Trifluoro-3-hydroxy-1H-indazolecarboxylic acids and esters from perfluorinated benzenedicarboxylic acids

Article abstract of DOI:10.1002/ejoc.200901102

Twelve new 3-hydroxyindazoles, each bearing three fluorine substituents and a CO₂R group (R = H, CH₃, C₂H₅) distributed around its 4-, 5-, 6-, and 7-positions, have been synthesized. They were studied by NMR in

Full text of DOI:10.1002/ejoc.200901102

FULL PAPER
DOI: 10.1002/ejoc.200901102
Trifluoro-3-hydroxy-1H-indazolecarboxylic Acids and Esters from
Perfluorinated Benzenedicarboxylic Acids
Carlos Pérez Medina,*[a] Concepción López,*[a] Rosa M. Claramunt,[a] and José Elguero[b]
Dedicated to Professor Josep Font on the occasion of his 70th birthday
Keywords: Nitrogen heterocycles / Indazoles / Tautomerism / Fluorine
Twelve new 3-hydroxyindazoles, each bearing three fluorine
substituents and a CO2R group (R = H, CH3, C2H5) distrib-
uted around its 4-, 5-, 6-, and 7-positions, have been synthe-
sized. They were studied by NMR in solution (1H, 13C, 15N,
19F) and in the solid state (13C, 15N). In solution, all of them
are 3-hydroxy tautomers: the a form. In the solid state, al-
though the 3-hydroxy tautomers are still the most frequent,
there are some cases of indazolin-3-ones – the b form – and
one example (12ab) of the very rare case in which both tauto-
mers are present.
their physicochemical properties. The twelve compounds
are represented in Scheme 1 (in the frame), together with
1H-indazol-3-ol (13) and 4,5,6,7-tetrafluoro-1H-indazol-3-
ol (14).
Introduction
For a long time, indazoles were mainly considered a sub-
set of pyrazoles (benzopyrazoles) but their individuality has
been becoming more and more apparent (our interest in
indazoles and their properties has been continuous over the
years).[1] This is mainly due to the presence of indazole sys-
tems in many drugs and to the fact that their aza derivatives
are related to purines. In the 2008 Chemical Abstracts, for
instance, there are 250 references to indazoles, of which
55% are patents and 45% publications. The indazole moi-
ety is a frequently found subunit in pharmaceuticals with
important biological[2] and powerful pharmacological ac-
tivities, including anti-inflammatory,[3] selective inhibition
of factor Xa,[4] anti-tumor,[5,6] anti-HIV,[7] anti-platelet ag-
gregation,[8] and antifungal activities,[9] plus serotonin 5-
HT3 receptor antagonist activity.[10] A field in which inda-
zoles are of particular relevance is as inhibitors of the dif-
ferent isoforms of nitric oxide synthase (NOS).[11] As a re-
sult of all these properties a variety of methods for the prep-
aration of indazoles have been reported.[12,13]
Results and Discussion
Synthesis
The title compounds were prepared by a method similar
to that described for 4,5,6,7-tetrafluoro-3-methyl-1H-ind-
azole[15] and 4,5,6,7-tetrafluoro-1H-indazol-3-ol (14).[1i]
Scheme 2 depicts the synthetic pathways that yielded the
5,6,7-trifluoro-substituted derivatives 1–3.
In general, reactions between hydrazine and tetrafluoro-
phthalate esters can take place either in the ortho or in the
para positions relative to the ester groups. In the first case
this would lead to 5,6,7-trifluoro-3-hydroxy-1H-indazole-4-
carboxylate esters (2 and 3) and in the second to hydrazine
derivatives. The ethyl ester 16 afforded 3, but the methyl
ester 17 yielded 18, isolated as dimethyl 3,4,6-trifluoro-5-[2-
(propan-2-ylidene)hydrazinyl]phthalate {1H NMR (CDCl3,
400 MHz): δ = 6.92 (s, 1 H, NH), 3.89 and 3.87 (s, 6 H,
–OCH3), 2.03 and 1.91 [s, 6 H, (CH3)2C=N–] ppm. 13C
NMR (CDCl3, 100 MHz): δ = 15.1 and 24.7 ppm [(CH3)2-
C=N–], 52.4 (–OCH3), 52.6 (–OCH3), 108.5 (C-2), 117.6
(C-1), 127.9 (C-5), 140.9 (C-3), 144.0 (C-6), 147.0 (C-4),
151.7 [(CH3)2C=N–], 162.5 (CO2CH3) and 163.2 (CO2CH3)
ppm}, under any conditions attempted (toluene, THF, or
DMF). The behavior of 17 is similar to that of tetrafluoro-
phthalonitrile.[16]
Because some indazolin-3-ones (or 3-hydroxyindazoles)
have shown high affinities for the NOS enzymes,[14] we de-
cided to synthesize a series of trifluoro derivatives of 3-hy-
droxyindazoles (5,6,7; 4,6,7; 4,5,7; 4,5,6), each bearing on
its remaining carbon atom (4; 5; 6; 7) a carboxy group
either free or in its ester form (methyl or ethyl) to modify
[a] Departamento de Química Orgánica y Bio-Orgánica, Facultad
de Ciencias, UNED,
Senda del Rey 9, 28040 Madrid, Spain
E-mail: c.medina@ucl.ac.uk
clopez@ccia.uned.es
rclaramunt@ccia.uned.es
Saponification of 3 gave 5,6,7-trifluoro-3-hydroxy-1H-
indazole-4-carboxylic acid (1), which on esterification with
methanol afforded 2.
[b] Instituto de Química Médica, CSIC,
Juan de la Cierva 3, 28006 Madrid, Spain
E-mail: iqmbe17@iqm.csic.es
890
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Trifluoro-3-hydroxy-1H-indazolecarboxylic Acids and Esters
Scheme 1.
Scheme 2.
The esters 20 and 21 (Scheme 3) were prepared from each substituted with a CO2R group at its 7-position, pre-
2,4,5,6-tetrafluoroisophthalic acid (19). Treatment of either dominating. In each case the ratio of isomers determined
20 or 21 with hydrazine in toluene at 60 °C in each case from the 1H NMR spectrum of the crude product was
afforded a mixture of isomers, with compounds 11 and 12, about 2 (7-CO2R):1 (5-CO2R).
Scheme 3.
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FULL PAPER
If this reaction was carried out in THF with addition of and 3 and in the NH signals of 11 and 12, and are presum-
hydrazine at room temperature, however, the 5-substituted ably due to intramolecular hydrogen bonds (IMHBs) with
derivatives 5 and 6 were the only compounds isolated, al- the ester group carbonyl moieties (Figure 1).
though in low yields. This is probably a consequence of
steric hindrance around the 2-position; it seems that hydraz-
ine is only able to overcome the energy barrier to reach
carbon C-2 when added at 60 °C.
Finally, the syntheses of 4,5,7-trifluoro-3-hydroxy-1H-
indazole-6-carboxylic acid (7) and its methyl and ethyl
esters 8 and 9 are shown in Scheme 4.
Figure 1. Intramolecular hydrogen bonds (IMHBs) present in 4-
CO2R and 7-CO2R 1H-indazoles.
With regard to the 19F NMR chemical shifts, the princi-
pal means to achieve reliable assignment was analysis of the
multiplicities of the signals due to carbon–fluorine cou-
1
3
plings, mainly the JC,F values of about 250 Hz. The JF,F
Scheme 4.
5
and JF,F values lie within normal ranges, with average val-
As depicted in the above schemes, the trifluoro-3-hy-
ues of 20 Hz.[1i] Assignment of the 13C NMR spectroscopic
data proved to be straightforward considering the large
number of 13C chemical shifts reported for indazoles,[18]
even though the spectra of these derivatives show complex
multiplets owing to the aforementioned 13C–19F couplings.
As the outcome of the analysis of all the data set, we
have summarized the shift effects for acids 1, 4, 7, and 10
(those of the esters are very similar) in relation to 14.[1i] The
averaged values of the four situations are shown on the
right-hand side of Figure 2. The effects on the 13C chemical
shifts are similar to those reported for monosubstituted
benzenes (fluorobenzene vs. benzoic acid): ipso –32.2 ppm,
droxy-1H-indazolecarboxylic acids 1, 4, 7, and 10 were ob-
tained in fair yields by hydrolysis of the corresponding es-
ters under mild conditions. Save in the case of the last-men-
tioned derivative, by-products resulting from decarboxyl-
1
ation were identified by H NMR in the reaction mixtures.
The loss of CO2 from perfluorinated aromatic acids has
been reported and can, depending on the reaction condi-
tions, predominate over nucleophilic substitution.[17]
NMR Studies
With the goal of achieving the complete characterization ortho 15.6 ppm, and para 9.0 ppm.[19] The ortho and para
of all the preceding indazole derivatives 1–12 we performed 19F chemical shifts and JC,F coupling constants are also
1
an NMR study in solution ([D6]DMSO, in some cases also very sensitive to the replacement of a F atom by a CO2H
including low-temperature experiments in [D8]THF at group. The effects are relatively homogeneous, notwith-
207 K). The data obtained are fully described in the Experi- standing that the pyrazole nucleus alters the symmetry of
mental.
In order to establish the main existing tautomeric form,
the benzene ring.
This kind of analysis is of double interest: i) it serves to
however, we next discuss the most representative features test the assignment of all signals, and ii) it establishes that
with reference to the already published 4,5,6,7-tetrafluoro- the predominant tautomer is the same in all of compounds
1H-indazol-3-ol (14).[1i]
1–12 and 14. All are either 3-hydroxy-1H-indazoles (a) or
The chemical shifts of the NH and OH protons, the as- mixtures very rich in this form (probably more than 95%).
signment of which was achieved by means of heteronuclear
15N NMR spectroscopic data (Table 1, data for 2, 5 and
1
1H–15N correlation experiments, clearly indicate that they 8 have not been recorded), obtained by H–15N 2D inverse
are 3-hydroxy-1H-indazoles (a), with values close to those proton heteronuclear shift correlation experiments in [D8]-
of 14a: δNH = 12.7, δOH = 11.3 ([D6]DMSO).[1i] The differ- THF at 207 K (no correlations were detected at room tem-
ences with regard to 14a are found in the OH signals of 2 perature), again indicate that these derivatives exist as 3-
Figure 2. Effects on the 13C chemical shifts (ppm, normal type), 19F chemical shifts (ppm, bold type), and on 1JC,F (Hz, italics) produced
by the replacement of a fluorine group in 14 by a carboxylic acid group as in acids 1, 4, 7 and 10.
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Trifluoro-3-hydroxy-1H-indazolecarboxylic Acids and Esters
Table 1. Solution 15N NMR chemical shifts (δ in ppm) and coupling constants (J in Hz).
1
3
4
6
7
9
10
11
12
14[a]
[b]
N-1
N-2
–229.0
–228.1
–227.7
–230.1
–229.7
–221.6
–220.2
–220.1
–233.4
1J = 96.7
–104.6
1J = 92.3
–105.4
1J = 91.6
–104.8
1J = 114.7
–111.5
[b]
–112.1
–111.4
–109.7
–109.5
–111.9
[a] From reference 1i. [b] Not observed either in [D8]THF at 207 K or in [D6]acetone at 185 K.
hydroxy-1H-indazoles.[1b,20,21] The abnormally high N-1 as the values are very similar to those of the corresponding
chemical shift value for 4,5,6-trifluoro-3-hydroxy-1H-ind- esters 6a, 9a, 11a, and 12a, and besides, N-2 protonation of
azole-7-carboxylic acid (10) and its two esters (11 and 12) indazoles should cause shifts of δ = –125 ppm.[22]
is explained by the presence of the intramolecular hydrogen
In conclusion, the 1H, 13C, and 15N NMR results demon-
bond shown above in Figure 1.
strate that compounds 1–12 exist in solution ([D6]DMSO
The effects on the 15N chemical shifts (ppm) due to the and [D8]THF) as the 3-hydroxyindazole tautomers (a).
replacement of a fluorine in 14a by a carboxylic group are
13C and 15N NMR chemical shifts in the solid state are
summarized in Scheme 5. The presence of zwitterions (zw) shown in Table 2. In particular, the δ15N values are con-
in solution in the cases of acids 4a, 7a, and 10a is excluded siderably shifted relative to what is observed in solution
Scheme 5.
Table 2. 13C and 15N CPMAS NMR chemical shifts (δ in ppm) at 300 K.
N-1
N-2
C-3
C-3a
C-4
C-5
C-6
C-7
C-7a
Other
1
2
3
–236.1
–227.7
–223.2
–134.0
155.0
105.7
110.3
138[c]
138[c]
138[c]
126.5
CO2H 170.2
–117.2
–115.2
156.1
155.6
106.1
106.0
106.1
106.0
148[c]
148[c]
140[c]
141[c]
140[c]
138[c]
129.2
128.0
CH3 54.5
CO 168.1
CH3 12.3, CH2 64.6
CO 166.9
CO2H 164.9
CH3 53.5
CO 163.7
CH3 11.8, CH2 63.8
CO 161.8
CO2H 166.8
CH3 55.2
CO 163.0
CH3 13.6, CH2 65.5
CO 162.1
CO2H 166.4
CH3 53.9
CO 164.9
CH3 12.8, 13.8
CH2 62.2
–223.4
4
5
–256.6
–228.8
–209.7
–135.3
158.4
156.1
99.9
100.9
148[c]
147[c]
104.1
100.9
148[c]
147[c]
135.1
134[c]
132.8
133.7
6
–228.7
–131.7
156.0
99.0
149[c]
99.0
149[c]
132[c]
132.2
7
8
–228.9
–230.0
–121.7
–123.5
154.6
154.8
102.4
103.0
139[c]
140[c]
139[c]
140[c]
109.7
108.3
139[c]
140[c]
126.0
125.8
9
–231.3
–123.0
155.1
104.0
143[c]
143[c]
106.5
143[c]
136.1
10
11
–247.9
–226.4
–209.4
–134.3
157.0
154.4
96.8
97.1
150[c]
148[c]
136[c]
133[c]
150[c]
148[c]
98.8
97.1
136.1
136.6
12
–222.0[a]
–242.7[b]
–123.9[a]
–204.2[b]
154.4[a]
156.1[b]
95.6
97.0
147[c]
135[c]
150[c]
98.2
99.2
135.1
136.8
CO 163.7
[a] Tautomer a. [b] Tautomer b. [c] Broad signal.
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(Table 1). This must be due either to changes in the tauto-
mer present in the solid state (large differences) or to inter-
molecular hydrogen bonding associations (small differ-
ences).
We will assume that the compounds studied in this work
crystallize with formation of dimers (Figure 3) of two types:
the indazolin-3-one[1b] type as in 13bb or the 3-hydroxy-1H-
indazole type as in 25aa,[21] both structures being connected
by double proton transfer.
Figure 3. Dimers formed by NH···O and OH···N intermolecular
hydrogen bonds.
From the most representative NMR criteria for tauto-
meric assignment – hydroxy (a), δN-1 (–222/–236 ppm),
δN-2 (–117/–135 ppm), δC-3 (153/156 ppm); oxo (b), δN-1
(–243/–257 ppm), δN-2 (–204/–210 ppm), δC-3 (156/
158 ppm) – we have established that in solution all deriva-
tives 1–12 exist as their 3-hydroxy-1H-indazole tautomers
(a). In the solid state, seven out of the eight esters maintain
the same tautomer (a). The only exception is ethyl 4,5,6-
trifluoro-3-hydroxy-1H-indazole-7-carboxylate (12), which
exists as a mixture of tautomers (Figure 4a and 4b), the
assignment of which is given in Figure 5.
Figure 4. Top) 13C NMR CPMAS spectrum of compound 12; 12a
in normal type and 12b in italics. Bottom) 15N NMR CPMAS
spectrum of compound 12; 12a in normal type and 12b in italics.
A comparative analysis of chemical shifts encountered
for the 3-hydroxy-1H tautomers in solution and in the solid
state for compounds 11, 12, and 7-nitro-1H-indazol-3-ol
(25)[21] is shown in Table 3, and led us to propose for 11 a
crystalline structure (11aa, Figure 6) fairly similar to that
of 25aa (Figure 4).
The δN-1 value for the 1H-3-hydroxy tautomer of 12 in
solution is practically the same as in the solid state; the
environment of N-1 scarcely varies as a result of the IMHBs
between the ethoxycarbonyl and the NH groups (Figure 1).
On the other hand, the signal for N-2 is shifted by almost
15 ppm due to the formation in the solid state of one hydro-
gen bond that does not exist in solution ([D8]THF). With
all these data taken into account, a plausible solid-state
structure for 12 could be the mixed dimer shown in Figure 6
(12ab). The slight difference (of 1.7 ppm) between the tau-
tomers of 12 seen in the case of δC-3, in comparison with
that of 8.4 ppm observed for 14, also supports the hypothe-
sis. The presence of two tautomers with a 1:1 stoichiometry
in a crystalline solid is a rare phenomenon; the closest ex-
ample is 3-methyl-1-phenylpyrazolin-5-one, which crys-
Figure 5. N-1, N-2 (bold type), and C-3 (normal type) chemical
shifts of 12 in solution and in the solid state.
Table 3. Differences (ppm) and ratios between solution and solid-
state chemical shifts.
11aa
N-1 difference 6.2
ratio 0.973
N-2 difference 24.6
ratio 0.817
12ab
25aa dimer
1.9
6.4
0.991
14.4
0.884
0.972
25.9
0.813
The two ethyl esters 6 and 9 and the carboxylic acid 7
tallizes in chains (catemer) formed by oxo and hydroxy tau- show the same trend: a slight variation in N-1 and a re-
tomers.[23,24]
markable increase in N-2. In addition to their existing as
A comparative analysis of chemical shifts similar to that their 3-hydroxy tautomers, the small chemical shift differ-
already discussed (Table 3) for other indazoles is presented ences between these two compound frameworks and their
in Table 4.
methyl analogues 5 and 8 suggest that these four derivatives
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Trifluoro-3-hydroxy-1H-indazolecarboxylic Acids and Esters
Figure 8. Values for δN-1, δN-2, and δC-3 of compounds 4 and 10
in solution and in the solid state.
Figure 6. Dimers formed by OH···N, OH···O and NH···N intermo-
lecular hydrogen bonds.
Conclusions
Table 4. Differences (ppm) between the solution and solid-state
chemical shifts, together with ratios.
Twelve trifluoro-3-hydroxyindazole carboxylic acids and
esters (Scheme 1) have been prepared in fair yields from
starting commercially available perfluorobenzenedicarbox-
ylic acids (3,4,5,6-tetrafluorophthalic acid, 2,4,5,6-tetra-
fluoroisophthalic acid, and 2,3,5,6-tetrafluoroterephthalic
acid). A discussion of the synthetic procedures – the in-
fluence of the experimental conditions, the formation of
isomers, as well as the decarboxylation by-products – is pre-
sented.
3
4
6
7
9
10
N-1
N-2
difference –5.6 –28.5 1.0
ratio
difference 10.6 –97.6 20.3
ratio 0.908 0.535 0.846 0.866 0.852 0.532
–1.2
1.6
–26.3
1.025 0.889 0.996 1.005 0.993 0.893
16.3 18.2 –97.9
should be arranged in similar modes in their crystalline
structures, probably involving N–H···N hydrogen bonds, al-
though involvement of the carbonyl oxygen in the alkoxy-
carbonyl group in hydrogen bonding cannot be ruled
out.[25,26] With regard to compound 3, the values reported
in Table 4 are significantly different; probably an IMHB be-
tween ethoxycarbonyl and OH groups prevents the forma-
tion of dimeric structures such as those shown in Figures 3
and 6. The expected molecular association for 3 should be
one of those typical for 1H-indazoles (NH···N dimers, tri-
mers, or catemers).[27] Compound 2 shows practically the
same 15N CPMAS chemical shift values as 3 (Table 2) and
so the same solid-state structure is expected for both (Fig-
ure 7).
In general, of the four possible tautomeric forms of 3-
hydroxyindazoles, only tautomers a (3-hydroxy-1H-ind-
azole) and b (indazolin-3-one) have been observed (Fig-
ure 9). Tautomer c is a 2H-3-hydroxyindazole and, like all
NH-indazoles, is much less stable than the 1H tauto-
mers.[1b,28,29,30] The non-aromatic character of tautomer d
explains its non-existence. In the solid state (X-ray determi-
nation), indazolinone itself [R = H (13)] exists as such
(13b).[1b] A search in the Cambridge Structural Database
(CSD)[31] shows that only for this compound (refcode FAD-
MIG) has an indazolinone structure been reported. A re-
cent publication based on X-ray crystallography as well as
13C and 15N CPMAS NMR describes a new polymorph of
13, but it is still tautomer 13b, whereas the 7-nitro derivative
25 crystallizes as the 3-hydroxy tautomer 25a (Figure 3).[21]
In this work, 3-hydroxyindazoles present a case of taut-
omerism in which the hydroxy (a) and oxo (b) tautomers
both have similar stabilities. The predominance of one form
or the other is modulated by the natures of the substituents
on the benzene ring and by the phase. In solution, every
combination of three fluorine atoms and one CO2R group
leads to the predominance of the OH tautomer (a), inde-
pendently of the presence or absence of IMHBs. In the solid
state, the situation is more balanced: although a still pre-
dominates (9.5 out of 12 cases), the oxo tautomer is present
Figure 7. Dimers formed by intermolecular N–H···N hydrogen
bonds.
Finally, compounds 4 and 10 exist in the solid state as in 2.5 cases (the 5-carboxylic acid 4b, the 7-carboxylic acid
indazolin-3-ones (b), as can be deduced from Figure 8, in 10b, and half the molecules of the 7-ethoxycarbonyl ester
which the structures of both tautomers and their corre- 12ab). In the absence of X-ray data, SSNMR proves to be
sponding δN-1, δN-2 and δC-3 values are reported.
a powerful tool for establishing the molecular structures of
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Figure 9. The four possible tautomers of 3-hydroxyindazoles.
Diethyl 2,4,5,6-Tetrafluoroisophthalate (21): Colorless oil, yield
85% (lit[35] b.p. 126–129 °C). 1H NMR (CDCl3, 400 MHz): δ = 1.31
(t, 3J = 7.1 Hz, 3 H, CO2CH2CH3), 4.35 (q, 3J = 7.1 Hz, 2 H,
CO2CH2CH3) ppm.
these heterocyclic compounds of major importance in order
to understand their biological and pharmaceutical activi-
ties.
Dimethyl 2,3,5,6-Tetrafluoroterephthalate (23): White solid, yield
1
98%, m.p. 80 °C (lit[36] 79–80 °C). H NMR (CDCl3, 400 MHz): δ
= 4.00 (s, 3 H, CO2CH3) ppm.
Experimental Section
General: All chemicals were used as provided without further puri-
fication. Melting points were determined by microscopy (Thermo-
Galen hot stage) or by DSC (Seiko 220C) with a scanning rate of
5.0 °Cmin–1. Thin-layer chromatography (TLC) was performed
with Merck silica gel (60 F254). Compounds were detected with
the aid of a 254 nm UV lamp. Silica gel (70–320 mesh) was em-
ployed for routine column chromatography separations with the
indicated eluents. Microanalyses were determined at the “Centro
de Análisis Elemental-UCM, Madrid” [Perkin–Elmer 240 (CHN)].
Diethyl 2,3,5,6-Tetrafluoroterephthalate (24): Colorless oil, yield
90% (lit[37] b.p. 155–158 °C). 1H NMR (CDCl3, 400 MHz): δ = 1.36
(t, 3J = 7.1 Hz, 3 H, CO2CH2CH3), 4.42 (q, 3J = 7.1 Hz, 2 H,
CO2CH2CH3) ppm.
5,6,7-Trifluoro-3-hydroxy-1H-indazole-4-carboxylic Acid (1): Ethyl
5,6,7-trifluoro-3-hydroxy-1H-indazole-4-carboxylate (3, 0.6 mmol,
150 mg) and sodium hydroxide (2 mmol, 80 mg) were dissolved in
water (5 mL) in a round-bottomed flask. The mixture was stirred
at room temperature for 24 h. Concentrated hydrochloric acid was
then added to reach pH 1 and the solution was cooled to 4 °C for
a further 24 h. After filtration, the mother liquor was extracted
with ethyl acetate (3ϫ20 mL). The extracts were combined and
dried with anhydrous magnesium sulfate, and after evaporation of
solvent the residue was combined with the precipitate. The resulting
solid was purified by column chromatography (hexane/diethyl ether
2:1). The product (100 mg) was obtained as a white solid (yield
72%); m.p. Ͼ300 °C (microscope). 1H NMR ([D6]DMSO,
400 MHz): δ = 12.6 (br. s, 1 H, NH), 11.4 (br. s, 1 H, OH) ppm.
13C NMR ([D6]DMSO, 100 MHz): δ = 156.6 (dd, 4J = 5.2, 4J =
Solution spectra were recorded with a Bruker DRX 400 spectrome-
ter (9.4 T, 400.13 MHz for 1H, 100.62 MHz for 13C, 376.50 MHz
for 19F, and 40.56 MHz for 15N). Chemical shifts (δ in ppm) are
given from internal solvent for 1H and 13C and from an external
reference (CFCl3) for 19F, whereas for 15N NMR nitromethane
(0.00) was used as external standard. Variable-temperature experi-
ments were recorded with the same spectrometer. A Bruker
BVT3000 temperature unit was used to control the temperature of
the cooling gas stream and an exchanger to achieve low tempera-
tures.
Solid-state 13C (100.73 MHz) and 15N (40.60 MHz) CPMAS NMR
spectra were obtained with a Bruker WB 400 spectrometer at 300 K
with use of a 4 mm DVT probehead. 13C spectra were originally
referenced to a glycine sample and the chemical shifts were then
3
3
2.7 Hz, C-3), 106.0 (dd, J = 5.7, J = 3.2 Hz, C-3a), 112.5 (m, C-
4), 144.4 (dd, 1J = 250.2, 2J = 13.3 Hz, C-5), 138.6 (ddd, 1J = 245.9,
2J = 20.4, J = 11.7 Hz, C-6), 136.6 (ddd, J = 254.3, J = 13.2, J
2
1
2
3
2
3
= 3.2 Hz, C-7), 127.3 (dd, J = 12.6, J = 2.5 Hz, C-7a), 165.0 (s,
CO2H) ppm. 19F NMR ([D6]DMSO, 376 MHz): δ = –143.1 (d,
recalculated to the Me4Si [for the carbonyl atom δ(glycine)
=
176.1 ppm] and 15N spectra to 15NH4Cl and then converted to the
nitromethane scale with the aid of the relationship: δ15N(MeNO2)
= δ15N(NH4Cl) – 338.1 ppm.
3JF-6 = 20.0 Hz, 1 F, F-5), –161.6 (dd, 3JF-5 = 20.0, 3JF-7 = 20.0 Hz,
3
1
F, F-6), –151.6 (d, JF-6
=
20.0 Hz,
1
F, F-7) ppm.
C8H3F3N2O3·H2O (250.13): calcd. C 38.41, H 2.01, N 11.20; found
C 38.21, H 1.75, N 10.83.
General Procedure for Esterifications: A solution of a diacid (15,
19, 22, 4.2 mmol, 1.0 g) in dry ethanol/methanol (10 mL) was pre-
pared in a three-necked, round-bottomed flask fitted with a reflux
condenser and a calcium chloride tube. The flask was placed in an
ice/water bath, thionyl chloride (1.4 mL) was then added dropwise,
and the mixture was heated at 60–65 °C for four days. After re-
moval of solvent, the resulting residue was purified by column
chromatography (hexane/diethyl ether 8:1).
Methyl 5,6,7-Trifluoro-3-hydroxy-1H-indazole-4-carboxylate (2): A
solution of 5,6,7-trifluoro-3-hydroxy-1H-indazole-4-carboxylic acid
(1, 0.26 mmol, 60 mg) in dry methanol (2 mL) was prepared in a
three-necked, round-bottomed flask. The flask was placed on a
water/ice bath and thionyl chloride (0.5 mL) was added dropwise
under argon. The mixture was heated at 50 °C for 48 h. The solu-
tion was then allowed to cool to room temperature and the solvent
was removed. Water (1 mL) was added to the residue and the re-
sulting suspension was kept at 4 °C for 2 h. After filtration, the
solid was washed with water and diethyl ether and dried in vacuo
to provide pure product (40 mg, yield 63%); m.p. 215–217 °C
Diethyl 3,4,5,6-Tetrafluorophthalate (16): White solid, yield 87%,
m.p. 30 °C (lit[32] 29 °C). 1H NMR (CDCl3, 400 MHz): δ = 1.39
(t, 3J = 7.1 Hz, 3 H, CO2CH2CH3), 4.42 (q, 3J = 7.1 Hz, 2 H,
CO2CH2CH3) ppm.
1
(microscope). H NMR ([D6]DMSO, 400 MHz): δ = 12.8 (br. s, 1
Dimethyl 3,4,5,6-Tetrafluorophthalate (17): White solid, yield 75%,
m.p. 72 °C (lit[33] 70–73 °C). 1H NMR (CDCl3, 400 MHz): δ = 3.95
(s, 3 H, CO2CH3) ppm.
H, NH), 10.9 (br. s, 1 H, OH), 3.91 (s, 3 H, CO2CH3) ppm. 13C
NMR ([D6]DMSO, 100 MHz): δ = 155.3 (dd, 4J = 5.2, 4J = 2.7 Hz,
3
3
2
C-3), 104.5 (dd, J = 4.8, J = 2.5 Hz, C-3a), 108.1 (dd, J = 13.9,
1
2
Dimethyl 2,4,5,6-Tetrafluoroisophthalate (20): Yellowish oil, yield
3J = 4.7 Hz C-4), 143.4 (dd, J = 248.2, J = 14.2 Hz, C-5), 138.1
1
2
1
84% (lit[34] m.p. 36–37.5 °C). 1H NMR (CDCl3, 400 MHz): δ = (ddd, J = 247.5, 2J = 19.4, J = 12.4 Hz, C-6), 137.0 (ddd, J =
2
3
2
3.87 (s, 3 H, CO2CH3) ppm.
256.4, J = 13.0, J = 4.1 Hz, C-7), 127.5 (d, J = 11.3 Hz, C-7a),
896
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 890–899

Trifluoro-3-hydroxy-1H-indazolecarboxylic Acids and Esters
1
2
4
53.1 (s, CO2CH3), 163.0 (s, CO2CH3) ppm. 19F NMR ([D6]DMSO, 6.3 Hz, C-6), 132.3 (ddd, J = 244.9, J = 16.3, J = 5.0 Hz, C-7),
376 MHz): δ = –144.4 (d, JF-6 = 18.4 Hz, 1 F, F-5), –161.2 (dd, 133.0 (m, C-7a), 52.7 (s, CO2CH3), 161.0 (s, CO2CH3) ppm. 19F
3
3
3
5
3JF-5 = 18.4, JF-7 = 18.4 Hz, 1 F, F-6), –150.0 (d, JF-6 = 18.4 Hz,
NMR ([D6]DMSO, 376 MHz): δ = –117.7 (d, JF-7 = 19.6 Hz, 1 F,
1 F, F-7) ppm. C9H5F3N2O3 (246.14): calcd. C 43.92, H 2.05, N F-4), –141.1 (br. s, F-6), –162.8 (dd, 3JF-6 = 19.6, JF-4 = 19.6 Hz,1
5
11.38; found C 43.83, H 2.18, N 11.10.
F, F-7) ppm. C9H5F3N2O3 (246.14): calcd. C 43.92, H 2.05, N
11.38; found C 44.15, H 2.24, N 11.21.
Ethyl 5,6,7-Trifluoro-3-hydroxy-1H-indazole-4-carboxylate (3): Hy-
drazine monohydrate (98%, 8.0 mmol, 400 mg) was added drop-
wise to a solution of diethyl 3,4,5,6-tetrafluorophthalate (16,
3.4 mmol, 1.0 g) in toluene (50 mL) in a three-necked, round-bot-
tomed flask. The mixture was heated at 80 °C for five days and the
toluene was then removed. The components of the resulting residue
were separated by column chromatography (hexane/diethyl ether
8:1 to 1:1) to give both recovered starting material and the pure
Ethyl 4,6,7-Trifluoro-3-hydroxy-1H-indazole-5-carboxylate (6): Di-
ethyl 2,4,5,6-tetrafluoroisophthalate (21, 1.7 mmol, 510 mg) was
dissolved in tetrahydrofuran (25 mL) in a three-necked, round-bot-
tomed flask. Hydrazine monohydrate (98%, 4.7 mmol, 235 mg)
was then added dropwise, and the resulting mixture was heated at
80 °C for 15 h. The solution is decanted while hot and the solvent
was removed under reduced pressure. The components of the resi-
product (150 mg, yield 17%); m.p. 200–202 °C (microscope). 1H due were separated by column chromatography (hexane/diethyl
NMR ([D6]DMSO, 400 MHz): δ = 12.8 (br. s, 1 H, NH), 11.0 (br. ether 4:1 to 1:1) to afford the pure product (90 mg, yield 20%);
3
3
1
s, 1 H, OH), 1.31 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 4.38 (q, J m.p. 259.6 °C (DSC). H NMR ([D6]DMSO, 400 MHz): δ = 12.9
3
=
7.1 Hz,
2
H,CO2CH2CH3) ppm. 13C NMR ([D6]DMSO, (br. s, 1 H, NH), 11.5 (br. s, 1 H, OH), 1.29 (t, J = 7.1 Hz, 3 H,
100 MHz): δ = 155.4 (dd, 4J = 4.5, 4J = 2.2 Hz, C-3), 104.5 (dd, J
CO2CH2CH3), 4.33 (q, 3J = 7.1 Hz, 2 H,CO2CH2CH3) ppm. 13C
3
3
2
3
2
= J = 5.3 Hz, C-3a), 108.5 (dd, J = 14.0, J = 5.0 Hz C-4), 143.3
NMR ([D6]DMSO, 100 MHz): δ = 155.2 (s, C-3), 100.7 (dd, J =
(dd, 1J = 247.5, 2J = 14.7 Hz, C-5), 138.1 (ddd, J = 247.3, J =
21.6, J = 4.5 Hz, C-3a), 150.2 (dd, J = 262.5, J = 6.3 Hz, C-4),
1
2
3
1
3
19.1, 2J = 12.3 Hz, C-6), 136.9 (ddd, 1J = 254.9, 2J = 13.2, 3J =
100.9 (dd, 2J = 2J = 16.9 Hz, C-5), 145.5 (ddd, 1J = 250.6, 2J =
3.9 Hz, C-7), 127.5 (d, J = 12.2 Hz, C-7a), 13.9 (s, CO2CH2CH3) 12.0, 3J = 5.7 Hz, C-6), 132.1 (ddd, 1J = 244.9, 2J = 17.0, 4J =
2
62.2 (s, CO2CH2CH3), 162.4 (s, CO2CH2CH3) ppm. 19F NMR 4.4 Hz, C-7), 132.9 (m, C-7a), 14.0 (s, CO2CH2CH3) 61.6 (s,
3
([D6]DMSO, 376 MHz): δ = –144.9 (d, JF-6 = 19.9 Hz, 1 F, F-5),
CO2CH2CH3), 160.5 (s, CO2CH2CH3) ppm. 19F NMR ([D6]-
–161.3 (dd, JF-5 = 19.9, JF-7 = 19.9 Hz, 1 F, F-6), –150.3 (d, DMSO, 376 MHz): δ = –118.2 (d, 5JF-7 = 19.6 Hz, 1 F, F-4), –141.3
3
3
3JF-6 = 19.9 Hz, 1 F, F-7) ppm. C10H7F3N2O3 (260.17): calcd. C (br. s, F-6), –162.8 (dd, 3JF-6 = 19.6, 5JF-4 = 19.6 Hz, 1 F, F-7) ppm.
46.16, H 2.71, N 10.77; found C 45.98, H 2.66, N 10.65.
4,6,7-Trifluoro-3-hydroxy-1H-indazole-5-carboxylic Acid
C10H7F3N2O3 (260.17): calcd. C 46.16, H 2.71, N 10.77; found C
46.12, H 2.77, N 10.55.
(4):
Methyl 4,6,7-trifluoro-3-hydroxy-1H-indazole-5-carboxylate (5,
0.53 mmol, 130 mg) and sodium hydroxide (1.8 mmol, 70 mg) were
dissolved in water (5 mL) in a round-bottomed flask. The mixture
was stirred at room temperature for 24 h. Concentrated hydrochlo-
ric acid was then added to reach pH 1 and the solution was cooled
to 4 °C for a further 24 h. After filtration, the precipitate is purified
by column chromatography (hexane/diethyl ether 3:1) to provide
the pure product as a white solid (110 mg, yield 89%); m.p.
Ͼ300 °C (microscope). A similar procedure was used to obtain 4
4,5,7-Trifluoro-3-hydroxy-1H-indazole-6-carboxylic Acid (7): A
solution of methyl 4,5,7-trifluoro-3-hydroxy-1H-indazole-6-carbox-
ylate (8, 0.60 mmol, 0.14 g) and sodium hydroxide (1.3 mmol,
0.05 g) in water (5 mL) was stirred at room temperature for 24 h.
Concentrated hydrochloric acid was then added to reach pH 1 and
the solution was cooled to 4 °C for a further 24 h. After filtration
of the precipitate, the pure product (110 mg , yield 79%) was col-
lected; m.p. Ͼ300 °C (microscope). A similar procedure was used
to obtain 7 from 9. 1H NMR ([D6]DMSO, 400 MHz): δ = 12.25
from 6. 1H NMR ([D6]DMSO, 400 MHz): δ = 12.30 (s, 1 H, NH), (s, 1 H, NH), 10.7 (br. s, 1 H, OH) ppm. 13C NMR ([D6]DMSO,
11.0 (br. s, 1 H, OH) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ =
100 MHz): δ = 154.4 (s, C-3), 103.7 (dd, J = 18.3, J = 4.4 Hz, C-
2
3
2
3
155.1 (s, C-3), 100.7 (dd, J = 22.1, J = 4.3 Hz, C-3a), 149.8 (dd,
3a), 138.3 (ddd, 1J = 249.4, 2J = 14.8, 4J = 4.4 Hz, C-4), 137.9
1J = 260.8, J = 6.4 Hz, C-4), 102.3 (dd, J = J = 17.4 Hz, C-5),
(ddd, J = 241.0, J = 14.0, J = 4.6 Hz, C-5), 110.7 (dd, J = 2J =
3
2
2
1
2
3
2
145.6 (ddd, 1J = 250.0, J = 11.8, J = 6.3 Hz, C-6), 132.1 (ddd, 1J
= 244.5, 2J = 16.9, 4J = 4.5 Hz, C-7), 132.7 (m, C-7a), 161.9 (s,
CO2H) ppm. 19F NMR ([D6]DMSO, 376 MHz): δ = –119.1 (d,
19.5 Hz, C-6), 139.8 (ddd, J = 253.6, J = 6.3, J = 3.8 Hz, C-7),
2
3
1
3
4
128.6 (dd, J = 18.3, J = 6.9 Hz, C-7a), 161.7 (s, CO2H) ppm. 19F
2
3
3
5
NMR ([D6]DMSO, 376 MHz): δ = –151.0 (dd, JF-5 = 21.4, JF-7
= 21.4 Hz, 1 F, F-4), –153.8 (dd, JF-4 = 21.4, JF-7 = 3.7 Hz, 1
F, F-5), –134.6 (dd, JF-4 = 21.4, JF-5 = 3.7 Hz, 1 F, F-7) ppm.
C8H3F3N2O3·H2O (250.13): calcd. C 38.41, H 2.01, N 11.20; found
C 38.17, H 2.08, N 10.62.
5JF-7 = 19.5 Hz, 1 F, F-4), –141.3 (d, JF-7 = 19.5 Hz, 1 F, F-6),
3
3
4
3
5
5
4
–163.4 (dd, JF-6
=
19.5, JF-4
=
19.5 Hz,1 F, F-7) ppm.
C8H3F3N2O3·0.5H2O (241.12): calcd. C 39.85, H 1.67, N 11.62;
found C 39.84, H 1.81, N 11.30.
Methyl 4,6,7-Trifluoro-3-hydroxy-1H-indazole-5-carboxylate (5): A
solution of dimethyl 2,4,5,6-tetrafluoroisophthalate (20, 2.7 mmol,
800 mg) in tetrahydrofuran (40 mL) was prepared in a three-necked
round-bottomed flask, and hydrazine monohydrate (98%,
6.0 mmol, 300 mg) was added dropwise. The solution was heated
at 50 °C for 3 h and, after cooling to room temperature, the precipi-
tate was filtered off and discarded. Column chromatography of the
residue obtained after removal of THF (hexane/diethyl ether 4:1 to
1:1) afforded the pure product (120 mg, yield 16%); m.p. 273.8 °C
(DSC). 1H NMR ([D6]DMSO, 400 MHz): δ = 13.0 (br. s, 1 H,
NH), 11.4 (br. s, 1 H, OH), 3.86 (s, CO2CH3) ppm. 13C NMR ([D6]-
Methyl 4,5,7-Trifluoro-3-hydroxy-1H-indazole-6-carboxylate (8): A
solution of dimethyl 2,3,5,6-tetrafluoroterephthalate (23, 2.4 mmol,
1.1 g) in tetrahydrofuran (60 mL) was prepared in a three-necked,
round-bottomed flask, and hydrazine monohydrate (98%,
8.0 mmol, 400 mg) was added dropwise. The mixture was heated at
60 °C for 6 h. After the solution had been allowed to cool to room
temperature, the precipitate was filtered off and discarded. The resi-
due obtained as a result of removal of THF was chromatographed
(hexane/diethyl ether 4:1 to 1:1) to afford the pure product (500 mg,
yield 45%); m.p. 243.9 °C (DSC). 1H NMR ([D6]DMSO,
400 MHz): δ = 12.9 (br. s, 1 H, NH), 11.4 (br. s, 1 H, OH), 3.92 (s,
3 H, CO2CH3) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 154.5
3
DMSO, 100 MHz): δ = 155.2 (s, C-3), 100.6 (dd, 2J = 22.6, J =
1
3
2
3
1
5.0 Hz, C-3a), 150.3 (dd, J = 263.1, J = 6.9 Hz, C-4), 100.4 (dd,
(m, C-3), 104.3 (dd, J = 20.0, J = 5.7 Hz, C-3a), 138.5 (ddd, J
2J = 2J = 15.1 Hz, C-5), 145.6 (ddd, 1J = 251.2, 2J = 12.6, 3J = = 249.9, J = 14.8, J = 3.9 Hz, C-4), 138.0 (ddd, J = 242.5, J =
2
4
1
2
Eur. J. Org. Chem. 2010, 890–899
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
897

C. Pérez Medina, C. López, R. M. Claramunt, J. Elguero
FULL PAPER
3
2
2
14.0, J = 3.8 Hz, C-5), 108.8 (dd, J = 18.8, J = 15.0 Hz, C-6),
temperature. The resulting mixture of compounds was chromato-
graphed (hexane/diethyl ether 4:1 to neat diethyl ether) to provide
1
3
4
2
140.5 (ddd, J = 251.7, J = 5.2, J = 2.5 Hz, C-7), 128.5 (dd, J =
18.4, 3J = 6.9 Hz, C-7a), 53.3 (s, CO2CH3), 160.9 (s, CO2CH3) ppm. first 11 (160 mg, yield 37%) and then 5 (120 mg, yield 28%); m.p.
3
1
19F NMR ([D6]DMSO, 376 MHz): δ = –150.6 (dd, JF-5 = 20.1,
265.7 °C (DSC). H NMR ([D6]DMSO, 400 MHz): δ = 12.19 (s, 1
5JF-7 = 20.1 Hz, 1 F, F-4), –153.6 (dd, JF-4 = 20.1, JF-7 = 3.4 Hz,
H, NH), 11.4 (br. s, 1 H, OH), 3.91 (s, 3 H, CO2CH3) ppm. 13C
3
4
5
4
1 F, F-5), –133.3 (dd, JF-4 = 20.1, JF-5 = 3.4 Hz, 1 F, F-7) ppm.
C9H5F3N2O3 (246.14): calcd. C 43.92, H 2.05, N 11.38; found C
44.42, H 2.27, N 10.88.
NMR ([D6]DMSO, 100 MHz): δ = 154.1 (m, C-3), 98.3 (d, 2J =
1
2
3
16.3 Hz, C-3a), 145.9 (ddd, J = 261.2, J = 11.3, J = 5.0 Hz, C-
4), 133.1 (ddd, 1J = 238.3, 2J = 18.2, 2J = 14.4 Hz, C-5), 152.2
1
2
3
2
(ddd, J = 262.5, J = 13.2, J = 3.2 Hz, C-6), 97.3 (dd, J = 10.4,
Ethyl 4,5,7-Trifluoro-3-hydroxy-1H-indazole-6-carboxylate (9): Hy-
drazine monohydrate (98%, 5.0 mmol, 250 mg) was added to a
solution of diethyl 2,3,5,6-tetrafluoroterephthalate (24, 2.4 mmol,
700 mg) in toluene (30 mL) in a three-necked, round-bottomed
flask. The mixture was heated at reflux for 24 h and was then al-
lowed to cool to room temperature. The precipitate formed was
filtered and dissolved in a saturated sodium hydrogen carbonate
solution (10 mL), which was extracted with diethyl ether
(3ϫ20 mL). The organic fractions were combined and dried with
anhydrous sodium sulfate. This solution was combined with the
mother liquor and solvents were removed under reduced pressure.
The resulting residue was then chromatographed (hexane/diethyl
ether 1:1) to recover most of the unreacted starting ester and to
provide the pure product (100 mg, yield 16%); m.p. 236.0 °C
(DSC). 1H NMR ([D6]DMSO, 400 MHz): δ = 12.9 (br. s, 1 H,
NH), 11.4 (br. s, 1 H, OH), 1.31 (t, 3J = 7.1 Hz, 3 H, CO2CH2CH3),
4.40 (q, 3J = 7.1 Hz, 2 H, CO2CH2CH3) ppm. 13C NMR ([D6]-
3J = 4.5 Hz, C-7), 135.5 (dd, J = 10.1, J = 6.3 Hz, C-7a), 52.3 (s,
3
3
CO2CH3), 161.9 (s, CO2CH3) ppm. 19F NMR ([D6]DMSO,
3
5
376 MHz): δ = –133.9 (dd, JF-5 = 21.9, JF-6 = 13.4 Hz, 1 F, F-4),
3
3
–172.3 (dd, JF-4 = 21.9, JF-6 = 21.9 Hz, 1 F, F-5), –128.5 (br. dd,
1 F, F-6) ppm. C9H5F3N2O3 (246.14): calcd. C 43.92, H 2.05, N
11.38; found C 43.90, H 2.21, N 11.24.
Ethyl 4,5,6-Trifluoro-3-hydroxy-1H-indazole-7-carboxylate (12): A
solution of diethyl 2,4,5,6-tetrafluoroisophthalate (21, 1.7 mmol,
500 mg) in toluene (25 mL) was heated to 60 °C in a three-necked,
round-bottomed flask, and hydrazine monohydrate (98%,
4.0 mmol, 200 mg) was then added dropwise. The mixture was
stirred at 60–65 °C for 18 h. The precipitate formed was filtered
while the solution was still hot. The resulting solid was purified by
column chromatography (hexane/diethyl ether 2:1) to provide 12
1
(270 mg, yield 61%); m.p. 257.5 °C (DSC). H NMR ([D6]DMSO,
400 MHz): δ = 12.1 (br. s, 1 H, NH), 11.3 (br. s, 1 H, OH), 1.33
(t, 3J = 7.1 Hz, 3 H, CO2CH2CH3), 4.41 (q, 3J = 7.1 Hz, 2 H,
CO2CH2CH3) ppm. 13C NMR ([D6]DMSO, 100 MHz): δ = 154.1
2
3
DMSO, 100 MHz): δ = 154.5 (m, C-3), 104.2 (dd, J = 19.4, J =
5.7 Hz, C-3a), 138.6 (ddd, 1J = 250.5, 2J = 14.7, J = 4.9 Hz, C-4),
4
1
2
3
2
2
1
2
138.1 (ddd, J = 242.4, J = 13.8, J = 3.8 Hz, C-5), 108.8 (dd, J
= 18.8, 2J = 15.1 Hz, C-6), 140.4 (ddd, 1J = 254.1, 3J = 6.3, 4J
= 3.8 Hz, C-7), 128.6 (dd, 2J = 17.6, 3J = 6.8 Hz, C-7a), 14.0 (s,
CO2CH2CH3) 62.3 (s, CO2CH2CH3), 160.4 (s, CO2CH2CH3) ppm.
(m, C-3), 98.3 (d, J = 16.3 Hz, C-3a), 145.8 (ddd, J = 261.4, J
3
1
2
2
= 12.1, J = 5.9 Hz, C-4), 133.1 (ddd, J = 238.6, J = 18.2, J =
13.2 Hz, C-5), 152.4 (ddd, 1J = 261.8, 2J = 13.2, J = 3.1 Hz, C-6),
3
2
3
3
3
97.5 (dd, J = 11.5, J = 4.7 Hz, C-7), 135.6 (dd, J = 10.0, J =
6.3 Hz, C-7a), 14.2 (s, CO2CH2CH3), 61.3 (s, CO2CH2CH3), 161.7
(s, CO2CH2CH3) ppm. 19F NMR ([D6]DMSO, 376 MHz): δ =
19F NMR ([D6]DMSO, 376 MHz): δ = –150.6 (dd, JF-5 = 21.1,
3
5JF-7 = 21.1 Hz, 1 F, F-4), –153.8 (dd, JF-4 = 21.1, JF-7 = 3.9 Hz,
3
4
5
4
3
4
1 F, F-5) –133.8 (dd, JF-4 = 21.1, JF-5 = 3.9 Hz, 1 F, F-7) ppm.
C10H7F3N2O3 (260.17): calcd. C 46.16, H 2.71, N 10.77; found C
46.05, H 2.83, N 10.63.
–134.1 (dd, JF-5 = 20.7, JF-6 = 13.8 Hz, 1 F, F-4), –172.3 (dd,
3JF-4 = 20.7, JF-6 = 20.7 Hz, 1 F, F-5), –128.0 (dd, JF-5 = 20.7,
4JF-4 = 13.8 Hz, 1 F, F-6) ppm. C10H7F3N2O3 (260.17): calcd. C
46.16, H 2.71, N 10.77; found C 46.08, H 2.81, N 10.73.
3
3
4,5,6-Trifluoro-3-hydroxy-1H-indazole-7-carboxylic Acid (10):
A
solution of ethyl 4,5,6-trifluoro-3-hydroxy-1H-indazole-7-carboxyl-
ate (12, 0.54 mmol, 140 mg) and sodium hydroxide (1.8 mmol,
70 mg) in water (5 mL) was stirred at room temperature for 24 h.
Concentrated hydrochloric acid was then added to reach pH 1 and
the solution was cooled to 4 °C for a further 24 h. After filtration
of the precipitate, the pure product was collected (120 mg, yield
96%). A similar procedure was used to obtain 10 from 11; m.p.
Ͼ300 °C (microscope). 1H NMR ([D6]DMSO, 400 MHz): δ =
11.92 (s, 1 H, NH), 11.2 (br. s, 1 H, OH) ppm. 13C NMR ([D6]-
DMSO, 100 MHz): δ = 154.0 (s, C-3), 98.5 (d, 2J = 16.3 Hz, C-3a),
Acknowledgments
This research has been financed by the Ministerio de Educación y
Ciencia (MEC) of Spain, CTQ2007-62113 project. Dr. Ibon Alkor-
ta’s scientific help is greatly appreciated.
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2
3
145.6 (ddd, 1J = 260.4, J = 11.5, J = 5.5 Hz, C-4), 133.1 (ddd, 1J
2
2
1
2
= 238.5, J = 18.5, J = 13.9 Hz, C-5), 152.2 (ddd, J = 261.1, J
3
2
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= 13.5, J = 2.8 Hz, C-6), 98.2 (dd, J = 11.3, J = 3.8 Hz, C-7),
136.2 (dd, J = 9.1, J = 6.7 Hz, C-7a), 163.4 (s, CO2H) ppm. 19F
3
3
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NMR ([D6]DMSO, 376 MHz): δ = –135.1 (dd, JF-5 = 21.7, JF-6
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three-necked, round-bottomed flask, and hydrazine monohydrate
(98%, 3.5 mmol, 175 mg) was then added dropwise. The mixture
was heated at reflux for 16 h and was then allowed to cool to room
898
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Eur. J. Org. Chem. 2010, 890–899

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Received: September 28, 2009
Published Online: December 22, 2009
Eur. J. Org. Chem. 2010, 890–899
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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