Mg-Al hydrotalcites as efficient catalysts for aza-Michael addition reaction: A green protocol

Article abstract of DOI:10.1016/j.molcata.2011.11.015

Mg-Al hydrotalcite was synthesized by a co-precipitation method. We have studied the effect of calcination temperature and hydration of the calcined phases on their catalytic activity for the synthesis of pyrazolo[1,5-a] pyrimidine derivatives (aza-Michae

Full text of DOI:10.1016/j.molcata.2011.11.015

Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
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Journal of Molecular Catalysis A: Chemical
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Mg–Al hydrotalcites as efficient catalysts for aza-Michael addition reaction:
A green protocol
Mohamed Mokhtara,b,∗, Tamer S. Saleha,c, Sulaiman N. Basahela
a Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21533, Saudi Arabia
b Physical Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
c Green Chemistry Department, National Research Centre, Dokki, Cairo 12622, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Mg–Al hydrotalcite was synthesized by a co-precipitation method. We have studied the effect of
calcination temperature and hydration of the calcined phases on their catalytic activity for the syn-
thesis of pyrazolo[1,5-a]pyrimidine derivatives (aza-Michael addition product). The structure of the
as-synthesized sample and the presence of the anions in the interlayer galleries of hydrotalcites, have
been determined by X-ray diffraction and FTIR spectroscopy. On calcining the material at 450 ◦C, it was
amorphous periclase phase. Re-hydration of the calcined phase resulted in the formation of hydrotalcite-
like phase. Such treatment to the as-synthesized hydrotalcite significantly changed the pore structure
and the BET-surface area as determined from N2 physisorption at 77 K. The as-synthesized Mg–Al-
hydrotalcite catalyst was found to be the most efficient for the aza-Michael reaction relative to the
activated solid catalysts tested. The high performance of this catalyst was attributed to the co-operative
contribution of its acidic and basic sites. We have shown that this microwave assisted reaction provides
an eco-friendly alternative to the conventional syntheses where soluble bases are used. Furthermore, the
reaction was performed over a considerably shorter time scale and generated significantly higher yields
than traditional methods.
Received 22 September 2011
Received in revised form
12 November 2011
Accepted 13 November 2011
Available online 23 November 2011
Keywords:
Mg–Al-hydrotalcite
Aza-Michael addition
Green protocol
Acidic/basic sites
Pyrazolo[1,5-a]pyrimidine
Microwave irradiations
© 2011 Elsevier B.V. All rights reserved.
as the structure of brucite, Mg(OH)2, in which some of the Mg2+
cations, coordinated octahedrally by hydroxyl groups, are substi-
1. Introduction
tuted by trivalent ions such as Al3+. The excess of positive charges
in the LDH layers is compensated by anions and water, located
in the interlayer spaces. The surface properties of the minerals
can be tailored with relative ease by variation of the cations in
the octahedral sheet during synthesis and by introducing differ-
ent compensating anions in the interlayer regions. A whole class of
catalytically active species can be made by performing a simple pre-
cipitation experiment, and it is worth noting that both the layered
hydroxides of metal mixtures and mixed metal oxides (MMO), (the
products obtained by thermal decomposition of LDH), are regarded
as catalytically active. Thus, it is unsurprising that the syntheses of
a variety of organic transformations including condensation, iso-
merization, anion exchangers and epoxidation reactions have been
carried out using hydrotalcite catalysts [6–16].
Conjugate addition to ␣,␤-unsaturated carbonyl compounds
(i.e. Michael addition) is one of the most important carbon–carbon
and carbon–heteroatom bond-forming strategies for synthetic
organic chemistry [17]. Common conjugate addition reactions
involve the addition of a protic nucleophile donor (e.g., Si, Sn,
N, P, O, S, Se, I, or H) to an alkene or alkyne acceptor that is
activated by an electron-withdrawing group (e.g., ketone, ester,
amide, nitrile, nitro, sulfonate, and phosphonate). Subsequently,
Many organic syntheses of fine chemicals use homogenous cat-
alysts like minerals or organic acids and bases. The uses of such
homogenous catalysts can be problematic since it can be difficult
to recover the catalyst, a large quantity of waste is produced, and
pipes can be corroded due to the salts used. A “green” alternative
for these reactions that has high yields and good selectivity, along
with a reduction in waste, can be carried out using solid acidic and
basic catalysts. Such solid catalysts provide benign processes, with
easier catalyst recovery procedures, and safer and easier operation
modes. Furthermore, they do not need a polar solvent and the reac-
tion can be conducted at higher temperatures or in vapor phase
under heterogeneous conditions [1].
Layered double hydroxides [LDHs], generally named hydrotal-
cites, and thermally activated LDH products are useful catalysts,
catalyst precursors and catalyst support materials for a broad range
of organic reactions [2–5]. The structure of LDH can be visualized
∗
Corresponding author at: Chemistry Department, Faculty of Science, King Abdu-
laziz University, Jeddah 21533, Saudi Arabia. Tel.: +966 2 6194983;
fax: +966 2 6952292.
E-mail address: mmokhtar2000@yahoo.com (M. Mokhtar).
1381-1169/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.molcata.2011.11.015

M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
123
The development of an efficient and green protocol for
aza-Michael addition of heterocyclic amines to ␣,␤-unsaturated
ketones still remains a challenging task and is highly desirable,
especially for the preparation of chemically important and bio-
logically active complex molecules. Microwave-assisted chemistry
provides a convenient platform to perform reactions very effi-
ciently in the absence of any organic solvents, under so-called dry
media conditions (solvent free condition). The advantages of using
dry media conditions range from faster reaction rates with differ-
ent selectivity to more economical conditions due to the absence
of organic solvents [40]. In addition microwave irradiation gives
remarkable rate enhancement, higher yields, greater selectivity and
easier manipulation.
Motivated by the aforementioned findings, and our ongoing
endeavors in the development of environmentally benign protocols
for fine chemical synthesis [41,42], we report Mg–Al-hydrotalcite
as solid catalyst, and its activated forms, for aza-Michael addition
of aminopyrazoles to enaminone derivatives under solvent-free
conditions using microwave irradiation.
O
Me
N
Me
N
N
N
N
2. Experimental
Fig. 1. Structure of Zaleplon.
2.1. Materials and methods
2.1.1. Materials
the resulting incipient enolate is trapped with a proton source.
There are a myriad of reported methodologies where successful
Michael addition involves the use of base, these include piperi-
dine in ethanol under reflux for 8 h [18], pyridine under reflux
for 4 h [19], or addition of drops of piperdine under microwave
irradiation [20]. However, these methodologies have one or more
disadvantages, which include the use of high boiling and hazardous
solvents, and the yields of the reactions tend not to be more than
70%. Aza-Michael additions have also been catalyzed using strong
acids, but some side reactions occur, therefore some researchers
have been working on the development of more mild catalytic
systems for such aza-conjugation reactions. A number of alterna-
tive methodologies using Lewis acid catalysts have been reported,
such asPtCl4·5H2O [21], Cu(OTf)2 [22], InCl3 [23], Yb(OTf3) [24,25],
LiClO4 [26], Bi(NO3)2 [27], FeCl3·6H2O [28], CeCl3·7H2O [29], ZnO
[30], Y(NO3)3·6H2O assisted under solvent free condition [31], silica
supported perchloric acid [32] and sulfated zirconia [33]. How-
ever, similar to the basic catalysts, many of the above methods
suffer from some drawbacks, for example the requirement for a
large excess of reagents, often it is necessary to use toxic sol-
vents such as 1,2-dichloroethane or acetonitrile, and some catalysts
are substrate-selective. Moreover, most of the above methods are
not successful with heterocyclic amines, which limit their appli-
cation, and more importantly, some of them have not been used
for aza-Michael reaction with ␣,␤-unsaturated ketones as Michael
acceptors. To our knowledge, a little has been reported on reac-
tivity of ␣,␤-unsaturated ketones and amines utilizing solid base
catalysts [34] and suffer from relatively low yield and long reaction
time.
Magnesium nitrate (Mg(NO3)2·6H2O; 98.9%), aluminum nitrate
(Al(NO3)3·9H2O; 99.1%), sodium carbonate (Na2CO3; 99.9%) and
sodium hydroxide (NaOH; 99.9%) were purchased from BDH Ltd.,
for the synthesis of hydrotalcite samples. The deionized water
was used during the synthesis. 3-(Dimethylamino)-1-phenylprop-
2-en-1-one 1a [43], 3-(dimethylamino)-1-(4-flurophenyl)prop-2-
en-1-one 1a [44] and 5-amino-1H-pyrazole derivatives 2b,c [45]
were prepared according to the reported literature.
2.1.2. Catalyst synthesis
The Mg–Al hydrotalcite sample with Mg/Al molar ratio equal to
2.0, was synthesized by a co-precipitation method at constant pH
[46]. A solution of 1 M Mg/Al nitrates was added dropwise to a vig-
orously stirred solution of 1 M Na2CO3/NaOH in a glass reactor at
room temperature and pH = 10. Finally, the sample was washed by
re-suspension in distilled water with gentle stirring, followed by fil-
tration. This washing/filtration step was repeated 5 times until the
precipitate was free from sodium ions as confirmed by ICP anal-
ysis. The precipitate was then dried in air at 80 ◦C for 16 h. Three
different catalysts were synthesized, characterized and tested, they
were: as-synthesized (HT-As), calcined at 450 ◦C (HT-450), dehy-
drated at 450 ◦C then rehydrated, in pre-boiled liquid water under
gentle stirring for 1 h at 25 ◦C (HT-450-H).
2.2. Characterization of the catalysts
Elemental chemical analysis was performed using inductively
coupled plasma-optical emission spectrometry (ICP-OES Plasma
400, Perkin Elmer, USA). Powder X-ray diffraction (XRD) patterns of
hydrotalcites were recorded with powder diffractometer (Bruker,
The aza-Michael addition reaction between 5-aminopyrazole
derivatives and enaminone is considered
synthesis of novel pyrazolo[1,5-a]pyrimidine derivatives [35].
The pyrazolo[1,5-a]pyrimidine moiety is privileged class
a precursor for
˚
Advance-8 system) using Cu K␣ radiation (ꢀ = 1.54056 A) in the
a
2ꢁ range from 2◦ to 80◦. FTIR spectra were recorded in the range
550–4000 cm−1 on Perkin Elmer Spectrum 100 FT-IR spectrome-
ter. The infrared spectra were recorded at room temperature for
the prepared products. The resulting FTIR spectral pattern was then
analyzed and matched with known signatures of identified materi-
als from the FTIR library. N2 physisorption at −196 ◦C using NOVA
3200e (Quantachrome, USA) was applied to characterize the BET-
surface area and the texture properties, namely total pore volume
(Vp) and pore diameter (Dp), of various investigated solid catalysts.
of pharmacophore, since compounds bearing this structural
unit possess a broad spectrum of biological activities [36,37]
and they have potent analgesic effects [38]. Also, there are
some pyrazolo[1,5-a]pyrimidine derivatives considered as ideal
non-benzodiazapine sedative/hypnotic drugs, for example Zale-
plon [39], marketed as SonataTM (N-(3-(3-cyanopyrazolo[1,5-
a]pyrimidin-7-yl)phenyl)-N-ethylacetamide(1) (Fig. 1), which is
used in the treatment of insomnia.

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M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
2.3. Characterizations of the reaction products
127.94, 129.41, 131.98, 136.59, 146.85, 148.09, 151.49, 155.29,
159.42; MS (m/z): 301(M+).
All melting points were measured on a Gallenkamp melting
point apparatus and are uncorrected. The infrared spectra were
recorded in KB risks on a pyeUnicam SP 3300 and Shimadzu
FTIR 8101 PC infrared spectrophotometers. The NMR spectra were
recorded on a Varian Mercury VX-300 NMR spectrometer. 1H spec-
tra were run at 300 MHz and 13C spectra were run at 75.46 MHz
in deuterated chloroform (CDCl3) or dimethyl sulphoxide (DMSO-
d6). Chemical shifts were related to that of the solvent. Mass
spectra were recorded on a Shimadzu GCMS-QP 1000 EX mass
spectrometer at 70 eV. Elemental analyses (C, H, N, S) were car-
ried out at the Microanalytical Center of Cairo University, Giza,
Egypt, the results were found to be in good agreement ( 0.3%)
with the calculated values. Microwave experiments were carried
out using CEM Discover LabmateTM microwave apparatus (300 W
with ChemDriverTM Software).
2.4.2.4. 2-Methyl-7-(4-flurophenyl)pyrazolo[1,5-a]pyrimidine (3d).
m.p. 135–137 ◦C, IR (KBr) vmax/cm−1: 1601 (C N); 1H NMR (CDCl3):
ı 2.08 (s, 3H, CH3), 6.12 (s, 1H, H-3), 6.89 (d, 2H, J = 4.8 Hz, H-
6), 7.14–7.78 (m, 4H, Ar-H), 8.20 (d, J = 4.8 Hz, 2H, H-5). 13C NMR
(CDCL3): ı 13.11, 92.54, 116.19, 118.23, 118.24, 127.50, 128.18,
128.19, 142.54, 144.17, 148.00, 152.45, 161.12; MS (m/z): 227(M+).
2.4.2.5. 7-(4-Flurophenyl)-2-phenylpyrazolo[1,5-a]pyrimidine (3e).
m.p. 169 ◦C, IR (KBr) vmax/cm−1: 1605 (C N); 1H NMR (CDCl3): ␦
6.39 (d, J = 4.2 Hz, 2H, H-6), 6.99 (s, 1H, H-3), 7.10–8.13 (m, 9H, Ar-
H), 8.51 (d, J = 4.2 Hz, 2H, H-5). 13C NMR (CDCL3): ı 90.52, 116.22,
118.84, 125.62, 125.65, 128.88, 128.94, 129.87, 129.88, 130.14,
130.15, 134.19, 142.62, 144.89, 148.78, 151.44, 161.62; MS (m/z):
289(M+).
2.4. Typical procedure for the catalyst test reaction
2.4.2.6. 7-(4-Flurophenyl)-2-(4-methoxyphenyl)pyrazolo[1,5-
a]pyrimidine (3f). m.p. 186–188 ◦C, IR (KBr) vmax/cm−1: 1601
(C N); 1H NMR (CDCl3): ı 3.89 (s, 3H, OCH3), 6.95 (s, 1H, H-3), 7.16
(d, J = 4.5 Hz, 2H, H-6), 7.25–8.13 (m, 8H, Ar-H), 8.26 (d, J = 4.5 Hz,
2H, H-5). 13C NMR (CDCL3): ı 54.12, 90.12, 113.11, 116.12, 118.15,
118.6, 123.24, 126.00, 128.99, 129.00, 131.98, 142.58, 144.45,
148.98, 151.11, 160.01, 161.59; MS (m/z): 319(M+).
2.4.1. Method A: microwave irradiation
HT-As (0.5 g), was added to an enaminone derivative(1a or 1b)
(10 mmol) and one of the 5-amino-1H-pyrazole derivatives (2a–c)
(10 mmol) in a mortar, the mixture was ground with a pestle at
room temperature then placed in an Pyrex tube in the microwave
reactor and irradiated for a suitable time (Table 3) with a 2 min
interval. The progress of the reaction was monitored by TLC. Upon
completion of the reaction, the mixture was cooled and the prod-
uct was extracted by dissolution in hot alcohol after evaporating the
volatile materials by vacuum, compounds 4a–c were re-crystallized
from ethanol. The catalyst used was redeemed by washing with
hot alcohol. Compound 4b was obtained in the presence of vari-
ous catalysts (such as HT-As, HT-450 and HT-450-H) and also in
neat conditions under microwave irradiation. It was found that all
catalysts used exhibited catalytic activity but HT-As was the most
effective of all the catalysts tested to promote the reaction with
high yield in short time (Table 2).
3. Results and discussion
3.1. Catalyst characterization
3.1.1. Elemental chemical analysis (ICP)
ICP analysis of HT-As was performed to determine its chemical
composition. The analysis revealed that the Mg/Al molar ratio was
1.8, which is very close to the nominal molar composition of the
pre-calculated Mg/Al molar ratio of 2. This result confirmed the
effectiveness of the precipitation process.
2.4.2. Method B: conventional method
3.1.2. X-ray diffraction (XRD)
These processes were performed on the same scale described
above for method A. Here the reactant and catalyst were put in
ethanol under reflux for 5–8 h (Table 4) until the starting materials
were no longer detectable by TLC. The products were obtained and
purified as described above in method A.
X-ray powder diffraction patterns of as-synthesized hydrotal-
cite (HT-As) are shown in Fig. 2. A phase analysis shows that only
a hydrotalcite layered structure is obtained (Ref. Pattern 22-0700,
JCPDS) with sharp and intense peaks for the (0 0 3), (0 0 6), (0 0 9),
(1 1 0) and (1 1 3) planes and broad peak for the (0 1 5) plane. The
crystal structure of the investigated HT-As was rhombohedral with
R-3m space group. The lattice parameters were calculated and the
average crystallite sizes were estimated from the Scherrer equation
using the FWHM of the basal reflection plane (0 0 3) and the non
basal line (1 1 0). The calculated lattice parameter a, which is mainly
related to the cation composition, was equal to 0.306 nm. The a
value decreases as the Al content increases from the initial value
of the Al-free brucite phase to the synthesized Mg/Al-hydrotalcite
[47]. The calculated cell parameter c, which is directly linked to the
interlayer distance, was equal to 2.34 nm, and the obtained crys-
tallite size was 19 nm. The longer dimension in the c direction is
mainly attributed to the relatively large distance between cation
sheets of hydrotalcites. The calcination of as-synthesized hydrotal-
cite phase at 450 ◦C (HT-450) led to the formation of an amorphous
magnesium oxide phase (periclase: Ref. Pattern 45-0946, JCPDS)
[48,49].
Physical and spectral data of the title compounds 3a–f are listed
below.
2.4.2.1. 2-Methyl-7-phenylpyrazolo[1,5-a]pyrimidine
(3a). m.p.
125 ◦C [lit. [43] m.p. 123–125 ◦C], IR (KBr) vmax/cm−1: 1599 (C N);
1H NMR (CDCl3): ı 2.29 (s, 3H, CH3), 6.28 (s, 1H, H-3), 6.96 (d, 2H,
J = 4.2 Hz, H-6), 6.99–8.01 (m, 5H, Ar-H), 8.33 (d, J = 4.2 Hz, 2H, H-5).
13C NMR (CDCL3): ı 13.71, 92.79, 115.09, 127.54, 128.49, 128.89,
133.45, 143.08, 146.11, 151.34, 157.44; MS (m/z): 209(M+).
2.4.2.2. 2,7-Diphenylpyrazolo[1,5-a]pyrimidine (3b). m.p. 157 ◦C
[lit. [43] m.p. 157 ◦C], IR (KBr) vmax/cm−1: 1601 (C N); 1H NMR
(CDCl3): ı 6.92 (d, J = 5.1 Hz, 2H, H-6), 6.99 (s, 1H, H-3), 7.42–8.24
(m, 10H, Ar-H),), 8.45 (d, J = 5.1 Hz, 2H, H-5). 13C NMR (CDCl3):
ı 91.59, 116.84, 126.45, 126.67, 128.88, 128.94, 129.88, 130.78,
132.00, 132.02, 145.78, 148.15, 151.44, 156.21; MS (m/z): 271(M+).
The liquid phase hydration of calcined hydrotalcite at 450 ◦C
(HT-450-H) did not fully match that of the initial hydrotalcite (HT-
As). The method of hydration of calcined hydrotalcite phase affects
the re-hydrated phase structure. The phase formed after liquid
water hydration of the calcined solid at 450 ◦C is a hydrotalcite-like
phase named meixnerite [49]. These changes in the phase structure
2.4.2.3. 2-(4-Methoxyphenyl)-7-phenylpyrazolo[1,5-a]pyrimidine
(3c). m.p. 172 ◦C, IR (KBr) vmax/cm−1: 1598 (C N); 1H NMR
(CDCl3): ı 3.61 (s, 3H, OCH3), 6.59 (s, 1H, H-3), 7.01 (d, J = 4.2 Hz,
2H, H-6), 7.38–8.01 (m, 9H, Ar-H), 8.33 (d, J = 4.2 Hz, 2H, H-5).
13C NMR (CDCL3): ı 52.80, 95.02, 113.26, 116.84, 126.02, 126.59,

M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
125
10
20
30
40
50
60
70
300
200
100
HT-450-H
HT-450
HT-450-H
0
400
HT-450
300
200
100
80000
60000
40000
20000
0
HT-As
HT-As
10
20
30
40
2Θ (o)
50
60
70
0.0
0.2
0.4
0.6
0.8
1.0
Relative Pressure (P/Po)
Fig. 2. XRD patterns of hydrotalcite and activated hydrotalcite samples.
Fig. 4. Adsorption/desorption isotherms of hydrotalcite and activated hydrotalcite
samples.
and pattern intensities affect the texture and catalytic properties of
the investigated catalysts.
of hydrotalcite [50], thus distinct from water adsorbed on clay min-
erals where the OH-stretching modes of weak hydrogen bonds
occur in the region between 3600 and 3500 cm−1. The shoulder
at 2809 cm−1 is assigned to hydroxyl interactions with carbonate
ions in the interlayer – more specifically it has been attributed to
the bridging mode H2O–CO3−2. A weak peak around 1630 cm−1 in
the infrared spectrum is attributed to the ␯ H2O mode of water
in the interlayer. The high vibration frequency is attributed to
symmetry restrictions induced by the hydrogen bonded carbonate
ions to hydroxyl groups of the hydroxide sheets. The peak around
1360 cm−1 related to ␯3 band of carbonate [51]. The carbonate band
of as-synthesized hydrotalcite was vanished completely upon cal-
cinations at 450 ◦C (HT-450). This is attributed to the complete
thermal decomposition of hydrotalcite phase into mixed metal
oxides, which complements the XRD data. However, the hydration
of the calcined phase (HT-450-H) led to the formation of hydroxyl
and carbonate groups in the interlayer gallery of activated oxide.
3.1.3. Fourier transform infrared spectroscopy (FTIR)
FTIR spectra of HT-As sample (Fig. 3) showed a broad band
at 3484 cm−1 assigned to the O–H stretching vibration, which is
ascribed to interlayer water and hydroxyl groups in hydroxide layer
HT-450-H
HT-450
3.1.4. N2-physisorption
Fig. 4 represents the N2 adsorption/desorption isotherms of all
the investigated samples. Type IV sorption isotherm with H3-type
hysteresis at relatively high relative pressure is displayed for all
samples. The isotherm exhibits an H3-type hysteresis at high rela-
tive pressure, which is typical for aggregates of plate-like particles
[52]. The enclosure of adsorption/desorption branches at relatively
high p/p0 = 0.7, for HT-As sample, could be attributed to the pres-
ence of large mesoporous structure and/or some macropores. This
kind of hysteresis is typical for the presence of open large pores,
which allow easy diffusion of the reactants through the materi-
als. On contrary to that, both HT-450 and HT-450-H samples show
an enclosure of adsorption/desorption branches at relatively low
p/p0 = 0.4. The fast increase in the amount of adsorbed nitrogen
in the range of very low relative pressures is an indication of the
presence of some microporosity. The specific surface area of HT-
As showed the smallest surface area of all the investigated solids,
HT-As
4000
3500
3000
2500
2000
1500
1000
wavenumber(cm-1)
Fig. 3. FTIR spectra of hydrotalcite and activated hydrotalcite samples.

126
M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
NH2
NH
O
MW
N
4
3
5
6
+
Catalyst
2
R
Ar
1
N
R
N
7
NMe2
N
-Me2NH
-H2O
Ar
3a-f
1a,b
2a-c
Ar
3
R
a
Me
Ph
b
Ph
Ph
c 4-OCH3Ph
Ph
d
e
f
Me
4-FPh
4-FPh
4-FPh
Ph
4-OCH3Ph
Scheme 1. Synthesis of pyrazolo[1,5-a]pyrimidine derivatives 3a–f.
NH2
O
MW
N
+
Catalyst
Ph
NH
N
N
NMe2
Ph
N
-Me2NH
-H2O
Ph
3b
1a
2b
Scheme 2. Synthesis of 2,7-diphenylpyrazolo[1,5-a]pyrimidine (3b) in absence and in presence of different catalysts under microwave irradiation.
Scheme 3. Suggested mechanism for the catalytic synthesis of pyrazolo[1,5-a]pyrimidines using MgAl-HT catalysts.

M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
127
Table 1
Table 3
Texture properties of different samples obtained from N2 adsorption/desorption
isotherms.
The efficiency of HT-As catalyst towards the synthesis of different pyrazolo[1,5-
a]pyrimidine derivatives 3a–f.
˚
Sample
SBET (m2/g)
Vp (cm3/g)
rp (A)
C-constant
Compound no.
Reaction
Yield
Lit. yield**
time* (min)
HT-As
HT-450
HT-450-H
86.26
171.26
138.59
0.1742
0.2854
0.2146
40.41
33.33
30.97
184.5
82.70
579.8
N
Me
N
N
Table 2
Reaction of 1a with 2b in absence and in presence of different catalysts carried out
under microwave irradiations.
Catalyst
Reaction timea (min)
Yield %
3a
15
93%
64% [43]
Blank experiment
HT-As
HT-450
No reaction
–
94
70
75
N
18
44
42
N
HT-450-H
N
a
Reaction conditions: solvent-free condition, 10 mmol of enaminone derivative
and 10 mmol of aminopyrazole derivative, 0.5 g of catalyst under microwave irradi-
ations.
3b
while the thermal treatment of hydrotalcite at 450 ◦C resulted in
a pronounced increase in the specific surface area (Table 1). Such
a behavior has been reported for hydrotalcites containing carbon-
ates and assigned to the formation of craters through the layers
due to evolution of CO2 and H2O [53]. Hydration of the calcined
hydrotalcite in the liquid phase by mechanical stirring resulted in
an increase in surface area due to the rupture of particles and a
marked exfoliation of the crystals [54].
18
92%
53% [43]
N
MeO
N
N
3c
18
92%
–
N
3.2. Catalytic activity study
Me
N
N
The catalytic activity of the as-synthesized and activated hydro-
talcites towards the aza-Michael addition reaction (Scheme 1) was
evaluated. Thus, the reaction of an enaminone (1a,b) with the 5-
amino-1H-pyrazole derivatives (2a–c) in the presence hydrotalcite
catalysts was carried out without solvent under microwave irradia-
tion, to obtain only one isolable product in each case, (as examined
by TLC) which were identified as pyrazolo[1,5-a]pyrimidine deriva-
tives 3a–f (Scheme 1).
All the isolated products 3a–f gave satisfactory elemental anal-
yses and the obtained spectroscopic data (IR, 1H NMR, 13C NMR,
MS) was consistent with their assigned structures. The IR spec-
tra of the products showed the absence of carbonyl absorption
band and amino group absorption bands. The mass spectra of the
isolated products, such as 3c, showed a peak corresponding to
the molecular ion at m/z 301 (see characterization of the reac-
tion products). Its 1H NMR spectrum revealed a singlet signal at
ı 3.61(OCH3), a singlet signal at ı 6.59(CH-3) and two doublet
signals at ı 7.01, 8.33 (J = 5.1 Hz) due to pyrimidine protons (CH-6,
CH-5), respectively, in addition to aromatic protons as a multiplet
at ı 7.38–8.01.
To find optimum conditions for the microwave assisted solvent
free reaction of 1a,b with 2a–c using the as-synthesized and acti-
vated hydrotalcites, the reaction of 1a with 2b, in absence and/or
presence of different hydrotalcite catalysts, was selected as a model
reaction (Scheme 2).
The results obtained from the catalytic test reaction are cited
in Table 2. In blank experiments (without a catalyst), no product
formation was observed.
We performed catalytic studies of HT-As and activated samples
by monitoring product formation; the activities of the catalysts
different significantly (Table 2). The target product was formed
with 100% conversion. It is shown from this table that using
the hydrotalcite and activated hydrotalcites as catalysts resulted
in acceptable yields of the products. The as-prepared hydrotal-
cite (HT-As) is the most effective catalyst for the synthesis of
F
3d
15
92%
–
N
F
N
N
3e
16
90%
N
F
MeO
N
N
3f
15
90%
–
*
Reaction conditions: solvent-free condition, 10 mmol of enaminone derivatives
and 10 mmol of aminopyrazole derivatives, 0.5 g of HT-As catalyst under microwave
irradiations.
**
Lit. conditions [43]: Reflux in ethanol/piperidine.
pyrazolo[1,5-a]pyrimidine derivative 3b, since the highest yield
was achieved in a shortest time. Therefore, this particular catalyst
was selected as the best catalyst to test the other reactions and the
results are summarized in Table 3. It is seen from Table 3 that HT-As
catalyst shows an efficient activity and higher % yield in comparison

128
M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
Table 4
Synthesis of pyrazolo[1,5-a]pyrimidine 3a–f under conventional method using HT-As catalyst.
Enaminone
Heterocyclic Amines
Products
Reaction time* (h)
Yield (%)
N
Me
N
N
NH2
Me
NH
N
2a
3a
5
79
O
N
N
N
NMe2
NH2
1a
NH
N
2b
3b
5
74
N
MeO
N
N
NH2
NH
MeO
N
2c
3c
6
76
N
Me
N
N
NH2
Me
NH
N
F
2a
3d
5
81
O
N
F
N
N
F
NMe2
1b
NH2
NH
N
2b
3e
6
77
N
MeO
N
N
NH2
NH
MeO
N
F
2c
3f
6
75
*
Reaction conditions: 10 mmol of enaminone derivative and 10 mmol of aminopyrazole derivative, 0.5 g of HT-As under reflux in ethanol.
to the literature data. Moreover, some new organic compounds
were synthesized using HT-As catalyst in short time (15–18 min)
and acceptable % yield.
The catalytic performance of HT-As, HT-450, and HT-450-H for
aza-Michael addition reaction depends on their acidic/basic site
nature. Calcinations of as-synthesized hydrotalcites often create
more Lewis basic sites [54]. Moreover, the hydration of the cal-
cined hydrotalcite sample usually gives hydrated phases with high
number of Brønsted basic sites [54]. Hence, one may conclude that
Brønsted basic hydroxyl groups are not alone sufficient, while con-
tributions of Lewis acidic sites (Al3+) might not be ruled out for
driving this reaction [55]. The location of Al3+ cation in the cationic
sheet is greatly affected by the calcination temperature and rehy-
dration process [56–59]. In our recent publication we have claimed
that the high propensity of trivalent Al-ions to migrate to tetrahe-
drally coordinated lattice sites upon calcination and rehydration

M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
129
Table 5
The
durability
test
of
the
HT-As
catalyst
towards
the
synthesis
of
pyrazolo[1,5-a]pyrimidine
derivative 3a–f.
Number of successive uses of HT-As catalyst/yield (%)
Compound no.
1st
2nd
3rd
4th
5th
Time to reach 100% conversion (min)
N
Me
N
N
3a
15/93
15/93
15/93
15/90
15/88
N
N
N
3b
18/92
18/92
18/91
18/88
20/86
N
MeO
N
N
3c
N
18/92
18/92
18/90
18/87
21/86
Me
N
N
F
3d
15/92
15/92
15/91
15/90
16/89
N
N
N
F
3e
15/90
15/90
15/89
15/88
18/86
N
MeO
N
N
F
3f
15/90
15/90
16/89
16/89
18/88
process [60]. Such changes in cation location affect the role of
Al3+ cation from the as-synthesized hydrotalcite (HT-As) to the
activated samples. Therefore, the pronounced efficiency of the as-
synthesized catalyst, over the activated ones, could be attributed to
the different roles played by Al3+ cation together with the Brønsted
basic sites of this particular catalyst, which acts as a bi-functional
catalyst [55]. Such bi-functionality is of use for reactions such as the
aza-Michael addition reaction since it can be carried out in acidic
or basic conditions.
These results encourage us to suggest a mechanism of the reac-
tion in which, to our knowledge, no established mechanism for
the formation of pyrazolo[1,5-a]pyrimidines using hydrotalcite as
a catalyst has been reported. A plausible mechanism is shown in
Scheme 3.

130
M. Mokhtar et al. / Journal of Molecular Catalysis A: Chemical 353–354 (2012) 122–131
Microwave condition
Reflux condition
The reactions carried out under microwave irradiation
show better yield in very short time relative to the clas-
100
90
80
70
60
50
40
30
20
10
0
sical preparation method (Fig. 5). The microwave shows
a
beneficial effect on the synthesis of pyrazolo[1,5-a]pyrimidine
derivatives, in which, a decrease in time of the above reac-
tions from 6 h in conventional procedure to around 20 min was
occurred.
It was necessary to study the durability of the HT-As cata-
lyst in the microwave assisted reactions. Therefore, each reaction
was repeated five times using a regenerated catalyst. The MgAl-
hydrotalcite (HT-As) catalyst was removed after the reaction by
filtration, washed with ethanol and dried under vacuo. The recov-
ered catalyst is reused several times and the time required to
accomplish the reaction was taken as an indication of catalytic
activity, and the results obtained are given in Table 5.
Table 5 shows that the regenerated catalyst performs the reac-
tions efficiently under constant reaction conditions even after being
used for 5 times. The slight decay observed in the catalytic activ-
ity of the HT-As catalyst on the 5th time of being used could be
attributed to temporary poisoning by organic contaminants and/or
to the change in the crystal structure of the catalyst under the
operating conditions. To confirm these speculations the catalyst
that had been reused 5 times under microwave irradiation condi-
tions were characterized using XRD.
3a
3b
3c
3d
3e
3f
Compounds
Fig. 5. Catalytic performance of HT-As under conventional and microwave condi-
tions: time to accomplish the reaction is given in graph bars.
It is shown in Fig. 6 that the intensity of the XRD patterns
increases after 5th time of being subjected to the irradiations
from the microwave during the reaction, which is indicative of an
increase in the degree of crystallinity of the hydrotalcite phase.
The undefined patterns are believed to relate to some organic
contaminants that are presumed to cause some temporary poi-
soning of the catalyst. These results explain the minor decay of
the HT-As catalyst after repeated re-use under these operating
conditions.
1
HT-As
HT-As-5th
1
1
2
2
2
1
1
2
1
2
2
4. Conclusions
2
2
1
An efficient benign method for the synthesis of pyrazolo[1,5-
a]pyrimidine derivatives using a MgAl-hydrotalcite catalyst, under
microwave irradiation has been established. A significantly higher
yield and shorter reaction time was observed when using the
as-synthesized Mg–Al-hydrotalcite rather than the other acti-
vated HT catalysts. The pronounced catalytic performance of the
as-synthesized Mg–Al-hydrotalcite is mainly due to appropriate
cooperative behavior of acid–base pair sites. A suggested mecha-
nism for aza-Michael addition reaction has been provided using an
as-synthesized Mg–Al-hydrotalcite bi-functional acid-base catalyst
for the first time. The prepared catalyst showed constant durability
until the 5th time of reuse under the specific operating conditions.
1
1
1
10
20
30
2Θ (o)
40
50
Fig. 6. XRD patterns of HT-As and HT-As catalyst after 5th time working conditions.
(1) Hydrotalcite phase and (2) organic contaminants.
It is presumed that the reaction proceeds via adsorption of
educts lone pair donation to the acidic sites (Al3+), while the
Brønsted basic sites (OH−) of the hydrotalcite facilitates the
nucleophilic addition via deprotonation/re-protonation process
resulting in the Michael addition adduct 4. A subsequent cycliza-
tion via dehydration then aromatization via loss of dimethyl amine
molecule produces the pyrazolo[1,5-a]pyrimidine derivatives.
In order to address for the advantage of microwave irradi-
ation on this reaction, the previously mentioned reaction were
carried out using conventional method using hydrotalcite cata-
lysts in ethanol as solvent (Table 4). The obtained results revealed
that the reactions are carried out in a longer time to attain a
much lower yield than that obtained using microwave proto-
col.
Acknowledgements
This work was supported by the deanship of scientific research
at King Abdulaziz University and Saudi Basic Industries Corporation
(SABIC) (project no. MS 3/11). The Authors are grateful to Dr Felicity
Sartain for her contribution to discussions and assistance during
this research.
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