On the reaction of some 5-polyfluoroaryl-1,2,4-oxadiazoles with methylhydrazine: synthesis of fluorinated indazoles

Article abstract of DOI:10.1016/j.tet.2008.10.094

The reaction of 5-polyfluoroaryl-1,2,4-oxadiazoles with methylhydrazine has been studied and the synthesis of fluorinated N-methylindazoles has been realized. Rearrangement reactions showed predominantly formation of N(1)-methylindazole regioisomers. Star

Full text of DOI:10.1016/j.tet.2008.10.094

Tetrahedron 65 (2009) 119–127
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
On the reaction of some 5-polyfluoroaryl-1,2,4-oxadiazoles
with methylhydrazine: synthesis of fluorinated indazoles
*
`
Antonio Palumbo Piccionello , Andrea Pace, Paola Pierro, Ivana Pibiri, Silvestre Buscemi, Nicolo Vivona
`
Dipartimento di Chimica Organica ‘E. Paterno`’, Universita degli Studi di Palermo, Viale delle ScienzedParco d’Orleans II, I-90128 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2008
Received in revised form 16 October 2008
Accepted 30 October 2008
Available online 5 November 2008
The reaction of 5-polyfluoroaryl-1,2,4-oxadiazoles with methylhydrazine has been studied and the
synthesis of fluorinated N-methylindazoles has been realized. Rearrangement reactions showed pre-
dominantly formation of N(1)-methylindazole regioisomers. Starting compounds were preliminarily
functionalized at the polyfluoroaryl moiety through fluorine displacement with nucleophiles (methanol,
methylamine, dimethylamine), allowing the obtainment of target indazoles substituted at the C(6)
position.
Keywords:
1,2,4-Oxadiazole
Indazole
Ó 2008 Elsevier Ltd. All rights reserved.
Rearrangements
Fluorinated heterocycles
1. Introduction
rearrangement of 5-tetrafluoroaryl-1,2,4-oxadiazoles 1, with hy-
drazine, leads easily to 3-amino-4,5,7-trifluoroindazoles 2 with
The indazole nucleus is a pharmaceutically important and
emerging heterocycle with a broad spectrum of activities, including
antiinflammatory,1 antitumor,2 anti-HIV,3 antimicrobial,4 contra-
ceptive,5 and have also been used as nNOS inhibitors.6 Particularly,
3-aminoindazole derivatives show potent dopamine receptor an-
tagonist activity, useful for antipsychotic treatment,7 and are
reported as non-steroidal antiinflammatory compounds with an-
algesic properties.7,8 In this context, fluorinated 3-aminoindazoles
have been identified as lead compounds for the treatment of psy-
chiatric disorders such as obsessive compulsive disorder and at-
tention deficit disorder,9 and are also reported as protein kinase
inhibitors, especially of Aurora-2 and GSK-3, useful for the treat-
ment of diseases associated with protein kinases, such as diabetes,
cancer, and Alzheimer’s disease.10 Due to their pharmaceutical
importance, the synthesis of fluorinated 3-aminoindazoles repre-
sents an interesting research field, so far limited to few examples,
mostly regarding monofluorinated derivatives.
various substituents linked to C(6) (Scheme 1).12
R'
H
R'
F
N
F
N
OH
N
F
F
H2NNH2
DMF
N
N
O
N
R
R
F
H
F
F
1
2
R = MeO, MeNH, (Me)2N;
R' = Me, Ph;
Scheme 1.
In this work we report the results concerning the reactivity of 5-
polyfluoroaryl-1,2,4-oxadiazoles 3a–d (Chart 1) with methylhy-
drazine, in order to evaluate the regiochemistry of the reaction with
an unsymmetrical bidentate nucleophile and to generalize the
ANRORC approach for the synthesis of mono-, di-, and trifluoro-3-
aminoindazole derivatives.
In the frame of our research on heterocycles reactivity, we
have recently reported some ANRORC-like (Addition of
Nucleophile, Ring-Opening, Ring-Closure) rearrangements of 5-
2. Results and discussion
perfluoroalkyl-1,2,4-oxadiazoles as
a valid approach for the
obtainment of target fluorinated compounds such as 1,2,4-tri-
1,2,4-Oxadiazoles 3a–d were obtained through the conventional
amidoxime route (see Section 4).13 In order to prevent the
formation of byproducts during the rearrangements,12 substrates
bearing a fluorine atom on the 40-position of the fluoroaryl moiety
have been preliminarily reacted with oxygen or nitrogen nucleo-
philes (ZH in Scheme 2) such as methanol, methylmine, and
azole, 1,2,4-oxadiazole, and 1,2,4-triazine.11 Moreover, ANRORC
* Corresponding author. Tel.: þ39 091 596903; fax: þ39 091 596825.
E-mail address: apalumbo@unipa.it (A. Palumbo Piccionello).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.094

120
A. Palumbo Piccionello et al. / Tetrahedron 65 (2009) 119–127
Ph
Ph
N
Ph
N
Ph
H
H
Y
Ph
N
N
Y
F
Y
F
X
N
N
Y
N
N
N
X
X
Z
X
Z
OH
N Me
O
O
OH
N
H2NNHMe
DMF
N
F
O
+
F
N
N
F
Z
F
F
Me
3d
3a-c
F
a: X = Y = F
b: X = F; Y = H
c: X = Y = H
4-6 a-c
9a-c: Z = OMe;
10a,c: Z = OMe;
12a,b: Z = NHMe;
14a-c: Z = NMe2.
a: X,Y = F;
11a-c: Z = NHMe;
13a-c: Z = NMe2.
b: X = F; Y = H;
c: X,Y = H.
Chart 1.
Scheme 3.
dimethylamine, under mild conditions, yielding the corresponding
40-substituted derivatives 4–6 (Scheme 2). The reactions occur
through an SNAr mechanism and represent an easy and straight-
forward strategy to introduce different functionalities in the target
indazoles. The observed substitution at the 40-position is in
agreement with previously reported SNAr reactions on 5-penta-
fluorophenyl-1,2,4-oxadiazoles.12,14 The reaction is favored by the
electron-withdrawing ability of the oxadiazole ring, which acti-
vates both the ortho and para positions, the latter being preferred as
the less hindered site.12,14 On the other hand, in the case of oxa-
diazole 3c, when methylamine was employed as nucleophile,
preferential formation of 20-subtituted isomer 7, despite 40-
regioisomer 5c, was observed (7/5c ratio 35:33); moreover, in the
case of oxadiazole 3b, with methoxide anion, subsequent attack
occurs at the 20-position, leading to the disubstituted derivative 8
(inset in Scheme 2). These results show, for the first time, the re-
activity of the 20-positions of 5-polyfluoro-1,2,4-oxadiazoles to-
ward nucleophiles.
Table 1
Products distribution for reactions of compounds 4–6 with methylhydrazine
Substrate (% recovered) X
Y
F
Z
N(1)-Methyl (% yield) N(2)-Methyl (% yield)
4a (None)
4b (41)
4c (None)
5a (5)
5b (30)
5c (52)
6a (4)
F
F
OMe
9a (68)
9b (34)
9c (77)
10a (16)
d
H OMe
H H OMe
F
F
H H NHMe 11c (37)
F
F
10c (4)
12a (10)
12b (5)
d
F
NHMe 11a (60)
H NHMe 11b (60)
F N(Me)2 13a (68)
H N(Me)2 13b (50)
14a (17)
14b (13)
14c (20)
6b (16)
6c (26)
H H N(Me)2 13c (39)
Ph
H
Ph
N
N
N
OH
H2N NHMe
DMF
N
N
O
N
Ph
Ph
Y
Y
F
3d
N
Me
15 (95%)
X
N
X
N
N
ZH
O
O
F
Z
a: X,Y = F
Scheme 4.
F
F
b: X = F; Y = H
c: X,Y = H
F
F
3a-c
4a-c: Z = OMe;
5a-c: Z = NHMe;
6a-c: Z = NMe2.
then deaminated with t-BuONO in DMF16 to N-methylindazoles
17 and 22, respectively. The latter derivatives were compared
with those obtained from two regiocomplementary synthesis
(Schemes 5 and 6).
N(1)-Methyl isomer 17 was also obtained, adapting a pre-
viously reported method,17 through condensation reaction of
4-methoxy-tetrafluorobenzaldehyde 19 with methylhydrazine
followed by base promoted cyclization of methylhydrazone 20
(Scheme 5).
In turn, an authentic sample of N(2)-methyl regioisomer 22 was
obtained by means of regioselective methylation of the parent
indazole 23, arising from 19, with Me3OBF4 (Scheme 6).18
The reported results can be rationalized on the basis of two
different pathways, which consider the initial nucleophilic attack
occurring at either the C(5) of the oxadiazole ring (path a) or at the
fluorine substituted 20-position of the aryl moiety (path b)
(Scheme 7).
Path a is a classic ANRORC-like rearrangement involving the
preferential attack of the less hindered unsubstituted nitrogen of
the nucleophile11d at the C(5) of the azole ring, giving 24, followed
by oxadiazole ring-opening into 25 and final cyclization into N(1)-
methylindazole regioisomers with nucleophilic displacement of an
o-fluorine from the fluoroaryl moiety.12 Path b considers at first
nucleophilic displacement of an o-fluorine, in the fluoroaryl moiety,
by either the NHMe end (path b-1) or the NH2 (path b-2) end of the
methylhydrazine nucleophile. Then, a nucleophilic attack of the
ZH = MeOH, MeNH2, Me2NH
Ph
N
Ph
N
F
N
N
O
O
O
Me
F
OMe
NHMe
7 (35%)
F
F
8 (28%)
Scheme 2.
1,2,4-Oxadiazoles 4–6 were reacted with an excess of methyl-
hydrazine in DMF at rt. Under these conditions, a mixture of fluo-
rinated N-methylindazole regioisomers 9–14 was obtained
(Scheme 3; Table 1). The mixtures were chromatographically re-
solved with the N(1)-methyl isomers eluting first. The regioisomers
were identified, by means of 1H NMR: the chemical shift of N-
methyl singlet is deshielded in the case of N(2)-methyl isomer with
respect to the N(1)-methyl one.15 Moreover, the H(4) signal of N(1)-
methyl regioisomers 11 and 13 is deshielded with respect to the
H(4) signal of N(2)-methyl isomers 12 and 14 (see Section 4).14
In all the cases preferential formation of N(1)-methyl isomer
was observed, and in the case of monofluorinated compound 3d,
N(1)-methyl isomer 15 was obtained in very high yield (95%)
(Scheme 4).
In order to unequivocally confirm the proposed structure of
the obtained N-methylindazole isomers, representative N-ind-
azol-3-yl-amidoximes 9a and 10a were hydrolyzed to the cor-
responding N-methyl-3-aminoindazoles 16 and 21, which were
b
nitrogen of the arylhydrazine intermediate 26 on the C(5) of
the oxadiazole ring leads to the formation of spiro-intermediate 27,

A. Palumbo Piccionello et al. / Tetrahedron 65 (2009) 119–127
121
F
F
H
F
NH2
N
F
F
t-BuONO
DMF/Δ
N
HCl
9a
N
N
MeO
MeO
EtOH/Δ
Me
Me
F
17
16
Py/ DMF
Δ
F
F
H
F
H
F
H
F
F
F
F
MeO
H2N NHMe
THF
O
t-BuOK
O
N
NHMe
MeOH
F
MeO
F
F
F
F
20
18
19
Scheme 5.
F
Ph
Ph
H
F
F
F
NH2
F
N
N
F
F
F
F
t-BuONO
DMF/Δ
HCl
N
N
N Me
10a
N Me
MeNH2
DMF
O
O
N
EtOH/Δ
MeO
MeO
N
MeO
MeO
NHMe
28 (85%)
F
F
F
22
F
21
4a
F
H
F
Scheme 8.
H2N NH2
N
19
THF/Δ
N
MeO
H
F
were not obtained. Moreover, the competition between the
two different nucleophilic sites of methylhydrazine was eval-
uated from reaction with 1,2,4-oxadiazole 3a in DMF with
1 equiv of nucleophile. The observed distribution of the
obtained 40-substituted methylhydrazino-regioisomers 29 and
30 confirms the preferential attack of the NHMe moiety of
methylhydrazine nucleophile under the reaction conditions
used (Scheme 9).
All these data suggest the preference for path b on rearrange-
ment reactions (see Scheme 7) with a regioselectivity that should
be affected from the balance between electrophilic character at 20-
position of the fluoroaryl moiety and accessibility of the electro-
philic site.
23
Scheme 6.
which, after ring-opening of the oxadiazolidine moiety, produces
final N-methylindazole isomers.
In order to asses the most electrophilic site between C(5) of
oxadiazole ring and 20-position of fluoroaryl moiety (and so the
preferred reaction path), representative oxadiazole 4a was reacted
with methylamine in DMF at rt (Scheme 8).
20-Substituted oxadiazole 28 was obtained in high yield
from nucleophilic displacement of a 20-fluorine, while prod-
ucts arising from a nucleophilic attack at the oxadiazole C(5)
Ph
Ph
Y
H
Ph
N
Y
Y
F
X
N
HN
X
N
OH
path a
N
X
Z
N
O
R = H;
O
a
N
Z
HN
R' = Me.
Z
NHMe
F
F
NHMe
F
NHR
NHR'
F
F
b
4-6
24
25
path b
Ph
N
Ph
H
Ph
Y
Y
N
N
O
N R'
N
O
Y
X
HN
X
path b-1
N
OH
X
Z
N
R = Me;
R' = H.
Z
N
Z
NHR'
N
N
R
Me
F
F
R
F
26
9,11,13
27
R = H;
path b-2
R' = Me.
Ph
H
Y
N
N
X
Z
OH
N Me
N
F
10,12,14
Scheme 7.

122
A. Palumbo Piccionello et al. / Tetrahedron 65 (2009) 119–127
Ph
Ph
Ph
F
F
F
N
N
N
F
F
F
N
N
H
N
N
H2N NHMe
DMF
O
H2N
O
O
+
Me
F
N
N
F
H
F
F
Me
F
F
F
29 (74%)
Scheme 9.
30 (6%)
3a
3. Conclusions
4.3.1. Reaction of 3b with methanol
Chromatography of the residue gave 4b (57%, from ethyl acetate/
petroleum ether 1:50), and 8 (28%, from ethyl acetate/petroleum
ether 1:20).
The synthesis of fluorinated N-methylindazoles has been per-
formed with a simple rearrangement of 1,2,4-oxadiazoles, with
preference for N(1) isomer. This reactivity is not limited to highly
fluorinated derivatives and has been extended to the obtainment
also of 7-fluoro- and 5,7-difluoro-indazoles as well as to the syn-
thesis of unfluorinated compound 15. The proposed strategy
represents a valid approach for the synthesis of various poly-
substituted indazoles of pharmacological interest, because it allows
selective introduction of fluorine atoms and preliminary function-
alization of C(6) of target molecules.
4.3.1.1. 5-(2,3,5-Trifluoro-4-methoxy-phenyl)-3-phenyl-1,2,4-oxadi-
azole 4b. Mp 80–82 ꢀC (petroleum ether); Rf¼0.60 (silica gel, ethyl
acetate/petroleum ether 1:20); 1H NMR (300 MHz, CDCl3)
d 4.20 (s,
3H, OCH3), 7.49–7.56 (m, 3H, ArH), 7.73–7.81 (m, 1H, H(6)), 8.15–
8.19 (m, 2H, ArH); 19F NMR (282 MHz, CDCl3)
d
ꢁ134.78 (m, 1F),
ꢁ136.23 (m, 1F), ꢁ152.46 (m, 1F); FTIR (Nujol) 1636 cmꢁ1. GC–MS
(m/z): 306 (Mþ, 100%). Anal. Calcd for C15H9F3N2O2: C, 58.83; H,
2.96; N, 9.15. Found: C, 59.00; H, 2.90; N, 9.20.
4. Experimental
4.3.1.2. 5-(3,5-Difluoro-2,4-dimethoxy-phenyl)-3-phenyl-1,2,4-oxa-
diazole 8. Mp 115–117 ꢀC (petroleum ether); Rf¼0.45 (silica gel, ethyl
4.1. General methods and materials
acetate/petroleum ether 1:20); 1H NMR (300 MHz, CDCl3)
d 4.09 (s, 3H,
p-OCH3), 4.16 (s, 3H, o-OCH3), 7.51–7.54 (m, 3H, ArH), 7.73 (dd, 1H,
Melting points were determined on a Reichart-Thermovar hot-
stage apparatus and are uncorrected. IR spectra (Nujol) were de-
J1¼2.8 Hz, J2¼13.4 Hz, H(6)), 8.15–8.19 (m, 2H, ArH); 19F NMR (282 MHz,
termined with a Shimadzu FTIR-8300 instrument; 1H NMR and 19
F
CDCl3)
d
ꢁ135.53 (d, 1F, J¼5.6 Hz), ꢁ146.52 (br s, 1F); FTIR (Nujol)
1596 cmꢁ1. GC–MS(m/z): 318 (Mþ,100%). Anal. CalcdforC16H12F2N2O3:
NMR spectra were recorded on a BRUKER 300 Avance spectrometer
with TMS or CFCl3, respectively, as an internal standard. GC–MS
determinations were carried out on a VARIAN STAR 3400 CX/SAT-
URN 2000 system. Flash chromatography was performed by using
silica gel (Merck, 0.040–0.063 mm) and mixtures of ethyl acetate
and petroleum ether (fraction boiling in the range of 40–60 ꢀC) in
various ratios. Compounds 3a–c13 (obtained in 78%, 80%, and 73%
yields, respectively) and 4a, 5a, 6a12 were obtained as previously
reported.
C, 60.38; H, 3.80; N, 8.80. Found: C, 60.40; H, 3.70; N, 8.60.
4.3.2. Reaction of 3c with methanol
4.3.2.1. 5-(2,3-Difluoro-4-methoxy-phenyl)-3-phenyl-1,2,4-oxadia-
zole 4c. Yield: 59%. Mp 135–138 ꢀC (petroleum ether); 1H NMR
(300 MHz, CDCl3)
d
4.02 (s, 3H, OCH3), 6.93 (ddd, 1H, J1¼1.8 Hz,
J2¼7.2 Hz, J3¼9.0 Hz, H(5)), 7.50–7.55 (m, 3H, ArH), 7.96 (ddd, 1H,
J1¼2.1 Hz, J2¼7.2 Hz, J3¼9.0 Hz, H(6)), 8.16–8.19 (m, 2H, ArH); 19F
NMR (282 MHz, CDCl3)
d
ꢁ135.73 (d, 1F, J¼16.9 Hz), ꢁ161.03 (d, 1F,
4.2. Synthesis of 5-(2-fluorophenyl)-3-phenyl-1,2,4-
oxadiazole 3d
J¼16.9 Hz); FTIR (Nujol) 1624 cmꢁ1. GC–MS (m/z): 288 (Mþ, 100%).
Anal. Calcd for C15H10F2N2O2: C, 62.50; H, 3.50; N, 9.72. Found: C,
62.60; H, 3.40; N, 9.80.
A
mixture of benzamidoxime (1.0 g, 7.35 mmol), pyridine
(0.059 mL, 8 mmol), and 2-fluorobenzoylchloride (8 mmol) in an-
hydrous toluene (100 mL) was heated to reflux for 4 h. After re-
moval of the solvent, the residue was chromatographed (ethyl
acetate/petroleum ether 1:20) giving oxadiazole 3d (68%): 5-(2-
fluorophenyl)-3-phenyl-1,2,4-oxadiazole 3d. Mp 94–95 ꢀC (petro-
leum ether); Rf¼0.70 (silica gel, ethyl acetate/petroleum ether
4.4. Reaction of oxadiazoles 3b,c with amines in DMF. General
procedure
To a mixture of oxadiazoles 3b,c (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 crystallized from an appropriate solvent, or
chromatographed giving desired compounds 5b,c and 6b,c.
1:20); 1H NMR (300 MHz, CDCl3)
d 7.27–7.38 (m, 2H, ArH, over-
lapped signals), 7.52–7.61 (m, 4H, ArH, overlapped signals), 8.18–
8.24 (m, 3H, ArH, overlapped signals); 19F NMR (282 MHz, CDCl3)
d
ꢁ111.38 (s, 1F); FTIR (Nujol) 1617 cmꢁ1. GC–MS (m/z): 240 (Mþ,
100%). Anal. Calcd for C14H9FN2O: C, 69.99; H, 3.78; N, 11.66. Found:
C, 69.90; H, 3.90; N, 11.50.
4.4.1. Reaction of 3b with methylamine
4.4.1.1. 5-[2,3,5-Trifluoro-4-(N-methylamino)-phenyl]-3-phenyl-1,2,
4.3. Reaction of oxadiazoles 3b,c with methanol. General
procedure
4-oxadiazole 5b. Yield: 93%. Mp 146–149 ꢀC (EtOH); 1H NMR
(300 MHz, DMSO-d6)
exch. with D2O), 7.64–7.72 (m, 4H, ArH, overlapped signals), 8.08–
8.12 (m, 2H, ArH); 19F NMR (282 MHz, CDCl3)
ꢁ138.60 (d, 1F,
J¼16.9 Hz), ꢁ140.53 (m, 1F), ꢁ158.79 (m, 1F); FTIR (Nujol) 3392,
1635 cmꢁ1 GC–MS (m/z): 305 (Mþ, 100%). Anal. Calcd for
d 3.10 (s, 3H, NHCH3), 6.76 (s, 1H, NHCH3,
Oxadiazole 3 (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 appropriate solvent, or chroma-
tographed giving 4b and 4c.
d
.
C15H10F3N3O: C, 59.02; H, 3.30; N, 13.77. Found: C, 59.10; H, 3.40; N,
13.70.

A. Palumbo Piccionello et al. / Tetrahedron 65 (2009) 119–127
123
4.4.2. Reaction of 3c with methylamine
4.5.1.1. (Z)-N-(1-Methyl-1H-indazol-3-yl)-N0-hydroxy-benzamidine
Chromatography of the residue gave 7 (35%, from ethyl acetate/
petroleum ether 1:50), recovered 3c (25%, from ethyl acetate/pe-
troleum ether 1:20), and 5c (33%, from ethyl acetate/petroleum
ether 1:5).
15. Yield: 95%. Mp 224–225 ꢀC (EtOH); Rf¼0.55 (silica gel, ethyl
acetate/petroleum ether 1:1); 1H NMR (300 MHz, DMSO-d6)
d 3.79
(s, 3H, N(1)CH3), 7.05 (ddd, 1H, J1¼1.0 Hz, J2¼6.6 Hz, J3¼6.9 Hz,
H(5)), 7.24–7.29 (m, 3H, ArH), 7.32–7.41 (m, 3H, ArH, overlapped
signals), 7.48 (d, 1H, J¼8.4 Hz, H(7)); 7.67 (d, 1H, J¼6.6 Hz, H(4)),
8.42 (s, 1H, NH, exch. with D2O), 10.54 (s, 1H, OH, exch. with D2O);
FTIR (Nujol) 3331, 3145, 1630, 1617 cmꢁ1. GC–MS (m/z): 266 (Mþ,
2%), 250 (Mþꢁ16, 71%), 104 (100%). Anal. Calcd for C14H14N4O: C,
67.65; H, 5.30; N, 21.04. Found: C, 67.50; H, 5.50; N, 21.00.
4.4.2.1. 5-[2,3-Difluoro-4-(N-methylamino)-phenyl]-3-phenyl-1,2,4-
oxadiazole 5c. Mp 165–166 ꢀC (EtOH); Rf¼0.35 (silica gel, ethyl
acetate/petroleum ether 1:5); 1H NMR (300 MHz, DMSO-d6)
d 2.91
(d, 3H, J¼5.0 Hz, NHCH3), 6.74–6.80 (m, 1H, H(5)), 7.05 (br q, 1H,
NHCH3, exch. with D2O, J¼5.0 Hz), 7.63–7.68 (m, 3H, ArH), 7.86–7.91
(m, 1H, H(6)), 8.11–8.14 (m, 2H, ArH); 19F NMR (282 MHz, CDCl3)
4.5.2. Reaction of oxadiazole 4a with methylhydrazine in DMF
Chromatography of the residue gave 9a (68%, from ethyl acetate/
petroleum ether 1:5) and 10a (16%, from ethyl acetate/petroleum
ether 1:2).
d
ꢁ137.07 (m, 1F), ꢁ165.81 (m, 1F); FTIR (Nujol) 3363, 1685,
1635 cmꢁ1 GC–MS m/z 287 (Mþ, 100%). Anal. Calcd for
.
C15H11F2N3O: C, 62.72; H, 3.86; N, 14.63. Found: C, 62.70; H, 3.90; N,
14.50.
4.5.2.1. (Z)-N-(4,5,7-Trifluoro-6-methoxy-1-methyl-1H-indazol-3-
yl)-N0-hydroxy-benzamidine 9a. Mp 169–172 ꢀC (EtOH); Rf¼0.45
(silica gel, ethyl acetate/petroleum ether 1:5); 1H NMR (300 MHz,
4.4.2.2. 5-[3,4-Difluoro-2-(N-methylamino)-phenyl]-3-phenyl-1,2,4-
oxadiazole 7. Mp 136–139 ꢀC (EtOH); Rf¼0.55 (silica gel, ethyl
acetate/petroleum ether 1:50); 1H NMR (300 MHz, DMSO-d6)
DMSO-d6)
d 3.91 (s, 3H, OCH3), 4.05 (s, 3H, N(1)CH3), 7.24–7.31 (m,
d
3.29–3.33 (m, 3H, NHCH3), 6.87 (ddd, 1H, J1¼7.0 Hz, J2¼9.0 Hz,
3H, ArH), 7.33–7.41 (m, 2H, ArH), 8.43 (s, 1H, NH, exch. with D2O),
J3¼10.0 Hz, H(5)), 7.63–7.71 (m, 3H, ArH), 7.77 (br s, 1H, NHCH3,
exch. with D2O), 7.86 (ddd, 1H, J1¼2.0 Hz, J2¼6.0 Hz, J3¼9.0 Hz,
10.53 (s, 1H, OH, exch. with D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ154.84 (t, 1F, J¼19.7 Hz), ꢁ161.56 (d, 1F, J¼20.1 Hz), ꢁ165.39 (d,
H(6)), 8.22–8.25 (m, 2H, ArH); 19F NMR (282 MHz, CDCl3)
d
ꢁ132.89
1F, J¼19.5 Hz); FTIR (Nujol) 3328, 3202, 1628 cmꢁ1. GC–MS (m/z):
350 (Mþ, 4%), 334 (Mþꢁ16, 43%), 104 (100%). Anal. Calcd for
C16H13F3N4O2: C, 54.86; H, 3.74; N, 15.99. Found: C, 54.90; H, 3.70;
N, 16.10.
(m, 1F), ꢁ160.46 (m, 1F); FTIR (Nujol) 3320, 1631 cmꢁ1. GC–MS (m/
z): 287 (Mþ,100%). Anal. Calcd for C15H11F2N3O: C, 62.72; H, 3.86; N,
14.63. Found: C, 62.60; H, 3.80; N, 14.70.
4.4.3. Reaction of 3b with dimethylamine
4.5.2.2. (Z)-N-(4,5,7-Trifluoro-6-methoxy-2-methyl-2H-indazol-3-
yl)-N0-hydroxy-benzamidine 10a. Mp 180–183 ꢀC (EtOH); Rf¼0.25
(silica gel, ethyl acetate/petroleum ether 1:2); 1H NMR (300 MHz,
4.4.3.1. 5-[2,3,5-Trifluoro-4-(N,N-dimethylamino)-phenyl]-3-phenyl-
1,2,4-oxadiazole 6b. Yield: 80%. Mp 119–121 ꢀC (petroleum ether);
DMSO-d6)
5H, ArH, overlapped signals), 8.83 (s, 1H, NH, exch. with D2O), 10.64
(s, 1H, OH, exch. with D2O); 19F NMR (282 MHz, CDCl3)
d 3.98 (s, 3H, OCH3), 4.09 (s, 3H, N(2)CH3), 7.29–7.34 (m,
1H NMR (300 MHz, CDCl3)
d
2.88 (t, 6H, J¼3.4 Hz, N(CH3)2), 7.29–
7.35 (m, 3H, ArH), 7.42 (ddd, 1H, J1¼2.7 Hz, J2¼7.6 Hz, J3¼15.4 Hz,
d
ꢁ155.36 (t,
H(6)), 7.94–7.98 (m, 2H, ArH); 19F NMR (282 MHz, CDCl3)
d
ꢁ128.05
1F, J¼19.6 Hz), ꢁ156.89 (d, 1F, J¼20.3 Hz), ꢁ162.83 (d, 1F,
J¼19.2 Hz); FTIR (Nujol) 3318, 1670, 1632 cmꢁ1. GC–MS (m/z): 350
(Mþ, 2%), 334 (Mþꢁ16, 36%), 104 (100%). Anal. Calcd for
C16H13F3N4O2: C, 54.86; H, 3.74; N, 15.99. Found: C, 54.70; H, 3.70;
N, 16.00.
(m, 1F), ꢁ140.02 (m, 1F), ꢁ148.31 (m, 1F); FTIR (Nujol) 1630 cmꢁ1
.
GC–MS (m/z): 319 (Mþ,100%). Anal. Calcd for C16H12F3N3O: C, 60.19;
H, 3.79; N, 13.16. Found: C, 60.10; H, 3.90; N, 13.30.
4.4.4. Reaction of 3c with dimethylamine
4.5.3. Reaction of oxadiazole 4b with methylhydrazine in DMF
Chromatography of the residue gave recovered 4b (41%, from
ethyl acetate/petroleum ether 1:20) and 9b (34%, from ethyl ace-
tate/petroleum ether 1:5).
4.4.4.1. 5-[2,3-Difluoro-4-(N,N-dimethylamino)-phenyl]-3-phenyl-
1,2,4-oxadiazole 6c. Yield: 73%. Mp 121–122 ꢀC (petroleum ether);
1H NMR (300 MHz, CDCl3)
d 3.09 (s, 6H, N(CH3)2), 6.64 (ddd, 1H,
J1¼1.8 Hz, J2¼8.1 Hz, J3¼9.3 Hz, H(5)), 7.49–7.54 (m, 3H, ArH), 7.80
(ddd, 1H, J1¼2.1 Hz, J2¼7.5 Hz, J3¼9.3 Hz, H(6)), 8.15–8.19 (m, 2H,
4.5.3.1. (Z)-N-(5,7-Difluoro-6-methoxy-1-methyl-1H-indazol-3-yl)-
N0-hydroxy-benzamidine 9b. Mp 163–166 ꢀC (EtOH); Rf¼0.43 (silica
gel, ethyl acetate/petroleum ether 1:5); 1H NMR (300 MHz, DMSO-
ArH); 19F NMR (282 MHz, CDCl3)
d
ꢁ137.31 (m, 1F), ꢁ154.08 (m, 1F);
FTIR (Nujol) 1627 cmꢁ1. GC–MS (m/z): 301 (Mþ, 100%). Anal. Calcd
for C16H13F2N3O: C, 63.78; H, 4.35; N, 13.95. Found: C, 63.80; H,
4.50; N, 13.90.
d6)
d 3.83 (s, 3H, OCH3), 4.01 (s, 3H, N(1)CH3), 7.25–7.32 (m, 3H,
ArH), 7.36–7.39 (m, 2H, ArH), 7.46 (d, 1H, J¼11.4 Hz, H(4)), 8.61 (s,
1H, NH, exch. with D2O), 10.64 (s, 1H, OH, exch. with D2O); 19F NMR
4.5. Reaction of 1,2,4-oxadiazoles 4–6 with methylhydrazine
in DMF. General procedure
(282 MHz, CDCl3)
d
ꢁ137.66 (m, 1F), ꢁ154.92 (br s, 1F); FTIR (Nujol)
3332, 1629 cmꢁ1. GC–MS (m/z): 332 (Mþ, 2%), 316 (Mþꢁ16, 46%),
104 (100%). Anal. Calcd for C16H14F2N4O2: C, 57.83; H, 4.25; N, 16.86.
Found: C, 57.90; H, 4.30; N, 16.70.
To a mixture of oxadiazoles 3d, 4–6 (1 mmol) in dry DMF (2 mL),
a large excess of methylhydrazine (3 mL; 0.3 mL in the case of de-
rivatives 4a, 5a, and 6a) was slowly added. After stirring for 24 h at
rt (3 h in the case of derivatives 4a, 5a and 6a), the mixture was
diluted with 1 M HCl (50 mL) and the formed precipitate extracted
with EtOAc (200 mL). The organic layer was dried over Na2SO4 and
evaporated. Chromatography of the residue gave N-methyl-
indazolyl-N0-hydroxy-benzamidines 9–15.
4.5.4. Reaction of oxadiazole 4c with methylhydrazine in DMF
Chromatography of the residue gave 9c (77%, from ethyl acetate/
petroleum ether 1:5) and 10c (4%, from ethyl acetate/petroleum
ether 1:2).
4.5.4.1. (Z)-N-(7-Fluoro-6-methoxy-1-methyl-1H-indazol-3-yl)-N0-hy-
droxy-benzamidine 9c. Mp 158–161 ꢀC (EtOH); Rf¼0.40 (silica gel,
ethyl acetate/petroleum ether 1:5); 1H NMR (300 MHz, DMSO-d6)
4.5.1. Reaction of oxadiazole 3d with methylhydrazine in DMF
Chromatography of the residue gave 15 (95%, from ethyl acetate/
petroleum ether 1:1).
d
3.82 (s, 3H, OCH3), 3.94 (s, 3H, N(1)CH3), 7.01 (dd, 1H, J1¼6.9 Hz,
J2¼8.7 Hz, H(5)), 7.25–7.32 (m, 3H, ArH), 7.37–7.40 (m, 2H, ArH), 7.46

124
A. Palumbo Piccionello et al. / Tetrahedron 65 (2009) 119–127
(d, 1H, J¼8.7 Hz, H(4)), 8.51 (s, 1H, NH, exch. with D2O), 10.59 (s, 1H,
4.5.6.2. (Z)-N-[5,7-Difluoro-6-(N-methylamino)-2-methyl-2H-indazol-
3-yl]-N0-hydroxy-benzamidine 12b. Mp 183–186 ꢀC (EtOH); Rf¼0.28
(silica gel, ethyl acetate/petroleum ether 1:2); 1H NMR (300 MHz,
OH, exch. with D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ164.44 (m, 1F);
FTIR (Nujol) 3338, 1674, 1647 cmꢁ1. GC–MS (m/z): 314 (Mþ, 1%), 298
(Mþꢁ16, 38%), 104 (100%). Anal. Calcd for C17H15FN4O: C, 61.14; H,
4.81; N, 17.83. Found: C, 61.10; H, 4.80; N, 17.90.
DMSO-d6) d 2.92–2.95 (m, 3H, NHCH3), 3.94 (s, 3H, N(2)CH3), 5.06–
5.08 (m, 1H, NHCH3, exch. with D2O), 6.70 (d, 1H, J¼11.1 Hz, H(4)),
7.22–7.30 (m, 3H, ArH), 7.34–7.37 (m, 2H, ArH), 8.61 (s,1H, NH, exch.
with D2O), 10.63 (s, 1H, OH, exch. with D2O); 19F NMR (282 MHz,
4.5.4.2. (Z)-N-(7-Fluoro-6-methoxy-2-methyl-2H-indazol-3-yl)-N0-hy-
droxy-benzamidine 10c. Mp 184–185 ꢀC (EtOH); Rf¼0.35 (silica gel,
ethyl acetate/petroleum ether 1:2); 1H NMR (300 MHz, DMSO-d6)
CDCl3)
d
ꢁ136.95 (d, 1F, J¼11.1 Hz), ꢁ157.86 (br s, 1F); FTIR (Nujol)
3586, 3340, 1653, 1647, 1630 cmꢁ1. GC–MS (m/z): 331 (Mþ, 5%), 315
(Mþꢁ16, 41%), 104 (100%). Anal. Calcd for C16H15F2N5O: C, 58.00; H,
4.56; N, 21.14. Found: C, 58.10; H, 4.7; N, 21.00.
d
3.86 (s, 3H, OCH3), 4.03 (s, 3H, N(2)CH3), 6.84 (dd, 1H, J1¼6.9 Hz,
J2¼9.0 Hz, H(5)), 7.03 (d, 1H, J¼9.0 Hz, H(4)), 7.23–7.29 (m, 3H, ArH),
7.36–7.39 (m, 2H, ArH), 8.75 (s,1H, NH, exch. with D2O),10.71 (s,1H,
OH, exch. with D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ163.38 (m, 1F);
4.5.7. Reaction of oxadiazole 5c with methylhydrazine in DMF
Chromatography of the residue gave recovered 5c (52%, from
ethyl acetate/petroleum ether 1:20) and 11c (37%, from ethyl ace-
tate/petroleum ether 1:5).
FTIR (Nujol) 3350, 3095,1635 cmꢁ1. GC–MS (m/z): 314 (Mþ,1%), 298
(Mþꢁ16, 52%), 104 (100%). Anal. Calcd for C16H15FN4O2: C, 61.14; H,
4.81; N, 17.83. Found: C, 61.30; H, 4.70; N, 17.90.
4.5.5. Reaction of oxadiazole 5a with methylhydrazine in DMF
Chromatography of the residue gave recovered 5a (5%, from
ethyl acetate/petroleum ether 1:20), 11a (60%, from ethyl acetate/
petroleum ether 1:5), and 12a (10%, from ethyl acetate/petroleum
ether 1:2).
4.5.7.1. (Z)-N-[7-Fluoro-6-(N-methylamino)-1-methyl-1H-indazol-
3-yl]-N0-hydroxy-benzamidine 11c. Mp 196–198 ꢀC (EtOH); Rf¼0.38
(silica gel, ethyl acetate/petroleum ether 1:5); 1H NMR (300 MHz,
DMSO-d6)
d 2.82 (s, 3H, NHCH3), 3.78 (s, 3H, N(1)CH3), 5.62 (s, 1H,
NHCH3, exch. with D2O), 6.59 (dd, 1H, J1¼7.5 Hz, J2¼8.4 Hz, H(5)),
7.24–7.31 (m, 4H, ArH, overlapped signals), 7.37–7.40 (m, 2H, ArH),
8.31 (s, 1H, NH, exch. with D2O), 10.53 (s, 1H, OH, exch. with D2O);
4.5.5.1. (Z)-N-[4,5,7-Trifluoro-6-(N-methylamino)-1-methyl-1H-
indazol-3-yl]-N0-hydroxy-benzamidine 11a. Mp 208 ꢀC dec (EtOH);
Rf¼0.35 (silica gel, ethyl acetate/petroleum ether 1:5); 1H NMR
19F NMR (282 MHz, CDCl3)
d
ꢁ167.61 (m, 1F); FTIR (Nujol) 3436,
3320, 3147, 1648, 1629 cmꢁ1. GC–MS (m/z): 313 (Mþ, 1%), 297
(Mþꢁ16, 46%), 104 (100%). Anal. Calcd for C16H16F N5O: C, 61.33; H,
5.15; N, 22.35. Found: C, 61.40; H, 5.10; N, 22.50.
(300 MHz, DMSO-d6)
d 3.00 (s, 3H, NHCH3), 3.84 (s, 3H,
N(1)CH3), 5.70 (s, 1H, NHCH3, exch. with D2O), 7.23–7.32 (m, 3H,
ArH), 7.38–7.40 (m, 2H, ArH), 8.24 (s, 1H, NH, exch. with D2O),
10.49 (s, 1H, OH, exch. with D2O); 19F NMR (DMSO-d6)
d
ꢁ153.20
4.5.8. Reaction of oxadiazole 6a with methylhydrazine in DMF
Chromatography of the residue gave recovered 6a (4%, from
ethyl acetate/petroleum ether 1:20), 13a (68%, from ethyl acetate/
petroleum ether 1:5), and 14a (17%, from ethyl acetate/petroleum
ether 1:2).
(t, 1F, J¼19.8 Hz), ꢁ160.27 (d, 1F, J¼20.1 Hz), ꢁ163.58 (d, 1F,
J¼17.0 Hz); FTIR (Nujol) 3370, 3340, 1672, 1623 cmꢁ1. GC–MS (m/
z): 349 (Mþ, 6%), 333 (Mþꢁ16, 45%), 104 (100%). Anal. Calcd for
C16H14F3N5O: C, 55.01; H, 4.04; N, 20.05. Found: C, 55.10; H, 4.00;
N, 20.20.
4.5.8.1. (Z)-N-[4,5,7-Trifluoro-6-(N,N-dimethylamino)-1-methyl-1H-
indazol-3-yl]-N0-hydroxy-benzamidine 13a. Mp 174–176 ꢀC (EtOH);
Rf¼0.51 (silica gel, ethyl acetate/petroleum ether 1:5); 1H NMR
4.5.5.2. (Z)-N-[4,5,7-Trifluoro-6-(N-methylamino)-2-methyl-2H-ind-
azol-3-yl]-N0-hydroxy-benzamidine 12a. Mp 176–178 ꢀC (EtOH);
Rf¼0.25 (silica gel, ethyl acetate/petroleum ether 1:2); 1H NMR
(300 MHz, DMSO-d6)
d 2.94 (s, 6H, N(CH3)2), 3.89 (s, 3H, N(1)CH3),
(300 MHz, DMSO-d6)
d
2.94 (s, 3H, NHCH3), 4.09 (s, 3H, N(2)CH3),
7.28–7.30 (m, 3H, ArH), 7.38–7.41 (m, 2H, ArH), 8.35 (s,1H, NH, exch.
5.34 (s, 1H, NHCH3, exch. With D2O), 7.26–7.37 (m, 5H, ArH, over-
lapped signals), 8.71 (s, 1H, NH, exch. with D2O), 10.59 (s, 1H, OH,
with D2O), 10.50 (s, 1H, OH, exch. with D2O); 19F NMR (CDCl3)
d
ꢁ146.88 (t,1F, J¼19.1 Hz), ꢁ154.66 (d,1F, J¼20.2 Hz), ꢁ156.93 (d,1F,
exch. with D2O); 19F NMR (DMSO-d6)
d
ꢁ153.69 (t, 1F, J¼19.6 Hz),
J¼18.3 Hz); FTIR (Nujol) 3391, 1652 cmꢁ1. GC–MS (m/z): 363 (Mþ,
3%), 347 (Mþꢁ16, 38%), 104 (100%). Anal. Calcd for C17H16F3N5O: C,
56.20; H, 4.44; N, 19.28. Found: C, 56.10; H, 4.50; N, 19.40.
ꢁ158.27 (d, 1F, J¼20.0 Hz), ꢁ162.43 (d, 1F, J¼16.8 Hz); FTIR (Nujol)
3330, 1635 cmꢁ1. GC–MS (m/z): 349 (Mþ, 1%), 333 (Mþꢁ16, 47%),
104 (100%). Anal. Calcd for C16H14F3N5O: C, 55.01; H, 4.04; N, 20.05.
Found: C, 55.10; H, 4.00; N, 20.20.
4.5.8.2. (Z)-N-[4,5,7-Trifluoro-6-(N,N-dimethylamino)-2-methyl-2H-
indazol-3-yl]-N0-hydroxy-benzamidine 14a. Mp 175–178 ꢀC (EtOH);
Rf¼0.36 (silica gel, ethyl acetate/petroleum ether 1:2); 1H NMR
4.5.6. Reaction of oxadiazole 5b with methylhydrazine in DMF
Chromatography of the residue gave recovered 5b (30%, from
ethyl acetate/petroleum ether 1:20), 11b (60%, from ethyl acetate/
petroleum ether 1:5), and 12b (5%, from ethyl acetate/petroleum
ether 1:2).
(300 MHz, DMSO-d6)
d 2.83 (s, 6H, N(CH3)2), 4.05 (s, 3H, N(1)CH3),
7.29–7.33 (m, 5H, ArH, overlappedsignals), 8.77 (s,1H, NH, exch. with
D2O),10.62 (s,1H, OH, exch. with D2O); 19F NMR (CDCl3)
d
ꢁ148.96 (t,
1F, J¼19.7 Hz), ꢁ155.78 (d,1F, J¼20.7 Hz), ꢁ157.28 (d,1F, J¼18.3 Hz);
FTIR (Nujol) 3350, 3187, 1670, 1653, 1628 cmꢁ1. GC–MS (m/z): 363
(Mþ, 4%), 347 (Mþꢁ16, 42%),104 (100%). Anal. Calcd forC17H16F3N5O:
C, 56.30; H, 4.6; N, 19.28. Found: C, 56.20; H, 4.44; N, 19.20.
4.5.6.1. (Z)-N-[5,7-Difluoro-6-(N-methylamino)-1-methyl-1H-indazol-
3-yl]-N0-hydroxy-benzamidine 11b. Mp 184–186 ꢀC (EtOH); Rf¼0.41
(silica gel, ethyl acetate/petroleum ether 1:5); 1H NMR (300 MHz,
DMSO-d6)
d
2.98–3.02 (m, 3H, NHCH3), 3.77 (s, 3H, N(1)CH3), 5.37–
4.5.9. Reaction of oxadiazole 6b with methylhydrazine in DMF
Chromatography of the residue gave recovered 6b (16%, from
ethyl acetate/petroleum ether 1:20), 13b (50%, from ethyl acetate/
petroleum ether 1:5), and 14b (13%, from ethyl acetate/petroleum
ether 1:2).
5.41 (m, 1H, NHCH3, exch. with D2O), 7.14 (d, 1H, J¼12.0 Hz, H(4)),
7.24–7.29 (m, 3H, ArH), 7.30–7.39 (m, 2H, ArH), 8.36 (s, 1H, NH,
exch. with D2O), 10.53 (s, 1H, OH, exch. with D2O); 19F NMR
(282 MHz, CDCl3)
d
ꢁ137.84 (d, 1F, J¼12.0 Hz), ꢁ158.70 (br s, 1F);
FTIR (Nujol) 3452, 3332, 3100, 1653, 1629 cmꢁ1. GC–MS (m/z):
331 (Mþ, 1%), 315 (Mþꢁ16, 47%), 104 (100%). Anal. Calcd for
C16H15F2N5O: C, 58.00; H, 4.56; N, 21.14. Found: C, 58.00; H, 4.50;
N, 21.10.
4.5.9.1. (Z)-N-[5,7-Difluoro-6-(N,N-dimethylamino)-1-methyl-1H-ind-
azol-3-yl]-N0-hydroxy-benzamidine 13b. Mp 140–142 ꢀC (EtOH);
Rf¼0.47 (silica gel, ethyl acetate/petroleum ether 1:5); 1H NMR

A. Palumbo Piccionello et al. / Tetrahedron 65 (2009) 119–127
125
(300 MHz, DMSO-d6)
d
2.90 (s, 6H, N(CH3)2), 3.81 (s, 3H, N(1)CH3),
100%). Anal. Calcd for C9H8F3N3O: C, 46.76; H, 3.49; N, 18.18. Found:
C, 46.80; H, 3.50; N, 18.10.
7.25–7.39 (m, 6H, ArH, overlapped signals), 8.50 (s, 1H, NH, exch.
with D2O), 10.58 (s, 1H, OH, exch. with D2O); 19F NMR (282 MHz,
CDCl3)
d
ꢁ129.38 (d, 1F, J¼8.5 Hz), ꢁ147.10 (br s, 1F); FTIR (Nujol)
4.6.2. 3-Amino-4,5,7-trifluoro-6-methoxy-2-methyl-2H-indazole 21
3171, 1628 cmꢁ1. GC–MS (m/z): 345 (Mþ, 2%), 329 (Mþꢁ16, 33%),
104 (100%). Anal. Calcd for C17H17F2N5O: C, 59.12; H, 4.96; N, 20.28.
Found: C, 59.10; H, 4.80; N, 20.40.
Yield: 38%. Mp 125–127 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
3.98
(s, 3H, OCH3), 4.12 (s, 3H, N(2)CH3), 4.27 (s, 2H, NH2, exch. with
D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ155.94 (t, 1F, J¼19.8 Hz),
ꢁ154.72 (d, 1F, J¼21.1 Hz), ꢁ165.36 (d, 1F, J¼19.4 Hz); FTIR (Nujol)
3454, 3376, 1681, 1654, 1617 cmꢁ1. GC–MS (m/z): 231 (Mþ, 100%).
Anal. Calcd for C9H8F3N3O: C, 46.76; H, 3.49; N, 18.18. Found: C,
46.90; H, 3.40; N, 18.10.
4.5.9.2. (Z)-N-[5,7-Difluoro-6-(N,N-dimethylamino)-2-methyl-2H-in-
dazol-3-yl]-N0-hydroxy-benzamidine 14b. Mp 180–181 ꢀC (EtOH);
Rf¼0.29 (silica gel, ethyl acetate/petroleum ether 1:2); 1H NMR
(300 MHz, DMSO-d6)
d 2.83 (s, 6H, N(CH3)2), 4.00 (s, 3H, N(2)CH3),
6.79 (dd, 1H, J1¼1.0 Hz, J2¼11.1 Hz, H(4)), 7.27–7.30 (m, 3H, ArH),
4.7. Deamination reaction of compounds 16 and 21. General
procedure
7.37–7.40 (m, 2H, ArH), 8.68 (s,1H, NH, exch. with D2O),10.67 (s,1H,
OH, exch. with D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ128.83 (d, 1F,
J¼11.1 Hz), ꢁ146.63 (br s, 1F); FTIR (Nujol) 3260, 1653, 1637 cmꢁ1
.
To a solution of amine 16 or 21 (1 mmol) in DMF (5 mL) a solu-
tion of t-BuONO (2 mmol) in dry DMF (2 mL) was slowly added.
After 2 h at 83 ꢀC under good stirring, the mixture was treated with
water (50 mL) and extracted with EtOAc (200 mL). The organic
layer was dried over Na2SO4 and evaporated. Chromatography of
the residue (from ethyl acetate/petroleum ether 1:5) gave fluori-
nated indazole 17 or 22.
GC–MS (m/z): 345 (Mþ, 6%), 329 (Mþꢁ16, 38%), 104 (100%). Anal.
Calcd for C17H17F2N5O: C, 59.12; H, 4.96; N, 20.28. Found: C, 59.20;
H, 5.10; N, 20.20.
4.5.10. Reaction of oxadiazole 6c with methylhydrazine in DMF
Chromatography of the residue gave recovered 6c (26%, from
ethyl acetate/petroleum ether 1:20), 13c (39%, from ethyl acetate/
petroleum ether 1:5), and 14c (20%, from ethyl acetate/petroleum
ether 1:2).
4.7.1. 4,5,7-Trifluoro-6-methoxy-1-methyl-1H-indazole 17
Yield: 55%. Mp 77–78 ꢀC (petroleum ether); Rf¼0.75 (silica gel,
ethyl acetate/petroleum ether 1:5); 1H NMR (300 MHz, CDCl3)
4.5.10.1. (Z)-N-[7-Fluoro-6-(N,N-dimethylamino)-1-methyl-1H-inda-
zol-3-yl]-N0-hydroxy-benzamidine 13c. Mp 158–160 ꢀC (EtOH);
Rf¼0.42 (silica gel, ethyl acetate/petroleum ether 1:5); 1H NMR
d
4.08 (s, 3H, OCH3), 4.13 (s, 3H, N(1)CH3), 8.05 (s,1H, H(3)); 19F NMR
(282 MHz, CDCl3)
J¼20.1 Hz), ꢁ164.25 (d, 1F, J¼16.9 Hz); FTIR (Nujol) 3130, 1665,
1648 cmꢁ1 GC–MS (m/z): 216 (Mþ, 100%). Anal. Calcd for
d
ꢁ150.77 (t, 1F, J¼19.7 Hz), ꢁ160.10 (d, 1F,
(300 MHz, DMSO-d6)
d
2.88 (s, 6H, N(CH3)2), 3.82 (s, 3H, N(1)CH3),
.
6.81 (dd, 1H, J1¼7.5 Hz, J2¼9.0 Hz, H(5)), 7.27–7.40 (m, 6H, ArH,
C9H7F3N2O: C, 50.01; H, 3.26; N, 12.96. Found: C, 50.0; H, 3.40; N,
13.10.
overlapped signals), 8.44 (s, 1H, NH, exch. with D2O), 10.57 (s, 1H,
OH, exch. with D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ152.20 (br s,1F);
FTIR (Nujol) 3342, 3200,1633 cmꢁ1. GC–MS (m/z): 327 (Mþ,1%), 311
(Mþꢁ16, 43%), 104 (100%). Anal. Calcd for C17H18FN5O: C, 62.37; H,
5.54; N, 21.39. Found: C, 62.40; H, 5.40; N, 21.70.
4.7.2. 4,5,7-Trifluoro-6-methoxy-2-methyl-2H-indazole 22
Yield: 57%. Mp 119–120 ꢀC (petroleum ether); Rf¼0.45 (silica gel,
ethyl acetate/petroleum ether 1:2); 1H NMR (300 MHz, CDCl3)
d
4.09 (s, 3H, OCH3), 4.22 (s, 3H, N(2)CH3), 8.01 (d, 1H, J¼2.4 Hz,
4.5.10.2. (Z)-N-[7-Fluoro-6-(N,N-dimethylamino)-2-methyl-2H-in-
dazol-3-yl]-N0-hydroxy-benzamidine 14c. Oil; Rf¼0.26 (silica gel,
ethyl acetate/petroleum ether 1:2); 1H NMR (300 MHz, DMSO-d6)
H(3)); 19F NMR (282 MHz, CDCl3)
d
ꢁ151.37 (t, 1F, J¼18.8 Hz),
ꢁ154.59 (d, 1F, J¼20.8 Hz), ꢁ163.25 (d, 1F, J¼16.3 Hz); FTIR (Nujol)
3113, 1585 cmꢁ1. GC–MS (m/z): 216 (Mþ, 100%). Anal. Calcd for
C9H7F3N2O: C, 50.01; H, 3.26; N, 12.96. Found: C, 49.80; H, 3.40; N,
12.90.
d
2.80 (s, 6H, N(CH3)2), 4.01 (s, 3H, N(2)CH3), 6.70 (dd, 1H, J1¼7.5 Hz,
J2¼9.0 Hz, H(5)), 6.96 (d,1H, J¼9.0 Hz, H(4)), 7.25–7.29 (m, 3H, ArH),
7.36–7.39 (m, 2H, ArH), 8.68 (s,1H, NH, exch. with D2O),10.67 (s,1H,
OH, exch. with D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ151.37 (br s, 1F);
4.8. Reaction of pentafluorobenzaldehyde 18 with methanol.
General procedure
FTIR (Nujol) 3451, 3294, 1639, 1618 cmꢁ1. GC–MS (m/z): 327 (Mþ,
4%), 311 (Mþꢁ16, 31%), 104 (100%). Anal. Calcd for C17H16F N5O: C,
62.37; H, 5.54; N, 21.39. Found: C, 62.40; H, 5.60; N, 21.30.
Pentafluorobenzaldehyde 18 (980 mg, 5 mmol) was added to
a solution of t-BuOK (616 mg, 5.5 mmol) in methanol (20 mL). After
1 h at rt, the solvent was removed. Chromatography of the residue
(from ethyl acetate/petroleum ether 1:50) gave 2,3,5,6-tetrafluoro-
4-methoxy-benzaldehyde 19. Yield: 60%; oil; Rf¼0.80 (silica gel, ethyl
4.6. Hydrolysis of fluorinated N-indazolyl-N0-hydroxy-
benzamidines 9a and 10a. General procedure
To a mixture of 9a or 10a (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 (50 mL), neutralized by the addition of solid NaHCO3, and
extracted with EtOAc (200 mL). The organic layer was dried over
Na2SO4 and evaporated. Crystallization of the residue from H2O/
EtOH (1:1) gave the corresponding fluorinated 3-aminoindazoles
16 or 21, respectively.
acetate/petroleum ether 1:50); 1H NMR (300 MHz, CDCl3)
d 4.21–
4.23 (m, 3H, OCH3), 10.20 (s, 1H, C(O)H); 19F NMR (282 MHz, CDCl3)
d
ꢁ149.21 (d, 2F, J¼15.0 Hz), ꢁ161.10 (d, 2F, J¼15.0 Hz); FTIR (Nujol)
1700 cmꢁ1. GC–MS (m/z): 208 (Mþ, 100%). Anal. Calcd for C8H4F4O2:
C, 46.17; H, 1.94. Found: C, 46.20; H, 2.00.
4.9. Reaction of 2,3,5,6-tetrafluoro-4-methoxy-benzaldehyde
19 with methylhydrazine
4.6.1. 3-Amino-4,5,7-trifluoro-6-methoxy-1-methyl-1H-indazole 16
To a solution of 19 (300 mg, 1.44 mmol) in THF (10 mL) an excess
of methylhydrazine (80 mL, 1.5 mmol) was added. After stirring for
5 h at rt, the solvent was removed, and the residue was tritured
with petroleum ether and filtered, giving methylhydrazone 20. E-
Methylhydrazone of 2,3,5,6-Tetrafluoro-4-methoxy-benzaldehyde 20.
Yield: 76%. Mp 103–105 ꢀC (EtOH); 1H NMR (300 MHz, DMSO-d6)
Yield: 84%. Mp 137–139 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
3.83
(s, 3H, OCH3), 4.05 (s, 3H, N(1)CH3), 5.50 (s, 2H, NH2, exch. with
D2O); 19F NMR (282 MHz, CDCl3)
d
ꢁ155.46 (t, 1F, J¼19.7 Hz),
ꢁ161.13 (d, 1F, J¼20.1 Hz), ꢁ167.79 (d, 1F, J¼19.5 Hz); FTIR (Nujol)
3450, 3299, 3202, 1666, 1654, 1629 cmꢁ1. GC–MS (m/z): 231 (Mþ,

126
A. Palumbo Piccionello et al. / Tetrahedron 65 (2009) 119–127
d
2.89 (s, 3H, NHCH3), 4.08 (s, 3H, OCH3), 7.20 (s, 1H, C(N)H), 8.24 (s,
1H, NHCH3, exch. with D2O); 19F NMR (282 MHz, CDCl3)
ꢁ149.59
(d, 2F, J¼16.9 Hz), ꢁ162.31 (d, 2F, J¼16.9 Hz); FTIR (Nujol) 3342,
1653 cmꢁ1 GC–MS (m/z): 236 (Mþ, 100%). Anal. Calcd for
4.14. Reaction of oxadiazole 3a with methylhydrazine in DMF
d
To a mixture of oxadiazole 3a (150 mg, 0.48 mmol) in dry DMF
(2 mL), methylhydrazine (1 equiv) was added. After stirring for
1 h at rt, the mixture was diluted with water (30 mL) and
extracted with EtOAc (200 mL). The organic layer was dried over
Na2SO4 and evaporated. Chromatography of the residue gave re-
covered oxadiazole 3a (20 mg, 13%, from ethyl acetate/petroleum
ether 1:20), 5-[2,3,5,6-tetrafluoro-4-(N-methylhydrazino)-phe-
nyl]-3-phenyl-1,2,4-oxadiazole 29 (100 mg, from ethyl acetate/
petroleum ether 1:5), and an unresolvable mixture of 29 and
5-[2,3,5,6-tetrafluoro-4-(N0-methyl-hydrazino)-phenyl]-3-phenyl-
1,2,4-oxadiazole 30 (36 mg, from ethyl acetate/petroleum ether
1:5). Mixture composition was determined by means of 1H NMR
from integration of –N(NH2)CH3 methyl signal at 3.29 ppm for 29
and –NHNHCH3 methyl signal at 2.64 ppm for 30, giving a 29/30
ratio 69:31.
.
C9H8F4N2O: C, 45.77; H, 3.41; N, 11.86. Found: C, 45.80; H, 3.40; N,
11.90.
4.10. Reaction of 2,3,5,6-tetrafluoro-4-methoxy-benzaldehyde
19 with hydrazine
To a solution 19 (570 mg, 2.75 mmol) in THF (10 mL) an excess of
hydrazine (3 mL) was added. The mixture was then heated to reflux
for 4 h. After removal of the solvent, the residue was treated with
water (30 mL) and extracted with EtOAc (150 mL). The organic layer
was dried over Na2SO4 and evaporated. Chromatography of the
residue (from ethyl acetate/petroleum ether 1:1) gave fluorinated
indazole 23.
4.10.1. 4,5,7-Trifluoro-6-methoxy-1H-indazole 23
4.14.1. 5-[2,3,5,6-Tetrafluoro-4-(N-methyl-hydrazino)-phenyl]-3-
phenyl-1,2,4-oxadiazole 29
Yield: 19%. Mp 181–182 ꢀC (EtOH); Rf¼0.65 (silica gel, ethyl ac-
etate/petroleum ether 1:1); 1H NMR (300 MHz, CDCl3)
d
4.12 (s, 3H,
Total yield: 74%. Mp 140–143 ꢀC (EtOH); Rf¼0.45 (silica gel, ethyl
OCH3), 8.16 (d, 1H, J¼3.3 Hz, H(3)); 19F NMR (282 MHz, CDCl3)
acetate/petroleum ether 1:5); 1H NMR (300 MHz, DMSO-d6)
d 3.29
d
ꢁ155.94 (t, 1F, J¼19.2 Hz), ꢁ156.84 (d, 1F, J¼21.1 Hz), ꢁ163.59 (d,
(t, 3H, N(NH2)CH3, J¼3.0 Hz), 5.12 (s, 2H, NH2, exch. with D2O), 7.65–
1F, J¼17.7 Hz); FTIR (Nujol) 3124, 3089, 3041 cmꢁ1. GC–MS (m/z):
202 (Mþ, 100%). Anal. Calcd for C8H5F3N2O: C, 47.54; H, 2.49; N,
13.86. Found: C, 47.50; H, 2.60; N, 13.80.
7.71 (m, 3H, ArH), 8.11–8.13 (m, 2H, ArH); FTIR (Nujol) 3380, 3289,
1646 cmꢁ1 GC–MS (m/z): 338 (Mþ, 100%). Anal. Calcd for
.
C15H10F4N4O: C, 53.26; H, 2.98; N, 16.56. Found: C, 53.40; H, 3.00; N,
16.40.
4.11. Synthesis of 4,5,7-trifluoro-6-methoxy-1-methyl-1H-
indazole 17
4.14.2. 5-[2,3,5,6-Tetrafluoro-4-(N0-methyl-hydrazino)-phenyl]-3-
phenyl-1,2,4-oxadiazole 30
A solution of 20 (100 mg, 0.424 mmol) in DMF/pyridine 1:1
mixture (4 mL) was heated to reflux for 5 h. The mixture was
treated with water (20 mL), neutralized with HCl 1 M, and extrac-
ted with EtOAc (100 mL). The organic layer was dried over Na2SO4
and evaporated. Chromatography of the residue (from ethyl ace-
tate/petroleum ether 1:5) gave fluorinated 1-methyl-1H-indazole
17 (20 mg, 22%).
Total yield: 6%; Rf¼0.40 (silica gel, ethyl acetate/petroleum ether
1:5); 1H NMR (300 MHz, DMSO-d6, data from 29þ30 mixture)
d
2.64 (d, 3H, NHNHCH3, J¼5.7 Hz), 5.08 (br q, 1H, NHNHCH3,
J¼5.7 Hz), 7.62–7.70 (m, 3H, ArH), 8.13–8.15 (m, 2H, ArH), 8.35 (br s,
1H, NHNHCH3, exch. with D2O).
Acknowledgements
4.12. Methylation of 4,5,7-trifluoro-6-methoxy-1H-
indazole 23
Financial support through the Italian MIUR and University of
Palermo is gratefully acknowledged.
To a solution of 23 (35 mg, 0.17 mmol) in EtOAc (5 mL), Me3OBF4
(33 mg, 0.22 mmol) was added. After 6 h at rt, the mixture was
diluted with EtOAc (50 mL), treated with saturated NaHCO3
(25 mL). The organic layer was recovered, dried over Na2SO4, and
evaporated. Chromatography of the residue (from ethyl acetate/
petroleum ether 1:5) gave fluorinated 2-methyl-2H-indazole 22
(23 mg, 64%).
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3-phenyl-1,2,4-oxadiazole 28
Yield: 85%. Mp 94–96 ꢀC (EtOH); 1H NMR (300 MHz, DMSO-d6)
d
3.10–3.14 (m, 3H, NHCH3), 4.16 (s, 3H, OCH3), 7.46 (s, 1H, NHCH3,
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F
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ꢁ141.60 (m, 1F), ꢁ145.53 (m, 1F), ꢁ161.43
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