Synthesis of fluorinated indazoles through ANRORC-like rearrangement of 1,2,4-oxadiazoles with hydrazine

Article abstract of DOI:10.1016/j.tet.2006.06.100

A series of 6-substituted fluorinated indazoles has been obtained through an ANRORC-like rearrangement (Addition of Nucleophile, Ring-Opening and Ring-Closure) of 5-tetrafluorophenyl-1,2,4-oxadiazoles with hydrazine. The initial addition of the bidentate

Full text of DOI:10.1016/j.tet.2006.06.100

Tetrahedron 62 (2006) 8792–8797
Synthesis of fluorinated indazoles through ANRORC-like
rearrangement of 1,2,4-oxadiazoles with hydrazine
*
Antonio Palumbo Piccionello, Andrea Pace, Ivana Pibiri, Silvestre Buscemi
ꢀ
and Nicolo Vivona
Dipartimento di Chimica Organica ‘E. Paternoꢀ’, Universitaꢀ degli Studi di Palermo, Viale delle Scienze,
Parco d’Orleans II, I-90128 Palermo, Italy
Received 22 March 2006; revised 12 June 2006; accepted 29 June 2006
Available online 25 July 2006
Abstract—A series of 6-substituted fluorinated indazoles has been obtained through an ANRORC-like rearrangement (Addition of
Nucleophile, Ring-Opening and Ring-Closure) of 5-tetrafluorophenyl-1,2,4-oxadiazoles with hydrazine. The initial addition of the bidentate
nucleophile to the electrophilic C(5) of the 1,2,4-oxadiazole ring, followed by ring opening and ring closure, leads to the formation of
fluorinated indazoles in high yield under mild experimental conditions. Functionalization of the C(6) in the final indazole nucleus was
preliminarily achieved through a nucleophilic aromatic substitution on the starting 5-pentafluorophenyl-1,2,4-oxadiazole.
Ó 2006 Elsevier Ltd. All rights reserved.
R
RF
R
1. Introduction
N
NH2OH
NH2NH2
N
N
N
N
N
RF
- NH2OH
74-94%
- NH2OH
70-91%
R
RF
N
H
O
2
O
The synthesis of fluorinated heterocycles has generated
much recent interest since these compounds have found use-
ful applications in pharmaceuticals, agrochemicals and in
materials science.1,2 In general, the various approaches to
achieve this goal include direct introduction of a fluorine
or fluoroalkyl group, modification of functional groups,
heterocyclization of open-chain fluorinated precursors and
ring transformation of a suitable fluorinated heterocyle.1,2
1
3
R
HO
F
O
N
N
F
Ph
N
Ph
N
O
N
NH2NH2
Z
N
N
RF
- H2O
65-92%
F
6
RF
N
H
O
F
R = Ph, Me
Z = NR'R", OMe
4
5
For the latter approach, ANRORC-like rearrangements,
which consist of the Addition of a Nucleophile followed
by Ring-Opening and Ring-Closure steps, represent a very
versatile strategy indeed.3 This reaction pattern is well docu-
mented in the azine series,3,4 but is quite rare in the case of
five-membered heterocyclic derivatives.3,5 In fact, only
electron-poor azoles or systems bearing strongly electron-
withdrawing groups present such reactivity.3,5
= ELECTROPHILIC CENTER
Scheme 1.
In these reactions, 1,2,4-oxadiazole 2 reacted as a 1,3-dielec-
trophilic reagent; in fact, the presence of a strongly electron-
withdrawing perfluorinated chain makes the C(5) (of the
azole ring) a good electrophilic site, and allows the initial
nucleophilic attack and ring-opening steps. The subsequent
cyclization, involving the original C(3) of the azole nucleus,
is driven by the formation of a more stable heterocyclic
system.6,7
In this context, we have recently investigated the reactivity
of 5-perfluoroalkyl-1,2,4-oxadiazoles 2 and 4 with bidentate
nucleophiles such as hydrazine or hydroxylamine, and
reported their ANRORC-like rearrangements into triazoles
1,6 1,2,4-oxadiazole regioisomers 37 or 1,2,4-triazinone
oximes 58 (Scheme 1).
In 3-benzoyl-5-perfluoroalkyl-1,2,4-oxadiazoles 4, the pres-
ence of a competing electrophilic centre in the side chain,
partially changes the reactivity of the system, which is
now identified as a 1,4-dielectrophile. The C(5) is still the
preferred initial site of attack, while the final cyclization,
involving the carbonyl linked at C(3) allowed the synthesis
of fluorinated triazines 5 (Scheme 1).8
Keywords: 1,2,4-Oxadiazole;Indazole;Fluorinatedheterocycles;ANRORC-
like rearrangements.
* Corresponding author. E-mail: sbuscemi@unipa.it
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.100

A. Palumbo Piccionello et al. / Tetrahedron 62 (2006) 8792–8797
8793
R
R
At this point, we became interested in verifying if the
electrophilic behaviour of the azole C(5) could also be
induced by fluorinated aryl substituents, and studied the re-
activity of 5-tetrafluorophenyl-substituted 1,2,4-oxadiazoles
6 (Scheme 1) with hydrazine as a bidentate nucleophile.
H
F
N
F
F
N
N
HO
N
F
Z
NH2NH2
O
N
Z
DMF r.t. 1h
F
F
NH2
F
F
6a-f
10
-HF
R
N
F
R
2. Results and discussion
N
H
F
F
N
N
OH
N
H
F
Z
Pentafluorophenyl oxadiazoles 9 were prepared through the
conventional amidoxime route, by reacting amidoximes
8a,b and pentafluorobenzoyl chloride 7 in the presence of
pyridine (Scheme 2).9,10
Z
N
F
N
H
12a-f
F
11
F
a: R = Ph; Z = NHMe 94%
b: R = Ph; Z = N(Me)2 93%
c: R = Me; Z = NHMe 98%
d: R = Me; Z = N(Me)2 96%
EtOH/HCl
F
F
F
F
R
F
O
R
H2N
HO
N
Py/Toluene/∆
F
e: R = Ph; Z = OMe
f: R = Me; Z = OMe
93%
93%
F
N
+
a:R = Ph
b:R = Me
N
Cl
O
F
F
F
NH2
N
F
F
Z
7
8a,b
9a 78%
9b 33%
F
F
(1) t-BuOK/MeOH
(2) NH2NH2/∆
F
F
CN
F
N
t-BuOK
H
for 13c
R'R''NH
DMF
MeOH
25%
13a-c
F
14
a: Z = NHMe 67-75%
b: Z = NMe2 65-78%
c: Z = OMe 92-98%
R
N
R
N
F
F
N
F
F
MeO
N
R'
O
O
Scheme 3.
N
F
F
"R
F
F
6a-d
6e,f
The proposed mechanism considers the attack of the hydra-
zine onto the C(5) of the oxadiazole ring as the initial step,
followed by the ring opening into 10 (the Z-configuration
of the amidoxime was expected on the basis of preservation
along the reaction process of the initial configuration present
in the oxadiazole ring).8 In fact, a possible alternative initial
attack on the 20-position of the fluorinated ring could be
excluded since 20-substitution was never observed in the
presence of other nitrogen nucleophiles, under the same
conditions, or with stronger nucleophiles such as methoxide
anion.
a: R = Ph; R' = Me; R" = H 96%
e: R = Ph 90%
f: R = Me 91%
b: R = Ph; R' = R" = Me
c: R = R' = Me; R" = H
d: R = R' = R" = Me
93%
94%
94%
Scheme 2.
On the basis of previous results,11 one can expect that the 40-
position of the pentafluorophenyl ring may easily undergo
a nucleophilic aromatic substitution in the presence of a
nucleophile, and this behaviour would interfere with the
studied hydrazinolysis reaction.12 Therefore we decided to
preliminarily functionalize the fluorinated ring at its C(4)
position by reaction with amines or methanol to obtain tetra-
fluorophenyl-1,2,4-oxadiazoles 6a–d or 6e,f, respectively
(Scheme 2).
On the other hand, once the open-chain intermediate 10 is
obtained, the cyclization into the stable heteroaromatic sys-
tem 12 constitutes the driving force for the displacement of
a fluorine from the C(2) of the fluorinated ring, by nucleo-
philic attack of the b-nitrogen of the bidentate nucleophile.
Surprisingly, the reaction of oxadiazoles 6a–f with hydra-
zine in DMF at rt did not produce 1,2,4-triazoles 11, which
were expected as a result of an initial nucleophilic attack on
the C(5) of the oxadiazole followed by a cyclization at the
C(3) position.6 The final cyclization step, instead, involves
the side-chain electrophilic site located on the 20-position
of the fluorinated aromatic ring, and, by substitution of a fluo-
rine atom through an intramolecular SNAr, produced ring
fluorinated 6-substituted N-indazolyl-amidoximes 12a–f
(Scheme 3) (yield range: 93–98%).
It is our opinion that the observed selectivity, between the
C(3) of the starting azole and the C(2) of the fluoroaryl
ring, for the final cyclization steps is determined by the
stability of the reaction products.13,14
The proposed mechanism is in agreement with classical
methodology reported for the synthesis of indazoles, through
the formation of a N(1)–C(7a) bond, by cyclization of
o-halo-arylhydrazones with the elimination of halogen-
hydric acid.15
The structures of 12a–f were confirmed by analytical and
spectroscopic data (1H NMR, 19F NMR, IR and HRMS).
Moreover, acidic hydrolysis of 12a–f yielded the corre-
sponding fluorinated 3-amino-indazoles 13. For comparison,
a sample of 13c was also prepared, in a one-pot reaction,
from pentafluorobenzonitrile 14 (Scheme 3).
3. Conclusions
The title reaction, performed under mild conditions, resulted
in excellent yields of the isolated products. This synthetic

8794
A. Palumbo Piccionello et al. / Tetrahedron 62 (2006) 8792–8797
protocol allowed the preparation of 6-substituted ring-fluori-
nated indazoles starting from easily accessible 1,2,4-oxadi-
azole precursors. This approach represents an interesting
synthetic methodology for fluorinated indazoles, also consid-
ering that such compounds are present in many pharmaceuti-
cally important structures, with a broad range of activities,
including antiinflammatory,16 antitumor,17 anti-HIV,18 anti-
microbial,19 contraceptive20 and as nNOS inhibitors.21
4.3.1. 5-[2,3,5,6-Tetrafluoro-4-(N-methylamino)-phenyl]-
3-phenyl-1,2,4-oxadiazole 6a. Yield: 0.31 g, 96%, mp
160–163 ꢀC (white crystals from H2O/EtOH); 1H NMR
(acetone-d6) d 3.18–3.26 (m, 3H), 6.26 (s, 1H, exch. D2O),
7.53–7.64 (m, 3H), 8.10–8.17 (m, 2H); 19F NMR (acetone-
d6) d ꢂ144.34 (br d, 2F, J¼15.3 Hz), ꢂ167.28 (br d, 2F,
J¼17.1 Hz); MS m/z 323 (M+, 100); IR (Nujol) 3435,
3380, 1690 cmꢂ1. Anal. Calcd for C15H9F4N3O: C, 55.73;
H, 2.81; N, 13.00. Found: C, 55.70; H, 2.90; N, 12.90.
The reported results clearly show how ANRORC-like rear-
rangements of five-membered heterocycles can be consid-
ered as a versatile synthetic strategy for the synthesis of
fluorinated heterocycles. Such an approach is not restricted
to perfluoroalkylated substrates but can also be applied to
polyfluoroarylated 1,2,4-oxadiazoles. Moreover, the leaving
group ability of the fluorine atom in the C(2) position of the
fluoroaryl ring allows the cyclization into benzofused
systems.
4.3.2. 5-[2,3,5,6-Tetrafluoro-4-(N,N-dimethylamino)-
phenyl]-3-phenyl-1,2,4-oxadiazole 6b. Yield: 0.31 g, 93%,
mp 120–122 ꢀC (white crystals from EtOAc); 1H NMR
(CDCl3) d 3.14 (t, 6H, JH–F¼2.7 Hz), 7.50–7.55 (m, 3H),
8.17–8.20 (m, 2H); 19F NMR (CDCl3) d ꢂ138.71 (br d,
2F, J¼18.0 Hz), ꢂ152.91 (br d, 2F, J¼17.1 Hz); MS m/z
337 (M+, 100); IR (Nujol) 1645 cmꢂ1. Anal. Calcd for
C16H11F4N3O: C, 56.98; H, 3.29; N, 12.46. Found: C,
57.00; H, 3.30; N, 12.40.
4. Experimental
4.3.3. 5-[2,3,5,6-Tetrafluoro-4-(N-methylamino)-phenyl]-
3-methyl-1,2,4-oxadiazole 6c. Yield: 0.25 g, 94%, mp 182–
184 ꢀC (white crystals from H2O/EtOH); 1H NMR (DMSO-
d6) d 2.47 (s, 3H), 3.11–3.14 (m, 3H); 7.06 (s, 1H, exch.
D2O); 19F NMR (DMSO-d6) d ꢂ132.82 (br d, 2F, J¼
15.9 Hz), ꢂ154.65 (br d, 2F, J¼15.9 Hz); MS m/z 261
(M+, 100); IR (Nujol) 3321, 3163, 1653 cmꢂ1. Anal. Calcd
for C10H7F4N3O: C, 45.99; H, 2.70; N, 16.09. Found: C,
46.10; H, 2.60; N, 16.00.
4.1. General methods and materials
Melting points were determined on a Reichart-Thermovar
hot-stage apparatus and are uncorrected. IR spectra (Nujol)
were determined with a Shimadzu FTIR-8300 instrument;
1H NMR spectra were recorded on a BRUKER AC 250 E
spectrometer with TMS as an internal standard; 19F NMR
spectra were recorded on a BRUKER AVANCE 300 spec-
trometer with CFCl3 as an internal standard. GC–MS deter-
minations were carried out on a VARIAN STAR 3400 CX/
SATURN 2000 system. Flash chromatography was per-
formed by using silica gel (Merck, 0.040–0.063 mm) and
mixtures of ethyl acetate and light petroleum (fraction
boiling in the range of 40–60 ꢀC) in various ratios. Com-
pound 9a was prepared in 78% as previously reported.9
4.3.4. 5-[2,3,5,6-Tetrafluoro-4-(N,N-dimethylamino)-
phenyl]-3-methyl-1,2,4-oxadiazole 6d. Yield: 0.26 g,
1
94%, mp 71–74 ꢀC (white crystals from EtOAc); H NMR
(CDCl3) d 2.52 (s, 3H), 3.12 (t, 6H, JH–F¼2.7 Hz); 19F
NMR (CDCl3) d ꢂ139.42 (br d, 2F, J¼18.9 Hz), ꢂ153.24
(br d, 2F, J¼17.7 Hz); MS m/z 275 (M+, 100); IR (Nujol)
1647 cmꢂ1. Anal. Calcd for C11H9F4N3O: C, 48.01; H,
3.30; N, 15.27. Found: C, 48.10; H, 3.30; N, 15.30.
4.2. Synthesis of 3-methyl-5-pentafluorophenyl-1,2,4-
oxadiazole 9b
4.4. Reaction of 5-pentafluorophenyl-1,2,4-oxadiazoles
9a,b with methanol. General procedure
A mixture of acetamidoxime 8b (0.74 g; 10 mmol), pyridine
(0.9 mL; 11 mmol) and pentafluorobenzoyl chloride 7
(2.54 g, 11 mmol) in anhydrous toluene (100 mL) was
refluxed for 4 h. After removal of the solvent, the residue
was treated with water (100 mL) and then extracted with
EtOAc (3ꢁ100 mL). The combined organic layers were
dried over Na2SO4 and evaporated. Chromatography of the
residue gave 1,2,4-oxadiazole 9b (0.82 g, 33%): mp 41–
42 ꢀC (white crystals from EtOAc); 1H NMR (CDCl3)
d 2.55 (s, 3H); MS m/z 250 (M+, 100); IR (Nujol)
1655 cmꢂ1. Anal. Calcd for C9H3F5N2O: C, 43.22; H,
1.21; N, 11.20. Found: C, 43.30; H, 1.20; N, 11.40.
Oxadiazole 9 (1 mmol) was dissolved in a solution of
t-BuOK (1.2 mmol) in dry MeOH (20 mL). After stirring
for 24 h at rt, the solvent was evaporated, the residue treated
with water (100 mL), filtered and crystallized from an appro-
priate solvent, giving 5-(2,3,5,6-tetrafluoro-4-methoxy-
phenyl)-1,2,4-oxadiazoles 6e,f.
4.4.1. 5-(2,3,5,6-Tetrafluoro-4-methoxy-phenyl)-3-phe-
nyl-1,2,4-oxadiazole 6e. Yield: 0.29 g, 90%, mp 103–
104 ꢀC (white crystals from H2O/EtOH); 1H NMR
(CDCl3) d 4.25 (t, 3H, JH–F¼2.1 Hz), 7.49–7.56 (m, 3H),
8.17–8.21 (m, 2H); 19F NMR (CDCl3) d ꢂ137.32 (br d,
2F, J¼19.5 Hz), ꢂ157.43 (br d, 2F, J¼17.1 Hz); MS m/z
324 (M+, 100); IR (Nujol) 1683 cmꢂ1. Anal. Calcd for
C15H8F4N2O2: C, 55.57; H, 2.49; N, 8.64. Found: C,
55.60; H, 2.50; N, 8.60.
4.3. Reaction of 5-pentafluorophenyl-1,2,4-oxadiazoles
9a,b with amines in DMF. General procedure
To a mixture of 5-pentafluorophenyl-1,2,4-oxadiazole 9
(1 mmol) in dry DMF (2 mL), the appropriate amine
(1.1 mmol) was slowly added. After stirring for 3 h at rt,
the mixture was diluted with water (50 mL) and the formed
precipitate filtered and re-crystallized from an appropriate
solvent, giving 6a–d.
4.4.2. 5-(2,3,5,6-Tetrafluoro-4-methoxy-phenyl)-3-
methyl-1,2,4-oxadiazole 6f. Yield: 0.24 g, 91%, mp 42–
1
43 ꢀC (white crystals from H2O/EtOH); H NMR (CDCl3)

A. Palumbo Piccionello et al. / Tetrahedron 62 (2006) 8792–8797
8795
d 2.54 (s, 3H), 4.24 (t, 3H, JH–F¼2.0 Hz); 19F NMR (CDCl3)
d ꢂ137.63 (br d, 2F, J¼19.2 Hz), ꢂ157.33 (br d, 2F,
J¼20.7 Hz); MS m/z 262 (M+, 100); IR (Nujol)
1653 cmꢂ1. Anal. Calcd for C10H6F4N2O2: C, 45.81; H,
2.31; N, 10.69. Found: C, 45.70; H, 2.30; N, 10.80.
(m, 2H), 8.39 (s, 1H, exch. D2O), 10.56 (s, 1H, exch. D2O),
13.21 (s, 1H, exch. D2O); 19F NMR (DMSO-d6) d ꢂ143.01
(t, 1F, J¼21.0 Hz), ꢂ146.79 (d, 1F, J¼20.7 Hz), ꢂ155.92
(d, 1F, J¼21.9 Hz); IR (Nujol) 3385, 3142, 3057, 1670,
1639 cmꢂ1; HRMS calcd for C15H11F3N4O2: 336.0834.
Found: 336.0835.
4.5. Reaction of 5-tetrafluorophenyl-1,2,4-oxadiazoles
6a–f with hydrazine in DMF. General procedure
4.5.6. (Z)-N-(4,5,7-Trifluoro-6-methoxy-1H-indazol-3-
yl)-N0-hydroxy-acetamidine 12f. Yield: 0.25 g, 93%, mp
208–211 ꢀC (white crystals from H2O/EtOH); 1H NMR
(DMSO-d6) d 1.96 (s, 3H), 4.07 (s, 3H), 8.08 (s, 1H, exch.
D2O), 9.80 (s, 1H, exch. D2O), 13.37 (s, 1H, exch. D2O);
19F NMR (DMSO-d6) d ꢂ144.96 (t, 1F, J¼18.6 Hz),
ꢂ146.52 (d, 1F, J¼18.3 Hz), ꢂ155.60 (br s, 1F); IR (Nujol)
3389, 3252, 1657 cmꢂ1. HRMS calcd for C10H9F3N4O2:
274.0678. Found: 274.0671.
To a mixture of oxadiazoles 6a–f (1 mmol) in dry DMF
(2 mL), an excess of hydrazine monohydrate (0.25 g,
5 mmol) was slowly added. After stirring for 3 h at rt, the
mixture was diluted with 1 M HCl (50 mL) and the formed
precipitate filtered. Re-crystallization of the residue from
H2O/EtOH (1:1) gave the corresponding (Z)-N-(4,5,7-tri-
fluoro-1H-indazol-3-yl)-N0-hydroxy-amidine 12.
4.5.1. (Z)-N-[4,5,7-Trifluoro-6-(N-methylamino)-1H-
indazol-3-yl]-N0-hydroxy-benzamidine 12a. Yield: 0.31 g,
4.6. Hydrolysis of (Z)-N-(4,5,7-trifluoro-1H-indazol-3-
yl)-N0-hydroxy-amidines 12a–f. General procedure
1
94%, mp 190–193 ꢀC (white crystals from H2O/EtOH); H
NMR (DMSO-d6) d 3.01 (s, 3H), 5.66 (s, 1H, exch. D2O),
7.28 (br s, 3H), 7.36 (br s, 2H), 8.22 (s, 1H, exch. D2O),
10.49 (s, 1H, exch. D2O), 12.64 (s, 1H, exch. D2O); 19F
NMR (DMSO-d6) d ꢂ153.20 (t, 1F, J¼19.8 Hz), ꢂ160.44
(d, 1F, J¼17.1 Hz), ꢂ163.42 (d, 1F, J¼21.0 Hz); IR (Nujol)
3404, 3336, 3134, 1670, 1632 cmꢂ1. HRMS calcd for
C15H12F3N5O: 335.0994. Found: 335.0990.
To a mixture of 12 (1.0 mmol) in ethanol (10 mL), concd
hydrochloric acid (0.5 mL) was added. The solution was
refluxed for 24 h. After removal of the solvent, the residue
was treated with water, neutralized by the addition of solid
NaHCO3 and extracted with EtOAc. The organic layer was
dried over Na2SO4 and evaporated. Crystallization of the
residue from the appropriate solvent gave the corresponding
3-amino-4,5,7-trifluoro-1H-indazoles 13a–c.
4.5.2. (Z)-N-[4,5,7-Trifluoro-6-(N,N-dimethylamino)-1H-
indazol-3-yl]-N0-hydroxy-benzamidine 12b. Yield: 0.32 g,
93%, mp 196–198 ꢀC (white crystals from H2O/EtOH); 1H
NMR (DMSO-d6) d 2.93 (s, 6H), 7.29 (br s, 3H), 7.37 (br s,
2H), 8.33 (s, 1H, exch. D2O), 10.53 (s, 1H, exch. D2O),
13.00 (s, 1H, exch. D2O); 19F NMR (DMSO-d6) d ꢂ147.68
(d, 1F, J¼20.1 Hz), ꢂ151.66 (t, 1F, J¼20.4 Hz), ꢂ156.73
4.6.1. 3-Amino-4,5,7-trifluoro-6-(N-methylamino)-1H-
indazole 13a. Yield: 0.15 g, 67% from 12a; 0.16 g, 75%
from 12c, mp 178–80 ꢀC (white crystals from H2O/EtOH);
1H NMR (DMSO-d6) d 3.01 (t, 3H, JH–F¼5 Hz), 5.22 (s,
2H, exch. D2O), 5.53 (s, 1H, exch. D2O), 11.74 (s, 1H,
exch. D2O); 19F NMR (DMSO-d6) d ꢂ145.65 (t, 1F, J¼
18.9 Hz), ꢂ152.28 (d, 1F, J¼19.2 Hz), ꢂ157.82 (d, 1F, J¼
20.7 Hz); MS m/z 216 (M+, 100); IR (Nujol) 3471, 3404,
3389, 3333, 3152, 1680 cmꢂ1; Anal. Calcd for C8H7F3N4:
C, 44.45; H, 3.26; N, 25.92. Found: C, 44.70; H, 3.20;
N, 25.80.
(d, 1F, J¼21.3 Hz); IR (Nujol) 3400, 3275, 1657 cmꢂ1
.
HRMS calcd for C16H14F3N5O: 349.1150. Found: 349.1143.
4.5.3. (Z)-N-[4,5,7-Trifluoro-6-(N-methylamino)-1H-
indazol-3-yl]-N0-hydroxy-acetamidine 12c. Yield: 0.27 g,
98%, mp 200–202 ꢀC (white crystals from H2O/EtOH); 1H
NMR (DMSO-d6) d 2.00 (s, 3H), 3.05 (t, 3H, J¼4.27 Hz),
5.74 (s, 1H, exch. D2O), 7.93 (s, 1H, exch. D2O), 9.76 (s,
1H, exch. D2O), 12.77 (s, 1H, exch. D2O); 19F NMR
(DMSO-d6) d ꢂ155.13 (t, 1F, J¼20.7 Hz), ꢂ160.21 (d, 1F,
J¼19.2 Hz), ꢂ162.94 (d, 1F, J¼13.5 Hz); IR (Nujol) 3386,
3269, 1676, 1647 cmꢂ1. HRMS calcd for C10H10F3N5O:
273.0837. Found: 273.0838.
4.6.2. 3-Amino-4,5,7-trifluoro-6-(N,N-dimethylamino)-
1H-indazole 13b. Yield: 0.14 g, 65% from 12b; 0.17 g,
78% from 12d, mp 149–150 ꢀC (white crystals from H2O/
1
EtOH); H NMR (DMSO-d6) d 2.91 (s, 6H), 5.35 (s, 2H,
exch. D2O), 12.10 (s, 1H, exch. D2O); 19F NMR (DMSO-
d6) d ꢂ140.11 (d, 1F, J¼19.8 Hz), ꢂ144.61 (t, 1F,
J¼20.7 Hz), ꢂ151.40 (d, 1F, J¼21.9 Hz); MS m/z 220
(M+, 100); IR (Nujol) 3429, 3392, 3342, 3170, 3132,
1670 cmꢂ1; Anal. Calcd for C10H9F3N4: C, 46.96; H, 3.94;
N, 24.34. Found: C, 47.10; H, 3.80; N, 24.50.
4.5.4. (Z)-N-[4,5,7-Trifluoro-6-(N,N-dimethylamino)-1H-
indazol-3-yl)-N0-hydroxy-acetamidine 12d. Yield: 0.27 g,
96%, mp 203–206 ꢀC (white crystals from H2O/EtOH); 1H
NMR (DMSO-d6) d 1.98 (s, 3H), 2.97 (s, 6H), 8.04 (s, 1H,
exch. D2O), 9.79 (s, 1H, exch. D2O), 13.17 (s, 1H, exch.
D2O); 19F NMR (DMSO-d6) d ꢂ147.46 (d, 1F, J¼
20.1 Hz), ꢂ153.73 (t, 1F, J¼20.7 Hz), ꢂ156.41 (br s, 1F);
IR (Nujol) 3384, 3265, 1675, 1647 cmꢂ1. HRMS calcd for
C11H12F3N5O: 287.0994. Found: 287.0988.
4.6.3. 3-Amino-4,5,7-trifluoro-6-methoxy-1H-indazole
13c. Yield: 0.20 g, 92% from 12e; 0.21 g, 98% from 12f,
mp 209–212 ꢀC (white crystals from H2O/EtOH); 1H
NMR (DMSO-d6) d 4.05 (s, 3H), 5.42 (s, 2H, exch. D2O),
12.31 (S, 1H, exch. D2O); 19F NMR (DMSO-d6) d
ꢂ143.42 (t, 1F, J¼19.2 Hz), ꢂ147.27 (d, 1F, J¼18.3 Hz),
ꢂ158.85 (d, 1F, J¼21.6 Hz); MS m/z 217 (M+, 100); IR
(Nujol) 3429, 3392, 3338, 3136, 3082, 1672 cmꢂ1; Anal.
Calcd for C8H6F3N3O: C, 44.25; H, 2.79; N, 19.35. Found:
C, 44.30; H, 2.80; N, 19.50.
4.5.5. (Z)-N-(4,5,7-Trifluoro-6-methoxy-1H-indazol-3-
yl)-N0-hydroxy-benzamidine 12e. Yield: 0.31 g, 93%, mp
185–188 ꢀC (white crystals from H2O/EtOH); 1H NMR
(DMSO-d6) d 4.07 (s, 3H), 7.25–7.30 (m, 3H), 7.33–7.40

8796
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4.7. Synthesis of 3-amino-4,5,7-trifluoro-6-methoxy-1H-
indazole 13c
Pentafluorobenzonitrile 14 (1.93 g, 10 mmol) was added to a
solution of t-BuOK (1.23 g, 11 mmol) in methanol (20 mL).
The solution was stirred at rt for 4 h and, after addition of
hydrazine monohydrate (0.5 g, 20 mmol), refluxed for 12 h.
The solvent was then evaporated under reduced pressure
and the residue chromatographed to yield 3-amino-4,5,7-
trifluoro-6-methoxy-1H-indazole 13c (0.5 g, 23%).
9. Buscemi, S.; Pace, A.; Palumbo Piccionello, A.; Pibiri, I.;
Vivona, N. Heterocycles 2004, 63, 1619–1628.
Acknowledgements
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Financial support through the Italian MIUR and University
of Palermo is gratefully acknowledged.
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