An efficient transition-metal-free synthesis of 1H-indazoles from arylhydrazones with montmorillonite K-10 under O2 atmosphere

Article abstract of DOI:10.1016/j.tetlet.2015.01.183

An efficient transition-metal-free synthetic method of 1H-indazoles has been developed. The reaction of arylhydrazones in the presence of montmorillonite K-10 in 1,2-dichlorobenzene at 130 °C afforded 1H-indazoles in good yields most likely via a sequenti

Full text of DOI:10.1016/j.tetlet.2015.01.183

Tetrahedron Letters 56 (2015) 1432–1436
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient transition-metal-free synthesis of 1H-indazoles from
arylhydrazones with montmorillonite K-10 under O2 atmosphere
⇑
Jin Yu, Jin Woo Lim, Su Yeon Kim, Jimin Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient transition-metal-free synthetic method of 1H-indazoles has been developed. The reaction of
arylhydrazones in the presence of montmorillonite K-10 in 1,2-dichlorobenzene at 130 °C afforded 1H-
indazoles in good yields most likely via a sequential intramolecular nucleophilic cyclization and an aer-
obic oxidation pathway.
Received 4 January 2015
Revised 26 January 2015
Accepted 28 January 2015
Available online 4 February 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
1H-Indazole
Montmorillonite K-10
Aerobic oxidation
ODCB
1H-Indazoles are pharmaceutically important nitrogen-contain-
ing heterocyclic compounds that show a broad range of biological
activities including anti-inflammatory, anti-tumor, platelet anti-
aggregation, and anti-HIV activity.1 Thus there have been reported
numerous synthetic approaches of 1H-indazoles.2–4 Among them
the following two types are used most frequently involving the
use of an aryne intermediate (Scheme 1, Eqs. 1–3)2 or an arylhyd-
razone (Scheme 1, Eqs. 4–7).3 Although the synthesis using aryne
intermediates could be used effectively in some cases,2,4d the
2a from benzophenone phenylhydrazone (1a) under the similar
reaction conditions. The indazole 2a could be formed by a sequen-
tial intramolecular nucleophilic cyclization catalyzed by an acid
catalyst, aerobic oxidation at the 7a-position of II, and the follow-
ing conversion to 2a via an aerobic oxidation process. In the cycli-
zation step of 1a to form 2,7a-dihydro-1H-indazole intermediate II,
the C@N double bond of hydrazone could act as an electron sink in
the presence of an acid catalyst. In addition, the aerobic oxidation
of II could occur readily to form III, because the radical at the
7a-position of II could be stabilized by both nearby allylic double
bond and adjacent lone pair electrons of nitrogen atom.5
Literature survey revealed that Frasca reported the synthesis of
1H-indazole from acetophenone p-nitrophenylhydrazone in the
presence of polyphosphoric acid (PPA), albeit in low yield (29%),
in the early 1960s.6 The mechanism was proposed as an acid-
catalyzed cyclization of acetophenone p-nitrophenylhydrazone to
2,7a-dihydro-1H-indazole intermediate (such as II in Scheme 2)
and the following dehydrogenation. However, the reaction of 1a
in the presence of PPA was ineffective (vide infra, entry 13 in
Table 1). Benzophenone was formed presumably due to hydrolytic
cleavage of C@N double bond.
synthesis of 1H-indazoles using arylhydrazones would be
a
synthetically more straightforward route.3,4g As an example,
1,3-diphenyl-1H-indazole could be prepared from benzophenone
phenylhydrazone under various conditions. Recently, the synthe-
ses involving the use of FeBr3/O2,3a PhI/Oxone/CF3COOH,3b
3d
TEMPO/base/O2,3c and Cu(OAc)2/base/O2 have been reported.
The use of Pb(OAc)4 or PbO2 has also been reported for this trans-
formation.3e–g In this Letter, we wish to report transition-metal-
free synthesis of 1H-indazoles from arylhydrazones in the presence
of montmorillonite K-10 in 1,2-dichlorobenzene (Scheme 1, Eq. 8).
Recently, we reported an expedient one-pot synthesis of poly-
substituted pyrazoles from a,b-unsaturated ketones and arylhydr-
azine hydrochlorides in 1,2-dichlorobenzene (130 °C) under O2
balloon atmosphere,5 as shown in Scheme 2. We suggested that
the conversion of pyrazoline intermediate I to pyrazole proceeds
via a facile aerobic oxidation at the allylic position of the interme-
diate I.5 Thus, we decided to examine the synthesis of 1H-indazole
Thus the reaction of 1a was examined in the presence of a mild
acid catalyst such as montmorillonite K-10,7 iodine, and silica gel.
The representative results are summarized in Table 1. The use of
montmorillonite K-10 at room temperature (entry 1) in 1,2-dichlo-
robenzene (ODCB) showed no reaction. The indazole 2a was
isolated in a reasonable yield (57%) at 80 °C (entry 2), and the
formation of a trace amount of benzophenone was observed. To
our delight, the yield of 2a increased to 81% by carrying out the
⇑
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
http://dx.doi.org/10.1016/j.tetlet.2015.01.183
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. Yu et al. / Tetrahedron Letters 56 (2015) 1432–1436
1433
R1
R1
N
R
TMS
OTf
RCH=N2 (0.5 equiv)
N
(1)
(2)
N
NHR2
CsF/CH3CN/rt/24 h
Yamamoto/Larock
N
N
R2
Ar
R1
Bao: FeBr3/O2/toluene/110 oC/16-24 h
(4)
(5)
(6)
(7)
PhI/Oxone/TFA/- 10 oC/30 min
Tanimori:
TMS
OTf
R1C(Cl)=NNHR2
Nie and Rao: TEMPO/NaHCO3/O2/DMSO/140 oC/8-20 h
Jiang: Cu(OAc)2/O2/DABCO/K2CO3/DMSO/120 oC/12 h
N
CsF/18-crown-6
CH3CN/rt/5 min
Moses
N
R2
R1
R1
R1
TMS
OTf
R1CH=NNHR2
N
This Work
(8)
(3)
N
N
NHR2
KF/CH3CN/sealed tube
Montmorillonite K-10
ODCB, 130 oC, 3 h
O2 balloon
N
N
air/100 oC/16 h
R2
R2
Wu and Shi
Scheme 1. Various synthetic routes of 1H-indazoles.
Ph
N
PhNHNH2HCl
H
N
H
N
Ph
H
Ph
H
Ph
O
ODCB, 130 o
C
N
N
N
N
N
HOO
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O2 balloon, 5 h
Ref. 5
Ph
Ph
Ph
Ph
Ph
I
Ph
N
PhHN
H
N
H
N
H
K-10
Ph
Ph
Ph
H
N
Ph
Montmorillonite K-10
ODCB, 130 oC
N
N
N
N
N
HOO
Ph
7a
O
2 balloon, 3 h
This Work
III
2a (87%)
1a
II
Scheme 2. Synthetic rationale of 1H-indazole 2a.
reaction at 130 °C (entry 3) in short time (3 h). The use of p-xylene
(entry 4) was less effective than ODCB. The reaction at 160 °C
(entry 5) showed a similar result. The best yield of 2a (87%) was
obtained (entry 6) by using reduced amount of K-10 (110%,
w/w). The use of lesser amount of K-10 reduced the yield (entry
7), and the use of montmorillonite KSF was less effective (entry
8). It is interesting to note that the reaction proceeded slowly even
without K-10 at 130 °C (entry 9). Intermolecular hydrogen bonding
between hydrazone molecules might assist the nucleophilic cycli-
zation process.8 The indazole 2a was formed in only a low yield
(9%) under N2 atmosphere (entry 10). The use of iodine (entry
11), silica gel (entry 12), and polyphosphoric acid (PPA, entry 13)
was found to be less effective. Based on the results, we decided
to use K-10 (150 mg/0.5 mmol of substrate, ca. 110%, w/w) in
ODCB at 130 °C.
Encouraged by the successful synthesis of 2a, various arylhyd-
razones 1b–l were prepared from aryl ketones and representative
arylhydrazines.9 The synthesis of 1H-indazoles was examined
under the optimized reaction conditions, and the results are sum-
marized in Table 2.10 When we used the hydrazones 1b–f, derived
from symmetrical diaryl ketones, the corresponding indazoles 2b–f
were obtained in good yields (72–88%). For the unsymmetrical
hydrazones 1g–l, a mixture of indazoles was formed. It is interest-
ing to note that an electron-rich arene moiety was involved selec-
tively in the oxidative coupling reaction. The unsymmetrical
hydrazones 1g (p-tolyl), 1i (p-methoxyphenyl), and 1l (1-naphthyl)
provided 2g0, 2i0, and 2l0 as the major products, respectively. In
comparison, the reactions of 1j (p-nitrophenyl) and 1k (2-pyridyl)
afforded 2j and 2k as the major products, respectively. The selec-
tive formation of 2h might be due to steric effect of the methyl
group at the ortho-position.
Table 1
Optimization of reaction conditions for the synthesis of 2aa
The relationship between the configuration of hydrazone and
the regioselectivity of indazoles is noteworthy. As an example,
4-methoxybenzophenone phenylhydrazone (1i) was prepared as
a syn/anti mixture (ca. 1:1). When we used this mixture as a
starting material, both indazoles 2i and 2i0 were obtained in a
ratio of 7:81. The result stated that the hydrazone could be
isomerized under the reaction conditions by protonation with
montmorillonite interlayer proton,7,11 as shown in Scheme 3.
The syn/anti ratio of 1i was not changed apparently in ODCB in
the presence of K-10 up to 70 °C. However, a dynamic equilibrium
must be present and anti-1i could be converted to syn-1i during
the reaction progress. As a result, 2i0 could be obtained as a major
product.
Entry
Conditions
2ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
K-10 (300 mg), ODCB, rt, 18 h
0
57
81
70
84
87
59
66
47
9
K-10 (300 mg), ODCB, 80 °C, 18 h
K-10 (300 mg), ODCB, 130 °C, 3 h
K-10 (300 mg), p-xylene, reflux, 10 h
K-10 (300 mg), ODCB, 160 °C, 2 h
K-10 (150 mg), ODCB, 130 °C, 3 h
K-10 (75 mg), ODCB, 130 °C, 18 h
KSF (150 mg), ODCB, 130 °C, 18 h
No additive, ODCB, 130 °C, 20 h
N2 atmosphere, K-10 (150 mg), ODCB, 130 °C, 3 h
Iodine (100 mg), ODCB, 130 °C, 2 h
Silica gel (500 mg), ODCB, 130 °C, 10 h
PPA (500 mg), ODCB, 130 °C, 3 h
67
58
0c
a
b
c
1a (136 mg, 0.5 mmol) and O2 balloon atmosphere were common in all entries.
Variable amount of benzophenone was formed.
Benzophenone was the major product.
As shown in Scheme 4, the phenylhydrazone 3a of benzil
was also converted to 3-benzoylindazole 4a4l in moderate yields

1434
J. Yu et al. / Tetrahedron Letters 56 (2015) 1432–1436
Table 2
NHPh
Ph
Synthesis of various indazoles 2 from hydrazones 1a
N
N
N
K-10 (200%, w/ w)
ODCB, 150 oC, 18 h
CF3
Montmorillonite K-10
NHAr3
CF3
ODCB, 130 oC, 3 h
N
O
2 balloon
2a l 2g' l'
- ( - )
1H-indazoles
O2 balloon
1a lb
Ar1
Ar2
-
3c
4c (40%)
Ph
NHPh
Ph
Ph
N
N
Ph
N
K-10 (200%, w/w)
N
N
N
N
N
N
N
N
ODCB, 150 oC, 18 h
COOEt
Ph
Ph
2g' (73%)
Ph
Me
COOEt
O2 balloon
2a (87%)
2g (11%)
Me
Ph
3d
Me
Cl
4d
(43%)
Me
Ph
Ph
Ph
N
N
N
N
Ph
N
Ph
N
N
N
N
Ph
N
Ph
Ph
N
N
N
N
N
H
O
N
H
O
N
F
H
F
N
H
O
N
H
Ph
N
2h (75%)
2i (7%)
2h' (12%)
Me
Ph
Ar
Ph
Ph
Ph
2b (72%)
F
Ph
Ar
OEt
Ph
N
N
3a
3b
3c
3d
1k
OMe
Ph
N
N
Scheme 5. Synthesis of 3-EWG-substituted indazoles.
2i' (81%)
Ph
MeO
2c (82%)
Ph
N
N
Ph
Ph
NHPh
Ph
Ph
NO2
O2N
K-10 (100%, w/w)
N
N
N
N
N
N
ODCB, 130 oC, 3 h
N
OMe
2d (88%)
2j (70%)
+
S
2j'
(-)
O
2 balloon
Ph
S
S
MeO
Cl
Ph
5
6 (81%)
Ph
Ph
6' (not formed)
N
N
N
N
N
N
N
N
N
N
Scheme 6. Synthesis of thieno[3,2-c]pyrazole 6.
Cl
2e (81%)
N
c
2k' (17%)c
2k
(46%)
Ph
(50%); however, the reaction was somewhat sluggish and an excess
amount of K-10 (200%, w/w) was used. Similarly, the reaction of
bis-methoxy derivative 3b afforded 4b in a similar yield (48%).
The reaction of trifluoromethyl derivative 3c also showed a
sluggish reactivity under the standard condition. Thus, the reaction
was carried out at elevated temperature (150 °C) in the presence of
an excess amount of K-10 (200%, w/w) for 18 h to produce the
indazole 4c3c in moderate yields (40%) along with intractable polar
side products, as shown in Scheme 5. Similarly, the reaction of 3d
afforded 4d2b in moderate yields (43%) under the same condition.
The sluggish reactivity of pyridine derivative 1k (Table 2), aroyl
derivatives 3a and 3b (Scheme 4), trifluoromethyl derivative 3c,
and ester derivative 3d might be attributed in part to a partial
intramolecular hydrogen bonding (shown in Scheme 5), which
makes the formation of indazoles difficult.
N
Ph
Ph
N
Me
2f (84%)
2l (9%)
2l' (74%)
Me
a
Conditions: hydrazones 1 (0.5 mmol), ODCB (1.5 mL), K-10 (150 mg), 130 °C, 3 h.
b Hydrazones 1a–l were prepared from the corresponding ketones and arylhydrazines
in EtOH in the presence of AcOH: 1a (Ar1 = Ar2 = Ar3 = Ph); 1b (Ar1 = Ar2 = Ph, Ar3 = p-
MePh); 1c (Ar1 = Ar2 = Ph, Ar3 = p-ClPh); 1d (Ar1 = Ar2= p-MeOPh, Ar3 = Ph); 1e
(Ar1 = Ar2 = p-ClPh, Ar3 = Ph); 1f (Ar1 = Ar2 = p-MePh, Ar3 = Ph); 1g (Ar1 = Ph, Ar2 = p-
MePh, Ar3 = Ph); 1h (Ar1 = Ph, Ar2 = o-MePh, Ar3 = Ph); 1i (Ar1 = Ph, Ar2 = p-MeOPh,
Ar3 = Ph); 1j (Ar1 = Ph, Ar2 = p-NO2Ph, Ar3 = Ph); 1k (Ar1 = Ph, Ar2 = 2-pyridyl, Ar3 = -
Ph); 1l (Ar1 = Ph, Ar2 = 1-naphthyl, Ar3 = Ph). The hydrazones 1g and 1i were obtained
as 1:1 syn/anti mixtures, and the hydrazones 1h, 1j–l were obtained as single isomers.
c K-10 (300 mg) was used and reaction time was 15 h.
As a next entry, the hydrazone 5 was prepared and subjected to
the standard condition, as shown in Scheme 6. The reaction affor-
ded thieno[3,2-c]pyrazole 63f in good yields (81%), and the indazole
60 was not formed at all.
Montmorillonite
NHAr3
Ar2
NHAr3
Ar2
Ar3HN
Ar1
H
interlayer H+
- H+
N
N
N
The most probable reaction mechanism could be proposed as
shown in Scheme 2, based on the suggested mechanism by Frasca
for the synthesis of indazole from hydrazone with the aid of an acid
catalyst6 and our previous paper for the synthesis of pyrazoles
Ar1
(Ar1 < Ar2 in priority)
Ar1
Ar2
1-syn
1
-anti
Scheme 3. syn–anti isomerization of arylhydrazone.
from a
,b-enones and arylhydrazine hydrochlorides.5
The formation of an intermediate II from 1a could be a polar
mechanism catalyzed by montmorillonite interlayer H+ as shown
in Scheme 2, and the conversion of II to indazole 2a would be an
aerobic oxidation involving a radical chain process.5
Ph
Ph
N
N
O
N
O
N
H
K-10 (200%, w/w)
ODCB, 130 oC, 18 h
However, radical mechanism involving a resonance-stabilized
hydrazonyl radical intermediate VII could not be ruled out com-
pletely at this stage,12,13 as shown in Scheme 7. Autoxidation of
O2 balloon
X
X
X
a
-azohydroperoxide IV has been reported.12 An
X
hydrazone 1a to
O-centered radical V could be generated by homolysis of the ini-
tially formed
-azohydroperoxide IV.14 The reaction of V and 1a
gave VI and a hydrazonyl radical VII. Otherwise, VII could be
3a
: X = H
4a (50%)
4b (48%)
3b: X= OMe
a
Scheme 4. Synthesis of 3-aroylindazoles.

J. Yu et al. / Tetrahedron Letters 56 (2015) 1432–1436
1435
Ph
N
Ph
N
Ph
N
Ph
N
Ph
N
Ph
H
N
N
O2
- H
1a
N
N
N
- HO
N
N
Ph
1a
+
2a
(- H2O)
Ph
Ph
Ph
Ph Ph
Ph
Ph
Ph
Ph
Ph
O
OH
OOH
VII
VI
(- H2O)
IV
V
VIII
1a
Scheme 7. Another plausible pathway for the formation of 2a.
T.; Fabis, F.; Rault, S. J. Org. Chem. 2010, 75, 2730–2732; (g) Inamoto, K.; Saito,
T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9, 2931–2934; (h)
Lebedev, A. Y.; Khartulyari, A. S.; Voskoboynikov, A. Z. J. Org. Chem. 2005, 70,
596–602; (i) Hattori, K.; Yamaguchi, K.; Yamaguchi, J.; Itami, K. Tetrahedron
2012, 68, 7605–7612; (j) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org.
Chem. 2008, 4073–4095. and further references cited therein; (k) Ben-Yahia, A.;
Naas, M.; Kazzouli, S. E.; Essassi, E. M.; Guillaumet, G. Eur. J. Org. Chem. 2012,
7075–7081; (l) Wang, C.-D.; Liu, R.-S. Org. Biomol. Chem. 2012, 10, 8948–8952.
produced by the reaction of 1a and hydroxyl radical. The hydrazo-
nyl radical VII was cyclized to form VIII, and a subsequent elimina-
tion of hydrogen radical afforded indazole 2a. The azocarbinol VI
could be converted to benzophenone.12b Both mechanisms shown
in Schemes 2 and 7 involved a radical process, thus we examined
the reaction of 1a in the presence of a radical inhibitor 2,6-
di-tert-butyl-4-methylphenol (BHT). The reaction rate was slowed
down to some extent in the presence of 1.0 equiv of BHT, and 1a
was recovered in appreciable amount (26%) along with 2a (68%)
under the standard reaction conditions (150 mg K-10, ODCB,
130 °C, 3 h, O2 balloon atmosphere).
In summary, we disclosed an efficient synthesis of 1H-indazoles
from arylhydrazones in the presence of montmorillonite K-10 in
ODCB at 130 °C in short time.15 The reaction most likely involved
a sequential intramolecular nucleophilic cyclization and an aerobic
oxidation pathway.
5. For our recent synthesis of pyrazoles from
a, b-enones and arylhydrazine
hydrochlorides, see: Yu, J.; Kim, K. H.; Moon, H. R.; Kim, J. N. Bull. Korean Chem.
Soc. 2014, 35, 1692–1696.
6. (a) Frasca, A. R. Tetrahedron Lett. 1962, 3, 1115–1119; (b) Dennler, E. B.; Frasca,
A. R. Tetrahedron 1966, 22, 3131–3141.
7. For reviews on montmorillonite-assisted organic synthesis, see: (a) Kumar, B.
S.; Dhakshinamoorthy, A.; Pitchumani, K. Catal. Sci. Technol. 2014, 4, 2378–
2396; (b) Kaur, N.; Kishore, D. J. Chem. Pharm. Res. 2012, 4, 991–1015; (c)
Kaneda, K. Synlett 2007, 999–1015; For montmorillonite-catalyzed synthesis of
pyrazoles, see: (d) Borkin, D. A.; Puscau, M.; Carlson, A.; Solan, A.; Wheeler, K.
A.; Torok, B.; Dembinski, R. Org. Biomol. Chem. 2012, 10, 4505–4508; (e) Landge,
S. M.; Schmidt, A.; Outerbridge, V.; Torok, B. Synlett 2007, 1600–1604; (f)
Braibante, M. E. F.; Braibante, H. T. S.; Tavares, L. C.; Rohte, S. F.; Costa, C. C.;
Morel, A. F.; Stuker, C. Z.; Burrow, R. A. Synthesis 2007, 2485–2490; (g) Yadav, J.
S.; Reddy, B. V. S.; Srinivas, M.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett.
2004, 45, 6033–6036; (h) Nikpassand, M.; Mamaghani, M.; Tabatabaeian, K.;
Abiazi, M. K. Mol. Diversity 2009, 13, 389–393.
Acknowledgments
8. For inter- and intramolecular hydrogen bonding of hydrazones, see: (a)
Kaberia, F.; Vickery, B.; Willey, G. R.; Drew, M. G. B. J. Chem. Soc., Perkin
Trans. II 1980, 1622–1626; (b) Su, X.; Lokov, M.; Kutt, A.; Leito, I.; Aprahamian,
I. Chem. Commun. 2012, 10490–10492; (c) Bertolasi, V.; Gilli, P.; Ferretti, V.;
Gilli, G.; Vaughan, K. New J. Chem. 1999, 23, 1261–1267.
9. The hydrazones were prepared by the reaction of diaryl ketones and
arylhydrazines in EtOH in the presence of AcOH at 80 °C. Compounds 1b, 1f–
h, 1j and 3a–c were purified by column chromatography. Compounds 1c–e, 1i,
1k, 1l, 3d and 5 were purified by washing crude hydrazones with EtOH. The
structures of prepared hydrazones were identified by comparison their melting
points and/or 1H NMR spectra with the reported.
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and Technology
(2014R1A1A2053606). Spectroscopic data were obtained from the
Korea Basic Science Institute, Gwangju branch.
Supplementary data
Supplementary data (experimental procedures and character-
ization data for the compounds 2a–2l, 4a–4d, and 6) associated
with this article can be found, in the online version, at http://dx.
doi.org/10.1016/j.tetlet.2015.01.183.
10. Typical procedure for the synthesis of indazole 2a: To a stirred solution of 1a
(136 mg, 0.5 mmol) in ODCB (1.5 mL) was added montmorillonite K-10
(150 mg, 110%, w/w), and the reaction mixture was heated to 130 °C under
O
2 balloon atmosphere for 3 h. The reaction mixture was filtered through a pad
of Celite and washed thoroughly with CH2Cl2. After removal of the volatiles and
column chromatographic purification process (hexanes/CH2Cl2, 5:1) 2a was
obtained as a white solid, 118 mg (87%). Other compounds were synthesized
similarly, and the selected spectroscopic data of 2b,3a 2d,3a 2g,4k 2g0,3b 2l, 2l0,
4b, and 63f are as follows.
References and notes
1. For biological activity of 1H-indazole derivatives, see: (a) Chen, H.-S.; Kuo, S.-C.;
Teng, C.-M.; Lee, F.-Y.; Wang, J.-P.; Lee, Y.-C.; Kuo, C.-W.; Huang, C.-C.; Wu, C.-
C.; Huang, L.-J. Bioorg. Med. Chem. 2008, 16, 1262–1278; (b) Lee, F.-Y.; Lien, J.-C.;
Huang, L.-J.; Huang, T.-M.; Tsai, S.-C.; Teng, C.-M.; Wu, C.-C.; Cheng, F.-C.; Kuo,
S.-C. J. Med. Chem. 2001, 44, 3746–3749; (c) Thangadurai, A.; Minu, M.;
Wakode, S.; Agrawal, S.; Narasimhan, B. Med. Chem. Res. 2012, 21, 1509–1523.
and further references cited therein; (d) Haddadin, M. J.; Conrad, W. E.; Kurth,
M. J. Mini-Rev. Med. Chem. 2012, 12, 1293–1300; (e) Ali, N. A. S.; Dar, B. A.;
Pradhan, V.; Farooqui, M. Mini-Rev. Med. Chem. 2013, 13, 1792–1800.
2. For synthesis of 1H-indazoles from arynes, see: (a) Jin, T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2007, 46, 3323–3325; (b) Liu, Z.; Shi, F.; Martinez, P. D. G.;
Raminelli, C.; Larock, R. C. J. Org. Chem. 2008, 73, 219–226; (c) Spiteri, C.;
Keeling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368–3371; (d) Li, P.; Wu, C.; Zhao, J.;
Rogness, D. C.; Shi, F. J. Org. Chem. 2012, 77, 3149–3158.
3. For synthesis of 1H-indazoles from arylhydrazones, see: (a) Zhang, T.; Bao, W. J.
Org. Chem. 2013, 78, 1317–1322; (b) Kashiwa, M.; Sonoda, M.; Tanimori, S. Eur.
J. Org. Chem. 2014, 4720–4723; (c) Hu, J.; Xu, H.; Nie, P.; Xie, X.; Nie, Z.; Rao, Y.
Chem. Eur. J. 2014, 20, 3932–3938; (d) Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H. J.
Org. Chem. 2013, 78, 3636–3646; (e) Gladstone, W. A. F.; Norman, R. O. C. J.
Chem. Soc. 1965, 3048–3052; (f) Gladstone, W. A. F.; Norman, R. O. C. J. Chem.
Soc. (C) 1966, 1527–1531; (g) Theilacker, W.; Raabe, C. Tetrahedron Lett. 1966, 7,
91–92.
Compound 2b:3a 72%; white solid, mp 88–90 °C (lit.3a 88–90 °C); 1H NMR
(CDCl3, 300 MHz) d 2.46 (s, 3H), 7.29 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H),
7.40–7.50 (m, 2H), 7.51–7.60 (m, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz,
1H), 8.02–8.14 (m, 3H); 13C NMR (CDCl3, 150 MHz) d 21.09, 110.65, 121.49,
121.73, 122.90, 122.99, 126.92, 127.72, 128.15, 128.79, 129.96, 133.29, 136.58,
137.60, 140.34, 145.72; ESIMS m/z 285 [M++H].
Compound 2d:3a 88%; white solid, mp 136–138 °C (lit.3a 132–134 °C); 1H NMR
(CDCl3, 300 MHz) d 3.90 (s, 6H), 6.93 (dd, J = 8.7 and 2.1 Hz, 1H), 7.06 (d,
J = 8.7 Hz, 2H), 7.12 (d, J = 2.1 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.8 Hz,
2H), 7.78 (d, J = 7.8 Hz, 2H), 7.91 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 9.0 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 55.34, 55.58, 91.86, 113.30, 114.22, 117.68, 122.36,
123.00, 125.79, 126.50, 128.87, 129.46, 140.21, 141.54, 145.91, 159.73, 159.88;
ESIMS m/z 331 [M++H].
Compound 2g:4k 11%; white solid, mp 92–94 °C (lit.4k 95–97 °C); 1H NMR
(CDCl3, 300 MHz) d 2.45 (s, 3H), 7.27–7.41 (m, 4H), 7.42–7.50 (m, 1H), 7.56 (t,
J = 8.1 Hz, 2H), 7.76–7.84 (m, 3H), 7.94 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 7.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz) d 21.36, 110.62, 121.66, 121.76, 122.97, 123.14,
126.57, 127.03, 127.63, 129.43, 129.52, 130.31, 138.13, 140.15, 140.27, 146.15;
ESIMS m/z 285 [M++H].
Compound 2g0:3b 73%; white solid, mp 122–124 °C; 1H NMR (CDCl3, 300 MHz)
d 2.54 (s, 3H), 7.14 (d, J = 8.1 Hz, 1H), 7.34–7.48 (m, 2H), 7.50–7.61 (m, 5H),
7.81 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H); 13C NMR
4. For other synthetic approaches of 1H-indazole derivatives, see: (a) Yu, D.-G.;
Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802–8805; (b) Thome, I.;
Besson, C.; Kleine, T.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52, 7509–7513; (c)
Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 2552–2555; (d) Markina, N. A.;
Dubrovskiy, A. V.; Larock, R. C. Org. Biomol. Chem. 2012, 10, 2409–2412; (e)
Wray, B. C.; Stambuli, J. P. Org. Lett. 2010, 12, 4576–4579; (f) Lefebvre, V.; Cailly,
(CDCl3, 75 MHz) d 22.02, 110.13, 121.12, 121.25, 123.05, 124.06, 126.54,
127.66, 128.16, 128.77, 129.39, 133.32, 137.48, 140.17, 140.91, 145.88; ESIMS
m/z 285 [M++H].
Compound 2l: 9%; colorless oil; 1H NMR (CDCl3, 300 MHz) d 7.25 (t, J = 7.5 Hz,
1H), 7.40 (t, J = 7.5 Hz, 1H), 7.46–7.67 (m, 6H), 7.73 (d, J = 8.1 Hz, 1H), 7.83–7.91
(m, 4H), 7.93–8.01 (m, 2H), 8.30–8.36 (m, 1H); 13C NMR (CDCl3, 75 MHz) d

1436
J. Yu et al. / Tetrahedron Letters 56 (2015) 1432–1436
110.62, 121.73, 121.86, 122.84, 125.08, 125.37, 126.00, 126.25, 126.40, 126.59,
125.97, 126.01, 128.22, 128.81, 129.46, 132.08, 132.86, 140.53, 143.28, 147.79;
127.30, 128.30, 128.32, 128.98, 129.46, 129.98, 131.95, 134.03, 139.68, 140.18,
ESIMS m/z 277 [M++H].
146.08; ESIMS m/z 321 [M++H]. Anal. Calcd for C23H16N2: C, 86.22; H, 5.03; N,
8.74. Found: C, 86.08; H, 5.27; N, 8.49.
11. For isomerization of hydrazone configuration under acidic conditions, see: (a)
Behforouz, M.; Bolan, J. L.; Flynt, M. S. J. Org. Chem. 1985, 50, 1186–1189; (b)
Muller, S.; List, B. Angew. Chem., Int. Ed. 2009, 48, 9975–9978.
Compound 2l0: 74%; white solid, mp 118–120 °C; 1H NMR (CDCl3, 300 MHz) d
7.39–7.52 (m, 3H), 7.53–7.66 (m, 5H), 7.76–7.90 (m, 6H), 7.91–7.97 (m, 1H),
8.17–8.23 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 111.17, 117.43, 122.98, 123.85,
124.62, 127.11, 127.30, 127.86, 128.54, 128.59, 128.87, 129.23, 129.46, 129.83,
130.04, 134.75, 138.44, 139.67, 148.27; ESIMS m/z 321 [M++H]. Anal. Calcd for
12. For autoxidation of hydrazones and the formation of
a-azohydroperoxides,
see: (a) Harej, M.; Dolenc, D. J. Org. Chem. 2007, 72, 7214–7221; (b) Chang,
Y.-M.; Profetto, R.; Warkentin, J. J. Am. Chem. Soc. 1981, 103, 7189–7195; (c)
Tezuka, T.; Ando, S. Chem. Lett. 1985, 1621–1624; (d) Tezuka, T.; Ando, S.
Chem. Lett. 1986, 1671–1674; (e) Pausacker, K. H. J. Chem. Soc. 1950, 3478–
3481.
C
23H16N2: C, 86.22; H, 5.03; N, 8.74. Found: C, 86.31; H, 5.29; N, 8.61.
Compound 4b: 48%; colorless oil; IR (film) 1640, 1622, 1598, 1502, 1457 cm-1
;
1H NMR (CDCl3, 300 MHz) d 3.87 (s, 3H), 3.89 (s, 3H), 6.89–7.21 (m, 4H), 7.45 (t,
J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 2H), 7.77 (d, J = 7.8 Hz, 2H), 8.38 (d, J = 8.4 Hz,
1H), 8.49 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 55.36, 55.55, 91.76,
113.42, 115.45, 120.07, 123.47, 124.16, 127.59, 129.57, 130.43, 132.98, 139.61,
141.06, 143.74, 160.22, 163.26, 186.89; ESIMS m/z 359 [M++H]. Anal. Calcd for
13. For the resonance stabilization of hydrazonyl radicals, see: (a) Adam, W.;
Schulte, C. M. O. J. Org. Chem. 2002, 67, 4569–4573; (b) Duan, X.-Y.; Zhou, N.-N.;
Fang, R.; Yang, X.-L.; Yu, W.; Han, B. Angew. Chem., Int. Ed. 2014, 53, 3158–3162.
14. It was reported that clay surfaces catalyzed the formation of hydroxyl radicals
from the decomposition of hydrogen peroxide, see: Gournis, D.; Karakassides,
M. A.; Petridis, D. Phys. Chem. Minerals 2002, 29, 155–158.
15. In order to check the efficiency of the protocol, a one-pot synthesis of 2a was
examined by the reaction of benzophenone and phenylhydrazine in ODCB;
however, 2a was obtained in low yields (35%) even in the presence of an excess
amount of K-10 (400%, w/w) at 160 °C for 4 days.
C
22H18N2O3: C, 73.73; H, 5.06; N, 7.82. Found: C, 73.90; H, 5.28; N, 7.76.
Compound 6:3f 81%; white solid, mp 136–138 °C (lit.3f 138–139 °C); 1H NMR
(CDCl3, 300 MHz) d 7.309 (d, J = 5.4 Hz, 1H), 7.314 (t, J = 8.4 Hz, 1H), 7.39 (t,
J = 8.4 Hz, 1H), 7.47–7.57 (m, 4H), 7.56 (d, J = 5.4 Hz, 1H), 7.86 (d, J = 8.4 Hz,
2H), 8.02 (d, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 110.84, 119.76, 121.47,