Copper(II) oxide nanoparticles as a highly active and reusable heterogeneous catalyst for the construction of phenyl-1: H -pyrazolo[3,4- b] pyridine derivatives under solvent-free conditions

Article abstract of DOI:10.1039/c6ra22445h

An efficient, highly active and resalable copper oxide nanoparticle catalyzed a regioselective cascade synthesis of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives via three-component domino reactions of aldehydes, alkynes and 3-methyl-1-phenyl-1H-pyrazol-5-amine under solvent-free conditions. Good to excellent yield, short reaction times, cost effectiveness; environmental friendliness, easy workup, and a recyclable catalyst are the important features of this protocol. This is the first endeavor towards the synthesis of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives from 3-methyl-1-phenyl-1H-pyrazol-5-amine, alkynes and aldehydes.

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Copper (II) oxide nanoparticles: as a highly active and reusable
heterogeneous catalyst for the construction of phenylꢀ1Hꢀpyrazolo[3,4ꢀ
b]pyridine derivatives under solventꢀfree conditions
Mudumala Veeranarayana Reddy, Yeon Tae Jeong*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An efficient, highly active and resalable copper oxide
nanoparticle catalyzed regioselective cascade synthesis of
phenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine derivatives via threeꢀ
Multiꢀcomponent reactions (MCRs), in which more than two
reactants combine in a sequential manner, have been widely used
as an influential approach in the total synthesis of natural
products, pharmaceuticals, diagnostics, agrochemicals and other
10 component domino reactions of aldehydes, alkynes and 3ꢀ
methylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀamine under solventꢀfree 50 important materials.3 In these MCRs offer significant advantages,
conditions have been described. Good to excellent yield, short
reaction times, cost effectiveness; environmental friendliness,
easy workup, and recyclable catalyst are the important
15 features of this protocol. This is the first endeavored towards
such as, generation of multiple stereocenters with a high
efficiency and atom economy, reduction of synthetic steps, waste
production, and energy consumption, economies of time and
labor, enhancement in the rate of reaction, and avoiding the
the
synthesis
of
phenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine 55 complicated purification processes and tedious protection and
derivatives from of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀamine,
alkynes and aldehydes.
deprotection of functional groups.4 The above merits make MCRs
suitable for the synthesis of sustainable and diversityꢀoriented
heterocyclic molecules from readily available starting materials.5
Nowadays, nanocatalysis has become more and more
20 important as
a
key green technology for the sustainable
On the third hand, in recent years, a great deal of
production of chiral and nonꢀracemic organic compounds and 60 observation has been given to the synthesis of polyheterocyclic
also to synthesize biologically important organic molecules in a
high enantioselective manner using such novel catalytic systems.1
In addition, the nanocatalysts might provide practical advantages
25 such as easy separation from the reaction mixture, high yield,
skeletons, which is endorsed to their comprehensive biological
activities in the field of biological/medicinal/material science,
pharmaceuticals and others.6 Amongst these, pyrazolo[3,4ꢀ
b]pyridines are polyheterocyclic molecules frequently found in
high thermal stability, good structural stability and efficient 65 various natural products. These molecules have attracted
recycling. In this context, Copper oxide nanoparticles (CuO NPs)
received considerable attention due to their exclusive chemical
and physical properties such as highꢀsurfaceꢀarea resulting in
30 high catalyst loading capacity, ease of handling, nonꢀvolatility,
significant interest owing to their wide range of biological
activities such as antiꢀtubercular activity, antiꢀmicrobial agents,
Alzheimer's disease, antiꢀcancer, antiꢀinflammatory, antiꢀviral,
antiꢀmalarial, cardiovascular, CNS depressant, neuroleptic,
and nonꢀflammable, readily available, inexpensive, high thermal 70 tuberculostatic and antiꢀoxidant activities.7 Some analogs have
stability, outstanding stability heterogeneous supports for
catalysts, easily separated from the reaction products for further
reusability. Despite its great importance, a few publications are
35 reported in the literature for its catalytic activity in various
organic transformations to get highly selective products.2
been also found to act as antiꢀproliferative agents, inhibitors of
glycogen synthase kinaseꢀ3 and potent antitumor agents.8 Due to
their extensive biological activities, pyrazoloꢀ[3,4ꢀb]pyridine
derivatives may be prepared via some classical methods, also
75 includes the treatment of 5ꢀaminopyrazole and substituted α,βꢀ
unsaturated compounds and other methods.9 Nevertheless, most
of these methods have one or more drawbacks, such as the use of
expensive catalysts, hazardous organic solvents, lower yields,
prolonged reaction time, harsh reaction conditions and poor
80 selectivity. Therefore, it is an essential area to further develop as
an efficient and environmentally benign approach for building
this type of heterocyclic compound is of prime importance.
On the other hand, synthetic organic chemistry has developed
efficient and versatile methods for the synthesis of diverse and
complex heterocyclic molecules with excellent regio, chemo,
40 diastereo, and enantioselectivity.
Department of Image Science and Engineering, Pukyong National
University, Busan, Korea, 608-737, *Corresponding author. Tel.: +82-
51-629-6411; fax: +82-51-629- 6408;e-mail: ytjeong@pknu.ac.kr
45
To the best of our knowledge, synthesis of phenylꢀ1Hꢀ
pyrazolo[3,4ꢀb]pyridine derivatives via C−H bond activation
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followed by C−C bond formation through intramolecular
cyclization in the presence of CuO NPs catalyst system have not
yet been explored. In continuation of our work in the
development of a new methodology for heterocyclic compounds
synthesis via MCRs under heterogeneous catalysts,10 herein, we
described a simple and efficient methods for the construction of
phenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine derivatives through oneꢀpot
threeꢀcomponent reaction of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀ
amine (1), alkynes (2aꢀd) and aldehydes (3aꢀh) catalyzed by CuO
With these overall results demonstrated that 10 mol%
of CuO NPs under solventꢀfree conditions at 80 °C are optimized
reaction conditions for the synthesis of 4a with high yield and
shorter reaction time.
5
55
On the other hand, from green chemistry pointꢀofꢀ
view, recyclability is one of the vital concerns in metal catalysis.
In this connection, herein, we examined the reusability of CuO
NPs on model reaction. After the completion of the reaction, the
catalyst was separated by centrifugation using ethyl acetate as a
10 NPs under neat conditions at 80 °C (Schemes 1).
60 solvent and washed three times with water and methanol and
dried in an oven at 80 °C. After that the dried catalyst could be
reused in four consecutive runs without the loss of significant
activity (Table1, entry 4), which confirmed that CuO NPs was
highly active, stable and recyclable up to the four runs without
65 loss of significant activity.
Table 1 Optimization of reaction conditions for the synthesis of 4aa
Entry Catalyst
(mol%)
Solvent
(mL)
Tem Time
(°C) (min)
Yield (%)b
Scheme 1: Synthesis of 6ꢀ(4ꢀbromophenyl)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀ3ꢀ
methylꢀ1ꢀphenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine (4a)
15
Our initial investigation to realize this new route for
phenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine derivatives focused on the
MCRs of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀamine (1, 1 mmol)
with 4ꢀbromobenzaldehyde (2a, 1 mmol) and 4ꢀchloroꢀ1ꢀ
ethynylbenzene (3a, 1 mmol) as model substrates. With the above
1
CuO NPs (5)
Neat
Neat
Neat
RT
80
600
150
200
90
45
2
CuO NPs (5)
CuO NPs (5)
80
20 reactants, we have conducted the reaction at RT in the presence
of 5 mol% of CuO NPs under solventꢀfree conditions for 10 h.
After completion of the reaction, 4a was isolated in 45% yield
(Table 1, entry 1) which was confirmed by the characterization of
NMR and HRMS. Encouraged by the aforementioned result, we
25 commenced to investigate the other parameters of the reaction
and the representative results are shown in Table 1. To our
gratifyingly, when changing reaction temperature from RT to 80
°C, the reaction proceeded rapidly to obtain the desired product in
80% within 150 min (Table 1, entry 2). In our endeavor to further
30 increase the yield of 4a, the experiment was investigated at 100
°C but we couldn’t obtain further better yield even prolong
reaction time (Table 1, entry 3). Subsequently, we screened the
amount of CuO NPs catalyst on model reaction at various
temperatures and results are summarized in Table 1. To our
35 surprise, the reaction occurred to afford the desired product 4a in
excellent yield (95%) for 90 min with 10 mol% of CuO NPs at 80
°C (Table 1, entry 4). To confirm the catalytic activity of the CuO
NPs a comparison study was examined with various copper metal
catalysts such CuO, CuCl2, Cu(OTf)3, Cu(OAc)2 under neat
40 conditions at 80 °C, and we observed that the desired product 4a
was obtained in moderate to good yields (Table 1, entries 9–12).
3
100
80
82
c4
5
CuO NPs (10) Neat
CuO NPs (15) Neat
CuO NPs (10) Neat
CuO NPs (10) Neat
CuO NPs (10) Neat
95, 93, 92, 90
80
90
95
65
85
95
85
72
84
74
70
81
6
RT
60
150
120
90
7
8
100
80
9
CuO (10)
Neat
Neat
125
140
120
142
225
180
10
11
12
13
14
CuCl2 (10)
80
Cu(OTf)3 (10) Neat
Cu(OAc)2 (10) Neat
80
Next, the model reaction has ben studied the effect of
different solvents, like MeOH, MeCN, THF, DMF, and toluene in
the presence of 10 mol% of CuO NPs at various temperatures
45 (Table 1, entries 13ꢀ17). In our observation at most of the solvent,
conditions found that the rate of reaction was lower and desired
product was obtained in moderate yield. We observed that the
solventꢀfree condition provided a superior yield in short reaction
time when compared with that of other solvents (Table 1, entry
50 4).
80
CuO NPs (10) MeOH (5) 60
CuO NPs (10) MeCN (5) 80
2
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15
16
17
CuO NPs (10) THF (5) 60
CuO NPs (10) DMF (5) 120
CuO NPs (10) Toluene (5)100
220
225
190
55
65
73
reaction occurred well in all these case and expected products
were obtained in excellent yields. A variety of functional groups
substituted on the aromatic ring of the aldehydes, including
10 methoxy, ethoxy, isopropyl and methyl have preceded the
reaction smoothly and resulted in the corresponding products in
good to excellent yields. The halogenꢀcontaining aldehydes such
as –Cl, ꢀBr, and ꢀF were also subjected to the reaction conditions,
and obtained in good to excellent yields of the desired products.
15
Subsequently, the scope of alkynes was investigated
and it was found that substituted phenylacetylene bearing –OMe,
ꢀBr ꢀCl were absolutely appropriate substrates for this
transformation, and the desired products were obtained in
moderate to excellent yields.
The optimized reaction conditions were then evaluated
for library synthesis of phenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine
derivatives (4aꢀy) employing 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀ
amine (1), with various phenyl acetylenes (2aꢀd) and different
aldehydes (3aꢀh) and results are summarized in Table 2. The
5
20 aReaction of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀamine (1, 1 mmol) with 4ꢀ
bromobenzaldehyde (2a, 1 mmol) and 4ꢀchloroꢀ1ꢀethynylbenzene (3a, 1
mmol); bIsolated yield; cCatalyst was reused four times.
Table 2 Synthesis of phenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine derivatives (4aꢀy)a
Entry
1
R
R1
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
4ꢀCl
3ꢀOMe
3ꢀOMe
4ꢀBr
4ꢀBr
4ꢀBr
4ꢀBr
4ꢀBr
Product
4a
Time (min)
90
Yieldb (%)
4ꢀBrꢀC6H4
95
93
95
92
96
93
94
93
90
91
92
91
92
92
95
2
4ꢀCNꢀC6H4
4b
4c
92
3
4ꢀMeꢀC6H4
85
4
4ꢀN(CH3)2ꢀC6H4
4ꢀOEtꢀC6H4
4ꢀ OMeꢀC6H4
4ꢀCHꢀ(CH3)C6H4
3ꢀ4ꢀ5ꢀOMeꢀC6H2
2ꢀBrꢀC6H4
4d
4e
102
85
5
6
4f
96
7
4g
4h
4i
105
98
8
9
105
110
95
10
11
12
13
14
15
2ꢀFꢀ5ꢀBrꢀC6H3
4ꢀCNꢀC6H4
4j
4k
4l
4ꢀFꢀC6H4
97
4ꢀCHꢀ(CH3)C6H4
4ꢀOHꢀC6H4
4m
4n
4o
106
99
4ꢀOEtꢀC6H4
100
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16
17
18
19
20
21
22
23
24
25
2ꢀ5ꢀMeꢀC6H3
3ꢀBrꢀC6H4
H
H
H
H
H
H
H
H
H
H
4p
4q
4r
101
92
90
91
90
89
92
94
92
93
94
95
3ꢀClꢀC6H4
98
2ꢀ6ꢀMeꢀC6H3
3ꢀFꢀC6H4
4s
105
96
4t
3ꢀOMeꢀC6H4
4ꢀCNꢀC6H4
4u
4v
4w
4x
4y
106
104
91
4ꢀCHꢀ(CH3)C6H4
4ꢀOEtꢀC6H4
3ꢀ4ꢀ5ꢀOMeꢀC6H2
92
90
aReaction of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀamine (1, 1 mmol), aldehydes (2, 1 mmol), alkynes (3, 1 mmol) catalyzed by CuO NPs under solventꢀfree
conditions at 80 ºC; bIsolated yield.
On basis of the results, we proposed the possible
reaction mechanism for this novel MCRs methodology (Scheme
2). At first, the imine, 5, was formed inꢀsitu from 3ꢀmethylꢀ1ꢀ
phenylꢀ1Hꢀpyrazolꢀ5ꢀamine (1) and the aldehydes (2aꢀd) and
then it follows the DielsꢀAlder type cycloaddition with Lewis
acid CuO NPs catalyzed terminal acetylides (3aꢀh) and resulted
in a Cu coordinated intermediate 6. Which on then undergoes an
5
10 oxidative removal of catalyst and followed by aromatization
leading to the formation 4.
Scheme 3. Possible schematic illustration of the synthesis of 4a & 4aʹ via
35 CuO NPs catalyzed Schiff base intermediate.
Scheme 2. Schematic illustration of CuO NPs catalyzed synthesis of 4aꢀy.
Experimental
General procedure for the synthesis of 6-(4-bromophenyl)-4-(4-
chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine
40 (4a).
Finally, for further justification of the usage of CuO
15 NPs catalyst, we also prepared the Schiff base intermediate of 1
and 2a of model reaction in the presence of the CuO NPs catalyst
separately and could be expected the formation of a copper
complex of Schiff base (7). After that, the obtained complex
intermediate was treated with 3a to get the final product, 4a
20 (Scheme 3). But, herein in addition to the expected product, 4a,
(80%) an unexpected stereoisomer, 4aʹ, (TLC) was also observed
as a minor product (15%). It is concluding that the CuO NPs
catalyst can act as a specific catalyst for alkynes.
A mixture of 3ꢀmethylꢀ1ꢀphenylꢀ1Hꢀpyrazolꢀ5ꢀamine
(1, 1.0 equiv.), 4ꢀbromobenzaldehyde (2a, 1.0 equiv.) and 4ꢀ
chloroꢀ1ꢀethynylbenzene (3a, 1.0 equiv.) are reacted in the
presence of CuO NPs (10 mol%) in neat conditions at 80 °C for
45 90 min. The completion of the reaction was monitored by TLC.
The reaction mixture was cooled to room temperature followed
by addition of ethyl acetate (10 mL) and filtered to recover the
catalyst. Then the filtrate was denser under reduced pressure and
obtained the solid product by washing with hexane and which
50 was recrystallized from ethanol to afford the pure product. The
precipitated CuO NPs was washed with methanol twice and then
dried under vacuum before reuse.
In summary, we have developed a novel and an
25 efficient cascade reaction for the construction of highly
functionalized phenylꢀ1Hꢀpyrazolo[3,4ꢀb]pyridine derivatives
catalyzed by CuO NPs under mild reaction conditions. This
methodology has the advantages of wide generality, high atomꢀ
economy efficiency, steric and functional group tolerance, high
30 yields, short reaction times, environmental friendly protocol and
reusability of the catalyst that keeps the catalyst efficiency after
four cycles even.
Supporting Information
All Compounds NMR spectra were provided as Supplementary
55 data.
4
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DOI: 10.1039/C6RA22445H
Copper (II) oxide nanoparticles: as a highly active and reusable
heterogeneous catalyst for the construction of phenyl-1H-
pyrazolo[3,4-b]pyridine derivatives under solvent-free conditions
Mudumala Veeranarayana Reddy, Yeon Tae Jeong*
Department of Image Science and Engineering; Pukyong National University, Busan 608-737, Korea,
Tel.: +82-51-629-6411; fax: +82-51-629- 6408; E-mail: ytjeong@pknu.ac.kr
R1
N
CuO NPs
NH2
N
N
+
R CHO
N
+
N
R
R1
Neat, 80 oC
(3)
(1)
(4)
(2)
We developed a simple and efficient method for the one-pot synthesis of phenyl-1H-
pyrazolo[3,4-b]pyridine derivatives in the presence of CuO NPs under solvent-free conditions
with higher yields and shorter reaction times.