Microwave-assisted and iodine mediated synthesis of 5-n-alkyl- cycloalkane[d]-pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and cyclic ketones

Article abstract of DOI:10.1016/j.tetlet.2014.02.015

5-n-Alkylcycloalkane[d]pyrazolo[3,4-b]pyridines were prepared by a microwave-assisted cyclocondensation reaction between 5-aminopyrazoles and cyclic ketones under solvent-free conditions and catalyzed by iodine. This procedure provides a simple one-step and environmentally friendly methodology with good yields for the synthesis of these compounds.

Full text of DOI:10.1016/j.tetlet.2014.02.015

Accepted Manuscript
Microwave-assisted and iodine mediated synthesis of 5-n-alkyl-cycloal-
kane[d]-pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and cyclic ketones
Jaime Gálvez, Jairo Quiroga, Braulio Insuasty, Rodrigo Abonia
PII:
S0040-4039(14)00236-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.02.015
TETL 44202
Reference:
Tetrahedron Letters
To appear in:
Received Date:
13 December 2013
Please cite this article as: Gálvez, J., Quiroga, J., Insuasty, B., Abonia, R., Microwave-assisted and iodine mediated
synthesis of 5-n-alkyl-cycloalkane[d]-pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and cyclic ketones,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.02.015
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Microwave-assisted and iodine mediated
synthesis of 5-n-alkyl-cycloalkane[d]pyrazolo[3,4-
b]pyridines from 5-aminopyrazoles and cyclic
ketones
Leave this area blank for abstract info.
Jaime Gálveza, Jairo Quirogaa, Braulio Insuastya, Rodrigo Aboniaa
aHeterocyclcic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia.

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Microwave-assisted and iodine mediated synthesis of 5-n-alkyl-cycloalkane[d]-
pyrazolo[3,4-b]pyridines from 5-aminopyrazoles and cyclic ketones
Jaime Gálveza , Jairo Quirogaa, , Braulio Insuastya, Rodrigo Aboniaa
aHeterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
5-n-Alkylcycloalkane[d]pyrazolo[3,4-b]pyridines were prepared by a microwave-assisted
cyclocondensation reaction between 5-aminopyrazoles and cyclic ketones under solvent-free
conditions and catalyzed by iodine. This procedure provides a simple one-step methodology
with good yields and environmentally friendly.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
5-Aminopyrazoles
Microwave irradiation
Cycloalkanones
Solvent-free reactions
Cycloalkanepyrazolopyridines
Currently, the Microwave-Assisted Organic Synthesis
(MAOS) is a powerful synthetic tool to carry out the synthesis of
a variety of organic compounds.1 Comparing with classical
methods, microwave-assisted reactions are a non-conventional
efficient energy source for synthetic chemistry and have gained
importance because of the simplicity in operation, milder reaction
conditions, increasing reaction rates and formation of cleaner
products, allowing the development of new molecules with
potential biological activity.1 Moreover, solvent-free microwave-
assisted reactions are having more popularity as they provide an
opportunity to work under conditions ecologically compatibles.2
In our interest to develop synthetic strategies to obtain
functionalized and interesting molecules such as pyrazolo[3,4-
b]pyridines with biological properties,7 we wish to report an
efficient method via
a
one-pot reaction between 5-
aminopyrazoles 18 and cyclic ketones 2, as an useful variant of
Skraup-Doebner-Miller fused-pyridine synthesis.6a
In an initial study, we tested the reaction between 3-methyl-1-
phenyl-1H-pyrazol-5-amine 1a and cyclopentanone 2a under
solvent-free conditions as a template reaction (Entry 2) to obtain
the Skraup-Doebner-Miller product, i.e. the spiro-compound 3a
(Scheme 1).6a
Pyrazolo[3,4-b]pyridines are an important group of nitrogen-
containing fused heterocyclics useful for medicinal and organic
chemistry because they have shown a wide spectrum of
biological and pharmacological activities.3 Among the most
important utilities, these compounds have been found as
antibacterial,
antidepressant,
antihyperglycemic,
anti-
inflammatory, antitumor and anxiolytic agents and are being used
in the treatment of Alzheimer’s diseases, drug addiction, and
infertility.4
On the other hand, molecular iodine has become an important
mild and efficient Lewis acid catalyst in organic synthesis due to
its benign characteristics as it is inexpensive, non-toxic,
insensitive to air and moisture, and can be easily removed from
the reaction mixture.5 Likewise, the molecular iodine has been
very useful in the synthesis of fused pyridines and quinolines by
Skraup or Doebner-Miller synthesis from anilines and carbonyl
compounds; becoming into an easier, regioselective and efficient
Scheme 1. Synthesis of alkyl-pyrazolo[3,4-b]pyridines.
After purification and opposite to the expected structure 3a,
the obtained product showed by the NMR experiments the
characteristics corresponding to the unplanned non-spiro but n-
alkylated and cycloalkane-fused pyrazolo[3,4-b]pyridine 4a.
methodology for the synthesis of this type of compounds.6
———
 Corresponding author. Tel.: +57-2-3393248; fax: +57-2-3392440; e-mail: jairo.quiroga@correounivalle.edu.co

2
Tetrahedron Letters
Usually, catalytic amounts of iodine and an excess of ketone
Under conventional heating the product was formed very
slowly and in low yield (Entry 1). Microwave irradiation made
faster the reaction but when 5 equivalents of 2a or a high load of
iodine (10 or 20 mol%) were used the product was obtained in
lower yields (Entries 2-4). Finally, ahead with others reports at
reflux or neat conditions, the reaction was optimized at 300W,
130 °C, using lesser amount of ketone with 3.0 equivalents of
cyclopentanone and 5 mol% of iodine (Entry 5) to obtain the n-
alkylated-cyclopentane[d]pyrazolo[3,4-b]pyridine 4a.9
are used in a Skraup-Doebner-Miller reaction6 and in order to
obtain the optimal reaction conditions, we performed the
optimization varying the equivalents of iodine respect to the 5-
aminopyrazole 1a and testing the effect of conventional heating
versus microwave irradiation (Table 1).
Table 1. Screening and optimization of the reaction conditions.
2a
Time
(min)
Entry
Conditions
Yield
equivalents
1
2
3
4
5
5.0
5.0
3.0
3.0
3.0
20 mol% I2, Neat, 150 °C
20 mol% I2, 300W, 150 °C
20 mol% I2, 300W, 130 °C
10 mol% I2, 300W, 130 °C
5 mol% I2, 300W, 130 °C
45
20
10
15
25
20
25
48
70
85
The scope and generality of the optimized method was further
demonstrated by the reaction of 5-aminopyrazoles 1 with
different cyclic ketones. In each case, the angular regioisomers
4a-o were obtained in good to excellent yields and high
regioselectivity (Table 2).
Table 2. Synthesis of 5-alkyl-pyrazolo[3,4-b]pyridines 3a-h.9
Entry
5-aminopyrazol
Ketone
Product
Time (min)
Yielda
1
25
85
2
3
4
5
65
75
70
15
15
5
6
20
15
80
80
7
30
78

3
8
17
72
9
16
25
58
90
10
11
10
68
12
12
60
13
20
68
14
13
55
15
10
64
aIsolated yields.

4
Tetrahedron Letters
1
The structures of all compounds were confirmed by H
confirmed the angular regiochemistry for compounds 4, but not
NMR, 13C NMR, 2D NMR spectra and MS analysis. Due to the
double nucleophilic nature of the 5-aminopyrazoles 1 we could
expect the formation of either a linear regioisomer type 4’ or an
angular regioisomer type 4.
the linear one (Figure 1).
A
possible mechanistic route for the described
cyclocondensation reaction is outlined in the Scheme 2.
According to Fotie6a presumably the first step involved the
condensation of the cyclopentanone with both nucleophilic
centers (i.e. 5-amino group and the C-4 carbon atom) of the 5-
aminopyrazol 1 leading to the formation of the Schiff base
intermediate 5. Then, the subsequent intramolecular 6π-
electrocyclization of 5 should afford the spiro-intermediate 7, and
although a spiro-dihydroderivative 3a is expected by a 1,5-
sigmatropic rearrangement of 7, instead it is finally oxidized by
air under thermal conditions and undergoes an aromatization
toward the isolated pyrazolo[3,4-b]pyridines 4.6 According to our
studies about pyrazolopyridine derivates, under air atmosphere
and thermal conditions is possible to obtain both dihydro and
oxidized derivates and the final product will depend on the
stability of the dihydroderivate and/or reaction conditions.7 It is
worth mentioning that the formation of the α,β-unsaturated
adduct 6 was observed and in some cases it was isolated and
characterized. Adduct 6 was in competence with the formation of
Schiff-base intermediate 5, for that reason it was necessary to use
an excess of the cyclic ketone in all cases.
Figure 1. HMBC correlations in the obtained pyrazolo[3,4-b]pyridines 4.
To determine the above, through HMBC experiment,
compound 4j was chosen due to its cyclohexyl fragment is
substituted with a methyl group being the 9-H proton and the C-
9b carbon atom exactly assigned from their H NMR and 13C
1
NMR spectra, respectively. Hence, a three-bonds HMBC
correlation observed between C-9b and H-9 atoms unequivocally
Scheme 2. Proposed mechanism for the formation of the 5-alkylpyrazolo[3,4-b]pyridines 4a-o.
In summary, we obtained the unplanned 5-alkyl-
pyrazolo[3,4-b]pyridines in good yields by an easy, direct and
References and notes
regioselective
cyclocondensation-aromatization
reaction
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catalyzed by molecular iodine under microwave irradiation.
This methodology offers a non-metal and solvent-free
reaction conditions and operational simplicity from
inexpensive reagents. Currently, this procedure is being
extended to other nucleophilic heterocyclic amines and the
biological and fluorescent properties of the new obtained
compounds are under investigation.
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Acknowledgments
Authors wish to thank the COLCIENCIAS and Universidad
del Valle for financial support.
Supplementary Data
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experimental procedure and characterization data of the obtained
compounds are given in supplementary material) associated with
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maximum power of 300W. The obtained compounds were purified on
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eluent.
Data
for
5-butyl-1-methyl-3-phenyl-3,6,7,8-
tetrahydrocyclopentane[d]pyrazolo[3,4-b]pyridine 4a. Yellow solid,
Yield 85%, m.p.: 63-65 °C. 1H NMR (400 MHz, CDCl3) δ ppm: 1.00 (t,
J=7.4 Hz, 3H), 1.41-1.53 (m, 2H), 1.77-1.88 (m, 2H), 2.25 (quin, J=7.5
Hz, 2H), 2.67 (s, 3H), 2.83-2.90 (m, 2H), 2.99 (t, J=7.4 Hz, 2H), 3.28 (t,
J=7.5 Hz, 2H), 7.19-7.26 (m, 1H), 7.45-7.53 (m, 2H), 8.40 (dd, J=8.8,
1.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ ppm: 13.9 (CH3), 14.0
(CH3), 22.6 (CH2), 24.5 (CH2), 30.2 (CH2), 30.4 (CH2), 31.6 (CH2), 36.0
(CH2), 113.1 (C), 120.3 (CH), 124.7 (C), 128.8 (CH), 131.4 (C), 140.3
(C), 141.7 (C), 147.0 (C), 150.9 (C), 158.4 (C). MS (70 eV) m/z (%):
305 (M+, 10), 290 (5), 276 (10), 264 (20), 263 (100), 262 (20), 77 (7).
1-methyl-5-pentyl-3-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-
c]isoquinoline 4f. Yellow oil, Yield 78%, 1H NMR (400 MHz, CDCl3) δ
ppm: 0.90-1.00 (m, 3H), 1.41-1.49 (m, 4H), 1.80-1.95 (m, 6H), 2.72 (s,
3H), 2.76 (t, J=4.5 Hz, 2H), 2.83 (t, J=7.6, 2H), 3.19 (t, J=4.5 Hz, 2H),
7.19-7.25 (m, 1H), 7.44-7.51 (m, 2H), 8.37 (dd, J=8.7, 1.1 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ ppm: 14.1 (CH3), 15.8 (CH3), 21.8 (CH2),
22.7 (CH2), 22.8 (CH2), 25.8 (CH2), 27.0 (CH2), 27.6 (CH2), 31.9 (CH2),
35.2 (CH2), 114.1 (C), 120.2 (CH), 123.8 (C), 124.6 (CH), 128.8 (CH),
140.1 (C), 140.8 (C), 142.0 (C), 149.3 (C), 161.5 (C). MS (70 eV) m/z
(%): 333 (M+, 10), 305 (12), 290 (19), 277 (62), 263 (100), 77 (20).
5-hexyl-1-methyl-3-phenyl-3,6,7,8,9,10-
hexahydrocycloheptane[d]pyrazo-lo[3,4-b]pyridine 4m. Yellow solid,
Yield 68%, m.p.: 89-91 °C. H NMR (400 MHz, CDCl3) δ ppm: 0.89-
1
0.98 (m, 3H), 1.31-1.42 (m, 4H), 1.42-1.52 (m, 2H), 1.65 (dt, J=10.6, 5.6
Hz, 2H), 1.70-1.84 (m, 4H), 1.87-1.95 (m, 2H), 2.74 (s, 3H), 2.92-3.00
(m, 4H), 3.19-3.25 (m, 2H), 7.19-7.26 (m, 1H), 7.48 (t, J=8.0 Hz, 2H),
8.37-8.42 (m, 2H). 13C NMR (101 MHz, CDCl3) δ ppm: 14.1 (CH3), 16.2
(CH3), 22.6 (CH2), 26.4 (CH2), 27.3 (CH2), 28.4 (CH2), 29.1 (CH2), 29.3
(CH2), 29.6 (CH2), 31.8 (CH2), 32.1 (CH2), 37.0 (CH2), 114.1 (C), 120.2
(CH), 124.5 (CH), 128.7 (CH), 130.4 (C), 140.0 (C), 141.7 (C), 147.4
(C), 149.6 (C), 159.9 (C). MS (70 eV) m/z (%): 361 (M+, 15), 332 (5),
318 (10), 304 (19), 291 (100), 276 (33), 262 (30), 43 (61).
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9. General procedure for the preparation of 5-alkyl-pyrazolo[3,4-
b]pyridines4a-h: Microwave experiment was carried out using a focused