Synthesis of pyrazolopyridines catalyzed by nano-CdZr4(PO4)6 as a reusable catalyst

Article abstract of DOI:10.1007/s11164-016-2585-9

Abstract: A simple and efficient method for the preparation of pyrazolopyridines by a multicomponent reaction of ethyl acetoacetate, an aldehyde, hydrazine and ammonium acetate using nano-CdZr₄(PO₄)₆ as an efficient cataly

Full text of DOI:10.1007/s11164-016-2585-9

Res Chem Intermed
DOI 10.1007/s11164-016-2585-9
Synthesis of pyrazolopyridines catalyzed
by nano-CdZr4(PO4)6 as a reusable catalyst
Javad Safaei-Ghomi1 Hossein Shahbazi-Alavi1
•
•
Reyhaneh Sadeghzadeh1 Abolfazl Ziarati2
•
Received: 11 February 2016 / Accepted: 19 May 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A simple and efficient method for the preparation of pyrazolopyridines by a
multicomponent reaction of ethyl acetoacetate, an aldehyde, hydrazine and ammonium
acetate using nano-CdZr4(PO4)6 as an efficient catalyst is presented. The main advan-
tages of this protocol include short reaction times, practical simplicity, high yields,
recyclable catalysts and applicability to wide range of substrates.
Graphical Abstract
R
R
O
N
N
N
H
N
H
N
H
O
O
O
O
O
O
nano-CdZr4(PO4)6
H
H
N
H
N
N
NH2NH2
NH2NH2
N
N
N
NH4OAc
O
N
HN
O
N
N
H
H
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2585-9)
contains supplementary material, which is available to authorized users.
&
Javad Safaei-Ghomi
safaei@kashanu.ac.ir
1
2
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan 51167,
Islamic Republic of Iran
School of Chemistry, College of Science, University of Tehran, Tehran 14155-6455,
Islamic Republic of Iran
123

J. Safaei-Ghomi et al.
Keywords Nano-CdZr4(PO4)6 Á Pyrazolopyridines Á Nanocatalyst Á
Multicomponent reaction
Introduction
Pyrazolopyridines are attractive targets in organic and medicinal chemistry owing to
their potency and wide spectrum of biological activities including antioxidant,
antitumor and antimicrobial [1, 2], treatment of Type 2 diabetes mellitus [3], anti-
virus [4], anti-Leishmania [5], protein kinase inhibitors [6] dopaminergic properties
[7] and can also serve as synthetic intermediates for many kinds of pharmaceuticals
or drug precursors [8–10]. Therefore, the development of simple methods for the
synthesis of pyrazolopyridines is a major challenge and an interesting field in
chemistry. The synthesis of pyrazolopyridine derivatives has been reported in the
presence of diverse catalysts such as carbonaceous material (C-SO3H) [11], L-
Proline [12], acetic acid [13] and p-TSA [14]. However, some of the reported
methods tolerate disadvantages including long reaction times, harsh reaction
conditions and use of toxic and non-reusable catalyst. Therefore, to avoid these
limitations, the exploration of an efficient, easily available catalyst with high
catalytic activity and short reaction time for the preparation of pyrazolopyridine is
still favored. Conventional step-by-step synthetic methods cannot actualize the
requirements of modern synthetic chemistry, but multicomponent reactions (MCRs)
have been developed as an efficient and powerful tool in modern synthetic organic
chemistry [15–18]. The possibility of accomplishing multicomponent reactions
under moderate conditions with a heterogeneous catalyst could improve their
effectiveness from operating cost and ecological points of view. Nanoparticles have
emerged as viable alternatives to conventional materials, as robust, high surface area
heterogeneous catalysts and catalyst supports [19, 20]. MZr4(PO4)6 structure
ceramics have been interested because of their unique properties and potential
applications in diverse fields [21, 22]. Herein we reported the use of nanocrystalline
CdZr4(PO4)6 ceramics as an efficient catalyst for the preparation of tetrahydropy-
razolopyridines by a multicomponent reaction of ethyl acetoacetate, an aldehyde,
hydrazine hydrate and ammonium acetate under reflux conditions in ethanol
(Scheme 1).
Experimental
All organic materials were purchased commercially from Sigma–Aldrich and Merck
and were used without further purification. A multiwave ultrasonic generator
(Sonicator 3200; Bandelin, MS 73, Germany), equipped with a converter/transducer
and titanium oscillator (horn), 12.5 mm in diameter, operating at 20 kHz with a
maximum power output of 200 W, was used for the ultrasonic irradiation. The
ultrasonic generator automatically adjusted the power level. All melting points are
uncorrected and were determined in capillary tube on Boetius melting point
123

Synthesis of pyrazolopyridines catalyzed by…
microscope. FT-IR spectra were recorded with KBr pellets using a Magna-IR,
spectrometer 550 Nicolet. NMR spectra were recorded on a Bruker Avance III
400 MHz spectrometer with DMSO-d6 as solvent and TMS as internal standard.
CHN compositions were measured by Carlo ERBA Model EA 1108 analyzer.
Powder X-ray diffraction (XRD) was carried out on a Philips diffractometer of
˚
X’pert Company with monochromatized Zr Ka radiation (k = 1.5406 A). In order
to investigate the particle size and morphology of the synthesis structures nano-
CdZr4(PO4)6, FE-SEM images of the products visualized by a HITACHI S4160
Field Emission Scanning Electron Microscope.
Preparation of nano-CdZr4(PO4)6
Nano-CdZr4(PO4)6 was prepared according to the procedure reported in the
literature [23]. ZrOCl2 was used as zirconium source. Firstly 1 mmol (322 mg) of
ZrOCl2Á8H2O and 1 mmol (266 mg) of Cd(OAC)2Á2H2O were added in 15 mL of
HO(CH2)2OH and sonicated at 30 W power to completely dissolution. Afterward
0.8 mL H3PO4 (85 %), 4 mmol of NH4Cl and 1.4 mL of CH3NH2 water solution
(25.0–30.0 %) were added consecutively and sonicated for 30 min. Then, the
reaction mixture was transferred into a Teflon-lined autoclave under autogenous
pressure at 200 °C for 5 days. When the reaction was completed, dispersed
precipitate was obtained. The solid was filtered and washed with distilled water and
ethanol several times. Subsequently product was dried at 50 °C for 5 h and calcined
at 700 °C for 2 h. Afterward the solid was added in 20 mL of DMF and sonicated at
95 W power for 2 h. Finally the resulting product was filtered, washed with distilled
water and absolute ethanol and dried at 150 °C for 2 h in vacuum to afford pure
nano-CdZr4(PO4)6 ceramics.
General procedure for the preparation of tetrahydrodipyrazolopyridines
A mixture of hydrazine hydrate (2.0 mmol) and ethyl acetoacetate (2 mmol) and
nano-CdZr4(PO4)6 (0.6 mol%) in EtOH (5 mL) was magnetically stirred at 25 °C
followed by addition of aldehyde (1.0 mmol) and ammonium acetate (4.0 mmol).
R
R
nano-CdZr4(PO4)6
O
O
+
NH4OAc
+
2 NH2NH2
+
OEt
N
N
ethanol
reflux
2
O
N
H
N
H
N
H
4
1
2
3
5
Scheme 1 Synthesis of tetrahydrodipyrazolo pyridines by nano-CdZr4(PO4)6
123

J. Safaei-Ghomi et al.
The reaction mixture was heated at reflux for 30–40 min and then cooled to
25 °C. The formed precipitate was isolated by filtration. The product was
dissolved in hot CH3OH and the catalyst was filtered. After cooling, the crude
products were precipitated. The precipitate was washed with EtOH to afford the
pure product and then dried well under vacuum pump (note: Hydrazine solutions
are hazardous because of their toxic, corrosive, flammable or explosive
properties. Hydrazine solutions should always be handled with great care. Avoid
inhaling the vapours from hydrazine solutions at all times and whenever possible
use a reliable fume hood. Avoid skin contact with hydrazine at all times).
Spectral data
3,5-Dimethyl-4-(4-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;40,30-e]
pyridine (5a)
Cream solid; m.p. 295–297 °C; IR (KBr): mmax 3329 (stretching, NH), 2963
(stretching, CH), 1603 (aromatic C=C), 1511 (stretching NO2), 1348 (stretching
NO2), 846 (C–H out of plan bending, para-substituted) cm-1; 1H NMR (400 MHz,
DMSO-d6) d 2.07 (s, 6H, 2CH3), 4.95 (s, 1H, CH), 7.34–7.36 (d, 2 H, J = 8 Hz,
2CH, ArH), 8.09–8.11 (d, 2 H, J = 8 Hz, 2CH, ArH), 11.25 (s, 3H, 3 NH) ppm; 13
C
NMR (100 MHz, DMSO-d6) d 10.75, 33.43, 103.62, 123.46, 129.25, 140.18,
146.09, 152.24, 161.34 ppm; Anal.Calcd. For C15H14N6O2: C, 58.06; H, 4.55; N,
27.08; Found C, 58.14; H, 4.51; N, 27.14.
3,5-Dimethyl-4-(4-methyl-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;40,30-e]
pyridine (5b)
White solid; m.p. 243–245 °C; IR (KBr): mmax 3300 (stretching, NH), 2924
1
(stretching, CH), 1602 (aromatic C=C), 1130 (stretching, C–N) cm-1; H NMR
(400 MHz, DMSO-d6) d 2.04 (s, 6H, 2CH3), 2.21 (s, 3H, CH3), 4.74 (s, 1H, CH),
6.98–7.00 (m, 4H, 4 CH of aromatic), 11.24 (s, 3H, 3 NH) ppm; 13C NMR
(100 MHz, DMSO-d6) d 10.84, 20.95, 32.84, 104.82, 127.81, 128.80, 134.68,
140.21, 140.72, 161.52 ppm; Anal.Calcd. For C16H17N5: C, 68.79; H, 6.13; N,
25.07; Found C, 68.72; H, 6.24; N, 25.14.
3,5-Dimethyl-4-(3-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;40,30-e]
pyridine (5c)
Cream solid; m.p. 286–288 °C; IR (KBr): mmax 3200 (stretching, NH), 2963
(stretching, CH), 1599 (aromatic C=C), 1527 (stretching, NO2), 1347 (stretching,
NO2), 1300 (stretching, C–N) cm-1; 1H NMR (400 MHz, DMSO-d6) d 2.05 (s, 6H,
2CH3), 4.97 (s, 1H, CH), 7.52 (m, 2 H, 2CH, ArH), 7.93 (s, 1H, CH, ArH), 8.02 (d, 1
H, J = 8 Hz, CH, ArH), 11.25 (s, 3H, 3 NH) ppm; 13C NMR (100 MHz, DMSO-d6)
d 10.74, 33.11, 103.74, 121.22, 122.32, 129.72, 135.20, 140.22, 146.26, 148.05,
123

Synthesis of pyrazolopyridines catalyzed by…
161.3 ppm; Anal.Calcd. For C15H14N6O2: C, 58.06; H, 4.55; N, 27.08; Found C,
58.17; H, 4.49; N, 27.15.
3,5-Dimethyl-4-(4-methoxy-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;40,30-e]
pyridine (5d)
Cream solid; m.p. 186–188 °C; IR (KBr): mmax 3267 (stretching, NH), 2924
1
(stretching, CH), 1597 (aromatic C=C), 1239 (stretching, C–O) cm-1; H NMR
(400 MHz, DMSO-d6) d 2.04 (s, 6H, 2 CH3), 3.69 (s, OCH3), 4.74 (s, 1H, CH),
6.74–6.76 (d, 2 H, J = 8 Hz, 2CH, ArH), 6.99–7.01 (d, 2 H, J = 8 Hz, 2CH, ArH),
11.32 (s, 3H, 3 NH) ppm; 13C NMR (100 MHz, DMSO-d6) d 10.82, 32.40, 55.51,
104.92, 113.53, 128.82, 135.66, 140.12, 146.18, 157.68 ppm; Anal.Calcd. For
C16H17N5O: C, 65.07; H, 5.80; N, 23.71; Found C, 65.12; H, 5.89; N, 23.77.
1,4,7,8-Tetrahydro-3,5-dimethyl-4-phenyldipyrazolo-[3,4-b:40,30-e]pyridine (5e)
White solid; m.p. 240–242 °C; IR (KBr): mmax 3181 (stretching, NH), 2924
1
(stretching, CH), 1600 (aromatic C=C), 1200 (stretching, C–N) cm-1; H NMR
(400 MHz, DMSO-d6) d 2.04 (s, 6H, 2CH3), 4.79 (s, 1H, CH), 7.09–7.19 (m, 5 H,
CH, ArH), 11.34 (s, 3H, 3 NH) ppm; 13C NMR (100 MHz, DMSO-d6) d 10.84,
33.24, 104.65, 125.84, 127.92, 128.16, 140.24, 143.82, 161.54 ppm; Anal.Calcd.
For C15H15N5: C, 67.90; H, 5.70; N, 26.40; Found C, 67.97; H, 5.77; N, 26.49.
3,5-Dimethyl-4-(2-methyl-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;40,30-e]
pyridine (5f)
White solid; m.p. 290–292 °C; IR (KBr): mmax 3300 (stretching, NH), 2923
1
(stretching, CH), 1602 (aromatic C=C), 1202 (stretching, C–N) cm-1; H NMR
(400 MHz, DMSO-d6) d 1.87 (s, 6H, 2CH3), 2.09 (s, 3H, CH3), 4.91 (s, 1H, CH),
7.03–7.17 (m, 4H, 4CH, ArH), 10.65 (s, 3H, 3 NH) ppm; 13C NMR (100 MHz,
DMSO-d6) d 10.88, 20.73, 32.83, 104.80, 125.51, 127.80, 128.85, 129.34, 134.69,
140.24, 140.74, 161.69 ppm; Anal.Calcd. For C16H17N5: C, 68.79; H, 6.13; N,
25.07; Found C, 68.88; H, 6.10; N, 25.15.
3,5-Dimethyl-4-(4-chloro-phenyl)-1,4,7,8-tetrahydrodipyrazolo [3,4-b;40,30-e]
pyridine (5g)
White solid; m.p. 255–257 °C; IR (KBr): mmax 3180 (stretching, NH), 2924
(stretching, CH), 1597 (aromatic C=C), 1091 (stretching, C–N), 607 (stretching, C–
Cl) cm-1; 1H NMR (400 MHz, DMSO-d6) d 2.05 (s, 6H, 2CH3), 4.79 (s, 1H, CH),
7.09–7.11 (d, J = 8 Hz, 2 H, 2 CH, ArH), 7.24–7.26 (d, J = 8 Hz, 2H, 2CH, ArH),
11.50 (s, 3H, 3 NH) ppm; 13C NMR (100 MHz, DMSO-d6) d 10.78, 32.67, 104.34,
128.06, 129.85, 130.49, 140.16, 142.78, 161.46 ppm; Anal.Calcd. For C15H14ClN5:
C, 60.10; H, 4.71; N, 23.36 Found C, 60.15; H, 4.78; N, 23.28.
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J. Safaei-Ghomi et al.
3,5-Dimethyl-4-(4-bromo-phenyl)-1,4,7,8-tetrahydrodipyrazolo [3,4-b;40,30-e]
pyridine (5h)
Yellow solid; m.p. 165–167 °C; IR (KBr): mmax 3100 (stretching, NH), 2924
(stretching, CH), 1598 (aromatic C=C), 1142 (stretching, C–N), 508 (stretching, C–
Br) cm-1; 1H NMR (400 MHz, DMSO-d6) d 2.06 (s, 6H, 2CH3), 4.78 (s, 1H, CH),
7.03–7.05 (d, J = 8 Hz, 2 H, 2 CH, ArH), 7.39–7.41 (d, J = 8 Hz, 2H, 2 CH, ArH),
11.50 (s, 3H, 3 NH) ppm; 13C NMR (100 MHz, DMSO-d6) d 10.23, 32.43, 104.45,
118.30, 129.62, 130.34, 131.85, 142.66, 157.42 ppm; Anal.Calcd. For C15H14BrN5:
C, 52.34; H, 4.10; N, 20.35 Found C, 52.39; H, 4.15; N, 20.30.
4-(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:40,30 e]pyridin-4-yl)-N,N-
dimethylaniline (5i)
Cream solid; m.p. 240–242 °C; IR (KBr): mmax 3200 (stretching, NH), 2950
1
(stretching, CH), 1598 (aromatic C=C), 1145 (stretching, C–N) cm-1; H NMR
(400 MHz, DMSO-d6) d 2.04 (s, 6H, 2CH3), 2.98 (s, 6 H, N(CH3)2), 4.64 (s, 1H,
CH), 6.56–6.58 (d, J = 8 Hz, 2 H, 2CH, ArH), 6.90–6.92 (d, J = 8 Hz, 2H, 2CH,
ArH), 11.28 (s, 3H, 3 NH) ppm; 13C NMR (100 MHz, DMSO-d6) d 10.84, 32.35,
40.92, 105.23, 112.73, 128.35, 131.64, 137.02, 149.05, 161.66 ppm; Anal.Calcd.
For C17H20N6: C, 66.21; H, 6.54; N, 27.25 Found C, 66.33; H, 6.59; N, 27.36.
3,5-Dimethyl-4-(4-hydroxy-phenyl)-1,4,7,8-tetrahydrodipyrazolo [3,4-b;40,30-e]
pyridine (5j)
White solid; m.p. 267–268 °C; IR (KBr): mmax 3266–3300 (stretching, NH and OH),
2924 (stretching, CH), 1562 (aromatic C=C) cm-1; 1H NMR (400 MHz, DMSO-d6)
d 2.03 (s, 6H, 2CH3), 4.65 (s, 1H, CH), 6.56–6.58 (d, J = 8 Hz, 2 H, 2CH, ArH),
6.88–6.90 (d, J = 8 Hz, 2H, 2CH, ArH), 9.10 (s, OH), 11.50 (s, 3H, 3NH) ppm; 13
C
NMR (100 MHz, DMSO-d6) d 10.32, 31.75, 104.5, 114.42, 128.23, 133.35, 139.76,
155.03, 161.04 ppm; Anal.Calcd. For C15H15N5O: C, 64.04; H, 5.37; N, 24.90;
Found C, 64.09; H, 5.30; N, 24.83.
3,5-Dimethyl-4-(2-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[3,4-b;40,30-e]
pyridine (5k)
Cream solid; m.p. 187–188 °C; IR (KBr): mmax 3300 (stretching, NH), 2925
(stretching, CH), 1604 (aromatic C=C), 1525 (stretching, NO2), 1360 (stretching,
NO2), 1177 (stretching, C–N) cm-1; 1H NMR (400 MHz, DMSO-d6) d 1.90 (s, 6H,
2 CH3), 5.43 (s, 1H, CH), 7.36–7.68 (m, 4 H, 4 CH, ArH), 10.95 (s, 3H, 3 NH) ppm;
13C NMR (100 MHz, DMSO-d6) d 10.02, 28.94, 101.94, 123.85, 127.12, 130.22,
131.64, 136.24, 138.62, 149.50, 160.54 ppm; Anal.Calcd. For C15H14N6O2: C,
58.06; H, 4.55; N, 27.08; Found C, 58.15; H, 4.43; N, 27.13.
123

Synthesis of pyrazolopyridines catalyzed by…
1,4-Bis[(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:40,30-e]pyridin-4-yl)]
benzene (5l)
Orange solid, m.p.[300 °C; IR (KBr): mmax 3200 (stretching, NH), 1591 (aromatic
1
C=C), 1200 (stretching, C–N) cm-1; H NMR (400 MHz, DMSO-d6) d 2.05 (s,
12H, 4CH3), 4.70 (s, 2H, 2CH), 6.94 (4 H, 4CH, ArH), 11.25 (s, 6H, 6NH) ppm; 13
C
NMR (100 MHz, DMSO-d6) d 10.70, 33.20, 104.55, 129.34, 134.43, 139.50,
160.20 ppm; Anal.Calcd. For C24H24N10: C, 63.70; H, 5.35; N, 30.95; Found C,
63.79; H, 5.44; N, 30.85; MS (EI, 70 eV): m/z 452 (M?).
Results and discussion
ZrOCl2 and Cd(OAc)2Á2H2O were utilized as the starting materials for the
preparation of nano-CdZr4(PO4)6. In this technique, the ultrasonic irradiation was
performed before and after solvothermal method. Sonication was used to speed
dissolution, by breaking the interactions between particles. When the solution
containing precursor is exposed via an ultrasound solvothermal route, extremely
high pressures and temperatures are produced to generate CdZr4(PO4)6 nuclei. At
the beginning of the reaction, the reactant particles and the moleculars of
methylamine disperse randomly in the glycol solution under ultrasound irradiation.
The CdZr4(PO4)6 form gradually around the methylamine moleculars. After
calcined at a high temperature, methylamine decomposed into carbon dioxide,
carbon monoxide and nitrogen oxide, thus the nano-CdZr4(PO4)6 were finally
obtained. The particle size diameter (D) of the nano-CdZr4(PO4)6 has been
calculated by the Debye–Scherrer equation (D = Kk/b cos h), where b FWHM
(full-width at half-maximum or half-width) is in radian and h is the position of the
maximum of the diffraction peak. K is the so-called shape factor, which usually
takes a value of about 0.9, and k is the X-ray wavelength. Figure 1 shows the XRD
spectra of nano-CdZr4(PO4)6. The pattern agrees well with the reported pattern for
nano-CdZr4(PO4)6 (JCPDS no. 45-0017). All the strong peaks appeared at
2h = 19.92, 22.08, 24.30, 25.02, 28.85, 31.12, 35.14, 38.50, 41.05, 42.71, 46.50,
48.32, 51.37, 55.42, 60.21, 63.72, 67.02, 70.87, 74.52 are indexed to the highly
crystalline monoclinic structure of nano-CdZr4(PO4)6. According to the Debye–
Scherrer equation, the average particle sizes of the as-synthesized nano-CdZr4
(PO4)6 were calculated and the results show that nano-CdZr4(PO4)6 was obtained
with an average diameter of 19–23 nm as confirmed by XRD analysis. In order to
investigate the morphology and particle size of nano-CdZr4(PO4)6, FE-SEM image
of nano-CdZr4(PO4)6 was presented in Fig. 2. The FE-SEM image shows particles
with diameters in the range of nanometers.
Initially, we carried out the MCR between hydrazine hydrate, ethyl acetoacetate,
4-nitrobenzaldehyde and ammonium acetate in the presence of different catalyst.
Meanwhile, we observed the effect of different solvents on the progress of reaction.
Ethanol was found to be the best solvent, in which the product was obtained in 94 %
yield. Unfortunately, when the model reaction was carried out in water, the desired
product was only obtained in 62 % yield.
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J. Safaei-Ghomi et al.
Fig. 1 XRD pattern of nano-CdZr4(PO4)6
Fig. 2 SEM images of nano-CdZr4(PO4)6
The model reaction was carried out in the presence of various catalysts such
Et3N, ZnS, nano-ZrO2, nano-CeO2, nano-CdZr4(PO4)6. When the reaction was
carried out using (0.6 mol%) nano-CdZr4(PO4)6 as the catalyst, the product could be
obtained in good yield (Table 1).
The recycling of nano-CdZr4(PO4)6 catalyst was checked and the results are
summarized in Fig. 3. The possibility of recycling of the catalyst is a significant
123

Synthesis of pyrazolopyridines catalyzed by…
Table 1 Optimization of reaction conditions
Entry
Catalyst (mol%)
Solvent
Time (min)
Yield (%)a
1
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
300
400
200
100
100
40
53
58
62
68
64
90
94
94
62
74
70
2
Et3N (20)
3
ZnS NPs (4)
4
Nano-ZrO2 (4)
5
Nano-CeO2 (3)
6
Nano-CdZr4(PO4)6 (0.4)
Nano-CdZr4(PO4)6 (0.6)
Nano-CdZr4(PO4)6 (0.8)
Nano-CdZr4(PO4)6 (0.6)
Nano-CdZr4(PO4)6 (0.6)
Nano-CdZr4(PO4)6 (0.6)
7
40
8
40
9
110
80
10
11
CH3CN
DMF
80
Hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol), 4-nitrobenzaldehyde (1 mmol) and ammo-
nium acetate (4 mmol)
a
Isolated yield
Fig. 3 Reusability of nano-CdZr4(PO4)6 as catalyst for the synthesis of 5a
process from different aspects such as environmental concerns, and commercial
applicable processes. In the recycling procedure of nanocrystalline CdZr4(PO4)6
ceramics, hot CH3OH was added to dilute the reaction mixture after terminating the
reaction. The catalyst was insoluble in the solvent and was separated by filtering.
The reusability of the catalyst was tested for eight runs, providing almost similar
yields of the desired product.
123

J. Safaei-Ghomi et al.
Fig. 4 SEM images of nano-CdZr4(PO4)6 before use (a) and after reuse of eight times (b)
The morphology of nano-CdZr4(PO4)6 was investigated by scanning electron
microscopy (SEM) before use and after reuse of eight times with images shown in
Fig. 4. The morphology of the nanoparticles remained almost unchanged before and
after reaction. We believe that, this is also the possible reason for the extreme
stability of the nano-CdZr4(PO4)6 presented herein. The extreme stability of the
nano-CdZr4(PO4)6 is mainspring of the continuous and high catalytic activity.
With these encouraging results in hand, we turned to explore the scope of the
reaction using different aromatic aldehydes as substrates under the optimized
reaction conditions (Table 2). In general the reactions are clean and high-yielding.
Several functional groups, such as Br, OH, Cl, NO2, OMe, N(CH3)2, and CH3, are
compatible under the reaction conditions. Interestingly, a variety of aromatic
aldehydes, including ortho, meta and para-substituted aryl aldehydes, participated
well in this reaction and gave the corresponding products in a good to excellent
yield (Table 2). The influence of electron-withdrawing and electron-donating
substituents on the aromatic ring of aldehydes upon the reaction yields was
investigated. It was shown that aromatic aldehydes with electron-withdrawing
groups reacted faster than those with electron-releasing groups. Meanwhile, the
practicable synthetic efficiency of this reaction was highlighted by the reaction of
terephthaldehyde, hydrazine hydrate, and ammonium acetate and ethyl acetoacetate
to give 1,4-Bis[(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:40,30-e]pyridin-4-yl)]
benzene (Scheme 2).
A plausible mechanism for the preparation of tetrahydrodipyrazolo pyridines
using nano-CdZr4(PO4)6 is shown in Scheme 3. The mechanism involves the initial
nucleophilic attack of hydrazine on the ethyl acetoacetate and subsequent
cyclization to form the pyrazolone and then, the reaction of pyrazolone with an
aldehyde to give intermediate II. In the next step, the reaction can be followed by
attack of the second pyrazolone ring that leads to the formation of III. Finally,
nucleophilic attack of ammonia on intermediate III followed by intramolecular
cyclization leads to product 5. In this mechanism, the surface atoms of nano-
CdZr4(PO4)6 activate the C=O groups for better reaction with nucleophiles. These
surface atoms behave as the centers where chemical reactions could be catalytically
stimulated.
123

Synthesis of pyrazolopyridines catalyzed by…
Table 2 Synthesis of tetrahydrodipyrazolo pyridines
Entry 5a–
5l
Aldehyde Product
Time
(min)
Yield
(%)a
Melting points (°C)
Reported
[References]
Found
NO2
CHO
1
2
5a
5b
40
45
94
[300 [24]
295–297
NO2
N
N
N
H
N
H
N
H
CHO
86
244–246 [24]
243–245
N
N
N
N
H
N
N
H
H
NO2
CHO
CHO
3
4
5c
42
48
90
84
286–288 [24]
185–187 [24]
286–288
186–188
NO2
N
N
H
N
H
N
H
MeO
5d
OMe
CHO
N
N
N
H
N
H
N
H
5
6
5e
5f
43
48
88
83
240–242 [24]
240–242
290–292
N
N
N
H
N
N
H
H
CHO
–
N
N
N
H
N
N
H
H
Cl
CHO
Cl
7
5g
40
92
254–256 [24]
255–257
N
N
N
H
N
N
H
H
123

J. Safaei-Ghomi et al.
Table 2 continued
Entry 5a–
5l
Aldehyde Product
Time
(min)
Yield
(%)a
Melting points (°C)
Reported
[References]
Found
Br
CHO
8
5h
40
91
165–167 [25]
165–167
Br
N
N
N
N
N
H
N
H
N
H
NMe2
CHO
9
5i
50
82
240–242 [24]
240–242
NMe2
CHO
N
N
H
N
N
H
H
OH
10
5g
50
80
267–268 [25]
267–268
OH
N
N
H
N
H
N
H
CHO
11
12
5k
40
45
91
85
187–188 [25]
187–188
NO2
O2N
N
N
N
N
H
N
H
H
H
N
5l
CHO
CHO
H
N
–
[300
H
N
N
N
N
HN
N
N
N
H
H
a
Isolated yield
Conclusion
In conclusion, we have developed a straightforward and efficient approach to
synthesis of tetrahydrodipyrazolopyridines by a simple one-pot pseudo six-
component reaction of hydrazine hydrate, ethyl acetoacetate, aldehydes and
ammonium acetate in the presence of nano-CdZr4(PO4)6 as catalyst. The method
123

Synthesis of pyrazolopyridines catalyzed by…
H
N
H
N
H
N
N
N
N
O
nano-CdZr4(PO4)6
O
O
NH4OAc
+
+
O
+
OEt
2 NH2NH2
ethanol
reflux
2
N
HN
N
N
H
H
4
1
2
3 l
5l
Scheme 2 Synthesis of 1,4-Bis[(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:40,30-e]pyridin-4-yl)]
benzene by nano-CdZr4(PO4)6
HN
N
O
O
O
H
H
I
+
N
EtO
H
H2N
O
HN
N
H
Ar
Ar
O
N
HN
N
N
NH
HN
O
O
O
III
Ar
Ar
NH3
II
Ar
N
N
N
NH
N
HN
N
H
N
N
H
H
HN
O
= nano-CdZr4(PO4)6
Scheme 3 Proposed mechanism for the pseudo six-component process
123

J. Safaei-Ghomi et al.
offers several advantages including rapid assembly of medicinally privileged
heterocyclic molecules, cleaner reaction profiles, use of easily available, high yields,
shorter reaction time and simple experimental and reusability of the catalyst. This
green nanocatalyst could be used for other significant organic reactions and
transformations. We hope that this article will serve to stimulate research in this
fascinating and very useful area of organic synthesis.
Acknowledgments The authors acknowledge a reviewer who provided helpful insights. Meanwhile, the
authors are grateful to university of Kashan for supporting this work by Grant No. 159196/XXII.
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