Heterocyclization of vic-substituted hydroxamic acid salts of acetylenyl-pyrazoles: A new procedure for the preparation of pyrazolo[3,4-c]pyridin-7-ones

Article abstract of DOI:10.3987/com-02-9572

Procedures for the preparation of 5-substituted pyrazolo[3,4-c]pyridin-7-ones and 5-substituted 6-hydroxypyrazolo[3,4-c]pyridin-7-ones have been developed based on heterocyclization of vic-acetylenylpyrazolylhydroxamic acids under the influence of copper(

Full text of DOI:10.3987/com-02-9572

HETEROCYCLES, Vol. 57, No. 12, 2002, pp. 2255 - 2260, Received, 17th July, 2002
HETEROCYCLIZATION
HYDROXAMIC ACID SALTS OF ACETYLENYL-
PYRAZOLES: NEW PROCEDURE FOR THE
OF
VIC-SUBSTITUTED
A
PREPARATION OF PYRAZOLO[3,4-c]PYRIDIN-7-ONES
Sergei F. Vasilevsky,1* Elena V. Mshvidobadze,1 and José Elguero2*
1Institute of Chemical Kinetics and Combustion, Siberian Branch of the Russian
Academy of Sciences, 630090, Novosibirsk, Russian Federation
2Instituto de Química Médica, C.S.I.C., Juan de laCierva, 3, E-28006 Madrid, Spain
Abstract– Procedures for the preparation of 5-substituted pyrazolo[3,4-c]pyridin-
7-ones and 5-substituted 6-hydroxypyrazolo[3,4-c]pyridin-7-ones have been
developed based on heterocyclization of vic-acetylenylpyrazolylhydroxamic acids
under the influence of copper(I) salts in dimethylformamide or with organic bases
in butanol or methanol.
One of the procedures for the synthesis of fused heterocyclic compounds involves cyclization of
ortho(vic)-functionalized aryl- and hetarylacetylenes.1-4 Previously, we have reported the cyclo-
condensation of hydrazides of vic-substituted acetylenylpyrazoles which lead to substituted six-membered
N-aminolactam rings.5 In the present paper, we describe the cyclization of vic-substituted acetylenic
derivatives of pyrazolylhydroxamic acids, a synthetic procedure previously unreported. To the best of our
knowledge, this is the first example of a hydroxamic acid group (CONHOH) involved in a cyclization
with an adjacent acetylenic group. The resulting pyrazolo[3,4-c]pyridin-7-ones belong to a class of
compounds with biological properties as phosphodiesterase IV (PDE IV) inhibitors (useful for the
treatment of asthma, cystic fibrosis, chronic bronchitis, cardiovascular and cerebrovascular diseases,
peripheral blood vessel diseases and urogenital tract diseases).6 Sakamoto has reported a related reaction:
the formation of carbolines and isoquinolines from the imines of ortho-ethynyl-carbaldehydes.7,8

Heterocyclization of vic-acetylenylpyrazolylhydroxamic acids can afford at least four compounds (A-D),
each of them presenting two tautomeric forms (either oxo/hydroxy or N-hydroxy/N-oxide). This is due to
the possibility of an attack by both the N and the O atoms of the functional hydroxylamino group to the
α- and β-carbon atoms of the triple bond (Scheme 1).
R
RHC
O
N
O
N
N
N
N
N
OH
OH
Me
Me
A2
C2
R
RHC
R
O
O
C
O
N
C
H
N
N
N
H
N
N
O
O
N
Me
Me
N
C1
A1
N
Me
OH
CHR
H
R
OH
N
N
OH
N
N
N
N
O
O
D1
Me
Me
B1
CH2R
R
O
N
N
O
N
N
N
N
O
OH
B2
Me
Me
D2
Scheme 1
The synthesis of the starting esters of pyrazole (1) (Scheme 2) and (5) (Scheme 3) was described in
previous works.9,10 Hydroxamic acid (2) was prepared in 90 % yield by boiling the methyl ester of the
corresponding 5-pyrazole carboxylic acid with an excess of hydroxylamine in methanol.

In general, it could be expected that the direction of cyclization of vic-acetylenylpyrazolylhydroxamic
acids, which bear two (O and N) atoms exhibiting different nucleophilicity, can be controlled by the
reaction conditions. The study of the heterocyclization of vic-acetylenylpyrazole-hydroxamic acids has
allowed to find some regularities of this process.
Ph
Ph
C
C
Ph
C
C
Et N
NH OH
3
2
N
O
O
OH
N
N
N
butanol
MeOH
N
N
N
O
N
O
Me
OH
Me
Me
Me
H
1
3
2
CuCl DMF
Ph
N
H
N
N
O
Me
4
Scheme 2
CH2OPh
C
CH2OPh
OH
C
NH2OH
MeOH
N
O
N
N
N
N
Me
O
O
Me
Me
5
6
Scheme 3
The cyclization of hydroxamic acid (2) occurs in milder conditions (in comparison with the
corresponding hydrazides) i.e. an organic base can be used instead of KOH. Thus, in the conditions
(heating at reflux for 4 h in presence of triethylamine in butanol) for heterocyclization of the acetylenic
derivative of hydroxamic acid with a phenyl fragment, the pyridine cycle is formed. The yield of δ-N-
hydroxylactam (3) is about 50 %. It should be noted that the phenoxymethyl derivative (5) can undergo

ring closure more easily than the phenyl derivative (1). Even in the mild conditions of heterocyclization
(in the presence of hydroxylamine) it is converted to compound (6). On the other hand, for the cyclization
of 2, a stronger base (triethylamine) is required. Possibly this is related to the opposite polarization of the
triple bond under the influence of the phenyl and phenoxymethyl groups.
The reaction performed in the presence of copper(I) chloride in boiling DMF (Scheme 2) is rather unex-
pected. Although, as in the case of 3 formation, there is an attack by the amide nitrogen atom resulting in
a 6-membered lactam (4) (20 %), the oxygen atom is lost in the final product (compare 3 and 4). The fact
that heterocyclization affords pyridones (3, 4 and 6) rather than the oxygen containing rings (Scheme 1, A
or C) is probably associated with the higher nucleophilicity of the N atom compared to the O atom.
From the above and our previous results,5 it can be concluded that the cyclization of acetylenic
derivatives of pyrazolylhydroxamic acids and of the hydrazides of pyrazolecarboxylic acids affords
exclusively fused pyrazolo[5.5] and [5.6] ring systems.
A comment about the tautomerism of 3, 4 and 6. In the solid state, the presence of a C=O band in IR
spectrum indicates that all of them exist in the pyridone form (3 and 6: Scheme 1, B1). In CDCl3, the
results are not conclusive (for instance, the signal at 9.09 ppm of 4 could be an NH or an OH), but it is
safe to assume that the tautomeric form is the same.11
ACKNOWLEDGMENT
This work was supported by RFBR grants (02-03-32265), CRDF REC-008, "Integration" program grant
of SB RAS, ACCU SB RAS No. 00-03-40135.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker AM-300 spectrometer. IR spectra were recorded on a Bruker
IFS 66 spectrometer (KBr). Mass spectra were recorded on a Finnigan SSQ-710 instrument (direct inlet,
El, 70 eV, ionization chamber temperature 220-270 °C). Column chromatography was carried out on
KSK silica gel (60-200 mesh). Melting points were determined with a Kofler apparatus.
Ethynylpyrazolecarboxylic acid methyl ester (1).9 A mixture of 2.86 g (10 mmol) of 1-methyl-4-iodo-
pyrazole-5-carboxylic acid,12 1.28 g (12.5 mmol) of phenylacetylene, 20 mg of CuI and 40 mg of
PdCl2(PPh3)2 in 50 mL of Et2NH was stirred at 50 ºC under argon atmosphere up to disappearance of
starting iodo derivative (TLC control). The reaction mixture was cooled and poured into ether, the
inorganic salts were filtered off and the solution was evaporated under reduced pressure. The residue was

filtered through silica gel (height/diameter of the column: 2 x 3 cm). Compound (1) was crystallized from
ethanol, yield 1.95 g, 75 %, mp 116-117 ºC, Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66.
Found: C, 70.06; H, 4.97; N, 11.33.
Hydroxamic acid of acetylenylpyrazole (2).In 15 mL of methanol was added 0.55g (24.0 mmol)of Na and
0.8 g (11.0 mmol) of hydroxylamine hydrochloride in 10 mL of methanol. The sodium chloride preci-
pitate was filtered off. To the free hydroxylamine thus prepared, was added 1 g (4.0 mol) of the methyl
ester of ethynylpyrazolecarboxylic acid (1). The reaction mixture was boiled for 15 min (TLC control).
Methanol was distilled off in vacuum, the residue was dissolved in water and acetic acid was added (pH =
5-6). Precipitate 2 was filtered off and crystallized from water (0.9 g, 90 %), mp 67-68 °C; ν/cm-1 (KBr):
3448 (NH), 3350 (OH), 2200 (C≡C), 1637 (C=O); δH (CDCl3) 1.90 (br, s, OH), 3.91 (s, N-CH3), 7.52 (s,
3-H), 8.31 (s, NH), 7.3-7.4 (m, Ph); MS (70 eV) m/z: 241 [M+] (3.1), 28.0 (41.6), 44.0 (79.3), 124.2
(16.0), 128.1 (16.7), 196.0 (43.8), 197.1 (100.0); C13H11N3O2, Mw: found m/z 241.08524; calcd
241.08512. Anal. Calcd for C13H11N3O2: C, 64.72; H, 4.60; N, 17.42. Found: C, 64.51; H, 4.29; N, 17.30.
Synthesis of 6-hydroxy-1-methyl-5-phenyl-1,6-dihydropyrazolo[3,4-c]pyridin-7-one (3) by cyclization of
the hydroxamic acid of phenylethynylpyrazole (2) with triethylamine. 0.2 g (0.8 mmol) of the hydroxamic
acid (2) and 2 mL of triethylamine in 5 mL of butanol were boiled for 4 h (TLC control). The solvent was
distilled off in a vacuum, the product (3) was recrystallized from ethanol (0.1g, 50%), mp 75-76°C;
νmax/cm-1 (KBr) 3350 (OH), 1666 (C=O); δH (CDCl3) 2.10 (br, s, OH), 4.15 (s, N-CH3), 6.56 (s, 4-H),
7.60 (s, 3-H), 7.1-7.4 (m, Ph); MS (70 eV) m/z: 241 [M+] (1.68), 28.0 (48.26), 124.0 (28.26), 195.8
(41.65), 197.0 (100.0). C13H11N3O2, Mw: found m/z 241.08522; calcd 241.08512. Anal. Calcd for
C13H11N3O2: C, 64.72; H, 4.60; N, 17.42. Found: C, 64.81; H, 4.93; N, 17.56.
Synthesis of 1-methyl-5-phenyl-1,6-dihydropyrazolo[3,4-c]pyridin-7-one (4) by cyclization of the
hydroxamic acid of phenylethynylpyrazole (2) with CuCl. 0.5 g (2 mmol) of hydroxamic acid (2), 0.12 g
CuCl (1.0 mmol) in 5 mL of dimethylformamide were boiled for 15 min in an atmosphere of argon (TLC
control). The reaction mixture was cooled and poured into chloroform and then was washed with
ammonia.. Chloroform solution was dried with Na2SO4 and filtered through alumina (3 x 1.5 cm), the
solvent was evaporated under reduced pressure. The product was recrystallized from ethanol (0.1 g, 20
%), mp 245-246 °C; ν/cm-1 (KBr): 3440 (NH), 1667 (C=O); δH (CDCl3) 4.38 (s, N-CH3), 6.70 (s, 4-H),
7.77 (3-H), 7.4-7.5 (m, Ph), 9.09 (NH); MS (70 eV) m/z: 225 [M+] (100.0), 28.0 (20.0), 77.1 (23.4), 104.1

(13.9), 273.9 (96.1), 226.0 (21.8). C13H11N3O, Mw: found m/z 225.08989; calcd 225.09021. Anal. Calcd
for C13H11N3O: C, 69.32; H, 4.92; N, 18.66. Found: C, 69.17; H, 5.11; N, 18.79.
Synthesis of 6-hydroxy-1-methyl-5-phenoxymethyl-1,6-dihydropyrazolo[3,4-c]pyridin-7-one (6). In 20
mL of methanol was added 0.89 g (39.0 mmol) of Na, and 1.42 g (20.0 mmol) of hydroxylamine
hydrochloride in 15 mL methanol. Precipitated sodium chloride was filtered off. To free hydroxylamine,
was added 1.77 g (7 mmol) of the methyl ester of ethynylpyrazolecarboxylic acid (5)10 and then heated 6
h at reflux (TLC control). Methanol was distilled off in a vacuum, the residue was dissolved in water and
acetic acid was added (pH = 5-6). The precipitate of 6 was filtered off and recrystallized from ethanol
(0.78 g 44 %), mp 209-210 °C; ν/cm-1 (KBr): 1656 (C=O), 3372 (OH); δH (CDCl3) 2.15 (br, s, OH),
4.37(s, N-CH3), 5.19 (s, CH2), 6.73 (s, 4-H), 7.76 (s, 3-H), 6.9-7.3 (m, Ph); MS (70 eV) m/z: 271 [M+]
(6.3), 147.9 (16.1), 162.0 (11.4), 177.9 (100.0). C14H13N3O3, Mw: found m/z 271.09528; calcd
271.09568. Anal. Calcd for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.87; H, 5.12; N, 15.64.
REFERENCES AND NOTES
1.
2.
S. F. Vasilevsky and E. V. Tretyakov, Liebigs Ann. Chem., 1995, 775.
S. F. Vasilevsky, E. V. Tretyakov, and J. Elguero, Synthesis and Properties of Acetylenic
Derivatives of Pyrazoles, Adv. Heterocycl. Chem., 2002, 82, 1.
3.
4.
5.
6.
T. Sakamoto, Y. Kondo, and M. Yamanaka, Heterocycles, 1988, 27, 2225.
E. V. Tretyakov, D. W. Knight, and S. F. Vasilevsky, J. Chem. Soc., Perkin Trans. 1, 1999, 3721.
S. F. Vasilevsky, E. V. Mshvidobadze, and J. Elguero, J. Heterocycl. Chem., 2002, 39, in press.
F. J. Urban, B. G. Anderson, S. L. Orrill, and P. J. Daniels, Organic Process Research &
Development, 2001, 5, 575.
7.
8.
9.
T. Sakamoto, A. Numata, H. Saitoh, and Y. Kondo, Chem. Pharm. Bull., 1999, 47, 1740.
T. Sakamoto, A. Numata, and Y. Kondo, Chem. Pharm. Bull., 2000, 48, 669.
M. S. Shvartsberg, S. F. Vasilevsky, T. V. Anisimova, and V. A. Gerasimov, Izv. Akad. Nauk SSSR,
Ser. Khim., 1981, 1342.
10. S. F. Vasilevsky, A. V. Pozdnyakov, and M. S. Shvartsberg, Izv. Akad. Nauk SSSR, Ser. Khim., 1985,
1367.
11. J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, The Tautomerism of Heterocycles, Academic
Press, New York, 1976.
12. S. F. Vasilevsky and M. S. Shvartsberg, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1071.