A new route to pyrazolo[3,4-c] and [4,3-c]pyridinones via heterocyclization of vic-substituted hydroxamic acids of acetylenylpyrazoles

Article abstract of DOI:10.1016/j.tet.2004.09.104

We report in this paper the synthesis of 6-substituted pyrazolo[4,3-c] pyridin-4-ones, 6-substituted 5-hydroxypyrazolo[4,3-c]pyridin-6-ones, 5-substituted pyrazolo[3,4-c]pyridin-7-ones and 5-substituted 6-hydroxypyrazolo[3,4-c]pyridin-7-ones by heterocyclization of vic-acetylenylpyrazol-hydroxamic acids under the influence of copper(I) salt in dimethylformamide or with organic bases in butanol or methanol. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.09.104

Tetrahedron 60 (2004) 11875–11878
A new route to pyrazolo[3,4-c] and [4,3-c]pyridinones via
heterocyclization of vic-substituted hydroxamic acids of
acetylenylpyrazoles
b,
Elena V. Mshvidobadze,a Sergei F. Vasilevskya, and Jose Elguero
*
*
aInstitute of Chemical Kinetics and Combustion, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk,
Russian Federation
b
´
´
Department of Medicinal Chemistry, Instituto de Quımica Medica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
Received 14 May 2004; revised 22 September 2004; accepted 24 September 2004
Available online 18 October 2004
Abstract—We report in this paper the synthesis of 6-substituted pyrazolo[4,3-c]pyridin-4-ones, 6-substituted 5-hydroxypyrazolo[4,3-c]
pyridin-6-ones, 5-substituted pyrazolo[3,4-c]pyridin-7-ones and 5-substituted 6-hydroxypyrazolo[3,4-c]pyridin-7-ones by heterocyclization
of vic-acetylenylpyrazol-hydroxamic acids under the influence of copper(I) salt in dimethylformamide or with organic bases in butanol or
methanol.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
facts prompted us to carry out a systematic investigation of
the cyclization of vic-substituted hydroxamic acids of
acetylenylpyrazoles. In the present article we report the
study of cyclization of (4-acetylenylpyrazolyl-3)- and
(3-acetylenyl-pyrazolyl-4)hydroxamic acids.
Pyrazolopyridines, due to their analogy with purines have
been the subject of many studies1,2 particularly in what
concerns their pharmacological properties, the five isomers,
[3,4-b], [3,4-c], [4,3-c], [4,3-b] and [1,5-a], displaying high
biological activity.3 We have already published two papers4,5
and one review6 on these fused systems, for example, on
the more common pyrazolo[3,4-c]pyridines4–6 and on the
less frequent pyrazolo[4,3-c]pyridines5 (for a recent report
on this last ring system see Ref. 3). In one of them4 we
reported that the heterocyclization of 4-acetylenylpyrazole-
5-hydroxamic acids under influence of copper(I) salt in
dimethylformamide or with organic bases in butanol or
methanol leads to 5-substituted pyrazolo[3,4-c]pyridin-7-
ones and 5-substituted 6-hydroxy-pyrazolo[3,4-c]pyridin-7-
ones.
2. Results and discussion
Heating the methyl esters of 1-methyl-4-phenylethynyl-
(1a) and 1-methyl-4-(phenoxymethyl-ethynyl)pyrazole-3
(1b) carboxylic acids with an excess of hydroxylamine in
boiling methanol leads to the corresponding 4-acetylenic
derivatives of pyrazole-3 hydroxamic acids 2a (95%) and
2b (87%) (see Scheme 1 and Section 3).
It is known that the electrophilicity of a triple bond and the
nucleophilicity of a functional group depend on their
position in the pyrazole ring. In fact, we showed earlier
that the direction of cycloisomerization of vic-functiona-
lized acetylenylpyrazoles depends on the mutual arrange-
ment of acetylenic and the other functional group.1,7 These
Keywords: Pyrazolopyridines; Cross-coupling; Hydroxamic acids; Hetar-
ylacetylenes; Heterocyclization.
* Corresponding authors. Fax: C7 3832 342350 (S.F.V.); tel.: C34 91
4110874; fax: C34 91 5644853 (J.E.);
e-mail addresses: vasilev@ns.kinetics.nsc.ru; iqmbe17@iqm.csic.es
Scheme 1. (a) NH2OH/MeOH. RZC6H5 (a), CH2OC6H5 (b).
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.104

11876
E. V. Mshvidobadze et al. / Tetrahedron 60 (2004) 11875–11878
Scheme 2. (a) NH2OH/MeOH, 12 h.
Isolation of the intermediate hydroxamic acid by interaction
of the isomeric methyl esters of 1-methyl-4-(phenoxy-
methylethynyl)pyrazole-5 carboxylic acids with an excess
of hydroxylamine in the same reaction conditions4 was not
possible and only the product of cyclization, namely the
N-hydroxylactame was obtained. This fact confirms the
necessity to study the reactivity of all the isomeric positions
of acetylenylpyrazoles.
Isolation of the hydroxamic acids in the case of 2a and 2b
allowed us to study the behavior of phenylethynyl (2a) and
phenoxymethylethynyl (2b) derivatives both in neutral and
basic conditions of heterocyclization (Scheme 4).
We have showed that heterocyclization of hydroxamic acids
could be carried out in the presence of a weaker organic base
(Et3N instead of KOH, as in Schemes 2 and 3). Thus, the
cycloisomerization of hydroxamic acids 2a and 2b occurs at
reflux of 2a and 2b in presence of Et3N in butanol and leads
to the formation of the corresponding N-hydroxylactames
7a (12 h) and 7b (3 h) (76 and 54%) derived from the
pyrazolo[3,4-c]pyridine skeleton.
Another result was obtained in the attempt to prepare
hydroxamic acids by interaction of the methyl esters of 1,5-
dimethyl-3-phenylethynylpyrazole-4-carboxylic acid (3a)5
with hydroxylamine in boiling methanol (Scheme 2). We
observed the formation of the product of cyclization, that is,
6-phenylpyrazolo[4,3-c]pyridin-4-one (4a, 44%), as well as
the product of hydrolysis of the starting ester, i.e. 1,5-
dimethyl-3-phenylethynylpyrazole-4 carboxylic acid
(5, 27%). Physical and spectral data of 5 are in agreement
with literature ones.8
The reaction performed in neutral conditions using CuCl in
boiling DMF, as well as in basic conditions, leads to the
6-membered aminolactames 8a and 8b (57 and 40%), the
N-oxygen atom being unexpectedly lost in the final product.
We propose (see Scheme 5) that pyrazolo[3,4-c]pyridines
8a and 8b are formed via tautomeric equilibrium followed
by thermal deoxygenation of tautomer I, by analogy to the
loss of the oxygen atom that takes place for N-oxides of
2-imidazoline derivatives.9 Thus, as follows from the above
data, the cyclization of acetylenic derivatives of pyrazo-
lylhydroxamic acids both in basic and neutral conditions
leads to 4-substituted pyrazolo[4,3-c]pyridin-6-one and 5-
substituted pyrazolo[3,4-c]pyridin-3-one.
The phenoxymethylethynyl derivative 3b6 leads directly
only to 5-hydroxy-2,3-dimethyl-6-phenoxymethyl-2,5-
dihydropyrazolo[4,3-c]pyridin-4-one (6b, 50%, Scheme 3),
without isolation of the hydroxamic acid intermediate.
3. Experimental
3.1. General
Melting points were determined with a Kofler apparatus.
Column chromatography was performed on silica gel
(Merck 60, 70–230 mesh). The Rf values were measured
on aluminium backed TLC plates of silica gel Silufol UV-
254 with the indicated eluent. NMR spectra were recorded
1
on a ‘Bruker Avance 300’ spectrometer at 25 8C. H NMR
Scheme 3. (a) NH2OH/MeOH.
chemical shifts (d in ppm) were given from internal CHCl3
(7.26) or DMSO-d6 (2.5) standards. Coupling constants (J in
Hz) were accurate to G0.2 Hz for 1H. Mass spectra
(HRMS) at 70 eV using electron impact mode were
performed on a Finnigan SSQ-710. The IR-spectra were
recorded in KBr pellets on a ‘Bruker IFS 66’ instrument.
Sodium, hydroxylamine hydrochloride, Et3N, CuCl
The different behavior of 4- and 3-acetylenylpyrazoles
(isolation of hydroxamic acids 2a,b and formation of
pyrazolo[4,3-c]pyridines 4a, 6b) is related to the reduced
electrophilicity of the ethynyl group in 4 position and the
higher nucleophilicity of the 5 position of the pyrazole ring.

E. V. Mshvidobadze et al. / Tetrahedron 60 (2004) 11875–11878
11877
Scheme 4. (a) Et3N/butanol; (b) CuCl/DMF/Argon. RZC6H5 (a), CH2OC6H5 (b).
Scheme 5.
(‘Aldrich’) were commercially available reactants. All the
organic solvents were of analytical quality.
Precipitate 2 was filtered off and crystallized from water
(2.30 g, 87.5%), mp 99–100 8C; n/cmK1 (KBr): 2244
(C^C), 3399 (NH), 1657 (C]O), 3364 (OH); d1H
(DMSO-d6) 1.52s (1H, OH); 3.89s (3H, NCH3); 4.94s
(2H, CH2); 7.53s [1H, H(5)], 6.95–7.36 m (5H, ArH); 9.18s
(1H, NH). Anal. Calcd for C14H13N3O3: C, 61.98; H, 4.89;
N, 15.49. Found: C, 62.13; H, 4.75; N, 15.25.
3.1.1. 1-Methyl-4-(phenylethynyl)pyrazolo-3-hydroxa-
mic acid (2a). 1.21 g (53.0 mmol) of Na was added to
30 mL of absolute methanol and then 1.76 g (24.0 mmol) of
hydroxylamine hydrochloride in 20 mL of absolute metha-
nol were added. The sodium chloride precipitate was filtered
off. To the prepared solution of free hydroxylamine was
added 2.2 g (9.10 mmol) of the methyl ester of ethynylpyr-
azolecarboxylic acid (1). The reaction mixture was refluxed
10 min (TLC control). Methanol was distilled off in
vacuum, the residue was dissolved in water and acetic
acid added (pHZ5–6). Precipitate 2a was filtered off and
crystallized from water (2.10 g, 95%), mp 133–134 8C; n/
cmK1 (KBr): 2223 (C^C), 3446 (NH), 1663 (C]O), 3368
(OH); d1H (DMSO-d6) 2.15s (1H, OH); 3.93s (3H, NCH3);
7.58s [1H, H(5)], 7.31–7.53 m (5H, ArH); 8.54s (1H, NH).
Anal. Calcd for C14H13N3O2: C, 64.72; H, 4.59; N, 17.42.
Found: C, 64.79; H, 4.60; N, 17.36.
3.1.3. 2,3-Dimethyl-6-phenyl-2,5-dihydropyrazolo[4,3-c]
pyridin-4-one (4a). 1.07 g (46.5 mmol) of Na was added to
20 mL of absolute methanol and then 1.56 g (22.6 mmol) of
hydroxylamine hydrochloride in 20 mL of absolute metha-
nol. The sodium chloride precipitate was filtered off. To
prepared solution of free hydroxylamine was added 1.95 g
(7.60 mmol) of the methyl ester of ethynylpyrazolecar-
boxylic acid 3a. The reaction mixture was boiled 12 h (TLC
control). Methanol was distilled off in vacuum, the residue
was dissolved in water and acetic acid added (pHZ5–6).
Precipitate 4a was filtered off and crystallized from EtOH
(0.68 g, 43.9%), mp 252–253 8C; n/cmK1 (KBr): 1651
(C]O), 3432 (NH); d1H (CDCl3) 2.64 [s, 3H, CH3 (3)];
3.87 (s, 3H, NCH3); 6.29 [s, 1H, H(7)]; 7.36–7.54 (m, 5H,
Ph); 8.3 (s, 1H, NH); MS (70 eV) m/z: 239 [M]C (100); 43
(8); 56 (14); 77 (10); 171 (7); 224 (9); 238 (51); 240 (17).
Mw: found m/z 239.10801 [M]C, C14H13N3O; calcd: MZ
239.10586.
3.1.2. 1-Methyl-4-(phenoxymethylethynyl)pyrazolo-3-
hydroxamic acid (2b). 1.40 g (61.0 mmol) of Na was
added to 30 mL of absolute methanol and then 2.10 g
(29.0 mmol) of hydroxylamine hydrochloride in 20 mL of
absolute methanol were added. The sodium chloride
precipitate was filtered off. To the prepared solution of
free hydroxylamine was added 2.63 g (9.7 mmol) of the
methyl ester of ethynylpyrazolecarboxylic acid 1. The
reaction mixture was boiled 10 min (TLC control).
Methanol was distilled off in vacuum, the residue was
dissolved in water and acetic acid added (pHZ5–6).
3.1.4. 5-Hydroxy-2,3-dimethyl-6-phenoxymethyl-2,
5-dihydropyrazolo[4,3-c]pyridin-4-one (6b). 1.22 g
(53.0 mmol) of Na were added to 25 mL of absolute
methanol and then 1.76 g (24.0 mmol) of hydroxylamine
hydrochloride in 25 mL of absolute methanol. To a prepared

11878
E. V. Mshvidobadze et al. / Tetrahedron 60 (2004) 11875–11878
solution of free hydroxylamine was added 2.23 g
(7.82 mmol) of the methyl ester of ethynylpyrazolecar-
boxylic acid (3b). The reaction mixture was refluxed 7 h
(TLC control). Methanol was distilled off in vacuum, the
residue was dissolved in water and acetic acid added (pHZ
5–6). Precipitate 6b was filtered off and crystallized from
water (1.32 g, 59.2%), mp 200.5–202 8C; n/cmK1 (KBr):
1665 (C]O), 3434 (OH); d1H (DMSO-d6) 2.64 [s, 3H, CH3
(3)]; 3.86 (s, 3H, NCH3); 6.44 [s, 1H, H(7)]; 5.07 (s, 2H,
CH2); 6.98–7.35 (m, 5H, Ph); 2.1 (s, 1H, OH); MS (70 eV)
m/z: 285 [M]C (28); 43 (17); 56 (31); 65 (13); 77 (13); 146
(15); 149 (51); 162 (61); 176 (61); 192 (100). C15H15N3O3,
Mw: found m/z 285.11146 [M]C; calcd: 285.11133. Anal.
Calcd for C15H15N3O3: C, 63.14; H, 5.29; N, 14.73. Found:
C, 62.89; H, 5.21; N, 14.47.
3.1.8. 2-Methyl-5-phenoxymethyl-2,6-dihydropyrazolo
[3,4-c]pyridin-7-one (8b). 1.0 g (3.70 mmol) of hydro-
xamic acid 2c, 0.20 g (2.00 mmol) CuCl in 12 mL of
dimethylformamide were refluxed 30 min in an atmosphere
of argon (TLC control). The reaction mixture was cooled
and poured into chloroform and then was washed with
aqueous ammonia. Chloroform solution was dried with
Na2SO4 and filtered through alumina (3!1.5 cm2), the
solvent was evaporated under reduced pressure. The product
8b was recrystallized from ethanol, yield 0.35 g, 40%, mp
236.5–237.5 8C; n/cmK1 (KBr): 3428 (NH), 1647 (C]O);
d1H (CDCl3) 3.91s (3H, NCH3); 4.76s (2H, CH2); 6.43s
[1H, H(4)]; 6.9–7.4 m (5H, ArH); 7.49s [1H, H(3)]; 10.1s
(1H, NH). Anal. Calcd for C14H13N3O2: C, 65.86; H, 5.13;
N, 16.46. Found: C, 66.13; H, 4.96; N, 16.47.
3.1.5. 6-Hydroxy-2-methyl-5-phenyl-2,6-dihydropyra-
zolo[3,4-c]pyridin-7-one (7a). 0.50 g (2.10 mmol) of the
hydroxamic acid of acetylenylpyrazole 2a and 5 mL of
triethylamine in 10 mL butanol were refluxed 12 h (TLC
control). The solvent was distilled off in vacuum, the
product 7a was recrystallized from ethanol. (0.38 g, 76%),
mp 228–230 8C; nmax/cmK1 (KBr) 3410 (OH), 1659
(C]O); d1H (CDCl3) 2.0s (1H, OH); 4.18s (3H, N-CH3);
6.47s (1H, 4-H); 7.3–7.5 m (5H, ArH); 7.65s [1H, H(3)];
d13C (CDCl3) 40.32 (NCH3); 94.01 [C(4)]; 116.09 [C(30)];
124.03–128.065 (Pho,m,p); 132.68 [C(7)]; 135.80 (Phi);
143.62 [C(7 )]; 147.77 [C(5)]; 175.47 (CO). Anal. Calcd
for C13H11N3O2: C, 64.72; H, 4.60; N, 17.42. Found: C,
64.44; H, 4.66; N, 17.35.
Acknowledgements
This work was supported by RFBR (33-03-40135) and
RFBR (02-03-32229) grants as well as by CRDF
(NO-008-XI).
References and notes
1. Greenhill, J. V. In Pyrazoles with Fused Six-membered
Heterocyclic Rings; Katritzky, A. R., Rees, C. W., Eds.;
Comprehensive Heterocyclic Chemistry; Pergamon: Oxford,
1984; Vol. 5, p 305.
3.1.6. 6-Hydroxy-2-methyl-5-phenoxymethyl-2,6-dihy-
dropyrazolo[3,4-c]pyridin-7-one (7b). 0.5 g (1.90 mmol)
of the hydroxamic acid of acetylenylpyrazole (2b) and 5 mL
of triethylamine in 10 mL butanol were refluxed 3 h (TLC
control). The solvent was distilled off in vacuum, the
product 7b was recrystallized. (0.27 g, 54%), mp 201–
202 8C [EtOH/H2O (5:3)]; nmax/cmK1 (KBr) 3440 (OH),
1660 (C]O); d1H (CDCl3) 2.7s (1H, OH); 4.08s (3H,
NCH3); 5.16s (2H, CH2); 6.54s (1H, H(4)]; 6.9–7.2 m (5H,
ArH); 7.56s [1H, H(3)]. Anal. Calcd for C14H13N3O3: C,
61.98; H, 4.80; N, 15.49. Found: C, 61.79; H, 4.75; N, 15.33.
2. Townsend, L. B.; Wise, D. S. In Bicyclic 5–6 Systems: Three
Heteroatoms 2:1; Katritzky, A. R., Rees, C. W., Scriven, E. F.,
Eds.; Comprehensive Heterocyclic Chemistry II; Pergamon:
Oxford, 1996; Vol. 7, p 283.
3. Commeiras, L.; Woodcock, S. C.; Baldwin, J. E.; Adlington,
R. M.; Cowley, A. R.; Wilkinson, P. J. Tetrahedron 2004, 60,
933.
4. Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J. Hetero-
cycles 2002, 57, 2255.
5. Vasilevsky, S. F.; Mshvidobadze, E. V.; Elguero, J.
J. Heterocycl. Chem. 2002, 39, 1229.
3.1.7. 2-Methyl-5-phenyl-2,6-dihydropyrazolo[3,4-c]
pyridin-7-one (8a). 0.3 g (1.2 mmol) of hydroxamic acid
2a, 0.13 g (1.30 mmol) CuCl in 4 mL of dimethylforma-
mide were refluxed 3 h under an atmosphere of argon (TLC
control). The reaction mixture was cooled and poured into
chloroform and then was washed with aqueous ammonia.
Chloroform solution was dried with Na2SO4 and filtered
through alumina (3!1.5 cm2), the solvent was evaporated
under reduced pressure. The product 8a was recrystallized
from ethanol, yield 0.17 g, 57%, mp 313–315 8C (lit.: mp.
314–315 8C10).
6. Vasilevsky, S. F.; Tretyakov, E. V.; Elguero, J. Adv.
Heterocycl. Chem. 2002, 82, 1.
7. Tretyakov, E. V.; Knight, D. W.; Vasilevsky, S. F. J. Chem.
Soc., Perkin Trans. 1 1999, 3721.
8. Vasilevsky, S. F. Doctor Thesis. Novosibirsk, 1986.
9. Klyatskaya, S. V.; Tretyakov, E. V.; Vasilevsky, S. F. Izv.
Akad. Nauk., Ser. Khim. 2002, 122. (Russ. Chem. Bull. Int. Ed.
2002, 51, 128).
10. Vasilevsky, S. F.; Shvartsberg, M. S. Izv. Akad. Nauk., Ser.
Khim. 1990, 2089.