A pseudo six-component process for the synthesis of tetrahydrodipyrazolo pyridines using an ionic liquid immobilized on a FeNi3 nanocatalyst

Article abstract of DOI:10.1039/c6ra02906j

A highly efficient method for the synthesis of tetrahydrodipyrazolopyridines by a multicomponent reaction of ethyl acetoacetate, an aldehyde, hydrazine and ammonium acetate using an ionic liquid (IL) supported on a FeNi₃ nanocatalyst is describ

Full text of DOI:10.1039/c6ra02906j

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ARTICLE TYPE
Pseudo six-component process for the synthesis of tetrahydrodipyrazolo
pyridines using Ionic liquid immobilized on FeNi3 nanocatalyst
Javad Safaei-Ghomi*, Reyhaneh Sadeghzadeh, Hossein Shahbazi-Alavi
5
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, P.O. Box 87317ꢀ51167, I. R.Iran
Corresponding author. Eꢀmail addresses: safaei@kashanu.ac.ir, Fax: +98ꢀ31ꢀ55912397; Tel.: +98ꢀ31ꢀ55912385
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
10
A highly efficient method for the synthesis of tetrahydrodipyrazolopyridines by a
multicomponent reaction of ethyl acetoacetate, an aldehyde, hydrazine and ammonium
acetate using ionic liquid (ILs) supported on FeNi3 nanocatalystis described. This method
provides several advantages including mild reaction conditions, applicability to wide range of
substrates, reusability of the catalyst and little catalyst loading.
viscosity, and catalysis activities.16ꢀ18 Although ILs possess some
advantages but their useful applications have been limited by
15 1. Introduction
Pyrazolopyridines represent a common scaffold in numerous
bioactive compounds and have a number of pharmacological
properties. The pyrazolopyridines exhibit important biological
properties such as antiꢀvirus,1 antiꢀLeishmania,2 protein kinase
20 inhibitors,3 PDE4B inhibitors,4 HIF 1ꢀαprolyl hydroxylase
inhibitors,5 BꢀRafV600Einhibitors,6 and dopaminergic properties.7
The synthesis of pyrazolopyridines has been reported using
MCRs in the presence of diverse catalysts including
carbonaceous material (CꢀSO3H),8 LꢀProline,9 acetic acid,10 and pꢀ
25 TSA.11 Many methods for the synthesis of pyrazolopyridines are
known, but some of these methods have certain drawbacks,
including long reaction times, use of toxic and nonꢀreusable
catalyst and utilize of specific conditions. Therefore, looking for
efficient and simple methods for the synthesis of
30 pyrazolopyridines is an attractive challenge. For this reason,
Multicomponent reactions (MCRs) are particularly well suited for
some difficulties in its recovery which lead to economical and
50 environmental problems. These problems can be overcome by
immobilization of ILs onto solid supports to obtain heterogeneous
catalysts.19 FeNi3core–shell nanoparticles were used as a suitable
catalyst in many reactions including synthesis of 1,3ꢀthiazolidinꢀ
20
4ꢀone, Triazolo[1,2ꢀa]indazoleꢀtriones,21 and synthesis of 4Hꢀ
55 benzo[b]pyrans.22 Recently, immobilized functional ionic liquids
as efficient, green, and reusable catalysts have been described by
Yang et al. and the results are compared with those of traditional
ILs.23 Herein, we reported the use of ionic liquid (ILs)
supported on FeNi3 nanocatalystis as an efficient catalyst for
60 the
preparation
of tetrahydrodipyrazolo pyridinesby
multicomponent reaction of ethyl acetoacetate, aldehydes,
hydrazine and ammonium acetate under reflux conditions in
ethanol (Scheme 1).
diversityꢀoriented
synthesis.12ꢀ13
Thus;
the
synthesis
65
<Scheme 1>
pyrazolopyridines by the multicomponent reactions with a
heterogeneous catalyst could enhance their efficiency from
35 economic and ecological points of view. To overcome the
separation problems of the nanocatalysts, magnetic materials
have emerged as recoverable catalysts. Separation of magnetic
2. Results and discussion
At first FeNi3 nanoparticles were prepared according to method
reported in the literature with some modifications.20,24 (Scheme
nanoparticles
is
easy,
convenient,
economical
and
environmentally benign.14ꢀ15 One of the most attractive
40 alternatives to catalyst supports are magnetic nanoparticles
(MNPs), which have witnessed increasing popularity due to their
high surface areas and improved disperse ability in the reaction
medium. In recent years, ionic liquids (ILs) as being
environmentalꢀfriendly reaction media had attracted significant
45 attention for their unique properties, such as high thermal
stability, negligible vapor pressure, suitable solvents, high
70 2). NanoꢀFeNi3 was capped with SiO2 generated from the
hydrolyzation of tetraethyl orthosilicate (TEOS). After being
coated with a SiO2 and organic layer, the typical core–shell
structure of the FeNi3ꢀILs MNPs can be observed. The structural
properties of synthesized FeNi3ꢀILs MNPs were analyzed by Xꢀ
75 ray power diffraction (XRD). As shown in Fig. 1.
<Scheme 2>
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ꢀ
the aid of ILs. FeNi3ꢀSO3 +NH3ꢀCH2CH2ꢀOH composed of
ꢀ
FeNi3ꢀSO3 as anion and +NH3ꢀCH2CH2ꢀOH as cation.
Fig. 1.
60
In order to investigate the morphology and particle size of
nanoparticles, SEM image of nanoparticles was presented in
Fig.2. The SEM image shows particles with diameters in the
range of nanometers. The results show that FeNi3ꢀILs MNPs were
obtained with an average diameter of 30–35 nm as conformed by
XRD analysis.
We also investigated recycling of FeNi₃ꢀILsMNPs as catalyst
under reflux conditions in ethanol. After completion of the
reaction, the catalyst was separated using an external magnet,
washed with methanol and dried with a vacuum pump. The
65 catalyst could be reused for eight times with a minimal loss of
activity. Perhaps, activity of FeNi₃ꢀILsMNPs is decreased by the
number of the regeneration (Yields 92 to 89%) (Fig. 5).
5
10
Fig. 2.
Fig. 5.
This structure was further supported by the FTꢀIR spectra. The
FTꢀIR spectrum of FeNi3ꢀILs MNPs showed the typical bands at
70
The extreme stability of the FeNi₃ꢀILsMNPs is mainspring of the
continuous and high catalytic activity. The morphology of FeNi₃ꢀ
ILsMNPs was investigated by scanning electron microscopy
(SEM) before use and after reuse of seven times with images
75 shown in Fig. 6. Interestingly, the shape and size of the
nanoparticles remained unchanged before and after reaction. We
suppose that, this is also the possible reason for the extreme
stability of theFeNi₃ꢀILsMNPs presented herein.
15 2920 and 2850 cm−1 attributed to CꢀH stretching vibrations of
alkyl chains. Moreover, the broad peak at 1053 cm−1 belonged to
S=O stretching vibrations in the sulphonate functional groups.
Bands at 1628 and1506 cm−1 were related to NꢀH bending
vibrations in the ammonium groups. These results indicated that
20 IL was successfully immobilized on FeNi3 MNPs (Fig 3).
Fig. 3.
80
Fig. 6.
The magnetic properties of the nanoparticles were characterized
25 using
a vibrating sample magnetometer (VSM). Magnetic
With these hopeful results in hand, we turned to explore the scope
of the reaction using diverse aromatic aldehydes as substrates
under the optimized reaction conditions (Table 2). In general the
measurement shows that FeNi3, and FeNi3ꢀILs MNPs have
saturation magnetization values of 59.2, and 39.1 emu/g
respectively (Fig 4).These results exhibit that catalyst can be
easily separated and recovered by an external magnetic field.
85 reactions are clean and highꢀyielding. Several functional groups,
such as Br, Cl, OH, NO2, OMe, N (CH3)2, and CH3, are
compatible under the reaction conditions. Interestingly, a variety
of aromatic aldehydes, including ortho, meta and paraꢀsubstituted
aryl aldehydes, participated well in this reaction and gave the
90 corresponding products in a good to excellent yield (Table 2).
The influence of electronꢀwithdrawing and electronꢀdonating
substituents on the aromatic ring of aldehydes upon the reaction
yields was investigated. It was shown that aromatic aldehydes
with electronꢀwithdrawing groups reacted faster than those with
95 electronꢀreleasing 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 5l (Scheme 3).
30
Fig. 4.
Initially, we carried out the MCR between hydrazine hydrate,
ethyl acetoacetate, 4ꢀnitrobenzaldehyde and ammonium acetate
35 under reflux condition in ethanol as a model reaction 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 92% yield. Unfortunately, when the model reaction
40 was carried out in water, the desired product was only
obtained in 58 % yield.
The model reaction was carried out in the presence of various
nanocatalysts such as Et3N, K2CO3, ZnO, CuO, FeCl₃, FeNi₃
NPs, ZnOꢀILs and CuOꢀILs NPs and FeNi₃ꢀILs MNPs. When the
45 reaction was carried out using FeNi₃ꢀILsMNPs (0.002 gr) as the
catalyst, the products were obtained in good to high yields.
100
Table 2
Scheme 3
A
plausible
mechanism
for
the
preparation
of
Table1
105 tetrahydrodipyrazolo pyridines using FeNi₃ꢀILsMNPs is shown in
Scheme 4. 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
110 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
50 Table 1 shows the influence of particles size on the activity of
FeNi3ꢀILs MNPs in the synthesis of tetrahydrodi
pyrazolopyridines. However, the activity of catalysts is
influenced by the acid– base properties and many other factors
such as size, surface area, geometric structure (particularly pore
55 structure), the distribution of sites and the polarity of the surface
sites.25 In this work, we evaluates an example in solidꢀbased
heterogeneous catalytic systems that have been developed with
2
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cyclization leads to product 5. The FeNi3ꢀILs MNPs has the
active sites of NH3+ as cation and FeNi3ꢀSO3ꢀ as anion.
3.4. General procedure for the preparation of
FeNi3/SiO2/SO3H nanoparticles
To a roundꢀbottomed flask (100 mL) FeNi3/SiO2 MNPs (0.40 g)
in CH2Cl2 (50 mL), was added chlorosulfonic acid (12 mmol)
55 dropwise over a period of 20 min at room temperature (Fig. 1).
After vigorous stirring for 24 h, the magnetic FeNi3/SiO2/SO3H
nanoparticles were collected by magnetic separation and washed
with ethanol and deionized water in sequence.
Scheme 4
5
3. Experimental
3.1. Chemicals and apparatus
The products were isolated and characterized by physical and
spectral data. H NMR and 13C NMR spectra were recorded on
Bruker Avanceꢀ400 MHz spectrometers in the presence of
10 tetramethylsilane as internal standard. The IR spectra were
recorded on FTꢀIR Magna 550 apparatus using with KBr plates.
Melting points were determined on Electro thermal 9200, and are
not corrected. The elemental analyses (C, H, N) were obtained
1
3.5. General procedure for the preparation of FeNi3-ILs
60 nanoparticles
Ethanolamine (5 mmol) was dispersed in dry CH2Cl2 (20 mL)
and FeNi3/SiO2/SO3H (0.1 g) nanoparticles were added. Then the
mixture was heated to 60 °C for 15 h under nitrogen atmosphere.
The resulting solid was separated by an external magnet and
65 washed 4 times with CH2Cl2, ethanol and H2O. After drying at
room temperature in vacuum, FeNi3ꢀILs was obtained as reddishꢀ
brown powder.
from a Carlo ERBA Model EA 1108 analyzer. FeNi
15 ILsMNPs have been measured with vibrating sample
₃ and FeNi₃ꢀ
a
magnetometer (VSM, PPMSꢀ9T) at 300 K in Iran (Kashan
university). Powder Xꢀray diffraction (XRD) was carried out on a
Philips diffractometer of X’pert Company with monochromatized
Cu Kα radiation (λ= 1.5406 Å). Microscopic morphology of
20 products was visualized by SEM (ZEISS).
3.6. General procedure for the preparation of
tetrahydrodipyrazolopyridines:
70 A mixture of hydrazine hydrate 80% (2.0 mmol) and ethyl
acetoacetate (2.0 mmol) and FeNi3ꢀILs MNPs (0.002 gr) in EtOH
(5 mL) was magnetically stirred at 25 °C followed by addition of
aldehyde (1.0 mmol) and ammonium acetate (4.0 mmol). The
reaction mixture was heated at reflux for 40ꢀ50 min and then
75 cooled to 25 °C. After completion of the reaction monitored by
TLC, 10 mL ethanol was added to the reaction mixture and the
catalyst FeNi3ꢀILs MNPs was separated by external magnetic
field. The precipitate was washed with EtOH to afford the pure
product and then dried well under vacuum pump.
3.2. Preparation of FeNi3nanoparticles
FeCl2·4H2O and NiCl2·6H2O (the total amount of Fe2+ and Ni2+
was 0.04 mol) were dissolved into 200 ml deionized water to
25 form a preliminary reaction solution. Certain amounts of sodium
hydroxide (NaOH) solution were added into the former solution
with moderate stirring. Adjust the amount of added NaOH
solution carefully so that the pH value was in the range
10≤pH≤13. At this moment, a dark brown suspension was
30 formed. 0.16 mol aqueous hydrazine (N2H4·H2O, 80%
concentration) was then added into the above suspension. This
reaction was continued for about 24 h. During this period, the pH
value was kept in the range 10≤pH≤13 by adding NaOH. Final
resulting particles were separated magnetically and washed
35 repeatedly until the pH value was 7. The suspension was
repeatedly washed, filtered for several times and dried at 100 ºC
in the air.
80 3.7. Spectral data
3,5-Dimethyl-4-(4-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[
3,4-b;4',3'-e]pyridine (5a) cream solid; m.p. 295ꢀ297 oC; IR
1
(KBr): νmax 3400, 2963, 1603, 1511, 1348, 1177, 846 cmꢀ1; H
NMR (400 MHz, DMSOꢀd6) δ 2.07 (s, 6H), 4.95 (s, 1H), 7.34ꢀ
85 7.36 (d, 2 H, J = 8 Hz), 8.09ꢀ8.11 (d, 2 H, J = 8 Hz), 11.25 (s,
3H)ppm;13C NMR (100 MHz, DMSOꢀd6) δ 10.75, 33.43,
103.62,123.46, 129.25, 140.18, 146.09, 152.24, 161.34 ppm;
Anal.Calcd.ForC15H14N6O2: C, 58.06; H, 4.55; N, 27.08; FoundC,
58.12; H, 4.50; N, 27.15;
3.3. General procedure for the preparation of
FeNi3/SiO2nanoparticles
40 FeNi3ꢀILs MNPs was prepared according to the procedure
reported in the literature with some modification.20 Firstly, a
mixture of ethanol (100 mL) and distilled water (20 mL) was
added to magnetic nanoparticles (FeNi3 NPs) (1 g), and the
resulting dispersion was sonicated for 15 min. After adding
45 ammonia water (3 mL), tetraethyl orthosilicate (TEOS, 2.2 mL)
was added to the reaction solution. The resulting dispersion was
under mechanically stirred continuously for 20 h at room
temperature. The magnetic FeNi3/SiO2 nanoparticles were
collected by magnetic separation and washed with ethanol and
50 deionized water in sequence.
90 3,5-Dimethyl-4-(3-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[
3,4-b;4',3'-e]pyridine (5b) cream solid; m.p. 286ꢀ288oC; IR
1
(KBr): νmax 3200, 2963, 2855, 1599, 1347 cmꢀ1; H NMR (400
MHz, DMSOꢀd6) δ 2.05 (s, 6H), 4.97 (s, 1H), 7.52 (m, 2 H), 7.93
(s, 1H), 8.02 (d, 1 H, J = 8 Hz), 11.25 (s, 3H) ppm; 13C NMR
95 (100 MHz, DMSOꢀd6) δ 10.74, 33.11, 103.74, 121.22, 122.32,
129.72, 135.20, 140.22, 146.26, 148.05, 161.3 ppm;
Anal.Calcd.For C15H14N6O2: C, 58.06; H, 4.55; N, 27.08; Found
C, 58.16; H, 4.48; N, 27.14;
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3,5-Dimethyl-4-(4-methyl-phenyl)-1,4,7,8-tetrahydro
4-(1,4,7,8-Tetrahydro-3,5-dimethyldipyrazolo[3,4-b:4',3'
e]pyridin-4-yl)-N,N-dimethylaniline (5i):cream solid; m.p. 240ꢀ
dipyrazolo[ 3,4-b;4',3'-e]pyridine (5c): white solid; m.p. 243ꢀ
o
1
o
245 C; IR (KBr): νmax 3300, 2924, 1602, 1512 cmꢀ1; H NMR 55 242 C; IR (KBr): νmax 3200, 2950, 1598, 1470, 1145, 751 cmꢀ1;
(400 MHz, DMSOꢀd6) δ 2.04 (s, 6H), 2.21 (s, 3H), 4.74 (s, 1H),
6.98ꢀ7.00 (m, 4 H), 11.24 (s, 3H) ppm; 13C NMR (100 MHz,
DMSOꢀd6) δ 10.84, 20.95, 32.84, 104.82, 127.81, 128.80, 134.68,
140.21, 140.72, 161.52 ppm; Anal.Calcd.ForC16H17N5: C, 68.79;
H, 6.13; N, 25.07; Found C, 68.71; H, 6.22; N, 25.12;
1H NMR (400 MHz, DMSOꢀd6) δ 2.04 (s, 6H), 2.98 (s, 6 H), 4.64
(s, 1H), 6.56ꢀ6.58 (d, J= 8 Hz, 2 H), 6.90ꢀ6.92 (d, J= 8 Hz, 2H),
11.28 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ 10.84,
32.35, 40.92, 105.23, 112.73, 128.35, 131.64, 137.02,
60 149.05,161.66 ppm; Anal.Calcd. For C17H20N6: C, 66.21; H,
6.54; N, 27.25 Found C, 66.33; H, 6.59; N, 27.37.
5
3,5-Dimethyl-4-(4-methoxy-phenyl)-1,4,7,8-tetrahydro
10 dipyrazolo [ 3,4-b;4',3'-e]pyridine (5d):cream solid; m.p. 186ꢀ
3,5-Dimethyl-4-(4-hydroxy-phenyl)-1,4,7,8-tetrahydro
pyrazolo [ 3,4-b;4',3'-e]pyridine (5j):White solid,; m.p. 267ꢀ268
oC; IR (KBr): νmax 3266, 2924, 1562, 1465, 1142, 859 cmꢀ1; H
di
o
188 C; IR (KBr): νmax 3267, 2924, 1597, 1510, 1348, 1239, 792
1
1
cmꢀ1; H NMR (400 MHz, DMSOꢀd6) δ 2.04 (s, 6H), 3.69 (s,
OCH3), 4.74 (s, 1H), 6.74ꢀ6.76 (d, 2 H, J = 8 Hz), 6.99ꢀ7.01 (d, 2 65 NMR (400 MHz, DMSOꢀd6) δ 2.03 (s, 6H), 4.65 (s, 1H), 6.56ꢀ
H, J = 8 Hz), 11.32 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6)
15 δ 10.82, 32.40, 55.51, 104.92, 113.53, 128.82, 135.66,140.12,
140.18, 157.68 ppm; Anal.Calcd.For C16H17N5O: C, 65.07; H,
5.80; N, 23.71; Found C, 65.12; H, 5.89; N, 23.75;
6.58 (d, J= 8 Hz, 2 H), 6.88ꢀ6.90 (d, J= 8 Hz, 2H), 9.10 (s, OH),
11.50 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ
10.32,31.75, 104.5, 114.42, 128.23, 133.35, 139.76, 155.03,
161.04 ppm; Anal.Calcd.ForC15H15N5O: C, 64.04; H, 5.37; N,
70 24.90; Found C, 64.09; H, 5.30; N, 24.82;
1,4,7,8-Tetrahydro-3,5-dimethyl-4-phenyldipyrazolo-[3,4-
o
b:4',3'-e]pyridine (5e):white solid; m.p. 240ꢀ242 C; IR (KBr):
3,5-Dimethyl-4-(2-nitro-phenyl)-1,4,7,8-tetrahydrodipyrazolo[
20 νmax 3181, 2924, 1600, 1523, 1484, 725 cmꢀ1; 1H NMR (400
MHz, DMSOꢀd6) δ 2.04 (s, 6H), 4.79 (s, 1H), 7.09ꢀ7.19 (m, 5 H),
11.34 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ 10.84,
3,4-b;4',3'-e]pyridine (5k):cream solid; m.p. 187ꢀ188 oC; IR
1
(KBr): νmax 3300, 2925, 1604, 1550, 1348, 1177, 846 cmꢀ1; H
NMR (400 MHz, DMSOꢀd6) δ 1.90 (s, 6H), 5.43 (s, 1H), 7.36ꢀ
33.24, 104.65, 125.84, 127.92, 128.16,140.24, 143.82, 161.54 75 7.68 (m, 4 H), 10.95 (s, 3H) ppm; 13C NMR (100 MHz, DMSOꢀ
ppm; Anal.Calcd.For C15H15N5: C, 67.90; H, 5.70; N, 26.40;
25 Found C, 67.95; H, 5.76; N, 26.49.
d6) δ 10.02, 28.94, 101.94, 123.85, 127.12, 130.22,131.64,
136.24, 138.62, 149.50, 160.54ppm; Anal.Calcd.For C15H14N6O2:
C, 58.06; H, 4.55; N, 27.08; Found C, 58.15; H, 4.43; N, 27.12;
3,5-Dimethyl-4-(2-methyl-phenyl)-1,4,7,8-tetrahydro
dipyrazolo [ 3,4-b;4',3'-e]pyridine (5f) White solid; m.p. 290ꢀ
1,4-Bis[(1,4,7,8-tetrahydro-3,5-dimethyldipyrazolo[3,4-
o
292 C; IR (KBr): νmax 3300, 2923, 1602, 1527, 1448, 747 cmꢀ1; 80 b:4',3'-e]pyridin-4-yl)] benzene (5l):Orange solid, m.p. >300oC;
1H NMR (400 MHz, DMSOꢀd6) δ 1.87 (s, 6H), 2.09 (s, 3H), 4.91
30 (s, 1H), 7.03ꢀ7.17 (m, 4 H), 10.65 (s, 3H) ppm; 13C NMR (100
MHz, DMSOꢀd6) δ 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;
IR (KBr): νmax 3186, 1591, 1508, 1200, 785, 608 cmꢀ1; H NMR
(400 MHz, DMSOꢀd6) δ 2.05 (s, 12H), 4.70 (s, 2H), 6.94 (4 H),
11.25 (s, 6H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ 10.70,
1
33.20, 104.55, 129.34, 134.43,
139.50, 160.20 ppm;
Anal.Calcd.For C16H17N5: C, 68.79; H, 6.13; N, 25.07; Found C, 85 Anal.Calcd.ForC24H24N10: C, 63.70; H, 5.35; N, 30.95; Found C,
68.88; H, 6.10; N, 25.17;
63.79; H, 5.44; N, 30.86; MS (EI, 70 eV): m/z 452 (M+).
35 3,5-Dimethyl-4-(4-chloro-phenyl)-1,4,7,8-tetrahydro
di
4. Conclusions
pyrazolo [ 3,4-b;4',3'-e]pyridine (5g): white solid; m.p. 255ꢀ
257oC; IR (KBr): νmax 3180, 2924, 1597, 1487, 1142, 1091 cmꢀ1;
1H NMR (400 MHz, DMSOꢀd6) δ 2.05 (s, 6H), 4.79 (s, 1H),
7.09ꢀ7.11 (d, J= 8 Hz, 2 H), 7.24ꢀ7.26 (d, J= 8 Hz, 2H), 11.50 (s,
40 3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ 10.78,32.67,
104.34, 128.06, 129.85, 130.49, 140.16, 142.78, 161.46ppm;
Anal.Calcd.ForC15H14ClN5: C, 60.10; H, 4.71; N, 23.36 Found
C, 60.15; H, 4.78; N, 23.29.
In conclusion, we have developed a straightforward and efficient
approach to synthesis of tetrahydrodipyrazolopyridines by a
90 simple oneꢀpot pseudo sixꢀcomponent reaction of hydrazine
hydrate, ethyl acetoacetate, aldehydes and ammonium acetate in
the presence of FeNi3ꢀILs nanoparticles as catalyst.
The procedure offers several advantages including short reaction
times, a simple procedure, high atom economy; excellent yields,
95 reusability of the catalyst and little catalyst loading. This green
nanocatalyst could be used for other significant organic reactions
and transformations. Further explorations of similar protocols are
underway in our laboratory. Meanwhile, this recoverable catalyst
will provide a regular platform for heterogeneous catalysis, green
100 chemistry, and environmentally benign protocols in the near
future. We hope that this article will serve to stimulate research in
this fascinating and very useful area of organic synthesis.
3,5-Dimethyl-4-(4-bromo-phenyl)-1,4,7,8-tetrahydro
di
45 pyrazolo [ 3,4-b;4',3'-e]pyridine (5h):yellow solid; m.p. 165ꢀ
o
167 C; IR (KBr): νmax 3100, 2924, 1598, 1487, 1142, 753 cmꢀ1;
1H NMR (400 MHz, DMSOꢀd6) δ 2.06 (s, 6H), 4.78 (s, 1H),
7.03ꢀ7.05 (d, J= 8 Hz, 2 H), 7.39ꢀ7.41 (d, J= 8 Hz, 2H), 11.50 (s,
3H) ppm; 13C NMR (100 MHz, DMSOꢀd6) δ 10.23, 32.43,
50 104.45,118.30, 129.62, 130.34, 131.85, 142.66, 157.42 ppm;
Anal.Calcd.ForC15H14BrN5: C, 52.34; H, 4.10; N, 20.35 Found C,
52.39; H, 4.15; N, 20.31.
4
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DOI: 10.1039/C6RA02906J
15. M. B. Gawande, P. S. Branco and R. S. Varma, Chem.
Soc. Rev., 2013,42, 3371ꢀ3393.
Acknowledgments
50
The authors acknowledge a reviewer who provided helpful
insights. The authors are grateful to University of Kashan for
supporting this work by Grant NO: 159196/XXI.
16. R. D. Rogers, K. R. Seddon, Science, 2003, 302, 792ꢀ793.
17. J. G. Huddleston, A. E. Visser, W. M. Reichert, H. D.
Willauer, G. A. Broker and R. D. Rogers, Green Chem.,
2001, 3, 156–164.
5
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
55 18. T. Welton, Coord. Chem. Rev., 2004, 248, 2459–2477.
19. S. M. Sadeghzadeh, RSC Adv., 2015, 5, 17319–17324.
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This journal is © The Royal Society of Chemistry [year]
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R
R
FeNi3 ꢀILs
O
O
+
NH4OAc
+
2 NH2NH2
+
N
N
ethanol
reflux
2
O
OEt
N
N
N
H
H
H
4
1
2
3
5
Scheme 1.Synthesis oftetrahydrodipyrazolo pyridines by FeNi3ꢀILs nanocatalyst
6
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FeNi3
Tetraethyoxysilane
Ethanolamine
FeNi3
O
FeNi3
_
SO3
FeNi3
ClSO3H
OH
O
Si
O
O
+H3N
O
O
_
SO3
Scheme 2. Schematic illustration of the synthesis for FeNi3ꢀILs MNPs
7

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H
H
H
N
N
N
N
N
O
FeNi3 ꢀILs
O
O
NH4OAc
+
+
O
+
2 NH2NH2
ethanol
reflux
2
N
HN
OEt
N
N
N
H
H
4
1
2
3 l
5l
Scheme 3.Synthesis of 1,4ꢀBis[(1,4,7,8ꢀTetrahydroꢀ3,5ꢀdimethyldipyrazolo[3,4ꢀb:4',3'ꢀe]pyridinꢀ4ꢀyl)] benzene by FeNi3ꢀ
ILsnanocatalyst
8
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SO3ꢀ
HN
N
+
NH3
O
OH
H
I
O
O
H
+
OH
-
SO3
N
EtO
H
+
NH3
H2N
O
HN
N
H
Ar
Ar
O
N
NH
HN
N
N
HN
O
O
O
III
Ar
Ar
NH3
II
HO
-
SO3
Ar
+
NH3
N
N
N
N
N
N
NH
N
H
HN
H
H
HN
O
Scheme 4.Proposed Mechanism for the pseudo sixꢀcomponent process
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Fig 1. XRD analysis of FeNi3ꢀILsMNPs
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Fig. 2. SEM images of FeNi3ꢀILs MNPs
11

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Fig 3.FTIR spectra of FeNi3ꢀILs MNPs
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Fig. 4. Roomꢀtemperature magnetization curves of the nanocatalysis
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Fig 5. Reusability of FeNi3ꢀILs MNPs as catalyst for the synthesis of 5a
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Fig 6. SEM of FeNi3ꢀILs MNPs (a) before use (b) after reuse of seven times
15

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Table 1.Optimization of reaction conditions using different catalystsa
Entry
Catalyst
Solvent (reflux)
EtOH
Time (min)
300
360
600
600
480
480
250
280
50
Yield%b
53
1
ꢀꢀꢀꢀꢀꢀꢀꢀꢀ
2
ꢀꢀꢀꢀꢀꢀꢀꢀꢀ
H2O
35
3
Et3N (10 mol%)
K2CO3 (5 mo1%)
ZnO NPs (3 mol%)
CuO NPs (3 mo1%)
FeCl3 (5 mol%)
FeNi3 NPs (2 mol%)
ZnOꢀILs NPs (0.003 gr)
CuOꢀILs NPs (0.003 gr)
EtOH
58
4
EtOH
62
5
EtOH
65
6
EtOH
62
7
EtOH
65
8
EtOH
74
9
EtOH
85
10
11
12
13
14
15
16
17
18
19
20
21
EtOH
50
80
FeNi3ꢀILs MNPs ≈ 30ꢀ35 nm (0.001 gr)
FeNi3ꢀILs MNPs ≈30ꢀ35 nm (0.002 gr)
FeNi3ꢀILs MNPs ≈50ꢀ55 nm (0.002 gr)
FeNi3ꢀILs MNPs ≈30ꢀ35 nm (0.003 gr)
FeNi3ꢀILs MNPs ≈30ꢀ35 nm (0.002 gr)
FeNi3ꢀILs MNPs ≈30ꢀ35 nm (0.002 gr)
FeNi3ꢀILs MNPs ≈30ꢀ35 nm (0.002 gr)
EtOH
50
87
EtOH
40
92
EtOH
40
88
EtOH
40
92
H2O
70
58
CH3CN
DMF
60
72
60
63
ꢀ
+
EtOH
80
68
HOꢀCH2ꢀCH2ꢀNH3 OOCH (20 mol%)
ꢀ
+
solventꢀfree
solventꢀfree
solventꢀfree
80
73
HOꢀCH2ꢀCH2ꢀNH3 OOCH (30 mol%)
ꢀ
+
80
78
HOꢀCH2ꢀCH2ꢀNH3 OOCH3 (30 mol%)
ꢀ
+
80
84
[HO3SOꢀCH2ꢀCH2ꢀNH2 ꢀSO3H]HSO4 (30 mol%)
a hydrazine hydrate (2 mmol), ethyl acetoacetate (2 mmol), 4ꢀnitrobenzaldehyde (1mmol) and ammonium acetate(4mmol)
bIsolated yield
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Table 2. Synthesis of tetrahydrodipyrazolo pyridines by FeNi3ꢀILs nanocatalyst
Entry
5a-5l
aldehyde
product
Time (min)
Yield%
m.p (ref.)
NO2
CHO
40
92
> 300 (26)
1
5a
N
N
NO2
N
H
N
N
H
H
NO2
CHO
45
52
84
78
286ꢀ288 (26)
2
5b
N
N
NO2
N
H
N
H
N
H
CHO
244ꢀ246
(26,28)
3
5c
N
N
N
H
N
H
N
H
MeO
CHO
50
48
80
86
185ꢀ187 (26)
240ꢀ242 (26)
4
5
5d
5e
OMe
CHO
N
N
N
H
N
H
N
H
N
N
N
N
H
N
H
H
CHO
54
82
6
5f
290ꢀ292
N
N
N
H
N
H
N
H
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Cl
CHO
7
5g
44
90
254ꢀ256
(26,28)
Cl
N
N
N
H
N
H
N
H
Br
CHO
8
5h
47
88
165ꢀ167 (27)
Br
N
N
N
H
N
H
N
H
NMe2
CHO
9
5i
43
50
53
85
240ꢀ242 (26)
267ꢀ268 (27)
187ꢀ188 (27)
NMe2
CHO
N
N
N
N
H
N
H
OH
H
82
10
5g
N
N
OH
N
H
N
H
N
H
CHO
NO2
O2N
N
84
11
5k
N
N
H
N
H
N
H
H
H
N
H
N
N
N
N
CHO
CHO
55
89
>300
12
5l
N
N
HN
N
N
H
H
aIsolated yield
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Graphical abstract
R
R
FeNi3 ꢀILs
O
O
O
O
O
N
N
ethanol
reflux
OEt
N
N
OEt
N
H
H
H
NH2NH2
NH2NH2
NH4OAc
A flexible and highly efficient protocol for the synthesis of tetrahydrodipyrazolo pyridines using FeNi3ꢀILs MNPs has been
developed.
19