Facile access to 1H-indazoles through iodobenzene-catalyzed C-H amination under mild, transition-metal-free conditions

Article abstract of DOI:10.1002/ejoc.201402488

The transition-metal- and halogen-free synthesis of N-aryl-substituted 1H-indazole and derivatives was accomplished on the basis of the iodobenzene-catalyzed intramolecular C-H amination of hydrazones under mild conditions. Reactions of hydrazones derived

Full text of DOI:10.1002/ejoc.201402488

Job/Unit: O42488
/KAP1
Date: 30-06-14 11:32:33
Pages: 5
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402488
Facile Access to 1H-Indazoles through Iodobenzene-Catalyzed C–H Amination
under Mild, Transition-Metal-Free Conditions
Mitsuhiro Kashiwa,[a] Motohiro Sonoda,[a] and Shinji Tanimori*[a]
Keywords: Hypervalent compounds / C–H activation / Amination / Nitrogen heterocycles / Cyclization
The transition-metal- and halogen-free synthesis of N-aryl-
substituted 1H-indazole and derivatives was accomplished
on the basis of the iodobenzene-catalyzed intramolecular C–
H amination of hydrazones under mild conditions. Reactions
of hydrazones derived from ketones and hydrazines with a
catalytic amount of iodobenzene in the presence of Oxone
as an oxidant in trifluoroacetic acid took place to afford 1H-
indazoles in moderate to good yields. A plausible reaction
mechanism was described on the basis of the control experi-
ments.
organic molecules.[12] We now report iodobenzene-cata-
lyzed oxidative C–H amination for the construction of
1H-indazoles from arylhydrazones by using Oxone
(2KHSO5·KHSO4·K2SO4) as a terminal oxidant under
mild reaction conditions (Scheme 1).
Introduction
1H-Indazole and its derivatives are known to be impor-
tant structural units for the development of pharmaceuti-
cally important molecules.[1] For instance, they present an-
tiarthritic,[2] anti-inflammatory,[3] and antifertility activi-
ties.[4] Traditional syntheses of 1H-indazoles often require
harsh reaction conditions, toxic reagents, and unstable in-
termediates, all of which have restricted their substrate
scope and their industrial application.[5] Recently, the tran-
sition-metal-catalyzed synthesis of 1H-indazoles was docu-
mented on the basis of intramolecular Buchwald–Hartwig-
type coupling reactions and/or C–H amination.[6] Although
these methods are effective under milder reaction condi-
tions than those required for the traditional synthesis,[5] the
high cost and toxicity of the transition metals restrict their
practical use. Accordingly, the development of a new proto-
col for the formation of 1H-indazole scaffolds under transi-
tion-metal-free conditions is highly desirable.[7]
Recently, the use of hypervalent iodine reagents in oxi-
dative reactions as metal-free reagents has received much
attention owing to their low toxicity and the fact that they
can be used under mild reaction conditions.[8] Many useful
carbon–carbon[9] and carbon–heteroatom[10] bond-forming
reactions have been documented in which a stoichiometric
amount of the hypervalent iodine reagent is used. More re-
cently, a catalytic process involving the use of m-chloroper-
oxybenzoic acid (mCPBA) as a terminal oxidant to avoid
the formation of undesired iodoarenes in an equimolar
amountwasreported.[11]Onthebasisofthisconcept,avarietyof
methods have been developed for the transformation of
Scheme 1. Synthesis of 1H-indazoles from hydrazones.
Results and Discussion
The reaction conditions were optimized by using phenyl-
hydrazone 1a as a model substrate (Table 1). Treatment of
1a with iodobenzene (30 mol-%) and mCPBA (1.5 equiv.)
as the oxidant in hexafluoroisopropanol (HFIP, 2 mL) as
the solvent for 24 h at room temperature afforded target
1H-indazole 2a in 9% yield (Table 1, Entry 1). Screening
of the solvents, including trifluoroethanol (TFE), toluene,
dichloromethane, methanol, acetic acid, and DMSO,
proved unsuccessful (Table 1, Entries 2–7). Fortunately, tar-
get 2a was obtained in 48% yield by using trifluoroacetic
acid (TFA) as the solvent (Table 1, Entry 8). Employing
other substituted iodoarenes, such as p-iodotoluene and p-
iodoanisole, and also iodine sources, such as iodine and tet-
rabutylammonium iodide, produced inferior results
(Table 1, Entries 9–12). Additionally, reactions performed
with oxidants such as tert-butyl hydroperoxide (TBHP),
hydrogen peroxide, and potassium persulfate were unsuc-
cessful (Table 1, Entries 13–15). To our delight, upon em-
ploying Oxone (potassium peroxymonosulfate) as the oxi-
dant, 2a was obtained in 41% yield (Table 1, Entry 16).
Lowering the temperature to –10 °C led to isolation of the
product in 90% yield (Table 1, Entry 18). Fortunately, low-
[a] Department of Bioscience and Informatics, Graduate School of
Life and Environmental Sciences, Osaka Prefecture University
1-1 Gakuencho, Nakaku, Sakai, Osaka 599-8531, Japan
E-mail: tanimori@bioinfo.osakafu-u.ac.jp
http://www.bioinfo.osakafu-u.ac.jp/~tanimori/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402488.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42488
/KAP1
Date: 30-06-14 11:32:33
Pages: 5
M. Kashiwa, M. Sonoda, S. Tanimori
SHORT COMMUNICATION
ering the quantity of iodobenzene from 30 to 10 mol-% led
to an acceptable yield of the product (84%; Table 1, En-
try 19). Control experiments without the use of iodo-
benzene and Oxone afforded 2a in 16 and 0% yield, respec-
tively (Table 1, Entries 20 and 21).
Table 1. Optimization of the reaction conditions for the cyclization
of phenylhydrazone 1a.[a]
Entry
Oxidant
Additive
Solvent
T
t
Yield[b]
[%]
[°C] [h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19[c]
20
21
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
mCPBA
70% aq. TBHP
30% H2O2
K2S2O8
Oxone
PhI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
HFIP
TFE
toluene r.t.
CH2Cl2 r.t.
MeOH r.t.
r.t.
r.t.
24
24
24
24
12
12
12
12
6
6
6
6
6
9
trace
0
0
0
AcOH
DMSO r.t.
r.t.
0
0
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
48
20
16
trace
trace
0
Scheme 2. Scope of the cyclization of hydrazones. Yields of the
products obtained after chromatography are given.
p-MeC6H4I
p-MeOC6H4I
I2
Bu4NI
PhI
PhI
PhI
PhI
PhI
PhI
PhI
–
Disappointingly, transformation of hydrazones with
benzyl, benzoyl, and p-toluenesulfonyl groups and transfor-
mation of a hydrazone without any substituents at the ter-
minal nitrogen atom could not be achieved under the opti-
mized conditions; the starting materials were recovered, and
this could partially be attributed to the instability of the
nitrenium ion [Scheme 3, Equation (1)].[12b] Also, reaction
of hydrazones 1l and 1m with methoxycarbonyl and methyl
groups instead of the aryl group afforded poor yields of
corresponding indazoles 2l and 2m [Scheme 3, Equa-
tion (2)].
6
6
6
0.5
0
0
41
81
90
84
16
0
Oxone
Oxone
Oxone
Oxone
–10 0.5
–10 0.5
–10 0.5
–10 0.5
–
PhI
[a] The reaction was performed with the iodine compound
(0.3 equiv.) and oxidant (1.5 equiv.) unless otherwise stated. [b] The
yield of 2a after flash chromatography. [c] The reaction was per-
formed with 10 mol-% of the additive.
With the optimized conditions in hand, we next investi-
gated the scope of the cyclization of a series of substituted
hydrazones (Scheme 2). Hydrazones 1b and 1c with meth-
oxy and methyl substituents on both benzene rings reacted
to give corresponding substituted 1H-indazoles 2b and 2c in
77 and 71% yield, respectively. Substrates 1d and 1e bearing
halogen substituents also gave target products 2d and 2e in
73 and 71% yield, respectively. As can be anticipated, the
substrate singly substituted with a methyl group provided a
mixture of regioisomeric products 2fa and 2fb. Interestingly,
if phenylhydrazone 1g with a methoxy group was employed
as the substrate, the reaction proceeded with high regio-
selectivity to afford 2g throughout the cyclization from the
electron-rich benzene ring. However, cyclization of bromo-
and nitro-substituted pyridine-ring-containing substrates
1h, 1i, and 1j preferentially occurred from the electron-rich
benzene ring to afford 2h, 2i, and 2j. Substrate 1k with a
Scheme 3. Unsuccessful and inefficient transformations.
A one-pot process without the isolation of hydrazone in-
substituent at the hydrazine-derived benzene ring also termediate 1a was achieved by using benzophenone and
underwent cyclization to afford 1H-indazole 2k in moderate phenylhydrazine as the starting materials (Scheme 4). The
yield.
reaction of both starting materials in the presence of an
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42488
/KAP1
Date: 30-06-14 11:32:33
Pages: 5
Facile Access to 1H-Indazoles
acid catalyst afforded hydrazone 1a, which was treated with B. Intramolecular nucleophilic substitution provides
iodobenzene and Oxone under the optimal conditions to indazole 2 via carbocation C. The liberated iodobenzene is
provide target indazole 2a in 61% yield.
reoxidized to A by Oxone.
Conclusions
We achieved the facile synthesis of multisubstituted 1H-
indazoles with an N-aryl substituent from readily available
hydrazones on the basis of iodobenzene-catalyzed oxidative
C–H aminations by using Oxone as a stable and inexpensive
oxidant under mild conditions within a short reaction time.
The scope and limitations of this transformation and also
valuable information with regard to the reaction mecha-
nism were partially elucidated (Schemes 3–5). This transfor-
mation avoids the use of a toxic transition-metal catalyst
and leaving groups, which require additional steps for pre-
functionalization. A range of functional groups [methoxy,
methyl, halogen (Br, Cl, and F), ester, and 4-pyridyl] were
accepted for this transformation to provide a series of func-
tionalized 1H-indazoles in moderate to good yields.
Scheme 4. The one-pot synthesis of 1H-indazole 2a. TsOH = p-
toluenesulfonic acid.
To obtain information about the reaction mechanism, we
next investigated the following control experiments. The re-
action of 1a was not suppressed if TEMPO (2,2,6,6-
tetramethylpiperidin-1-oxyl), a radical-trapping reagent,
was added [Scheme 5, Equation (1)]. As expected, the reac-
tion with PhIO afforded product 2a in almost the same effi-
ciency [Scheme 5, Equation (2)].
Experimental Section
General Procedure: Oxone (0.60 mmol, 1.5 equiv.) was added to a
stirred solution of hydrazone 1 (0.40 mmol, 1.0 equiv.) and iodo-
benzene (10 mol-%) in TFA (2 mL) at –10 °C. The mixture was
stirred for 30 min and then quenched with water, diluted with
CHCl3, and washed with water (3ϫ 10 mL). The combined organic
layers were dried (Na2SO4), and the solvents were removed under
reduced pressure. The residue was purified by column chromatog-
raphy (hexane/ethyl acetate) to afford pure substituted 1H-indazole
2.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, complete characterization data of
all the new compounds, and copies of the 1H NMR and 13C NMR
spectra.
Scheme 5. Control experiments.
Acknowledgments
A plausible catalytic cycle for this transformation is
shown in Scheme 6.[12b] The oxidation of iodobenzene by
Oxone affords hypervalent iodine(III) species A, which re-
acts with hydrazone 1 to form nitrenium ion intermediate
We thank Dr. Toshifumi Dohi, College of Pharmaceutical Sciences,
Ritsumeikan University, for a kind discussion.
[1] N. A. S. Ali, B. A. Dar, V. Pradhan, M. Farooqui, Mini-Rev.
Med. Chem. 2013, 13, 1792.
[2] G. A. Bistocchi, G. D. Meo, M. Pedini, A. Ricci, H. Brouilhet,
S. Boucherie, M. Rabaud, P. Jacquignon, Farmaco, Ed. Sci.
1981, 36, 315.
[3] L. Mosti, L. Sansebastiano, P. Fossa, P. Schenone, F. Mattioli,
Farmaco 1992, 47, 357.
[4] D. A. Buthala, T. J. Lobl, Cytobios 1979, 25, 23.
[5] For a review, see: A. Schmidt, A. Beutler, B. Snovydovych, Eur.
J. Org. Chem. 2008, 4073.
[6] For palladium catalysis, see: a) J. J. Song, N. K. Yee, Org. Lett.
2000, 2, 519; b) J. J. Song, N. K. Yee, Tetrahedron Lett. 2001,
42, 2937; c) C. S. Cho, D. K. Lim, N. H. Heo, T.-J. Kim, S. C.
Shim, Chem. Commun. 2004, 104; d) K. Inamoto, M. Katsuno,
T. Yoshino, I. Suzuki, K. Hiroya, T. Sakamoto, Chem. Lett.
2004, 33, 1026; e) K. Inamoto, M. Katsuno, T. Yoshino, Y.
Arai, K. Hiroya, T. Sakamoto, Tetrahedron 2007, 63, 2695; f)
K. Inamoto, T. Saito, M. Katsuno, T. Sakamoto, K. Hiroya,
Org. Lett. 2007, 9, 2931; for copper catalysis, see: g) D. Viña,
Scheme 6. Plausible catalytic cycle.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42488
/KAP1
Date: 30-06-14 11:32:33
Pages: 5
M. Kashiwa, M. Sonoda, S. Tanimori
SHORT COMMUNICATION
E. del Olmo, J. L. López-Pérez, A. San Feliciano, Org. Lett.
2007, 9, 525; h) X. Xiong, Y. Jiang, D. Ma, Org. Lett. 2012,
14, 2552; i) T. Kylmälä, S. Udd, J. Tois, R. Franzén, Tetrahe-
dron Lett. 2010, 51, 3613; j) X. Li, L. He, H. Chen, W. Wu, H.
Jiang, J. Org. Chem. 2013, 78, 3636; for iron catalysis, see: k)
D. K. O’Dell, K. M. Nicholas, Heterocycles 2004, 63, 373; l)
B. J. Stokes, C. V. Vogel, L. K. Urnezis, M. Pan, T. G. Driver,
Org. Lett. 2010, 12, 2884; m) T. Zhang, W. Bao, J. Org. Chem.
2013, 78, 1317; for rhodium catalysis, see: n) D.-G. Yu, M. Suri,
F. Glorius, J. Am. Chem. Soc. 2013, 135, 8802.
23, 1534; h) R. Samanta, J. O. Bauer, C. Strohmann, A. P. An-
tonchick, Org. Lett. 2012, 14, 5518; i) W. Zhong, S. Liu, J.
Yang, X. Meng, Z. Li, Org. Lett. 2012, 14, 3336; j) H. J. Kim,
S. H. Cho, S. Chang, Org. Lett. 2012, 14, 1424; k) X. Ban, Y.
Pan, Y. Lin, S. Wang, Y. Du, K. Zhao, Org. Biomol. Chem.
2012, 10, 3606; l) A. Lishchynskyi, K. Muñiz, Chem. Eur. J.
2012, 18, 2212; m) J. A. Souto, Y. González, A. Iglesias, D.
Zian, A. Lishchynskyi, K. Muñiz, Chem. Asian J. 2012, 7, 1103;
n) H. Liu, X. Wang, Y. Gu, Org. Biomol. Chem. 2011, 9, 1614;
o) Y.-B. Kang, L. H. Gade, J. Am. Chem. Soc. 2011, 133, 3658;
p) W. Zhong, J. Yang, X. Meng, Z. Li, J. Org. Chem. 2011, 76,
9997; q) M. Fujita, M. Wakita, T. Sugimura, Chem. Commun.
2011, 47, 3983; r) A. A. Kantak, S. Potavathri, R. A. Barham,
K. M. Romano, B. Deboef, J. Am. Chem. Soc. 2011, 133,
19960; s) C. Röben, J. A. Souto, Y. González, A. Lishchynskyi,
K. Muñiz, Angew. Chem. Int. Ed. 2011, 50, 9478; Angew. Chem.
2011, 123, 9650; t) A. Yoshimura, V. N. Nemykin, V. V. Zhdan-
kin, Chem. Eur. J. 2011, 17, 10538.
[7] Recently, the base-catalyzed synthesis of substituted indazoles
under mild, transition-metal-free conditions was developed: I.
Thomé, C. Besson, T. Kleine, C. Bolm, Angew. Chem. Int. Ed.
2013, 52, 7509; Angew. Chem. 2013, 125, 7657.
[8] For some recent reviews, see: a) M. Ochiai, K. Miyamoto, Eur.
J. Org. Chem. 2008, 4229; b) T. Dohi, Y. Kita, Chem. Commun.
2009, 2073; c) I. Tellitu, E. Domínguez, Trends Heterocycl.
Chem. 2011, 15, 23; d) E. A. Merritt, B. Olofsson, Synthesis
2011, 517; e) M. Brown, U. Farid, T. Wirth, Synlett 2013, 24,
424; f) V. V. Zhdankin, Hypervalent Iodine Chemistry, Wiley,
Chichester, 2014; g) F. V. Singh, T. Wirth, Chem. Asian J. 2014,
9, 950.
[9] a) R. Samanta, J. Lategahn, A. P. Antonchick, Chem. Commun.
2012, 48, 3194; b) J. Wang, Y. Yuan, R. Xiong, D. Zhang-
Negrerie, Y. Du, K. Zhao, Org. Lett. 2012, 14, 2210; c) Y. Gu,
D. Wang, Tetrahedron Lett. 2010, 51, 2004.
[10] a) J. A. Souto, C. Martínez, I. Velilla, K. Muñiz, Angew. Chem.
Int. Ed. 2013, 52, 1324; Angew. Chem. 2013, 125, 1363; b) U.
Farid, T. Wirth, Angew. Chem. Int. Ed. 2012, 51, 3462; Angew.
Chem. 2012, 124, 3518; c) J. A. Souto, P. Becker, A. Iglesias, K.
Muñiz, J. Am. Chem. Soc. 2012, 134, 15505; d) J. A. Souto, D.
Zian, K. Muñiz, J. Am. Chem. Soc. 2012, 134, 7242; e) Y.
Zheng, X. Li, C. Ren, D. Zhang-Negrerie, Y. Du, K. Zhao, J.
Org. Chem. 2012, 77, 10353; f) Y.-B. Kang, L. H. Gade, J. Org.
Chem. 2012, 77, 1610; g) Z. Yu, L. Ma, W. Yu, Synlett 2012,
[11] a) M. Ochiai, Y. Takeuchi, T. Katayama, T. Sueda, K. Miyam-
oto, J. Am. Chem. Soc. 2005, 127, 12244; b) T. Dohi, A. Maruy-
ama, M. Yoshimura, K. Morimoto, H. Tohma, Y. Kita, Angew.
Chem. Int. Ed. 2005, 44, 6193; Angew. Chem. 2005, 117, 6349.
[12] a) M. Ito, H. Kubo, I. Itani, K. Morimoto, T. Dohi, Y. Kita,
J. Am. Chem. Soc. 2013, 135, 14078; b) S. K. Alla, R. K. Ku-
mar, P. Sadhu, T. Punniyamurthy, Org. Lett. 2013, 15, 1334; c)
M. Ngatimin, R. Frey, C. Andrews, D. W. Lupton, O. E. Hutt,
Chem. Commun. 2011, 47, 11778; d) V. V. Zhdankin, J. Org.
Chem. 2011, 76, 1185; e) T. Dohi, T. Nakae, Y. Ishikado, D.
Kato, Y. Kita, Org. Biomol. Chem. 2011, 9, 6899; f) A. P. An-
tonchick, R. Samanta, K. Kulikov, J. Lategahn, Angew. Chem.
Int. Ed. 2011, 50, 8605; Angew. Chem. 2011, 123, 8764; g) T.
Dohi, N. Takenaga, K.-I. Fukushima, T. Uchiyama, D. Kato,
M. Shiro, H. Fujioka, Y. Kita, Chem. Commun. 2010, 46, 7697.
Received: April 25, 2014
Published Online: ᭿
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42488
/KAP1
Date: 30-06-14 11:32:33
Pages: 5
Facile Access to 1H-Indazoles
C–H Amination
M. Kashiwa, M. Sonoda,
S. Tanimori* ..................................... 1–5
Facile Access to 1H-Indazoles through
Iodobenzene-Catalyzed C–H Amination
under Mild, Transition-Metal-Free Con-
ditions
Transition-metal- and halogen-free syn-
thesis of N-aryl-substituted 1H-indazole
and derivatives is accomplished on the
basis of the iodobenzene-catalyzed intra-
molecular C–H amination of hydrazones
in the presence of Oxone in trifluoroacetic
acid at –10 °C. The 1H-indazole derivatives
are obtained in moderate to good yields
(up to 90%).
Keywords: Hypervalent compounds / C–H
activation / Amination / Nitrogen hetero-
cycles / Cyclization
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5