Synthesis of polyfluorinated arylhydrazines, arylhydrazones and 3-methyl-1-aryl-1H-indazoles

Article abstract of DOI:10.1016/j.jfluchem.2018.06.011

Polyfluorinated arylhydrazones were synthesized starting from 1-(4-amino-tetrafluorophenyl)ethanone and polyfluorinated arylhydrazines by action of p-toluenesulfonic acid in good yields. The resulting mixtures of E- and Z-isomers were next treated with K₂CO₃ in MeCN at room temperature. Under these mild reaction conditions Z-isomers underwent intramolecular nucleophilic cyclization to form 3-methyl-1-aryl-1H-indazole derivatives, while E-isomers were not active and were isolated unchanged. Molecular and crystal structures of prepared polyfluorinated (E)-arylhydrazones as well as selected 3-methyl-1-aryl-1H-indazoles were solved by the X-ray diffraction analysis. Meanwhile, the polyfluorinated acetophenone reacted with hydrazine in THF in the absence of a catalyst through a condensation–nucleophilic substitution cascade process to form a 3-methyl-1H-indazole derivative in excellent yield.

Full text of DOI:10.1016/j.jfluchem.2018.06.011

Accepted Manuscript
Title: Synthesis of polyfluorinated arylhydrazines, hydrazones
and 3-methyl-1-aryl-1H-indazoles
Authors: Larisa Politanskaya, Irina Bagryanskaya, Evgeny
Tretyakov
PII:
S0022-1139(18)30205-7
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.06.011
FLUOR 9189
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
15-5-2018
27-6-2018
29-6-2018
Please cite this article as: Politanskaya L, Bagryanskaya I, Tretyakov E, Synthesis of
polyfluorinated arylhydrazines, hydrazones and 3-methyl-1-aryl-1H-indazoles, Journal
of Fluorine Chemistry (2018), https://doi.org/10.1016/j.jfluchem.2018.06.011
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Synthesis of polyfluorinated arylhydrazines, hydrazones and 3-
methyl-1-aryl-1H-indazoles

Larisa Politanskaya , Irina Bagryanskaya, Evgeny Tretyakov
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of Russian
Academy of Sciences, 9 Ac. Lavrentiev Ave., Novosibirsk 630090, Russian Federation
Novosibirsk State University, 2 Pirogova Str., Novosibirsk 630090, Russian Federation

Corresponding author. Tel.: +7-383-330-6859; fax: +7-383-330-9752; e-mail: plv@nioch.nsc.ru
Graphical abstract
Highlights



Directed synthesis of polyfluorinated 3-methyl-1-aryl-1H-indazole derivatives
p-TSA-promoted condensation of p-aminoacetophenone and arylhydrazines
Selective intramolecular nucleophilic cyclization of polyfluorinated (Z)-arylhydrazones
Abstract Polyfluorinated arylhydrazones were synthesized starting from 1-(4-amino-
tetrafluorophenyl)ethanone and polyfluorinated arylhydrazines by action of p-toluenesulfonic
acid in good yields. The resulting mixtures of E- and Z-isomers were next treated with K
2
CO in
3
MeCN at room temperature. Under these mild reaction conditions Z-isomers underwent
intramolecular nucleophilic cyclization to form 3-methyl-1-aryl-1H-indazole derivatives, while
E-isomers were not active and were isolated unchanged. Molecular and crystal structures of
prepared polyfluorinated (E)-arylhydrazones as well as selected 3-methyl-1-aryl-1H-indazoles
were solved by the X-ray diffraction analysis. Meanwhile, the polyfluorinated acetophenone
reacted with hydrazine in THF in the absence of a catalyst through a condensation–nucleophilic
substitution cascade process to form a 3-methyl-1H-indazole derivative in excellent yield.
Keywords polyfluorinated arylhydrazines, p-TSA-induced condensation, C-F activation,
polyfluorinated azaheterocycles, 1H-indazole derivatives, (E)-arylhydrazones
1
. Introduction
Indazoles are an important class of heterocyclic compounds having a wide range of
biological and pharmaceutical applications [1]. There is enormous potential in the synthesis of
novel heterocyclic systems to be used as building blocks for the next generation of
pharmaceuticals as antibacterial, antidepressant and anti-inflammatory [1]. Besides some

indazole derivatives are able to exhibit hypotensive and bradycardic [2], anticancer [3], anti-HIV
4], antifungal [5], antispermatogenic [6] activities or selective NOS [7] or factor Xa [8]
inhibitory properties.
A broad variety of biological activities of indazole derivatives inspires the developments of
[
new approaches to their synthesis as well as optimizations of known methods for the preparation
of the indazole ring system [1,9–11]. The most widely employed method for the construction of
1
-R-1H-indazoles involves the condensation–nucleophilic substitution cascade or two step
reaction of 2-haloarylcarbonylic compounds with hydrazine [2,7,12–14] or arylhydrzines [8,15–
1], respectively.
It is known that the introduction of a fluorine atom into biologically active compounds
2
alter their supramolecular structure [14] and pharmacological properties. These changes may be
ascribed to changes in pKa, lipophilicity, conformation, chemical-metabolic stability or the
propensity to participate in intermolecular interactions [2].
For this reason, an important task is the synthesis of a series of structurally diverse 1-aryl-
1
H-indazoles, containing fluorine atoms in both aromatic moieties to further investigate their
biological properties. In this work we studied the interaction of 1-(4-amino-2,3,5,6-
tetrafluorophenyl)ethanone, obtained via p-toluenesulfonic acid (p-TSA) induced transformation
of p-trimethylsilylethynylaniline [22], with a series of polyfluorinated arylhydrazines as well as
hydrazine.
Results and Discussion
First, a representative series of fluorinated arylhydrazines (2a–e) were prepared via the
aromatic nucleophilic substitution of a fluorine atom in haloarenes 1 (Scheme 1).
Scheme 1. Synthesis of arylhydrazines 2.
The reactions were carried out in boiling alcohol and were terminated after disappearance
of F NMR signals belonging to the starting compounds in reaction mass test portion. The
1
9
substitution of the fluorine atom took place most easily in substrates 1d and 1e activated to the
N
S Ar-reaction. Less active haloarenes 1b,c were also successfully transformed in arylhydrazines
2
, but more than 10 h were required for complete conversion. The data on optimized
experimental conditions and the yields of the products formed are summarized in Scheme 1.
Target compounds 2 were isolated by precipitation via dilution of the reaction mass with water.

After that, polyfluorinated arylhydrazines 2 were reacted with 1-(4-amino-
tetrafluorophenyl)ethanone (3) in the presence of p-TSA and anhydrous MgSO in boiling
4
toluene medium. Previously, these reaction conditions were successfully used for effective
condensation of polyfluorinated 2-aminoacetophenones with trifluorobenzaldehyde to form the
quinolone core [23]. As shown in Table 1, in all cases, the condensation reactions between 2 and
3
were successfully carried out to produce polifluorinated arylhydrazones 4a–e in an almost
quantitative yield. The presence of a strong electron withdrawing group in the structure of
arylhydrazine 2d and 2e deactivates them to the condensation reaction with 3, and as a result, the
reaction time required to complete the process increases (Table 1, entries 4, 5).
Table 1. Synthesis of polifluorinated arylhydrazones 4.
Entry Arylhydrazine 2 t (h) Product 4
1 3
Yield (%)
94
2
5
96
3
5
94

4
20
88
5
23
95
1
9
On the basis of analysis of the F NMR spectra of the reaction product, it was found that
arylhydrazones 4 were formed as mixtures of E- and Z-isomers (4-E and 4-Z respectively) in
approximately equal proportions. To our disenchantment, attempts to separate them by the thin-
layer chromatography (TLC) method were not successful. Thus, in the case of 4d, only small
quantities of individual Z-isomer (4d-Z) was separated from the mixture, in an amount sufficient
for his analytical characterization (5%). In this regard, further study of the cyclization reaction 4
leading to 3-methyl-1-aryl-1H-indazole (5) was carried out with mixtures of E- and Z-isomers.
Arylhydrazone 4d served as the model substrate to select appropriate reaction conditions for the
ring closure process (Table 2).
Table 2. Optimization of reaction conditions for cyclization of 4d in 5d.
a
Entry Solvent Base
T, °C
t, h Yield , %
b
1
2
3
4
5
6
7
8
THF
–
67 (reflux)
r.t.
3
n.r.
n.r.
n.r.
n.d.
n.r.
n.d.
n.d.
THF
K
2
2
CO
3
3
60
THF
K
CO
67 (reflux) 10
c
THF
DBU
Et NF×H
DBU
67 (reflux)
50
1
MeCN
MeCN
DMF
DMF
4
2
O
24
1
82 (reflux)
100
K
2
CO
3
3
d
K
2
CO
3
r.t.
60
35

9
1
MeCN
MeCN
K
2
2
CO
3
3
r.t.
90
24
43
0
K
CO
+ CuI (1 eq) r.t.
n.d.
a
Isolated yield of 5, compounds 4 were not isolated.
No reactions, 4d remain intact.
No desired product
5
b
c
d
f
Given that substrates 4 are polyfluorinated compounds, activated to S Ar-reaction, we
N
initially attempted to synthesize 3-methyl-1-aryl-1H-indazole by refluxing of 4d in THF in the
absence of any catalyst (Table 2, entry 1). Nonetheless, these conditions, as well as stirring of
substrate solution in the presence of K
the desired product: arylhydrazone 4d remained unchanged (Table 2, entries 2, 3). The use of
Et NF monohydrate as a base in a solution of MeCN at 50 °C also did not lead to the
2
CO at room temperature (r.t.) or refluxing did not give
3
4
heterocyclization either (Table 2, entry 5). Interaction of 4d with DBU in boiling THF or MeCN
gave rise to a complex mixture of products that did not contain desired cyclization products
(Table 2, entries 4, 6).
An attempt to conduct the intramolecular C-N bond-forming cyclizations of 4d under the
conditions described in ref. [18] (K
2
CO /DMF/100 °C) resulted in the totally gumming of the
3
reaction mixture (Table 2, entry 7). A decreasing in the temperature of this reaction allowed us to
obtain 3-methyl-1-aryl-1H-indazole 5f, containing a modified amino group due to its
condensation with molecule DMF (Table 2, entry 8). Replacement of this solvent by MeCN at
19
r.t. enabled us to obtain the desired compound 5d, however, based on the F NMR data of the
reaction mass, only Z-isomer (4d-Z) participated in the cyclization, despite the long reaction
duration (Table 2, entry 9). To increase the yield of target product 5d, CuI was applied to the
intramolecular amination of 4d as catalyst [16,19]; however, this additive induced side reactions
(
Table 2, entry 10). Accordingly, the only acceptable result with 43% yield was obtained under
the reaction condition with K CO (2 eq) at r.t. in anhydrous MeCN.
2
3
After the reaction conditions have been established, polyfluorinated hydrazones 4a–e were
subjected to the cyclization to investigate the reaction scope and synthesize various 3-methyl-1-
1
9
aryl-1H-indazole derivatives. The reactions were terminated after disappearance of F NMR
signals belonging to 4-Z (the required reaction time was approximately 120 h). Compounds 4-E
and 5 were separated by TLC and completely characterized; the results are summarized in Table
3
.
Table 3. Synthesis of polyfluorinated 3-methyl-1-aryl-1H-indazole derivatives 5.
Entry Arylhydrazone 4 Arylhydrazone 4-E
Yield of 3-Methyl-1-aryl-1H-
-E (%) indazole 5
Yield of
5 (%)
4

1
4a
42
35
2
4b
44
45
3
4
5
4c
4d
4e
45
40
41
38
45
47
Thus, under these mild conditions, Z-isomers 4-Z were selectively transformed via
intramolecular nucleophilic substitution of a fluorine atom, thus giving polyfluorinated 3-methyl-
-aryl-1H-indazole derivatives 5 in good yields, whereas E-isomers 4-E were not active and
1
were isolated unchanged. In this regard, this reaction can be considered a method for obtaining
pure polyfluorinated (E)-arylhydrazones.

In addition we evaluated the possibility of synthesis of polyfluorinated 3-methyl-1H-
indazole 6 directly from aminoacetophenone 3 and hydrazine hydrate in one step, in the absence
of catalyst and THF as a solvent. Fortunately, desired product 6 formed in a good yield (88%;
Scheme 2).
Scheme 2. Synthesis of 4,5,7-trifluoro-3-methyl-1H-indazol-6-amine 6.
1
19
13
The structures of all new products were confirmed by H, F, C NMR; infrared (IR)
spectroscopy; and high-resolution mass spectrometry (HRMS). The molecular and crystal
structures of 4(a–e)–E and 5b,e were solved by X-ray crystallography (Fig. 1 and 2).
4
a-E
4b-E
4c-E
4
d-E
4e-E
Fig. 1. Molecular structures of polyfluorinated (E)-arylhydrazones 4(a–e)–E.
Molecular structures of compounds 4(a–e)–E and 5b,e as well as comments on packing of
all compounds are given as Supplementary Materials. The main tendency in crystal packing is

forming π-stacks as result of polyfluoroarene-polyfluoroarene interactions and H-bonds of N–
H…N, N–H…F and C–H…F types.
5
b
5e
Fig. 2. Molecular structures of polyfluorinated 3-methyl-1-aryl-1H-indazoles 5b,e.
The indazoles 5b and 5e are packed in monoclinic, P2
group, respectively. The asymmetric unit of 5b includes three independent molecules. Two of
them are bounded by H-bond between NH group and N atom of the indazole ring as well as C–
1
/c, and rhombohedral, R-3, space
2
F…π, and π…π interactions. Orientation of the polyfluorophenyl substituent in 5b is described
by torsion angles C8N1C10C15 equal to –55.1, 55.6, and 79.5°. In compound 5e, the
halogenated phenyl group is almost perpendicular to the plane of the indazole ring; the torsion
angle C8N1C10C15 is equal to 85.4°.
3
. Conclusion
In summary, we described a simple and efficient protocol for the synthesis of
polyfluorinated arylhydrazines, arylhydrazones, and 3-methyl-1-aryl-1H-indazoles: biologically
important aza-heterocyclic scaffolds. It was shown that Z-isomers of arylhydrazones (obtained
from 4-amino-tetrafluoracetophenone) undergo intramolecular cyclization in presence of K
2
CO
3
in MeCN at r.t. to produce 3-methyl-1-aryl-1H-indazoles in good yields. This method is
applicable to a variety of substrates and is compatible with an amino group: an easily modifiable
substituent. At the same time, E-isomers remain unchanged and can be isolated as individual
compounds in good yields too.
4
. Experimental section
4
.1 General
All solvents were purified using standard procedures. Toluene was kept over CaH before
2
use. The starting 1-(4-amino-tetrafluorophenyl)ethanone (3) was synthesized according to
previously described methods [22]. Other chemicals were obtained from commercial sources and
were used without further purification. Preparative TLC was performed on Merck precoated
silica gel 60 PF254 containing gypsum. Visualization of the developed chromatograms was

performed by UV light. To obtain analytically pure samples, the solid synthesized compounds
were crystallized from hexane.
1
NMR spectra were recorded on a Bruker Avance-300 (300.13 MHz for H and 282.37
1
9
1
13
MHz for F), Avance-400 (400.13 MHz for H and 100.62 MHz for C), and DRX-500 (500.13
1
13
MHz for H, 125.76 MHz for C) spectrometers. CDCl
with residual CHCl (δ = 7.26) or CDCl (δ = 77.0) and acetone (δ
28.6 and 205.0) being employed as internal standards. C (δ = 163.0) was used as external
3
and acetone-d
6
were used as solvents,
3
H
3
C
H
= 2.15) or acetone-d
6
(δ
C
=
6
F
6
F
1
9
13
reference for recording the F NMR spectra. C NMR spectra were recorded with C–H spin
decoupling. Masses of molecular ions were determined by HRMS on a DFS Thermo scientific
instrument (EI, 70 eV), or by Hybrid Quadrupole Time of Flight mass spectrometer (microTOF-
Q, Bruker) equipped with Atmospheric Pressure Electrostatic Spray Ionization (API-ES).
Melting points were recorded on a Mettler-Toledo FP81 Thermosystem apparatus. The IR
spectra were recorded on a Bruker Vector 22 spectrometer (KBr or thin film).
The structures of all new polyfluorinated compounds 2–6 prepared here were
1
9
1
13
corroborated by their F, H and C NMR, high-resolution mass spectrometry, and IR-
spectroscopy data (see Supplementary data). Signals in the NMR spectra of 2–6 were assigned
on the basis of spin coupling constants, which are typical for polyfluorinated benzenes [22 – 26].
4
4
.2. Synthetic procedures
.2.1. Arylhydrazines 2a–e; General Procedure
To a solution of halogenbenzene 1 (50 mmol) in EtOH (30 mL) was added hydrazine
monohydrate (5.0 g, 0.1 mol). The reaction mixture was refluxed for 1÷20 h (see Scheme 1),
cooled to r.t., poured into H O (100 mL) and kept at 5 °C for 3 h. The precipitate was filtered
and recrystallized from hexane.
2
4
.2.1.1. (2,3,5,6-Tetrafluorophenyl)hydrazine (2a)
White solid; yield: 7.2 g (80%); mp 87.3–88.5 °C (lit value [27a], m.p. 87–88 °C). IR (KBr):
3
1
6
346, 3250, 3172, 3099, 1655, 1635, 1533, 1487, 1470, 1394, 1381, 1315, 1263, 1169, 1146,
–
1 1
086, 980, 910, 852, 818, 731, 712, 688, 600, 486, 449 cm . H NMR (300 MHz, CDCl
.54 (m, J (H ,F ) = 10.0 Hz, J (H ,F ) = 7.2 Hz, 1 H, H ), 5.33 (s, 1 H, NH), 3.98 (s, 2 H, NH
3
): δ =
4
3
4
2
4
2
).
1
3
1
3
3
2
3
2
3
C NMR (126 MHz, CDCl ): δ = 146.1 (dm, J (C ,F ) = 245.7 Hz, J (C ,F ) = 12.4 Hz, C ),
3
1
2
2
2
2
3
2
2
1
2
1
1
9
37.4 (dm, J (C ,F ) = 240.9 Hz, J (C ,F ) = 16.3 Hz, C ), 130.8 (tm, J (C ,F ) = 9.6 Hz, C ),
6.2 (t, J (C ,F ) = 23.2 Hz, C ). F NMR (282 MHz, CDCl ): δ = –141.7 (m, J (F ,F ) = 22.4
2
4
3
4
19
3
2
3
3
4
3
2
3
2
4
2
Hz, J (F ,H ) = 10.0 Hz, 2 F, F ), –160.2 (m, J (F ,F ) = 22.4 Hz, J (F ,H ) = 7.2 Hz, 2 F, F ).
HRMS (EI): m/z [M] calcd for C
+
6
H
4
F
4
2
N : 180.0305; found: 180.0308. Anal. Calcd for
C
6
H
4
F
4
2
N : C, 40.01; H, 2.24; N, 15.55. Found: C, 39.75; H, 2.25; N, 15.38.
4
.2.1.2. (Perfluorophenyl)hydrazine (2b)
White solid; yield: 6.8 g (69%); mp 73.9–75.0 °C (lit value [27a], m.p. 76.0–77.5 °C). IR (KBr):
3
7
NH
346, 3255, 3169, 3122, 1655, 1630, 1529, 1483, 1319, 1271, 1134, 1030, 1012, 993, 943, 847,
–
1 1
81, 602, 563, 482, 457 cm . H NMR (300 MHz, CDCl ): δ = 5.12 (s, 1 H, NH), 3.93 (s, 2 H,
3
1
3
1
2
2
2
1
2
). C NMR (126 MHz, CDCl ): δ = 138.3 (dm, J (C ,F ) = 243.4 Hz, C ), 137.8 (dm, J
3
3
3
3
1
4
4
2
4
3
4
2
(
(
C ,F ) = 250.0 Hz, C ), 135.4 (dt, J (C ,F ) = 247.6 Hz, J (C ,F ) = 13.9 Hz, C ), 126.0 (td, J
C ,F ) = 10.9 Hz, C ). F NMR (282 MHz, CDCl ): δ = –159.3 (dm, J (F ,F ) = 22 Hz, J (F ,F )
1
2
1
19
3
2
3
4
3

2
3
2
3
4
3
4
3
=
=
4.8 Hz, 2 F, F ), –164.7 (m, J (F ,F ) = 22 Hz, J (F ,F ) = 21.6 Hz, 2 F, F ), –168.2 (tt, J (F ,F )
4
2
3
+
21.6 Hz, J (F ,F ) = 4.8 Hz, 1 F, F ). HRMS (EI): m/z [M] calcd for C
6
H
3
F
5
2
N : 198.0210;
found: 198.0208.
4
.2.1.3. (4-Bromo-2,3,5,6-tetrafluorophenyl)hydrazine (2c)
White solid; yield: 9.3 g (72%); mp 76.9–77.3 °C (lit value [27b], m.p. 79–80 °C). IR (KBr):
3
7
371, 3261, 3144, 3030, 1639, 1622, 1512, 1481, 1354, 1300, 1165, 1138, 1095, 989, 928, 791,
–
1
1
13
46, 590, 492 cm . H NMR (300 MHz, CDCl
3
): δ 5.38 (s, 1 H, NH), 3.98 (s, 2 H, NH ). C
2
1
3
3
2
3
2
3
NMR (126 MHz, CDCl ): δ = 145.0 (ddt, J (C ,F ) = 245.3 Hz, J (C ,F ) = 13.8 Hz, C ), 137.7
3
1
2
2
2
2
3
2
2
1
2
1
(
(
ddt, J (C ,F ) = 243.5 Hz, J (C ,F ) = 16.2 Hz, C ), 129.7 (tm, J (C ,F ) = 10.4 Hz, C ), 88.7
t, J (C ,F ) = 23.0 Hz, C ). F NMR (282 MHz, CDCl
2
4
3
4
19
3
2
3
): δ = –136.3 (dm, J (F ,F ) = 22 Hz, 2
3
2
3
2
+
F, F ), –158.4 (dm, J (F ,F ) = 22 Hz, 2 F, F ). HRMS (EI): m/z [M] calcd for C
6
H
3
F
4
BrN :
2
2
2
57.9410; found: 257.9411. Anal. Calcd for C
7.80; H, 1.21; N, 10.90.
6
H
3
F
4
BrN : C, 27.82; H, 1.17; N, 10.82. Found: C,
2
4
.2.1.4. (2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)hydrazine (2d)
White solid; yield: 11.6 g (94%); mp 76.0–78.2 °C (lit value [27c], m.p. 84 °C). IR (KBr): 3365,
3
7
4
269, 1662, 1620, 1512, 1471, 1421, 1392, 1338, 1302, 1232, 1188, 1146, 1090, 991, 935, 818,
–
1 1
79, 742, 712, 685, 596, 492, 453, 434 cm . H NMR (400 MHz, CDCl ): δ = 5.61 (s, 1 H, NH),
3
1
3
1
3
3
3
.05 (s, 2 H, NH
2
). C NMR (126 MHz, CDCl ): δ = 144.6 (dm, J (C ,F ) = 258 Hz, C ), 136.3
3
1
2
2
2
2
3
2
2
1
2
1
(
(
ddt, J (C ,F ) = 242.0 Hz, J (C ,F ) = 15.7 Hz, C ), 133.4 (tm, J (C ,F ) = 8.7 Hz, C ), 121.1
qm, J (CF
1
2
4
4
19
3
,F) = 273.0 Hz, CF
3
), 98.4 (m, J (C ,CF ) = 35 Hz, C ). F NMR (282 MHz,
3
2
2
3
2
CDCl
3
): δ = –53.9 (t, J (CF
3
,F ) = 21.1 Hz, 3 F, CF
3
), –144.1 (m, J (F ,F ) ≈ J (F ,CF
3
) = 21 Hz,
2
3
2
3
+
2
2
3
F, F ), –155.2 (dm, J (F ,F ) ≈ 21 Hz, 2 F, F ). HRMS (EI): m/z [M] calcd for C
7
H
3
F
7
2
N :
48.0179; found: 248.0178. Anal. Calcd for C
7
H
3
F
7
2
N : C, 33.89; H, 1.22; N, 11.29. Found: C,
3.97; H, 1.25; N, 11.12.
4
.2.1.5. (2,4,6-Trichloro-3,5-difluorophenyl)hydrazine (2e)
White solid; yield: 12.1 g (98%); mp 121.6 °C (dec.) (lit value [27d], m.p. 121–122 °C). IR
(
1
KBr): 3361, 3261, 3192, 2926, 1593, 1581, 1495, 1435, 1419, 1365, 1294, 1254, 1132, 1080,
–
1 1
068, 955, 847, 771, 739, 706, 667, 582, 457, 420 cm . H NMR (300 MHz, CDCl
3
): δ = 5.73
1
3
1
3
3
(s, 1 H, NH), 3.99 (s, 2 H, NH
2
). C NMR (100 MHz, CDCl
3
): δ = 153.6 (dd, J (C ,F ) = 248.6
3
1
2
2
3
2
2
4
3
4
Hz, C ), 140.1 (s, C ), 109.2 (dm, J (C ,F ) = 20.8 Hz, C ), 104.3 (t, J (C ,F ) = 22.6 Hz, C ).
1
9
3
+
F NMR (282 MHz, CDCl
Cl : 245.9324; found: 245.9326. Anal. Calcd for C
Found: C, 29.16; H, 1.25.
3
): δ = –113.3 (s, 2 F, F ). HRMS (EI): m/z [M] calcd for
C
6
H
3
F
2
3
N
2
6
H
3
F
2
Cl : C, 29.12; H, 1.22.
3
N
2
4
.2.2. Arylhydrazones 4a–e; General Procedure
To a solution of 3 (0.35 g, 1.7 mmol) in toluene (10 mL), 2 (2.5 mmol), p-TSA
monohydrate (0.32 g, 1.7 mmol), and MgSO (0.61 g, 5.1 mmol) were added, and the mixture
4
was heated at reflux for 3–23 h (see Table 1) with stirring. The mixture was allowed to cool to
r.t., placed directly onto a chromatography plate (silica gel), and air-dried. Arylhydrazones 4 (as
a racemic mixture) were isolated by TLC with EtOAc/hexane (1:7) as an eluent (R
f
≈ 0.5) in 88–
9
6% yields (see Table 1).

4
(
.2.2.1. (Z)-2,3,5,6-Tetrafluoro-4-(1-(2-(2,3,5,6-tetrafluoro-4-
trifluoromethyl)phenyl)hydrazono)ethyl)aniline (4d-Z)
Yellowish oil; yield: 34 mg (5%); Rf = 0.58 (EtOAc/hexane, 1:10, twice). IR (thin): 3500, 3358,
3
1
213, 1664, 1620, 1525, 1508, 1497, 1450, 1427, 1340, 1248, 1228, 1178, 1146, 1097, 1078,
–
1 1
026, 970, 931, 901, 879, 789, 737, 715, 696, 656 cm . H NMR (500 MHz, CDCl
3
): δ = 7.23
1
3
(s, 1 H, NH), 4.30 (s, 2 H, NH
2
), 2.30 (s, 3 H, CH
3
). C NMR (100 MHz, CDCl
3
): δ = 145.0
1
12 12
12
1
4
4
4
3
1
(dm, J (C ,F ) = 256 Hz, C ), 142.7 (dm, J (C ,F ) = 247 Hz, C ), 139.4 (s, C ), 136.6 (dm, J
1
1
11
1
5
5
11
5
2
6
5
6
10
(
C ,F ) ≈ J (C ,F ) ≈ 246 Hz, C + C ), 128.6 (tt, J (C ,F ) = 13.9 Hz, C ), 127.3 (m, C ),
1
14
2
13
13
2
3a
4
1
=
21.2 (qm, J (CF
3
,F) = 272.6 Hz, C ), 99.2 (m, J (C ,CF
3
) = 35 Hz, C ), 98.1 (m, J (C ,F )
3
a
9
19
12
21.0 Hz, C ), 24.0 (s, C ). F NMR (282 MHz, CDCl
3
): δ = –56.6 (t, J (CF
3
,F ) = 21.1 Hz, 3
4
5
4
12 11
12
F, CF
3
), –142.3 (dm, J (F ,F ) ≈ 22 Hz, 2 F, F ), –143.8 (m, J (F ,F ) ≈ J (F ,CF
3
) = 21 Hz, 2
1
2
11 12
11
5
4
5
F, F ), –157.6 (dm, J (F ,F ) ≈ 20 Hz, 2 F, F ), –161.1 (dm, J (F ,F ) ≈ 22 Hz, 2 F, F ). HRMS
+
(EI): m/z [M] calcd for C15
H
6
F
11
3
N : 437.0381; found: 437.0376.
4
.2.3. N,N-Dimethyl-N'-(4,5,7-trifluoro-3-methyl-1-(2,3,5,6-tetrafluoro-4-
(trifluoromethyl)phenyl)-1H-indazol-6-yl)formimidamide (5f)
To a solution of 4d (0.16 g, 0.36 mmol) in DMF (5 mL) calcined powder of K
2
CO (0.10
3
g, 0.72 mmol) was added. The reaction mixture was stirred at r.t. in a closed flask for 60 h, then
placed directly onto a chromatography plate (silica gel), and air-dried. The 1-aryl-1H-indazole 5f
was isolated by TLC with EtOAc/hexane as an eluent.
Yellowish solid; yield: 60 mg (35%); Rf = 0.61 (EtOAc/hexane, 1:10, twice); mp 100.9 °C(dec.).
IR (KBr): 3491, 3396, 3336, 3213, 2964, 2937, 2893, 1709, 1668, 1556, 1502, 1479, 1435, 1383,
–
1 1
1
354, 1282, 1142, 1097, 1011, 987, 945, 862, 793, 779, 715, 663, 629, 596 cm . H NMR (300
MHz, CDCl
3
): δ = 8.00 (s, 1 H, CH), 2.94 (s, 3 H, NCH
3
), 2.86 (s, 3 H, NCH’
3
), 2.64 (s, 3 H,
1
3
14
3
1
12 12
CH
3
). C NMR (126 MHz, CDCl
3
): δ = 162.6 (s, C ), 146.4 (t, C ), 144.5 (dm, J (C ,F ) =
2
12 11
12
1
11 11
11
1
2
62.4 Hz, J (C ,F ) = 19 Hz, C ), 143.4 (dm, J (C ,F ) = 256.2 Hz, C ), 140.0 (ddm, J
4
4
2
4
5
4
1
5
5
2
5
4
(
C ,F ) = 249.5 Hz, J (C ,F ) = 12.7 Hz,C ), 136.8 (ddm, J (C ,F ) = 239.0 Hz, J (C ,F ) =
5
1
7
7
7
8
2
6
5
2
1
4.9 Hz, C ), 131.3 (dm, J (C ,F ) = 234.2 Hz, C ), 128.5 (m, C ), 126.6 (tm, J (C ,F ) ≈ J
6
7
6
1
16 16
16
2
3a
4
(
C ,F ) = 16.2 Hz, C ), 121.0 (qm, J (C ,F ) = 272 Hz, C ), 107.2 (d, J (C ,F ) = 18.8 Hz,
3
a
13
15
15’
9
19
C ), 99.4 (m, C ), 36.5 (s, C ), 31.5 (s, C ), 13.5 (s, C ). F NMR (282 MHz, CDCl
3
): δ = –
1
2
12
11
5
7.4 (t, J (CF
3
,F ) = 21.9 Hz, 3 F, CF
3
), –141.1 (m, 2 F, F ), –145.4 (m, 2 F, F ), –152.4 (t, J
7
5
7
4
7
5
7
5
4
5
(
F ,F ) ≈ J (F ,F ) = 19.2 Hz, 1 F, F ), –162.7 (m, J (F ,F ) = 19.2 Hz, J (F ,F ) = 5 Hz, 1 F, F ),
4
7
4
5
4
+
–
C
163.1 (dm, J (F ,F ) = 19.7 Hz, J (F ,F ) = 5 Hz, 1 F, F ). HRMS (EI): m/z [M] calcd for
: 472.0740; found: 472.0735.
18
H
10
F
10
N
4
4
.2.4. 1-Aryl-1H-indazole 5 and arylhydrazone 4-E; General Procedure
To a solution of 4 (racemic mixture) (0.8 mmol) in MeCN (10 mL) calcined powder of
K
2
CO (0.22 g, 1.6 mmol) was added. The reaction mixture was stirred at r.t. in a closed flask for
3
1
1
20 h, then placed directly onto a chromatography plate (silica gel), and air-dried. The 1-aryl-
H-indazole 5 and arylhydrazone 4-E were isolated by TLC with EtOAc/hexane as an eluent.
4
.2.4.1. (E)-2,3,5,6-Tetrafluoro-4-(1-(2-(2,3,5,6-tetrafluorophenyl)hydrazono)ethyl)aniline (4a-
E)
White solid; yield: 124 mg (42%); Rf = 0.42 (EtOAc/hexane, 1:10, 5 times); mp 147.4 °C (dec.).
IR (KBr): 3496, 3398, 3361, 3203, 3101, 1655, 1635, 1525, 1508, 1495, 1462, 1425, 1325, 1269,
–
1 1
1
173, 1138, 1070, 1014, 937, 930, 862, 822, 750, 712, 808, 428 cm . H NMR (300 MHz,

1
3
12
13 11
13
CDCl ): δ = 7.17 (m, 1 H, NH), 6.63 (m, J (H ,F ) = 9.9 Hz, J (H ,F ) = 7.0 Hz, 1 H, H ),
3
1
3
1
12 12
4
=
2
.06 (s, 2 H, NH
2
), 2.24 (t, 3 H, CH
3
). C NMR (126 MHz, CDCl ): δ = 146.2 (dm, J (C ,F )
245.5 Hz, C ), 144.3 (dm, J (C ,F ) = 246.4 Hz, C ), 139.3 (s, C ), 137.5 (ddm, J (C ,F ) =
44.8 Hz, J (C ,F ) = 16.1 Hz, C ), 136.3 (ddm, J (C ,F ) = 238.9 Hz, J (C ,F ) = 16.6 Hz,
C ), 126.4 (tt, J (C ,F ) = 14.2 Hz, C ), 125.1 (m, C ), 106.6 (t, J (C ,F ) = 16.2 Hz, C ), 97.3
3
1
2
1
4
4
4
3
1
11 11
2
11 12
11
1
5
5
2
5
4
5
2
6
5
6
10
2
3a
4
3a
2
13 12
13
9
19
(
(
2
t, J (C ,F ) = 23.2 Hz, C ), 16.2 (s, C ). F NMR (282 MHz, CDCl ): δ = –141.2 (m, J
3
1
2
11
12 13
12
4
11 12
F ,F ) = 21 Hz, J (F ,H ) = 9.9 Hz, 2 F, F ), –146.4 (dm, 2 F, F ), –157.7 (dm, J (F ,F ) =
11
13
11
5
+
1 Hz, J (F ,H ) = 7 Hz, 2 F, F ), –163.4 (dm, 2 F, F ). HRMS (EI): m/z [M] calcd for
: 369.0507; found: 369.0498.
,5,7-Trifluoro-3-methyl-1-(2,3,5,6-tetrafluorophenyl)-1H-indazol-6-amine (5a)
C
14
H
7
F
8
N
3
4
White solid; yield: 98 mg (35%); Rf = 0.67 (EtOAc/hexane, 1:10, 5 times); mp 106.2–106.3 °C.
IR (KBr): 3491, 3350, 3209, 3090, 2935, 1674, 1643, 1620, 1554, 1514, 1502, 1477, 1396, 1356,
–
1 1
1
273, 1255, 1207, 1182, 1159, 1115, 1016, 939, 872, 856, 785, 712, 640, 444 cm . H NMR
1
3
12
13 11
13
(300 MHz, Acetone-d
6
): δ = 7.78 (m, J (H ,F ) = 10.4 Hz, J (H ,F ) = 7.4 Hz, 1 H, H ), 5.46
1
3
1
11 11
(s, 2 H, NH
2
), 2.57 (s, 3 H, CH
3
). C NMR (126 MHz, Acetone-d ): δ = 146.8 (dm, J (C ,F )
6
1
1
3
1
12 12
2
12 11
12
=
1
(
≈
247.0 Hz, C ), 145.6 (s, C ), 144.2 (ddm, J (C ,F ) = 251.7 Hz, J (C ,F ) = 15 Hz, C ),
1
4
4
2
4
5
4
1
5
5
2
40.6 (ddd, J (C ,F ) = 246.3 Hz, J (C ,F ) = 12.2 Hz, C ), 137.3 (ddd, J (C ,F ) = 237.4 Hz, J
5
4
5
1
7
7
7
8
2
6
5
C ,F ) = 14.6 Hz, C ), 131.6 (dm, J (C ,F ) = 233.4 Hz, C ), 129.8 (m, C ), 128.7 (t, J (C ,F )
2
6
7
6
2
10 11
10
2
13 12
J (C ,F ) = 16.3 Hz, C ), 120.9 (tm, J (C ,F ) = 14.4 Hz, C ), 107.7 (t, J (C ,F ) = 23.4
1
3
2
3a
4
3a
9
19
Hz, C ), 106.2 (d, J (C ,F ) = 20.0 Hz, C ), 13.4 (s, C ). F NMR (282 MHz, Acetone-d
6
): δ
1
1
12
7
5
7
4
=
–138.5 – –139.0 (m, 2 F, F ), –146.9 (m, 2 F, F ), –152.3 (t, J (F ,F ) ≈ J (F ,F ) = 20.2 Hz, 1
7
5
4
+
F, F ), –162.0 – –162.2 (m, 2 F, F + F ). HRMS (EI): m/z [M] calcd for C14
H
6
F
7
N : 349.0444;
3
found: 349.0443.
4
.2.4.2. (E)-2,3,5,6-Tetrafluoro-4-(1-(2-(perfluorophenyl)hydrazono)ethyl)aniline (4b-E)
Yellowish solid; yield: 136 mg (44%); Rf = 0.44 (EtOAc/hexane, 1:10, twice); mp 89.7–91.2 °C.
IR (KBr): 3502, 3415, 3377, 3207, 2929, 2856, 1666, 1608, 1522, 1495, 1458, 1427, 1373, 1329,
–
1 1
1
315, 1174, 1122, 1030, 1003, 968, 935, 893, 876, 789, 737, 611, 565 cm . H NMR (300 MHz,
1
3
CDCl
CDCl
3
): δ = 6.94 (s, 1 H, NH), 4.08 (s, 2 H, NH
2
), 2.25 (t, 3 H, CH ). C NMR (126 MHz,
): δ = 146.0 (dm, J (C ,F ) = 245.8 Hz, C ), 141.3 (s, C ), 140.2 (dm, J (C ,F ) = 246.4
Hz, C ), 139.6 (dm, J (C ,F ) = 249 Hz, C ), 137.8 (ddm, J (C ,F ) = 239.0 Hz, J (C ,F ) =
6.3 Hz, C ), 137.6 (dtt, J (C ,F ) = 233 Hz, J (C ,F ) = 13.7 Hz, C ), 128.0 (tt, J (C ,F ) =
4.0 Hz, C ), 122.3 (tm, J (C ,F ) = 11.4 Hz, C ), 108.0 (t, J (C ,F ) = 16.7 Hz, C ), 17.8 (s,
C ). F NMR (282 MHz, CDCl ): δ = –143.5 (dm, 2 F, F ), –153.9 (dm, J (F ,F ) = 23 Hz, J
F ,F ) = 3.8 Hz, 2 F, F ), –160.4 (dm, 2 F, F ), –161.5 (m, J (F ,F ) = 23.3 Hz, J (F ,F ) =
1.8 Hz, 2 F, F ), –163.7 (tt, J (F ,F ) = 21.8 Hz, J (F ,F ) = 3.8 Hz, 1 F, F ). HRMS (EI):
3
1
4
4
4
3
1
11 11
3
1
1
1
12 12
12
1
5
5
2
5
4
5
1
13 13
2
13 12
13
2
6
5
1
1
6
2
10 11
10
2
3a
4
3a
9
19
4
11 12
3
1
1
13
11
5
12 11
12 13
(
2
1
2
13 12
13 11
13
+
m/z [M] calcd for C14
H
6
F
9
3
N : 387.0413; found: 387.0414.
4
,5,7-Trifluoro-3-methyl-1-(perfluorophenyl)-1H-indazol-6-amine (5b)
White solid; yield: 132 mg (45%); Rf = 0.67 (EtOAc/hexane, 1:10, twice); mp 94.5–95.4 °C. IR
(
1
KBr): 3491, 3336, 3209, 1674, 1624, 1556, 1514, 1493, 1473, 1383, 1358, 1263, 1236, 1176,
–
1 1
117, 1086, 991, 941, 897, 779, 744, 727, 677, 617 cm . H NMR (300 MHz, CDCl
3
): δ = 4.04
1
3
3
1
(s, 2 H, NH
2
), 2.63 (s, 3 H, CH
3
). C NMR (126 MHz, CDCl
3
): δ = 145.4 (t, C ), 143.9 (dm, J
1
1
11
11
1
12 12
2
12 11
12
(
(
2
C ,F ) = 255.1 Hz, C ), 141.5 (dm, J (C ,F ) = 257 Hz, J (C ,F ) = 14.2 Hz, C ), 139.5
1
4
4
4
1
13 13
13
1
5
5
dm, J (C ,F ) = 249 Hz, C ), 137.5 (dm, J (C ,F ) = 253 Hz, C ), 136.2 (dm, J (C ,F ) =
2
5
4
5
1
7
7
7
8
38.7 Hz, J (C ,F ) = 15.0 Hz, C ), 130.9 (dm, J (C ,F ) = 234.6 Hz, C ), 128.6 (m, C ), 126.0
2
6
5
2
6
7
6
2
10 11
10
2
(dd, J (C ,F ) ≈ J (C ,F ) = 16.4 Hz, C ), 115.3 (tm, J (C ,F ) = 15 Hz, C ), 106.8 (d, J

3
a
4
3a
9
19
11
(
1
1
C ,F ) = 19.7 Hz, C ), 13.4 (s, C ). F NMR (282 MHz, CDCl ): δ = –147.1 (dm, 2 F, F ), –
3
7
5
7
4
7
13 12
13
52.8 (t, J (F ,F ) ≈ J (F ,F ) = 19.2 Hz, 1 F, F ), –154.0 (t, J (F ,F ) = 21.5 Hz, 1 F, F ), –
1
2
5
7
5
4
5
62.8 (m, 2 F, F ), –163.8 (dd, J (F ,F ) = 19.7 Hz, J (F ,F ) = 4.6 Hz, 1 F, F ), –164.1 (dm, J
4
7
4
5
4
+
(
F ,F ) = 18.9 Hz, J (F ,F ) = 4.6 Hz, 1 F, F ). HRMS (EI): m/z [M] calcd for C14
H
5
F
8
3
N :
3
67.0350; found: 367.0353.
4
.2.4.3. (E)-4-(1-(2-(4-Bromo-2,3,5,6-tetrafluorophenyl)hydrazono)ethyl)-2,3,5,6-
tetrafluoroaniline (4c-E)
Yellowish solid; yield: 154 mg (45%); Rf = 0.37 (EtOAc/hexane, 1:10, 4 times); mp 148.2 °C
(
1
dec.). IR (KBr): 3500, 3442, 3371, 3336, 3203, 1664, 1641, 1614, 1497, 1458, 1431, 1371,
335, 1315, 1271, 1192, 1144, 1122, 1020, 960, 939, 893, 876, 841, 696, 658, 579 cm . H
–
1 1
1
3
NMR (300 MHz, CDCl
NMR (126 MHz, Acetone-d
C ), 145.5 (dm, J (C ,F ) = 242.6 Hz, C ), 141.2 (s, C ), 139.6 (ddt, J (C ,F ) = 248.2 Hz, J
(
2
3
): δ = 7.18 (s, 1 H, NH), 4.07 (s, 2 H, NH
2
), 2.24 (t, 3 H, CH
3
). C
1
12 12
2
12 11
6
): δ = 146.2 (ddt, J (C ,F ) = 242.3 Hz, J (C ,F ) = 14.2 Hz,
1
2
1
4
4
4
3
1
11 11
2
1
1
12
11
1
5
5
2
5
4
5
C ,F ) = 16.1 Hz, C ), 137.1 (ddm, J (C ,F ) = 237.6 Hz, J (C ,F ) = 17.0 Hz, C ), 129.1 (tt,
6
5
6
10
2
3a
4
3a
2
13 12
J (C ,F ) = 14.2 Hz, C ), 126.4 (m, C ), 106.4 (t, J (C ,F ) = 17.2 Hz, C ), 90.1 (t, J (C ,F )
23.2 Hz, C ), 17.3 (s, C ). F NMR (282 MHz, CDCl
1
3
9
19
12
=
3
): δ = –135.8 (dm, 2 F, F ), –146.4
4
11
5
+
(dm, 2 F, F ), –155.8 (dm, 2 F, F ), –163.3 (dm, 2 F, F ). HRMS (EI): m/z [M] calcd for
C
14
H
6
F
8
BrN
3
: 446.9612; found: 446.9614.
1
-(4-Bromo-2,3,5,6-tetrafluorophenyl)-4,5,7-trifluoro-3-methyl-1H-indazol-6-amine (5c)
White solid; yield: 130 mg (38%); Rf = 0.72 (EtOAc/hexane, 1:10, 4 times); mp 149.6–152.2 °C.
IR (KBr): 3487, 3350, 3211, 1672, 1622, 1554, 1524, 1498, 1475, 1400, 1354, 1261, 1157, 1115,
–
1 1
1
5
(
026, 1011, 976, 939, 837, 783, 756, 737, 725, 606 cm . H NMR (300 MHz, Acetone-d
6
): δ =
1
3
1
.45 (s, 2 H, NH
2
), 2.59 (s, 3 H, CH
3
). C NMR (126 MHz, Acetone-d
C ,F ) = 245.7 Hz, J (C ,F ) = 13.8 Hz, C ), 145.9 (m, C ), 144.4 (ddm, J (C ,F ) = 252.8
Hz, J (C ,F ) = 15.7 Hz,C ), 140.5 (ddd, J (C ,F ) = 246.8 Hz, J (C ,F ) = 12.9 Hz, C ),
37.2 (ddd, J (C ,F ) = 237.1 Hz, J (C ,F ) = 15.2 Hz, C ), 131.6 (dm, J (C ,F ) = 233.4 Hz,
C ), 129.7 (m, C ), 128.8 (tm, J (C ,F ) ≈ J (C ,F ) = 18.0 Hz, C ), 120.0 (t, J (C ,F ) = 13.8
Hz, C ), 106.2 (dm, J (C ,F ) = 20.7 Hz, C ), 101.3 (t, J (C ,F ) = 23.0 Hz, C ), 13.4 (s,
C ). F NMR (282 MHz, Acetone-d ): δ = –136.2 (dm, 2 F, F ), –148.3 (dm, 2 F, F ), –155.2
tm, J (F ,F ) ≈ J (F ,F ) = 20.9 Hz, 1 F, F ), –164.8 – –164.9 (m, 2 F, F + F ). HRMS (EI): m/z
6
): δ = 145.9 (ddm, J
1
2
12
2
12 11
12
3
1
11 11
2
11 12
11
1
4
4
2
4
5
4
1
5
5
2
5
4
5
1
7
7
1
7
8
2
6
5
2
6
7
6
2
10 11
1
0
2
3a
4
3a
2
13 12
13
9
19
12
11
6
7
5
7
4
7
5
4
(
[
+
M] calcd for C14
H
5
F
7
BrN : 426.9550; found: 426.9556.
3
4
.2.4.4. (E)-2,3,5,6-Tetrafluoro-4-(1-(2-(2,3,5,6-tetrafluoro-4-
(trifluoromethyl)phenyl)hydrazono)ethyl)aniline (4d-E)
White solid; yield: 140 mg (40%); Rf = 0.42 (EtOAc/hexane, 1:10, 3 times); mp 88.8 °C (dec.).
IR (KBr): 3491, 3452, 3358, 3209, 2928, 2854, 1659, 1547, 1514, 1497, 1466, 1429, 1379, 1336,
1
5
NH
308, 1246, 1221, 1178, 1146, 1107, 1078, 1016, 974, 939, 874, 789, 737, 712, 673, 634, 579,
–
1 1
32, 490, 474, 442 cm . H NMR (300 MHz, Acetone-d ): δ = 8.81 (s, 1 H, NH), 5.59 (s, 2 H,
6
1
3
1
12 12
1
2
), 2.37 (s, 3 H, CH
3
). C NMR (100 MHz, Acetone-d ): δ = 145.0 (dm, J (C ,F ) ≈ J
6
4
4
12
4
3
1
1
11 11
11
(
1
C ,F ) ≈ 256 Hz, C + C ), 142.4 (s, C ), 137.5 (dm, J J (C ,F ) = 247.0 Hz, C ), 136.3 (dm,
J (C ,F ) = 237.4 Hz, C ), 129.5 (m, C ), 128.5 (tt, J (C ,F ) = 18.6 Hz, C ), 121.8 (q, J
5
5
5
10
2
6
5
6
1
1
4
2
3a
4
3a
13
9
19
(CF ,F) = 273.4 Hz, C ), 105.3 (t, J (C ,F ) = 16.7 Hz, C ), 98.5 (m, C ), 16.5 (s, C ). F
3
1
2
NMR (282 MHz, Acetone-d
6
): δ = –57.1 (t, J (CF
3
,F ) = 21.2 Hz, 3 F, CF
3
), –146.5 (m, J
1
2
11
12
12
4
5
4
(
F ,F ) ≈ J (F ,CF
3
) ≈ 21 Hz, 2 F, F ), –148.6 (dm, J (F ,F ) ≈ 22 Hz, 2 F, F ), –157.1 (dm, J

5
4
5
11 12
11
+
(
F ,F ) ≈ 22 Hz, 2 F, F ), –165.4 (dm, J (F ,F ) = 22.0 Hz, 2 F, F ). HRMS (EI): m/z [M]
calcd for C15 : 437.0381; found: 437.0378.
,5,7-Trifluoro-3-methyl-1-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)-1H-indazol-6-amine
5d)
H
6
F
11
N
3
4
(
White solid; yield: 150 mg (45%); Rf = 0.67 (EtOAc/hexane, 1:10, 3 times); mp 151.4–152.5 °C.
IR (KBr): 3491, 3334, 3207, 1655, 1624, 1558, 1502, 1479, 1435, 1383, 1352, 1282, 1254, 1186,
–
1 1
1
d
144, 1120, 1014, 987, 945, 864, 793, 779, 735, 715, 629 cm . H NMR (300 MHz, Acetone-
1
3
6
): δ = 5.53 (s, 2 H, NH
2
), 2.60 (s, 3 H, CH
3
). C NMR (126 MHz, Acetone-d
6
): δ = 145.9 (t,
3
1
12 12
2
12 11
12
1
11 11
C ), 144.6 (dm, J (C ,F ) = 260 Hz, J (C ,F ) = 16 Hz, C ), 143.6 (dm, J (C ,F ) = 252.7
1
1
1
4
4
2
4
5
4
1
5
5
Hz, C ), 139.9 (ddm, J (C ,F ) = 247 Hz, J (C ,F ) = 13 Hz,C ), 136.7 (dm, J (C ,F ) = 237.4
Hz, J (C ,F ) = 14.7 Hz, C ), 131.0 (dm, J (C ,F ) = 234.3 Hz, C ), 128.7 (m, C ), 128.5 –
28.2 (m, C + C ), 121.0 (qm, J (C ,F ) = 274.4 Hz, C ), 108.8 (m, C ), 105.7 (d, J
2
5
4
5
1
7
7
7
8
6
10
1
14 14
14
13
2
1
(
=
1
3
a
4
3a
9
19
12
C ,F ) = 20.3 Hz, C ), 12.6 (m, C ). F NMR (282 MHz, Acetone-d
6
): δ = –55.2 (t, J (CF ,F )
3
1
2
11
7
5
7
4
22.0 Hz, 3 F, CF
3
), –140.8 (m, 2 F, F ), –144.7 (m, 2 F, F ), –152.0 (t, J (F ,F ) ≈ J (F ,F ) =
7
5
7
5
4
5
4
7
8.7 Hz, 1 F, F ), –160.9 (m, J (F ,F ) = 17.8 Hz, J (F ,F ) = 7 Hz, 1 F, F ), –161.5 (dm, J (F ,F )
19.3 Hz, J (F ,F ) = 7 Hz, 1 F, F ). HRMS (EI): m/z [M] calcd for C15
4
5
4
+
=
H
5
F
10
3
N : 417.0318;
found: 417.0321.
4
.2.4.5. (E)-2,3,5,6-Tetrafluoro-4-(1-(2-(2,4,6-trichloro-3,5-difluorophenyl)-
hydrazono)ethyl)aniline (4e-E)
Yellowish solid; yield: 143 mg (41%); Rf = 0.31 (EtOAc/hexane, 1:10, twice); mp 161.1 °C
(
1
dec.). IR (KBr): 3516, 3458, 3417, 3348, 3194, 1664, 1601, 1529, 1493, 1452, 1414, 1383,
323, 1259, 1173, 1138, 1113, 1074, 1009, 935, 881, 816, 781, 731, 700, 621 cm . H NMR
–
1 1
1
3
(
(
500 MHz, Acetone-d
6
): δ = 8.13 (s, 1 H, NH), 5.59 (s, 2 H, NH
2
), 2.37 (t, 3 H, CH ). C NMR
3
1
12 12
12
1
4
4
126 MHz, Acetone-d
6
): δ = 155.1 (dd, J (C ,F ) = 246.5 Hz, C ), 146.0 (dm, J (C ,F ) =
4
3
10
1
5
5
2
5
4
2
42.8 Hz, C ), 141.4 (m, C ), 141.0 (t, C ), 137.5 (ddm, J (C ,F ) = 237.1 Hz, J (C ,F ) = 16.3
5
2
6
5
6
2
11 12
11
2
Hz, C ), 129.6 (tt, J (C ,F ) = 14.5 Hz, C ), 111.7 (ddt, J (C ,F ) = 17.3 Hz, C ), 106.5 (t, J
(
Acetone-d
3
a
4
3a
2
13 12
13
9
19
C ,F ) = 17.0 Hz, C ), 106.1 (t, J (C ,F ) = 22.9 Hz, C ), 17.8 (t, C ). F NMR (282 MHz,
1
2
4
5
6
): δ = –112.3 (s, 2 F, F ), –145.4 (dm, 2 F, F ), –163.3 (dm, 2 F, F ). HRMS (EI): m/z
+
[M] calcd for C14
H
6
F
6
Cl : 434.9526; found: 434.9529.
3
N
3
4
,5,7-Trifluoro-3-methyl-1-(2,4,6-trichloro-3,5-difluorophenyl)-1H-indazol-6-amine (5e)
White solid; yield: 156 mg (47%); Rf = 0.69 (EtOAc/hexane, 1:10, twice); mp 122.1–122.6 °C.
IR (KBr): 3412, 3311, 3207, 2931, 1672, 1624, 1578, 1551, 1516, 1479, 1454, 1433, 1390, 1373,
–
1 1
1
348, 1207, 1147, 1107, 1076, 1024, 943, 793, 773, 739, 708, 661, 432 cm . H NMR (400
1
3
MHz, Acetone-d
6
): δ = 5.41 (s, 2 H, NH
2
), 2.60 (s, 3 H, CH
3
). C NMR (126 MHz, Acetone-d ):
δ = 155.0 (dm, J (C ,F ) = 250.5 Hz, C ), 145.6 (m, C ), 141.1 (ddd, J (C ,F ) = 246.2 Hz, J
6
1
12 12
12
3
1
4
4
2
4
5
4
1
5
5
2
5
4
5
(
C ,F ) = 12.2 Hz, C ), 137.8 (ddd, J (C ,F ) = 237.1 Hz, J (C ,F ) = 14.7 Hz, C ), 137.0 (m,
1
0
1
7
7
7
8
2
6
5
2
6
7
C ), 132.0 (dm, J (C ,F ) = 233.0 Hz, C ), 131.1 (m, C ), 129.1 (tm, J (C ,F ) ≈ J (C ,F ) =
6
2
11 12
11
2
13 12
13
1
(
6.2 Hz, C ), 120.8 (dm, J (C ,F ) = 16 Hz, C ), 114.9 (t, J (C ,F ) = 22.2 Hz, C ), 106.6
2
3a
4
3a
9
19
dm, J (C ,F ) = 20 Hz, C ), 14.0 (s, C ). F NMR (282 MHz, Acetone-d ): δ = –112.2 (s, 2 F,
6
1
2
7
5
7
4
7
5
7
F ), –152.9 (t, J (F ,F ) ≈ J (F ,F ) = 19.2 Hz, 1 F, F ), –163.9 (dd, 1 F, J (F ,F ) = 18.9 Hz, J
F ,F ) = 3.8 Hz, F ), –164.2 (dd, 1 F, J (F ,F ) = 19.6 Hz, J (F ,F ) = 3.8 Hz, F ). HRMS (EI):
5
4
5
4
7
4
5
4
(
+
m/z [M+H] calcd for C14
H
6
F
5
Cl
3
3
N : 415.9547; found: 415.9546.
4
.2.5. 4,5,7-Trifluoro-3-methyl-1H-indazol-6-amine (6)

To a solution of 3 (0.19 g, 0.9 mmol) in THF (5 mL), hydrazine monohydrate (0.5 mL, 9
mmol) and MgSO (0.32 g, 2.7 mmol) were added, and the mixture was heated at reflux for 5 h
4
with stirring. The mixture was allowed to cool to r.t., placed directly onto a chromatography
plate (silica gel), and air-dried. The title product 6 was isolated by TLC with EtOAc/hexane as
an eluent.
White solid; yield: 159 mg (88%); Rf = 0.44 (EtOAc/hexane, 1:3, 3 times); mp 183.4 °C (dec.).
IR (KBr): 3417, 3309, 3203, 3165, 3122, 3101, 3061, 3026, 2883, 1680, 1628, 1603, 1556, 1514,
–
1 1
1
462, 1385, 1342, 1242, 1188, 1169, 1097, 987, 943, 795, 719, 667, 471, 445 cm . H NMR
1
3
(
(
300 MHz, Acetone-d
126 MHz, Acetone-d
6
): δ = 12.04 (s, 1 H, NH), 5.09 (s, 2 H, NH
2
), 2.51 (s, 3 H, CH
3
). C NMR
5
3
1
4
4
2
4
6
): δ = 141.4 (m, C ), 140.2 (ddd, J (C ,F ) = 243.7 Hz, J (C ,F ) = 12.6
4
1
5
5
2
5
4
5
1
7
7
Hz, C ), 136.4 (ddd, J (C ,F ) = 234.4 Hz, J (C ,F ) = 14.9 Hz, C ), 131.4 (dm, J (C ,F ) =
7
8
2
6
5
2
6
7
6
2
2
31.6 Hz, C ), 130.2 (m, C ), 126.0 (tm, J (C ,F ) ≈ J (C ,F ) = 14.9 Hz, C ), 105.5 (dm, J
C ,F ) = 20 Hz, C ), 13.2 (s, C ). F NMR (282 MHz, Acetone-d ): δ = –157.1 (t, J (F ,F ) ≈ J
F ,F ) = 19.2 Hz, 1 F, F ), –162.0 (dd, 1 F, J (F ,F ) = 19.4 Hz, J (F ,F ) = 4.0 Hz, F ), –168.0
dd, 1 F, J (F ,F ) = 19.0 Hz, J (F ,F ) = 4.0 Hz, F ). HRMS (EI): m/z [M] calcd for C
3
a
4
3a
9
19
7
5
(
(
(
6
7
4
7
5
7
5
4
5
4
7
4
5
4
+
8
H
6
F
3
N :
3
2
01.0508; found: 201.0505.
4
.3. Crystallographic Study
X-ray crystallography study of the crystals were carried out on a Bruker Kappa Apex II
CCD diffractometer using φ,ω-scans of narrow (0.5°) frames with Mo Kα radiation (λ = 0.71073
Å) and a graphite monochromator. The structure was solved by direct methods and refined by
full-matrix least-squares method against all F2 in anisotropic approximation using the SHELX-
9
7 programs set [28]. The hydrogen atoms positions were calculated with the riding model,
except for NH groups. The hydrogen atom positions for NH groups were located from
2
2
difference Fourier map and refined isotropic. Absorption corrections were applied using the
empirical multiscan method with the SADABS program [29]. Full crystallographic data of
polufluorinaned compounds 4(a–e)–E and 5b,e can be obtained free of charge via
http://www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223 336 033; or e-mail:
deposit@ccdc.cam.ac.uk. The obtained crystal structures were analyzed for short contacts
between non-bonded atoms using PLATON [30] and MERCURY programs [31].
4
.3.1. Crystallographic data for 4a-E
The deposition number CCDC 1842981. T 200(2) K, C14
H
7
N
3
F
8
, FW = 369.23, triclinic, P-1, a =
7
1
.2508(4), b = 13.8641(8), c = 14.3708(7) Ǻ,  = 73.950(2), β = 89.049(2), γ = 77.435(2)°, V =
353.6(1) Å , Z = 4, Dcalc = 1.812 g cm , (Mo-Kα) = 0.188 mm , F(000) = 736, 24162
3
-3
-1
measured reflections (θmax = 27.55°, completeness 99.4%), 6218 independent (Rint = 0.0295), 465
parameters, R = 0.0378 (for 4724 observed I > 2σ(I)), wR = 0.1074 (all data), GooF = 1.04,
1
2
-3
largest diff. peak and hole 0.46 and -0.45 e.A . The crystal structure of 4a-E is formed by two
crystallographically independent molecules.
4
.3.2. Crystallographic data for 4b-E
The deposition number CCDC 1842982. T 296(2) K, C14
.1702(3), b = 13.3645(7), c = 14.6860(7) Ǻ,  = 116.948(2), β = 93.271(2), γ = 91.863(2)°, V =
H
6
N
3
F , FW = 387.22, triclinic, P-1, a =
9
8

3
-3
-1
1
424.1(1) Å , Z = 4, Dcalc = 1.806 g cm , (Mo-Kα) = 0.193 mm , F(000) = 768, 29308
measured reflections (θmax = 27.55°, completeness 99.6%), 6555 independent (Rint = 0.0315), 483
parameters, R = 0.0374 (for 4735 observed I > 2σ(I)), wR = 0.1090 (all data), GooF = 1.01,
1
2
-3
largest diff. peak and hole 0.23 and -0.28 e.A . The crystal structure of 4b-E is formed by two
crystallographically independent molecules.
4
.3.3. Crystallographic data for 4c-E
The deposition number CCDC 1842983. T 296(2) K, C14
a = 7.7917(8), b = 7.9334(9), c = 14.164(2) Ǻ,  = 88.675(4), β = 80.134(4), γ = 60.658(3)°, V =
H
6
N
3
F Br, FW = 448.13, triclinic, P-1,
8
3
-3
-1
7
50.1(1) Å , Z = 2, Dcalc = 1.984 g cm , (Mo-Kα) = 2.836 mm , F(000) = 436, 13035 measured
reflections (θmax = 27.53°, completeness 99.4%), 3441 independent (Rint = 0.0428), 242
parameters, R = 0.0578 (for 2825 observed I > 2σ(I)), wR = 0.1494 (all data), GooF = 1.05,
largest diff. peak and hole 0.81 and -0.78 e.A .
1
2
-3
4
.3.4. Crystallographic data for 4d-E
The deposition number CCDC 1842984. T 298(2) K, C15
P2
H
6
N
3
F
11, FW = 437.23, monoclinic,
3
1
/c, a = 12.055(2), b = 9.943(1), c = 13.915(2) Ǻ, β = 101.951(5)°, V = 1631.7(4) Å , Z = 4,
-3
-1
D
2
2
calc = 1.780 g cm , (Mo-Kα) = 0.196 mm , F(000) = 864, 22457 measured reflections (θmax
7.09°, completeness 99.7%), 3573 independent (Rint = 0.0569), 299 parameters, R
257 observed I > 2σ(I)), wR = 0.1121(all data), GooF = 1.01, largest diff. peak and hole 0.20
=
1
= 0.0423 (for
2
-3
and -0.18 e.A .
4
.3.5. Crystallographic data for 4e-E
The deposition number CCDC 1842985. T 200(2) K, C14
H
6
N
3
F
6
Cl
3
, FW = 436.57, triclinic, P-1,
a = 7.7317(7), b = 8.1799(8), c = 13.847(1) Ǻ,  = 94.959(4), β = 96.182(3), γ = 115.312(3)°, V
3
-3
-1
=
778.5(1) Å , Z = 2, Dcalc = 1.862 g cm , (Mo-Kα) = 0.659 mm , F(000) = 432, 16548
measured reflections (θmax = 30.2°, completeness 99.3%), 4578 independent (Rint = 0.0355), 242
parameters, R = 0.0327 (for 4040 observed I > 2σ(I)), wR = 0.0990 (all data), GooF = 1.05,
largest diff. peak and hole 0.47 and -0.41 e.A .
1
2
-3
4
.3.6. Crystallographic data for 5b
The deposition number CCDC 1842986. T 200(2) K, C14
P2
H
5
N
3
F
8
, FW = 367.21, monoclinic,
3
1
/c, a = 11.8823(5), b = 20.1955(7), c = 17.5902(7) Ǻ, β = 100.101(2)°, V = 4155.7(3) Å , Z =
-3
-1
1
2, Dcalc = 1.761 g cm , (Mo-Kα) = 0.183 mm , F(000) = 2184, 80508 measured reflections
max = 28.30°, completeness 99.7%), 10304 independent (Rint = 0.0388), 299 parameters, R
.0481 (for 7343 observed I > 2σ(I)), wR = 0.1494 (all data), GooF = 1.04, largest diff. peak and
(
θ
1
=
0
2
-3
hole 0.57 and -0.44 e.A . The crystal structure of 5b is formed by three crystallographically
independent molecules.
4
.3.7. Crystallographic data for 5e
The deposition number CCDC 1842987. T 200(2) K, C14
rhombohedral, R-3, a = b = 19.6684(6), c = 21.3164(9) Ǻ, V = 7141.4(4) Å , Z = 18, Dcalc
H
5
N
3
F
5
Cl
3
, FW = 416.56,
3
=
-
3
-1
1
2
.743 g cm , (Mo-Kα) = 0.634 mm , F(000) = 3708, 46100 measured reflections (θmax
=
7.35°, completeness 99.9%), 3602 independent (Rint = 0.0528), 233 parameters, R = 0.0512 (for
1

2
655 observed I > 2σ(I)), wR = 0.1752 (all data), GooF = 1.06, largest diff. peak and hole 0.45
2
-3
and -0.58 e.A .
Acknowledgment
This work has been supported by the Russian Ministry of Science and Education under 5-
00 Excellence Programme. The centre of collective using (CCU) of the Novosibirsk Institute of
1
Organic Chemistry of SB RAS is acknowledged.
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