Synthesis of some novel fluorinated pyrazolo[3,4-b]pyridines

Article abstract of DOI:10.1081/SCC-200039427

Reaction of 5-amino-3-substituted pyrazoles (1a-c) and 5-amino-1,3- disubstituted pyrazoles (1d-i) with fluorinated-β-diketones (2) results in the formation of the single isomer of pyrazolo[3,4-b]pyridines (4a-h). A one-pot procedure for the synthesis of

Full text of DOI:10.1081/SCC-200039427

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Synthesis of Some
Novel Fluorinated
Pyrazolo[3,4‐b]Pyridines
S. P. Singh a , Rajesh Naithani b , Ranjana Aggarwal
a & Om Prakash a
a Department of Chemistry, University of
Kurukshetra, Kurukshetra, Haryana, India
b Department of Chemistry, University of Illinois at
Chicago, Chicago, Illinois, 60607, USA
Published online: 10 Jan 2011.
To cite this article: S. P. Singh , Rajesh Naithani , Ranjana Aggarwal & Om Prakash
(2004): Synthesis of Some Novel Fluorinated Pyrazolo[3,4‐b]Pyridines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:23, 4359-4367
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 23, pp. 4359–4367, 2004
Synthesis of Some Novel Fluorinated
Pyrazolo[3,4-b]Pyridines
1
S. P. Singh,1 Rajesh Naithani,2, Ranjana Aggarwal,
*
and Om Prakash1
1Department of Chemistry, University of Kurukshetra, Kurukshetra,
Haryana, India
2Department of Chemistry, University of Illinois at Chicago, Chicago,
Illinois, USA
ABSTRACT
Reaction of 5-amino-3-substituted pyrazoles (1a–c) and 5-amino-1,3-
disubstituted pyrazoles (1d–i) with fluorinated-b-diketones (2) results
in the formation of the single isomer of pyrazolo[3,4-b]pyridines
(4a–h). A one-pot procedure for the synthesis of title compounds starting
from a-cyanoacetophenones along with a possible mechanistic pathway
for the formation of the title compounds is described.
Key Words: a-Cyanoacetophones; Fluorinated-b-diketones; Pyra-
zolo[3,4-b]pyrimidines
*
Correspondence: Rajesh Naithani, Department of Chemistry, University of Illinois at
Chicago, Chicago, IL 60607, USA; E-mail: naithani@uic.edu.
4359
DOI: 10.1081/SCC-200039427
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4360
Singh et al.
The pyrazolopyridine nucleus has aroused great interest in recent years due
to a wide variety of biological activities associated with it. Anti-
inflammatory, antipyretic, analgesic, bactericidal, vasodilating, respiration
stimulating, bronchodilating, and hypotensive activities of this system have
been reported in the literature.[1–3] Pyrazolopyridines have been shown to
possessusefulpropertiesasantimetabolitesinthebiochemicalsynthesisofpurine.
In addition to this, it has been observed that the incorporation of fluorine
in many heterocyclic systems generates increased lipid solubility, thus
enhancing the rates of absorption and transport of drug in vivo. In fact, the
trifluoromethyl group is one of the most lipophilic of all the substituents.[4]
The above observations, coupled with the ongoing program in our laboratory
for the synthesis of novel fluorinated heterocyclic systems, prompted us to
undertake the synthesis of a few pyrazolo[3,4-b]pyridines.[5–7]
A number of methods have been reported in the literature describing the
synthesis of pyrazolo[3,4-b]pyridines.[8–11] Synthesis of several fluorinated
1-H-pyrazolo[3,4-b]pyridines by condensation of 5-amino-1,3 disubstituted
pyrazole with fluorinated-b-diketones have been reported by Joshi et al.[11]
The reaction ws shown to proceed through intermediate (3) formed by the
nucleophilic attack of the amino group on the COCF3 (path a) (Scheme 1).
However, the attack on the other carbonyl carbon (path b) was not considered
by these workers. There are reports that triflouromethyl-b-diketones react
with water and ethanol, presumably to give a tetrahedral adduct. It ws specu-
lated that there are various tautomeric equilibria of the fluorinated diketones,
resulting in the possibility of a nucleophilic attack on either carbonyl
function of the diketone.[6] Reaction at the CH2CO would generate another
intermediate, giving the cyclized isomeric pyrazolo[3,4-b]pyridines (6) with
the CF3 group at position 4 of the pyrazolopyridine moiety (Scheme 1).
Furthermore, no concrete data were given in the support of structure 4d–i
proposed for the pyrazolo[3,4-b]pyridines.[11]
Formation of a similar type of intermediates was reported as a result of
the reaction of 1-unsubstituted pyrazoles with fluorinated b-diketones[11]
(Scheme 2). Two products were reported to be formed on cyclization invol-
ving either position 1 or 4 of the pyrazole moiety. Again, the intermediate
(5) formed by the attack of the NH2 group on the other carbonyl (path b)
was not considered, which would produce another pair of the isomeric
pyrazolo[3,4-b]pyridines (6 and 8).
In order to shed more light on such reactions, the present investigation
treats several NH-substituted and NH-unsubstituted 5-aminopyrazoles (1)
with trifluoromethyl-b-diketones (2). Reaction of 3-substituted-5-aminopyra-
zoles with trifluoromethyl-b-diketones resulted in the exclusive formation
of the single isomer that may have structures 4d–i or 6d–i. Identification
of these compounds was established by applying 19F NMR spectroscopy.

Synthesis of Pyrazolo[3,4-b]pyridines
4361
Scheme 1.
It has already been reported in the literature that the CF3 at positions 2
and 4 adjacent to the nitrogen display fluorine signals at d 262 and 268,
respectively.[12] The relative difference in value at position 2 may be attributed
to the presence of nitrogen at adjacent positions attached via a double bond.
In agreement with this report, compound 4h was obtained from the
reaction of 1i with 1,1,1,5,5,5,hexafluoroacetylacetone. The 19F NMR of all
these molecules displayed a signal at d 262, thus revealing their structures
as 4d–h.
The reaction of several NH-unsubstituted 5-aminopyrazoles with dike-
tones again led to the formation of the single isomer (Scheme 3). The presence
of free NH was revealed the presence of NH stretch at 3250 cm21
.
Structure 4 was preferred upon the basis of signal at d 262 in the 19F NMR
spectra, thus ruling out the other structures.

4362
Singh et al.
Scheme 2.
The following conclusions may be drawn from the above studies:
1. As reported in the literature, the reaction of 5-aminopyrazoles with
fluorinated b-diketones is initiated exclusively by the attack of the
amino group on the carbonyl carbon adjoining the CF3 group
(Scheme 4).
2. Cyclization of the intermediate (3) formed by the nucleophilic
attack of the amino groups on the COCF3) involves position 4 of
the pyrazole moiety (Scheme 4).
The mechanistic pathway for the formation of the isomer 4 has been
depicted in Scheme 4.
The new synthesized fluorinated pyrazolo[3,4-b]pyridines have been
1
characterized by elemental analysis, infrared (IR), H NMR, and 19F NMR
spectroscopy, and mass spectral analysis.

Synthesis of Pyrazolo[3,4-b]pyridines
4363
Scheme 3.
All the protons resonated in the aromatic region, confirming the
formation of the pyrazolo[3,4-b]pyridines. The 19F signal at d 262 indicated
that the carbonyl adjacent to the trifluoromethyl group is the center for nucleo-
philic attack.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
The 1H NMR (d) were obtained at 300 MHz using Bruker-300 MHz

4364
Singh et al.
Scheme 4.
FT NMR instrument. The 19F NMR (d) were determined at 75 MHz using
Bruker-300 MHz. Mass spectra were recorded on a Kratos MS-50 instrument,
and the microanalyses were performed on a Perkin Elmer-2400 instrument.
IR spectra were recorded on Elmer Paragon, 1000 PL Fourier transform
infrared (FTIR) spectrophotometer.
Pyrazolo[3,4-b]Pyridines (4a–h)
General Procedure: 5-Amino-3-Substituted Pyrazoles
Procedure A (via Isolation of 5-Amino-3-Substituted Pyrazoles) (1a):
a-Cyanoacetophenone (2.9 g, 0.02 mol) was dissolved in 50 mL of
ethanol, and an equimolar amount of hydrazine hydrate was added to it,
along with 1 mL of acetic acid. The reaction mixture was refluxed for
5–6 h. Excess solvent was removed by distillation. The crude product so
obtained was recystallized using ethanol.
Yield: 59% (3.29 g), m.p. 1228C; lit. m.p. 1238C.[13]

Synthesis of Pyrazolo[3,4-b]pyridines
4365
1-H-4-Trifluoro-6-(2-Thienyl)-3-(Phenyl)Pyrazolo[3,4-b]Pyridines (4a):
The compound 1a (1.6 g, 0.01 mol) was dissolved in acetic acid,
and 1-(2-thienyl)-3,3,3-trifluoroacetyl acetone was added to it in equimolar
ratio. The reaction mixture was heated to reflux at about 10–12 h. Excess
solvent was removed, and the crude product thus obtained was crystallized
from ethanol.
Yield: 67% (2.31 g), m.p. 1528C.
The rest of the compounds were prepared similarly.
One-Pot Procedure (Procedure B)
General Procedure
The compounds (4a–h) were also prepared by employing an one-pot
procedure. a-Cyanoacetophenone (0.01 mol) was dissolved in 50 mL of the
ethanol, and an equivalent amount of hydrazine was added to it, along with
1 mL of acetic acid. The reaction mixture was refluxed for 6 h. Formation of
the intermediate (1a) can be confirmed by monitoring the thin-layer chroma-
tography (TLC). Excess solvent can be removed by distillation. An equimolar
amount of the triflourinated diketone was added with an appropriate amount of
acetic acid. The reaction mixture was refluxed for 12 h. Excess acetic acid was
removed, and the compound crystallized from ethanol. All the other com-
pounds 4b–h were prepared similarly.
1
(4a): Yield 80% (2.76 g), m.p. 1528C; IR (KBr); v 3251 (s). H NMR
(CDCl3, 300 MHz), 7.20–8.28 (m, 10H, Ar-H). 19F NMR (CCl3F,
75 MHz): 262 (C4-CF3). Elemental Analysis: Calculated for
C17H10F3N3S: C, 59.13; H, 2.95; N, 12.17. Found: C, 58.89; H, 2.99;
N, 11.60.
1
(4b): Yield 76% (2.37 g), m.p. 1408C; IR (KBr); v 3258 (s). H NMR
(CDCl3, 300 MHz), 7.25–8.25 (m, 12H, Ar-H). 19F NMR (CCl3F,
75 MHz): 262 (C4-CF3). Elemental Analysis: Calculated for
C19H12F3N3: C, 67.76; H, 3.54; N, 12.39. Found: C, 68.05; H, 2.89;
N, 11.88. MS, Mþ, m/z, 339.
1
(4c): Yield 73% (2.73 g), m.p. 1808C; IR (KBr); v 3251 (s) H NMR
(CDCl3, 300 MHz), 3.94 (s, 3H, OCH3), 6.97–7.98 (m, 9H, Ar-H).
19F NMR (CCl3F, 75 MHz): 262(s, C4-CF3). Elemental Analysis:
Calculated for C18H12F3N3SO: C, 57.60; H, 3.20; N, 11.20. Found:
C, 56.67; H, 2.73; N, 11.08. MS, Mþ, m/z, 375.
1
(4d): Yield 68% (3.25 g), m.p. 2208C; H NMR (CDCl3, 300 MHz),
7.02–8.28 (m, 13H, Ar-H), 19F NMR (CCl3F, 75 MHz): 262
(C4-CF3). Elemental Analysis: Calculated for C24H13F3N3S2: C,

4366
Singh et al.
60.54; H, 2.89; N, 12.20. Found: C, 60.25; H, 2.73; N, 11.71. MS, Mþ,
m/z, 339.
(4e): Yield 59% (2.78), m.p. 2188C; 1H NMR (CDCl3, 300 MHz),
7.02–8.80 (m, 15H, Ar-H), 19F NMR (CCl3F, 75 MHz): 262
(C4-CF3). Elemental Analysis: Calculated for C26H15F3N4S: C, 66.10;
H, 3.18; N, 11.86. Found: C, 65.67; H, 2.71; N, 11.46.
(4f): Yield 74% (3.3 g), m.p. 1408C; 1H NMR (CDCl3, 300 MHz),
3.92 (s, 3H, OCH3), 7.02–8.80 (m, 13H, Ar-H). 19F NMR (CCl3F,
75 MHz): 262 (C4-CF3). Elemental Analysis: Calculated for
C26H16F3N3OS: C, 63.85; H, 3.55; N, 9.31. Found: C, 63.40; H, 3.51;
N, 9.62.
(4g): Yield 72% (3.2 g), m.p. 2228C; 1H NMR (CDCl3, 300 MHz),
3.92 (s, 3H, OCH3), 7.25–8.25 (m, 15H, Ar-H). 19F NMR (CCl3F,
75 MHz): d 262 (C4-CF3). Elemental Analysis: Calculated for
C26H18F3N3SO: C, 70.11; H, 3.94; N, 10.08. Found: C, 70.07; H,
4.01; N, 9.64.
1
(4h): Yield 70% (2.84 g), m.p. 2348C; H NMR (CDCl3, 300 MHz),
7.25–8.25 (m, 11H, Ar-H), 19F NMR (CCl3F, 75 MHz): d 262
(C4-CF3), d 268 (C6-CF3). Elemental Analysis: Calculated for
C20H11F6N3: C, 58.68; H, 3.65; N, 9.36. Found: C, 58.96; H, 3.55;
N, 9.31.
ACKNOWLEDGMENTS
We are thankful to the RSIC, Punjab University Chandigarh, India, for
1
19F NMR and H NMR spectra, elemental analysis, and IR spectra. Thanks
are due to Ranbaxy Laboratories, New Delhi, India, for the financial
assistance.
REFERENCES
1. Fuller, R.; Kobayashi, Y. Biomedical Aspect of Fluorine Chemistry;
Elsevier: Amsterdam, 1982.
2. Basetelli, N.; Cerchelli, G.; Floris, B. Substituent effects in keto-enol tau-
tomerism. Part 3. Influence of substitution on the equilibrium composition
of b-dicarbonyl compounds. Tetrahedron 1988, 44, 2997.
3. Alexander, J.O.; Wheeler, G.R.; Hill, H.H.; Morris, M.P. Effects of 4-
hydroxypyranazolo(3,4-d)pyrimidine upon the catabolism of purines by

Synthesis of Pyrazolo[3,4-b]pyridines
4367
various tissues of the rat and upon the rate of growth of morris 5123-C
hepatoma. Biochem. Pharmacol. 1966, 15, 881.
4. Elien, G.B.; Gallawan, S.; Nathan, H.; Bicher, S.; Randler, R.W.;
Hichings, G.H. Potentiation by inhibition of drug degradation: 6-substi-
tuted purines and xanthine oxidase. Biochem. Pharmacol. 1963, 12, 85.
5. Singh, S.P.; Kumar, D.; Kapoor, J.K. Synthesis and nuclear magnetic res-
onance study of isomeric 1-(benzothiazolyl-2-yl)-3(5)-trifluoromethyl
pyrazoles. J. Chem. Res. (S) 1993, 163.
6. Singh, S.P.; Kapoor, J.K.; Kumar, D.; Threadgill, M.D. Reaction of
hydrazinoquinolines with trifluoromethyl-beta diketones: structural and
mechanistic studies. J. Flourine Chem. 1997, 83, 73.
7. Singh, S.P.; Kumar, D.; Batra, H.; Naithani, R.; Roza, J.; Elguero, J. The
reaction between hydrazines and beta-dicarbonyl compounds: proposal
for a mechanism. Can. J. Chem. 2000, 78, 1109.
8. Bulow, C. Synthesis of derivatives of 1,2,7-pyrazopyridin. A new variety
of homocondensed bis heterocyclic compounds. Ber. 1911, 43, 3401.
9. Ratajezyk, J.D.; Swett, L.R. The cycloaddition of 5-amino 1,3-dimethyl-
pyrazole with ethylacetoacetate -synthesis of isomeric pyrazolopyridones.
J. Heterocycl. Chem. 1975, 12, 5179.
10. Stanton, J.L.; Spreacher, A.V.; Went, P. Synthesis of pyridine derivatives
from 3-formyl chromones. J. Heterocycl. Chem. 1981, 18, 607.
11. Joshi, K.C.; Pathak, V.N.; Garg, U. Synthesis of some fluyorine contain-
ing 5-amino-1,3 disubstituted pyrazoles pyrazoles and 1H-pyrazolo[3,4-
b]pyridines. J. Heterocycl. Chem. 1979, 16, 1141.
12. Numann, D.; Gilkes, G.; Kischkewitz, J. Vergleich der trifluoromethyl
iereungseigenschafen von (CF3)2Hg, CF3I und (CF3)2Te am beispel
der reaktionen mit cyclohexen benzol und pyridine. J. Fluorine Chem.
1985, 30, 73.
13. Grandberg, I.; Ting, W.P.; Kost, N.A. Synthesis of 5-aminopyrazoles and
their sulfonamide derivatives. Zh. Obschei. Khim. 1961, 31, 2311.
Received in the USA August 2, 2004