL, 10 mmol) was refluxed in ethanol
(20 mL) under electrical heating for 1 h and then left to cool to
room temperature. The formed precipitates were collected by fil-
tration, washed with ethanol and dried. Recrystallization using
DMF afforded yellow crystals of the corresponding pyrazolo[3,4-
d]pyridazine derivatives 8a–f.
2.3.2.2. 3-Acetyl-4-(4-flurobenzoyl)-1-phenylpyrazole
(5b). mp.
130–132 ◦C, IR (KBr) ꢁmax/cm−1: 1680, 1644 (2C O), 1594 (C N),
1H NMR (CDCl3): ı 2.66 (s, 3H, CH3), 7.55–7.81 (m, 9H, ArH’s),
8.22 (s, 1H, pyrazole-5-CH), 13C NMR (CDCl3): ı 27.14, 119.88,
123.33, 128.37, 128.41, 129.82, 130.21, 130.73, 131.76, 136.72,
138.91, 150.38 189.24, 192.93, MS (m/z): 308 (M+), Anal. Calcd for
C18H13FN2O2 (308.31): C, 70.12; H, 4.25; N, 9.09%. Found: C, 70.33;
H, 4.16; N, 8.97%.
Physical and spectral data of the compounds 8a–f listed below.
2.4.2.1. 7-Methyl-2,4-diphenyl-2H-pyrazolo[3,4-d]pyridazine (8a).
mp. 239 ◦C, IR (KBr) ꢁmax/cm−1: 1596 (C N), 1H NMR (DMSO-d6):
ı 2.96 (s, 3H, CH3), 7.18–7.82 (m, 10H, ArH’s), 8.76 (s, 1H-pyrazole),
13C NMR (DMSO-d6): ı 17.93, 110.23, 121.38, 124.54, 126.41,
126.42, 128.41, 129.85, 129.86, 129.97, 133.85, 141.12, 142.48,
148.04, 152.00, 154.20. MS (m/z): 286 (M+). Anal. Calcd for
C18H14N4 (286.32): C, 75.51; H, 4.92; N, 19.57%. Found: C, 75.83;
H, 4.77; N, 19.40%.
2.3.2.3. 3-Acetyl-4-benzoyl-1-(4-flurophenyl)pyrazole
(5c). mp.
148 ◦C, IR (KBr) ꢁmax/cm−1: 1685, 1643 (2C O), 1594 (C N), 1H
NMR (CDCl3): ı 2.68 (s, 3H, CH3), 7.10–7.81 (m, 9H, ArH’s), 8.41
(s, 1H, pyrazole-5-CH), 13C NMR (CDCl3): ı 27.04, 112.56, 117.29,
117.30, 119.72, 119.73, 127.11, 128.58, 129.79, 129.80, 131.04,
134.78, 137.37, 147.00, 160.01, 190.59, 194.98, MS (m/z): 308 (M+),
2.4.2.2. 4-(4-Fuorophenyl)-7-methyl-2-phenyl-2H-pyrazolo[3,4-
d]pyridazine (8b). mp. 251 ◦C, IR (KBr) ꢁmax/cm−1: 1593 (C N), 1
H
NMR (DMSO-d6): ı 2.82 (s, 3H, CH3), 7.25–7.95 (m, 9H, ArH’s), 8.68

T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
15
(s, 1H-pyrazole), 13C NMR (DMSO-d6): ı 17.56, 109.89, 113.33,
120.07, 120.08, 123.57, 127.54, 128.49, 128.50, 130.25, 132.47,
138.05, 141.00, 148.32, 153.10, 162.33. MS (m/z): 304 (M+). Anal.
Calcd for C18H13FN4 (304.32): C, 71.04; H, 4.31; N, 18.41%. Found:
C, 71.36; H, 4.17; N, 18.24%.
Table 1
The yield of pyrazole derivative 5a obtained using various solid base catalysts under
microwave irradiation.
Entry
Catalyst
Time (min)
Yielda (%)
1
2
3
4
5
6
None
>90
59
40
>60
7
0
82
58
14
91
94
Basic alumina
KF/basic alumina
K2CO3
MgO
Mg–Al HT
2.4.2.3. 2-(4-Fluorophenyl)-7-methyl-4-phenyl-2H-pyrazolo[3,4-
d]pyridazine (8c). mp. 276 ◦C, IR (KBr) ꢁmax/cm−1: 1599 (C N), 1
H
4
NMR (DMSO-d6): ı 2.89 (s, 3H, CH3), 7.69–8.12 (m, 9H, ArH’s), 8.66
(s, 1H-pyrazole), 13C NMR (DMSO-d6): ı 17.91, 111.58, 116.25,
116.26, 119.01, 123.89,123.90, 127.01, 128.63, 128.64, 131.98,
134.00, 134.75, 139.59, 148.09, 152.66, 163.84. MS (m/z): 304 (M+).
Anal. Calcd for C18H13FN4 (304.32): C, 71.04; H, 4.31; N, 18.41%.
Found: C, 71.29; H, 4.20; N, 18.27%.
a
MW power: 330 W; reaction temperature 120 ◦C.
The results are indicating that Mg–Al HT catalyst offered the higher
yield of the desired product (94%) within very short reaction time
(4 min) under microwave irradiation. The next best catalyst is
MgO, which offered 91% yield within 7 min, but we were unable
to recover the catalyst from the reaction mixture, probably MgO
might reacted with HCl (byproduct in the reaction) to form unde-
sirable MgCl2 salt. To further show the significance of this work, the
catalytic activity of Mg–Al HT is compared with activity of triethyl-
amine (frequently used homogeneous catalyst in the literature).
The yield of pyrazole derivative 5a is around 80%, when we used tri-
ethylamine as a catalyst at the same reaction conditions. This result
is indicating that Mg–Al HT not only offering better catalytic activ-
ity but also green in nature. The reaction product was identified
as the pyrazole structure 5a in all cases, although there were two
regioisomeric cycloadducts 5a and 7a seemed possible (Scheme 2).
However, the regioisomer 5a was assigned for the reaction prod-
ucts on the basis of its 1H NMR spectrum, in which, in the pyrazole
ring system, C-4 is the most electron-rich carbon; thus, H-4 is
expected to appear at a higher field, typically at ı 5–6 region.
On the other hand, H-5 is linked to a carbon attached to a nitro-
gen atom and therefore, it is deshielded and appeared typically in
the region ı 7.5–9.5. The 1H NMR spectra of the isolated reaction
product revealed, in each case, a singlet signal in the region of ı
8.68–9.67 as well as the absence of any signals around ı 5–6 ppm,
which indicates the presence of the pyrazole H-5 rather than H-4 in
the structure of the isolated product. These facts confirm the exist-
ence of regioisomer 5a and rules out the other alternative structure
7a. Unambiguous structure determination of the obtained prod-
ucts is therefore crucial to rationalize the observed regioselectivity.
Structure elucidation was conveniently achieved on the basis of
the long-range C–H connectivities (gHMBC 100 spectra) showed
by pyrazole proton toward two C O. On this basis, the analysis of
gHMBC spectra of the product led us to attribute the signal at ı
195.75 ppm to the quaternary carbon (carbonyl group) owing to its
correlation peaks with the pyrazole proton at ı 8.11 ppm; on the
other hand, the signal at ı 189.94 ppm is attributed to the other
carbonyl carbon owing to its correlation peak with the signal at ı
2.69 ppm easily assigned to the methyl group protons of the acetyl
group. This observationindicatingthat only one carbonylfunctional
group correlate to the pyrazole proton which in accordance to the
2.4.2.4. 2,4-Bis(4-fluorophenyl)-7-methyl-2H-pyrazolo[3,4-
d]pyridazine(8d). mp. >300 ◦C, IR (KBr) ꢁmax/cm−1: 1595 (C N), 1
H
NMR (DMSO-d6): ı 2.78 (s, 3H, CH3), 7.13–7.82 (m, 8H, ArH’s), 8.71
(s, 1H-pyrazole), 13C NMR (DMSO-d6): ı 17.15, 110.18, 114.98,
114.99, 118.00, 118.01, 123.89,125.10, 128.06, 128.64, 128.65,
133.08, 139.18, 147.96, 151.54, 163.54, 165.00. MS (m/z): 322 (M+).
Anal. Calcd for C18H12F2N4 (322.31): C, 67.08; H, 3.75; N, 17.83%.
Found: C, 67.35; H, 3.62; N, 17.68%.
2.4.2.5. 7-Methyl-4-phenyl-2-(4-(trifluoromethyl)phenyl)-2H-
pyrazolo[3,4-d]pyridazine (8e). mp. 282 ◦C, IR (KBr) ꢁmax/cm−1
:
1594 (C N), 1H NMR (DMSO-d6): ı 2.82 (s, 3H, CH3), 7.39–8.19
(m, 9H, ArH’s), 8.69 (s, 1H-pyrazole), 13C NMR (DMSO-d6): ı 17.42,
111.23, 121.11,121.12, 122.56, 123.54,123.55, 125.16, 125.17,
128.45, 128.98, 130.54, 130.55, 131.08, 134.98, 138.65, 141.00,
149.23, 152.35. MS (m/z): 354 (M+). Anal. Calcd for C19H13F3N4
(354.33): C, 64.40; H, 3.70; N, 15.81%. Found: C, 64.72; H, 3.56; N,
15.63%.
2.4.2.6. 4-(4-Fluorophenyl)-7-methyl-2-(4-
(trifluoromethyl)phenyl)-2H-pyrazolo[3,4-d]pyridazine
>300 ◦C, IR (KBr) ꢁmax/cm−1: 1592 (C N), 1H NMR (DMSO-d6): ı
2.67 (s, 3H, CH3), 7.51–7.89 (m, 8H, ArH’s), 8.71 (s, 1H-pyrazole), 13
(8f). mp.
C
NMR (DMSO-d6): ı 16.98, 110.87, 114.12, 114.13, 121.00,121.01,
122.54, 124.12,124.13, 126.00, 126.67, 128.16, 128.17, 128.98,
138.65, 141.14, 148.98, 152.02, 163.42. MS (m/z): 372 (M+). Anal.
Calcd 11 for C19H12F4N4 (372.32): C, 61.29; H, 3.25; N, 15.05%.
Found: C, 61.58; H, 3.14; N, 14.87%.
3. Results and discussion
3.1. Catalytic regioselective 1,3-dipolar cycloaddition reaction of
nitrilimines with enaminones
Solid basic catalysts, namely, MgO, Al2O3, KF/Al2O3, K2CO3 and
Mg–Al HT were tested for the 1,3-DC reaction (Scheme 2) of the
enaminone 3 with the nitrilimine 2a (generated from the hydra-
zonoyl chloride 1a).
The reaction was performed without solvent using solid base
catalyst under microwave irradiation to obtain only one isolable
product in each case (as examined by TLC and 1H NMR spec-
troscopy).
To investigate the reactivity of hydrazonoyl hydrochlorides 2a–c
with enaminone derivatives, E-3-(dimethylamino)-1-phenylprop-
2-en-1-one (3a) was used as the model dipolarophile substrates.
E-3-(dimethylamino)-1-phenylprop-2-en-1-one was allowed to
react with various aromatic hydrazonoyl hydrochlorides 2a–c
bearing various substituents to the nitrilimine group. The 1,3-DC
reaction smoothly proceeded to give the corresponding pyrazole
derivative in good yields (14–94%, see the entries 1–6 in Table 1).
Fig. 2. Diagnostic correlations in the gHMBC (red arrows) in compounds 5a. (For
interpretation of the references to color in this figure legend, the reader is referred
to the web version of the article.)

16
T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
Scheme 2. Regioselective synthesis of pyrazole derivative 5a using various solid base catalysts.
structure 5a (Fig. 2), therefore these results confirm the existence
of regioisomer 5a and rules out the other alternative structure 7a.
The reaction product was identified as the pyrazole structure 5a
(Scheme 2) which was assumed to be formed via initial 1,3-DC
of the nitrilimine 2a to the activated double bond in the enam-
inone 3a to afford the non-isolable dihydropyrazole intermediate
4a followed by elimination of dimethylamine yielding the pyrazole
derivative 5a. In order to study the advantage of microwave irra-
diation on the rate of 1,3-DC reaction, the previously mentioned
reaction was carried out by conventional electrical heating using
Mg–Al HT as catalyst (Table 2).
reaction in which it is possible to decrease the reaction time signif-
icantly from several hours to minutes with higher yields. We also
performed the reactions without catalyst under both microwave
and conventional methods and no reaction products were observed
even after 90 min and 18 h under microwave and conventional
heating, respectively.
Table 2
The yields of pyrazole derivatives 5a using Mg–Al HT catalyst under conventional
and microwave irradiations conditions.
The conventional heating method in oil bath needed 8 h to
obtain 75% yield of the product. The obtained results revealed that
the reactions required longer time to attain considerable yields
under conventional heating methods and the yields are lower than
that obtained using microwave protocol. From these results it is evi-
dent that microwave irradiation showed beneficial effect on 1,3-DC
Catalyst
Microwave condition
Conventional condition
Time (min)
Yield (%)
Time (h)
Yield (%)
None
Mg–Al HT
>90
4
0
94
>20
8
0
75
MW power: 330 W; reaction temperature: 120 ◦C.

T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
17
Scheme 3. Regioselective synthesis of pyrazole derivatives 5a–f using Mg–Al HT catalyst.
The scope and generality of this protocol was tested by var-
ious derivatives of hydrazonyl halides 1b–c as shown in the
Scheme 3 under the optimized reaction conditions and correspond-
ing pyrazole derivatives were obtained in excellent yields under
microwave protocol (90–94%, Table 3).
The yields of pyrazole derivatives with trifluromethyl moi-
ety (entries 5 and 6) are relatively lower than derivatives with
simple fluorine group. This could be explained by the fact that tri-
fluromethyl groups are highly hydrophobic in nature and might be
repulsive to the reactive hydroxyl groups in the Mg–Al HT catalyst
Table 3
The efficiency of Mg–Al HT catalyst toward the synthesis of pyrazole derivatives 5a–f under both conventional and microwave irradiations conditions.
Entry
Hydrazonyl chloride
Products
Microwave condition
Time (min)
Conventional condition
Yield (%)
94
Time (h)
8
Yield (%)
1
4
75
2
3
4
4
5
5
92
92
91
8
8
9
75
75
76
5
6
6
6
90
90
8
8
75
75
MW power: 330 W; reaction temperature: 120 ◦C.

18
T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
Table 4
The durability test of the Mg–Al HT catalyst toward the synthesis of pyrazole derivatives 5a–f.
Compound No.
Number of successive uses of Mg–Al HT as catalyst
1st
2nd
3rd
4th
5th
5a
5b
5c
5d
5e
5f
4
4
5
5
6
6
4
4
5
5
6
6
4
4
5
5
6
6
4
4
5
5
7
7
5
5
6
7
7
7
Time to reach 100%
conversion (min)
1H, 13C NMR and mass spectra results are in complete agreement
with structure 8a–f. All reaction times were determined by fol-
lowing the reaction progress via thin layer chromatography (TLC)
and all products obtained were determined by elemental analy-
ses, NMR, IR and mass spectroscopy data. These results are clearly
indicating that microwave technology for heating has been shown
to be more energy efficient than conventional method. Microwave
irradiation is rapid and volumetric with the whole material heated
simultaneously. In contrast, conventional heating is slow and the
heat is introduced into the sample from the surface.
and also the effect of electron withdrawing ability of trifluromethyl
group cannot be ignored for low activity. It was observed that the
percentage yield was low under conventional heating conditions
and the reaction time increased greatly. Again, microwave irradia-
tion showed beneficial effect on 1,3-DC reaction in terms of reaction
time and percentage yields. The reusability of the Mg–Al HT catalyst
was checked for several reaction cycles under microwave irradi-
ation, the catalyst removed after the completion of the reaction
by filtration, washed with hot ethanol and dried under vacuo. The
recovered catalyst was reused for five times using the same reaction
conditions under microwave irradiation.
Table 4 shows that the regenerated catalyst performs the reac-
tions efficiently under the same reaction conditions even after
being used for five times. The slight decay observed in the catalytic
activity of the Mg–Al HT catalyst on the fourth and fifth time and
the decay of activity could be attributed to the weight loss of the
catalyst during the working up in each time. These results are indi-
cating the microwave stability and robust nature of the Mg–Al HT
catalyst for 1,3-DC reaction.
A further confirmation of the regioselective synthesis of pyra-
zoles 5a–f (not other regioisomer 7) comes from its reaction with
hydrazine hydrate under both microwave and conventional con-
dition to afford a yellow-colored product, which was identified as
the pyrazolo[3,4-d]pyridazine 8a–f (Scheme 4 and Table 5). The
microwave protocol offered 85% to 90% yields in 3 min, but the
conventional heating method needed 120 min to offer 73% of yield.
The IR spectra of compounds 5a–f showed two carbonyl absorp-
tion bands, which were disappeared in the IR spectrum of the
pyrazolo[3,4-d]pyridazine products 8a–i. In addition to the IR data,
3.2. Catalyst characterization
A through characterization of fresh and used catalysts was per-
formed to understand the role of Mg–Al HT structure in the catalytic
activity for 1,3-DC reaction. XRD patterns of the fresh and used cat-
alysts after 1st run and 5th run are shown in Fig. 3. As synthesized
catalyst shows characteristic (0 0 3), (0 0 6), (0 0 9) and (1 1 3) reflec-
tions at 2ꢂ = 11.4, 22, 35, and 61.8◦ corresponding to Mg–Al HT [28]
with formula Mg6Al3(OH)6CO3·4H2O.
The XRD patterns of used catalysts are very similar and
shown different reflections due to a new phase. Removal of
interlayer carbonate ions after the reaction evidenced by the
shifting and broadening of the reflections and this less crys-
talline phase can be considered as meixnerite HT with formula
of Mg6Al2(OH)18·4H2O. Dehydroxylation and decarbonation of
HTs into Mg(Al)Ox mixed oxides and reconstruction of mixed
oxides into HT analog after exposure water was observed by many
research groups [29].
In the present study, the formation of meixnerite phase could
be explained the fact that the carbonate ions in the pure Mg–Al
HT are reacting with the HCl which is formed during the reac-
−
tion. It is possible that the formed meixnerite could have HCO3
ions as compensating anions in the interlayer instead of the orig-
inal carbonate ions. It is interesting to note that reflections due
to magnesium chloride or aluminum chloride crystal structures
were not observed and this observation revealing that HCl is not
reacting with the metal ions, but with the interlayer anions. For
further understanding of structural reorganization of the Mg–Al
Table 5
Synthesis of pyrazolo[3,4-d]pyridazine under microwave and conventional
procedures.
Compound No.
Microwave condition
Conventional condition
Time (min)
Yield (%)
Time (min)
Yield (%)
8a
8b
8c
8d
8e
8f
3
3
3
3
3
3
89
90
85
88
89
88
60
60
60
60
120
120
78
80
73
76
73
71
MW power: 330 W; reaction temperature: 120 ◦C.
Scheme 4. Synthesis of pyrazolo[3,4-d]pyridazine 8a–f derivatives.

T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
19
2-
3
CO
300
200
100
500
400
300
200
3000
2000
1000
0
After 5th run
Al-O-Al
Fresh catalyst
-
3
Mg-O-Mg
NO
After 1st run
After 1st run
After 5th run
2000 1800 1600 1400 1200 1000
Wavenumber (cm-1)
800
600
400
Fig. 5. Raman spectra of fresh and used catalysts.
Fresh
to the fact that the formed HCl (bi-product of dehydrohalogena-
tion of hydrazonoyl chlorides) could be reacting with interlayer
anions.
Structural analysis of the catalysts was further studied by Raman
spectroscopy. The Raman spectra of the fresh and spent −catalysts
2−
were shown in Fig. 5. The presence of CO3
and NO3 ions is
reflected by sharp bands around 1063 cm−1 and 716 cm−1, respec-
tively. In the lower region, the two bands at around 471 cm−1 and
548 cm−1 are appeared in all three spectra. These bands were con-
10
20
30
40
50
60
70
80
2 Theta (degrees)
sidered to be due to the linkage bonds, such as Mg
O Mg and
Fig. 3. XRD patterns of fresh and used catalysts.
Al Al linkage in the HT layers respectively [32]. The intensities
O
of all bands showed significant decrease upon the increase of num-
ber of runs confirming the HT structural damage due to interaction
with the evolved HCl. The confirmation of presence of intercalates
carbonate ions from FTIR and Raman analyses revealing that HCO3−
ions are compensating with the carbonate ions.
Fig. 6 shows the N2 adsorption–desorption isotherms and the
pore size distribution patterns (in the inset) of fresh and used cata-
lysts. The fresh Mg–Al HT sample exhibited type-II isotherm which
was typical of mesoporous materials and slit shaped pores based
on the Brunauer, Deming, Deming and Teller (BDDT) classifica-
tion [33]. The sample was found to exhibit type B hysteresis loop
(based on the De Boer idealization). The designation type-II was
not withstanding the hysteresis loop, which normally corresponds
to the type-IV model, because there was no plateau at high P/Po
values. This isotherm was characteristic of clay minerals either of
the cationic or anionic type such as hydrotalcites [34].
HT, we analyzed the samples with FTIR and Raman spectroscopy
methods.
Fig. 4 shows the FTIR spectra of fresh and spent Mg–Al HT
catalysts after 1st and 5th catalytic runs. All the spectra were
characterized with stretching vibrations of interlayer carbonate
ions at 1355 cm−1, along with the O H stretching of the hydroxyl
group and deformation vibration of H2O at 3450 cm−1. The peak
at 1637 cm−1 in all the samples can be attributed to the bending
mode of the interlayer water [30]. In the region of the spectra below
1000 cm−1 the lattice absorption bands, which can be assigned
to the Al O (around 755 cm−1) and Mg O (around 645 cm−1
)
stretching modes [31]. It is interesting to note that the intensity
of all the peaks due to interlayer ions and metal-oxygen bonds are
decreasing with the increase of number of runs. This might be due
The adsorption–desorption isotherms of type-IV were observed
for the used catalyst samples. A mesoporous structure based on
the BDDT classification was observed. Both of the samples showed
hysteresis loop type-A, indicative of cylindrical pores based on the
De Boer idealization. The pore size distribution pattern of fresh
sample shows unimodal pore distribution with single peak around
260
-CO32-
-OH
240
220
200
180
160
140
120
100
80
-OH
Mg-O
Al-O
Fresh catalyst
After 1st run
After 5th run
˚
100 A.
˚
˚
However, a bimodal distribution with two peaks at 8 A and 100 A
was observed for used samples. The different surface properties for
the re-used samples could be related to some disaggregation of the
HT layers due to some atomic level overheating during microwave
treatment at the reaction conditions used for the reactions. This
gives to the formation of surface-defective sites which are respon-
sible for the new porosity and the decrease in the surface area could
be attributed to the pore blockage by a small amount of insolu-
ble coke species. In order to obtain information about the basicity
of the samples, we used the CO2-TPD technique. The CO2-TPD
60
600 900 1200 1500 1800 2100 2400 2700 3000 3300 3600 3900
Wavenumber (cm-1)
Fig. 4. FTIR spectra of fresh and used catalysts.

20
T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
60
160
140
120
100
80
Fresh
Fresh
Fifth run
First run
55
50
45
40
35
30
25
20
15
10
5
60
40
20
0
0.0
0.2
0.4
0.6
0.8
1.0
100
200
300
400
500
600
700
800
Relative Pressure (P/Po)
Temperature (oC)
200
Fig. 7. TPD patterns of fresh and used catalysts.
After 1st run
180
160
140
120
100
80
requires surface hydroxyl groups [36]. The fresh Mg–Al HT sample
showed total five desorption peaks. The low temperature peaks at
150 ◦C, 260 ◦C and 400 ◦C are due to the desorption weakly bounded
CO2 and decomposition of residual carbonate ions presented in the
Mg–Al HT sample. A similar observation was made by Abello et al.
[37] when they performed the blank test on the Mg–Al HT. The
fresh catalyst also showed two main desorption peaks at 460 ◦C and
660 ◦C. The first peak was mainly attributed to bicarbonate groups
formed by the interaction of CO2 with hydroxyl groups in the Mg–Al
HT and the second peak was tentatively attributed to the formation
of strongly bonded surface metal carbonate species. The used cat-
alysts showed a main desorption peak at 420 ◦C and a small peak
between 510 and 520 ◦C. Diez et al. [38] reported that the desorp-
tion peak at about 420 ◦C can be attributed to the contribution of
mainly bi-dentate carbonates species, together with bicarbonate
species. The appearance of a peak at 540 ◦C is due to the presence
of mono-dentate species. The results are demonstrating that all of
the OH sites are evaluated by CO2-TPD experiments, but also that
the OH groups are still presented in the used samples are actu-
ally more accessible in structurally transformed Mg–Al HT catalyst.
Moreover, the presence of the two peaks suggesting the existence of
OH groups with different strength. The differences in CO2 uptake
values between fresh and used catalysts can be attributed to the
existence of irregularities or linear defects in the platelets of the
microwave exposed samples. The consistent activity of the cata-
lysts under microwave irradiation even after 5th recycle run with
short reaction times can be explained by the fact that the Mg–Al
HT catalyst is not decomposing into respective Mg and Al oxides
under microwave irradiation and still possessed considerably high
basic strength. As we observed the reactivity data in Table 1, Mg or
Al oxides alone are unable to offer superior activity than Mg–Al HT
catalyst.
60
40
20
0
0.0
0.2
0.4
0.6
0.8
1.0
Relative Pressure (P/Po)
160
140
120
100
80
After 5th run
60
40
20
0
0.0
0.2
0.4
0.6
0.8
1.0
Relative pressure (P/Po)
3.3. Regioselective 1,3-dipolar cycloaddition mechanism over
Mg–Al HT catalyst
Fig. 6. N2 isotherms and pore size distribution patterns of fresh and used catalysts.
patterns of the catalysts are shown in Fig. 7. CO2 uptake is related
to several types of basic sites and is caused by different types of
carbonate coordination in the interlayer space of HTs. It is known
that several types of species such as mono-dentate, bi-dentate and
bicarbonate anions usually formed during the saturation of CO2
with HTs [35]. Mono-dentate and bi-dentate carbonate formation
involves low-coordination oxygen anions and are therefore consid-
ered as strong basic sites and the formation of bicarbonate anions
A proposed mechanism for formation of the pyrazole deriva-
tive over Mg–Al HT catalyst is shown in Scheme 5. The first step
is base induced dehydrohalogenation of the hydrazonoyl chloride
under mild conditions to provide nitrilimine which produced ‘in
situ’. The second step involves the 1,3-dipolar cycloaddation reac-
tion of nitrilimine with enaminone to produce the cycloadduct in
a highly regioselective fashion. In the final step, the cycloadduct
undergoes an elimination of–NMe2 group by reacting with HCl

T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
21
Scheme 5. Plausible regioselective 1,3-dipolar cycloaddition mechanism over Mg–Al HT catalyst.
at the pyrazoline ring affording pyrazole derivative. A simulta-
Appendix A. Supplementary data
2−
neous reaction between HCl and CO3
ions presented in the
Mg–Al HT causes the formation of meixnerite, analog of HT
structure.
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.molcata.2012.11.009.
4. Conclusions
References
[1] S. Fustero, M. Sanchez-Rosell, P. Barrio, A. Simn-Fuentes, Chem. Rev. 111 (2011)
6984.
[2] X.H. Liu, P. Cui, B.A. Song, P.S. Bhadury, H.L. Zhu, S.F. Wang, Bioorg. Med. Chem.
16 (2008) 4075.
[3] H. Foks, D. Pancechowska-Ksepko, A. Kedzia, Z. Zwolska, M. Janowiec, E.
Augustynowicz-Kopec II, Farmaco 60 (2005) 513.
[4] A.M. Gilbert, A. Failli, J. Shumsky, Y. Yang, A. Severin, G. Singh, W. Hu, D. Keeney,
P.J. Petersen, A.H. Katz, J. Med. Chem. 49 (2006) 6027.
[5] A.H. Shamroukh, M.E.A. Zaki, E.M.H. Morsy, F.M. Abdel-Motti, F.M.E. Abdel-
Megeid, Arch. Pharm. Chem. Life Sci. 340 (2007) 345.
[6] O. Prakash, R. Kumar, V. Parkash, Eur. J. Med. Chem. 43 (2008) 435.
[7] R. Storer, C.J. Ashton, A.D. Baxter, M.M. Hann, C.L.P. Marr, A.M. Mason, P.L. Myers,
S.A. Noble, H.R. Penn, N.G. Weir, G. Niall, J.M. Woods, P.L. Coe, Nucleotides 18
(1999) 203.
In summary, we report an efficient microwave assisted green
protocol for regioselective 1,3-DC of nitrilimines with the enam-
inone derivatives over different base solid catalysts. Mg–Al HT
catalyst showed a great advantage over all the investigated solid
base catalysts. Microwave irradiation method offered high yields
of pyrazole derivatives in very short reaction time over Mg–Al
HT solid catalyst. A thorough catalyst characterization reveals that
strong basic sites of the HTs are responsible for the consistent
catalyticperformance. Mg–Al HT maintainedits structuraland text-
ural properties even after five catalytic runs, which appears crucial
to obtain high yields of the product.
[8] M.J. Genin, C. Biles, B.J. Keiser, S.M. Poppe, S.M. Swaney, W.G. Tarpley, Y. Yagi,
D.L. Romero, J. Med. Chem. 43 (2000) 1034.
[9] G. Daidone, B. Maggio, S. Plescia, D. Raffa, C. Musiu, C. Milia, G. Perra, M.E.
Marongiu, Eur. J. Med. Chem. 33 (375) (1998) 21.
Acknowledgements
[10] S.A. Gamage, J.A. Spicer, G.W. Rewcastle, J. Milton, S. Sohal, W. Dangerfield, P.
Mistry, N. Vicker, P.A. Charlton, W.A. Denny, J. Med. Chem. 45 (2002) 740.
[11] R.N. Comber, R.J. Gray, J.A. Secrist, Carbohydr. Res. 216 (1991) 441.
[12] A.M. Farag, A.S. Mayhoub, S.E. Barakat, A.H. Bayomi, Bioorg. Med. Chem. 16
(2008) 881.
This project was funded by the Deanship of Scientific Research
(DSR), King Abdulaziz University, Jeddah under Grant No. 32-
130D1432. The authors, therefore, acknowledge DSR with thanks
for their technical and financial support.
[13] S.R. Donohue, C. Halldin, V.W. Pike, Tetrahedron Lett. 49 (2008) 2789.
[14] R. Huisgen, Angew. Chem. Int. Ed. 2 (1963) 565.

22
T.S. Saleh et al. / Journal of Molecular Catalysis A: Chemical 367 (2013) 12–22
[15] (a) M.L. Kantam, V.S. Jaya, B. Sreedhar, M.M. Rao, B.M. Choudary, J. Mol. Catal.
A: Chem. 256 (2006) 273;
[26] (a) M. Mokhtar, T.S. Saleh, N.S. Ahmed, S.A. Al-Thabaiti, R.A. Al-Shareef, Ultra-
son. Sonochem. 18 (2011) 172;
(b) S. Chassaing, A.S.S. Sido, A. Alix, M. Kumarraja, P. Pale, J. Sommer, Chem.
Eur. J. 14 (2008) 6713;
(b) M. Mokhtar, T.S. Saleh, S.N. Basahel, J. Mol. Catal. A: Chem. 353–354 (2012)
122.
(c) K. Namitharan, M. Kumarraja, K. Pitchumani, Chem. Eur. J. 15 (2009) 2755;
(d) T. Katayama, K. Kamata, K. Yamaguchi, N. Mizuno, ChemSusChem 2 (2009)
59;
[27] M. Mokhtar, A. Inayat, J. Ofili, W. Schwieger, Appl. Clay Sci. 50 (2010) 176.
[28] J.C.A.A. Roelofs, D.J. Lensveld, A.J. van Dillen, K.P. deJong, J. Catal. 203 (2001)
184.
(e) N. Candelon, D. Lastcoures, A.K. Diallo, J.R. Aranzaes, D. Astruc, J.M. Vincent,
Chem. Commun. (2008) 741.
[29] (a) S. Abello, F. Medina, D. Tichit, J.J. Perez-Ramirez, J.C. Groen, J.E. Sueiras, P.
Salagre, Y. Cesteros, Chem. Eur. J. 11 (2005) 728;
[16] W.C. Tseng, L.Y. Wang, T.S. Wu, F.F. Wong, Tetrahedron 67 (2011) 5339.
[17] K. Yamaguchi, T. Oishi, T. Katayama, N. Mizuno, Chem. Eur. J. 15 (2009)
10464.
[18] G. Broggini, L. Garanti, G. Molteni, G. Zecchi, Heterocycles 45 (1997) 1945.
[19] B.F. Bonini, M.C. Franchini, D. Gentili, E. Locatelli, A. Ricci, Syn. Lett. 14 (2009)
2328.
(b) K.K. Rao, M. Gravelle, J.V. Sanchez, F. Figueras, J. Catal. 173 (1998) 115;
(c) K.L. Erickson, T.E. Bostrom, R.L. Frost, Mater. Lett. 59 (2004) 226;
(d) J.C.A.A. Roelofs, A.J. van Dillen, K.P. de Jong, Catal. Lett. 74 (2001) 91.
[30] P. Kustrowski, D. Sulkowska, L. Chmielarz, A. Rafalska-Lasocha, B. Dudek, R.
Dziembaj, Micropor. Mesopor. Mater. 78 (2005) 11.
[31] J.T. Kloprogge, R.L. Frost, Appl. Catal. A: Gen. 184 (1999) 61.
[32] J.T. Kloprogge, L. Hickey, R.L. Frost, Appl. Clay Sci. 18 (2001) 37.
[33] O. Bergada, I. Vicente, P. Salagre, Y. Cesteros, F. Medina, J.E. Sueiras, Micropor.
Mesopor. Mater. 101 (2007) 363.
[34] F. Prinetto, G. Ghiotti, P. Graffin, D. Tichit, Micropor. Mesopor. Mater. 39 (2000)
229.
[35] R.J. Chimentao, S. Abello, F. Medina, J. Llorca, J.E. Sueiras, Y. Cesteros, P. Salagre,
J. Catal. 252 (2007) 249.
[20] A.F. Hegarty, M.P. Cashman, F.L. Scott, J. Chem. Soc. Chem. Commun. (1971)
684.
[21] A. Lemos, J.A. Lourenco, Tetrahedron Lett. 50 (2009) 1311.
[22] F. Cavani, F. Trefiro, A. Vaccari, Catal. Today 11 (1991) 173.
[23] C.O. Kappe, Angew. Chem. Int. Ed. 43 (2004) 6250.
[24] H. Kaddar, J. Hamelin, H. Benhaoua, J. Chem. Res. (S) (1999) 718.
[25] (a) R.M. Shaaban, T.S. Saleh, A.M. Farag, Heterocycles 71 (2007) 1765;
(b) M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A.M. Farag, Eur. J. Med. Chem. 46
(2011) 3690;
[36] F. Prinetto, G. Ghiotti, R. Durand, D. Tichit, J. Phys. Chem. B 104 (2000) 1117.
[37] S. Abello, F. Medina, D. Tichit, J. Perez-Ramirez, X. Rodriguez, J.E. Sueiras, P.
Salagre, Y. Cesteros, Appl. Catal. A: Gen. 281 (2005) 191.
[38] V.K. Diez, C.R. Apesteguia, J.I. Di Cosimo, J. Catal. 215 (2003) 220.
(c) M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A. Mansour, A.M. Farag, Bioorg. Med.
Chem. 16 (2008) 6344.