Synthesis of 3-indazolecarboxylic esters and amides via Pd-catalyzed carbonylation of 3-iodoindazoles

Article abstract of DOI:10.1055/s-0030-1260199

A straightforward and effective procedure for the preparation of 1H-indazole-3-carboxylic acid esters and amides was developed. A series of functionalized 3-iodoindazoles were subjected to Pd-catalyzed carbonylations in the presence of methanol or amines,

Full text of DOI:10.1055/s-0030-1260199

PAPER
3089
Synthesis of 3-Indazolecarboxylic Esters and Amides via Pd-Catalyzed
Carbonylation of 3-Iodoindazoles
S
ynthesis of 3-Ind
a
a
zolecarbox
n
ylic Esters
a
s
nd Amide
-
s
Peter Buchstaller,*a Kai Wilkinson,a Kasimir Burek,b Yasmin Nisarb
a
Merck Serono, Merck KGaA, Frankfurter Straße 250, 64293 Darmstadt, Germany
Fax +49(6151)723129; E-mail: hans.peter.buchstaller@merck.de
b
Performance Materials, Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany
Received 10 May 2011; revised 13 July 2011
be prepared separately. Kelly et al. reported that the typi-
cal conditions of the hydrolysis/diazotization/reduction
protocol were not applicable to their substrate.8 In their
account, the authors established an alternative route, but
Abstract: A straightforward and effective procedure for the prepa-
ration of 1H-indazole-3-carboxylic acid esters and amides was de-
veloped. A series of functionalized 3-iodoindazoles were subjected
to Pd-catalyzed carbonylations in the presence of methanol or
amines, yielding the title compounds in moderate to good yield. For this variation was neither superior to the former method in
the majority of examples, the reaction proceeded cleanly under mild
terms of the number of synthetic steps, nor in the overall
conditions, which were readily tolerated by a diverse range of func-
tional groups that allow further synthetic transformations.
yield of the target products desired by us. Intramolecular
coupling of appropriately substituted diazonium salts is
the key step of another reported approach to the title com-
Key words: carbonylation, esters, amides, alkoxycarbonylation,
pounds.9 However, the laborious synthesis required to ac-
aminocarbonylation, iodoindazole, palladium catalysis
cess the aryl acetic acid precursors and the varying yields
of the cyclization reaction limit this approach. Finally,
The design and synthesis of small molecules that are valu-
able therapeutic agents is one of the main objectives of or-
ganic and medicinal chemistry. Many examples confirm
that substituted heterocyclic compounds can be useful
agents in a broad range of therapeutic areas. In particular,
substituted indazoles play an increasingly important role
in drug discovery, and their synthesis1 as well as their abil-
ity to interact with a variety of diverse targets2 has been
well-documented. Moreover, the synthesis of appropriate-
ly substituted indazole derivatives is of interest to medic-
inal chemists due to their pharmacophoric relationship to
privileged structures such as indoles and benzimidazoles.
carboxylation of 5-methoxyindazole at the 3-position
with carbon dioxide and potassium carbonate at high tem-
perature and pressure to give the 3-carboxy derivative was
reported in the literature once only.10 Thus, together, the
repertoire of available methods for the synthesis of the ti-
tle compounds is not satisfactory. For this reason, we
sought a method for the preparation of 1H-indazole-3-car-
boxylic acid esters and amides of sufficient brevity and
generality to allow the synthesis of a wide variety of de-
rivatives.
3-Iodoindazoles have proven to be valuable intermediates
for the metal-catalyzed preparation of indazole deriva-
tives.11,12 These substrates are easily accessible by iodina-
tion of indazoles11,12 (Scheme 1) and, hence, we regarded
them as reasonable intermediates for the development of
a new synthetic route. In this paper, we report the prepa-
ration of substituted 1H-indazole-3-carboxylic acid esters
In the course of a medicinal chemistry program, we were
interested in the synthesis of indazoles bearing carboxylic
acid amides at the 3-position. This scaffold has proven to
exhibit broad versatility, which is reflected in its utiliza-
tion in the therapy of a diverse range of diseases. In the
last two years alone, several patents have appeared claim-
ing such derivatives as therapeutics for the treatment of
different diseases such as muscular dystrophy,3 cancer,4
diabetes,5 and pain.6
O
OMe
I
i
ii
R1
N
R1
R1
N
N
Although many indazole-3-carboxylic acid derivatives
have been prepared from substituted 1H-indazole-3-car-
boxylic acids as starting material, the reported methods
for the synthesis of these building blocks have several
limitations. Varying yields of the desired acids were re-
ported for the most widespread approach, which com-
prises the conversion of substituted isatins in a three-step
reaction sequence.7 In addition, in many cases, the re-
quired isatins are not commercially available and have to
N
N
N
H
H
H
2a–m
1a–m
3a–m
iii
R2
O
N
R3
R1
N
N
H
4a–q
Scheme 1 Reagents and conditions: (i) I2, KOH, DMF, r.t., 1–2.5 h;
(ii) [Pd], CO (1 bar), Et3N, MeOH/toluene, 70 °C, overnight; (iii)
[Pd], CO (2 bar), Et3N, amine, THF, 110 °C, overnight.
SYNTHESIS 2011, No. 19, pp 3089–3098
Advanced online publication: 01.09.2011
DOI: 10.1055/s-0030-1260199; Art ID: T48411SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

3090
H.-P. Buchstaller et al.
PAPER
Table 1 Effect of Catalyst and Conditions on the Methoxycarbonylation of 3-Iodoindazole (2a)a
O
OMe
I
catalyst
CO (1 bar)
N
N
Et3N, MeOH
70 °C, overnight
N
N
H
H
2a
3a
Entry
Catalyst
Solvent
Base
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
TMEDA
Yield (%)b
1
2
3c
4
5
6
7
8
9
Pd(OAc)2, DPEphos
toluene–MeOH
toluene–MeOH
toluene–MeOH
toluene–MeOH
toluene–MeOH
toluene–MeOH
toluene–MeOH
toluene–MeOH
MeOH
78
70
62
ndd
49e
88
85
88
76
67
62
78
65
Pd(OAc)2, Xantphos
(BINAP)PdCl2
Pd(OAc)2, (t-Bu)3P
Pd(OAc)2, Ph3P
Pd(OAc)2, cataCXiumA
Pd(OAc)2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(OAc)2, DPEphos
10
Pd(OAc)2, Xantphos
MeOH
11
12
13
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
MeOH
THF–MeOH
toluene–MeOH
a Reagents and conditions: 2a/Et3N (1:1.5–1.7), catalyst (2–4 mol%), ligand (2–8 mol%), 70 °C, 1 bar CO, overnight.
b Yield of isolated product.
c Reaction time: 4 d; addition of catalyst (2 mol%) after 2 d; temperature 95 °C after 3 d.
d 15% product after 44 h (HPLC).
e No complete conversion after 48 h; 16% starting material recovered.
and amides through palladium-catalyzed carbonylation of 4 and 5). Whereas ligands such as Xantphos or DPE-Phos
3-iodoindazoles.
with Pd(OAc)2 as precursor provided a good yield of com-
pound 3a (Table 1, entries 1 and 2), the reaction using
(BINAP)PdCl2 required a higher temperature (95 °C) and
the addition of more catalyst to drive the reaction to com-
pletion; nevertheless, the isolated yield was lower
(Table 1, entry 3). Excellent yields were achieved with
the systems Pd(OAc)2–cataCXium A (di-1-adamantyl-
n-butylphosphane) or Pd(OAc)2-dppf [dppf = 1,1¢-
Recently, comprehensive reviews have illustrated that a
diverse set of reaction conditions have been used for
alkoxycarbonylation reactions.13 A large number of dif-
ferent examples confirm that various reaction parameters
such as catalyst, base, temperature, and pressure can be
varied. Thus, in order to more rapidly establish suitable
reaction conditions, we concentrated on conditions that
we successfully applied previously for other aryl halide
substrates. To this end, we focused on varying the cata-
lyst, and kept other parameters such as base, temperature,
and pressure constant in the majority of examples. The re-
sults of the methoxycarbonylation using 3-iodoindazole
(2a) as a model substrate are summarized in Table 1.
bis(diphenylphosphino)ferrocene].
Furthermore,
Pd(dppf)2Cl2·CH2Cl2, in the presence of an excess of dppf,
also proved to be a highly active catalyst, providing 88%
yield of the desired 3-indazole methyl carboxylate after
work-up and purification (Table 1, entries 6–8). Several
experiments that were conducted to investigate the impact
of the solvent revealed that a 1:1 mixture of toluene–
MeOH was more favorable (Table 1, entries 9–12). Final-
ly, it was found that use of tetramethylethylendiamine
(TMEDA) as base under the optimized conditions was
less suitable than use of triethylamine (Table 1, entry 13).
In general, the reaction of 3-iodoindazole with methanol
in the presence of CO proceeded smoothly and provided
the desired methyl 1H-indazole-3-carboxylate. Studies on
the catalyst system (Table 1, entry 1–8) revealed that most
of the applied catalyst systems were suitable for the de-
sired conversion. In two cases, the conversion of the start-
ing material was incomplete even after an extended
reaction time; this was observed with Pd(OAc)2–(t-Bu)3P
or Pd(OAc)2–PPh3 as the catalyst system (Table 1, entries
The tolerance of a wide variety of functional groups to the
reaction conditions is of considerable benefit. Hence, hav-
ing defined an optimal catalyst system and conditions, we
sought to explore the scope of the reaction. To this end, we
Synthesis 2011, No. 19, 3089–3098 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Indazolecarboxylic Esters and Amides
3091
employed substituted 3-iodoindazoles under the opti-
mized conditions (Table 1, entry 7). It was important to
investigate how functional groups that would allow fur-
ther synthetic transformations tolerated these compara-
tively mild conditions. The substrates 2 were easily
accessible by iodination of indazoles, as shown in
Scheme 1.11,12
Table 2 Synthesis of Methyl 1H-Indazole-3-carboxylate Deriva-
tives 3a–ma
O
OMe
4
5
R1
N
6
N
7
H
3a–m
The results obtained with all the employed substrates are
summarized in Table 2, which shows that the methoxy-
carbonylation could be successfully applied to substituted
indazole-derivatives bearing either electron-withdrawing
or electron-donating residues, and moderate to excellent
isolated yields (38–83%) were obtained in all cases. 5-
Fluoro-3-iodoindazole (2b) was coupled cleanly and gave
the desired product 3b in 71% yield. Even selectivity be-
tween different halides was possible, as shown with prod-
ucts 3c,d. Dialkoxycarbonylation was anticipated to be
problematic. In the case of the bromo-substituted sub-
strate 2c, this side product was formed in about 30%
(HPLC) when Pd(dppf)2Cl2·CH2Cl2 was used. Interest-
ingly, by adding additional dppf ligand, formation of the
dialkoxycarbonylation product could be suppressed com-
pletely. In the reactions with the chloro-substituted sub-
strate 2d [in toluene–MeOH (1:1) or THF–MeOH (1:1)]
no side product was obtained. This is in accordance with
the general observation that aryl chlorides are inert under
most conditions and that their presence in the substrate
does not present a challenge.13 Electron-donating substit-
uents such as methyl or methoxy groups at different posi-
tions of the iodoindazole substrate did not significantly
impact the reaction, and we obtained the expected prod-
ucts 3e–i in good yield.
Entry Com- R1
pound
Catalyst
Yield
(%)b
1
3a
3b
3c
3d
3e
3f
H
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2
88
71
70
74
68
66
83
68
64
78
69
71
69
40
60
23
38
2c
3
5-F
5-Br
4
6-Cl
5
4-Me
6-Me
6-Me
7-Me
5-OMe
5-OMe
6-OMe
5-COOEt
6-CN
5-NO2
5-NO2
6-NO2
6-NO2
6
7
3f
8
3g
3h
3h
3i
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(OAc)2, cataCXiumA
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
9c
10
11
12
3j
13c
14
3k
3l
15d
16
3l
Many examples of Pd-catalyzed reactions in the literature
suggest that general conditions for all substrates rarely ex-
ist and that, often, minor modifications of the conditions
lead to an improvement in an individual case. We also ob-
served this for substrates 2f and 2h. In the former case, 3f
was obtained in 83% yield when no additional ligand was
added, whereas in the latter case the yield of 3h was sig-
3m
17d
3m
a Reagents and conditions: 3-iodoindazole–Et3N (1:1.5–1.7),
Pd(dppf)2Cl2·CH2Cl2 (3 mol%), dppf (4 mol%), toluene–MeOH,
70 °C, CO (1 bar), overnight.
nificantly improved by using an alternative catalyst sys- b Yield of isolated product.
tem [Pd(OAc)2, cataCXium A]. 3-Iodoindazoles bearing
c Reaction at 80 °C.
d Temperature raised to 80 °C after 24 h; additional Pd(dppf)2Cl2·
electron-withdrawing moieties, such as a carboxylic acid
ester (2j) or a cyano group (2k), also reacted cleanly to af-
ford the desired compounds in good yields. Only the nitro-
substituted substrates were difficult to convert, which is in
accordance with reports in the literature. It has been de-
scribed that side reactions such as reduction by carbon
monoxide, often occur in palladium-catalyzed reactions.14
Indeed, when the nitro-substituted substrates 2l and 2m
were treated under the usual conditions, the desired inda-
zole derivatives were obtained in low yield. In both cases,
however, the yield could be significantly improved by
slightly modifying the reaction conditions; thus, increases
in the yields of compound 3l and 3m to 60 and 38%, re-
spectively, were achieved by applying a higher tempera-
ture (80 °C) and through the addition of additional
catalyst (1.5 mol%) and ligand (2 mol%).
CH2Cl2 (1.5 mol%) and dppf (2 mol%) added after 48 h.
We further extended the scope of the present methodology
to include aminocarbonylation reactions, which repre-
sents a convenient synthetic route to secondary and tertia-
ry amides. The model substrates chosen were butyl-
methyl-amine and, again, 3-iodoindazole (3a), which
could be employed in the same way as bromoindoles,15
without a protecting group. As illustrated by recent com-
prehensive reviews, this type of amide formation has pre-
viously been applied to a diverse set of aryl and heteroaryl
halides.13
It is well-known that both alkoxycarbonylations and
aminocarbonylations can often be conducted under
similar conditions. Hence, we decided to retain
Pd(dppf)2Cl2·CH2Cl2 as catalyst, which provided the best
Synthesis 2011, No. 19, 3089–3098 © Thieme Stuttgart · New York

3092
H.-P. Buchstaller et al.
PAPER
which was formed by reaction of the acyl complex with
the indazole NH group. To suppress this competitive nu-
cleophilic attack, we shortened the incubation time of aryl
iodide, Pd-catalyst, and CO, and added the amine after 10
minutes. However, formation of the side-product could
not be completely suppressed, and the isolated yield was
only marginally improved (Table 3, entries 5–7). Whereas
a larger excess of butyl-methyl-amine also did not affect
the yield, decreasing the temperature to 100 °C showed an
adverse effect (Table 3, entries 8 and 9).
Table 3 Aminocarbonylation of 3-Iodoindazole (2a) with Butyl-
methyl-aminea
Me
O
Pd(dppf)2Cl2⋅CH2Cl2
N
I
dppf
CO (2 bar)
N
N
Et3N
N
N
H
H
butyl-methyl-amine
110 °C, overnight
2a
4a
Entry
Catalyst
Solvent
toluene
toluene
THF
Yield (%)b
1c
2
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
Pd(dppf)2Cl2·CH2Cl2, dppf
16
64
58
52
68
58
71
69
60
After establishing suitable conditions, we sought to ex-
plore the scope of the reaction. As for the alkoxycarbony-
lation, substrates bearing various electron-donating or
electron-withdrawing substituents such as methyl, meth-
oxy, cyano, or nitro groups were tolerated, and the desired
amides, with the exception of the fluoro-substituted com-
pound 4b, were obtained in moderate to good isolated
yields (30–71%). However, in comparison to the corre-
sponding esters, the yields of the amides were noticeably
lower (Table 4). In all the examples, the predominant side
reaction during aminocarbonylation was deiodination.
We assume that this side reaction is mainly caused by the
higher temperature and pressure that were used compared
to those used for the alkoxycarbonylations. This was espe-
cially pronounced in the case of 5-fluoro-3-iodoindazole
(2b), for which the desired product 3b was isolated in only
19%. The reactions with other halogen-substituted sub-
strates, 2c and 2d, gave better yields (Table 4, entries 2–
4). Variable results were obtained with electron-donating
substituents such as a methyl group at different positions
of the iodoindazole substrate. Whereas compound 2g cou-
pled cleanly, approximately 40% deiodination (HPLC)
was observed in the reaction with iodoindazole 2e. Simi-
lar observations were made for the reactions with sub-
strates 2h–k.
3
4d
5e
6e
7f
8g
9h
THF
THF
toluene
THF
THF
THF
a Reagents and conditions: 3-iodoindazole/Et3N/butyl-methyl-amine
(1:1.4:1.4), Pd(dppf)2Cl2·CH2Cl2 (4 mol%), dppf (5 mol%), 110 °C,
CO (2 bar), overnight.
b Yield of isolated product.
c 3-Iodoindazole/Et3N/butyl-methyl-amine (1:1.5:1.4), Pd(dp-
pf)2Cl2·CH2Cl2 (3 mol%), dppf (4 mol%), CO (2 bar), 90–100 °C,
34 h.
d CO pressure 7 bar, reaction time 4.5 h.
e Addition of butyl-methyl-amine after 30 min.
f Addition of butyl-methyl-amine after 10 min.
g 2.1 equiv butyl-methyl-amine.
h Reaction temperature 100 °C.
results in the previous study. Unfortunately, only low con-
version was observed under these conditions after
20 hours, therefore, the temperature was raised to 100 °C.
Although these harsher conditions drove the reaction to
completion, several side-reactions, for example, deiodina-
tion, occurred, and the desired amide was afforded in only
low yield. This result clearly indicated that fine-tuning of
the reaction parameters was required (Table 3, entry 1). A
significantly better result was achieved by raising the tem-
perature to 110 °C in toluene (see above). Changing the
solvent from toluene to THF had no impact on the isolated
yield, whereas higher pressure adversely affected the
yield of 4a (Table 3, entries 2–4). We then focussed on the
influence of the order of addition of the reaction partners.
Based on knowledge of the catalytic cycle, we reasoned
that this could be pivotal for the successful aminocarbon-
ylation of 3-iodoindazoles. Thus, when the autoclave con-
taining the aryl iodide and Pd-catalyst in THF was
incubated with carbon monoxide for 30 minutes prior to
the addition of amine, the reaction proceeded smoothly
and provided the desired amide in good yield. However,
the same procedure was not advantageous with toluene as
solvent. In both reactions, indazol-1-yl(1H-indazol-3-
yl)methanone (5) was identified as a major impurity,
Moderate to good yields of the desired amides were ob-
tained when the deiodination was less pronounced
(Table 4, entries 7–10). Again, only the nitro-substituted
substrates were difficult to convert. In this case, in addi-
tion to compounds resulting from deiodination, other side-
products were generated in the course of the reaction, and
the isolated yield was moderate (Table 4, entries 11–12).
To explore the generality of the protocol further, a limited
number of aminocarbonylation reactions were conducted
with 3-iodoindazole (2a) as a substrate using primary and
secondary aliphatic amines. Although primary amines
gave cleaner reactions, the type of amine had no clear im-
pact on the isolated yield of the desired amides (Table 4,
entries 13–17).
In summary, in the present study we have developed a
straightforward and effective procedure for the prepara-
tion of 1H-indazole-3-carboxylic acid esters and amides.
We report efficient protocols for alkoxycarbonylations
and aminocarbonylations of substituted 3-iodoindazoles
that are catalyzed by various Pd-catalyst systems. For the
majority of examples, the reaction proceeds cleanly under
fairly mild conditions which are compatible with a variety
Synthesis 2011, No. 19, 3089–3098 © Thieme Stuttgart · New York

PAPER
Synthesis of 3-Indazolecarboxylic Esters and Amides
3093
Table 4 Synthesis of Methyl 1H-Indazole-3-carboxamides 4a–qa
of the amides, mixtures of rotamers were characteristic. High-reso-
lution mass spectra were recorded with a Waters Micromass GCT
Premier spectrometer (EI, 70 eV; accuracy <3 mDa; mass range:
25–800 amu). Flash chromatography was performed on an Isco
CombiFlash Companion instrument using pre-packed reversed-
phase flash columns and mixtures of H2O–MeCN containing 0.1%
HCOOH. The combined fractions were concentrated in vacuo and
the aqueous residue was rendered basic and extracted with EtOAc.
The organic layer was dried (Na2SO4) and concentrated in vacuo.
Preparative HPLC was performed with an Agilent system (1200 se-
ries) using a Chromolith prep RP-18e 100–25 column and mixtures
of H2O–MeCN containing 0.1% HCOOH. The combined fractions
were concentrated in vacuo and the aqueous residue was rendered
basic and extracted with EtOAc. The organic layer was dried
(Na2SO4) and concentrated in vacuo. Reactions were carried out in
a 10–25 mL autoclave of the tinyclave steel series from Büchi Glas
Uster AG, consisting of borosilicate glass 3.3 and stainless steel.
The autoclave is designed for the use of pressures up to 10 bar and
temperatures up to 200 °C.
R2
O
N
R3
R1
N
N
H
4a–q
Entry Compound R1
R2
R3
Yield
(%)b
1
2
4a
4b
4c
4d
4e
4f
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Et
71
19
44
43
30
65
32
51
51
35
38
31
31
36
45
44
46
5-F
3
5-Br
6-Cl
4-Me
7-Me
5-OMe
6-OMe
5-COOEt
6-CN
5-NO2
6-NO2
H
4
Indazoles 1a–c, 1e, 1l and 1m were commercially available. Inda-
zole 1k was prepared according to the method of Bartsch and
Yang.16 Indazoles 1d,16 1f,16 1g,16 1h,12 1i,17 1j18 and 3-iodoinda-
zoles 2a,11 2c,12 2g,19 2h,12 2k,20 2l12 and 2m,21 were obtained as de-
scribed in the literature.
5
6
7
4g
4h
4i
The 3-iodoindazole substrates 2b, 2d–f, 2i and 2j were obtained ac-
8
cording to the method developed by Crestey et al.12
9
5-Fluoro-3-iodo-1H-indazole (2b)
10
11
12
13
14
15
16
17
4j
Obtained from 5-fluoro-1H-indazole (1b; 2.00 g, 14.69 mmol), io-
dine (7.46 g, 29.38 mmol) and KOH (2.06 g, 36.73 mmol) in DMF
(40 mL) at r.t. for 1 h.
4k
4l
Yield: 3.58 g (93%); brown solid; mp 166 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.62 (br s, 1 H, NH), 7.61 (dd,
J = 9.1, 4.1 Hz, 1 H, 7-H), 7.34 (td, J = 9.1, 2.4 Hz, 1 H, 6-H), 7.19
(dd, J = 8.8, 2.4 Hz, 1 H, 4-H).
HRMS (EI): m/z [M]+ calcd for C7H4FIN2: 261.9403; found:
261.9409.
4m
4n
4o
4p
4q
H
-(CH2)5-
-(CH2)2O(CH2)2-
H
H
H
n-Pr
6-Chloro-3-iodo-1H-indazole (2d)
H
H
Bn
Obtained from 6-chloro-1H-indazole (1d; 1.00 g, 6.55 mmol), io-
dine (3.33 g, 13.11 mmol) and KOH (0.92 g, 16.38 mmol) in DMF
(20 mL) at r.t. for 1 h.
a Reagents and conditions: 3-iodoindazole/Et3N/amine (1:1.4:1.4),
Pd(dppf)2Cl2·CH2Cl2 (4 mol%), dppf (5 mol%), THF, 110 °C, CO
(2 bar), overnight.
Yield: 1.75 g (96%); yellowish solid; mp 193 °C.
b Yield of isolated product.
1H NMR (400 MHz, DMSO-d6): d = 13.63 (br s, 1 H, NH), 7.66 (d,
J = 1.3 Hz, 1 H, 7-H), 7.46 (d, J = 8.6 Hz, 1 H, 4-H), 7.21 (dd,
J = 8.6, 1.7 Hz, 1 H, 5-H).
13C NMR (75 MHz, DMSO-d6): d = 140.6, 132.4, 125.7, 122.1,
121.9, 110.0, 93.7.
HRMS (EI): m/z [M]+ calcd for C7H4ClIN2: 277.9108; found:
277.9095.
of functional groups, allowing further synthetic transfor-
mations. Given the brevity and generality of the method
for the preparation of 1H-indazole-3-carboxylic acid es-
ters and amides, and the fact that all the previously report-
ed methods for the synthesis of these building blocks have
several limitations, we believe that this approach will find
widespread application.
3-Iodo-4-methyl-1H-indazole (2e)
Obtained from 4-methyl-1H-indazole (1e; 1.00 g, 7.57 mmol), io-
dine (3.84 g, 15.13 mmol) and KOH (1.06 g, 18.92 mmol) in DMF
(20 mL) at r.t. for 2 h.
All solvents and reagents were obtained from commercial suppliers
and were used without further purification. Melting points were de-
termined with a HWS (SGV 500 Plus) capillary melting point appa-
Yield: 1.50 g (77%); yellow solid; mp 176 °C.
1
1H NMR (400 MHz, DMSO-d6): d = 13.42 (br s, 1 H, NH), 7.41 (d,
J = 8.4 Hz, 1 H, 7-H), 7.25 (dd, J = 8.4, 7.0 Hz, 1 H, 6-H), 6.89 (d,
J = 6.9 Hz, 1 H, 5-H), 2.76 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 140.7, 130.5, 126.8, 123.6,
122.1, 108.5, 90.1, 18.3.
ratus and are uncorrected. H NMR spectra were recorded with a
Bruker Avance II 400 (400 MHz) spectrometer and 13C NMR spec-
tra were acquired with a Bruker DPX 300 (75 MHz) spectrometer
using DMSO-d6 as solvent. Chemical shifts (d) are reported in parts
per million (ppm) relative to DMSO as internal reference. The spec-
tra of the obtained compounds were all in accordance with the ex-
pected 1H-indazole-3-carboxylic acid esters and amides. In the case
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H.-P. Buchstaller et al.
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HRMS (EI): m/z [M]+ calcd for C8H7IN2: 257.9654; found:
257.9651.
1H NMR (400 MHz, DMSO-d6): d = 13.93 (br s, 1 H, NH), 8.08 (dt,
J = 8.2, 0.9 Hz, 1 H, 4-H), 7.67 (dt, J = 8.4, 1.1 Hz, 1 H, 7-H), 7.46
(ddd, J = 8.2, 6.9, 1.1 Hz, 1 H, 5-H), 7.32 (ddd, J = 8.4, 6.9, 0.9 Hz,
1 H, 6-H), 3.93 (s, 3 H, OCH3).
3-Iodo-6-methyl-1H-indazole (2f)
Obtained from 6-methyl-1H-indazole (1f; 0.20 g, 1.51 mmol), io-
dine (0.77 g, 3.03 mmol) and KOH (0.21 g, 3.78 mmol) in DMF (4
mL) at r.t. for 1 h; purified by flash chromatography.
13C NMR (75 MHz, DMSO-d6): d = 162.7, 140.8, 135.0, 126.6,
122.8, 122.1, 120.9, 111.0, 51.5.
HRMS (EI): m/z [M]+ calcd for C9H8N2O2: 176.0586; found:
176.0585.
Yield: 0.23 g (59%); colorless solid; mp 163 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.32 (br s, 1 H, NH), 7.37–
7.25 (m, 2 H, 4-H, 7-H), 7.03 (d, J = 8.3 Hz, 1 H, 5-H), 2.44 (s, 3 H,
CH3).
HRMS (EI): m/z [M]+ calcd for C8H7IN2: 257.9654; found:
257.9649.
Methyl 5-Fluoro-1H-indazole-3-carboxylate (3b)
Compound 3b was obtained by the general procedure, starting from
5-fluoro-3-iodo-1H-indazole (2b; 180 mg, 0.69 mmol).
Yield: 94 mg (71%); colorless solid; mp 214–215 °C (Lit.23
208 °C).
3-Iodo-6-methoxy-1H-indazole (2i)
1H NMR (400 MHz, DMSO-d6): d = 14.08 (br s, 1 H, NH), 7.78–
7.69 (m, 2 H, 4-H, 7-H), 7.37 (td, J = 9.2, 2.5 Hz, 1 H, 6-H), 3.93 (s,
3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 162.4, 158.5 (d, J = 238.5 Hz),
137.9, 135.11 (d, J = 5.7 Hz), 122.3 (d, J = 11.1 Hz), 116.30 (d,
J = 27.7 Hz), 113.0 (d, J = 10.0 Hz), 104.9 (d, J = 24.7 Hz), 51.6.
Obtained from 6-methoxy-1H-indazole (1i; 1.03 g, 6.95 mmol), io-
dine (3.53 g, 13.90 mmol) and KOH (0.98 g, 17.38 mmol) in DMF
(20 mL) at r.t. for 1 h; purified by flash chromatography.
Yield: 1.50 g (79%); yellow solid; mp 171 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.18 (br s, 1 H, NH), 7.28 (d,
J = 8.8 Hz, 1 H, 4-H), 6.93 (d, J = 2.0 Hz, 1 H, 7-H), 6.82 (dd,
J = 8.8, 2.1 Hz, 1 H, 5-H), 3.83 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 159.7, 141.6, 121.6, 121.2,
113.5, 93.1, 91.0, 55.4.
HRMS (EI): m/z [M]+ calcd for C9H7FN2O2: 194.0492; found:
194.0494.
Methyl 5-Bromo-1H-indazole-3-carboxylate (3c)
Compound 3c was obtained by the general procedure, starting from
5-bromo-3-iodo-1H-indazole (2c; 200 mg, 0.62 mmol).
HRMS (EI): m/z [M]+ calcd for C8H7IN2O: 273.9603; found:
273.9606.
Yield: 110 mg (70%); colorless solid; mp 222 °C (Lit.23 208–
210 °C).
1H NMR (400 MHz, DMSO-d6): d = 14.10 (br s, 1 H, NH), 8.21 (dd,
J = 1.8, 0.6 Hz, 1 H, 4-H), 7.67 (d, J = 8.9 Hz, 1 H, 7-H), 7.58 (dd,
J = 8.9, 1.8 Hz, 1 H, 6-H), 3.94 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 162.2, 139.6, 134.5, 129.5,
123.5, 123.0, 115.6, 113.3, 51.7.
Ethyl 3-Iodo-1H-indazole-5-carboxylate (2j)
Obtained from ethyl 3-iodo-1H-indazole-5-carboxylate (1j; 2.45 g,
12.88 mmol), iodine (6.54 g, 25.76 mmol) and KOH (1.81 g, 32.2
mmol) in DMF (40 mL) at r.t. for 2.5 h; purified by flash chroma-
tography.
Yield: 2.05 g (50%); colorless solid; mp 170 °C (dec).
1H NMR (400 MHz, DMSO-d6): d = 13.85 (br s, 1 H, NH), 8.07 (dd,
J = 1.5, 0.7 Hz, 1 H, 4-H), 8.0 (dd, J = 8.8, 1.5 Hz, 1 H, 6-H), 7.66
(dd, J = 8.8, 0.7 Hz, 1 H, 7-H), 4.36 (q, J = 7.1 Hz, 2 H, CH2CH3),
1.36 (t, J = 7.1 Hz, 3 H, CH2CH3).
13C NMR (75 MHz, DMSO-d6): d = 165.6, 142.3, 127.4, 126.7,
123.1, 110.8, 95.7, 60.7, 14.2.
HRMS (EI): m/z [M]+ calcd for C9H7BrN2O2: 253.9691; found:
253.9697.
Methyl 6-Chloro-1H-indazole-3-carboxylate (3d)
Compound 3d was obtained by the general procedure, starting from
6-chloro-3-iodo-1H-indazole (2d; 200 mg, 0.72 mmol).
HRMS (EI): m/z [M]+ calcd for C10H9IN2O2: 315.9688; found:
Yield: 112 mg (74%); off-white solid; mp 211–212 °C.
315.9709.
1H NMR (400 MHz, DMSO-d6): d = 14.02 (br s, 1 H, NH), 8.07 (dd,
J = 8.7, 0.6 Hz, 1 H, 4-H), 7.77 (d, J = 1.8 Hz, 1 H, 7-H), 7.35 (dd,
J = 8.7, 1.8 Hz, 1 H, 5-H), 3.93 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 162.3, 141.2, 135.3, 131.7,
123.6, 122.5, 120.8, 110.7, 51.7.
HRMS (EI): m/z [M]+ calcd for C9H7ClN2O2: 210.0196; found:
210.0193.
Synthesis of Methyl 1H-Indazole-3-carboxylates (3); General
Procedure
The 3-iodoindazole substrate 2a–m (1 equiv) was dissolved in tol-
uene–MeOH (1:1; substrate concentration 3–6 wt%) and Et3N (1.5–
1.7 equiv) was added. The autoclave was flushed with nitrogen sev-
eral times. The catalyst (3 mol%) and the ligand (4 mol%) were sus-
pended in toluene in a glove-box and stirred for several minutes.
The catalyst suspension was transferred into the autoclave via sy-
ringe under a counterflow of nitrogen. The autoclave was pressur-
ized with CO (1 bar) and the reaction was performed at 70 °C
overnight. After cooling to r.t., the solution was evaporated to dry-
ness, and the residue was purified by preparative HPLC.
Methyl 4-Methyl-1H-indazole-3-carboxylate (3e)
Compound 3e was obtained by the general procedure, starting from
3-iodo-4-methyl-1H-indazole (2e; 110 mg, 0.43 mmol).
Yield: 55 mg (68%); off-white solid; mp 141 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.76 (s, 1 H, NH), 7.45 (d,
J = 8.4 Hz, 1 H, 7-H), 7.30 (dd, J = 8.3, 7.0 Hz, 1 H, 6-H), 7.08–
6.99 (m, 1 H, 5-H), 3.88 (s, 3 H, OCH3), 2.71 (s, 3 H, CH3).
Methyl 1H-Indazole-3-carboxylate (3a)
Compound 3a was obtained by the general procedure, starting from
3-iodo-1H-indazole (2a; 100 mg, 0.41 mmol).
Yield: 64 mg (88%); colorless solid; mp 170–171 °C (Lit.22 168–
170 °C).
13C NMR (75 MHz, DMSO-d6): d = 163.3, 141.4, 135.8, 131.3,
126.7, 123.8, 121.0, 108.5, 51.6, 21.3.
HRMS (EI): m/z [M]+ calcd for C10H10N2O2: 190.0742; found:
190.0749.
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Synthesis of 3-Indazolecarboxylic Esters and Amides
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Methyl 6-Methyl-1H-indazole-3-carboxylate (3f)
Compound 3f was obtained by the general procedure, starting from
3-iodo-6-methyl-1H-indazole (2f; 80 mg, 0.31 mmol).
HRMS (EI): m/z [M]+ calcd for C12H12N2O4: 248.0797; found:
248.0799.
Methyl 6-Cyano-1H-indazole-3-carboxylate (3k)
Compound 3k was obtained by the general procedure, starting from
6-cyano-3-iodo-1H-indazole (2k; 200 mg, 0.74 mmol).
Yield: 49 mg (83%); colorless solid; mp 148 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.74 (br s, 1 H, NH), 7.94 (d,
J = 8.3 Hz, 1 H, 4-H), 7.43 (d, J = 1.1 Hz, 1 H, 7-H), 7.15 (dd,
J = 8.4, 1.1 Hz, 1 H, 5-H), 3.91 (s, 3 H, OCH3), 2.46 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.7, 141.5, 136.5, 134.8,
125.0, 120.5, 120.4, 110.1, 51.5, 21.3.
HRMS (EI): m/z [M]+ calcd for C10H10N2O2: 190.0742; found:
190.0736.
Yield: 103 mg (69%); colorless solid; mp 238–240 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.32 (s, 1 H, 7-H), 8.24 (dd,
J = 8.5, 0.9 Hz, 1 H, 4-H), 7.65 (dd, J = 8.5, 1.3 Hz, 1 H, 5-H), 3.95
(s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 162.0, 139.6, 124.8, 124.0,
122.4, 121.2, 118.9, 117.2, 108.9, 51.9.
Methyl 7-Methyl-1H-indazole-3-carboxylate (3g)
Compound 3g was obtained by the general procedure, starting from
3-iodo-7-methyl-1H-indazole (2g; 100 mg, 0.39 mmol).
HRMS (EI): m/z [M]+ calcd for C10H7N3O2: 201.0538; found:
201.0532.
Methyl 5-Nitro-1H-indazole-3-carboxylate (3l)
Compound 3l was obtained by the general procedure, starting from
3-iodo-5-nitro-1H-indazole (2l; 110 mg, 0.38 mmol).
Yield: 50 mg (68%); colorless solid; mp 163 °C.
1H NMR (400 MHz, DMSO-d6): d = 14.0 (br s, 1 H, NH), 7.94–7.85
and 7.26–7.17 (2 × m, 3 H, 5-H, 6-H, 7-H), 3.92 (s, 3 H, OCH3),
2.55 (s, 3 H, CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.8, 141.0, 135.2, 126.4,
123.0, 122.0, 121.0, 118.2, 51.5, 16.5.
HRMS (EI): m/z [M]+ calcd for C10H10N2O2: 190.0742; found:
190.0744.
Yield: 50 mg (60%); off-white solid; mp 236–238 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.92 (dd, J = 2.2, 0.6 Hz, 1 H,
4-H), 8.27 (dd, J = 9.2, 2.2 Hz, 1 H, 6-H), 7.89 (dd, J = 9.2, 0.6 Hz,
1 H, 7-H), 3.98 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 161.8, 143.3, 142.7, 137.6,
121.5, 121.1, 118.1, 112.4, 52.1.
Methyl 5-Methoxy-1H-indazole-3-carboxylate (3h)
Compound 3h was obtained by the general procedure, starting from
HRMS (EI): m/z [M]+ calcd for C9H7N3O4: 221.0437; found:
221.0425.
3-iodo-5-methoxy-1H-indazole (2h; 110 mg, 0.40 mmol).
Yield: 65 mg (78%); colorless solid; mp 181–182 °C (Lit.24 187.5–
189 °C).
1H NMR (400 MHz, DMSO-d6): d = 13.84 (br s, 1 H, NH), 7.58 (d,
J = 9.0 Hz, 1 H, 7-H), 7.43 (d, J = 1.9 Hz, 1 H, 4-H), 7.10 (dd,
J = 9.0, 2.4 Hz, 1 H, 6-H), 3.92 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 162.9, 155.8, 136.7, 134.3,
123.0, 118.8, 112.2, 99.9, 55.3, 51.4.
HRMS (EI): m/z [M]+ calcd for C10H10N2O3: 206.0691; found:
206.0691.
Methyl 6-Nitro-1H-indazole-3-carboxylate (3m)
Compound 3m was obtained by the general procedure, starting
from 3-iodo-6-nitro-1H-indazole (2m; 110 mg, 0.38 mmol).
Yield: 32 mg (38%); off-white solid; mp 252–254 °C.
1H NMR (400 MHz, DMSO-d6): d = 8.59 (d, J = 1.5 Hz, 1 H, 7-H),
8.28 (d, J = 8.9 Hz, 1 H, 4-H), 8.14 (dd, J = 8.0, 1.5 Hz, 1 H, 5-H),
3.97 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 161.9, 146.0, 139.8, 135.4,
125.1, 122.2, 117.2, 108.2, 51.9.
HRMS (EI): m/z [M]+ calcd for C9H7N3O4: 221.0437; found:
Methyl 6-Methoxy-1H-indazole-3-carboxylate (3i)
221.0427.
Compound 3i was obtained by the general procedure, starting from
3-iodo-6-methoxy-1H-indazole (2i; 170 mg, 0.62 mmol).
Synthesis of 1H-Indazole-3-carboxamides (4); General Proce-
dure
Yield: 88 mg (69%); colorless solid; mp 191–193 °C.
The 3-iodoindazole substrates 2a–e and 2g–m (1 equiv) were dis-
solved in toluene or THF (substrate concentration 2 wt%) and Et3N
(1.4 equiv) was added. The autoclave was flushed with nitrogen
several times. The catalyst and the ligand were suspended in toluene
in a glove-box and stirred for several minutes. The catalyst suspen-
sion was transferred into the autoclave via syringe in a counterflow
of nitrogen. The autoclave was pressurized with CO (2 bar) and ex-
panded after 10 min stirring before the addition of the correspond-
ing amine, which was transferred via syringe in a counterflow of
nitrogen. The autoclave was again charged with CO (2 bar), and the
reaction was carried out at 110 °C overnight. After cooling to r.t.,
the solution was evaporated to dryness and the residue was purified
by preparative HPLC or flash chromatography.
1H NMR (400 MHz, DMSO-d6): d = 13.64 (br s, 1 H, NH), 7.91 (d,
J = 8.8 Hz, 1 H, 4-H), 7.01 (d, J = 1.9 Hz, 1 H, 7-H), 6.94 (dd,
J = 8.9, 2.2 Hz, 1 H, 5-H), 3.90 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3).
13C NMR (75 MHz, DMSO-d6): d = 162.5, 158.7, 141.9, 134.7,
121.4, 116.6, 114.8, 91.2, 55.1, 51.3.
HRMS (EI): m/z [M]+ calcd for C10H10N2O3: 206.0691; found:
206.0678.
5-Ethyl 3-Methyl 1H-Indazole-3,5-dicarboxylate (3j)
Compound 3j was obtained by the general procedure, starting from
ethyl 3-iodo-1H-indazole-5-carboxylate (2j; 200 mg, 0.63 mmol).
Yield: 111 mg (71%); off-white solid; mp 190.5–192 °C.
N-Butyl-N-methyl-1H-indazole-3-carboxamide (4a)
Compound 4a was obtained by the general procedure, starting from
3-iodo-1H-indazole (2a; 200 mg, 0.82 mmol) and purified by flash
chromatography.
1H NMR (400 MHz, DMSO-d6): d = 14.25 (br s, 1 H, NH), 8.74 (dd,
J = 1.5, 0.8 Hz, 1 H, 4-H), 8.02 (dd, J = 8.8, 1.6 Hz, 1 H, 6-H), 7.77
(dd, J = 8.8, 0.8 Hz, 1 H, 7-H), 4.37 (q, J = 7.1 Hz, 2 H, OCH2CH3),
3.96 (s, 3 H, OCH3), 1.36 (t, J = 7.1 Hz, 3 H, OCH2CH3).
Yield: 134 mg (71%); colorless solid; mp 97–99 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.44 (br s, 1 H, NH), 7.99–
7.92 (m, 1 H, 4-H), 7.58 (dd, J = 8.2, 4.2 Hz, 1 H, 7-H), 7.43–7.36
13C NMR (75 MHz, DMSO-d6): d = 165.7, 162.3, 142.6, 136.4,
126.9, 124.6, 123.6, 121.7, 111.4, 60.8, 51.8, 14.2.
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N-Butyl-N,4-dimethyl-1H-indazole-3-carboxamide (4e)
Compound 4e was obtained by the general procedure, starting from
3-iodo-4-methyl-1H-indazole (2e; 200 mg, 0.78 mmol) and purified
by preparative HPLC.
(m, 1 H, 6-H), 7.19 (t, J = 7.5 Hz, 1 H, 5-H), 3.85–3.7 and 3.62–
3.44 (2 × m, 2 H, 1¢-CH2), 3.31 and 3.04 (2 × s, 3 H, NCH3), 1.65–
1.55 (m, 2 H, 2¢-CH2), 1.42–1.14 (m, 2 H, 3¢-CH2), 0.95 and 0.80
(2 × t, J = 7.4 Hz and J = 7.3 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 163.3, 163.0, 140.1, 139.4,
139.2, 126.4, 122.7, 121.5, 121.4, 110.3, 49.6, 47.1, 36.5, 33.4,
30.2, 28.7, 19.6, 19.2, 13.7, 13.5.
HRMS (EI): m/z [M]+ calcd for C13H17N3O: 231.1372; found:
231.1375.
Yield: 57 mg (30%); off-white solid; mp 57–58.5 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.20 (br s, 1 H, NH), 7.38 (d,
J = 8.5 Hz, 2 H, 7-H), 7.32–7.24 (m, 1 H, 6-H), 6.93 (d, J = 6.9,
1 H, 5-H), 3.58–3.50 and 3.29–3.20 (2 × m, 2 H, 1¢-CH2), 3.06 and
2.88 (2 × s, 3 H, NCH3), 2.45 and 2.44 (2 × s, 3 H, CH3), 1.69–1.57
and 1.55–1.44 (2 × m, 2 H, 2¢-CH2), 1.43–1.33 and 1.14–1.03
(2 × m, 2 H, 3¢-CH2), 0.97 and 0.69 (2 × t, J = 7.4 Hz and
J = 7.4 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 164.8, 164.6, 139.6, 139.4,
139.1, 129.8, 125.9, 120.8, 120.7, 119.6, 119.4, 107.1, 49.1, 45.4,
35.5, 31.6, 29.0, 27.6, 18.8, 18.2, 17.8, 13.0, 12.6.
N-Butyl-5-fluoro-N-methyl-1H-indazole-3-carboxamide (4b)
Compound 4b was obtained by the general procedure, starting from
5-fluoro-3-iodo-1H-indazole (2b; 200 mg, 0.76 mmol) and purified
by preparative HPLC.
Yield: 36 mg (19%); solid; mp 171–173 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.60 (br s, 1 H, NH), 7.70–
7.60 (m, 2 H, 4-H, 7-H), 7.32 (td, J = 9.1, 2.5 Hz, 1 H, 6-H), 3.83
and 3.53 (2 × t, J = 7.2 Hz and 7.1 Hz, 2 H, 1¢-CH2), 3.36 and 3.05
(2 × s, 3 H, NCH3), 1.68–1.54 (m, 2 H, 2¢-CH2), 1.44–1.13 (m, 2 H,
3¢-CH2), 0.95 and 0.83 (2 × t, J = 7.1 Hz and 7.3 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.8, 162.5, 157.7 (d,
J = 236.7 Hz), 139.3, 139.1, 137.2, 123.1 (d, J = 11.0 Hz), 116.0 (d,
J = 27.7 Hz), 112.1 (d, J = 9.9 Hz), 105.5 (d, J = 24.0 Hz), 49.6,
47.3, 36.5, 33.6, 30.2, 28.7, 19.6, 19.2, 13.7, 13.6.
HRMS (EI): m/z [M]+ calcd for C14H19N3O: 245.1528; found:
245.1533.
N-Butyl-N,7-dimethyl-1H-indazole-3-carboxamide (4f)
Compound 4f was obtained by the general procedure, starting from
3-iodo-7-methyl-1H-indazole (2g; 190 mg, 0.74 mmol) and puri-
fied by preparative HPLC.
Yield: 118 mg (65%); beige solid; mp 94–95 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.49 (br s, 1 H, NH), 7.75 (d,
J = 8.0 Hz, 1 H, 4-H), 7.16 (d, J = 6.9 Hz, 1 H, 6-H), 7.13–7.04 (m,
1 H, 5-H), 3.75 and 3.52 (2 × t, J = 7.3 Hz and 7.1 Hz, 2 H, 1¢-CH2),
3.29 and 3.04 (2 × s, 3 H, NCH3), 2.54 (s, 3 H, CH3), 1.67–1.55 (m,
2 H, 2¢-CH2), 1.35 (dd, J = 14.3, 7.3 Hz, 1 H, 3¢-CH2), 1.20 (dd,
J = 14.5, 7.3 Hz, 1 H, 3¢-CH2), 0.95 and 0.81 (2 × t, J = 7.2 Hz and
7.3 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 163.5, 163.2, 140.3, 139.7,
139.5, 126.1, 122.5, 121.7, 120.2, 118.8, 49.7, 47.0, 36.5, 33.4,
30.3, 28.7, 19.6, 19.2, 16.6, 13.8, 13.6.
HRMS (EI): m/z [M]+ calcd for C13H16FN3O: 249.1277; found:
249.1288.
5-Bromo-N-butyl-N-methyl-1H-indazole-3-carboxamide (4c)
Compound 4c was obtained by the general procedure, starting from
5-bromo-3-iodo-1H-indazole (2c; 200 mg, 0.62 mmol) and purified
by preparative HPLC.
Yield: 85 mg (44%); off-white solid; mp 181–183 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.66 (br s, 1 H, NH), 8.16 (s,
1 H, 4-H), 7.58 (d, J = 8.7 Hz, 1 H, 7-H), 7.52 (dd, J = 8.8, 1.8 Hz,
1 H, 6-H), 3.81 and 3.52 (2 × t, J = 7.4 Hz and 7.3 Hz, 2 H, 1¢-CH2),
3.34 and 3.04 (2 × s, 3 H, NCH3), 1.67–1.54 (m, 2 H, 2¢-CH2), 1.41–
1.15 (m, 2 H, 3¢-CH2), 0.94 and 0.82 (2 × t, J = 7.2 Hz and 7.3 Hz,
3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.6, 162.3, 138.9, 138.8,
138.6, 129.2, 124.5, 123.9, 123.8, 114.1, 112.6, 49.6, 47.3, 36.5,
33.6, 30.2, 28.6, 19.6, 19.2, 13.7, 13.6.
HRMS (EI): m/z [M]+ calcd for C14H19N3O: 245.1528; found:
245.1523.
N-Butyl-5-methoxy-N-methyl-1H-indazole-3-carboxamide (4g)
Compound 4g was obtained by the general procedure, starting from
3-iodo-5-methoxy-1H-indazole (2h; 190 mg, 0.69 mmol) and puri-
fied by flash chromatography.
Yield: 58 mg (32%); off-white solid; mp 112–114 °C.
HRMS (EI): m/z [M]+ calcd for C13H16BrN3O: 309.0477; found:
309.0475.
1H NMR (400 MHz, DMSO-d6): d = 13.32 (br s, 1 H, NH), 7.49 (d,
J = 8.9 Hz, 1 H, 7-H), 7.38 (s, 1 H, 4-H), 7.04 (dd, J = 9.0, 2.4 Hz,
1 H, 6-H), 3.89–3.74 (m, 4 H, 1¢-CH2, OCH3), 3.58–3.47 (m, 1 H,
1¢-CH2), 3.35 and 3.04 (2 × s, 3 H, NCH3), 1.67–1.54 (m, 2 H, 2¢-
CH2), 1.43–1.14 (m, 2 H, 3¢-CH2), 0.95 and 0.82 (2 × t, J = 6.6 Hz
and J = 6.9 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 163.4, 163.1, 154.8, 138.6,
138.4, 136.0, 128.6, 123.6, 118.6, 111.4, 100.6, 55.2, 49.6, 47.2,
36.5, 33.5, 30.2, 28.7, 19.6, 19.2, 13.7, 13.6.
N-Butyl-6-chloro-N-methyl-1H-indazole-3-carboxamide (4d)
Compound 4d was obtained by the general procedure, starting from
6-chloro-3-iodo-1H-indazole (2d; 200 mg, 0.72 mmol) and purified
by preparative HPLC.
Yield: 82 mg (43%); off-white solid; mp 140–142 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.56 (br s, 1 H, NH), 8.02–
7.93 (m, 1 H, 4-H), 7.67 (s, 1 H, 7-H), 7.22 (dd, J = 8.7, 1.7 Hz, 1 H,
5-H), 3.76 and 3.52 (2 × t, J = 7.4 Hz and 7.3 Hz, 2 H, 1¢-CH2), 3.31
and 3.04 (2 × s, 3 H, NCH3), 1.65–1.54 (m, 2 H, 2¢-CH2), 1.41–1.28
and 1.26–1.13 (2 × m, 2 H, 3¢-CH2), 0.94 and 0.8 (2 × t, J = 7.3 Hz
and 7.3 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.7, 162.4, 140.5, 139.5,
139.4, 131.4, 128.6, 123.2, 123.1, 122.2, 121.6, 109.9, 49.6, 47.1,
36.4, 33.4, 30.1, 28.6, 19.5, 19.1, 13.6, 13.4.
HRMS (EI): m/z [M]+ calcd for C14H19N3O2: 261.1477; found:
261.1478.
N-Butyl-6-methoxy-N-methyl-1H-indazole-3-carboxamide (4h)
Compound 4h was obtained by the general procedure, starting from
3-iodo-6-methoxy-1H-indazole (2i; 170 mg, 0.62 mmol) and puri-
fied by preparative HPLC.
Yield: 83 mg (51%); beige solid; mp 124–126 °C.
HRMS (EI): m/z [M]+ calcd for C13H16ClN3O: 265.0982; found:
265.0985.
1H NMR (400 MHz, DMSO-d6): d = 13.17 (br s, 1 H, NH), 7.84–
7.76 (m, 1 H, 4-H), 6.94 (s, 1 H, 7-H), 6.82 (dd, J = 8.87, 2.03 Hz,
1 H, 5-H), 3.83 (s, 3 H, OCH3), 3.77 and 3.50 (2 × t, J = 7.28 Hz
and 7.14 Hz, 2 H, 1¢-CH2), 3.30 and 3.02 (2 × s, 3 H, NCH3), 1.65–
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Synthesis of 3-Indazolecarboxylic Esters and Amides
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1.52 (m, 2 H, 2¢-CH2), 1.42–1.13 (m, 2 H, 3¢-CH2), 0.94 and 0.80
(2 × t, J = 7.2 and 7.3 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 164.6, 164.2, 160.0, 142.6,
140.5, 140.3, 123.4, 118.7, 114.9, 92.1, 56.5, 50.8, 48.3, 37.6, 34.6,
31.3, 29.8, 20.7, 20.3, 14.9, 14.7.
N-Butyl-N-methyl-6-nitro-1H-indazole-3-carboxamide (4l)
Compound 4l was obtained by the general procedure, starting from
3-iodo-6-nitro-1H-indazole (2m; 200 mg, 0.69 mmol) and purified
by preparative HPLC and flash chromatography.
Yield: 58 mg (31%); colorless solid; mp 175.5–177 °C (dec.).
HRMS (EI): m/z [M]+ calcd for C14H19N3O2: 261.1477; found:
261.1471.
1H NMR (400 MHz, DMSO-d6): d = 14.14 (br s, 1 H, NH), 8.50 (s,
1 H, 7-H), 8.19 (d, J = 8.9 Hz, 1 H, 4-H), 8.02 (dd, J = 8.9, 1.9 Hz,
1 H, 5-H), 3.77 and 3.54 (2 × t, J = 7.4 and 7.3 Hz, 2 H, 1¢-CH2),
3.33 and 3.07 (2 × s, 3 H, NCH3), 1.68–1.55 (m, 2 H, 2¢-CH2), 1.42–
1.15 (m, 2 H, 3¢-CH2), 0.95 and 0.81 (2 × t, J = 7.3 and 7.3 Hz, 3 H,
4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.3, 162.0, 146.1, 139.9,
139.7, 138.8, 126.0, 123.0, 122.9, 116.0, 107.3, 95.4, 49.7, 47.2,
36.5, 33.5, 30.2, 28.6, 19.6, 19.2, 13.7, 13.5.
Ethyl 3-[Butyl(methyl)carbamoyl]-1H-indazole-5-carboxylate
(4i)
Compound 4i was obtained by the general procedure, starting from
ethyl 3-iodo-1H-indazole-5-carboxylate (2j; 200 mg, 0.63 mmol)
and purified by preparative HPLC.
Yield: 98 mg (51%); beige solid; mp 153–155 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.78 (br s, 1 H, NH), 8.71–
8.64 (m, 1 H, 4-H), 7.98 (dd, J = 8.8, 1.6 Hz, 1 H, 6-H), 7.73–7.67
(m, 1 H, 7-H), 4.35 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.78 and 3.54
(2 × t, J = 7.4 and 7.3 Hz, 2 H, 1¢-CH2), 3.33 and 3.07 (2 × s, 3 H,
NCH3), 1.68–1.55 (m, 2 H, 2¢-CH2), 1.36 (t, J = 7.1 Hz, 3 H,
OCH2CH3), 1.41–1.30 and 1.26–1.14 (2 × m, 2 H, 3¢-CH2), 0.95
and 0.79 (2 × t, J = 7.3 and 7.3 Hz, 3 H, 4¢-CH3).
HRMS (EI): m/z [M]+ calcd for C13H16N4O3: 276.1222; found:
276.1221.
N,N-Diethyl-1H-indazole-3-carboxamide (4m)
Compound 4m was obtained by the general procedure, starting
from 3-iodo-1H-indazole (2a; 200 mg, 0.82 mmol) and purified by
preparative HPLC.
13C NMR (75 MHz, DMSO-d6): d = 167.3, 164.1, 163.8, 143.4,
142.2, 142.1, 128.2, 126.1, 126.0, 124.8, 124.0, 112.1, 62.0, 51.1,
48.7, 37.9, 35.0, 31.6, 30.1, 21.0, 20.6, 15.7, 15.2, 15.0.
HRMS (EI): m/z [M]+ calcd for C16H21N3O3: 303.1583; found:
303.1583.
Yield: 56 mg (31%); colorless solid; mp 172.5–174 °C.
1H NMR (400 MHz, DMSO-d6): d = 13.40 (br s, 1 H, NH), 7.97 (d,
J = 8.2 Hz, 1 H, 4-H), 7.58 (d, J = 8.4 Hz, 1 H, 7-H), 7.39 (ddd,
J = 8.2, 6.9, 1.0 Hz, 1 H, 6-H), 7.19 (ddd, J = 7.9, 6.9, 0.8 Hz, 1 H,
5-H), 3.80–3.68 and 3.58–3.46 (2 × m, 4 H, CH2), 1.19 (t,
J = 7.0 Hz, 6 H, CH3).
N-Butyl-6-cyano-N-methyl-1H-indazole-3-carboxamide (4j)
Compound 4j was obtained by the general procedure, starting from
6-cyano-3-iodo-1H-indazole (2k; 200 mg, 0.74 mmol) and purified
by preparative HPLC.
13C NMR (75 MHz, DMSO-d6): d = 162.8, 140.2, 139.3, 126.5,
122.7, 121.5, 121.4, 110.3, 42.5, 40.1, 14.7, 12.8.
HRMS (EI): m/z [M]+ calcd for C12H15N3O: 217.1215; found:
217.1215.
Yield: 67 mg (35%); beige solid; mp 160–162 °C.
1H NMR (400 MHz, DMSO-d6): d = 14.01 (br s, 1 H, NH), 8.26–
8.21 (m, 1 H, 7-H), 8.17–8.11 (m, 1 H, 4-H), 7.53 (dd, J = 8.4,
1.1 Hz, 1 H, 5-H), 3.76 and 3.53 (2 × t, J = 7.40 and 7.34 Hz, 2 H,
1¢-CH2), 3.31 and 3.06 (2 × s, 3 H, NCH3), 1.66–1.55 (m, 2 H, 2¢-
CH2), 1.41–1.13 (m, 2 H 3¢-CH2), 0.94 and 0.8 (2 × t, J = 7.3 and
7.3 Hz, 3 H, 4¢-CH3).
13C NMR (75 MHz, DMSO-d6): d = 161.3, 161.0, 138.8, 138.6,
137.7, 123.7, 122.4, 122.0, 118.0, 115.3, 107.5, 48.5, 46.1, 35.4,
32.4, 29.0, 27.5, 18.4, 18.0, 12.6, 12.4.
1H-Indazol-3-yl-(1-piperidyl)methanone (4n)
Compound 4n was obtained by the general procedure, starting from
3-iodo-1H-indazole (2a; 200 mg, 0.82 mmol) and purified by pre-
parative HPLC.
Yield: 68 mg (36%); light-brown solid; mp 199–201 °C (dec.) (Lit.9
206–208 °C).
1H NMR (400 MHz, DMSO-d6): d = 13.08 (br s, 1 H, NH), 7.91 (d,
J = 8.2 Hz, 1 H, 4-H), 7.55 (d, J = 8.4 Hz, 1 H, 7-H), 7.41–7.32 (m,
1 H, 6-H), 7.22–7.09 (m, 1 H, 5-H), 3.84–3.69 (m, 4 H, 1¢-CH2),
1.74–1.49 (m, 6 H, 2¢-CH2, 3¢-CH2).
13C NMR (75 MHz, DMSO-d6): d = 161.9, 140.2, 139.1, 126.4,
122.6, 121.4, 121.3, 110.4, 47.3, 42.7, 26.4, 25.5, 24.2.
HRMS (EI): m/z [M]+ calcd for C13H15N3O: 229.1215; found:
229.1214.
HRMS (EI): m/z [M]+ calcd for C14H16N4O: 256.1324; found:
256.1333.
N-Butyl-N-methyl-5-nitro-1H-indazole-3-carboxamide (4k)
Compound 4k was obtained by the general procedure, starting from
3-iodo-5-nitro-1H-indazole (2l; 200 mg, 0.69 mmol) and purified
by preparative HPLC.
1H-Indazol-3-yl-(morpholino)methanone (4o)
Compound 4o was obtained by the general procedure, starting from
3-iodo-1H-indazole (2a; 200 mg, 0.82 mmol) and purified by pre-
parative HPLC.
Yield: 85 mg (45%); colorless solid; mp 156–158 °C (Lit.9 178–
179 °C).
1H NMR (400 MHz, DMSO-d6): d = 13.50 (br s, 1 H, NH), 7.99 (d,
J = 8.2 Hz, 1 H, 4-H), 7.60 (d, J = 8.4 Hz, 1 H, 7-H), 7.41 (ddd,
J = 8.2 Hz, 6.9 Hz, 1.0 Hz, 1 H, 6-H), 7.26–7.18 (m, 1 H, 5-H),
4.15–3.95 (m, 2 H, CH2), 3.80–3.60 (m, 6 H, CH2).
13C NMR (75 MHz, DMSO-d6): d = 161.9, 140.2, 138.4, 133.4,
126.6, 125.8, 122.8, 121.7, 121.5, 120.4, 120.1, 110.5, 110.0, 66.4,
47.1, 42.3.
Yield: 73 mg (38%); beige solid; mp 121.5 °C (dec.).
1H NMR (400 MHz, DMSO-d6): d = 14.09 (br s, 1 H, NH), 8.91 (s,
1 H, 4-H), 8.24 (dd, J = 9.2, 2.1 Hz, 1 H, 6-H), 7.90–7.71 (m, 1 H,
7-H), 3.82 and 3.55 (2 × t, J = 7.4 and 7.3 Hz, 2 H, 1¢-CH2), 3.38
and 3.08 (2 × s, 3 H, NCH3), 1.7–1.55 (m, 2 H, 2¢-CH2), 1.43–1.16
(m, 2 H, 3¢-CH2), 0.95 and 0.83 (2 × t, J = 7.3 and 7.3 Hz, 3 H, 4¢-
CH3).
13C NMR (75 MHz, DMSO-d6): d = 162.0, 161.7, 142.5, 142.0,
141.9, 141.8, 122.2, 121.4, 119.4, 119.3, 111.6, 95.4, 49.6, 47.4,
36.5, 33.7, 30.2, 28.6, 19.6, 19.2, 13.7, 13.5.
HRMS (EI): m/z [M]+ calcd for C13H16N4O3: 276.1222; found:
276.1228.
Synthesis 2011, No. 19, 3089–3098 © Thieme Stuttgart · New York

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H.-P. Buchstaller et al.
PAPER
(4) Aletru, M.; Damour, D.; Monseau, C.; Mougenot, P.;
HRMS (EI): m/z [M]+ calcd for C12H13N3O2: 231.1008; found:
231.1008.
Namane, C.; Nardi, F.; Nemecek, P.; Philippo, C. PCT Int.
Appl. WO 2009/010660, 2009; Chem. Abstr. 2009, 150,
168344.
N-Propyl-1H-indazole-3-carboxamide (4p)
Compound 4p was obtained by the general procedure, starting from
3-iodo-1H-indazole (2a; 200 mg, 0.82 mmol) and purified by pre-
parative HPLC.
Yield: 74 mg (44%); off-white solid; mp 115.5–117.5 °C (Lit.9
135–136 °C).
1H NMR (400 MHz, DMSO-d6): d = 13.49 (br s, 1 H, NH), 8.31 (t,
J = 5.8 Hz, 1 H, NH), 8.17 (d, J = 8.2 Hz, 1 H, 4-H), 7.60 (d,
J = 8.4 Hz, 1 H, 7-H), 7.45–7.36 (m, 1 H, 6-H), 7.23 (t, J = 7.5 Hz,
1 H, 5-H), 3.36–3.21 (m, 2 H, 1¢-CH2), 1.63–1.50 (m, 2 H, 2¢-CH2),
0.90 (t, J = 7.4 Hz, 3 H, 3¢-CH3).
(5) Wagner, H.; Langkopf, E.; Eckhardt, M.; Streicher, R.;
Schoelch, C.; Schuler-Metz, A.; Pautsch, A. PCT Int. Appl.
WO 2009/016119, 2009; Chem. Abstr. 2009, 150, 168522.
(6) (a) Buchler, I. P.; Hayes, M. J.; Hedge, S. G.; Hockerman, S.
L.; Jones, D. E.; Kortum, S. W.; Rico, J. G.; Tenbrink, R. E.;
Wu, K. K. PCT Int. Appl. WO 2009/106982, 2009; Chem.
Abstr. 2009, 151, 313542. (b) Buchler, I. P.; Hayes, M. J.;
Hedge, S. G.; Hockerman, S. L.; Jones, D. E.; Kortum, S.
W.; Rico, J. G.; Tenbrink, R. E.; Wu, K. K. PCT Int. Appl.
WO 2009/106980, 2009; Chem. Abstr. 2009, 151, 313541.
(c) Alisi, M. A.; Cazzolla, N.; Furlotti, G.; Guglielmotti, A.;
Polenzani, L. PCT Int. Appl. WO 2009/062883, 2009;
Chem. Abstr. 2009, 150, 539708.
13C NMR (75 MHz, DMSO-d6): d = 162.2, 141.0, 138.4, 126.4,
121.8, 121.6, 121.4, 110.5, 40.1, 22.6, 11.4.
HRMS (EI): m/z [M]+ calcd for C11H13N3O: 203.1059; found:
203.1055.
(7) Harada, H.; Morie, T.; Hirokawa, Y.; Terauchi, H.;
Fujiwara, I.; Yoshida, N.; Kato, S. Chem. Pharm. Bull. 1995,
43, 1912.
(8) Elliott, E. L.; Bushell, S. M.; Cavero, M.; Tolan, B.; Kelly,
T. R. Org. Lett. 2005, 7, 2449.
(9) Yoshida, T.; Matsuura, N.; Yamamoto, K.; Doi, M.;
Shimada, K.; Morie, T.; Kato, S. Heterocycles 1996, 43,
2701.
N-Benzyl-1H-indazole-3-carboxamide (4q)
Compound 4q was obtained by the general procedure, starting from
3-iodo-1H-indazole (2a; 200 mg, 0.82 mmol) and purified by pre-
parative HPLC.
Yield: 95 mg (46%); light-brown solid; mp 158.5 °C (dec.).
(10) Buchheit, K.-H.; Gamse, R.; Giger, R.; Hoyer, D.; Klein, F.;
Klöppner, E.; Pfannkuche, H.-J.; Mattes, H. J. Med. Chem.
1995, 38, 2331.
(11) Collot, V.; Dallemagne, P.; Bovy, R. P.; Rault, S.
Tetrahedron 1999, 55, 6917.
(12) Crestey, F.; Collot, V.; Stiebing, S.; Rault, S. Synthesis 2006,
3506.
(13) (a) Grigg, R.; Mutton, S. P. Tetrahedron 2010, 66, 5515.
(b) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem.
Int. Ed. 2009, 48, 4114. (c) Barnard, C. F. J.
1H NMR (400 MHz, DMSO-d6): d = 13.55 (br s, 1 H, NH), 8.90 (t,
J = 6.3 Hz, 1 H, NH), 8.17 (d, J = 8.1 Hz, 1 H, 4-H), 7.61 (d,
J = 8.4 Hz, 1 H, 7-H), 7.45–7.18 (m, 7 H, 5-H), 4.51 (d, J = 6.3 Hz,
2 H, CH2).
13C NMR (75 MHz, DMSO-d6): d = 162.3, 158.1, 141.1, 140.8,
139.9, 138.2, 128.2, 127.3, 126.9, 126.6, 126.5, 126.4, 122.0, 121.5,
121.4, 110.6, 43.0, 41.8.
HRMS (EI): m/z [M]+ calcd for C15H13N3O: 251.1059; found:
251.1038.
Organometallics 2008, 27, 5402.
(14) Tsuji, J. Palladium Reagents and Catalysts: New
Perspectives for the 21st Century; Wiley: Chichester (UK),
2004.
(15) Kumar, K.; Zapf, A.; Michalik, D.; Tillack, A.; Heinrich, T.;
Böttcher, H.; Arlt, M.; Beller, M. Org. Lett. 2004, 6, 7.
(16) Bartsch, R. A.; Yang, I.-W. J. Heterocycl. Chem. 1984, 21,
1063.
Indazol-1-yl-(1H-indazol-3-yl)methanone (5)
1H NMR (500 MHz, DMSO-d6): d = 13.92 (br s, 1 H), 10.42 (s,
1 H), 8.21 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 8.1 Hz, 1 H), 7.88 (dd,
J = 7.8, 1.4 Hz, 1 H), 7.79–7.74 (m, 1 H), 7.71 (d, J = 8.5 Hz, 1 H),
7.53–7.46 (m, 1 H), 7.40 (td, J = 7.7, 0.8 Hz, 1 H), 7.34 (t,
J = 7.5 Hz, 1 H).
(17) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org.
Chem. 2006, 71, 8166.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
(18) Batt, D. G.; Petraitis, J. J.; Houghten, G. C.; Modi, D. P.;
Cain, G. A.; Corjay, M. H.; Mousa, S. A.; Bouchard, P. J.;
Forsythe, M. S.; Harlow, P. P.; Barbera, F. A.; Spitz, S. M.;
Wexler, R. R.; Jadhav, P. K. J. Med Chem. 2000, 43, 41.
(19) Yager, K.; Chu, S.; Appelt, K.; Li, X. U.S. Pat. Appl. Publ.
US2005/54697, 2005; Chem. Abstr. 2005, 142, 316830.
(20) Arrington, K. L.; Fraley, M. E.; Garbaccio, R. M.; Huang, S.
Y.; Lindsley, C. W.; Steen, J. T.; Yang, F. PCT Int. Appl.
WO 2006/086255, 2006; Chem. Abstr. 2006, 145: 249199.
(21) Wrzeciono, U.; Nieweglowska, W.; Szot, M. Pharmazie
1979, 34, 399.
Acknowledgment
We wish to express our gratitude to our colleagues Rolf
Winkelmann, Markus Knoth, Matthias Fritzsche and Frank Enders
for analytical support, and to Bastian Spruth for the syntheses of the
starting materials.
(22) Georg, G. I.; Tash, J. S.; Chakrasali, R.; Jakkaraj, S. R. U.S.
Pat. Appl. Publ. US2006/47126, 2006; Chem. Abstr. 2006,
144, 274268.
(23) Schmidt, A.; Snovydovych, B.; Habeck, T.; Droettboom, P.;
Gjikaj, M.; Adam, A. Eur. J. Org. Chem. 2007, 4909.
(24) Piozzi, F.; Ronchi, A. U. Gazz. Chim. Ital. 1963, 93, 3.
References
(1) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org.
Chem. 2008, 4073.
(2) Cerecetto, H.; Gerpe, A.; González, M.; Arán, V. J.;
Ochoa de Ocáriz, C. Mini-Rev. Med. Chem. 2005, 5, 869.
(3) Wynne, G. M.; Wren, S. P.; Van Well, R. M.; Chancellor, D.
R.; Schroeer, F. PCT Int. Appl. WO 2009/121623, 2009;
Chem. Abstr. 2009, 151, 425741.
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