Water-mediated one-pot synthetic route for pyrazolo[3,4-b]quinolines

Article abstract of DOI:10.1016/j.tetlet.2010.05.117

First time one-pot water-mediated synthetic route has been developed by carrying condensation of 2-chloro-3-formyl quinolines and hydrazine hydrate/phenyl hydrazine using thermal/microwave energy resources. The route is convenient, eco-friendly, and scala

Full text of DOI:10.1016/j.tetlet.2010.05.117

Tetrahedron Letters 51 (2010) 3980–3982
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Tetrahedron Letters
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Water-mediated one-pot synthetic route for pyrazolo[3,4-b]quinolines
*
Jyotirling R. Mali, Umesh R. Pratap, Dhanaji V. Jawale, Ramrao A. Mane
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
First time one-pot water-mediated synthetic route has been developed by carrying condensation of 2-
chloro-3-formyl quinolines and hydrazine hydrate/phenyl hydrazine using thermal/microwave energy
resources. The route is convenient, eco-friendly, and scalable.
Received 26 February 2010
Revised 23 May 2010
Accepted 25 May 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazolo[3,4-b]quinolines
Green chemistry
Microwave
One-pot synthesis
Pyrazole and its derivatives are gaining importance in medicinal
and organic chemistry. They have displayed broad spectrum of
pharmacological and biological activities such as anti-bacterial,
anti-depressant, and anti-hyperglycemic.1 Quinoline derivatives
are found to process anti-malarial, anti-inflammatory, anti-tuber-
culosis, and anti-breast cancer activities.2
Keeping in view the potential biological activities of the pyra-
zoles and quinolines, the chemists have tried to synthesize and
evaluate bioactivities of molecules having these ring systems in a
molecular frame work as in fused or bonded forms. One of the such
forms, pyrazolo[3,4-b]quinolines have displayed bioactivities, such
as anti-viral, anti-microbial, and anti-malarials.3
Considering the applicability of pyrazolo[3,4-b]quinolines, sev-
eral attempts are made to provide convenient synthetic routes.
The literature reveals that the widely used methods for obtaining
the pyrazolo[3,4-b]quinolines are using 2-chloro-3-formyl
quinolines as precursors/starting materials. In one of the routes,
the 2-chloro-3-formyl quinolines have been condensed with
hydrazine hydrate/phenyl hydrazine in refluxed ethanol and ob-
tained moderate yields of the pyrazolo[3,4-b]quinolines.4 The neat
one-pot condensation of the 2-chloro-3-formyl quinolines and
hydrazine hydrate/phenyl hydrazine using organic catalyst, P-TSA
under microwave has also been reported.5
It has been recorded that in these routes the products, pyrazol-
o[3,4-b]quinolines, obtained were not found to be pure and always
accompanying with intermediate Schiff bases, 1-[(2-chloroquino-
lin-3-yl)methylene]hydrazines/1-[(2-chloroquinolin-3-yl)methy-
lene]-2 phenylhydrazines. To avoid this difficulty the attempts are
found to be directed to get the target products in pure form with
unambiguous structures by following multistep synthetic route.
The reported multistep route covers (i) the protection of 2-chloro-
3-formyl quinolines; (ii) then the nucleophilic displacement of
chloro by hydrazine hydrate to 1-[3-(1,3-dioxolan-2-yl)quinolin-
2-yl]hydrazines; and (iii) the deprotection and cyclization of
intermediates, 1-[3-(1,3-dioxolan-2-yl)quinolin-2-yl]hydrazines
to pyrazolo[3,4-b]quinolines.6
The above literature routes are found to have one or other kinds
of difficulties and therefore not convenient. Keeping the above
scope in mind and in continuation of our earlier efforts toward
the syntheses of biodynamic heterocycles,7 here we thought to de-
velop a simple, eco-friendly, and economic synthetic one-pot route
for pyrazolo[3,4-b]quinolines (Scheme 1).
The literature reveals that recently water and polyethylene gly-
col have been gaining important as clean, safe, and recyclable med-
ia for various organic transformations.8 Polyethylene glycol is
being relatively expensive than water, the attempts are therefore
directed to carry the organic transformation using thermal or
R1
R1
H
O
H2O
/ MW
N
H2N
R3
N
N
Cl
N
R3
N
R2
R2
2a-h
1a
2a: R1 = H, R2 = H, R3= H
2b: R1 = OMe, R2 = H, R3 = H
2c: R1 = Me, R2 = H, R3 = H
2d: R1 = H, R2 = Et, R3 = H
2e: R1 = H, R2 = H, R3= Ph
2f: R1 = OMe, R2 = H, R3 = Ph
2g: R1 = Me, R2 = H, R3 =Ph
2h: R1 = H, R2 = Et, R3 =Ph
* Corresponding author. Tel.: +91 240 2403313; fax: +91 240 2400291.
E-mail address: manera@indiatimes.com (R.A. Mane).
Scheme 1. Synthesis of pyrazolo[3,4-b]quinolines.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.117

J. R. Mali et al. / Tetrahedron Letters 51 (2010) 3980–3982
3981
Table 1
Med. Chem. 2001, 36, 539; (c) Kees, K. L.; Fitzgerald, J. J.; Steiner, K. E., Jr.;
Mattes, J. F.; Mihan, B.; Tosi, T.; Mondoro, D.; McCaleb, M. L. J. Med. Chem. 1996,
39, 3920.
Physical parameters of pyrazolo[3,4-b]quinolines
Entry
Products
Time (h)
Yieldsa (%)
Mp (°C)
Reported (Lit.)4
2. (a) Craig, J. C.; Person, P. E. J. Med. Chem. 1971, 14, 1221; (b) Dillard, R. D.;
Pavey, D. E.; Benslay, D. N. J. Med. Chem. 1973, 16, 251; (c) De Souza, M. V.;
Pais, K. C.; Kaiser, C. R.; Peralta, M. A.; Ferreira, M.; De, L.; Lourenco, M. C. S.
Bioorg. Med. Chem. 2009, 17, 1474; (d) Shi, A.; Nguyen, T. A.; Battina, S. K.;
Rana, S.; Takemoto, D. J.; Chiang, P. K.; Hua, D. H. Bioorg. Med. Chem. Lett.
2008, 18, 3364.
3. (a) Smirnoff, P.; Crenshaw, R. R. Antimicrob. Agents Chemother. 1977, 11, 571; (b)
Selvi, S. T.; Nadaraj, V.; Mohan, S.; Sasi, R.; Hema, M. Bioorg. Med. Chem. 2006,
14, 3896; (c) Stein, R. G.; Beil, J. H.; Singh, T. J. Med. Chem. 1970, 13, 153.
4. Rajendran, S. P.; Manonmani, M.; Vijayalakshmi, S. Org. Prep. Proc. Int. 1994, 26,
384.
5. Paul, S.; Gupta, M.; Gupta, R.; Loupy, A. Tetrahedron Lett. 2001, 42, 3827.
6. Afghan, A.; Baradarani, M. M.; Joule, J. A. Arkivoc 2009, 20. and references cited
therein.
7. (a) Mahalle, S. R.; Netankar, P. D.; Bondge, S. P.; Mane, R. A. Green Chem. Lett.
Rev. 2008, 2, 103; (b) Pratap, U. R.; Mali, J. R.; Jawale, D. V.; Mane, R. A.
Tetrahedron Lett. 2009, 50, 1352; (c) Mali, J. R.; Pratap, U. R.; Netankar, P. D.;
Mane, R. A. Tetrahedron Lett. 2009, 50, 5025.
8. For Water: (a) Narayan, S.; Maludoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275; (b) Chakraborti, A. K.;
Rudrawar, S.; Jadhav, K. B.; Kaur, G.; Chankeshwara, S. V. Green Chem. 2007, 9,
1335; (c) Habib, P. M.; Kavala, V.; Raju, B. R.; Kuo, C.-W.; Huang, W.-C.; Yao, C.-
F. Eur. J. Org. Chem. 2009, 4503; (d) Cozzi, P. G.; Zoli, L. Angew. Chem., Int. Ed.
2008, 47, 4162; (e) Huang, J.; Zhang, X.; Armstrong, D. W. Angew. Chem., Int. Ed.
2007, 46, 9073; (f) Shapiro, N.; Vigalok, A. Angew. Chem., Int. Ed. 2008, 47, 2849;
For Polyethylene Glycol: (a) Vasudevan, V. N.; Rajender, S. V. Green Chem. 2001,
3, 146; (b) Haimov, A.; Neumann, R. Chem. Commun. 2002, 876; (c) Heiss, L.;
Gais, H. J. Tetrahedron Lett. 1995, 36, 3833; (d) Tenemura, K.; Suzuki, T.; Nishida,
Y.; Horaguchi, T. Chem. Lett. 2005, 34, 576; (e) Kamble, V. T.; Davane, B. S.;
Chavan, S. A.; Bhosale, R. B. Aust. J. Chem. 2007, 60, 302.
A
B
A
B
Found
1
2
3
4
5
6
7
8
2ab
2bb
2cb
2dc
2eb
2fb
7
8
7
9
7
1.5
1.5
1.5
1.7
1.7
2
91
91
91
90
91
90
89
85
93
93
93
92
93
90
89
87
202–204
217–219
176 (d)
164–166
171–172
149–151
179–181
175–176
203–204
217–218
175 (d)
–
172 (d)
150 (d)
176–178
—
8
2gb
2hc
9
2
10
2.5
d: Decomposed. A: Conventional heating; B: Microwave heating.
a
Isolated yields
b
Elemental analyses of the products 2a, 2b, 2c, 2e, 2f, and 2g have not been done
as these products are reported in the literature and the isolated products were pure
and their melting points are in good agreement with those reported.4
c
C, H, and N analyses of products 2d and 2h have been carried out and the results
are in agreement with the corresponding calculated values.
microwave resources in water. It is also reported that boiling water
under microwave irradiation behaves as hydrophobic medium and
helps to form homogenous mass with organic substrates/reagents
present with it and hence accelerates the rate of reaction.9
The above-referred utility of water as medium has prompted to
attempt one-pot cyclocondensation of 2-chloro-3-formyl quino-
lines and hydrazine hydrate/phenyl hydrazine using thermal and
microwave energy resources. It was noticed that the cyclocondensa-
tion leading to the titled compounds has occurred under these con-
ditions. To optimize the condition required for this one-pot route,
the following attempts were made by carrying reference reaction
using 2-chloro-3-formyl quinoline and hydrazine hydrate/phenyl
hydrazine. It was observed that pyrazolo[3,4-b]quinoline was ob-
tained with better to excellent yield (91%), when one-pot condensa-
tion of 2-chloro-3-formyl quinoline and molar excess of hydrazine
hydrate/phenyl hydrazine was carried under reflux for 7 h using
thermal energy.
The same condensation when carried using identical mole pro-
portions as above in refluxed water under microwave irradiation
found to give 93% of pyrazolo[3,4-b]quinoline within 1.5 h. Using
these optimized conditions the other pyrazolo[3,4-b]quinolines
have been synthesized and their characteristic details are recorded
in Table 1.
Thus developed route is one-pot and would be going under
completion via intermediate hydrazone (Schiff base) formation
and subsequent to that cyclization. The products obtained are free
from impurities and the medium used is readily available, cheaper,
and safe.
9. Hayes, B. L. Mircowave Synthesis: Chemistry at the Speed of Light; CEN
Publishing: Matthews, NC, 2002; (b) Dallinger, D.; Kappe, C. O. Chem. Rev.
2007, 107, 2563; (c) Polshettiwar, V.; Verma, R. S. Acc. Chem. Res. 2008, 41,
629.
10. Experimental: All chemicals and solvents were purchased from Spectrochem
and S. D. Fine-chem. (India). All the melting points were recorded by open
capillary method and are uncorrected. The reactions were carried out in a
Milstone MicroSYNTH Labstation for Synthesis, MW oven having a maximum
power output of 1200 W. 1H NMR and 13C NMR spectra were recorded with a
Bruker Avance 400 spectrometer operating at 400 MHz and 100 MHz using
DMSO-d6 solvent and tetramethylsilane (TMS) as the internal standard. Mass
spectra were recorded on Single-Quadrupole Mass Detector 3100, Waters. The
observed molecular ions are having 1 amu higher m/z in the spectra than the
expected. Elemental analyses were performed on CHNS auto analyzer, Thermo
Finnigan.
General procedures (A and B) for the synthesis of pyrazolo[3,4b]quinolines (2a–h)
(A) Conventional (thermal) method:
A mixture of 2-chloro-3-formyl quinolines 1 (5 mmol), hydrazine hydrate 98%
(15 mmol), and phenyl hydrazine (7.5 mmol) was refluxed with stirring in
water (25 mL). The progress of the reaction was monitored by TLC using
hexane–ethyl acetate (7:3). On completion of the reaction, the reaction mass
was cooled and thus the obtained solid was filtrated, washed with water, and
dried. The crude products were crystallized from ethanol. The other details of
the products are recorded in Table 1.
(B) Non-conventional (microwave irradiation) method:
A mixture of 2-chloro-3-formyl quinolines 1 (5 mmol), hydrazine hydrate 98%
(15 mmol) and phenyl hydrazine (7.5 mmol) was refluxed with stirring in
water (25 mL) under microwave irradiation at 1000 W for 1.5–2.5 h. The
progress of the reaction was monitored by TLC using hexane–ethyl acetate
(7:3). After completion of the reaction, the reaction mass was cooled and thus
the obtained solid was filtrated, washed with water, and dried. The crude
products were crystallized from ethanol. The other details of the products are
recorded in Table 1.
In conclusion, first time the cyclocondensation of substituted
2-chloro-3-formyl quinolines and hydrazine hydrate/phenyl
hydrazine has been carried out using water as a reaction medium
and obtained better yields of pyrazolo[3,4-b]quinolines. Thus, here
we have provided safe, economic, and convenient synthetic route
for biodynamic pyrazolo[3,4-b]quinolines.
Experimental procedure of the synthesized compounds and
their characterization data are incorporated in the reference
part.10,11
11. Spectral data of compounds: 1H-Pyrazolo[3,4-b]quinoline (2a): Yellow solid;
mp: 202–204 °C. 1H NMR (400 MHz, DMSO-d6): 7.50 (t, 1H, J = 8 Hz), 7.80 (t,
1H, J = 8 Hz), 8.00 (d, 1H, J = 8 Hz), 8.15 (d, 1H, J = 8 Hz), 8.44 (s, 1H), 8.95 (s,
1H), 13.56 (s, 1H). 13C NMR (100 MHz, DMSO-d6): 115.87, 123.37, 123.95,
127.77, 129.66, 130.43, 130.54, 134.15, 147.72, 151.59. Mass: m/z 170 (M+). 6-
Methoxy-1H-pyrazolo[3,4-b]quinoline (2b): Yellow solid; mp: 217–219 °C. 1H
NMR (400 MHz, DMSO-d6): 3.90 (s, 3H), 7.44–7.48 (m, 2H), 7.91 (d, 1H,
J = 8 Hz), 8.36 (s, 1H), 8.78 (s, 1H), 13.47 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
55.40, 105.68, 115.82, 124.33, 124.67, 128.30, 129.13, 133.36, 144.17, 150.80,
154.86. Mass: m/z 200 (M+). 6-Methyl-1H-pyrazolo[3,4-b]quinoline (2c):
Yellow solid; mp: 176 °C. 1H NMR (400 MHz, DMSO-d6): 2.74 (s, 3H); 7.39 (t,
1H, J = 1.2 Hz and J = 8 Hz); 7.66 (d, 1H, J = 6.4 Hz); 7.99 (d, 1H, J = 8 Hz); 8.42
(s, 1H); 8.92 (s, 1H). 13.65 (s, 1H). 13C NMR (100 MHz, DMSO-d6): 18.45, 115.51
123.00, 123.77, 127.64, 130.01, 130.76, 133.91, 134.84, 146.94, 151.14. Mass:
m/z 184 (M+). 8-Ethyl-1H-pyrazolo[3,4-b]quinoline (2d): Yellow solid; mp:
164–166 °C. 1H NMR (400 MHz, DMSO-d6): dppm 1.35 (t, 3H), 3.27 (q, 2H), 7.41
(t, 1H, J = 8 Hz), 7.63 (d, 1H, J = 8 Hz), 7.95 (d, 1H, J = 8 Hz), 8.41 (s, 1H), 8.91 (s,
1H), 13.63 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): 14.97, 24.48, 115.51,
123.11, 123.91, 127.65, 128.47, 130.85, 133.89, 140.55, 146.25, 151.17. Mass:
m/z 198 (M+). Elemental Anal. Calcd: C12H11N3 C, 73.09; H, 5.58; N, 21.30.
Acknowledgment
The authors are thankful to Professor D. B. Ingle for his invalu-
able discussions and guidance.
References and notes
1. (a) Liu, X. H.; Cui, P.; Song, B. A.; Bhadury, P. S.; Zhu, H. L.; Wang, S. F. Bioorg.
Med. Chem. 2008, 16, 4075; (b) Erhan, P.; Mutlu, A.; Tayfun, U.; Dilek, E. Eur. J.

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J. R. Mali et al. / Tetrahedron Letters 51 (2010) 3980–3982
Found: C, 73.03; H, 5.50; N, 21.23. 8-Ethyl-1-phenyl-1H-pyrazolo[3,4-
(100 MHz, DMSO-d6): 15.05, 23.69, 119.71, 125.51, 126.36, 127.48, 127.55,
128.08, 129.03, 129.12, 129.26, 130.68, 133.61, 137.62, 141.10, 144.54, 144.59,
146.95. Mass: m/z 274 (M+). Elemental Anal. Calcd: C18H15N3: C, 79.12; H, 5.49;
N, 15.38. Found: C, 79.05; H, 5.44; N, 15.32.
b]quinoline (2h): Yellow solid; 175–176 °C. 1H NMR (400 MHz, DMSO-d6):
dppm 1.29 (t, 3H), 3.10 (q, 2H), 6.82–7.45 (m, 5H, Ar-H), 7.60 (t, 1H, J = 8 Hz),
7.65 (d, 1H, J = 8 Hz), 7.97 (d, 1H, J = 8 Hz), 8.23 (s, 1H), 8.86 (s, 1H). 13C NMR