Synthesis of N-aryl-3H-indazol-3-imine and N-aryl-1H-indazol-3-amine via Na2WO4/H2O2 mediated by intramolecular N–N coupling

Article abstract of DOI:10.1016/j.tet.2021.132023

A fast and convenient method for synthesis of N-aryl-1H-indazol-3-amine and N-aryl-3H-indazol-3-imine compounds has been described via intramolecular oxidative cyclization of the 2-amino-Nˊ-arylbenzimidamide intermediates by Na₂WO₄/H₂O₂ in excellent yields. This procedure has several advantages such as mild reaction conditions, short reaction time, and excellent yields, making this methodology practical.

Full text of DOI:10.1016/j.tet.2021.132023

Tetrahedron 84 (2021) 132023
Contents lists available at ScienceDirect
Tetrahedron
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Synthesis of N-aryl-3H-indazol-3-imine and N-aryl-1H-indazol-3-
amine via Na2WO4/H2O2 mediated by intramolecular NeN coupling
,
Mahdieh Sadat Sajadi a, Ali Darehkordi a *, Seyed Mohammad Sadegh Hosseini b
a Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan, 77176, Iran
b Department of Chemical Engineering, Faculty of Engineering, Vali-e-Asr University of Rafsanjan, Rafsanjan, 77176, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A fast and convenient method for synthesis of N-aryl-1H-indazol-3-amine and N-aryl-3H-indazol-3-
imine compounds has been described via intramolecular oxidative cyclization of the 2-amino-Nˊ-aryl-
benzimidamide intermediates by Na2WO4/H2O2 in excellent yields. This procedure has several advan-
tages such as mild reaction conditions, short reaction time, and excellent yields, making this
methodology practical.
Received 16 November 2020
Received in revised form
1 February 2021
Accepted 10 February 2021
Available online 18 February 2021
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
N-aryl-1H-indazol-3-amine
N-aryl-3H-indazol-3-imine
2-amino-Nˊ-arylbenzimidamide
Na2WO4/H2O2
1. Introduction
used as a structurally novel, potent inhibitor of receptor tyrosine
kinases (RTK), vascular endothelial growth factor (VEGF) and
N-heterocyclic compounds are of unique structural units and
widely exist in the bioactive molecular and natural products [1].
Among them indazoles with a broad spectrum of pharmacological
activities are very important. The biological and medicinal prop-
erties of indazoles have prompted immense research effort aimed
at synthetic routes and medicinal functionalization of the nucleus
[2]. Indazole derivatives have been has been known as anticancer
[3], antibacterial [4], antiprotozoal [5], and anti-inflammatory
agents [6], and as inhibitors of protein kinase [7], HIV protease
[8], nitric oxide synthase [9], and monoamine oxidase [10]. Fig. 1
shows some typical biologically active compounds containing
indazole scaffold that are used as core structures synthetic drugs
such as Benzadac [11], Lonidamine [12], Granisetron [13] and 7-
nitroindazole [14].
platelet-derived growth factor (PDGF) (Fig. 2).
Moreover, the 3-aminoindazoles are able to mimic the adenine
nucleus of ATP for the design of ATP-competitive receptor tyrosine
kinase inhibitors with potent antitumor activities [19]. There are
various methods for the synthesis of 3-aminoindazole. For
example, in 2008, Michael and et al. reported the synthesis of 3-
aminoindazoles compounds in the presence of hydrazine with
thioamides [20]. The methods for the preparation of these com-
pounds typically involved the reaction of a 2-haloaryl nitrile with
hydrazine to provide the 3-aminoindazole, the leaving group used
for the reaction to succeed is mainly fluorine. The main drawback of
these methods is the low yields and harsh conditions when fluo-
robenzonitriles are deactivated by an electron-donating group [18].
We required
a general method for the preparation of 3-
In the recent years, there has been great interest in the appli-
cation of 3-aminoindazole as agents interacting with a variety of
biological targets including kinase inhibitors [15], MCH receptor 1
antagonist [16], HIV protease inhibitors [17], factor XIa inhibitors
and CB1 receptor inhibitors [18]. For example, Linifanib has been
aminoindazoles which avoided the use of harshly acidic condi-
tions, protecting groups, or metal catalysis while allowing for the
incorporation of elaborated amines.
Amidines, in addition to being used in the synthesis of quina-
zoline compounds, can be used in the synthesis of heterocycle
nitrogen-riched indazole by an oxidative NeN bond formation [21].
The formation of NeN bond has been recently utilized for the
synthesis of heterocycles and azo compounds [22]. The advantages
of this method include not need to leaving group on the heteroatom
or pre-functionalization and avoided challenging to prepare
* Corresponding author.
E-mail
addresses:
darehkordi@vru.ac.ir,
adarehkordi@yahoo.com
(A. Darehkordi).
https://doi.org/10.1016/j.tet.2021.132023
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

M.S. Sajadi, A. Darehkordi and S.M.S. Hosseini
Tetrahedron 84 (2021) 132023
Scheme 2. Synthesis of 2-amino-N0-phenylbenzimidamide derivatives.
(Scheme 2) [32].
In continues of work, we carried out cyclization 1 in presents of
different solvents and catalysts. To find the optimized conditions
for synthesis N-aryl-1H-indazol-3-amine and N-aryl-3H-indazol-3-
imine derivatives by an oxidative NeN bond formation, reaction of
2-amino-N’-(p-tolyl)benzimidamide (1a) was selected as a model
reaction. Various catalysts, and solvents were used at ambient
temperature. The results have been summarized in Table 1.
Fig. 1. Selected biologically active compounds with an indazole core.
As shown on Table 1, in absent oxidant, at room temperature,
CH3OH as solvent and Cu(OAc)2 or Cu(NO3)2 as catalyst, no desired
product was observed, according to the TLC (n-Hexane: EtOAc 3:1)
(Table 1, entries 1 and 2). Also, addition of H2O2 as an oxidant in
presence different catalysts such as CuBr2, ZnSO4, TiO2, ZnO and KI/
I2 not improved the yield of the desired product, in some cases
these led to a complicated result, according to the TLC (n-Hexane:
EtOAc 3:1) (Table 1, entries 3e9). When we used H2O2 in presence
of Na2WO4 as catalyst in CH3OH solvent at room temperature cor-
responding product was produced in good yields (60%) (Table 1,
entry 10). To improve the yields, various solvents such as DMSO,
Fig. 2. Linifanib structure.
Table 1
Scheme 1. Synthesis of N-aryl-1H-indazol-3-amine and N-aryl-3H-indazol-3-imine
Optimization of conditions for synthesis the N-(p-tolyl)-1H-indazol-3-amine and N-
derivatives.
(p-tolyl)-3H-indazol-3-imine.a.
building blocks containing an NeN bond [23].
Many tungstate-based catalytic systems have been reported to
be active for oxidation reactions with aqueous hydrogen peroxide
solutions [24,25]. Newly tungsten peroxide, has been used for
oxidation of alcohols to aldehydes or ketones as practical meth-
odology. This oxidant is prepared from hydrogen peroxide (H2O2)
and catalytic amount of sodium tungstate dihydrate
(Na2WO4$2H2O. Also, attention has been especially attracted to a
method of ‘green’ oxidation with use of tungsten peroxide [26,27].
In this way, oxidation of alcohol to ketone or aldehyde was carried
out by using N,N-dimethylacetamide, hydrogen peroxide, and a
catalytic amount of disodium tungstate dihydrate under neutral
conditions as a green method.[28]Also, sodium tungstate are used
as an active and highly selective catalyst to oxidation of various
primary or secondary origin renewable alcohols by hydrogen
peroxide as green oxidant [29].
Entry Catalyst/Oxidant Catalyst (mmol) Solvent
Time (h) Yield
(%)
2
3
1
2
3
4
5
6
7
8
9
Cu(OAC)2/-
Cu(NO3)2/-
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.025
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
5
5
5
5
5
5
5
5
5
e
e
e
e
e
5
e
e
e
e
e
Cu(OAc)2/H2O2
Cu(NO3)2/H2O2
CuBr2/H2O2
ZnSO4/H2O2
TiO2/H2O2
10
10
10
10
10
e
Due to the above mentioned and in continues of our research for
the synthesis of heterocyclic compounds with biological activity
[30,31]. Herein, we report a Na2WO4/H2O2-mediated oxidative
NeN bond formation reaction to produce N-aryl-1H-indazol-3-
amine and N-aryl-3H-indazol-3-imine from 2-amino-Nˊ-arylben-
zimidamides (Scheme 1).
ZnO/H2O2
I2/KI
e
e
10
11
12
13
14
15
16
17
18
19
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
0.025
0.025
0.025
0.025
0.025
0.025
0.025
0.050
0.012
0.006
MeOH
DMSO
DMF
THF
EtOH
2
4
4
3
3
20 40
e
e
e
e
e
10
10
10
2. Results and discussion
Toluene 0.75
30 50
30 50
38 57
25 50
20 40
DCM
DCM
DCM
DCM
0.75
0.5
1
For the synthesis of our target molecules, in the first, we syn-
thesized 2-amino-Nˊ-arylbenzimidamides derivatives (1a-j), from
reaction of o-aminobenzonitrile and aniline derivatives in the
presence of AlCl3 at 150e180 ꢀC according to the literature reported
2
a
Conditions: H2O2 (2.0 mmol).
2

M.S. Sajadi, A. Darehkordi and S.M.S. Hosseini
Tetrahedron 84 (2021) 132023
Table 2
Synthesis of N-aryl-1H-indazol-3-amine and N-aryl-3H-indazol-3-imine derivatives under optimized conditions.a.
DMF, THF, EtOH, toluene, and DCM were used. According to Table 1,
DCM and toluene provide better yields within 0.5 h under same
reaction conditions (Table 1, entries 11e16). Therefore, DCM was
selected as solvent on the basis of economic costs and environ-
mental safety. Also, the results show that the reaction efficiency
increases with increasing the amount of catalyst (Table 1, entire 17).
In the next set of experiments the influence of different amount
Na2WO4 on the outcome of the model reaction were studied. Our
finding indicates the best conditions reaction and oxidant for this
reaction are 0.050 mmol Na2WO4 (Table 1, entries 17e19).
Thus, the optimized reaction conditions for the synthesis of N-
disubstituted indazoles are 2-amino-Nˊ-arylbenzimidamides
(0.5 mmol), Na2WO4 (0.050 mmol) and H2O2 (2.0 mmol) in DCM at
ambient temperature for 0.5 h.
structures of products confirmed by IR, 1H NMR and 13C NMR
spectra.
In the next step we tried to change the conditions reaction so
that only one of the two products 2 and 3 are produced. We sug-
gested if the time and amounts of oxidants were increased and also
the reaction was carried out at the presence of O2 the ratio com-
pounds 2 and 3 can be changed. Therefore, for the testing of this
hypothesis, the reaction cyclization of 2-amino-N’-(4-
methoxyphenyl)benzimidamide was selected as
a
model
(Table 3). At the first, we used H2Wo4/H2O2 with (0.05:2) ratio in
the toluene solvent. In this case after 12 h the products 2c and 3c
were obtained with ratios 30:63% (Entry 2, Table 3). When we used
H2Wo4/H2O2 with (0.05:4) and (0.05:6) ratios, after 6 h the com-
pound 2c was not obtained, and only product 3c was observed
(75%) (Entry 3 and 4, Table 3). Also, we examined H2WO4/H2O2/KI,
I2 (0.05:2:0.025) as oxidant system, it is interesting, in these con-
ditions we didn’t observed any product. Finally, the reaction was
carried out under O2 atmosphere and H2WO4/H2O2 (0.05:2). In
In order to the investigation of electronic effect on the reaction
time and yield, various amidine contains electron withdrawing and
electron releasing groups, were used (Table 2). The reaction pro-
ceeds without significant differences in reaction time or yield. The
3

M.S. Sajadi, A. Darehkordi and S.M.S. Hosseini
Tetrahedron 84 (2021) 132023
Table 3
obtain indazole derivatives which are of great importance in me-
dicinal chemistry.
Optimization of conditions for synthesis the N-(4- methoxyphenyl)-3H-indazol-3-
imine.a.
4. Experimental section
4.1. General information
All chemicals and solvents were purchased from commercial
sources and used without further purification unless otherwise
stated. Melting points were obtained by a Bamslead Electrothermal
9200 apparatus and are uncorrected. Infrared spectra were recor-
ded on a Thermo Scientific, Nicolet iS10 Fourier transform IR
spectrometer (Thermo Fisher Scientific, Waltham, MA) in KBr with
absorption in cmꢁ1. All of the NMR spectra were recorded on a
Varian model UNITYInova 500 MHz (1H: 500 13C: 125 MHz) NMR
spectrometer. Chemical shifts of 1H and 13C NMR are reported in
parts per million (ppm) from tetramethylsilane (TMS) Chemical
shifts are given in ppm relative to TMS as an internal standard in
DMSO-d6 or CDCl3 as a solvent, the coupling constants J are given in
Hz and spectra were recorded in parts per million (ppm).
Entry Oxidants
Oxidant (mmol)) Solvent Time (h) Yield (%)
2c
3c
1
2
3
4
5
6
Na2WO4/H2O2
0.05/2
0.05/2
0.05/4
0.05/6
Toluene 0.25
Toluene 12
16 34
30 63
Na2WO4/H2O2
Na2WO4/H2O2
Na2WO4/H2O2
H2WO4/H2O2/KI, I2 0.05/2/0.025
H2WO4/H2O2/O2 0.05/2
Toluene
Toluene
Toluene
Toluene
6
6
6
5
e
e
e
e
75
75
e
86
a
Conditions: H2WO4 (0.05 mmol).
4.2. Synthetic procedures
4.2.1. General procedure for the synthesis of compounds 1
A mixture of aryl amines (15 mmol) and o-aminobenzonitrile
(10 mmol) were carefully heated until a homogenous melt. Anhy-
drous aluminium chloride (15 mmol) was added in many portions
with swirling. The resulted mixture was then heated at 150e180 ꢀC
during 1 h. Then 10% hydrochloric acid (25 ml) was added, and after
dissolving the post-reaction mixture, 2 M sodium hydroxide solu-
tion was added until PH ¼ 6. The obtained solution was extracted
with chloroform (3 ꢂ 10 ml). The aqueous layer was separated and
basified with 2 M sodium hydroxide solution. The white precipitate
was filtered off, washed with water until neutral reaction, air dried,
and crystallized from a benzeneepetroleum ether mixture.
General procedure for the synthesis of compounds 2 or 3.
To a solution of 2-amino-Nˊ-arylbenzimidamides 1 (0.5 mmol)
in CH2Cl2 (2 mL), H2O2 (2 mmol, 35%) and Na2WO4$2H2O
(0.050 mmol) were added and the mixture stirred for 0.5 h at room
temperature. Then, solvent was evaporated, water was added
(10 mL) to the mixture, and then extracted with CH3Cl (2 X 7 mL).
The extracts were combined and dried over anhydrous Na2SO4,
filtered, and purified using plate chromatography with EtOAc/n-
Hexane (1:3) to afford the corresponding product 2 or 3.
Scheme 3. Proposed reaction mechanism using tetraperoxotungstate.
N-(p-tolyl)-1H-indazol-3-amine (2a)
Yellow oil (38% yield); IR KBr(ῡmax, cmꢁ1): 3346.48 (NeH),
1691.50 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 11.87 (s, 1H,
these conditions we didn’t obtained compound 2c as product and
only compound 3c was produced in 85% yield (entry 6, Table 3).
A possible mechanism for this reaction is proposed in Scheme 3.
At the first, Na2WO4 (a) and H2O2 give Na2[W(O2)4] (b).
Although thermal cleavage of WeO bond occurs. The formation of
intermediate c can be rationalized by the nucleophilic attack of
amidine 1 with tetraperoxotungstate b. After formation of inter-
mediate d the cyclization reaction occurs by an oxidative NeN bond
formation and removing of the water molecule, the intermediate e
was synthesized which can be tautomerized to product 2 or by
further oxidation produce compound 3.
NeH), 8.68 (s, 1H, NeH), 7.92 (d, 1H, J ¼ 8.5 Hz, HeAr), 7.55 (d, 2H,
J ¼ 8.5 Hz, HeAr), 7.34 (dd, 1H, J ¼ 8.5 Hz, J ¼ 1 Hz, HeAr), 7.29 (td,
1H, J ¼ 7.5 Hz, J ¼ 1 Hz, HeAr), 7.14 (d, 2H, J ¼ 8.5 Hz, HeAr), 6.99
(td, 1H, J ¼ 7.5 Hz, J ¼ 1 Hz HeAr), 2.22 (s, 3H, Me); 13C NMR
(125 MHz, DMSO d6)
120.4, 119.6, 118.5, 116.2, 114.7, 109.9, 20.7 (Me).
d
¼ 141.7,139.3,134.1,129.6,129.4,127.6,127.0,
4.3. N-(o-tolyl)-1H-indazol-3-amine (2b)
Yellow oil (34% yield); 1H NMR (500 MHz, DMSO d6)
d
¼ 7.69 (d,
1H, J ¼ 8.5 Hz, HeAr), 7.42e7.44 (m, 2H, HeAr), 7.35e7.38 (m, 1H,
HeAr), 7.314 (d, 1H, J ¼ 7.5 Hz, HeAr), 7.20 (d, 1H, J ¼ 8.5 Hz, HeAr),
7.10 (td, 1H, J ¼ 7.0 Hz, J ¼ 1.0 Hz, HeAr), 6.66e6.69 (m, 1H, HeAr),
5.92 (s, 2H), 2.01 (s, 3H, Me); 13C NMR (125 MHz, DMSO d6)
3. Conclusions
In summary, we have successfully synthesized a new series of
indazole derivatives in excellent yields via oxidative NeN bond
formation reaction of 2-amino-Nˊ-arylbenzimidamides derivatives.
This method constitutes a fast, facile, and inexpensive route to
d
¼ 148.2, 142.0, 137.9, 135.9, 131.3, 129.5, 128.2, 127.1, 126.9, 121.8,
116.3, 115.9, 108.3, 17.6 (Me).
N-(4-methoxyphenyl)-1H-indazol-3-amine (2c)
Cream oil (38% yield); IR KBr(ῡmax, cmꢁ1): 3450.19 (NeH),
4

M.S. Sajadi, A. Darehkordi and S.M.S. Hosseini
Tetrahedron 84 (2021) 132023
1616.40 (C]N); 1H NMR (500 MHz, CDCl3)
d
¼ 8.07 (dd, 1H,
1569.19 (C]N); 1H NMR (500 MHz, CDCl3)
d
¼ 9.19 (s, 1H, NeH),
J ¼ 7.5 Hz, J ¼ 0.5 Hz, HeAr), 8.03 (d, 1H, J ¼ 9.0 Hz HeAr), 7.83e7.87
(m, 3H), 7.75 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 7.67 (td, 1H,
J ¼ 8 Hz, J ¼ 1 Hz, HeAr), 7.03 (d, 1H, J ¼ 9.0 Hz, HeAr), 6.96 (d, 2H,
J ¼ 9.0 Hz HeAr), 3.88 (s, 3H, OMe); 13C NMR (125 MHz, CDCl3)
7.56 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.36e7.40 (m, 5H, HeAr), 7.11 (td, 1H,
J ¼ 7.0 Hz, J ¼ 2.0 Hz, HeAr), 7.01 (t, 2H, J ¼ 8.5 Hz, HeAr), 6.21 (s,
1H, NeH); 13C NMR (125 MHz, CDCl3)
d
¼ 143.4, 137.9, 130.4, 127.5,
124.5, 119.9, 119.4, 118.1, 115.8, 115.4, 115.0, 114.3, 112.1.
N-(p-tolyl)-3H-indazol-3-imine (3a)
d
¼ 160.5, 140.6, 135.6, 133.5, 132.9, 131.1, 130.0, 129.8, 125.8, 122.9,
115.3, 114.5, 114.3, 55.5 (OMe).
Red solid (57% yield); mp ¼ 164e166 ꢀC; 1H NMR (500 MHz,
N-(3-ethylphenyl)-1H-indazol-3-amine (2d)
DMSO d6)
d
¼ 8.10 (d, 1H, J ¼ 7.5 Hz, HeAr), 7.96 (d, 1H, J ¼ 7.5 Hz,
Cream oil (36% yield); IR KBr(ῡmax, cmꢁ1): 3384.59 (NeH),
HeAr), 7.89 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 7.83 (td, 1H,
J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 7.44 (d, 2H, J ¼ 8.5 Hz, HeAr), 7.28 (d,
2H, J ¼ 8.5 Hz, HeAr), 2.34 (s, 3H, Me); 13C NMR (125 MHz, DMSO
1610.45 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 11.92 (s, 1H,
NeH), 8.70 (s, 1H, NeH), 7.93 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.51 (bs, 1H,
HeAr), 7.48 (dd, 1H, J ¼ 8.7 Hz, J ¼ 1.5 Hz, HeAr), 7.35 (d, 1H,
J ¼ 8.5 Hz, HeAr), 7.30 (td, 1H, J ¼ 8.0 Hz, J ¼ 1.0 Hz, HeAr), 7.13 (t,
1H, J ¼ 8.0 Hz, HeAr), 7.00 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 6.63
(d, 1H, J ¼ 7.5 Hz, HeAr), 2.56 (q, 2H, J ¼ 7.5 Hz, CH2), 1.90 (t, 3H,
d6)
d
¼ 161.7, 155.8, 145.9, 138.3, 138.1, 134.2, 133.0, 130.0, 129.6,
126.2, 122.8, 116.0, 109.9, 21.2 (Me).
N-(o-tolyl)-1H-indazol-3-amine (3b)
Orange solid (61% yield); mp ¼ 170e172 ꢀC; IR KBr(ῡmax, cmꢁ1):
J ¼ 7.5 Hz, Me); 13C NMR (125 MHz, DMSO d6)
d
¼ 145.4, 144.5,
1629.78 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 8.05 (d, 1H,
132.9,132.0, 129.0, 128.9, 127.0, 120.4, 118.7, 118.6, 115.5, 113.6, 110.0,
28.8 (CH2), 14.3 (Me).
J ¼ 7.0 Hz, HeAr), 7.85 (bs, 2H, HeAr), 7.71 (bs, 1H, HeAr), 7.62 (d,
1H, J ¼ 7.5 Hz, HeAr), 7.49 (d, 1H, J ¼ 6.5 Hz, HeAr), 7.44 (d, 1H,
N-(3,4-dimethylphenyl)-1H-indazol-3-amine (2e)
J ¼ 6.5 Hz, HeAr), 7.35 (t, 1H, J ¼ 7.0 Hz, HeAr), 2.69 (s, 3H, Me); 13
C
White oil (34% yield); IR KBr(ῡmax, cmꢁ1): 3449.98 (NeH),
NMR (125 MHz, DMSO d6)
132.1, 132.0, 127.2, 118.7, 117.2, 115.8, 112.1, 17.6 (Me).
d
¼ 153.3,150.2,139.4,134.7,134.5,133.2,
1638.30 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 11.85 (s, 1H,
NeH), 8.57 (s, 1H, NeH), 7.92 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.44 (s, 1H,
HeAr), 7.40 (dd, 1H, J ¼ 7.5 Hz, J ¼ 1.5 Hz, HeAr), 7.33 (dd, 1H,
J ¼ 8.5 Hz, J ¼ 1.0 Hz, HeAr), 7.29 (td, 1H, J ¼ 8.0 Hz, J ¼ 1.0 Hz,
HeAr), 6.99 (td, 2H, J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 2.18 (s, 3H, Me),
N-(4-methoxyphenyl)-3H-indazol-3-imine (3c)
Red solid (57% yield); mp ¼ 133e135 ꢀC; 1H NMR (500 MHz,
CDCl3)
d
¼ 8.03 (d, 2H, J ¼ 9.0 Hz, HeAr), 7.87 (dd, 1H, J ¼ 8.0 Hz,
J ¼ 1.0 Hz, HeAr), 7.81 (dd, 1H, J ¼ 7.5 Hz, J ¼ 1.5 Hz, HeAr), 7.66 (td,
1H, J ¼ 8.0 Hz, J ¼ 1.5 Hz, HeAr), 7.49 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.0 Hz,
HeAr), 7.03 (d, 2H, J ¼ 9.0 Hz, HeAr), 3.91 (s, 3H, OMe); 13C NMR
2.13 (s, 3H, Me); 13C NMR (125 MHz, DMSO d6)
d
¼ 141.0, 136.3,
130.0, 129.8, 126.9, 120.5, 120.4, 119.7, 118.5, 117.6, 113.8, 111.7, 109.9,
20.2 (Me), 18.9 (Me).
(125 MHz, CDCl3)
d
¼ 163.3, 153.6, 146.9, 133.5, 133.2, 130.0, 125.8,
117.1, 116.9, 114.4, 113.8, 112.5, 109.9, 55.6 (OMe).
N-(3-ethylphenyl)-3H-indazol-3-imine (3d)
4.4. N-mesityl-1H-indazol-3-amine (2f)
Orange solid (59% yield); mp ¼ 120e122 ꢀC; IR KBr(ῡmax, cmꢁ1):
White oil (36% yield); IR KBr(ῡmax, cmꢁ1): 3241.75 (NeH),
1618.75 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 8.11 (d, 1H,
1617.64 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 11.43 (s, 1H,
J ¼ 7.5 Hz, HeAr), 7.96 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.91 (td, 1H,
J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 7.85 (td, 1H, J ¼ 8.0 Hz, J ¼ 1.0 Hz,
HeAr), 7.36 (t, 1H, J ¼ 7.5 Hz, HeAr), 7.26 (d, 1H, J ¼ 8.0 Hz, HeAr),
7.16 (d, 1H, J ¼ 7.5 Hz, HeAr), 2.64 (q, 2H, J ¼ 7.5 Hz, CH2), 1.20 (t, 3H,
NeH), 7.54 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.41 (s, 1H, NeH), 7.21e7.23 (m,
2H, HeAr), 6.86 (bs, 3H, HeAr), 2.23 (s, 3H, Me), 2.11 (s, 6H, 2Me);
13C NMR (125 MHz, DMSO d6)
129.0, 128.9, 126.5, 120.5, 118.0, 114.1, 110.0, 1.9.9, 20.9(Me), 18.7
(2Me).
d
¼ 148.3, 142.0, 137.3, 135.1, 133.9,
J ¼ 7.5 Hz, Me); 13C NMR (125 MHz, DMSO d6)
d
¼ 147.7, 146.2,
1450.0, 134.3, 133.2, 132.2, 131.9, 129.2, 127.3, 124.8, 123.0, 122.7,
116.0, 28.4 (CH2), 15.8 (Me).
N-(3-bromophenyl)-1H-indazol-3-amine (2g)
White oil (32% yield); IR KBr(ῡmax, cmꢁ1): 3431.77(NeH),
N-(3,4-dimethylphenyl)-3H-indazol-3-imine (3e)
1620.37 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 12.11 (s, 1H,
Orange solid (60% yield); mp ¼ 142e144 ꢀC; IR KBr(ῡmax, cmꢁ1):
NeH), 9.11 (s, 1H, NeH), 8.08 (bs, 1H, HeAr), 7.94 (d, 1H, J ¼ 8.0,
HeAr), 7.54 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.39 (d, 1H, J ¼ 8.5, HeAr), 7.33
(t, 1H, J ¼ 8.0 Hz, HeAr), 7.19 (t, 1H, J ¼ 7.5 Hz, HeAr),7.04 (t, 1H,
J ¼ 7.5 Hz, HeAr), 6.94 (d, 1H, J ¼ 7.5 Hz, HeAr); 13C NMR (125 MHz,
1616.68 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 8.08 (dd, 1H,
J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 7.95 (d, 1H, J ¼ 7.5 Hz, HeAr), 7.89 (t,
1H, J ¼ 7.5 Hz, HeAr), 7.83 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.0 Hz, HeAr), 7.34
(s, 1H, HeAr), 7.29 (dd, 1H, J ¼ 8.0 Hz, J ¼ 2.0 Hz, HeAr), 7.22 (d, 1H,
J ¼ 8.0 Hz, HeAr), 2.26 (s, 3H, Me), 2.25 (s, 3H, Me); 13C NMR
DMSO d6)
119.0, 118.2, 115.1, 114.8, 110.2.
d
¼ 145.1, 144.7, 140.9, 130.9, 127.2, 122.3, 121.5, 120.2,
(125 MHz, DMSO d6)
d
¼ 155.5, 145.8, 145.3, 137.3, 137.0, 134.2,
N-(4-bromophenyl)-1H-indazol-3-amine (2h)
132.9, 130.4, 129.6, 127.3, 123.6, 122.7, 116.0, 19.8 (Me), 19.5 (Me).
N-mesityl-3H-indazol-3-imine (3f)
Cream solid (32% yield); IR KBr(ῡmax, cmꢁ1): 3413.51 (NeH),
1619.14 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 12.05 (s, 1H,
Red solid (59% yield); mp ¼ 141e143 ꢀC; IR KBr(ῡmax, cmꢁ1):
NeH), 9.02 (s, 1H, NeH), 7.92 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.64 (d, 2H,
J ¼ 9.0, HeAr), 7.36e7.40 (m, 3H, HeAr), 7.32 (t, 1H, J ¼ 8.5 Hz,
HeAr), 7.03 (t, 1H, J ¼ 7.0 Hz, HeAr); 13C NMR (125 MHz, DMSO d6)
1650.62 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 8.19 (d, 1H,
J ¼ 7.0 Hz, HeAr), 7.93e7.97 (m, 2H, HeAr), 7.90 (d, 1H, J ¼ 8.5 Hz,
HeAr), 7.00 (s, 1H, HeAr), 6.88 (s, 1H, HeAr), 1.96 (s, 6H, 2Me), 1.92
d
¼ 144.9, 142.8, 140.9, 132.0, 131.7, 127.2, 124.0, 120.2, 118.9, 118.0,
(s, 3H, Me); 13C NMR (125 MHz, DMSO d6)
d
¼ 157.8, 147.1, 145.1,
114.7, 110.1, 110.0.
134.6,134.0, 133.6,129.4, 128.6,126.2, 125.0, 124.0, 123.2,116.3, 20.8
(Me), 18.5 (Me), 18.0 (Me).
N-(4-chlorophenyl)-1H-indazol-3-amine (2i)
Cream solid (31% yield); 1H NMR (500 MHz, DMSO d6)
d
¼ 12.04
N-(3-bromophenyl)-3H-indazol-3-imine (3g)
(s, 1H, NeH), 9.01 (s, 1H, NeH), 7.92 (d, 1H, J ¼ 7.5 Hz, HeAr), 7.69
(dd, 2H, J ¼ 9.0 Hz, J ¼ 1.5 Hz, HeAr), 7.37 (d, 1H, J ¼ 8.5 Hz, HeAr),
7.32 (t, 1H, J ¼ 7.5 Hz, HeAr),7.27 (dd, 2H, J ¼ 9.0 Hz, J ¼ 1.5 Hz,
HeAr), 7.02 (t, 1H, J ¼ 8.0 Hz, HeAr); 13C NMR (125 MHz, DMSO d6)
Orange solid (63% yield); mp ¼ 100e102 ꢀC; 1H NMR (500 MHz,
DMSO d6)
d
¼ 8.07 (dt, 1H, J ¼ 7.5 Hz, J ¼ 1 Hz, HeAr), 7.98e7.99 (m,
1H, HeAr), 7.93 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.85 (m, 1H, HeAr),
7.83e7.84 (m, 1H, HeAr), 7.79e7.82 (m, 1H, HeAr), 7.73 (td, 1H,
J ¼ 8.0 Hz, J ¼ 1.5 Hz, HeAr), 7.59 (t, 1H, J ¼ 8.0 Hz, HeAr); 13C NMR
d
¼ 141.0, 139.3, 134.9, 128.8, 127.2, 126.4, 120.2, 118.8, 117.8, 117.6,
116.3, 110.9, 110.1.
(125 MHz, DMSO d6)
d
¼ 153.1,152.4,135.5,134.7,134.5,132.9,132.1,
N-(4-fluorophenyl)-1H-indazol-3-amine (2j)
124.8, 123.7, 123.0, 117.6, 116.8, 112.4.
Cream oil (30% yield); IR KBr(ῡmax, cmꢁ1): 3449.34 (NeH),
N-(4-bromophenyl)-3H-indazol-3-imine (3h)
5

M.S. Sajadi, A. Darehkordi and S.M.S. Hosseini
Tetrahedron 84 (2021) 132023
Orange solid (63% yield); mp ¼ 184e185 ꢀC; IR KBr(ῡmax, cmꢁ1):
ꢀ
ꢀ
[5] F. Lopez-Vallejo, R. Castillo, L. Yepez-Mulia, J.L. Medina-Franco, J. Biomol.
Screen 16 (2011) 862e868.
1701.53 (C]N); 1H NMR (500 MHz, DMSO d6)
d
¼ 8.11 (d, 1H,
[6] C. Cheekavolu, M. Muniappan, J. Clin. Diagn. Res. 10 (2016) FF01.
[7] K.W. Woods, J.P. Fischer, A. Claiborne, T. Li, S.A. Thomas, G.D. Zhu, R.B. Diebold,
X. Liu, Y. Shi, V. Klinghofer, E.K. Han, R. Guan, R.S. Magnone, E.F. Johnson,
J.J. Bouska, A.M. Olson, R.D. Jong, T. Oltersdorf, Q. Li, Bioorg. Med. Chem. 14
(2006) 6832e6846.
J ¼ 7.0 Hz, HeAr), 7.96 (d,1H, J ¼ 7.5 Hz, HeAr), 7.91 (t,1H, J ¼ 7.0 Hz,
HeAr), 7.87 (dd, 1H, J ¼ 8.0 Hz, J ¼ 1.0 Hz, HeAr), 7.64 (d, 2H, J ¼
8.5 Hz, HeAr), 7.38 (d, 2H, J ¼ 8.5 Hz, HeAr); 13C NMR (125 MHz,
DMSO d6)
127.2, 123.0, 120.6, 116.1, 115.7.
d
¼ 158.0, 157.4, 148.1, 146.7, 134.4, 133.6, 133.4, 132.2,
[8] M. Patel, J.D. Rodgers, R.J. McHugh Jr., B.L. Johnson, B.C. Cordova, R.M. Klabe,
L.T. Bacheler, S.E. Viitanen, S.S. Ko, Bioorg. Med. Chem. Lett
3217e3220.
[9] P.K. Moore, R.C. Babbedge, P.Z.A.G. Wallace, Z.A. Gaffen, S.L. Hart, Br. J. Phar-
macol. 108 (1993) 296e297.
[10] N.T. Tzvetkov, S. Hinz, P. Küppers, M. Gastreich, C.E. Müller, J. Med. Chem. 57
(2014) 6679e6703.
9 (1999)
N-(4-chlorophenyl)-3H-indazol-3-imine (3i)
Orange solid (64% yield); mp ¼ 179e180 ꢀC; IR KBr(ῡmax, cmꢁ1):
1592.42 (C]N);1H NMR (500 MHz, DMSO d6)
d
¼ 8.12 (d, 1H,
J ¼ 7.5 Hz, HeAr), 7.94 (d,1H, J ¼ 7.5 Hz, HeAr), 7.91 (t,1H, J ¼ 7.5 Hz,
HeAr), 7.87 (d, 1H, J ¼ 7.5 Hz, HeAr),7.51 (d, 2H, J ¼ 8.0 Hz, HeAr),
7.47 (d, 2H, J ¼ 8.0 Hz, HeAr); 13C NMR (125 MHz, DMSO d6)
[11] L. Soldo, A. Ruggieri, C. Milanese, M. Pinza, A. Guglielmotti, Ophthalmic Res. 36
(2004) 145e150.
[12] M.T. Gatto, B. Tita, M. Artico, L. Saso, Contraception 65 (2002) 277e278.
[13] S.K.V. Vernekar, H.Y. Hallaq, G. Clarkson, A.J. Thompson, L. Silvestri,
S.C. Lummis, M. Lochner, J. Med. Chem. 53 (2010) 2324e2328.
[14] B. Thomas, K.S. Saravanan, K.P. Mohanakumar, Neurochem. Int. 52 (2008)
990e1001.
[15] S. Antonysamy, G. Hirst, F. Park, P. Sprengeler, F. Stappenbeck, R. Steensma,
M. Wilson, M. Wong, Bioorg. Med. Chem. Lett 19 (2009) 279e282.
[16] A. Vasudevan, A.J. Souers, J.C. Freeman, M.K. Verzal, J. Gao, M.M. Mulhern,
D. Wodka, J.K. Lynch, K.M. Engstrom, S.H. Wagaw, S. Brodjian, B. Dayton,
D.H. Falls, E. Bush, M. Brune, R.D. Shapiro, K.C. Marsh, L.E. Hernandez,
C.A. Collins, P.R. Kym, Bioorg. Med. Lett. 15 (2005) 5293e5297.
[17] J.D. Rodgers, P.Y.S. Lam, B.L. Johnson, H. Wang, S.S. Ko, S.P. Seitz, G.L. Trainor,
P.S. Anderson, R.M. Klabe, L.T. Bacheler, B. Cordova, S. Garber, C. Reid,
M.R. Wright, C.H. Chang, S. Erickson-Viitanen, Chem. Biol. 5 (1998) 597e608.
[18] V. Lefebvre, T. Cailly, F. Fabis, S. Rault, J. Org. Chem. 75 (2010) 2730e2732.
[19] J. Lee, H. Choi, K.H. Kim, S. Jeong, J.W. Park, C.S. Baeka, S.H. Lee, Bioorg. Med.
Chem. Lett 18 (2008) 2292e2295.
d
¼ 157.3, 146.3, 146.2, 134.4, 133.4, 132.1, 129.3, 129.2, 127.0, 123.0,
121.3, 116.1, 109.9.
N-(4-fluorophenyl)-3H-indazol-3-imine (3j)
Cream solid (65% yield); mp ¼ 181e184 ꢀC; IR KBr(ῡmax, cmꢁ1):
1592.11 (C]N); 1H NMR (500 MHz, CDCl3)
d
¼ 8.05e8.08 (m, 2H,
HeAr),8.89 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.85 (d, 1H, J ¼ 7.5 Hz, HeAr),
7.70 (td, 1H, J ¼ 7.5 Hz, J ¼ 1.5 Hz HeAr), 7.56 (t, 1H, J ¼ 7.5 Hz,
HeAr), 7.25 (d, 1H, J ¼ 8.0 Hz, HeAr), 7.22 (t, 1H, J ¼ 9.0 Hz, HeAr);
13C NMR (125 MHz, CDCl3)
133.6, 133.2, 130.8, 125.6, 125.8, 117.1, 116.4, 116.2.
d
¼ 166.3, 162.4, 153.0, 149.8, 144.0,
Declaration of competing interest
[20] M.J. Burke, B.M. Trantow, Tetrahedron Lett. 49 (2008) 4579e4581.
[21] K. Sudheendran, D. Schmidt, W. Frey, J. Conrad, U. Beifuss, Tetrahedron 70
(2014) 1635e1645.
[22] M. Ramanathan, Y.H. Wang, S.T. Liu, Org. Lett. 17 (2015) 5886e5889.
[23] (a) Q. Wu, Y. Zhang, S. Cui, Org. Lett. 16 (2014) 1350e1353;
(b) A. Tam, I.S. Armstrong, T.E. La Cruz, Org. let. 15 (2013) 3586e3589;
(c) L.E. Evans, M.D. Cheeseman, K. Jones, Org. let. 14 (2012) 3546e3549;
(d) C.M. Counceller, C.C. Eichman, B.C. Wray, J.P. Stambuli, Org. let. 10 (2008)
1021e1023.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
[24] Y. Ishii, K. Yamawaki, T. Ura, H. Yamada, T. Yoshida, M. Ogawa, J. Org. Chem. 53
(1988) 3587e3593.
[25] K. Sato, M. Aoki, M. Ogawa, T. Hashimoto, D. Panyella, R. Noyori, Bull. Chem.
Soc. Jpn. 70 (1997) 905e915.
We are thankful to the Office of Graduate Studies of Vali-e-Asr
University of Rafsanjan, for partial support of this work.
[26] K. Sato, M. Aoki, J. Takagi, K. Zimmermann, R. Noyori, Bull. Chem. Soc. Jpn. 72
(1999) 2287e2306.
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6