Direct access to 3-aminoindazoles by Buchwald-Hartwig C-N coupling reaction

Article abstract of DOI:10.1055/s-0030-1260110

An efficient synthesis of various N-substituted 3-aminoindazoles using Buchwald-Hartwig C-N coupling reaction is described. Several parameters were varied, including the nature of the halogen atom and the protecting group of the starting materials, as well as the effects of the catalyst system, base, solvent, and reaction time. The efficiency of microwave versus conventional heating was also compared to test the outcome of the reaction. Thus, by applying this recent knowledge about metal-catalyzed aminations, an alternative for the direct synthesis of primary 3-aminoindazoles has been provided. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0030-1260110

PAPER
2651
Direct Access to 3-Aminoindazoles by Buchwald–Hartwig C–N Coupling
Reaction
S
ynthesis of 3-A
l
minoi
o
ndazole
s
by
d
uchwald–H
i
artwig
e
C
–N Coupling Lohou, Valérie Collot,* Silvia Stiebing, Sylvain Rault
CERMN UPRES EA-4258, FR CNRS INC3M, UFR des Sciences Pharmaceutiques, Bd Becquerel, 14032 Caen Cedex, France
Fax +33(2)31566803; E-mail: valerie.collot@unicaen.fr
Received 21 April 2011
amination starting from 3-nitroindazole was found,15 but
it required very hard conditions. Thus, the preparation of
such products typically involved an aromatic nucleophilic
substitution between hydrazine and benzonitriles or
Abstract: An efficient synthesis of various N-substituted 3-ami-
noindazoles using Buchwald–Hartwig C–N coupling reaction is de-
scribed. Several parameters were varied, including the nature of the
halogen atom and the protecting group of the starting materials, as
well as the effects of the catalyst system, base, solvent, and reaction thioamides16 substituted in ortho position by a leaving
group like fluorine,3b,4,17 or also sometimes by chlorine18
time. The efficiency of microwave versus conventional heating was
or a nitro group.19 Moreover, finally using similar cycliza-
also compared to test the outcome of the reaction. Thus, by applying
this recent knowledge about metal-catalyzed aminations, an alterna-
tion conditions, introduction of the amino group could
tive for the direct synthesis of primary 3-aminoindazoles has been
also result from the reaction of different amines on the 2-
provided.
halobenzyl chloroimidates, which were synthesized by
Key words: indazoles, amination, cross-coupling, palladium, cop-
the addition of a protected hydrazine on 2-halobenzyl
per, microwave promoted amination
acids followed by chlorination.20 A new approach, which
allows the direct incorporation of elaborated amines at the
3 position of the indazole nucleus, is therefore needed.
To prepare new valuable building blocks in medicinal
In the past few years, the metal-catalyzed Buchwald–
chemistry, design and synthesis of new polyfunctional-
Hartwig amination21 of aryl halides has become an impor-
tant method for the synthesis of arylamines, which offers
considerable advantages over the classical processes like
the Ullmann-type C–N bond formation,22 since nonacti-
vated substrates can be used in relatively mild reaction
conditions. However, application of this coupling to vari-
ous heterocyclic structures is still a relatively unexplored
process23 and only a few isolated examples using this re-
action from 3-chloro-24 or 3-bromoindazoles were
found.5,25 Consequently, it was envisaged that it would be
interesting to carry out and report a general procedure for
this kind of C–N cross-coupling at the 3-position of the in-
dazole ring. With this in mind, the applicability of palla-
dium- and copper-catalyzed amination protocols were
evaluated on various 3-halogenoindazoles (Scheme 1).
Several reaction parameters were varied, including the na-
ture of halogen atom and protecting group, as well as the
effects of catalyst system, base, solvent, and reaction time.
The efficiency of microwave versus conventional heating
was also compared to test the outcome of the reaction.
Thus, by applying this recent knowledge about metal-cat-
alyzed aminations, an alternative has been provided for
the direct synthesis of primary 3-aminoindazoles by C–N
cross-coupling of the corresponding bromo compounds
ized indazole libraries1 have been developed since a few
years in our laboratory, particularly those corresponding
to 2-aza bioisosteres of tryptophan, tryptamine, seroto-
nine, and melatonine.2 Indeed, the indazole scaffold
seems to be able to interact with a variety of targets and is
already found in a great number of products displaying a
wide range of biological activities including, for example,
kinase inhibitors,3 HIV protease inhibitors,4 MCH recep-
tor 1 antagonists,5 sodium channel modulators,6 nitric ox-
ide synthase inhibitors like 7-NI,7 and 4-NI,8 and also in
lead compounds like granisetron,9 a 5-HT3 receptor antag-
onist, YC-1,10
a
guanylyl cyclase activator or
lonidamine,11 and a mitochondrial hexokinase inhibitor.
We have also been interested for a long time in the devel-
opment of metal-catalyzed cross coupling reactions.
Suzuki,10b,12 Heck,2a,13 and Sonogashira14 reactions have
been carried out at position 3 of the indazole nucleus, and
also on its benzene ring. Recently, our attention was
turned to the synthesis of various N-substituted 3-ami-
noindazoles using Buchwald–Hartwig C–N coupling re-
action. Indeed, to the best of our knowledge, only a few 3-
N-alkyl or N-arylamino derivatives have been described
in the literature despite the fact that such compounds
could have a very interesting potential – notably antineo-
plastic,3 antiviral,4 anorexigen,5 and neuroprotective6
properties. However, because of the lack of reactivity in
traditional nucleophilic substitution reactions at the 3 po-
sition of this heterocycle, only one example of such direct
NR2R3
X
R1
N
N
N
R1
R1
N
N
N
H
PG
X = halogen
PG = protecting group
H
SYNTHESIS 2011, No. 16, pp 2651–2663
x
x.
x
x
.
2
0
1
1
Advanced online publication: 21.07.2011
DOI: 10.1055/s-0030-1260110; Art ID: Z42211SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2652
E. Lohou et al.
PAPER
Table 1 Synthesis of Protected 3-Halo-1H-indazoles 4 and 5a–h
Copper-Catalyzed and Microwave-Promoted Amina-
tion of a 3-Iodoindazole Derivative
X
R
Indazoles 2 and 3 (%)Indazoles 4 and 5 (%)
One of our initial attempts was the investigation of the ap-
plication of microwave-promoted21k,29 C–N bond-forming
methodology to our protected 3-halogenoindazoles. A
number of literature methods were examined using a vari-
ety of state of the art ligands for both Pd and Cu. Unfortu-
nately, among our disappointing preliminary attempts,
particularly starting from 3-bromo derivatives by reacting
with various palladium catalyst systems in different sol-
vents (toluene, DMF, 1,4-dioxane),30 we had to modify
our strategy to obtain the expected N-substituted 3-ami-
noindazoles. Thus, taking into account the important de-
velopment of catalytic Ullmann-type amination, the
coupling reaction of N-methylpiperazine with the 3-iodo-
indazole 4 was carried out in the presence of copper(I)
iodide31 as the catalyst, proline as the ligand, potassium
carbonate as the base, and DMSO as the solvent at 140 °C
in a microwave reactor for 30 minutes.32 Using this proto-
col, 6 was first obtained in only 33% yield after purifica-
tion by column chromatography on silica gel, but this
result was improved by preparing this compound with a
yield of 49%, using aluminum oxide instead of the more
acidic silica gel for chromatography. In a likewise fash-
ion, N-benzylpiperazine, N-benzyloxycarbonylpipera-
zine, and morpholine were combined with 4 leading to
compounds 7–9, respectively, in good yields. In contrast,
only traces of the desired product 10 were recovered from
the reaction with aniline, which is a poor reagent for this
coupling. In summary, we have successfully demonstrat-
ed the efficiency of the CuI/proline amination system on
a 3-iodoindazole derivative and secondary cyclic amines
under microwave irradiation (Scheme 3 and Table 2).
However, in order to compare other reaction conditions,
and to expand the range of the N-substituted 3-aminoinda-
zoles to primary amines, we decided in the second part of
this project, to investigate the new palladium-catalyzed
Buchwald–Hartwig C–N coupling protocols under con-
ventional oil-bath heating conditions in a sealed tube.
I
H
2
68
64
77
68
45
91
60
81
54
4
55
88
99
88
63
59
69
79
42
Br
Br
Br
Br
Br
Br
Br
Br
H
3a
3b
3c
3d
3e
3f
5a
5b
5c
5d
5e
5f
4-O2N
4-Cl
5-MeO
5-O2N
5-Cl
6-O2N
6-Cl
3g
3h
5g
5h
with benzophenone imine followed by an acidic hydroly-
sis of the obtained imino derivatives.
Synthesis of New Protected 3-Halogenoindazoles
First, indazoles 1a–h were prepared from the correspond-
ing 2-methylanilines according to a previously successful
method developed in our laboratory.8,26 Then, iodination
or bromination reactions10b,27 were selectively carried out
at the 3 position of these derivatives with iodine or bro-
mine in DMF at room temperature to provide the 3-iodo-
indazole 2 and the different 3-bromoindazoles 3a–h in
moderate to high yields. In addition, it was required to
protect the nitrogen atom of the indazole nucleus at this
stage to avoid a possible catalyst poisoning during the
Buchwald–Hartwig C–N coupling. Indeed, a first attempt
of metal-catalyzed amination carried out on the unprotect-
ed 3-bromoindazole failed. Accordingly, taking into ac-
count a previously described work about indazole
protection by a tetrahydropyran-2-yl (THP) group,12b
optimization of this procedure was tried starting from
3-halogenoindazoles synthesized by us and using dihy-
dropyran and a catalytic amount of PTSA in ethyl acetate
under reflux conditions.28 Thus, this protocol provided
THP-protected indazoles 4 and 5a–h in good yields.
Moreover, THP was used as N-protecting group instead of
the classical 2-(trimethylsilyl)ethoxymethyl (SEM)
group,12b particularly because of its lower cost and its eas-
ier deprotection step (Scheme 2 and Table 1).
I
NR1R2
i
N
N
N
N
THP
THP
4
6–10
Scheme 3 Reagents and conditions: i) HNR1R2 (2 equiv), CuI (0.2
equiv), proline (0.4 equiv), K2CO3 (3 equiv), DMSO, microwave hea-
ting at 140 °C, 30 min (under argon), 27–51%.
X
X
i or ii
iii
N
N
N
R
R
R
N
N
N
Palladium-Catalyzed Amination of Different 3-Bro-
moindazole Derivatives
H
H
THP
1a–h
2 X = I
3a–h X = Br
4 X = I
5a–h X = Br
The palladium-catalyzed amination of 3a was first carried
out with N-methylpiperazine using conditions developed
by Buchwald [Pd2(dba)3, BINAP, and t-BuONa in reflux-
ing toluene],21b,c,23d but the corresponding C–N coupling
Scheme 2 Reagents and conditions: i) I2 (2 equiv), KOH (3.75
equiv), DMF, r.t., 1 h, 68%; ii) Br2 (1.5 equiv), DMF, r.t., 2–72 h, 45–
77%; iii) DHP (2 equiv), PTSA (cat.), EtOAc, reflux, 3–48 h, 42–
99%.
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Aminoindazoles by Buchwald–Hartwig C–N Coupling
2653
isolated in an excellent 73% yield. Next, with these opti-
mized conditions, the palladium-catalyzed amination of
the 3-bromoindazole derivative 3a was investigated with
various secondary cyclic amines to synthesize the differ-
ent 3-amino-substituted indazoles 7–9 and 11, which were
still formed in the yields of 17–64%, considering the un-
favorable negative charge at the 3 position of indazole. In
fact, the poor result obtained with unprotected piperazine
even in excess (1.5 equiv) was not surprising, taking into
account the formation of a 3,3¢-amino-substituted inda-
zole dimer derivative. Subsequently, the coupling of 3a
was successfully carried out with different primary aro-
matic amines to afford the expected amino compounds 10,
12–14 in moderate to excellent yields (19–87%) depend-
ing on the electron-withdrawing or electron-donating
groups present in the anilines used (Scheme 4 and
Table 3). In fact, it can be noted that the yields obtained
with morpholine and aniline appear generally at least
comparable to the few results available in the litera-
ture.24b,25 Then, the use of benzylamine, a primary aliphat-
ic amine for this C–N coupling gave us the amino
derivative 15 in a yield of 23%. Furthermore, amination of
the different 4-, 5-, or 6-substituted 3-bromoindazole de-
rivatives 3b–f and 3h with N-benzyloxycarbonylpipera-
zine provided the corresponding N-substituted 3-
aminoindazoles 16–21 in 18–42% yields (Scheme 4 and
Table 4).
Table 2 Copper-Catalyzed and Microwave-Promoted Amination of
3-Iodoindazole 4 with Various Amines
HNR1R2
Products 6–10
Yield (%)
Me
N
N
49
N
Me
H
H
H
N
N
N
THP
6
7
8
Bn
N
N
43
N
Bn
N
N
N
THP
Cbz
N
N
51
N
N
Cbz
N
N
THP
O
Table 3 Palladium-Catalyzed Amination of 3-Bromoindazole 3a
with Various Amines
HNR2R3
Product 6–15
Time Yield
(h)
24
(%)
73
N
N
27
H
N
O
Me
N
N
THP
N
9
H
H
H
N
N
N
N
N
N
Me
H
N
N
N
THP
traces
H2N
N
6
7
8
N
Bn
THP
N
10
N
product 6 in this case was obtained only in 30% yield.
With the aim of improving this procedure, a new mono-
dentate ligand (dicyclohexylphosphinobiphenyl)30 was
tested under the same conditions in toluene instead of the
BINAP bidentate in a polar solvent (1,4-dioxane). Unfor-
tunately, these conditions provided the desired product 6
in a similar yield also along with a lot of starting material
and a debrominated derivative. To decrease the formation
of this by-product resulting from a b-elimination often ob-
served with this kind of amines, it was decided to evaluate
again another methodology using a different palladium
catalyst system [Pd(OAc)2/Xantphos]33 and above all
Cs2CO3 as a weaker base in 1,4-dioxane under reflux con-
ditions.34 Gratifyingly, with this protocol, 6 was finally
7
29
Bn
N
N
THP
Cbz
N
N
8
24
64
31
Cbz
N
N
THP
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

2654
E. Lohou et al.
PAPER
Table 4 Palladium-Catalyzed Amination of Different 3-Bromoin-
dazole Derivatives 3b–f and 3h with Various Amines
Table 3 Palladium-Catalyzed Amination of 3-Bromoindazole 3a
with Various Amines (continued)
R1
HNR2R3
Product 16–20
Time Yield
(h) (%)
HNR2R3
Product 6–15
Time Yield
(h)
(%)
Cbz
H
N
N
NO2
N
6
4
N
4-O2N
6
17
N
N
N
N
N
N
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
H
H
H
H
H
H
N
N
N
N
N
N
N
H
24 21
H
N
N
N
N
N
THP
THP
O
16
11
Cbz
N
N
N
6
24
38
52
Cl
N
O
H
N
4-Cl
6
7
6
6
40
18
37
29
N
N
N
THP
THP
9
17
H
Ph
N
Cbz
N
8
7
87
19
N
H2N
N
N
THP
5-MeO
5-O2N
5-Cl
MeO
10
N
Br
N
H
N
THP
18
Br
H2N
N
Cbz
N
N
THP
12
13
N
O2N
OMe
H
N
N
N
6
24
31
65
OMe
H2N
N
THP
N
19
THP
Cbz
N
OMe
H
N
N
OMe
OMe
Cl
OMe
6
54
23
N
N
H2N
N
N
THP
THP
20
14
15
Cbz
H
N
Bn
N
H2N
N
24
N
N
6-Cl
6
42
THP
N
N
Cl
THP
21
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PAPER
Synthesis of 3-Aminoindazoles by Buchwald–Hartwig C–N Coupling
2655
in palladium-catalyzed C–N couplings. With this in mind
and starting directly from the variously substituted 3-bro-
moindazole derivatives 3a, 3d, and 3g, the previously de-
scribed optimum Buchwald–Hartwig reaction conditions
were so applied using benzophenone imine. After acidic
hydrolysis of the obtained, but not necessarily isolated
imino compounds 24–26, with ethanolic HCl at room
temperature, this new procedure finally furnished us the
expected unprotected primary 3-aminoindazoles 27–29 in
good two-step yields (35, 67, and 49%, respectively)
(Scheme 6).
Br
NR2R3
N
i
R1
R1
N
N
N
THP
THP
3a–f,h
6–21
Scheme 4 Reagents and conditions: i) HNR2R3 (1.2 equiv),
Pd(OAc)2 (0.1 equiv), Xantphos (0.12 equiv), Cs2CO3 (2.8 equiv),
1,4-dioxane, reflux, 6–24 h (under argon), 17–87%.
In addition, we found that treatment of the protected inda-
zoles 7 and 10 with ethanolic HCl35 at room temperature
was able to cleave the THP in good yields to furnish the
unprotected derivatives 22 and 23 (37 and 84%, respec-
tively) (Scheme 5).
Ph
Br
N
Ph
ii
NH2
N
i
N
R
N
R
R
NR1R2
NR1R2
N
N
N
THP
THP
24, 25, 26
H
i
N
N
3a,d,g
27, 28, 29
N
N
Scheme 6 Reagents and conditions: i) Benzophenone imine (1.2
equiv), Pd(OAc)2 (0.1 equiv), Xantphos (0.12 equiv), Cs2CO3 (2.8
equiv), 1,4-dioxane, reflux, 6–24 h (under argon); ii) EtOH–HCl, r.t.,
0.5–72 h, 35–67% (over two steps).
H
THP
7, 10
22, 23
Scheme 5 Reagents and conditions: i) EtOH–HCl, r.t., 2–3 h, 37–
84%.
To conclude, two efficient protocols for the synthesis of
various 3-aminoindazoles in moderate to high yields have
been developed both under microwave irradiation and tra-
ditional heating conditions. Thus, one of the most impor-
tant advantages of the microwave-promoted copper-
catalyzed amination method was of course the high-speed
synthesis of the desired products, but better results were
here in general obtained with the palladium-catalyzed C–
N coupling procedure under conventional heating condi-
tions. Considering the biological properties of indazole
derivatives, this methodology allowing the facile intro-
duction of indazole moiety on various scaffolds could be
very useful for medicinal chemists to achieve new valu-
able building blocks. Further studies concerning develop-
ment of new substituted indazole derivatives are currently
in progress. In fact, taking into account our recent knowl-
edge with regard to the synthesis of different primary 3-
aminoindazoles, we notably try to carry out the opposite
C–N coupling considering the bigger availability of halo-
geno aromatic compounds.
Thus, we have successfully demonstrated that various N-
substituted 3-aminoindazoles can be synthesized by a di-
rect palladium-catalyzed Buchwald–Hartwig amination
under conventional heating conditions starting from the
corresponding 3-bromoindazole derivatives in a short
time of 6–8 hours. However, the extension of reaction
time to 24 hours23d sometimes allowed us to improve our
results, for example, in 52, 65, and 21% yield for inda-
zoles 9, 13, and 16, respectively, instead of 38, 31, and 4%
yield, respectively, after 6 hours of reaction. The amina-
tion conditions proposed in this paper result from a long
and important devising and seem to be optimal for this po-
sition on this heterocycle with a good variety of tested
amines, which could of course still be extended.
Direct Synthesis of N-Unsubstituted 3-Aminoindazoles
by C–N Cross-Coupling of the Corresponding Bromo
Compounds with Benzophenone Imine
The classical synthesis of N-unsubstituted 3-aminoinda-
zoles implicates the formation of the pyrazole moiety
starting from 2-halobenzonitriles and hydrazine.3e,4,17c,18
Moreover, Lefebvre and co-workers developed a similar
cyclization avoiding the addition of hydrazine and includ-
ing a palladium-catalyzed amination with the benzophe-
none hydrazone.36 However, the major inconvenience of
these methods is the poor availability of the starting mate-
rials. Then, it could perhaps be possible to obtain these
compounds with a nitration at 3-position followed by a re-
duction, but it would need conditions not always compat-
ible with different functions eventually present on the
benzene ring. On the other hand, Wolfe and co-workers37a
reported in 1997 the use of commercially available ben-
zophenone imine37 as a convenient surrogate for ammonia
All commercial reagents were used as received without further pu-
rification. Reaction mixtures were stirred magnetically and moni-
tored by TLC using 0.2 mm Macherey-Nagel Polygram SIL G/
UV254 or ALOX N/UV254 precoated plates. Column chromatogra-
phy was performed using CarloErba-SDS 60A 70–200 mm silica gel
or Al2O3. Melting points were determined on a Kofler melting point
apparatus. IR spectra were taken with a PerkinElmer spectrum X
FT-IR spectrometer. 1H NMR (400 MHz) and 13C NMR (100 MHz)
spectra were recorded on a Jeol Lambda 400 Spectrometer. Chemi-
cal shifts (d) are expressed in parts per million downfield from TMS
as an internal standard and the coupling constants are in hertz. Mass
spectra were recorded on a Jeol JMS GCMate with ionizing poten-
tial of 70 eV and with pfk as internal standard. Elemental analyses
were performed at the ‘Institut de Recherche en Chimie Organique
Fine’, Rouen, France.
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

2656
E. Lohou et al.
PAPER
IR (KBr): 3168, 2965, 1618, 1302, 1198, 841, 778, 739 cm–1.
3-Iodo-1H-indazole (2)
Indazole (1a; 3.0 g, 25.3 mmol) was added to a stirred mixture of
KOH (5.3 g, 94.9 mmol, 3.75 equiv) and I2 (12.8 g, 50.6 mmol, 2
equiv) in DMF (40 mL). After 1 h at r.t., EtOAc (60 mL) was added,
and the organic layer was washed successively with aq Na2S2O3 (3
× 30 mL) and brine (3 × 30 mL), dried (MgSO4), filtered, and evap-
orated in vacuo. The crude material was purified by flash column
chromatography on silica gel (EtOAc–cyclohexane, 1:3) to give 2
as a yellow solid; yield: 4.2 g (68%); mp 140 °C; Rf = 0.4 (silica gel;
EtOAc–cyclohexane, 1:3).
1H NMR (DMSO-d6): d = 7.21 (d, J = 6.8 Hz, 1 H), 7.37 (t, J = 6.8
Hz, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 13.75 (s, 1 H).
13C NMR (DMSO-d6): d = 110.3, 118.0, 118.2, 122.0, 124.5, 128.2,
142.4.
HRMS (EI): m/z calcd for C7H4BrClN2 [M+]: 229.9246; found:
229.9238.
3-Bromo-5-methoxy-1H-indazole (3d)
Starting from 5-methoxy-1H-indazole (1d; 3.0 g, 20.2 mmol) and
following the general procedure, the product 3d was obtained as a
white solid; yield: 2.1 g (45%); mp 178 °C; Rf = 0.2 (silica gel;
EtOAc–cyclohexane, 1:4).
IR (KBr): 3435, 3153, 1619, 1471, 1314, 1237, 1013, 737, 600
cm–1.
1H NMR (CDCl3): d = 7.23 (t, J = 7.6 Hz, 1 H), 7.45 (t, J = 7.4 Hz,
1 H), 7.52 (d, J = 8.1 Hz, 1 H), 7.70 (d, J = 8.6 Hz, 1 H), 12.48 (s, 1
IR (KBr): 3161, 2944, 1634, 1514, 1489, 1295, 1217, 1179, 1014,
823, 728 cm–1.
1H NMR (CDCl3): d = 3.89 (s, 3 H), 6.93 (s, 1 H), 7.12 (d, J = 8.8
Hz, 1 H), 7.40 (d, J = 9.8 Hz, 1 H), 10.42 (s, 1 H).
13C NMR (CDCl3): d = 55.7, 98.7, 111.2, 120.8, 122.0, 123.4, 136.8,
155.4.
H).
13C NMR (CDCl3): d = 93.5, 111.0, 121.4, 122.0, 127.5, 128.2,
140.8.
Anal. Calcd for C7H5IN2: C, 34.45; H, 2.07; N, 11.48. Found: C,
34.33; H, 2.22; N, 11.27.
3-Bromo-1H-indazoles 3a–h; General Procedure
Anal. Calcd for C8H7BrN2O: C, 42.32; H, 3.11; N, 12.34. Found: C,
42.32; H, 3.09; N, 12.47.
To a cooled solution of the chosen indazole 1a–h in DMF (5–20
mL) was added at 0 °C dropwise Br2 (1.5 equiv). After the end of
addition, the mixture was stirred for 2–72 h at r.t. The mixture was
diluted with EtOAc (40 mL), the organic layer was washed succes-
sively with aq Na2S2O3 (3 × 20 mL) and brine (3 × 20 mL), dried
(MgSO4), filtered, and evaporated in vacuo. The crude material was
purified by flash column chromatography on silica gel (EtOAc–cy-
clohexane, 1:6 to 1:2) to give the expected 3-bromoindazoles 3a–h.
3-Bromo-5-nitro-1H-indazole (3e)
Starting from 5-nitro-1H-indazole (1e; 10.0 g, 61.0 mmol) and fol-
lowing the general procedure, the product 3e was obtained as a
white solid; yield: 13.5 g (91%); mp 226 °C; Rf = 0.2 (silica gel;
EtOAc–cyclohexane, 1:3).
IR (KBr): 3447, 3141, 2919, 1741, 1682, 1621, 1533, 1492, 1340,
1283, 1089, 787, 701 cm–1.
1H NMR (DMSO-d6): d = 7.76 (d, J = 8.8 Hz, 1 H), 8.24 (dd,
J = 8.8, 2.0 Hz, 1 H), 8.45 (s, 1 H).
13C NMR (DMSO-d6): d = 112.1, 117.1, 121.5, 122.2, 123.6, 142.2,
142.9.
3-Bromo-1H-indazole (3a)
Starting from 1H-indazole (1a; 1.5 g, 12.7 mmol) and following the
general procedure, the product 3a was obtained as a yellow solid;
yield: 1.6 g (64%); mp 124 °C; Rf = 0.4 (silica gel; EtOAc–cyclo-
hexane, 1:3).
IR (KBr): 3437, 2915, 1623, 1329, 1241, 1024, 733 cm–1.
1H NMR (CDCl3): d = 7.21 (t, J = 6.8 Hz, 1 H), 7.44 (t, J = 6.8 Hz,
1 H), 7.63 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 8.8 Hz, 1 H), 12.75 (s, 1
HRMS (EI): m/z calcd for C7H4BrN3O2 [M+]: 240.9486; found:
240.9490.
3-Bromo-5-chloro-1H-indazole (3f)
H).
Starting from 5-chloro-1H-indazole 1f (1 g, 6.5 mmol) and follow-
ing the general procedure, the product 3f was obtained as a beige
solid; yield: 0.9 g (60%); mp 212 °C; Rf = 0.1 (silica gel; EtOAc–
cyclohexane, 1:6).
13C NMR (CDCl3): d = 110.2, 120.2, 121.8, 122.9, 123.1, 128.1,
141.1.
HRMS (EI): m/z calcd for C7H5BrN2 [M+]: 195.9636; found:
195.9642.
IR (KBr): 3434; 3141, 1476, 1268, 920, 790, 615 cm–1.
1H NMR (DMSO-d6): d = 7.54 (d, J = 10.8 Hz, 1 H), 7.70 (d, J = 8.8
3-Bromo-4-nitro-1H-indazole (3b)
Hz, 1 H), 7.71 (s, 1 H).
Starting from 4-nitro-1H-indazole (1b; 1.0 g, 6.0 mmol) and follow-
ing the general procedure, the product 3b was obtained as a yellow
solid; yield: 1.1 g (77%); mp 228 °C, Rf = 0.2 (silica gel; EtOAc–
cyclohexane, 1:2).
13C NMR (DMSO-d6): d = 112.9, 118.3, 119.7, 123.0, 126.1, 128.0,
139.6.
HRMS (EI): m/z calcd for C7H4BrClN2 [M+]: 229.9246; found:
229.9244.
IR (KBr): 3161, 2922, 1530, 1347, 1299, 1154, 1026, 998, 793, 730
cm–1.
1H NMR (DMSO-d6): d = 7.61 (t, J = 7.8 Hz, 1 H), 7.91 (d, J = 7.8
Hz, 1 H), 8.00 (d, J = 7.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 112.3, 117.2, 117.3, 118.6, 126.8, 141.3,
142.9.
HRMS (EI): m/z calcd for C7H4BrN3O2 [M+]: 240.9486; found:
240.9488.
3-Bromo-6-nitro-1H-indazole (3g)
Starting from 6-nitro-1H-indazole (1g; 1.0 g, 6.0 mmol) and follow-
ing the general procedure, the product 3g was obtained as a yellow
solid; yield: 1.2 g (81%); mp 206 °C; Rf = 0.2 (silica gel; EtOAc–
cyclohexane, 1:3).
IR (KBr): 3349, 1591, 1526, 1339, 1019, 882, 786, 657 cm–1.
1H NMR (DMSO-d6): d = 7.83 (d, J = 8.8 Hz, 1 H), 8.01 (dd,
J = 8.8, 2.0 Hz, 1 H), 8.48 (s, 1 H), 14.07 (s, 1 H).
3-Bromo-4-chloro-1H-indazole (3c)
Starting from 4-chloro-1H-indazole (1c; 0.6 g, 4.0 mmol) and fol-
lowing the general procedure, the product 3c was obtained as a yel-
low solid; yield: 0.6 g (68%); mp 236 °C; Rf = 0.2 (silica gel;
EtOAc–cyclohexane, 1:4).
13C NMR (DMSO-d6): d = 107.8, 115.9, 120.8, 121.0, 125.2, 139.5,
146.9.
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

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Synthesis of 3-Aminoindazoles by Buchwald–Hartwig C–N Coupling
2657
Anal. Calcd for C7H4BrN3O2: C, 34.74; H, 1.67; N, 17.36. Found:
C, 34.45; H, 1.44; N, 16.86.
3-Bromo-4-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(5b)
Starting from 3-bromo-4-nitro-1H-indazole (3b; 0.8 g, 3.3 mmol)
and following the general procedure, the product 5b was obtained
as a beige solid; yield: 1.1 g (99%), mp 142 °C; Rf = 0.3 (silica gel;
EtOAc–cyclohexane, 1:3).
3-Bromo-6-chloro-1H-indazole (3h)
Starting from 6-chloro-1H-indazole (1h; 1.0 g, 6.5 mmol) and fol-
lowing the general procedure, the product 3h was obtained as an or-
ange solid; yield: 0.8 g (54%); mp 193 °C; Rf = 0.3 (silica gel;
EtOAc–cyclohexane, 1:4).
IR (KBr): 3168, 2925, 1624, 1459, 1325, 1023, 924, 798, 587 cm–1.
1H NMR (CDCl3): d = 7.22 (d, J = 9.8 Hz, 1 H), 7.52 (s, 1 H), 7.71
(d, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): d = 109.9, 121.3, 121.9, 123.1, 123.3, 134.8,
141.4.
HRMS (EI): m/z calcd for C7H4BrClN2 [M+]: 229.9246; found:
229.9250.
IR (KBr): 2947, 1737, 1529, 1447, 1362, 1249, 1189, 1079, 1040,
998, 726 cm–1.
1H NMR (CDCl3): d = 1.70–1.75 (m, 3 H), 2.03–2.14 (m, 2 H),
2.50–2.54 (m, 1 H), 3.75 (dt, J = 10.3, 2.9 Hz, 1 H), 3.96 (d,
J = 11.7 Hz, 1 H), 5.77 (dd, J = 8.8, 2.9 Hz, 1 H), 7.51 (t, J = 7.8 Hz,
1 H), 7.83 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H).
13C NMR (CDCl3): d = 21.8, 24.8, 29.0, 67.1, 86.0, 115.2, 116.3,
118.4, 118.8, 126.5, 142.1, 142.4.
HRMS (EI): m/z calcd for C12H12BrN3O3 [M+]: 325.0061; found:
325.0066.
1-THP-3-halogeno-1H-indazoles 4 and 5a–h; General Proce-
dure
3-Bromo-4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(5c)
Starting from 3-bromo-4-chloro-1H-indazole (3c; 0.5 g, 2.2 mmol)
and following the general procedure, the product 5c was obtained as
an orange solid; yield: 0.6 g (88%); mp 118 °C; Rf = 0.5 (silica gel;
EtOAc–cyclohexane, 1:5).
To a solution of the chosen 3-halogenoindazole 2 or 3a–h dissolved
in EtOAc (20–50 mL) were added successively a catalytic amount
of PTSA and 3,4-dihydro-2H-pyrane (DHP, 2 equiv). The reaction
mixture was heated under reflux for 3–48 h and then neutralized
with NH4OH (3 × 20 mL). After the addition of EtOAc (40 mL), the
organic layer was washed with brine (3 × 20 mL), dried (MgSO4),
filtered, and evaporated in vacuo. The crude material was purified
by flash column chromatography on silica gel (EtOAc–cyclohex-
ane, 1:6 to 1:3) to give the expected protected indazoles 4 and 5a–h.
IR (KBr): 2937, 1607, 1491, 1439, 1245, 1183, 1079, 1041, 1004,
773, 731 cm–1.
1H NMR (CDCl3): d = 1.66–1.74 (m, 3 H), 2.05–2.14 (m, 2 H),
2.50–2.54 (m, 1 H), 3.72 (t, J = 10.8 Hz, 1 H), 3.99 (d, J = 11.7 Hz,
1 H), 5.66 (dd, J = 8.8, 3.0 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H), 7.31
(t, J = 7.8 Hz, 1 H), 7.51 (d, J = 8.8 Hz, 1 H).
3-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4)
Starting from 3-iodo-1H-indazole (2; 1 g, 4.1 mmol) and following
the general procedure, the product 4 was obtained as an orange sol-
id; yield: 0.7 g (55%); mp 75 °C; Rf = 0.7 (silica gel; EtOAc–cyclo-
hexane, 1:4).
13C NMR (CDCl3): d = 22.2, 24.9, 29.1, 67.3, 85.6, 109.4, 119.8,
120.5, 122.8, 126.8, 128.0, 141.9.
Anal. Calcd for C12H12BrClN2O: C, 45.67; H, 3.83; N, 8.88. Found:
C, 45.26; H, 3.71; N, 8.67.
IR (KBr): 2956, 1614, 1460, 1377, 1209, 1039, 1078, 746, 575
cm–1.
1H NMR (CDCl3): d = 1.69–1.81 (m, 3 H), 2.05–2.16 (m, 2 H),
2.52–2.62 (m, 1 H), 3.73 (dt, J = 11.7, 3.0 Hz, 1 H), 4.03 (dd,
J = 10.7, 2.0 Hz, 1 H), 5.69 (dd, J = 9.3, 3.0 Hz, 1 H), 7.23 (t,
J = 6.8 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H),
7.56 (d, J = 8.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.4, 24.9, 29.4, 67.5, 85.6, 93.3, 110.2,
121.6, 121.9, 127.6, 128.9, 139.9.
3-Bromo-5-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-inda-
zole (5d)
Starting from 3-bromo-5-methoxy-1H-indazole (3d; 0.7 g, 3.1
mmol) and following the general procedure, the product 5d was ob-
tained as a white solid; yield: 0.6 g (63%); mp 104 °C; Rf = 0.7 (sil-
ica gel; EtOAc–cyclohexane, 1:3).
IR (KBr): 2943, 1672, 1625, 1502, 1452, 1222, 1077, 1032, 913,
880, 813, 745, 619 cm–1.
1H NMR (CDCl3): d = 1.65–1.79 (m, 3 H), 2.05–2.16 (m, 2 H),
2.47–2.55 (m, 1 H), 3.72 (dt, J = 11.2, 2.9 Hz, 1 H), 3.88 (s, 3 H),
4.01 (d, J = 11.7 Hz, 1 H), 5.63 (dd, J = 9.3, 2.0 Hz, 1 H), 6.90 (s, 1
H), 7.10 (dd, J = 9.3, 2.0 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.4, 25.0, 29.3, 55.7, 67.3, 85.6, 99.0,
111.5, 120.2, 121.0, 124.7, 136.2, 155.5.
HRMS (EI): m/z calcd for C13H15BrN2O2 [M+]: 310.0316; found:
310.0311.
Anal. Calcd for C12H13IN2O: C, 43.92; H, 3.99; N, 8.54. Found: C,
43.62; H, 4.03; N, 8.63.
3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (5a)
Starting from 3-bromo-1H-indazole (3a; 2 g, 10.1 mmol) and fol-
lowing the general procedure, the product 5a was obtained as a yel-
low solid; yield: 2.5 g (88%); mp 65 °C; Rf = 0.6 (silica gel; EtOAc–
cyclohexane, 1:6).
IR (KBr): 2941, 1651, 1617, 1463, 1326, 1200, 1081, 911, 747
cm–1.
1H NMR (CDCl3): d = 1.70–1.77 (m, 3 H), 2.09–2.14 (m, 2 H),
2.51–2.56 (m, 1 H), 3.73 (t, J = 10.8 Hz, 1 H), 4.02 (d, J = 11.7 Hz,
1 H), 5.68 (dd, J = 9.8, 2.9 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 7.44
(t, J = 7.8 Hz, 1 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1
H).
13C NMR (CDCl3): d = 22.4, 25.0, 29.3, 67.4, 85.4, 110.3, 120.4,
121.9, 122.1, 124.4, 127.7, 140.5.
3-Bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(5e)
Starting from 3-bromo-5-nitro-1H-indazole (3e; 1 g, 4.1 mmol) and
following the general procedure, the product 5e was obtained as a
white solid; yield: 0.8 g (59%); mp 121 °C; Rf = 0.5 (silica gel;
EtOAc–cyclohexane, 1:3).
IR (KBr): 2944, 1615, 1520, 1349, 1209, 1080, 1040, 913, 785
cm–1.
1H NMR (CDCl3): d = 1.70–1.76 (m, 3 H), 2.11–2.17 (m, 2 H),
2.47–2.51 (m, 1 H), 3.76 (dt, J = 10.3, 2.9 Hz, 1 H), 4.00 (d,
HRMS (EI): m/z calcd for C12H13BrN2O [M+]: 280.0211; found:
280.0208.
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

2658
E. Lohou et al.
PAPER
J = 10.8 Hz, 1 H), 5.74 (dd, J = 10.3, 2.9 Hz, 1 H), 7.70 (d, J = 9.8
Hz, 1 H), 8.31 (dd, J = 10.7, 2.0 Hz, 1 H), 8.60 (s, 1 H).
13C NMR (CDCl3): d = 21.9, 24.8, 29.2, 67.3, 86.2, 111.4, 118.2,
122.6, 124.0, 124.4, 142.4, 143.2.
yl)-1H-indazole (4) dissolved in DMSO (2–3 mL), CuI (0.2 equiv),
proline (0.4 equiv), K2CO3 (3 equiv), and the chosen amine (2
equiv) were combined in a microwave tube fitted with a crimped
septum cap. The tube was evacuated and then filled with argon sev-
eral times. The reaction mixture was heated in a microwave at
140 °C for 30 min. Then, after the addition of EtOAc (30 mL), the
organic layer was washed with brine (3 × 20 mL), dried (MgSO4),
filtered, and evaporated in vacuo. The crude material was purified
by flash column chromatography on Al2O3 often using a solvent
gradient (EtOAc–cyclohexane, 1:12 to 1:3 sometimes followed by
CH2Cl2–MeOH, 99.5:0.5 to 99:1) to give the desired N-substituted
3-aminoindazoles 6–10.
Anal. Calcd for C12H12BrN3O3: C, 44.19; H, 3.71; N, 12.88. Found:
C, 44.33; H, 3.57; N, 12.96.
3-Bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(5f)
Starting from 3-bromo-5-chloro-1H-indazole (3f; 0.4 g, 1.7 mmol)
and following the general procedure, the product 5f was obtained as
a yellow solid; yield: 0.4 g (69%); mp 76 °C; Rf = 0.4 (silica gel;
EtOAc–cyclohexane, 1:6).
Method II; Palladium-Catalyzed Amination of Different 3-Bro-
moindazole Derivatives: In a dry sealed tube, anhyd 1,4-dioxane (3
mL), Pd(OAc)2 (0.1 equiv), Xantphos (0.12 equiv), and the chosen
amine (1.2 equiv) were added under argon and the mixture was pre-
heated at 100 °C in an oil bath for 5 min. After cooling, the desired
3-bromoindazole derivative 5a–f or 5h and Cs2CO3 (2.8 equiv)
were also combined under argon with the premixed solution. Then,
the reaction mixture was heated under reflux for 6–24 h. After the
addition of EtOAc (30 mL), the organic layer was washed with
brine (3 × 20 mL), dried (MgSO4), filtered, and evaporated in vac-
uo. The crude material was purified by flash column chromatogra-
phy on Al2O3 (EtOAc–cyclohexane, 1:12 to 1:2 or CH2Cl2–MeOH,
99:1 to 95:5) to give the expected N-substituted 3-aminoindazoles
6–21.
IR (KBr): 2943, 1483, 1443, 1261, 1199, 1080, 1041, 1006, 911,
800, 789 cm–1.
1H NMR (CDCl3): d = 1.67–1.74 (m, 3 H), 2.08–2.15 (m, 2 H),
2.47–2.51 (m, 1 H), 3.73 (t, J = 10.8 Hz, 1 H), 3.99 (d, J = 9.8 Hz,
1 H), 5.65 (dd, J = 8.8, 2.9 Hz, 1 H), 7.38 (dd, J = 8.8, 1.9 Hz, 1 H),
7.53 (d, J = 9.8 Hz, 1 H), 7.59 (s, 1 H).
13C NMR (CDCl3): d = 22.1, 24.9, 29.2, 67.2, 85.8, 111.8, 119.6,
121.0, 125.3, 127.7, 128.4, 139.0.
Anal. Calcd for C12H12BrClN2O: C, 45.67; H, 3.83; N, 8.88. Found:
C, 45.83; H, 3.80; N, 9.23.
3-Bromo-6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(5g)
Starting from 3-bromo-6-chloro-1H-indazole (3g; 1.5 g, 6.2 mmol)
and following the general procedure, the product 5g was obtained
as a beige solid; yield: 1.6 g (79%); mp 134 °C; Rf = 0.5 (silica gel;
EtOAc–cyclohexane, 1:4).
3-(4-Methylpiperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
indazole (6)
Starting from 4 (0.2 g, 0.6 mmol) (method I) or 5a (0.3 g, 1 mmol)
(method II) and following the general procedure, the product 6 was
obtained as a yellow oil with method I (0.09 g, 49%) and with meth-
od II (0.2 g, 73%); Rf = 0.3 (Al2O3; CH2Cl2–MeOH, 99:1).
IR (KBr): 3074, 2977, 1525, 1343, 1208, 1079, 1039, 1004, 807,
729 cm–1.
1H NMR (CDCl3): d = 1.70–1.79 (m, 3 H), 2.12–2.15 (m, 2 H),
2.47–2.53 (m, 1 H), 3.80 (dt, J = 9.8, 3.9 Hz, 1 H), 4.03 (d, J = 11.7
Hz, 1 H), 5.77 (dd, J = 9.2, 2.0 Hz, 1 H), 7.74 (d, J = 8.8 Hz, 1 H),
8.10 (dd, J = 8.8, 2.0 Hz, 1 H), 8.56 (s, 1 H).
IR (neat): 2931, 1611, 1519, 1445, 1262, 1220, 1143, 1037, 805,
742 cm–1.
1H NMR (CDCl3): d = 1.70–1.73 (m, 3 H), 1.96–2.14 (m, 2 H), 2.38
(s, 3 H), 2.53–2.58 (m, 1 H), 2.64 (t, J = 4.9 Hz, 4 H), 3.48–3.50 (m,
4 H), 3.71 (t, J = 10.8 Hz, 1 H), 4.05 (d, J = 9.8 Hz, 1 H), 5.54 (dd,
J = 9.8, 2.0 Hz, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1
H), 7.45 (d, J = 8.8 Hz, 1 H), 7.68 (d, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.9, 25.1, 29.3, 46.3, 49.3, 54.9, 67.6, 84.9,
109.8, 116.5, 119.4, 121.1, 126.5, 141.4, 151.6.
13C NMR (CDCl3): d = 22.0, 24.8, 29.3, 67.5, 86.2, 107.6, 116.7,
121.4, 122.1, 127.6, 139.2, 147.4.
Anal. Calcd for C12H12BrN3O3: C, 44.19; H, 3.71; N, 12.88. Found:
C, 44.88; H, 3.73; N, 12.87.
HRMS (EI): m/z calcd for C17H24N4O [M+]: 300.1950; found:
3-Bromo-6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(5h)
300.1953.
Starting from 3-bromo-6-chloro-1H-indazole (3h; 0.7 g, 3.2 mmol)
and following the general procedure, the product 5h was obtained
as a yellow solid; yield: 0.4 g (42%); mp 92 °C; Rf = 0.7 (silica gel;
EtOAc–cyclohexane, 1:4).
3-(4-Benzylpiperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
indazole (7)
Starting from 4 (0.2 g, 0.6 mmol) (method I) or 5a (0.3 g, 1 mmol)
(method II) and following the general procedure, the product 7 was
obtained as a yellow oil with method I (0.1 g, 43%) and with method
II (0.1 g, 29%); Rf = 0.4 (Al2O3; CH2Cl2–MeOH, 99.5:0.5).
IR (KBr): 2924, 2837, 1613, 1465, 1333, 1208, 1083, 1041, 1004,
969, 793, 773 cm–1.
1H NMR (CDCl3): d = 1.66–1.77 (m, 3 H), 2.05–2.13 (m, 2 H),
2.48–2.51 (m, 1 H), 3.73 (t, J = 9.8 Hz, 1 H), 4.01 (d, J = 11.7 Hz,
1 H), 5.62 (dd, J = 9.8, 2.9 Hz, 1 H), 7.20 (d, J = 9.8 Hz, 1 H), 7.52
(d, J = 8.8 Hz, 1 H), 7.60 (s, 1 H).
13C NMR (CDCl3): d = 22.2, 24.9, 29.2, 67.4, 85.8, 110.4, 110.5,
121.4, 122.0, 123.1, 134.4, 140.8.
HRMS (EI): m/z calcd for C12H12BrClN2O [M+]: 313.9821; found:
313.9835.
IR (neat): 2937, 1611, 1451, 1219, 1039, 910, 740 cm–1.
1H NMR (CDCl3): d = 1.72–1.75 (m, 3 H), 1.96–2.12 (m, 2 H),
2.50–2.58 (m, 1 H), 2.66 (t, J = 4.9 Hz, 4 H), 3.44–3.51 (m, 4 H),
3.60 (s, 2 H), 3.70 (t, J = 10.7 Hz, 1 H), 4.05 (d, J = 6.8 Hz, 1 H),
5.54 (dd, J = 9.8, 2.0 Hz, 1 H), 7.04 (t, J = 7.8 Hz, 1 H), 7.27–7.30
(m, 2 H), 7.34 (t, J = 6.8 Hz, 2 H), 7.38 (d, J = 6.8 Hz, 2 H), 7.44 (d,
J = 8.8 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.8, 25.1, 29.2, 49.4, 52.7, 63.0, 67.5, 84.8,
104.4, 109.8, 116.2, 119.3, 121.1, 126.4, 127.0, 128.1, 129.1, 141.4,
151.7.
Buchwald–Hartwig C–N Coupling Synthesis of N-Substituted
3-Aminoindazoles 6–21; General Procedure
HRMS (EI): m/z calcd for C23H28N4O [M+]: 376.2263; found:
Method I; Copper-Catalyzed and Microwave-Promoted Amination
of a 3-Iodoindazole Derivative: 3-Iodo-1-(tetrahydro-2H-pyran-2-
376.2267.
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Aminoindazoles by Buchwald–Hartwig C–N Coupling
2659
4-[1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl]piperazin-1-
carboxylic Acid Benzyl Ester (8)
Starting from 4 (0.2 g, 0.6 mmol) (method I) or 5a (0.3 g, 1 mmol)
(method II) and following the general procedure, the product 8 was
obtained as a yellow oil with method I (0.1 g, 51%) and with method
II (0.3 g, 64%); Rf = 0.1 (Al2O3; EtOAc–cyclohexane, 1:8).
1H NMR (CDCl3): d = 1.71–1.76 (m, 3 H), 1.99–2.14 (m, 2 H),
2.52–2.56 (m, 1 H), 3.09 (t, J = 4.9 Hz, 4 H), 3.38–3.47 (m, 4 H),
3.71 (t, J = 10.8 Hz, 1 H), 4.05 (d, J = 9.8 Hz, 1 H), 5.30 (s, 1 H),
5.55 (dd, J = 9.8, 2.9 Hz, 1 H), 7.05 (t, J = 7.8 Hz, 1 H), 7.33 (t,
J = 6.8 Hz, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.9, 25.1, 29.3, 45.6, 50.5, 67.6, 84.9,
109.9, 116.5, 119.5, 121.1, 126.6, 141.5, 152.0.
HRMS (EI): m/z calcd for C16H22N4O [M+]: 286.1793; found:
IR (neat): 2939, 1704, 1611, 1520, 1434, 1243, 1220, 1078, 1038,
911, 742 cm–1.
1H NMR (CDCl3): d = 1.72–1.75 (m, 3 H), 1.96–2.12 (m, 2 H),
2.50–2.54 (m, 1 H), 3.42–3.44 (m, 4 H), 3.67–3.69 (m, 1 H), 3.72 (t,
J = 4.9 Hz, 4 H), 4.04 (d, J = 9.8 Hz, 1 H), 5.18 (s, 2 H), 5.54 (dd,
J = 9.8, 3.0 Hz, 1 H), 7.06 (t, J = 7.8 Hz, 1 H), 7.33–7.38 (m, 4 H),
7.38 (d, J = 3.9 Hz, 2 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.65 (d, J = 7.8
Hz, 1 H).
13C NMR (CDCl3): d = 22.9, 25.1, 29.3, 43.5, 49.5, 67.2, 67.6, 84.8,
109.9, 116.4, 119.7, 120.8, 126.7, 127.9, 128.0, 128.5, 136.6, 141.4,
151.3, 155.32.
286.1786.
(4-Bromophenyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-
yl]amine (12)
Starting from 5a (0.3 g, 1 mmol) and following method II, the prod-
uct 12 was obtained as an orange solid (0.07 g, 19%); mp 130 °C;
Rf = 0.3 (Al2O3; EtOAc–cyclohexane, 1:8).
IR (KBr): 3402, 2923, 1614, 1549, 1487, 1290, 1214, 1021, 803,
733 cm–1.
HRMS (EI): m/z calcd for C24H28N4O3 [M+]: 420.2161; found:
420.2179.
1H NMR (CDCl3): d = 1.74–1.80 (m, 3 H), 2.05–2.18 (m, 2 H),
2.58–2.62 (m, 1 H), 3.74 (t, J = 8.8 Hz, 1 H), 4.08 (d, J = 11.7 Hz,
1 H), 5.62 (dd, J = 9.3, 2.0 Hz, 1 H), 6.27 (s, 1 H), 7.11 (t, J = 6.8
Hz, 1 H), 7.29–7.33 (m, 2 H), 7.38 (d, J = 9.8 Hz, 2 H), 7.42 (d,
J = 6.8 Hz, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 7.8 Hz, 1 H).
3-(Morpholin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(9)
Starting from 4 (0.2 g, 0.8 mmol) (method I) or 5a (0.3 g, 1 mmol)
(method II) and following the general procedure, the product 9 was
obtained as a beige oil with method I (0.06 g, 27%) and with method
II (0.1 g, 52%); Rf = 0.1 (Al2O3; EtOAc–cyclohexane, 1:12).
13C NMR (CDCl3): d = 22.8, 25.1, 29.4, 67.6, 84.8, 110.0, 112.5,
116.4, 118.3, 119.5, 120.2, 127.6, 131.9, 140.6, 141.2, 143.8.
HRMS (EI): m/z calcd for C17H18BrN4O [M+]: 373.0663; found:
373.0652.
IR (KBr): 2957, 1611, 1520, 1443, 1221, 1118, 1079, 1022, 909,
742 cm–1.
(4-Methoxyphenyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-
3-yl]amine (13)
Starting from 5a (0.3 g, 1 mmol) and following method II, the prod-
uct 13 was obtained as a beige solid (0.2 g, 65%); mp 140 °C;
Rf = 0.3 (Al2O3; EtOAc–cyclohexane, 1:4).
1H NMR (CDCl3): d = 1.71–1.76 (m, 3 H), 1.97–2.17 (m, 2 H),
2.53–2.56 (m, 1 H), 3.39–3.50 (m, 4 H), 3.71 (t, J = 11.7 Hz, 1 H),
3.91 (t, J = 4.9 Hz, 4 H), 4.05 (d, J = 9.8 Hz, 1 H), 5.55 (dd, J = 9.8,
2.9 Hz, 1 H), 7.05 (t, J = 7.8 Hz, 1 H), 7.34 (t, J = 6.8 Hz, 1 H), 7.45
(d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.9, 25.2, 29.3, 50.0, 66.8, 67.7, 84.9,
109.9, 116.4, 119.6, 121.0, 126.7, 141.5, 151.7.
IR (KBr): 3363, 2954, 1614, 1548, 1510, 1451, 1245, 1212, 1073,
1037, 911, 828, 743 cm–1.
1H NMR (DMSO-d6): d = 1.75–1.80 (m, 3 H), 2.00–2.09 (m, 2 H),
2.46–2.50 (m, 1 H), 3.75–3.78 (m, 1 H), 3.77 (s, 3 H), 3.91 (d,
J = 8.8 Hz, 1 H), 5.72 (d, J = 8.8 Hz, 1 H), 6.95 (d, J = 8.8 Hz, 2 H),
7.14 (t, J = 6.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.60 (d, J = 8.8
Hz, 1 H), 7.72 (d, J = 8.8 Hz, 2 H), 8.02 (d, J = 7.8 Hz, 1 H), 8.81
(s, 1 H).
HRMS (EI): m/z calcd for C16H21N3O2 [M+]: 287.1634; found:
287.1632.
Phenyl[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl]amine
(10)
Starting from 4 (0.2 g, 0.6 mmol) (method I) or 5a (0.4 g, 1.5 mmol)
(method II) and following the general procedure, the product 10 was
obtained as a yellow solid with method I (traces) and with method
II (0.4 g, 87%); mp 166 °C; Rf = 0.3 (Al2O3; EtOAc–cyclohexane,
1:10).
13C NMR (DMSO-d6): d = 22.5, 24.9, 29.0, 55.2, 66.4, 83.5, 109.6,
114.0, 116.0, 117.2, 119.2, 120.2, 127.0, 136.2, 140.2, 145.0, 152.6.
HRMS (EI): m/z calcd for C19H21N3O2 [M+]: 323.1634; found:
323.1633.
IR (neat): 3350, 2953, 1606, 1549, 1445, 1214, 1025, 743 cm–1.
(3,4-Dimethoxyphenyl)[1-(tetrahydro-2H-pyran-2-yl)-1H-in-
dazol-3-yl]amine (14)
Starting from 5a (0.3 g, 1 mmol) and following method II, the prod-
uct 14 was obtained as a beige solid (0.2 g, 54%); mp 95 °C; Rf = 0.3
(Al2O3; EtOAc–cyclohexane, 1:3).
1H NMR (CDCl3): d = 1.74–1.79 (m, 3 H), 2.05–2.18 (m, 2 H),
2.60–2.63 (m, 1 H), 3.74 (t, J = 8.8 Hz, 1 H), 4.07 (d, J = 9.8 Hz, 1
H), 5.62 (dd, J = 9.3, 3.0 Hz, 1 H), 6.27 (s, 1 H), 6.92 (t, J = 6.8 Hz,
1 H), 7.09 (t, J = 7.8 Hz, 1 H), 7.29 (t, J = 7.8 Hz, 2 H), 7.38–7.42
(m, 3 H), 7.49 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.8, 25.1, 29.4, 67.5, 84.8, 109.9, 116.3,
116.8, 119.6, 119.9, 120.3, 127.2, 129.0, 140.6, 142.4, 144.2.
IR (KBr): 3370, 2934, 1616, 1513, 1451, 1207, 1026, 910, 731
cm–1.
1H NMR (CDCl3): d = 1.65–1.78 (m, 3 H), 2.04–2.18 (m, 2 H),
2.56–2.62 (m, 1 H), 3.73 (t, J = 10.8 Hz, 1 H), 3.87 (s, 6 H), 4.04 (d,
J = 11.7 Hz, 1 H), 5.59–5.61 (m, 1 H), 6.25 (s, 1 H), 6.81 (d, J = 7.8
Hz, 1 H), 7.06 (t, J = 7.8 Hz, 1 H), 7.26 (s, 1 H), 7.38 (t, J = 7.8 Hz,
1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.47 (d, J = 8.8 Hz, 1 H), 7.49 (d,
J = 7.8 Hz, 1 H).
HRMS (EI): m/z calcd for C18H19N3O [M+]: 293.1528; found:
293.1527.
3-(Piperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
(11)
Starting from 5a (0.3 g, 1 mmol) and following method II, the prod-
uct 11 was obtained as a yellow oil (0.05 g, 17%); Rf = 0.1 (Al2O3;
CH2Cl2–MeOH, 95:5).
IR (neat): 3420, 2921, 1610, 1520, 1222, 1037, 909, 803 cm–1.
13C NMR (CDCl3): d = 22.8, 25.2, 29.3, 55.7, 56.3, 67.2, 84.6,
102.4, 108.6, 109.7, 112.1, 116.4, 119.6, 119.7, 127.2, 136.4, 140.7,
143.3, 145.0, 149.3.
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E. Lohou et al.
PAPER
HRMS (EI): m/z calcd for C20H23N3O3 [M+]: 353.1739; found:
353.1744.
IR (neat): 2939, 1701, 1624, 1521, 1489, 1431, 1240, 1122, 1078,
1036, 909, 811, 760, 699 cm–1.
1H NMR (CDCl3): d = 1.70–1.74 (m, 3 H), 1.96–2.12 (m, 2 H),
2.48–2.52 (m, 1 H), 3.35–3.38 (m, 4 H), 3.69–3.71 (m, 1 H), 3.72 (t,
J = 4.9 Hz, 4 H), 3.84 (s, 3 H), 4.02 (d, J = 6.8 Hz, 1 H), 5.17 (s, 2
H), 5.49 (d, J = 9.8 Hz, 1 H), 6.96 (s, 1 H), 7.04 (dd, J = 8.8, 2.0 Hz,
1 H), 7.33–7.39 (m, 6 H).
13C NMR (CDCl3): d = 22.8, 25.1, 29.3, 43.4, 50.0, 55.9, 67.2, 67.6,
85.2, 100.6, 111.1, 116.5, 118.6, 127.9, 128.0, 128.1, 128.5, 136.6,
137.2, 154.0, 155.3.
Benzyl[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl]amine
(15)
Starting from 5a (0.3 g, 1 mmol) and following method II, the prod-
uct 15 was obtained as a yellow oil (0.07 g, 23%); Rf = 0.2 (Al2O3;
EtOAc–cyclohexane, 1:12).
IR (neat): 3370, 2939, 2855, 1613, 1549, 1449, 1340, 1217, 1077,
1034, 742, 699 cm–1.
1H NMR (CDCl3): d = 1.59 (s, 2 H), 1.71–1.76 (m, 3 H), 1.98–2.12
(m, 2 H), 2.56–2.59 (m, 1 H), 3.71 (t, J = 10.7 Hz, 1 H), 4.07 (d,
J = 9.8 Hz, 1 H), 4.17 (s, 1 H), 5.53 (dd, J = 9.8, J = 3.0 Hz, 1 H),
7.02 (t, J = 6.8 Hz, 1 H), 7.29 (t, J = 6.8 Hz, 1 H), 7.30 (d, J = 7.8
Hz, 1 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.39 (t, J = 8.8 Hz, 1 H), 7.46–
7.48 (m, 3 H).
HRMS (EI): m/z calcd for C25H30N4O4 [M+]: 450.2267; found:
450.2276.
4-[5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl]pip-
erazin-1-carboxylic Acid Benzyl Ester (19)
Starting from 5e (0.3 g, 1 mmol) and following method II, the prod-
uct 19 was obtained as a red solid (0.2 g, 37%); mp 170 °C; Rf = 0.1
(Al2O3; EtOAc–cyclohexane, 1:8).
13C NMR (CDCl3): d = 23.1, 25.2, 29.5, 48.4, 67.7, 84.9, 109.5,
115.8, 119.2, 127.1, 127.3, 128.2, 128.5, 128.8, 139.8, 141.4, 149.6.
HRMS (EI): m/z calcd for C19H21N3O [M+]: 307.1684; found:
307.1674.
IR (KBr): 2938, 1697, 1611, 1530, 1473, 1432, 1323, 1224, 1128,
1076, 1035, 739 cm–1.
1H NMR (CDCl3): d = 1.60–1.74 (m, 3 H), 2.00–2.17 (m, 2 H),
2.45–2.50 (m, 1 H), 3.45–3.50 (m, 4 H), 3.70–3.72 (m, 1 H), 3.74 (t,
J = 4.9 Hz, 4 H), 4.03 (d, J = 11.7 Hz, 1 H), 5.18 (s, 2 H), 5.57 (dd,
J = 9.3, 2.9 Hz, 1 H), 7.33–7.39 (m, 5 H), 7.50 (d, J = 9.8 Hz, 1 H),
8.23 (dd, J = 8.8, 1.9 Hz, 1 H), 8.67 (s, 1 H).
13C NMR (CDCl3): d = 22.4, 25.0, 29.2, 43.4, 49.2, 67.3, 67.6, 85.3,
110.2, 115.6, 119.1, 121.9, 127.9, 128.1, 128.5, 136.6, 140.9, 143.1,
153.2, 155.3.
4-[4-Nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl]pip-
erazin-1-carboxylic Acid Benzyl Ester (16)
Starting from 5b (0.3 g, 1 mmol) and following method II, the prod-
uct 16 was obtained as a red solid (0.1 g, 21%); mp 50 °C; Rf = 0.4
(Al2O3; EtOAc–cyclohexane, 1:3).
IR (KBr): 2926, 1701, 1618, 1528, 1424, 1344, 1242, 1118, 1082,
1041, 731 cm–1.
1H NMR (CDCl3): d = 1.68–1.72 (m, 3 H), 2.02–2.15 (m, 2 H),
2.48–2.52 (m, 1 H), 3.08–3.10 (m, 4 H), 3.70–3.72 (m, 5 H), 3.97
(d, J = 11.7 Hz, 1 H), 5.16 (s, 2 H), 5.65 (dd, J = 9.2, 2.9 Hz, 1 H),
7.32–7.38 (m, 5 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1
H), 7.80 (d, J = 8.8 Hz, 1 H).
13C NMR (CDCl3): d = 22.2, 25.0, 26.9, 29.2, 43.5, 51.4, 67.1, 85.2,
108.3, 115.8, 117.4, 125.8, 127.8, 128.0, 128.5, 136.7, 142.6, 143.6,
150.2, 155.3.
HRMS (EI): m/z calcd for C24H27N5O5 [M+]: 465.2012; found:
465.2019.
4-[5-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-
yl]piperazin-1-carboxylic Acid Benzyl Ester (20)
Starting from 5f (0.3 g, 1 mmol) and following method II, the prod-
uct 20 was obtained as an orange solid (0.1 g, 29%); mp 98 °C;
Rf = 0.5 (Al2O3; EtOAc–cyclohexane, 1:5).
HRMS (EI): m/z calcd for C24H27N5O5 [M+]: 465.2012; found:
465.2026.
IR (KBr): 2926, 1704, 1533, 1469, 1430, 1221, 1078, 1034, 986,
910, 752, 695 cm–1.
1H NMR (CDCl3): d = 1.69–1.72 (m, 3 H), 1.96–2.11 (m, 2 H),
2.48–2.50 (m, 1 H), 3.14–3.17 (m, 2 H), 3.36–3.40 (m, 2 H), 3.68–
3.70 (m, 1 H), 3.71 (t, J = 4.9 Hz, 4 H), 4.02 (d, J = 11.7 Hz, 1 H),
5.18 (s, 2 H), 5.50 (dd, J = 9.3, 2.9 Hz, 1 H), 7.29 (dd, J = 8.8, 2.0
Hz, 1 H), 7.33–7.38 (m, 5 H), 7.39 (d, J = 6.8 Hz, 1 H), 7.62 (s, 1 H).
13C NMR (CDCl3): d = 22.7, 25.1, 29.2, 43.5, 49.5, 67.2, 67.5, 85.0,
111.2, 117.3, 120.1, 125.1, 127.2, 128.0, 128.5, 129.3, 136.6, 139.9,
150.8, 155.3.
4-[4-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-
yl]piperazin-1-carboxylic Acid Benzyl Ester (17)
Starting from 5c (0.3 g, 1 mmol) and following method II, the prod-
uct 17 was obtained as a colorless oil (0.2 g, 40%); Rf = 0.2 (Al2O3;
EtOAc–cyclohexane, 1:4).
IR (neat): 2935, 1696, 1608, 1512, 1431, 1382, 1243, 1113, 1080,
1040 cm–1.
1H NMR (CDCl3): d = 1.70–1.74 (m, 3 H), 1.95–2.12 (m, 2 H),
2.47–2.52 (m, 1 H), 3.30–3.34 (m, 4 H), 3.70–3.73 (m, 5 H), 4.01
(d, J = 10.7 Hz, 1 H), 5.17 (s, 2 H), 5.54 (dd, J = 9.3, 2.9 Hz, 1 H),
7.07 (d, J = 7.8 Hz, 1 H), 7.23 (t, J = 7.8 Hz, 1 H), 7.32–7.38 (m, 6
H).
13C NMR (CDCl3): d = 22.5, 25.0, 29.1, 43.7, 51.8, 67.1, 67.4, 84.8,
108.6, 115.5, 121.2, 126.4, 127.3, 127.8, 128.0, 128.5, 136.7, 142.5,
151.7, 155.4.
HRMS (EI): m/z calcd for C24H27ClN4O3 [M+]: 454.1771; found:
454.1783.
4-[6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-
yl]piperazin-1-carboxylic Acid Benzyl Ester (21)
Starting from 5h (0.3 g, 1 mmol) and following method II, the prod-
uct 21 was obtained as an orange oil (0.2 g, 42%); Rf = 0.4 (Al2O3;
EtOAc–cyclohexane, 1:2).
HRMS (EI): m/z calcd for C24H27ClN4O3 [M+]: 454.1771; found:
454.1774.
IR (neat): 2940, 1697, 1621, 1435, 1242, 1121, 1078, 1038, 910,
734, 698 cm–1.
1H NMR (CDCl3): d = 1.70–1.72 (m, 3 H), 1.94–2.12 (m, 2 H),
2.48–2.50 (m, 1 H), 3.20–3.22 (m, 2 H), 3.39–3.41 (m, 2 H), 3.68–
3.71 (m, 5 H), 4.01–4.04 (m, 1 H), 5.17 (s, 2 H), 5.46 (d, J = 6.8 Hz,
1 H), 6.77 (d, J = 8.8 Hz, 1 H), 7.32–7.38 (m, 6 H), 7.50 (d, J = 8.8
Hz, 1 H).
4-[5-Methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-
yl]piperazin-1-carboxylic Acid Benzyl Ester (18)
Starting from 5d (0.3 g, 1 mmol) and following method II, the prod-
uct 18 was obtained as a yellow oil (0.08 g, 18%); Rf = 0.1 (Al2O3;
EtOAc–cyclohexane, 1:8).
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

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Synthesis of 3-Aminoindazoles by Buchwald–Hartwig C–N Coupling
2661
13C NMR (CDCl3): d = 22.8, 25.1, 29.2, 43.7, 49.3, 49.9, 67.2, 67.4,
84.5, 95.3, 110.8, 112.8, 121.4, 128.0, 128.5, 136.5, 136.6, 142.9,
151.3, 155.2, 155.3.
HRMS (EI): m/z calcd for C24H27ClN4O3 [M+]: 454.1771; found:
454.1780.
at r.t. Then, the acidic mixture was neutralized with aq 2 N NaOH
and the EtOH was evaporated in vacuo. The obtained residue was
dissolved in EtOAc (30 mL) and a pH-dependent extraction was
carried out. First, an acidic aqueous layer was used to hold the de-
sired primary 3-aminoindazoles and eliminate the simultaneously
synthesized benzophenone in the organic layer. Then, the expected
compounds were extracted from an alkaline aqueous layer with
EtOAc (3 × 20 mL) and the combined organic layers were washed
with brine (3 × 20 mL), dried (MgSO4), filtered, and evaporated in
vacuo. Finally, the expected unprotected primary 3-aminoindazoles
27–29 were directly isolated.
Unprotected N-Substituted 3-Aminoindazoles 22 and 23; Gen-
eral Procedure
Indazole 7 or 10 was introduced in ethanolic HCl (5–6 mL) and the
mixture was stirred for 2–3 h at r.t. Then, the acidic mixture was
neutralized with aq 2 N NaOH and the EtOH was evaporated in vac-
uo. After addition of EtOAc (30 mL) to the residue, the organic lay-
er was washed with brine (3 × 20 mL), dried (MgSO4), filtered, and
evaporated in vacuo. Finally, the expected unprotected N-substitut-
ed 3-aminoindazoles 22 and 23 were directly isolated.
3-Amino-1H-indazole (27)
Step I
Benzhydrylidene[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-
yl]amine (24)
Starting from 5a (0.4 g, 1.5 mmol) and following the general proce-
dure, the product 24 was obtained as a yellow solid (0.6 g, 99%); mp
115 °C; Rf = 0.5 (silica gel; EtOAc–cyclohexane, 1:3).
3-(4-Benzylpiperazin-1-yl)-1H-indazole (22)
Starting from 7 (0.07 g, 0.2 mmol) and following the general proce-
dure, the product 22 was obtained as an orange oil (0.02 g, 37%);
Rf = 0.4 (Al2O3; EtOAc–cyclohexane, 1:1).
IR (KBr): 2922, 1609, 1488, 1320, 1285, 1199, 1027, 746, 696
cm–1.
IR (KBr): 3214, 2931, 2819, 1617, 1517, 1452, 1343, 1256, 1166,
1007, 738, 699 cm–1.
1H NMR (CDCl3): d = 2.69 (t, J = 4.8 Hz, 4 H), 3.48 (t, J = 4.9 Hz,
4 H), 3.68 (s, 2 H), 7.02–7.07 (m, 1 H), 7.32–7.39 (m, 7 H), 7.71 (d,
J = 8.8 Hz, 1 H), 9.16 (s, 1 H).
13C NMR (CDCl3): d = 49.7, 52.9, 63.2, 109.9, 115.4, 119.2, 121.1,
126.8, 127.1, 128.3, 129.2, 138.1, 142.8, 153.4.
1H NMR (CDCl3): d = 1.63–1.70 (m, 3 H), 1.86–2.00 (m, 2 H),
2.28–2.32 (m, 1 H), 3.47–3.61 (m, 1 H), 3.69–3.71 (m, 1 H), 5.62
(dd, J = 6.3, 2.9 Hz, 1 H), 6.99 (t, J = 7.8 Hz, 1 H), 7.22–7.30 (m, 7
H), 7.41 (d, J = 7.8 Hz, 4 H), 7.49 (d, J = 5.9 Hz, 1 H), 7.87 (d,
J = 7.8 Hz, 1 H).
13C NMR (CDCl3): d = 21.7, 25.1, 28.7, 65.9, 84.1, 109.7, 118.4,
120.5, 126.5, 127.8, 128.1, 128.6, 129.1, 129.8, 131.0, 137.3, 139.4,
140.6, 150.9, 171.8.
HRMS (EI): m/z calcd for C18H20N4 [M+]: 292.1688; found:
292.1686.
HRMS (EI): m/z calcd for C25H23N3O [M+]: 381.1841; found:
381.1851.
Phenyl(1H-indazol-3-yl)amine (23)
Starting from 10 (0.05 g, 0.2 mmol) and following the general pro-
cedure, the product 23 was obtained as a brown solid (0.03 g, 84%);
mp 96 °C; Rf = 0.9 (silica gel; EtOAc–cyclohexane, 1:3).
Step II
3-Amino-1H-indazole (27)
Starting from 24 (0.6 g, 1.5 mmol) and following the general proce-
dure, the product 27 was obtained as a beige solid (0.07 g, 35%); mp
164 °C; Rf = 0.2 (silica gel; EtOAc).
IR (neat): 3412, 3251, 2924, 1619, 1603, 1555, 1497, 1446, 1338,
1261, 1077, 1026, 740, 686 cm–1.
1H NMR (DMSO-d6): d = 6.78 (t, J = 6.8 Hz, 1 H), 7.01 (t, J = 6.8
Hz, 1 H), 7.23 (t, J = 7.8 Hz, 2 H), 7.31 (t, J = 6.8 Hz, 1 H), 7.36 (d,
J = 8.8 Hz, 1 H), 7.64 (d, J = 7.8 Hz, 2 H), 7.93 (d, J = 8.8 Hz, 1 H),
8.73 (s, 1 H), 11.92 (s, 1 H).
13C NMR (DMSO-d6): d = 109.4, 114.5, 115.6, 118.1, 118.5, 119.5,
126.5, 128.5, 140.5, 143.1, 144.8.
IR (KBr): 3314, 1616, 1535, 1494, 1344, 1044, 744 cm–1.
1H NMR (DMSO-d6): d = 5.32 (s, 2 H), 6.85–6.89 (m, 1 H), 7.18–
7.21 (m, 2 H), 7.65 (d, J = 8.8 Hz, 1 H), 11.35 (s, 1 H).
13C NMR (DMSO-d6): d = 109.3, 114.0, 117.4, 120.2, 126.1, 141.4,
149.0.
HRMS (EI): m/z calcd for C7H7N3 [M+]: 133.0640; found:
133.0634.
HRMS (EI): m/z calcd for C13H11N3 [M+]: 209.0953; found:
209.0963.
3-Amino-5-nitro-1H-indazole (28)
Step I
Benzhydrylidene[5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-in-
dazol-3-yl]amine (25)
Starting from 5e (0.3 g, 1 mmol) and following the general proce-
Two-Step Synthesis of Unprotected Primary 3-Aminoindazoles
27–29; General Procedure
Step I: Buchwald–Hartwig C–N Coupling of Different 3-Bromoin-
dazole Derivatives with Benzophenone Imine: In a dry sealed tube,
anhyd 1,4-dioxane (3 mL), Pd(OAc)2 (0.1 equiv), Xantphos (0.12
equiv), and benzophenone imine (1.2 equiv) were added under ar-
gon and the mixture was preheated at 100 °C in an oil bath for 5
min. After cooling, the desired 3-bromoindazole derivative 5a, 5e,
or 5g and Cs2CO3 (2.8 equiv) were also combined under argon with
the premixed solution. Then, the reaction mixture was heated under
reflux for 6–24 h. After the addition of EtOAc (30 mL), the organic
layer was washed with brine (3 × 20 mL), dried (MgSO4), filtered,
and evaporated in vacuo. The crude material was purified by flash
column chromatography on silica gel (EtOAc–cyclohexane, 1:8 to
1:3) to give the expected 3-iminoindazoles 24–26.
dure, the product 25 was synthesized, but not purified.
Step II
3-Amino-5-nitro-1H-indazole (28)
Starting from the crude material obtained during step I and follow-
ing the general procedure, the product 28 was obtained as an orange
solid (0.1 g, 67% over two steps); mp 159 °C; Rf = 0.1 (silica gel;
EtOAc–cyclohexane, 1:1).
IR (KBr): 3438, 1617, 1521, 1473, 1325, 1261, 1066, 1023, 804,
740 cm–1.
Step II: Acidic Hydrolysis of the Previously Synthesized 3-Iminoin-
dazole Derivatives: The chosen indazole 24–26 was introduced in
ethanolic HCl (15–20 mL) and the mixture was stirred for 0.5–72 h
1H NMR (DMSO-d6): d = 3.56 (s, 2 H), 7.42 (d, J = 8.8 Hz, 1 H),
8.13 (d, J = 10.8 Hz, 1 H), 8.97 (s, 1 H).
Synthesis 2011, No. 16, 2651–2663 © Thieme Stuttgart · New York

2662
E. Lohou et al.
PAPER
13C NMR (DMSO-d6): d = 109.8, 113.2, 119.6, 121.3, 138.9, 142.7,
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HRMS (EI): m/z calcd for C7H6N4O2 [M+]: 178.0490; found:
178.0487.
3-Amino-6-nitro-1H-indazole (29)
Step I
Benzhydrylidene[6-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-in-
dazol-3-yl]amine (26)
Starting from 5g (0.3 g, 1 mmol) and following the general proce-
dure, the product 26 was obtained as a yellow solid (0.2 g, 59%); mp
142 °C; Rf = 0.4 (silica gel; EtOAc–cyclohexane, 1:8).
IR (KBr): 2957, 2918, 2870, 1608, 1422, 1343, 1199, 1020, 738,
696 cm–1.
1H NMR (CDCl3): d = 1.62–1.65 (m, 3 H), 1.90–1.94 (m, 2 H),
2.26–2.30 (m, 1 H), 3.65–3.75 (m, 2 H), 5.69 (dd, J = 7.3, 3.9 Hz, 1
H), 7.22–7.26 (m, 4 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz,
2 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.85 (d, J = 10.7, 2.0 Hz, 1 H), 7.87
(d, J = 8.8 Hz, 2 H), 8.38 (s, 1 H).
13C NMR (CDCl3): d = 21.4, 24.9, 28.7, 66.1, 84.9, 107.0, 115.3,
121.2, 121.4, 128.0, 128.2, 129.0, 129.9, 131.5, 136.9, 138.8, 139.2,
146.6, 151.0, 173.3.
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HRMS (EI): m/z calcd for C25H22N4O3 [M+]: 426.1692; found:
426.1707.
Step II
3-Amino-6-nitro-1H-indazole (29)
Starting from 26 (0.2 g, 0.5 mmol) and following the general proce-
dure, the product 29 was obtained as a red solid (0.07 g, 84%); mp
210 °C; Rf = 0.1 (silica gel; EtOAc–cyclohexane, 1:1).
IR (KBr): 3370, 1711, 1627, 1518, 1347, 1057, 787, 730 cm–1.
1H NMR (DMSO-d6): d = 5.72 (s, 2 H), 7.71 (d, J = 8.8 Hz, 1 H),
7.90 (d, J = 8.8 Hz, 1 H), 8.11 (s, 1 H), 12.11 (s, 1 H).
13C NMR (DMSO-d6): d = 105.9, 111.7, 116.7, 121.6, 139.6, 146.2,
149.7.
HRMS (EI): m/z calcd for C7H6N4O2 [M+]: 178.0490; found:
178.0488.
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Acknowledgment
We thank Dr. Rémi Legay for the high-resolution mass spectrome-
try measurements.
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Synthesis of 3-Aminoindazoles by Buchwald–Hartwig C–N Coupling
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