Reductive heterocyclizations via indium-iodine-promoted conversion of 2-nitroaryl imines or 2-nitroarenes to 2,3-diaryl-substituted indazoles

Article abstract of DOI:10.1039/b707240f

While N-(2-nitrobenzylidene)anilines produced mixtures of 2,1-benzisoxazoles and 3-anilino-2-aryl-2H-indazoles in the presence of indium and iodine in MeOH, N-(2-nitrobenzylidene)anilines were transformed into 3-anilino-2-aryl-2H-indazoles as the predominant major product through the change of the solvent from protic MeOH to aprotic THF. In an indium-mediated one-pot reductive reaction, 2-benzaldehydes and anilines in THF were also successfully transformed into the corresponding indazoles. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b707240f

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Reductive heterocyclizations via indium–iodine-promoted conversion of
2-nitroaryl imines or 2-nitroarenes to 2,3-diaryl-substituted indazoles
Gil Hwan Ahn,a Jung June Lee,a Young Moo Jun,a Byung Min Leeb and Byeong Hyo Kim*a
Received 14th May 2007, Accepted 8th June 2007
First published as an Advance Article on the web 28th June 2007
DOI: 10.1039/b707240f
While N-(2-nitrobenzylidene)anilines produced mixtures of 2,1-benzisoxazoles and
3-anilino-2-aryl-2H-indazoles in the presence of indium and iodine in MeOH,
N-(2-nitrobenzylidene)anilines were transformed into 3-anilino-2-aryl-2H-indazoles as the
predominant major product through the change of the solvent from protic MeOH to aprotic THF. In
an indium-mediated one-pot reductive reaction, 2-benzaldehydes and anilines in THF were also
successfully transformed into the corresponding indazoles.
Thus, of special interest to us is the possibility of utilizing
the indium-promoted reaction for the efficient synthesis of 2,3-
The indazole subunit in organic molecules is an important
disubstituted indazoles as an extension of the study on the
Introduction
structure in many drug substances with a wide range of phar-
macological effects: e.g. antitumor,1 antimicrobial,2 antiplatelet,3
reductive cyclization reaction of 2-nitroarenes, as only a limited
number of applications of indium, other than carbon–carbon
anti-HIV,4 and anti-iflammatory.5 For the construction of the 2H-
indazole skeleton, the reduction of N-(2-nitrobenzylidene)amines
using triethylphosphite, and the thermal decomposition of N-(2-
azidobenzylidene)amines are widely used;6a,6b other approaches
for the construction of the 2H-indazole skeleton such as
transition-metal catalyzed reactions were also employed.6c Re-
cent examples of syntheses of 2H-indazoles include the fol-
lowing: copper-mediated cyclizations of 1-(2-ethynylphenyl)-3,3-
dialkyltriazenes,7 DDQ oxidation of pyrazoles made from the
Baylis–Hillman adducts of 2-cyclohexen-1-one,8 and cyclizations
of o-nitrobenzylamines under ethanolic conditions.9 There are
few reports, however, of general and efficient syntheses of N-
substituted indazoles.
In our previous study of heterocyclic compound formation
via the reductive cyclization reaction of nitroarenes,10 it was
found that the nitro group can be reduced through chemical or
electrochemical methods, and it can trigger heterocycliza-
tion towards nitrogen-containing heterocycles, such as 2,1-
benzisoxazoles, benzotriazoles, benzimidazoles, and quinolines
when it has a proper functional group such as carbonyl or imino
group at the ortho position. Moreover, reductive heterocyclizations
using indium were also successfully used in transformations
forming heterocyclic compounds such as 2,1-benzisoxazoles,10i
benzimidazoles,10l and quinolines.10m These indium-mediated re-
ductive heterocyclizations are noteworthy as indium has been
receiving increasing interest due to its applications in organic
transformations.11 In particular, among the applications of indium
in organic chemistry, indium-mediated reactions in aqueous media
have been focused on for synthetic applications because of
environmental issues and the ease of these reactions, which obviate
the need for inflammable anhydrous organic solvents and inert
atmospheres.11b
bond formation, are found in the literature.12 Thus, the one-pot
synthetic approach to new 2,3-disubstituted indazoles through
the direct conversion of 2-nitro-substituted iminobenzenes using
indium and iodine, which can be useful in biological, agricultural,
and industrial applications, is reported herein.13 As far as we know,
there are few applicable general methods for the synthesis of 2,3-
disubstituted indazole derivatives, and all the indazoles that were
synthesized in this study were new compounds accordingly.
Results and discussion
As indium and related reagents turned out to have reasonable
reductive properties, heterocyclizations of substituted 2-nitroben-
zaldehydes, 2ꢀ-nitroacetophenone, and 2-nitrobenzophenones
were examined in a preliminary study.14 As described in this earlier
communication, the reductive cyclization reactions of 2-nitroaryl
aldehydes and ketones to 2,1-benzisoxazoles appear generally
applicable in most cases, and all of the substrates were consumed
within 1.5–6 hours to give the corresponding 2,1-benzisoxazoles
in 80–95% yields. However, the reductive cyclization of N-(2-
nitrobenzylidene)aniline in the presence of indium–iodine in
MeOH produced a mixture of 2,1-benzisoxazole (56%) and 3-
anilino-2-phenyl-2H-indazole (27%) (Table 1, entry 1).
The formation of 3-anilino-2-phenyl-2H-indazole was some-
what unexpected, and the reactions of halo- or methoxy- sub-
stituted N-(2-nitrobenzylidene)anilines exhibited similar results,
producing mixtures of 2,1-benzisoxazoles and 3-anilino-2-phenyl-
2H-indazoles (entries 2–4). It is presumed that the formation
of 3-anilino-2-phenyl-2H-indazoles might have occurred due to
the nucleophilic participation of in situ-formed anilines, which
are supposed to be leaving groups when 2,1-benzisoxazoles are
formed. As indazole derivatives have also attracted much attention
due to their pharmaceutical activities, and as the 2,3-disubstituted
indazole derivatives in this study are new compounds that could
not be easily synthesized using any of the known conventional
methods, it is thought that a reinvestigatiton at the point of the
aDepartment of Chemistry, Kwangwoon University, Seoul, 139-701, Korea.
E-mail: bhkim@kw.ac.kr; Fax: +82 29 424 635; Tel: +82 29 405 247
bKorea Research Institute of Chemical Technology, Taejon, 305-600, Korea
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Table 1 Reductive cyclization of the 2-nitroiminobenzenes (1.0 mmol) in the presence of indium (3.0 equiv.) and iodine (0.8 equiv.) in MeOH (3 ml) at
50 ◦C.14
Entry
1
Substrate
Time/h
4
Product (% yielda)
+
+
2
6
3
4
6
6
+
+
5
6
a Isolated yield. b Trace amount of N-[(2-amino-3-methoxyphenyl)methylene]benzamine was observed.
reductive cyclization reactions of N-(2-nitrobenzylidene)aniline
derivatives to the indazoles as the major product instead of 2,1-
benzisoxazoles would be valuable. Thus, it was decided that the
reaction would be controlled, focusing on the 3-anilino-2-phenyl-
2H-indazole formation to develop a new and valuable synthetic
methodology for the one-pot reductive indazole synthesis from
nitroarenes. Thus, various reaction conditions were carefully
reinvestigated to find the indazole-formation-favored reaction
conditions.
best results in terms of indazole formation. The reaction of N-
[(2-nitrophenyl)methylene]benzene (1.0 mmol), indium (3 equiv.),
iodine (0.8 equiv.) and aniline (20 equiv.) in THF at 50 ◦C
produced the desired (2-phenyl-2H-indazol-3-yl)phenylamine (2)
in a 75% isolated yield (entry 8), accompanied by only a small GC-
detectable amount of 2,1-benzisoxazole as a by-product, which
was the most desired result of this study.
To test the usefulness of the newly developed reaction con-
ditions for the synthesis of indazole derivatives, various N-(2-
nitrobenzylidene)anilines (i.e. 2-nitroiminobenzene derivatives)
were examined using the optimized reaction conditions. For
the starting substrate, 2-nitroiminobenzenes were prepared using
diversely substituted 2-nitrobenzaldehydes and 4-substituted ani-
lines as shown in eqn (1).
1) Indium-mediated reductive reaction of
N-(2-nitrobenzylidene)anilines in the presence of aniline additive
whose structure is the same as that of the anilino-subunit of the
N-(2-nitrobenzylidene)anilines
As was assumed, the indazoles might have come from the contribu-
tion of in situ-formed anilines. First, how the aniline concentration
influences the reaction was checked by adding the corresponding
aniline to the reaction mixture. Thus, heterocyclizations of N-
[(2-nitrophenyl)methylene]benzene in the presence of an excess
amount of aniline that was a leaving group of the reaction were
examined. A reaction of N-(2-nitrobenzylidene)aniline in the pres-
ence of indium (3 equiv.), iodine (0.8 equiv.), and aniline (20 equiv.)
in MeOH showed an improved indazole–2,1-benzisoxazole ratio
(Table 2, entry 2) compared to the same reaction without aniline
additive. However, 2,1-benzisoxazole was still one of the major
products. In the mean time, as shown in Table 2, by changing
the solvent from protic MeOH to aprotic solvent, the formation
of 2,1-benzisoxazole was drastically reduced (Table 2, entries 4–
15). Among the aprotic solvents that were tried, THF showed the
(1)
In most cases, 2-nitroiminobenzenes were successfully cyclized,
giving the desired indazoles within 4 hours in moderate to
good yields, as shown in Table 3, independent of the posi-
tions and characters of the substituent, R, which were H, Cl,
Me, OMe, and OCH2O. For the anilino site, the structure
of Rꢀ somehow influenced the direction of the heterocycliza-
tion of 2-nitroiminobenzenes. The heterocyclizations of N-(2-
nitrobenzylidene)anilines to give the desired indazoles worked
well when Rꢀ was H, an electronegative fluoro atom, or a
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Table 2 Indium-mediated reductive heterocyclizations of the N-(2-nitrobenzylidene)aniline (1.0 mmol) under various reaction conditions
Entry
In–I2–aniline (equiv.)
Solvent
T/◦C
50 ◦
Time/h
Product (% yielda 1 : 2)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
3 : 0.8 : 0
MeOH (3 ml)
MeOH (3 ml)
THF–H2O (3 ml, 1 ml)
CH3CN (3 ml)
CHCl3 (3 ml)
CH2Cl2 (3 ml)
THF (5 ml)
THF (5 ml)
THF (5 ml)
THF (3 ml)
THF (3 ml)
C
4
4
5
5
8
8
6
4
4
12
6
6
10
6
3
56 : 27
27 : 30
3 : 0.8 : 20
3 : 0.8 : 20
3 : 0.8 : 20
3 : 0.8 : 20
3 : 0.8 : 20
3 : 0.8 : 10
3 : 0.8 : 20
3 : 0.8 : 30
3 : 0.8 : 20
3 : 0.8 : 20
3 : 1.5 : 20
2 : 0.8 : 20
4 : 0.8 : 20
3 : 0.8 : 20
50 ◦C
50 ◦
50 ◦
50 ◦
50 ◦
50 ◦
50 ◦
50 ◦
rt
C
C
C
C
C
C
C
trace : 22b
trace : 25b
trace : 38b
trace : 50b
trace : 71
trace : 75 (82b)
trace : 70
trace : 38
trace : 60
trace : 30
trace : 30
trace : 38
trace : 68
50 ◦
50 ◦
50 ◦
50 ◦
C
C
C
C
THF (3 ml)
THF (3 ml)
THF (3 ml)
THF (5 ml)
reflux
a Isolated yield. b GC yield with an internal standard.
hyperconjugative electron-donating methyl group. However, when
Rꢀ was the relatively strong electron-donating methoxy group, the
reaction produced an indazole and 2,1-benzisoxazole mixture, as
shown in Table 4. At the moment, it is not clear why electron-
rich aryl substituents of iminobenzenes favor the formation of
2,1-benzisoxazoles.
substituted product (13) was increased gradually with the addition
of more p-toluidine to the reaction mixture, and the reactions of
N-[(2-nitrophenyl)methylene]benzene in the presence of indium
(3 equiv.), iodine (0.8 equiv.), and more than 10 equiv. of p-
toluidine produced p-tolyl-substituted indazole (13) as the major
product. The mixed substituted products 34 and 35 (the exact
structure of each compound, whether 34 or 35, was not deter-
mined) were observed when less than 10 equiv. of p-toluidine were
used. It is evident that externally added p-toluidine controls the
structure of the 2,3-substituents of indazole. Without doubt, the
structure of C in eqn (2) came from structure B of the added
aniline.
2) Indium-mediated reductive reaction of
N-(2-nitrobenzylidene)anilines in the presence of aniline additive
whose structure is different from the anilino subunit of the
N-(2-nitrobenzylidene)anilines
The following question arose after the results of the indium-
mediated reductive reaction of N-(2-nitrobenzylidene)anilines in
the presence of aniline additive whose structure is the same as
those of anilino subunit of N-(2-nitrobenzylidene)anilines (i.e. the
A = B system in eqn (2)), were obtained: should the structure of
the added aniline (B) be the same as that of the imino part (A)
of the substrate? Since the substituents at the 2- and 3-positions
of the indazole product seem to have come from the excessively
added anilines, the original structure of A may not be left over
as the 2,3-substituents of the product. Thus, even if the aniline
(B) whose structure is different from that of A were added, the
resulting product may produce the 2,3-aryl-substituted indazole
product with a C = B structure (eqn (2)).
Thus the reactions of various N-(2-nitrobenzylidine)anilines
(R = H, Cl, OMe, OCH2O; Rꢀ = H) in the presence of an excess
of various 4-Rꢀ-substituted anilines were examined, and the B = C
structure in eqn (2) was expected to be seen. The results are shown
in Table 6. The reactions gave the indazole product with the B =
C structure, as expected. In most cases, the yield of each reaction
was slightly lower than the yields of the reactions described in
Table 4, while the yield of the reactions when 4-methoxyaniline
was used improved compared to the reactions described in Table 4.
Without doubt, the reactions of N-(2-nitrobenzylidine)anilines in
the presence of an excess of 4-Rꢀ-substituted anilines could be as
useful as the reactions shown in Table 3 for the syntheses of diverse
2,3-disubstituted indazoles.
3) Indium-mediated reductive reaction directly starting from
2-nitrobenzaldehydes and anilines toward indazoles
As mentioned earlier, the starting substrates, 2-nitroimino-
benzenes, were prepared from the reactions of 2-nitroben-
zaldehydes with anilines in the presence of MgSO4 in THF at
room temperature. In addition, the cyclization reactions of 2-
nitroiminobenzenes to give indazoles were also done in THF. As
long as both the 2-nitroiminobenzene preparation reaction and the
(2)
To verify the effect of the added aniline, several con-
trol experiments were conducted (Table 5), where varied
amounts of p-toluidine were added to the reaction of N-(2-
nitrobenzylidene)aniline. As expected, the amount of p-tolyl-
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Table 3 Indium-mediated reactions of 2-nitroiminobenzenes (0.2 M) in the presence of indium (3 equiv.), iodine (0.8 equiv.), and anilines (20 equiv.)
whose structure is the same as that of the anilino subunit of the N-(2-nitrobenzylidene)anilines in THF at 50 ◦Ca
Entry
1
Substrate
Time/h
4
Product (% yieldb)
2
3
4
4
4
4
5
4
6
7
4
4
4
4
3
4
8
9
10
11
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Table 3 Cont.
Entry
12
Substrate
Time/h
4
Product (% yieldb)
13
14
15
16
17
18
4
4
4
4
4
3
19
20
3
4
a Most reactions produced trace to several % of 2,1-benzisoxazoles as a by-product. b Isolated yield. c 22% of 2,1-benzisoxazole was observed.
following cyclizations of 2-nitroiminobenzenes to give indazoles
are done in the same solvent using similar reaction conditions, a
one-pot reaction would be possible instead of a two-step synthesis.
Thus, the one-pot synthesis starting from 2-nitrobenzaldehydes
was examined. First, 2-nitrobenzaldehyde in the presence of 20
equiv. of aniline and Na2SO4 (4 equiv.) in THF was stirred
for 12 hours to obtain the corresponding 2-nitroiminobenzene
in situ, then it was mixed with indium (3 equiv.) and iodine
(0.8 equiv.) in THF for the reductive cyclization to indazole. The
procedure worked well, as expected, with a 52% yield, which was
slightly lower than that of the two-step synthesis. It is believed
that the reduced yield was caused primarily by the loss of the
product when the solution was transferred by cannula, since the
reaction scale is quite small for cannular transferring. It would
also be useful, however, to consider that the overall yield of the
previous two-step synthesis is 69% [(i) imine preparation, 92%;
and (ii) reductive cyclization, 75%, in entry 1, Table 3]. Thus,
various substituted benzaldehydes were examined under these
one-pot reaction conditions for the synthesis of 2,3-disubstituted
indazoles. The results are summarized in Table 7. Most of the
reactions worked well with reasonable yields. Moreover, some of
the reactions showed better yields compared to the previous two-
step synthesis (entries 2, 6, 9, 11, 13, and 14 in Table 7).
As described in three sections (1), (2), and (3), all the reaction
conditions were successful for indazole synthesis. Moreover, based
on the results, we could propose that reductive cyclizations may
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Table 4 Indium-mediated reactions of 2-nitroiminobenzenes (Rꢀ = OMe) (0.2 M) in the presence of indium (3 equiv.), iodine (0.8 equiv.), and aniline
(20 equiv.) in THF at 50 ◦
C
Product (% yielda)
Entry
1
Substrate
Time/h
2
A
B
2
3
4
2
3
2
trace
5
2
2
6
a Isolated yield.
Table 5 Indium-mediated reductive reaction of the N-(2-nitrobenzylidene)aniline (1 mmol, 0.2 M) in the presence of indium (3 equiv.), iodine (0.8 equiv.),
and p-toluidine (20 equiv.) in THF at 50 ◦
C
Product (% yielda)
Entry
p-Toluidine/equiv.
Time/h
2
34/35 (or 35/34)
13
1
2
3
4
5
6
7
0.5
1
2
3
5
10
20
5
5
4
4
4
3
3
12
8
3
7/6
12/14
10/15
5/8
2/2
1/1
5
12
35
38
48
51
52
1
—
—
—
—
a GC yield with an internal standard and structure of 34 and 35 was determined by GCMS only. All reactions produced GC-detectable amount of
2,1-benzisoxazoles.
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Table 6 Indium-mediated reactions of the 2-nitroiminobenzenes (0.2 M) in the presence of indium (3 equiv.)/iodine (0.8 equiv.) and aniline additive
(20 equiv.) whose structure is different from that of the anilino-subunit of the N-(2-nitrobenzylidene)anilines in THF at 50 ◦
C
Product (% yielda)
Entry
1
Substrate
Time/h
3
Rꢀ
A
B
CH3
trace
2
3
4
3
3
3
CH3
CH3
CH3
trace
trace
5
6
3
3
CH3
CH3
trace
trace
trace
trace
7
8
3
3
3
3
F
F
F
F
9
10
trace
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Table 6 Cont.
Product (% yielda)
Entry
11
Substrate
Time/h
3
Rꢀ
F
A
B
trace
12
13
14
15
2
2
2
2
OCH3
OCH3
OCH3
OCH3
trace
trace
16
2
OCH3
a Isolated yield.
start at the same stage, i.e. N-(2-nitrobenzylidene)aniline, which is
the starting substrate in section (1). A plausible path for indazole
(major) and 2,1-benzisoxazole (trace or minor in THF, major in
MeOH) formation is shown in Scheme 1. Loss of water can be
a good driving force for the indazole-formation reaction, which
is possibly caused by the push–pull assistance of aniline and
aromatization of the product.
Experimental
1. General considerations
Most of the chemical reagents were purchased from Aldrich and, in
most cases, were used without further purification. Solvents were
purchased and dried using the standard method. 1H NMR spectra
were recorded on a 400 MHz Jeol instrument, and 13C NMR spec-
tra were recorded on a 100 MHz Jeol instrument. Chemical shifts
were reported in ppm relative to the residual solvent as an internal
standard. HRMS spectra were recorded on a JEOL JMS-DX 303
mass spectrometer and GC/MS were recorded on an HP6890 mass
spectrometer. Infrared (IR) spectra were recorded using MB104
FTIR (ABB Bomem Inc.). Melting points were determined on
an electrothermal apparatus and were uncorrected. All the major
products were isolated by flash column chromatography on silica
gel (230–400 mesh ATSM, purchased from Merck) with eluents
of mixed solvents (ethyl acetate and hexane).
Conclusion
New indium-mediated reductive cyclizations towards indazoles
were developed in three different ways. One way is the indium-
mediated reductive reaction of N-(2-nitrobenzylidene)anilines in
the presence of aniline additive whose structure is the same as that
of the anilino subunit of N-(2-nitrobenzylidene)anilines. Another
way is the similar reductive reaction of N-(2-nitrobenzylidene)-
anilines in the presence of aniline additive whose structure is
different from that of the anilino subunit of N-(2-nitrobenzyl-
idene)anilines. The third method is an indium-mediated reductive
reaction starting from 2-nitrobenzaldehydes and anilines to give
indazoles, which is an efficient one-pot preparation of inda-
zoles under mild conditions. In conclusion, a simple and
efficient method for the preparation of indazoles from 2-nitro-
benzaldehydes or N-(2-nitrobenzylidene)anilines using indium–
iodine in THF under mild conditions is described in this paper.
2. General procedure for the reductive intermolecular coupling
reaction
2-1. Indium-mediated reductive reaction of N-(2-nitrobenzy-
lidene)anilines in the presence of aniline. The N-(2-nitro-
benzylidene)aniline derivative (1.0 mmol) was added to a mixture
of indium powder (345 mg, 3.0 mmol) and iodine (203 mg,
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Table 7 Indium-mediated reductive reactions starting from the 2-nitrobenzaldehydes and anilines yielding indazoles
Entry
1
Substrate
Time/h
4
Rꢀ
H
Product (% yielda)
2
3
4
4
3
3
H
H
H
5
3
H
6
7
3
3
4
4
4
4
H
H
8
CH3
CH3
CH3
CH3
9
10
11
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Table 7 Cont.
Entry
12
Substrate
Time/h
4
Rꢀ
Product (% yielda)
CH3
13
14
15
16
17
18
4
4
4
4
4
4
CH3
CH3
F
F
F
F
19
20
4
4
F
F
a Isolated yield. b Combined yield of two-step synthesis (eqn (1) and Table 3).
0.8 mmol) in THF (5 ml). The reaction mixture was stirred at 50 ◦C
under a nitrogen atmosphere. After the reaction was complete,
the reaction mixture was diluted with CH2Cl2 (30 ml), filtered
through Celite, poured into a 10% NH4Cl solution, and extracted
with CH2Cl2 (3 × 30 ml). The combined organic extracts were
dried over MgSO4, filtered, and concentrated. The residue was
eluted with ethyl acetate–hexane (v/v = 2/98–20/80) through a
silica gel column to give the corresponding indazoles in 22–75%
yield. The structures of the indazoles were fully characterized
by 1H NMR, 13C NMR, FTIR, MS, and HRMS. The X-ray
crystal structure of one of the indazoles, (4-chloro-2-phenyl-2H-
indazole-3-yl)phenylamine, was obtained for decisive structure
determination.14
2-2. Indium-mediated reductive reaction starting from 2-nitro-
benzaldehydes and anilines to give indazoles. To a solution of 2-
nitrobenzaldehyde in THF (2 ml), aniline (1.9 g, 20 mmol) and
Na2SO4 (574 mg, 4 mmol) were added, and the mixture was
stirred for 12 hours at 50 ◦C. After the reaction was complete,
the mixture was transferred into another round-bottomed flask,
using a filter-tipped cannula to remove the Na2SO4, and was
washed with THF (3 ml). To the transferred solution, indium
powder (345 mg, 3 mmol) and iodine (203 mg, 0.8 mmol) were
added, and the mixture was stirred at 50 ◦C under a nitrogen
atmosphere. The completed reaction mixture was filtered through
Celite, poured into a 1% HCl solution, and extracted with CH2Cl2
(3 × 30 ml). The resulting extracts were dried over MgSO4, filtered,
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Scheme 1
concentrated, and purified by column chromatography on silica
gel, using ethyl acetate–hexane. The corresponding indazoles were
obtained in 14–58% yield.
(7-Methoxy-2-phenyl-2H-indazol-3-yl)phenylamine (8). White
solid; TLC (30% ethyl acetate–hexane) Rf 0.41; mp 183.7–186.2 ◦C
(ethyl acetate–hexane); mmax(KBr)/cm−1 3200, 3098, 3027, 1703,
1604 and 1503; 1H NMR (300 MHz, CDCl3; Me4Si) d = 7.67 (3H,
d, J 6.8 Hz, Ph), 7.53–7.30 (3H, m, Ph), 7.23 (3H, dd, J 8.3 and
7.7 Hz, Ph), 6.93 (3H, d, J 7.9 Hz, Ph), 6.80 (1H, d, J 7.7 Hz, Ph),
6.58 (1H, d, J 7.9 Hz, Ph), 5.70 (1H, s, NH) and 4.04 (3H, s, OCH3)
ppm; 13C NMR (75 MHz; CDCl3; Me4Si) d = 150.3, 143.6, 141.9,
138.4, 132.7, 129.4, 129.1, 128.5, 125.1, 121.8, 120.6, 117.3, 115.1,
112.1, 103.3 and 55.4 ppm; m/z (EI) 315.1376 (M+ C20H17N3O
requires 315.1372), 300 (18), 286 (19), 79 (11) and 77 (22).
(2-Phenyl-2H-indazol-3-yl)phenylamine (2). White solid, TLC
(30% ethyl acetate–hexane) Rf 0.51; mp 152.0–153.9 ◦C (ethyl
acetate–hexane); mmax(KBr)/cm−1 3222, 3182, 3121, 1927, 1776 and
1601; 1H NMR (300 MHz, CDCl3; Me4Si) d = 7.70–7.60 (3H, m,
Ph), 7.47–7.35 (4H, m, Ph), 7.32–7.19 (3H, m, Ph), 7.00–6.88 (2H,
m, Ph), 6.80 (2H, m, Ph) and 5.77 (1H, s, NH) ppm; 13C NMR
(75 MHz; CDCl3; Me4Si) d = 148.4, 143.8, 138.6, 123.3, 129.4,
129.2, 128.4, 127.0, 124.8, 121.1, 120.5, 120.2, 118.0, 115.8 and
115.0 ppm; m/z (EI) 285.1264 (M+ C19H15N3 requires 285.1266),
269 (6) and 167 (6).
(7-Methyl-2-phenyl-2H-indazol-3-yl)phenylamine (10). White
solid; TLC (30% ethyl acetate–hexane) Rf 0.55; mp 161–162 ◦C
(ethyl acetate–hexane); mmax(KBr)/cm−1 3215, 3114, 2955, 1597,
1
1532 and 1360; H NMR (400 MHz, CDCl3; Me4Si) d = 7.62
(4-Chloro-2-phenyl-2H-indazol-3-yl)phenylamine (4). White
solid; TLC (30% ethyl acetate–hexane) Rf 0.46; mp 178.4–180.1 ◦C
(ethyl acetate–hexane); mmax(KBr)/cm−1 3225, 3036, 1601, 1256,
749 and 690; 1H NMR (300 MHz, CDCl3; Me4Si) d = 7.67–7.58
(3H, m, Ph), 7.40–7.29 (3H, m, Ph), 7.21–7.11 (3H, m, Ph),
7.00 (1H, d, J 7.1 Hz, Ph), 6.82 (1H, dd, J 7.3 and 7.5 Hz,
Ph), 6.57 (2H, d, J 7.7 Hz, Ph) and 5.92 (1H, s, NH) ppm; 13C
NMR (75 MHz; CDCl3; Me4Si) d = 149.2, 145.5, 138.6, 132.5,
129.2, 129.0, 128.5, 127.1, 125.3, 124.5, 121.8, 120.3, 116.8, 115.1
and 114.7 ppm; m/z (EI) 319.0874 (M+ C19H14ClN3 requires
319.0876), 283 (11), 207 (9), 178 (7) and 77 (23).
(2H, d, J 7.8 Hz, Ph), 7.42–7.45 (2H, m, Ph), 7.36–7.39 (1H, m,
Ph), 7.19–7.23 (3H, m, Ph), 7.05 (1H, d, J 6.1 Hz, Ph), 6.87–6.91
(2H, m, Ph), 6.76 (2H, d, J 8.0 Hz, Ph), 5.65 (1H, s, NH) and 2.64
(3H, s, CH3) ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 148.68,
143.85, 138.68, 132.47, 129.43, 129.28, 128.47, 128.04, 125.88,
125.11, 121.41, 120.44, 117.60, 115.45, 114.90 and 16.78 ppm;
m/z (EI) 299.1432 (M+ C20H17N3 requires 299.1422), 283 (14), 268
(3), 207 (9) and 77 (25).
(5-Methyl-2-phenyl-2H-indazol-3-yl)phenylamine (11). White
solid; TLC (30% ethyl acetate–hexane) Rf 0.48; mp 184–185 ◦C
(ethyl acetate–hexane); mmax(KBr)/cm−1 3233, 3056, 2910, 1602,
1499 and 1319; 1H NMR (400 MHz, CDCl3; Me4Si) d = 7.61–7.65
(3H, m, Ph), 7.44–7.48 (2H, m, Ph), 7.38–7.42 (1H, m, Ph), 7.22–
7.26 (2H, m, Ph), 7.15–7.17 (2H, m, Ph), 6.92 (1H, t, J 7.6 Hz, Ph),
6.78 (2H, d, J 7.6 Hz, Ph), 5.60 (1H, s, NH) and 2.36 (3H, s, CH3)
ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 147.51, 144.24,
138.79, 131.11, 130.85, 130.05, 129.52, 129.22, 128.35, 124.77,
120.31, 117.92, 117.84, 116.51, 114.64 and 21.72 ppm; m/z (EI)
299.1418 (M+ C20H17N3 requires 299.1422), 283 (11), 192 (6), 165
(5) and 116 (6).
(5-Chloro-2-phenyl-2H-indazol-3-yl)phenylamine (6). White
solid; TLC (30% ethyl acetate–hexane) Rf 0.43; mp 179–181 ◦C
(ethyl acetate–hexane); mmax(KBr)/cm−1 3232, 3130, 3037, 1937
1
and 1601; H NMR (300 MHz, CDCl3; Me4Si) d = 7.64–7.59
(3H, m, Ph), 7.52–7.36 (4H, m, Ph), 7.28–7.21 (3H, m, Ph), 6.94
(1H, dd, J 7.3 and 7.1 Hz, Ph), 6.77 (2H, d, J 7.7 Hz, Ph) and
5.70 (1H, s, NH) ppm; 13C NMR (75 MHz; CDCl3; Me4Si) d =
146.7, 143.5, 138.3, 132.0, 129.6, 129.3, 128.8, 128.4, 126.7, 125.1,
124.7, 120.9, 119.6, 118.8, 116.1, 115.4 and 115.0 ppm; m/z (EI)
319.0877 (M+ C19H14ClN3 requires 319.0876), 283 (10), 178 (6)
and 77 (23).
(2-Phenyl-2H-5,7-dioxa-1,2-diaza-s-indacen-3-yl)-phenylamine
(12). White solid; TLC (30% ethyl acetate–hexane) Rf 0.44; mp
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205–206.5 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3261, 2908,
1507, 1208, 835 and 742; 1H NMR (400 MHz, CDCl3; Me4Si) d =
7.58–7.61 (2H, m, Ph), 7.40–7.44 (2H, m, Ph), 7.33–7.37 (1H, m,
Ph), 7.20–7.26 (2H, m, Ph), 6.96 (1H, s, Ph), 6.88 (1H, t, J 7.4 Hz,
Ph), 6.73 (2H, dd, J 8.2 and 0.8 Hz, Ph), 6.57 (1H, s, Ph), 5.91
(2H, s, CH2) and 5.52 (1H, s, NH) ppm; 13C NMR (100 MHz;
CDCl3; Me4Si) d = 149.87, 146.11, 145.22, 144.20, 138.84, 131.52,
129.56, 129.20, 127.97, 124.38, 120.28, 114.56, 112.12, 100.97,
94.61 and 94.44 ppm; m/z (EI) 329.1163 (M+ C20H15N3O3 requires
329.1164), 313 (3), 270 (4) and 77 (17).
141.60, 141.28, 137.96, 135.91, 132.96, 129.64, 129.42, 129.30,
124.49, 120.97, 116.78, 114.99, 112.16, 102.81, 55.05, 20.89 and
20.33 ppm; m/z (EI) 343.1692 (M+ C22H21N3O requires 343.1685),
328 (14), 314 (16), 208 (6), 193 (6) and 106 (5).
[7-Methyl-2-(4-methylphenyl)-2H-indazol-3-yl]-4-methylphenyl-
amine (17). White solid; TLC (30% ethyl acetate–hexane) Rf
0.61; mp 192.5–194 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1
3232, 3034, 2919, 1610, 1544 and 748; 1H NMR (400 MHz,
CDCl3; Me4Si) d = 7.50–7.53 (2H, m, Ph), 7.25–7.27 (2H, m, Ph),
7.19 (1H, d, J 8.4 Hz, Ph), 7.02–7.06 (3H, m, Ph), 6.87 (1H, dd,
J 8.4 and 1.7 Hz, Ph), 6.71–6.74 (2H, m, Ph), 5.54 (1H, s, NH),
2.64 (3H, s, CH3), 2.40 (3H, s, CH3) and 2.28 (3H, s, CH3) ppm;
13C NMR (100 MHz; CDCl3; Me4Si) d = 148.61, 141.36, 138.51,
136.23, 133.10, 129.97, 129.91, 129.85, 127.89, 125.75, 125.00,
120.99, 117.74, 115.35, 114.90, 21.12, 20.52 and 16.79 ppm; m/z
(EI) 327.1737 (M+ C22H21N3 requires 327.1735), 311 (9), 205 (5)
and 91 (10).
[2-(4-Methylphenyl)-2H-indazol-3-yl]-4-methylphenylamine (13).
White solid; TLC (30% ethyl acetate–hexane) Rf 0.53; mp 162–
163 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3404, 3057, 2984,
1611, 1516 and 1264; 1H NMR (400 MHz, CDCl3; Me4Si) d = 7.69
(1H, d, J 8.0 Hz, Ph), 7.52 (2H, d, J 8.0 Hz, Ph), 7.36 (1H, d, J
8.0 Hz, Ph), 7.26–7.31 (3H, m, Ph), 7.05 (2H, d, J 8.0 Hz, Ph), 6.96
(1H, t, J 8.0 Hz, Ph), 6.75 (2H, d, J 8.0 Hz, Ph), 5.61 (1H, s, NH),
2.40 (3H, s, CH3) and 2.30 (3H, s, CH3) ppm; 13C NMR (100 MHz;
CDCl3; Me4Si) d = 148.34, 141.21, 138.54, 136.09, 132.86, 130.09,
129.95, 129.85, 126.84, 124.68, 120.66, 120.32, 117.86, 115.39,
115.15, 21.13 and 20.52 ppm; m/z (EI) 313.1576 (M+ C21H19N3
requires 313.1579), 297 (16), 192 (8), 165 (5) and 106(5).
[5-Methyl-2-(4-methylphenyl)-2H-indazol-3-yl]-4-methylphenyl-
amine (18). White solid; TLC (30% ethyl acetate–hexane) Rf
0.57; mp 162–163 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1
3262, 3029, 2918, 1615, 1514 and 798; 1H NMR (400 MHz,
CDCl3; Me4Si) d = 7.58 (1H, d, J 8.8 Hz, Ph), 7.47 (2H, d, J
8.3 Hz, Ph), 7.21 (2H, d, J 8.3 Hz, Ph), 7.11–7.14 (2H, m, Ph),
7.01 (2H, d, J 8.3 Hz, Ph), 6.68 (2H, d, J 8.3 Hz, Ph), 5.87
(1H, s, NH), 2.37 (3H, s, CH3), 2.34 (3H, s, CH3) and 2.29 (3H, s,
CH3) ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 147.32,
141.74, 138.33, 136.21, 131.57, 130.36, 129.97, 129.84, 129.76,
129.62, 124.55, 118.05, 117.66, 115.98, 114.80, 21.69, 21.12 and
20.52 ppm; m/z (EI) 327.1728 (M+ C22H21N3 requires 327.1735),
311 (10), 206 (5) and 91 (10).
[4-Chloro-2-(4-methylphenyl)-2H-indazol-3-yl]-4-methylphenyl-
amine (14). Pale yellowish white solid; TLC (30% ethyl acetate–
hexane) Rf 0.56; mp 223–224.5 ◦C (ethyl acetate–hexane);
1
mmax(KBr)/cm−1 3407, 3057, 2985, 1617, 1264 and 735; H NMR
(400 MHz, CDCl3; Me4Si) d = 7.60 (1H, d, J 8.6 Hz, Ph), 7.55
(2H, d, J 8.30 Hz, Ph), 7.17–7.21 (3H, m, Ph), 6.99 (1H, d, J
7.08 Hz, Ph), 6.95 (2H, d, J 8.30 Hz, Ph), 6.49 (2H, d, J 8.30 Hz,
Ph), 5.75 (1H, s, NH), 2.35 (3H, s, CH3) and 2.23 (3H, s, CH3)
ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 149.13, 143.24,
138.60, 136.28, 132.87, 129.80, 129.72, 129.68, 127.01, 125.38,
124.33, 121.60, 116.81, 115.01, 114.87, 21.13 and 20.50 ppm; m/z
(EI) 347.1176 (M+ C21H18ClN3 requires 347.1189), 331 (5), 297 (7),
165 (6) and 91 (11).
[2-(4-Methylphenyl)-2H-5,7-dioxa-1,2-diaza-s-indacen-3-yl]-4-
methylphenylamine (19). White solid; TLC (30% ethyl acetate–
hexane) Rf 0.43; mp 215–216 ◦C (ethyl acetate–hexane);
1
mmax(KBr)/cm−1 3385, 3029, 2894, 1741, 1512, 1197 and 833; H
[5-Chloro-2-(4-methylphenyl)-2H-indazol-3-yl]-4-methylphenyl-
amine (15). Pale yellowish white solid; TLC (30% ethyl acetate–
hexane) Rf 0.50; mp 157.5–159 ◦C (ethyl acetate–hexane);
mmax(KBr)/cm−1 3399, 3053, 2987, 1612, 1519 and 1263; 1H NMR
(400 MHz, CDCl3; Me4Si) d = 7.57 (1H, d, J 9.1 Hz, Ph), 7.45
(2H, d, J 8.2 Hz, Ph), 7.31 (1H, s, Ph), 7.18–7.25 (3H, m, Ph),
7.05 (2H, d, J 8.2 Hz, Ph), 6.70 (2H, d, J 8.2 Hz, Ph), 5.74 (1H, s,
NH), 2.37 (3H, s, CH3) and 2.30 (3H, s, CH3) ppm; 13C NMR
(100 MHz; CDCl3; Me4Si) d = 146.67, 140.89, 138.88, 135.84,
132.64, 130.48, 130.12, 129.94, 128.26, 126.19, 124.58, 119.45,
118.91, 115.53, 115.41, 21.14 and 20.55 ppm; m/z (EI) 347.1191
(M+ C21H18ClN3 requires 347.1189), 331 (6), 165 (5), 136 (5) and
91 (14).
NMR (400 MHz, CDCl3; Me4Si) d = 7.46 (2H, d, J 8.1 Hz, Ph),
7.22 (2H, d, J 8.1 Hz, Ph), 7.03 (2H, d, J 8.1 Hz, Ph), 6.96 (1H, s,
Ph), 6.66 (2H, d, J 8.1 Hz, Ph), 6.55 (1H, s, Ph), 5.93 (2H, s, CH2),
5.41 (1H, s, NH), 2.38 (3H, s, CH3) and 2.28 (3H, s, CH3) ppm;
13C NMR (100 MHz; CDCl3; Me4Si) d = 149.71, 145.93, 144.89,
141.71, 137.96, 136.34, 132.09, 130.02, 129.76, 129.69, 124.26,
114.87, 114.47, 100.88, 94.81, 94.36, 21.09 and 20.50 ppm; m/z
(EI) 357.1494 (M+ C22H19N3O2 requires 357.1477), 341 (5), 118 (5)
and 91 (14).
[2-(4-Fluorophenyl)-2H-indazol-3-yl]-4-fluorophenylamine (20).
White solid; TLC (30% ethyl acetate–hexane) Rf 0.44; mp 162–
163.5 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3417, 3232, 3044,
2991, 1624 and 1517; 1H NMR (400 MHz, CDCl3; Me4Si) d = 7.68
(1H, d, J 8.9 Hz, Ph), 7.58–7.62 (2H, m, Ph), 7.29–7.33 (2H, m,
Ph), 7.11–7.16 (2H, m, Ph), 6.99 (1H, t, J 8.0 Hz, Ph), 6.91–6.95
(2H, m, Ph), 6.71–6.74 (2H, m, Ph) and 5.69 (1H, s, NH) ppm;
13C NMR (100 MHz; CDCl3; Me4Si) d = 163.52, 161.04, 158.78,
156.40, 148.46, 139.82, 139.79, 134.70, 134.67, 132.71, 127.41,
126.70, 126.61, 121.41, 119.87, 118.01, 116.43, 116.39, 116.35,
116.29, 116.16, 116.06 and 115.49 ppm; m/z (EI) 321.1068 (M+
C19H13F2N3 requires 321.1078), 305 (10), 197 (6) and 95 (13).
[7-Methoxy-2-(4-methylphenyl)-2H-indazol-3-yl]-4-methylphenyl-
amine (16). White solid; TLC (30% ethyl acetate–hexane) Rf
0.38; mp 211.5–214 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1
1
3296, 3027, 2948, 1610, 1511 and 1242; H NMR (400 MHz,
CDCl3; Me4Si) d = 7.41 (2H, d, J 8.1 Hz, Ph), 7.06 (2H, d, J
8.1 Hz, Ph), 6.96 (2H, d, J 8.1 Hz, Ph), 6.77–6.86 (2H, m, Ph),
6.64 (2H, d, J 8.1 Hz, Ph), 6.47 (1H, d, J 7.0 Hz, Ph), 5.87 (1H, s,
NH), 3.92 (3H, s, OCH3), 2.27 (3H, s, CH3) and 2.24 (3H, s,
CH3) ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 150.10,
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[4-Chloro-2-(4-fluorophenyl)-2H-indazol-3-yl]-4-fluorophenyl-
amine (21). White solid; TLC (30% ethyl acetate–hexane) Rf
0.63; mp 145–147 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3386,
141.74, 138.33, 136.21, 131.57, 130.36, 129.97, 129.84, 129.76,
129.62, 124.55, 118.05, 117.66, 115.98, 114.80, 21.69, 21.12 and
20.52 ppm; m/z (EI) 327.1728 (M+ C22H21N3 requires 327.1735),
311 (10), 206 (5) and 91 (10).
1
3044, 1621, 1507, 1217 and 788; H NMR (400 MHz, CDCl3;
Me4Si) d = 7.61–7.66 (2H, m, Ph), 7.59 (1H, d, J 8.8 Hz, Ph), 7.21
(1H, dd, J 8.8 and 7.1 Hz, Ph), 7.03–7.10 (2H, m, Ph), 7.01 (1H,
d, J 7.1 Hz, Ph), 6.81–6.87 (2H, m, Ph), 6.48–6.53 (2H, m, Ph)
and 5.93 (1H, s, NH) ppm; 13C NMR (100 MHz; CDCl3; Me4Si)
d = 163.49, 161.01, 158.74, 156.36, 149.22, 141.23, 141.21, 134.79,
134.75, 132.99, 127.40, 126.34, 126.26, 125.18, 121.91, 116.87,
116.30, 116.22, 116.19, 116.09, 115.96, 115.86 and 114.76 ppm;
m/z (EI) 355.0696 (M+ C19H12ClF2N3 requires 355.0688), 319 (13),
210 (8) and 95 (16).
[2-(4-Methoxyphenyl)-2H-indazol-3-yl]-4-methoxyphenylamine
(26). White solid; TLC (30% ethyl acetate–hexane) Rf 0.34; mp
175.5–178 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3360, 3053,
2969, 2839, 1511 and 1239; 1H NMR (400 MHz, CDCl3; Me4Si)
d = 7.65 (1H, d, J 8.3 Hz, Ph), 7.54–7.58 (2H, m, Ph), 7.26–7.29
(2H, m, Ph), 6.96–7.00 (2H, m, Ph), 6.91 (1H, dd, J 8.3 and 1.4 Hz,
Ph), 6.80–6.84 (4H, m, Ph), 5.57 (1H, s, NH), 3.85 (3H, s, OCH3)
and 3.78 (3H, s, OCH3) ppm; 13C NMR (100 MHz; CDCl3; Me4Si)
d = 159.48, 154.44, 148.27, 136.94, 133.99, 131.54, 126.75, 126.19,
120.35, 120.22, 117.63, 117.57, 114.77, 114.37, 114.25, 55.55 and
55.43 ppm; m/z (EI) 345.1475 (M+ C21H19N3O2 requires 345.1477),
330 (32), 209 (10) and 122 (6).
[5-Chloro-2-(4-fluorophenyl)-2H-indazol-3-yl]-4-fluorophenyl-
amine (22). White solid; TLC (30% ethyl acetate–hexane) Rf 0.50;
mp 157.5–159 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3399,
1
3053, 2987, 1612, 1519 and 1263; H NMR (400 MHz, CDCl3;
[4-Chloro-2-(4-methoxyphenyl)-2H-indazol-3-yl]-4-methoxy-
phenylamine (27). Pale yellowish wh◦ite solid; TLC (30% ethyl
acetate–hexane) Rf 0.39; mp 144–146 C (ethyl acetate–hexane);
Me4Si) d = 7.57 (1H, d, J 9.1 Hz, Ph), 7.45 (2H, d, J 8.2 Hz, Ph),
7.31 (1H, s, Ph), 7.18–7.25 (3H, m, Ph), 7.05 (2H, d, J 8.2 Hz, Ph),
6.70 (2H, d, J 8.2 Hz, Ph) and 5.74 (1H, s, NH) ppm; 13C NMR
(100 MHz; CDCl3; Me4Si) d = 146.67, 140.89, 138.88, 135.84,
132.64, 130.48, 130.12, 129.94, 128.26, 126.19, 124.58, 119.45,
118.91, 115.53, 115.41, 21.14 and 20.55 ppm; m/z (EI) 347.1191
(M+ C21H18ClN3 requires 347.1189), 331 (6), 165 (5), 136 (5) and
91 (14).
1
mmax(KBr)/cm−1 3361, 3057, 2972, 2839, 1507, 1241 and 737; H
NMR (400 MHz, CDCl3; Me4Si) d = 7.50–7.55 (3H, m, Ph), 7.14
(1H, dd, J 8.5 and 7.2 Hz, Ph), 6.94 (1 H, d, J 7.2 Hz, Ph), 6.80–
6.84 (2H, m, Ph), 6.66–6.70 (2H, m, Ph), 6.49–6.53 (2H, m, Ph),
5.92 (1H, s, NH), 3.73 (3H, s, OCH3) and 3.67 (3H, s, OCH3) ppm;
13C NMR (100 MHz; CDCl3; Me4Si) d = 159.36, 153.89, 148.92,
139.09, 133.47, 131.71, 126.85, 125.68, 125.28, 121.23, 116.55,
116.41, 114.56, 114.52, 114.04, 55.38 and 55.31 ppm; m/z (EI)
379.1082 (M+ C21H18ClN3O2 requires 379.1088), 364 (48), 243 (6)
and 122 (5).
[7-Methoxy-2-(4-fluorophenyl)-2H-indazol-3-yl]-4-fluorophenyl-
amine (23). White solid; TLC (30% ethyl acetate–hexane) Rf
0.38; mp 211.5–214 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1
1
3296, 3027, 2948, 1610, 1511 and 1242; H NMR (400 MHz,
CDCl3; Me4Si) d = 7.41 (2H, d, J 8.1 Hz, Ph), 7.06 (2H, d, J
8.1 Hz, Ph), 6.96 (2H, d, J 8.1 Hz, Ph), 6.77–6.86 (2H, m, Ph),
6.64 (2H, d, J 8.1 Hz, Ph), 6.47 (1H, d, J 7.0 Hz, Ph), 5.87 (1H, s,
NH) and 3.92 (3H, s, OCH3) ppm; 13C NMR (100 MHz; CDCl3;
Me4Si) d = 150.10, 141.60, 141.28, 137.96, 135.91, 132.96, 129.64,
129.42, 129.30, 124.49, 120.97, 116.78, 114.99, 112.16, 102.81,
55.05, 20.89 and 20.33 ppm; m/z (EI) 343.1692 (M+ C22H21N3O
requires 343.1685), 328 (14), 314 (16), 208 (6), 193 (6) and 106 (5).
[5-Chloro-2-(4-methoxyphenyl)-2H-indazol-3-yl]-4-methoxy-
phenylamine (28). Pale yellowish wh◦ite solid; TLC (30% ethyl
acetate–hexane) Rf 0.43; mp 179–181 C (ethyl acetate–hexane);
mmax(KBr)/cm−1 3227, 3039, 2932, 1616 and 1514; 1H NMR
(400 MHz, CDCl3; Me4Si) d = 7.54 (1H, dd, J 8.6 and 0.6 Hz,
Ph), 7.47–7.51 (2H, m, Ph), 7.22 (1H, dd, J 1.9 and 0.6 Hz, Ph),
7.17 (1H, dd, J 8.6 and 1.9 Hz, Ph), 6.91–6.95 (2H, m, Ph), 6.76–
6.83 (4H, m, Ph), 5.71 (1H, s, NH), 3.82 (3H, s, OCH3) and 3.78
(3H, s, OCH3) ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d =
159.74, 154.75, 146.59, 136.45, 133.74, 131.24, 126.63, 128.17,
126.17, 125.70, 119.23, 118.95, 117.74, 114.95, 114.51, 55.60
and 55.51 ppm; m/z (EI) 379.1086 (M+ C21H18ClN3O2 requires
379.1088), 364 (25), 243 (11) and 122 (10).
[7-Methyl-2-(4-fluorophenyl)-2H-indazol-3-yl]-4-fluorophenyl-
amine (24). White solid; TLC (30% ethyl acetate–hexane) Rf 0.61;
mp 192.5–194 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3232,
1
3034, 2919, 1610, 1544 and 748; H NMR (400 MHz, CDCl3;
Me4Si) d = 7.50–7.53 (2H, m, Ph), 7.25–7.27 (2H, m, Ph), 7.19
(1H, d, J 8.4 Hz, Ph), 7.02–7.06 (3H, m, Ph), 6.87 (1H, dd, J
8.4 and 1.7 Hz, Ph), 6.71–6.74 (2H, m, Ph), 5.54 (1H, s, NH)
and 2.64 (3H, s, OCH3) ppm; 13C NMR (100 MHz; CDCl3;
Me4Si) d = 148.61, 141.36, 138.51, 136.23, 133.10, 129.97, 129.91,
129.85, 127.89, 125.75, 125.00, 120.99, 117.74, 115.35, 114.90,
21.12, 20.52 and 16.79 ppm; m/z (EI) 327.1737 (M+ C22H21N3
requires 327.1735), 311 (9), 205 (5) and 91 (10).
[7-Methoxy-2-(4-methoxyphenyl)-2H-indazol-3-yl]-4-methoxy-
phenylamine (29). White solid; TLC (30% ethyl acetate–hexane)
Rf 0.13; mp 148–150 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1
3215, 3174, 3046, 2951, 2832, 1508 and 1254; 1H NMR (400 MHz,
CDCl3; Me4Si) d = 7.51–7.55 (2H, m, Ph), 6.89–6.93 (2H, m, Ph),
6.82–6.83 (2H, m, Ph), 6.78 (4H, br s, Ph), 6.52 (1H, dd, J 8.0 and
1.7 Hz, Ph), 5.61 (1H, s, NH), 3.99 (3H, s, OCH3), 3.81 (3H, s,
OCH3) and 3.76 (3H, s, OCH3) ppm; 13C NMR (100 MHz; CDCl3;
Me4Si) d = 159.48, 154.40, 150.17, 141.81, 136.95, 134.05, 131.57,
126.46, 120.89, 117.48, 115.84, 114.76, 114.21, 112.29, 103.00,
55.57, 55.46 and 55.27 ppm; m/z (EI) 375.1579 (M+ C22H21N3O3
requires 375.1583), 360 (15), 346 (5), 329 (5), 238 (7) and 122(17).
[5-Methyl-2-(4-fluorophenyl)-2H-indazol-3-yl]-4-fluorophenyl-
amine (25). White solid; TLC (30% ethyl acetate–hexane) Rf
0.57; mp 162–163 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1 3262,
1
3029, 2918, 1615, 1514 and 798; H NMR (400 MHz, CDCl3;
Me4Si) d = 7.58 (1 H, d, J 8.8 Hz, Ph), 7.47 (2H, d, J 8.3 Hz, Ph),
7.21 (2H, d, J 8.3 Hz, Ph), 7.11–7.14 (2H, m, Ph), 7.01 (2H, d, J
8.3 Hz, Ph), 6.68 (2H, d, J 8.3 Hz, Ph), 5.87 (1H, s, NH) and 2.37
(3H, s, CH3) ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 147.32,
[7-Methyl-2-(4-methoxyphenyl)-2H-indazol-3-yl]-4-methoxy-
phenylamine (30). White solid; TLC (30% ethyl acetate–hexane)
2484 | Org. Biomol. Chem., 2007, 5, 2472–2485
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Rf 0.37; mp 141–143 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1
3211, 3007, 2954, 2837, 1507 and 1239; H NMR (400 MHz,
K. W. McIntyre, V. Patil-koota, D. J. Shuster, L. A. Turk, G. Yang and
K. Leftheris, J. Med. Chem., 2003, 46, 2110–2116.
6 (a) J. I. G. Cadogan, M. Cameron-Wood, R. K. Mcakie and R. J. G.
Searle, J. Chem. Soc., 1965, 4831–4837; (b) L. Krbech and H. Takimoto,
J. Org. Chem., 1964, 29, 1150–1152; (c) M. Akazome, T. Kondo and Y.
Watanabe, J. Org. Chem., 1994, 59, 3375–3380.
7 D. B. Kimball, T. J. R. Weakley, R. Herges and M. M. Haley, J. Am.
Chem. Soc., 2002, 124, 13463–13473.
8 K. Y. Lee, S. Gowrisankar and J. N. Kim, Tetrahedron Lett., 2005, 46,
5387–5391.
1
CDCl3; Me4Si) d = 7.55 (1 H, d, J 8.8 Hz, Ph), 7.49–7.55 (2H, m,
Ph), 7.11 (1H, dd, J 8.8 and 1.3 Hz, Ph), 7.05 (1H, br s, Ph), 6.91–
6.95 (2H, m, Ph), 6.78–6.82 (2H, m, Ph), 6.72–6.76 (2H, m, Ph),
5.53 (1H, s, NH), 3.82 (3H, s, OCH3), 3.77 (3H, s, OCH3) and 2.33
(3H, s, CH3) ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 159.47,
154.15, 147.32, 137.59, 132.51, 131.77, 130.04, 129.78, 126.16,
118.07, 117.52, 116.77, 115.23, 114.86, 114.38, 55.61, 55.50 and
21.68 ppm; m/z (EI) 359.1634 (M+ C22H21N3O2 requires 359.1638),
344 (27), 223 (8) and 122 (5).
9 A. D. Mills, M. Z. Nazer, M. J. Haddadin and M. J. Kurth, J. Org.
Chem., 2006, 71, 2687–2689.
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and B. M. Lee, Heterocycles, 1997, 45, 235–240; (c) W. Baik, D. I. Kim,
H. J. Lee, W.-J. Chung, B. H. Kim and S. W. Lee, Tetrahedron Lett.,
1997, 38, 4579–4580; (d) B. H. Kim, S. K. Kim, Y. S. Lee, Y. M. Jun, W.
Baik and B. M. Lee, Tetrahedron Lett., 1997, 38, 8303–8306; (e) B. H.
Kim, Y. M Jun, Y. R. Choi, D. B. Lee and W. Baik, Heterocycles, 1998,
48, 749–754; (f) B. H. Kim, Y. S. Lee, W. Kwon, Y. Jin, J. A. Tak, Y. M.
Jun, W. Baik and B. M. Lee, Heterocycles, 1998, 48, 2581–2592; (g) W.
Baik, C. H. Yoo, S. Koo, H. Kim, Y. H. Hwang, B. H. Kim and S. W.
Lee, Heterocycles, 1999, 51, 1779–1783; (h) B. H. Kim, D. B. Lee, D. H.
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2000, 41, 2137–2140; (j) B. H. Kim, D. H. Kim, H. J. Park, R. Han,
Y. M. Jun and W. Baik, Bull. Korean Chem. Soc., 2001, 22, 1163–1166;
(k) B. H. Kim, R. Han, T. H. Han, Y. M. Jun, W. Baik and B. M. Lee,
Heterocycles, 2002, 57, 5–10; (l) B. H. Kim, R. Han, J. S. Kim, Y. M.
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S. Chen, S. J. Lee, F. Qi, X. Wu and B. H. Kim, Heterocycles, 2006, 68,
1675–1684.
[5-Methyl-2-(4-methoxyphenyl)-2H-indazol-3-yl]-4-methoxy-
phenylamine (31). White solid; TLC (30% ethyl acetate–hexane)
Rf 0.47; mp 136–139 ◦C (ethyl acetate–hexane); mmax(KBr)/cm−1
1
3175, 3033, 2940, 2829, 1508 and 1241; H NMR (400 MHz,
CDCl3; Me4Si) d = 7.47–7.50 (2H, m, Ph), 7.08 (1H, d, J 8.0 Hz,
Ph), 7.01 (1H, d, J 6.8 Hz, Ph), 6.88–6.83 (2H, m, Ph), 6.80 (1H,
dd, J 8.0 and 1.7 Hz, Ph), 6.76 (3H, br s, Ph), 5.64 (1H, s, NH),
3.78 (3H, s, OCH3), 3.74 (3H, s, OCH3) and 2.60 (3H, s, CH3)
ppm; 13C NMR (100 MHz; CDCl3; Me4Si) d = 159.52, 154.35,
148.53, 137.06, 134.17, 131.67, 127.58, 126.50, 125.66, 120.54,
117.76, 117.51, 114.73, 114.40, 113.94, 55.55, 55.46 and 16.76 ppm;
m/z (EI) 359.1634 (M+ C22H21N3O2 requires 359.1634), 344 (32),
223 (6), 208 (6) and 122 (5).
11 (a) H. Yamamoto and K. Oshima, Main Group Metals in Organic
Synthesis, Wiley-VCH, Weinheim, 2004, vol. 1, ch. 8, pp. 323–386;
(b) C. J. Li and T. H. Chan, Organic Reactions in Aqueous Media,
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Acknowledgements
This work was supported by the Korean Government through
a Korea Research Foundation Grant (MOEHRD, KRF-2005-
C00250), and partly by Kwangwoon University in the year 2006.
12 (a) H. Yamamoto and K. Oshima, Main Group Metals in Organic
Synthesis, Wiley-VCH: Weinheim, 2004, 1, 323-386; (b) C. J. Li and
T. H. Chan, Organic Reactions in Aqueous Media, Wiley-Interscience,
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The Royal Society of Chemistry 2007
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