One-pot three-component synthesis of pyrano [3,2- b ]pyrazolo[4,3- e ]pyridin-8(1 H)-ones

Article abstract of DOI:10.1021/co3001204

An efficient one-pot synthesis of novel pyrano[3,2-b]pyrazolo[4,3-e] pyridin-8(1H)-ones via three-component condensation of kojic acid, 1-H-pyrazol-5-amines and aldehydes in the presence of a catalytic amount of Zn(OTf)₂ followed by H₂O₂-mediated oxidation is reported. Furthermore, the synthesis of 1′H-spiro[indoline-3,4′- pyrano[2,3-b]pyrazolo[3,4-e]pyridine]-2,8′(9′H)-diones were chosen for the library validation.

Full text of DOI:10.1021/co3001204

Research Article
pubs.acs.org/acscombsci
One-Pot Three-Component Synthesis of Pyrano
[3,2‑b]pyrazolo[4,3‑e]pyridin-8(1H)‑ones
Shirin Safaei,† Iraj Mohammadpoor-Baltork,*,† Ahmad Reza Khosropour,*,† Majid Moghadam,†
Shahram Tangestaninejad,† Valiollah Mirkhani,† and Hamid Reza Khavasi‡
†Catalysis Division, Department of Chemistry, University of Isfahan, Isfahan 81746-73441, Iran
‡Department of Chemistry, University of Shahid Beheshti, Tehran 19396-4716, Iran
S
* Supporting Information
ABSTRACT: An efficient one-pot synthesis of novel pyrano-
[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones via three-compo-
nent condensation of kojic acid, 1-H-pyrazol-5-amines and
aldehydes in the presence of a catalytic amount of Zn(OTf)2
followed by H2O2-mediated oxidation is reported. Further-
more, the synthesis of 1′H-spiro[indoline-3,4′-pyrano[2,3-
b]pyrazolo[3,4-e]pyridine]-2,8′(9′H)-diones were chosen for the library validation.
KEYWORDS: three-component, Zn(OTf)2, H2O2, kojic acid, 1-H-pyrazol-5-amines
peroxidation inhibitory and protective effects against neuro-
degenerative diseases induced by free radicals activators.19
Furthermore, Kojic acid derivatives have shown effective
bioactivities as anti-HIV,20 antibacterial,21 antidiabetes,22
hepatitis C virus inhibitory23 and tyrosinase inhibitors.24
Therefore, the synthesis of kojic acid derivatives has been
received with great attention in bioorganic and medicinal
chemistry.
INTRODUCTION
■
Recently, multicomponent reactions (MCRs) have shown to
afford efficient access to highly complex final products in a
single step. They have proven to be fast, convergent, atom
efficient reactions often avoiding complicated purifications.1
These reactions have emerged as a valuable tool in the synthesis
of drug libraries because they have significant advantages over
conventional reaction strategies to generate biologically active
scaffolds with significant structural diversity.2 Consequently,
designing novel MCRs for the synthesis of diverse drug-like
molecules has been the focus of many researchers.
Multiheterocyclic compounds have shown a wide spectrum
of biological activities for access to the pharmaceutical and
medicinal products.3 In particular, pyrazolo[3,4-b]pyridines
have emerged as a potentially interesting scaffold for bio-
logically active compounds because of their structural analogy
to purine bases, an important constituent of DNA and RNA
nucleosides.4 These heterocycles have been identified as anti-
inflammatory,5 antibacterial,6 antiherpetic,7 and selective
inhibitors of A1 adenosine receptors.8 They have also been
reported as a potent treatment of Alzheimer’s and gastro-
intestinal diseases as well as drug addiction and infertility.4,9
Moreover, the existence of pyranopyridines in the framework of
several biologically active compounds as well as natural
alkaloids of plant origin10 has encouraged researchers to
synthesize and investigate their potential biological activities.
For instance, pyrano[2,3-b]pyridines are known to exhibit
antiallergic,11 anti-inflammatory,12 antiproliferative,13 antihypo-
tensive,14 anti-antimicrobial,15 and antiasthmatic activities.16
Kojic acid, is a natural substance produced by various fungal
or bacterial strains, such as Aspergillus oryzae, Penicillium or
acetobacter species. This compound acts as a natural antioxidant
and scavenger of reactive oxygen species.17 Also, its manganese
complex showed potent radio-protective activity,18 lipid
Similarly, spiro-oxindole substructures received much
attention from the synthetic community,25 prompted by their
appearance in the core structure of many pharmacological
agents and neutral alkaloids.26 Considering the above reports,
designing a new synthetic pathway to generate diverse fused-
complex structural compounds, which are a multicombination
of these highly bioactive heterocycles, is a great challenge in the
modern drug discovery.
As a consequence of our interest in heterocyclic synthesis,27
herein we wish to report a three component synthesis of
pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-one derivatives in
the presence of Zn(OTf)2 followed by H2O2-mediated
oxidation.
RESULTS AND DISCUSSION
■
At the outset, the reaction of kojic acid (1 mmol), 1,3-diphenyl-
1H-pyrazol-5-amine (1 mmol), and benzaldehyde (1 mmol)
was selected as a template reaction to investigate the catalyst
effect at 120 °C under solvent-free conditions (Table 1, entries
1−8). A comparison of catalytic activity between Brønsted and
Lewis acids showed highest catalytic activity of Zn(OTf)2 under
solvent-free conditions at 120 °C (Table 1, entry 1). Moreover,
Received: September 26, 2012
Revised: February 7, 2013
© XXXX American Chemical Society
A
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a
Table 1. Optimization of the Reaction Conditions for Three-Component Synthesis of 4{1,1,1}
b
b
entry
catalyst (mol %)
time (h)
yield (%)
92
4:5
1
2
3
4
5
6
7
8
Zn(OTf)2 (10)
no catalyst
1
10
1
65:35
p-TSA (10)
57
55
43
80
52
78
93
75
92
85
75:25
75:25
70:30
65:35
70:30
70:30
65:35
65:35
65:35
65:35
sulfamic acid (10)
ZnCl2 (10)
1
1
InCl3 (10)
1
ZrOCl4 (10)
Bi(OTf)3 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (12)
Zn(OTf)2 (8)
1
1
c
9
1
d
10
1
11
12
1
1
a
Kojic acid (1 mmol), 1,3-diphenyl-1H-pyrazol-5-amine (1 mmol), benzaldehyde (1 mmol), catalyst (10 mol %), under solvent-free condition, at
b
c
d
120 °C. Isolated yield. Reaction was performed at 130 °C. Reaction was performed at 110 °C.
a
no reaction occurred in the absence of the catalyst even after 10
h (Table 1, entry 2). A higher reaction temperature (130 °C)
does not make an obvious difference in the yield of product
(93%, Table 1, entry 9), but a lower reaction temperature of
110 °C decreased the conversion to 75% (Table 1, entry 10).
The catalyst amount is another crucial factor, as lower yields
were obtained when the same reaction was carried out using a
lower amount of the catalyst (Table 1, entries 11, 12).
Accordingly, performing the reaction solvent free in the
presence of 10 mol % of Zn(OTf)2 at 120 °C was chosen as
the optimal conditions.
To optimize the aromatization of 4{1,1,1}, the model
reaction was performed in the presence of different oxidants
and solvents (Table 2, entries 1−9). As illustrated, H2O2 (2
equiv) in acetonitrile is sufficient for this transformation, and
the desired product was obtained in excellent yield (Table 2,
entry 5).
It is noteworthy that the effect of oxygen is negligible on
improving the yield of the final product. So, with the optimized
reaction conditions in hand, we considered to introduce more
diversities in the pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-
one scaffold via the novel one-pot reaction of kojic acid, 1-H-
pyrazol-5-amines, and aryl aldehydes (Figure 1). We found that
Zn(OTf)2 is an efficient catalyst for the synthesis of a large
spectrum of pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones
by this reaction (Table 3).
Table 2. Evaluation of Potential Oxidants
b
entry
oxidant (equiv)
time (min)
yield (%)
c
1
2
3
4
5
6
7
CAN (2)
30
30
30
30
30
30
30
30
30
45
55
50
87
94
81
94
80
88
NaIO4 (2)
MnO2 (2)
t-BuOOH (2)
H2O2 (2)
H2O2 (1.5)
H2O2 (2.5)
H2O2 (2)
d
8
e
9
H2O2 (2)
a
The reaction was carried out with oxidant (2 equiv) in CH3CN (3
b
c
mL) at reflux temperature. Isolated yield. CAN: ceric (IV)
d
ammonium nitrate. The reaction was performed in 3 mL of
methanol. The reaction was performed in 3 mL of ethanol.
e
It was generally observed that high to excellent yields of the
products were obtained in all cases. The aryl aldehydes carrying
electron-donating groups could be smoothly converted to the
desired products (87−92% yields, Table 3, entries 4−6, 12 and
13). The coupling of aryl aldehydes containing electron-
withdrawing groups also afforded the corresponding products
in high to excellent yields.
Moreover, this reaction works well with aliphatic aldehydes
and heteroaromatic carbaldehydes such as thiophene-2-
carbaldehyde (Table 3, entries 9, 10). The successful
production of pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-one
derivatives indicated that this one-pot reaction is general for
such transformations. Based on these considerations, we
explored a new and facile reaction for the synthesis of
pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-one derivatives by
a straightforward process.
To further expand the scope of this new MCR and because
of extensive applications of spiro-oxindole heterocycles in
medicinal chemistry, the synthesis of 1′H-spiro[indoline-3,4′-
pyrano[3,2-b]pyrazolo[4,3-e]pyridine]-2,8′(9′H)-diones were
also examined. As shown in Scheme 1, the reaction of isatin
with 1H-pyrazol-5-amines and kojic acid in the presence of
B
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Figure 1. Diversity of reagents.
Table 3. Synthesis of Pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-one Derivatives 5
a
entry
product
yield (%)
1
2
5{1,1,1}
5{1,1,2}
5{1,1,3}
5{1,1,4}
5{1,1,5}
5{1,1,7}
5{1,1,10}
5{1,1,11}
5{1,1,16}
5{1,1,17}
5{1,2,2}
5{1,2,6}
5{1,2,7}
5{1,2,8}
5{1,2,9}
5{1,2,10}
5{1,2,12}
5{1,2,13}
5{1,2,14}
5{1,2,15}
89
86
90
92
90
87
94
95
82
86
93
90
89
96
96
91
90
93
88
89
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
a
Isolated yield.
C
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Scheme 1. Synthesis of 1′H-Spiro[indoline-3,4′-pyrano[3,2-b]pyrazolo[4,3-e]pyridine]-2,8′(9′H)-diones 7
Figure 2. X-ray Crystallography structure of compound 5{1,1,3}.
Scheme 2. Possible Mechanism for the Synthesis of Pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones
catalytic amounts of Zn(OTf)2 proceeded efficiently to furnish
the corresponding spiro products 7 in high yields.
The structures of the products were identified by their FTIR,
1H NMR, 13C NMR, mass spectroscopy, and elemental
analysis. Furthermore, the structure of 5{1,1,3} was confirmed
by X-ray crystallographic analysis (CCDC 894834, Figure 2).
A plausible mechanism for the formation of pyrano[3,2-
b]pyrazolo[4,3-e]pyridin-8(1H)-one is proposed in Scheme 2.
The condensation of 1H-pyrazol-5-amine 2 with the keto form
of kojic acid in the presence of the catalyst gave the
intermediate 8. Nucleophilic attack of 8 to the aldehyde 3
To the best of our knowledge, there is no report on the
synthesis of pyrano[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones
through the MCR of aldehydes, 1H-pyrazol-5-amines, and
kojic acid. Therefore, such a synthesis can be considered as a
powerful and practical method for the preparation of a new
class of kojic acid fused heterocyclic derivatives.
D
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furnished the intermediate 9, which upon intramolecular
cyclization and dehydration gave 4. In the last step, the
intermediate 4, by further oxidation and subsequent aromatiza-
tion, was converted to the desired product 5.
AUTHOR INFORMATION
Corresponding Author
*Fax: +98(311)6689732. Phone: +98(311)7932705. E-mail:
imbaltork@sci.ui.ac.ir (I.M.-B.), arkhosropour@chem.ui.ac.ir
(A.R.K.).
■
CONCLUSION
Funding
■
The authors are grateful to the Center of Excellence of
Chemistry and Research Council of the University of Isfahan
for financial support of this work.
We have demonstrated a simple and efficient route for the one-
pot, three-component synthesis of pyrano[3,2-b]pyrazolo[4,3-
e]pyridin-8(1H)-ones and 1′H-spiro[indoline-3,4′-pyrano[3,2-
b]pyrazolo[4,3-e]pyridine]-2,8′(9′H)-diones using readily avail-
able starting materials. The significant features of this method
are short reaction times, high yields of the products, operational
simplicity, and easy workup procedure, which make it an
applicable method for the synthesis of diverse libraries.
Notes
The authors declare no competing financial interest.
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■
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[3,2-b]pyrazolo[4,3-e]pyridin-8(1H)-one 5{1,1,5}. A mix-
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mmol), and Zn(OTf)2 (0.036 g, 0.1 mmol) was stirred at 120
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=
1
3373, 3060, 2959, 1636, 1455, 1352, 1103, 840, 755 cm−1. H
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5.82 (t, J = 5.6 Hz, 1H, OH), 6.50 (s, 1H, CH), 7.05−7.11 (m,
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all products and crystallographic
data for compound 5{1,1,3}. This material is available free of
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