New application of heterocyclic diazonium salts: Synthesis of new pyrazolo[3,4-d][1,2,3]triazin-4-ones

Article abstract of DOI:10.1002/ejoc.200701109

7-Substituted 3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-ones 2a-d were conveniently prepared by direct diazotization of 5-aminopyrazole-4- carbonitriles 1a-d in HCl media. Different reaction conditions and the effects of substituents on N-1 of the pyrazole ring were studied. A possible mechanistic exlpanation of the observed process is proposed. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701109

FULL PAPER
DOI: 10.1002/ejoc.200701109
New Application of Heterocyclic Diazonium Salts: Synthesis of New
Pyrazolo[3,4-d][1,2,3]triazin-4-ones
Elizabeth L. Moyano,*[a] Juan Pablo Colomer,[a] and Gloria I. Yranzo*[a]
Keywords: Diazonium ions / Pyrazolotriazines / Aminopyrazoles / Nitrogen heterocycles
7-Substituted 3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-
ones 2a–d were conveniently prepared by direct diazotiza-
tion of 5-aminopyrazole-4-carbonitriles 1a–d in HCl media.
Different reaction conditions and the effects of substituents
on N-1 of the pyrazole ring were studied. A possible mechan-
istic exlpanation of the observed process is proposed.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
To the best of our knowledge, all of the methodologies
previously used for the preparation of these compounds in-
volve several steps with variable yields.[1b] We now report a
one-step synthesis of pyrazolo[3,4-d][1,2,3]triazin-4-ones
2a–d (Scheme 1) by diazotization of 5-amino-1H-pyrazole-
4-carbonitriles 1a–d. We also describe the effect of different
reaction conditions for the diazotization process of com-
pound 1a that explain the formation of the side products.
Introduction
Polyfunctionally substituted heterocyclic compounds are
present as important core structures in many biologically
active compounds, both natural and synthetic. In this con-
text, 5-aminopyrazoles are versatile reagents and have been
extensively used as precursors in the preparation of several
polysubstituted fused pyrazoles.[1] In addition, a large
number of synthetic compounds containing the 1,2,3-tri-
azine ring also present biological activity and nowadays are
widely used as pharmaceuticals, herbicides, pesticides, dyes,
etc.[2] As condensed heterocyclic systems are of considerable
importance, not only for their potential biological activity
Results and Discussion
3,7-Dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-ones 2a–d
but also because of their value as synthons in organic trans- were prepared by diazotization of the easily accessible 5-
formations, we were interested in the synthesis of new pyra- amino-1H-pyrazole-4-carbonitriles 1a–d[1c] by treatment
zolo[3,4-d][1,2,3]triazin-4-ones, which are structurally re- with aqueous NaNO2 and a mixture of HCl/AcOH (3:1) as
lated to the compounds described above. These systems are the acid reagents.
also structural analogues of the naturally occurring purine
In all cases compounds 2a–d were obtained in moderate
nucleosides adenosine and guanosine, so they could be use- to good yields, together with other products such as pyr-
ful chemotherapeutic agents.[3]
azolecarbonitriles 4 and 5 and, in the cases of 1a and 1c,
Scheme 1. Diazotization reaction of pyrazoles 1a–d.
the fused pyrazoles 3a and 3c, respectively. These results are
shown in Scheme 1 and Table 1. The formation of com-
pounds 2–5 can be explained by different mechanisms as
discussed below.
[a] INFIQC – Department of Organic Chemistry, Faculty of
Chemical Sciences, National University of Córdoba,
Córdoba, Argentina
Fax: +54-351-4333030
E-mail: lauramoy@fcq.unc.edu.ar
Eur. J. Org. Chem. 2008, 3377–3381
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3377

E. L. Moyano, J. P. Colomer, G. I. Yranzo
FULL PAPER
Table 1. Yields of products in the diazotization reaction of pyr- moderate yields.[1b,6] Thus, when diazotization of com-
azoles 1a–d.
pound ia was performed under the same conditions as used
Pyrazole
R
Product yield[a]
for pyrazole 1, the pyrazolotriazinone 2a was obtained as
main product (85% yield). However, the stability of the dia-
zonium salt is strongly dependant on the substitution of the
pyrazole ring; it has been reported that in the case of 5-
amino-1-[6-(p-tolyl)pyridazin-3-yl]-1H-pyrazole-4-carbox-
amide, the intramolecular cyclization to the corresponding
triazinone did not take place, and it was possible to isolate
the stable diazonium salt prior to the subsequent reac-
tions.[7]
Route (b) in Scheme 2 is another possibility for the for-
mation of 2. In spite of the fact that no 4-chloro-7H-pyraz-
olo[3,4-d][1,2,3]triazines ii were found in the reaction mix-
ture, we cannot discount the presence of these compounds.
It is well established that chloro-substituted fused com-
pounds such as ii are unstable and decompose or hydrolyze
under acidic conditions:[1b] the hydrolysis of 4-chloro-2H-
pyrazolo[3,4-c]pyridazines in cyclization reactions of 4-alk-
ynylpyrazole-3-diazonium chloride has been described, for
example.[8] In that case, the hydroxy derivatives were found
at higher temperatures while the chloro derivatives were
found at lower temperatures. For this reason we decided to
perform the diazotization of compound 1a at –15 and
–20 °C. In this case, 2a (72%), 3a (9%), 4a (9%), and 5a
(1%) were obtained as the main products, whereas no tri-
azine iia was detected.
2
3
4
5
1a
1b
1c
1d
Ph
p-FC6H4
Bn
77.0
69.8
50.0
47.0
6.9
–
4.6
–
8.3
2.7
1.3
1.2
1.2
1.0
1.1
1.0
tBu
[a] Yields of isolated products.
The expected products from the diazotization reaction
of 1a–d would be the chlorinated products ii (Scheme 2);[4]
instead of these, however, pyrazolotriazinones 2a–d were
obtained. These could possibly be formed in three ways as
depicted in Scheme 2: (a) the hydrolysis of the cyano groups
to give 5-amino-1H-pyrazole-4-carboxamides i, diazotiza-
tion of the amino group, and subsequent cyclization of the
diazonium salt, (b) the initial formation of the chloropyr-
azolotriazine ii followed by hydrolysis to give the final prod-
uct, and/or (c) the cyclization between the diazoic acid and
the nitrilium ion, followed by addition of the nucleophilic
species.
The third possibility [route (c)] was opportunely sug-
gested by a referee, and we found it to be another possible
explanation of the experimental results. In this case, the ini-
tially formed diazoic acid could undergo protonation at the
nitrile group, followed by cyclization and addition of chlo-
rine or water to give ii or product 2, respectively. The for-
mation of nitrilium ion intermediates is reasonable under
the diazotization reaction conditions, and it is also known
that this reactive species may cyclize with appropriate ter-
minators.
At this point and with the experimental results shown
above, we are not able to determine whether compounds
2a–d are formed through a single mechanism – (a), (b), or
(c) – or by some combination of the mechanisms depicted
Scheme 2. Tentative mechanism for the formation of pyrazolotri-
azinones 2.
In order to provide some information to confirm or re- in Scheme 2.
fute the proposed mechanisms, some experiments were car-
Going back to Scheme 1, it can be seen that compounds
ried out. Route (a) suggests that the hydrolysis of the cyano 3a and 3c were formed in lower yields on treatment of 1a
group is faster than the diazotization reaction, so amides i and 1c, respectively. The formation of these compounds
may be formed. To check whether the cyano group is stable could be explained in terms of an intramolecular coupling
under the acidic conditions of these reactions, pyrazole 1a of the diazonium intermediates with the aromatic rings.
was subjected to an acid mixture and water in the absence This reaction has been used in the synthesis of imidazo[2,1-
of NaNO2 for 24 h. After this time, carboxamide ia (57.8%) c][1,2,4]triazines from 2-amino-N-phenylimidazoles[9] and
(Scheme 2) was obtained, which may be evidence of the for- in the preparation of pyrazolo[3,4-c]cinnolines from 5-
mation of this intermediate under diazotization conditions. amino-4-arylpyrazoles. In reactions of the benzyl derivative
Anyway, no carboxamide ia was found in reactions of 1a 1c, which afforded 10H-pyrazolo[5,1-c][1,2,4]benzotriaz-
when NaNO2 was used. This may be explained in at least epine-3-carbonitrile (3c), 8H-pyrazolo[5,1-a]isoindole-3-
two ways: diazotization and cyclization of the amide might carbonitrile (6) (Scheme 3) was also found. This compound
be faster than hydrolysis [route (a)] or diazotization [route may be formed by nitrogen elimination from benzotriazine
(b)] of 1, or by other competitive processes.[5] Treatment of 3c or by nitrogen elimination from the diazonium ion fol-
amides like i with sodium nitrite in hydrochloric acid has lowed by an internal electrophilic substitution, probably
been reported to afford the corresponding fused triazines in through a pyrazolyl cation intermediate.
3378
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3377–3381

New Pyrazolo[3,4-d][1,2,3]triazin-4-ones
remarkable that the nature of the substituent on N-1 of the
pyrazole ring influences the course of the cyclization reac-
tion of the diazonium salt. Thus, in our case the salt was
more stable with aryl substituents than with alkyl substitu-
ents, probably due to π-electronic effects. The presence of
the fluorine atom in the para position of the phenyl ring
also affected the formation of pyrazolotriazines: in this case
the yield of 2b was lower than that of 2a, and no 1,2,4-
triazine 3b was observed. It is clear that electrophilic substi-
tution was not promoted by the inductive withdrawing ef-
fect of fluorine. In a continuation of the study of these reac-
tions, we decided to change the nature of the acid medium
to see if this change has any influence on the product com-
position (Table 2). Thus, when diazotization of 1a was car-
ried out in HCl/AcOH (1:4) (Entry B), pyrazole 4a was the
main product, and no pyrazolotriazinone was obtained.
This result shows that at higher concentrations of AcOH,
displacement of the diazonium group by a nucleophilic
chloride ion is favored over the reaction of the diazo group
with the CN group. The elimination of nitrogen from the
diazonium salt was also accelerated when the reaction mix-
ture was irradiated at 350 nm for only 6 h. In this case, com-
plete conversion of the starting material to give an 81%
yield of the chloro derivative 4 was observed, with com-
pounds 2a and 5 as minor products.
Scheme 3. Mechanism for the formation of fused derivatives 3a and
3c.
Compounds 4 (Scheme 1) are the expected products
when the diazotization solution is stirred in the presence of
concentrated HCl or for long periods; under these condi-
tions the diazonium ion can be substituted by chlorine.[10]
It is known that this process takes place by different mecha-
nisms – ionic or free radical – and that this is strongly de-
pendant on the reaction conditions.[11] The intermediacy of
aryl cations in the decomposition of aryldiazonium tetra-
fluoroborates has been proposed,[5,12] whereas a radical
mechanism could be involved in reactions of diazonium ha-
lides (Cl– and Br–).[13]
The formation of pyrazoles 5 (Scheme 1) can easily be
explained by a hydro-dediazoniation process. This behavior
was also observed in reactions of imidazolediazonium fluo-
roborates, which undergo facile photoextrusion of nitrogen
followed by fluorination or hydrogenation when reactions
are carried out in ethanol.[5a] To investigate whether the
same process was taking place in our experiments, a reac-
tion of 1a in the presence only of HCl in ethanol (no
AcOH) was performed. Pyrazole 5a was the main product
(49.9%), and only a 18.4% yield of 2a was obtained
(Table 2). The mechanism of this process is unknown, but
it may be that a heteroaryl cation intermediate is trapped
by the solvent and that this reaction is improved when etha-
nol is employed.[12]
Conclusions
Pyrazolotriazines 2a–d were obtained from aminopyr-
azoles 1a–d in a one-step process. In the cases of pyrazoles
1a and 1c, electrophilic substitution of the phenyl ring by
the diazonium ion or by the heterocyclic cation was ob-
served as a competitive process. According to the results
obtained for compound 1a, a change of diazotization reac-
tion conditions affects the different product compositions.
The stability of the diazonium ion has an important effect
on the course of the reaction.
Experimental Section
General: NMR spectra were recorded with Bruker AC 200 and 400
spectrometers. Chemical shifts are reported in ppm relative to in-
ternal TMS. All chemicals were of reagent grade and were used
without purification. High-resolution mass spectra were recorded
with an Agilent LCTOF instrument. Column chromatography was
carried out on grade 60 silica gel (70–230). Compounds 1a–d were
prepared from the monosubstituted hydrazine (1a), the monosub-
stituted hydrazine hydrochlorides (1b, 1d), or the monosubstituted
hydrazine dihydrochloride (1c) and ethoxymethylenemalononitrile
by the methodology described in the literature.[1c] Pyrazolotriaz-
inones 2a–d were prepared in 47–77% yields and minor products
3a,c, 4a–d, 5a–d and 6 were isolated in very low yields (1–8%).
Table 2. Diazotization conditions for the reactions of pyrazole 1a.
Method
Conditions[a]
Acids
Yield[b]
3a 4a
Other
2a
5a
A
B
C
D
HCl/AcOH (3:1)[c]
HCl/AcOH (1:4)[c]
HCl/AcOH (1:4)[c]
1  HCl
t = 20 h
t = 20 h
hν, t = 6 h
76.7 8.3 1.2 6.9
0.0 0.0 78.0 8.4
6.0 0.0 81.3 6.2
EtOH, t = 20 h 18.4 0.0 0.0 49.9
[a] All reactions were performed at a concentration of [NaNO2]ac
= 1 , and the temperature was from 0 °C to room temp. [b] Per-
centages of isolated products. [c] Ratio of volumes.
General Procedure for Diazotization of Aminopyrazoles 1a–d: Aque-
ous NaNO2 (1.0 mmol, 1 mL) was added to a well-stirred and co-
oled solution (0–5 °C) of the pyrazole (1 mmol) in a mixture of
HCl/AcOH (3:1, 20 mL) over a period of 10 min. The reaction mix-
ture was allowed to warm to room temperature and stirred for 20 h.
According to the literature,[7,10,14] the course of the cycli-
zation reaction of the pyrazolediazonium ion markedly de-
pends on the electrophilicity of the diazo group and the
stability of the salt under the reaction conditions. It is also After this time, the precipitate of pyrazolotriazinone was filtered
Eur. J. Org. Chem. 2008, 3377–3381
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3379

E. L. Moyano, J. P. Colomer, G. I. Yranzo
FULL PAPER
off, and the residue was diluted with water (10 mL), extracted with
dichloromethane (3ϫ30 mL), and dried with anhydrous MgSO4.
The resulting solution was concentrated to dryness, and the solid
was then subjected to chromatographic column separation with
dichloromethane and dichloromethane/ethyl acetate (4:1).
0.654 mmol). The compound was obtained as white solid after col-
umn chromatography, m.p. 143.0 °C (dec.). Yield 47% (0.1188 g).
1H NMR (CD3CN, 200 MHz): δ = 1.88 (s, 9 H), 8.19 (s, 1 H),
12.85 (br., 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 29.87,
63.13, 132.58, 138.46, 148.27, 155.00 ppm.
5-Amino-1-phenyl-1H-pyrazole-4-carbonitrile (1a): This compound
was obtained as white crystals, m.p. 140.0–140.5 °C (EtOH). Yield
63% (3.1314 g). 1H NMR (CDCl3, 200MHz): δ = 4.64 (s, 2 H),
Pyrazolo[5,1-c][1,2,4]benzotriazine-3-carbonitrile (3a): This com-
pound was isolated as a yellow solid after column chromatography.
1
Yield 7% (0.0146 g). H NMR (CD3CN, 400MHz): δ = 7.97 (t, J
7.40–7.59 (m, 5 H), 7.63 (s, 1 H) ppm. 13C NMR (CDCl3, = 7 Hz, 1 H), 8.18 (t, J = 7 Hz, 1 H), 8.51 (d, J = 8 Hz, 1 H), 8.65 (s,
50.33 MHz): δ = 75.95, 114.22, 124.33, 128.96, 130.01, 137.05,
1 H), 8.75 (d, J = 8 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 88.79, 111.51, 114.79, 125.29, 128.94, 131.68, 136.72, 139.93,
146.09, 146.38 ppm. MS: m/z (%) = 195 (100) [M]+, 140 (57), 113
141.39, 150.09 ppm.[15]
5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (1b): This
compound was obtained as a white powder, m.p. 177.0–178.0 °C
+
(31), 102 (25). HRMS (ESI+): calcd. for C10H11N5 196.0623;
found 196.0621.
1
(MeOH). Yield 97% (1.6436 g). H NMR (CDCl3, 200 MHz): δ =
4.62 (s, 2 H), 7.16–7.28 (m, 2 H), 7.44–7.54 (m, 2 H), 7.62 (s, 1
H) ppm. 13C NMR [(CD3)2CO, 50.33 MHz]: δ = 75.69, 114.59,
117.20 (J = 23.8 Hz), 127.82 (J = 8.9 Hz), 135.03, 142.13, 152.16,
162.91 (J = 245.6 Hz) ppm. MS: m/z (%) = 203 (97) [M + 1]+, 202
10H-Pyrazolo[5,1-c][1,2,4]benzotriazepine-3-carbonitrile (3c): In
this case the reaction was carried out with 1c (0.5715 g,
2.883 mmol). The compound was isolated from the crude reaction
product together with compound 6. Yield 5% (0.0275 g). 1H NMR
(100) [M]+, 123 (16), 122 (18), 121 (19), 96 (33), 95 (57), 75 (39). [(CD3)2CO, 400 MHz]: δ = 5.20 (s, 2 H), 7.65 (d, J = 8 Hz, 1 H),
HRMS: calcd. for C10H7FN4 203.0733; found 203.0734.
7.50–7.57 (m, 2 H), 7.81–7.83 (m, 1 H), 7.94 (s, 1 H) ppm.
5-Amino-1-benzyl-1H-pyrazole-4-carbonitrile (1c): This compound
5-Chloro-1-phenyl-1H-pyrazole-4-carbonitrile (4a): This compound
was obtained as white crystals, m.p. 141.2–142.7 °C. Yield 70%
was obtained as colorless crystals after column chromatography,
1
(0.7136 g). H NMR (CD3CN, 200 MHz): δ = 4.49 (s, 2 H), 5.07 m.p. 79.2–80.4 °C. Yield 8% (0.0183 g). 1H NMR (CDCl3,
(s, 2 H), 7.22–7.42 (m, 5 H), 7.80 (s, 1 H) ppm. 13C NMR (CD3CN,
50.33 MHz): δ = 56.55, 79.21, 114.74, 128.88, 129.14, 129.76,
200 MHz): δ = 7.54 (m, 5 H), 7.96 (s, 1 H) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 94.49, 111.50, 125.14, 129.56, 129.83, 133.38,
137.10, 142.63 ppm. MS (EI): m/z (%) = 205 (33) [M + 2]+, 204
(96), 203 (100) [M]+, 168 (27), 141 (48), 77 (77), 51 (39). HRMS
136.42, 137.34, 158.49 ppm. MS (EI): m/z (%)
= 199 (94)
[M + 1]+, 198 (96) [M]+, 93 (96), 92 (100), 91 (100).
+
(ESI+): calcd. for C10H7ClN3 204.0329; found 204.0326.
5-Amino-1-tert-butyl-1H-pyrazole-4-carbonitrile (1d): This com-
pound was obtained as yellow crystals, m.p. 92.9–94.5 °C. Yield
5-Chloro-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (4b): This
1
65% (0.6600g). H NMR [(CD3)2CO, 200 MHz]: δ = 1.55 (s, 9 H), compound was obtained as a yellow solid after column chromatog-
4.43 (s, broad, 2 H), 7.21 (s, 1 H) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 29.07, 60.10, 78.23, 114.58, 138.38, 150.00 ppm.
MS: m/z (%) = 164 (12) [M]+, 108 (100), 57 (25).
raphy, m.p. 121.0–122.0 °C. Yield 3% (0.0063 g). 1H NMR (CDCl3,
200 MHz): δ = 7.35–7.47 (m, 2 H), 7.69–7.78 (m, 2 H), 8.24 (s, 1
H) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 94.63, 111.39, 116.69
(J = 23.1 Hz), 127.25 (J = 9.5 Hz), 133.11, 133.52, 142.71, 163.07
(J = 250.9 Hz) ppm. MS (EI): m/z (%) = 224 (26) [M + 3]+, 223
(32) [M + 2]+, 222 (92) [M + 1]+, 221 (100) [M]+, 187 (30), 186
(35), 160 (52), 159 (72), 132 (22), 96 (54), 95 (90), 75 (73).
7-Phenyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one
(2a):
This compound was obtained as white crystals after column
chromatography, m.p. 137.1 °C (dec.). Yield 77% (0.1781 g). 1H
NMR (CD3CN, 400 MHz): δ = 7.51 (t, J = 7.0 Hz, 1 H), 7.62 (t,
J = 7.4 Hz, 2 H), 8.06 (d, J = 7.8 Hz, 1 H), 8.36 (s, 1 H), 12.85 (s, 1 1-Benzyl-5-chloro-1H-pyrazole-4-carbonitrile (4c): In this case the
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 108.13, 122.82, 128.76,
129.67, 135.39, 137.87, 147.93, 154.04. HRMS (ESI+): calcd. for
C10H8N5O+ 214.0729; found 214.0724.
reaction was carried out with 1c (0.5715 g, 2.883 mmol). The com-
pound was obtained as a yellow solid after column chromatog-
raphy. Yield 1% (0.0082 g). 1H NMR (CDCl3, 400 MHz): δ = 5.35
(s, 2 H), 7.29 (d, J = 9 Hz, 2 H), 7.33–7.39 (m, 3 H), 7.81 (s, 1 H)
ppm. MS (EI): m/z (%) = 217 (16) [M]+, 182 (14), 91 (100), 65 (18).
7-(4-Fluorophenyl)-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-
one (2b): This derivative was obtained as a white power after col-
umn chromatography, m.p. 153.7 °C (dec.). Yield 70% (0.1678 g).
1H NMR [(CD3)2CO, 400 MHz]: δ = 7.43 (m, 2 H), 8.20 (m, 2 H),
8.43 (s, 1 H), 14.02 (br. signal, 1 H) ppm. 13C NMR [(CD3)2CO,
100 MHz]: δ = 108.14, 116.26, 116.49, 125.01, 125.10, 134.68,
134.70, 135.19, 148.60, 154.20, 161.11, 163.56 ppm. HRMS (ESI+):
calcd. for C10H7FN5O+ 232.0635; found 232.0633.
1-tert-Butyl-5-chloro-1H-pyrazole-4-carbonitrile (4d): In this case
the reaction was carried out with 1d (0.1074 g, 0.654 mmol). The
compound was obtained as colorless crystals after column
chromatography, m.p. 114.0–115.0 °C. Yield 1% (0.0014 g). 1H
NMR [(CD3)2CO, 200 MHz]: δ = 1.65 (s, 9 H), 7.56 (s, 1 H) ppm.
13C NMR [(CD3)2CO, 50.3 MHz]: δ = 29.37, 63.30, 95.60, 96.34,
110.57, 130.83, 139.32 ppm. MS (EI): m/z (%) = 185 (3) [M + 2]+,
183 (9) [M]+, 168 (5), 130 (7), 128 (21), 91 (2), 64 (2), 57 (100), 56
(95).
7-Benzyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (2c): In
this case the reaction was carried out with 1c (0.5715 g,
2.883 mmol). The compound was obtained as colorless crystals af-
ter column chromatography, m.p. at 176.7 °C (dec.). Yield 50%
1-Phenyl-1H-pyrazole-4-carbonitrile (5a): This pyrazole was ob-
(0.1188 g). 1H NMR [(CD3)2CO, 400 MHz]: δ = 5.71 (s, 2 H), 7.33– tained as white crystals after column chromatography, m.p. 91.9–
7.48 (m, 5 H), 8.69 (s, 1 H), 13.46 (s, 1 H) ppm. 13C NMR 92.6 °C. Yield 1% (0.0022 g). 1H NMR (CDCl3, 200 MHz): δ =
[(CD3)2CO, 100 MHz]: δ = 58.29, 107.73, 128.98, 129.29, 129.37,
129.72, 136.47, 154.89, 158.17 ppm. MS: m/z (%) = 228 (15) [M +
7.37–7.55 (m, 4 H), 7.67 (d, J = 8 Hz, 1 H), 7.99 (s, 1 H), 8.30 (s,
1 H) ppm. 13C NMR (CDCl3, 100MHz): δ = 94.52, 113.17, 128.32,
1]+, 227 (15) [M]+, 185 (20), 184 (19), 92 (42), 91 (100), 65 (30). 120.08, 128.46, 129.94, 131.95, 138.92, 143.19 ppm. HRMS (ESI+):
HRMS (ESI+): calcd. for C11H10N5O+ 228.0885; found 228.0881.
calcd. for C10H8N3 170.0718; found 170.0713.
+
7-tert-Butyl-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (2d):
In this case the reaction was carried out with 1d (0.1074 g,
1-(4-Fluorophenyl)-1H-pyrazole-4-carbonitrile (5b): This compound
was obtained as a yellow solid after column chromatography. m.p.
3380
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3377–3381

New Pyrazolo[3,4-d][1,2,3]triazin-4-ones
168.0–169.0 °C. Yield 1% (0.0019 g). 1H NMR (CDCl3, 400 MHz):
δ = 7.31–7.40 (m, 2 H), 7.90–7.97 (m, 2 H), 8.18 (s, 1 H), 8.99 (s,
1 H) ppm. 13C NMR (CDCl3, 100MHz): δ = 94.7, 112.98, 116.67,
117.13, 122.00, 122.17, 132.00, 142.47, 143.44, 159.82, 164.78 ppm.
Org. Chem. 1956, 21, 1240–1256; d) U. Hanefeld, C. Rees, A.
White, D. Williams, J. Chem. Soc. Perkin Trans. 1 1996, 1545–
1552; e) L. Toledo Sherman, E. Derety, J. Slon-Usakiewicz, W.
Ng, J. Dai, J. Foster, P. Redden, M. Uger, L. Liao, A. Paster-
nak, N. Reid, J. Med. Chem. 2005, 48, 3221–3230.
[2] a) E. Shaw, D. Woolley, J. Biol. Chem. 1952, 194, 401–409; b)
J. Kelley, D. Wilson, V. Styles, H. Soroko, J. Hunt, E. Briggs,
E. Clarke, W. Whittingham, Bioorg. Med. Chem. Lett. 2007,
17, 5222–5226; c) M. Migawa, L. Townsend, J. Org. Chem.
2001, 66, 4776–4782.
[3] a) F. Seela, M. Lindner, V. Glacüon, W. Lin, J. Org. Chem.
2004, 69, 4695–4700; b) M. Migawa, J. Drach, L. Townsend, J.
Med. Chem. 2005, 48, 3840–3851; c) S. Manfredini, R. Bazzan-
ini, P. Baraldi, M. Guarneri, D. Simoni, M. Marongiu, A. Pani,
E. Tramontano, P. La Colla, J. Med. Chem. 1992, 35, 917–924.
[4] J. Beck, J. Yahner, J. Org. Chem. 1976, 10, 1733–1734.
[5] a) K. Kirk, L. Cohen, J. Am. Chem. Soc. 1973, 95, 4619–4624;
b) K. Kirk, W. Nagai, L. Cohen, J. Am. Chem. Soc. 1973, 95,
8389–8392.
1-Benzyl-1H-pyrazole-4-carbonitrile (5c): In this case the reaction
was carried out with 1c (0.5715 g, 2.883 mmol). The compound was
obtained as a yellow solid after column chromatography. Yield 1%
1
(0.0060 g). H NMR (CDCl3, 400 MHz): δ = 5.32 (s, 2 H), 7.24–
7.26 (m, 2 H), 7.38–7.39 (m, 3 H), 7.75 (s, 1 H), 7.82 (s, 1 H) ppm.
MS (EI): m/z (%) = 183 (36) [M]+, 182 (62), 91 (100), 65 (22).
1-tert-Butyl-1H-pyrazole-4-carbonitrile (5d): In this case the reac-
tion was carried out with 1d (0.1074 g, 0.654 mmol). The com-
pound was identified in the reaction mixture. Yield 1% (0.0010 g).
MS (EI): m/z (%) = 149 (19) [M]+, 134 (37), 94 (82), 57 (86), 56
(100), 41 (67).
8H-Pyrazolo[5,1-a]isoindole-3-carbonitrile (6): In this case the reac-
tion was carried out with 1c (0.5715 g, 2.883 mmol). The com-
pound was isolated from the crude reaction product together with
compound 3c. Yield 1% (0.0060 g). 1H NMR [(CD3)2CO,
400 MHz]: δ = 5.34 (s, 2 H), 7.28 (d, J = 7 Hz, 2 H), 7.32–7.40 (m,
1 H), 7.50–7.57 (m, 1 H), 7.83–7.86 (m, 1 H), 8.15 (s, 1 H) ppm.
MS (EI): m/z (%) = 181 (100) [M]+, 154 (91), 127 (39).
[6] a) P. Schmidt, K. Eichenberger, M. Wihelm, Angew. Chem.
1961, 73, 15–22; b) C. Cheng, J. Heterocycl. Chem. 1968, 5,
195–1997; c) J. Montgomery, A. Laseter, A. Shortnacy, S. Clay-
ton, H. Thomas, J. Med. Chem. 1975, 18, 564–567.
[7] A. Shamroukh, A. Rashad, H. Sayed, Phosphorus Sulfur Sili-
con 2005, 180, 2347–2360.
[8] E. Tretyakov, D. Knight, S. Vasilevsky, J. Chem. Soc. Perkin
Trans. 1 1999, 3721–3726.
[9] I. Pavlov, K. Kobrakov, S. Bogza, Chem. Heterocycl. Compd.
2004, 40, 964–965.
[10] R. Butler, Chem. Rev. 1975, 75, 241–257.
Acknowledgments
This work was financially supported by the National Research
Council of Argentina (CONICET) and the Secretary of Sciences
and Technology – National University of Córdoba (SECyT-UNC).
The authors are grateful for the contributions of Ms. Noelia Ce-
ballos and Ms. Silvia Soria Castro.
[11] H. Zollinger, Acc. Chem. Res. 1973, 6, 335–341.
[12] S. Milanesi, M. Fagnoni, A. Albini, Chem. Commun. 2003,
216–217.
[13] G.-J. Meyer, K. Rossler, G. Stocklin, J. Am. Chem. Soc. 1979,
101, 3121–3123.
[14] P. Baraldi, A. Casolari, M. Guarneri, S. Manfredini, G. Pollini,
D. Simoni, V. Zanirato, Synthesis 1988, 78–81.
[15] N. P. Peet, J. Heterocycl. Chem. 1986, 23, 193.
[1] a) A. El-Dean, A. Geies, J. Chem. Res. (S) 1997, 352–353; b)
J. Kelley, D. Wilson, V. Styles, F. Soroko, B. Cooper, J. Hetero-
cycl. Chem. 1995, 32, 1417–1421; c) C. Cheng, R. Robins, J.
Received: November 25, 2007
Published Online: May 20, 2008
Eur. J. Org. Chem. 2008, 3377–3381
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3381