FULL PAPERS DOI: 10.1002/adsc.
201700824
Divergent Synthesis of 1H-Indazoles and 1H-Pyrazoles from
Hydrazones via Iodine-Mediated Intramolecular Aryl and
sp3 CH Amination
Wei Wei,a Zhen Wang,a Xikang Yang,a Wenquan Yu,a,* and Junbiao Changa,*
a
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan Province 450001, PeopleQs
Republic of China
Fax: (+
+ 86)-(0)371-6778-1588; phone: (+
+ 86)-(0)371-6778-1788; e-mail: wenquan_yu@zzu.edu.cn or
changjunbiao@zzu.edu.cn
Received: June 27, 2017; Revised: July 28, 2017; Published online: September 25, 2017
Supporting information for this article is available under https://doi.org/10.1002/adsc.201700824.
Abstract: A divergent intramolecular CH amination
of hydrazones has been developed employing molec-
ular iodine (I2) as the sole oxidant. The required hy-
drazone substrates were readily obtained by conden-
sation of hydrazines with the corresponding ketones.
In the presence of potassium iodide, I2-mediated oxi-
dative cyclization of diaryl and tert-butyl aryl ketone
hydrazones produced 1H-indazoles via direct aryl C
H amination. Under similar reaction conditions, pri-
mary and secondary alkyl ketone hydrazones were
Introduction
Nitrogen-containing heterocyclic frameworks such as
indazoles and pyrazoles which contain two adjacent
nitrogen atoms, are found in many compounds with
diverse biological and pharmaceutical properties,[1] in-
cluding anti-inflammatory[2] and antimicrobial drugs,[3]
kinase inhibitors,[4] and anti-HIV agents.[5] Derivatives
of these N-heterocyclic compounds also find wide-
spread applications in agricultural chemistry[6] and
material science[7] and, consequently, considerable re-
search efforts have been devoted to their synthe-
sis.[1be,8] Recently, several approaches involving intra-
molecular CH amination of hydrazone precursors
have been developed for the synthesis of indazoles or
pyrazoles through catalyzed aerobic oxidation[9] or
using hypervalent iodine reagents.[10] These are ele-
gant methods, but they have drawbacks, such as limit-
ed substrate scopes or low yields due to the relative
instability of the hydrazone substrates. Thus it is im-
portant to develop simpler and more efficient ap-
proaches, especially those that could lead to either of
these heterocyclic frameworks.
Carbon-nitrogen (CN) bond formation is one of
the most fundamental and important reactions in or-
Adv. Synth. Catal. 2017, 359, 3378 3387
transformed into 1H-pyrazole products in a reaction
involving sp3 CH amination. This synthetic method-
ology does not involve transition metals, and is op-
erationally simple, providing a facile access to inda-
zole and pyrazole derivatives in an efficient and scal-
able fashion.
Keywords: CH amination; hydrazones; 1H-inda-
zoles; iodine; 1H-pyrazoles
ganic synthesis. In earlier decades, transition metal-
catalyzed coupling reactions, especially Buchwald
Hartwig amination,[11] have become powerful and reli-
able tools for C@N bond formation and have been
used to synthesize various alkaloids. Built on these
achievements, C@N bond formation though direct C
H functionalization[12] has received considerable at-
tention in recent years owing to its advantages, such
as the rich source of hydrocarbons, high step efficien-
cy and atom economy. Previously, we had established
several CH amination reactions employing molecu-
lar iodine as the sole oxidant under transition metal-
free conditions to produce heterocycles, such as pyra-
zoles,[13] triazolopyridines,[14] and benzimidazoles.[15]
As a continuation of this work, we describe in this
paper the I2-mediated cyclization reactions of readily
accessible hydrazones for the synthesis of 1H-inda-
zoles and 1H-pyrazoles via intramolecular aryl and
sp3 CH amination reactions, respectively.
Results and Discussion
The required hydrazone substrates can be readily ob-
tained by the condensation of hydrazines with the cor-
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Table 1. Optimization of the reaction conditions for 1H-indazole synthesis.[a]

Entry Base Additive Solvent Temperature Time [h] Yield[b]

1 K2CO3 KI DCE r.t. 1 38%
2 K2CO3 KI DCE reflux 0.5 45%
3 K2CO3 KI toluene r.t. 0.5 61%
4 K2CO3 KI toluene reflux 0.5 44%
5 K2CO3 KI 1,4-dioxane reflux[c] 1.5 53%
6 K2CO3 KI DMF 100 8C[c] 1 43 %
7 K2CO3 KI DMSO 80 8C[c] 1 trace
8 K2CO3 KI DMSO 100 8C 0.5 trae
9 K3PO4 KI toluene r.t. 3 52%
10 NaOAc KI toluene refluxc 4 85 %[d]
11 KOAc KI toluene reflux 4 59%
12 NaOAc toluene reflux 2 79%
[a]
Optimal reaction conditions (entry 10): 1a (0.5 mmol), I2 (1 mmol), KI (1.05 mmol), NaOAc (2.25 mmol), toluene, reflux.
[b]
Isolated yields are given.
[c]
The conversion rate is slow at lower temperatures.
[d]
The yields for both 0.5 and 6 mmol scales.

responding ketones. The I2/KI-mediated oxidative
cyclization of 1a using K2CO3 as the base in 1,2-di-
chloroethane (DCE) solution, produces within 1 h the
desired 1H-indazole (2a) in 38% yield (Table 1,
entry 1). The major by-product is diphenyl ketone,
formed via hydrolysis. Increasing the temperature ac-
celerates the conversion rate and results in a slightly
improved yield (entry 2). Further screening of a series
of commonly used solvents (entries 38) suggests that
toluene is an ideal medium for this reaction. In the
presence of K2CO3, the reaction in toluene at room
temperature is complete within 0.5 h, producing prod-
uct 2a with a higher yield (entry 3) than under reflux
(entry 4). Replacement of K2CO3 with K3PO4 affects
both the conversion rate and the yield of 2a (entry 9
vs. entry 3). When NaOAc was utilized as the base,
the conversion was slow at room temperature. At the
reflux temperature, the cyclization of 1a was complete
within 4 h and produced 2a with a significantly im-
proved yield (entry 10). The reaction can also be con-
veniently conducted on a gram scale. However, use of
KOAc as the base decreases the yield of the product
(entry 11). Consistent with our previous results,[15] KI
favors such aryl CH amination reactions, and in the
absence of KI, the yield of the product was slightly re-
duced (entry 12).
Having established the optimal reaction conditions,
we examined the substrate scope of the reaction. Var-
ious hydrazones were then subjected to the above oxi-
dative cyclization conditions (Scheme 1). The present
synthetic method is compatible with both electron-do-
nating groups (EDGs) and electron-withdrawing
groups (EWGs) as R3 on the N-phenyl ring (2ao).
Generally, substrates bearing EWGs (2eo) produce
the corresponding products in higher yields than the
EDG-substituted compounds (2bd). This could be
because the presence of EWGs can increase the sta-
bility of the hydrazone substrates, diminishing the hy-
drolysis side reactions. During the cyclization of hy-
drazones bearing EDGs, the corresponding diaryl
ketone by-products, formed by hydrolysis can be ob-
served by TLC. In light of the low stability of the 4-
methoxy-substituted hydrazone (1d), this intermediate
was not isolated. Upon completion of the first-step
condensation, the solvent was removed and the result-
ing crude hydrazone (1d) was subjected directly to
the I2/KI-mediated cyclization conditions, which also
affords the desired product (2d) in a satisfactory
yield. The presence of strong EWGs (2h, 2j) or ortho-
substitution (2k, 2n) on the N-phenyl moiety (R3)
makes the transformation in toluene slower. Changing
the solvent to chlorobenzene with a higher boiling
point accelerates the conversion rate and produces
the desired 1H-indazoles (2h, 2j, 2k, and 2n) in good
yields.[16] The relatively low yield of N-tert-butylinda-
zole 2p could be due to the poor stability of the corre-
sponding intermediate (1p).
Hydrazones derived from substituted diphenyl ke-
tones can also be cyclized successfully, forming the
corresponding 1H-indazoles (2qz) (Scheme 2), with
the p-methoxyphenyl compound giving the best yield
(2r). Good regioselectivity is observed in the cycliza-
tion of substrates from unsymmetrical diaryl ketones
(2vz). The presence of EDGs favors the cyclization

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Scheme 1. Substrate scope of the R3 group for indazole syn-
thesis. Optimal reaction conditions: 1 (0.5 mmol), I2
(1 mmol), KI (1.05 mmol), NaOAc (2.25 mmol), toluene,
reflux (isolated yields are given).
process, with methoxy substitution giving the best se-
lectivity (2w).
Encouraged by the successful cyclization of diaryl
ketone hydrazones, we continued to explore the sub-
strate scope, replacing the aromatic R2 group with ali-
phatic groups. Considering that EWGs can increase
the stability of hydrazones and the para-nitrophenyl
(PNP) group can be removed[17] for further derivatiza-
tion, 4-nitrophenylhydrazine was chosen for substrate
preparation. tert-Butyl ketone hydrazone is smoothly
converted into the expected 1H-indazole (2aa)
(Scheme 2) in excellent yield under the optimum cy-
clization conditions, but the reaction of methyl ketone
Adv. Synth. Catal. 2017, 359, 3378 3387
hydrazone 1ab fails to produce the desired product
(2ab). This could be due to side reactions caused by
the methyl group of the substrate in the presence of
iodine.[18] For the substrates derived from primary and
secondary alkyl aryl ketones, the corresponding 1H-
pyrazole products (3acah) (Table 2) instead were
formed in moderate to good yields in place of the in-
dazoles. This reaction involves sp3 CH amination
(see Scheme 3B). The relatively lower yields for pyra-
Table 2. Substrate scope of the R2 group for pyrazole syn-
thesis.[a]
[a]
Optimal reaction conditions: 1 (0.5 mmol), I2 (1 mmol),
NaOAc (2.25 mmol), toluene, reflux.
[b]
Isolated yields are given.
[c]
The reaction resulted in the dihydropyrazole G as the
major product which was further converted into 3ac by
DDQ (see the Experimental Section).
[d]
Chlorobenzene was used as the solvent.
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Scheme 2. Substrate scope of R1 and R2 groups for indazole synthesis. Optimal reaction conditions: 1 (0.5 mmol), I2
(1 mmol), KI (1.05 mmol), NaOAc (2.25 mmol), toluene, reflux (isolated yields are given).

zole synthesis are due to the formation of the corre-
sponding ketones and some other by-products as
shown by TLC analysis. Parallel experiments (e.g., for
the synthesis of 3ag and 3ah) indicated that the yields
are not altered with or without KI. The structure of
pyrazole 3ae was confirmed by X-ray crystallogra-
phy.[19] The isobutyl-containing substrate (1ah) was
converted into a 4,5-dimethylpyrazole product (3ah)
via a 1,2-methyl migration process. A plausible mech-
anism for this transformation is proposed in
Scheme 3C.
Tentative mechanisms for these I2-mediated CH
amination reactions are proposed in Scheme 3. Taking
the cyclization of hydrazone 1a as an example, the
base-promoted iodination of 1a first forms an iodide
A. The C@I bond in A is then cleaved with concomi-
tant electrocyclic ring closure to give intermediate B.
Finally, subsequent deprotonation by base affords the
1H-indazole framework 2a. In the case of the hydra-
zone 1ac, the resulting iodide intermediate C may un-
dergo b-elimination to produce, after tautomerization,
a vinylhydrazone E. Intramolecular cycloadditon of E
results in dihydropyrazoles F and G. The intermediate
G has been isolated and characterized by 1H NMR
and mass spectra (see the Experimental Section). Fur-
ther oxidative aromatization of the dihydropyra-
zole(s) affords the pyrazole product 3ad. For the reac-
tion of the isobutyl substrate (1ah), further iodination
of the dihydropyrazole H gives an iodide I. Then,
cleavage of the C@I bond in intermediate I triggers
the 1,2-methyl shift to generate compound J. Subse-
quent deprotonation of J by base leads to the 4,5-di-
methylpyrazole 3ah.
Conclusions
In summary, the intramolecular CH amination reac-
tions of hydrazones employing molecular iodine as
the sole oxidant have been investigated. Under the
optimal reaction conditions, diaryl and tert-butyl aryl
ketone hydrazones are successfully cyclized into 1H-
indazoles by direct aryl CH amination. Oxidative
cyclization of primary and secondary alkyl ketone
substrates affords the corresponding 1H-pyrazole
products in a process involving sp3 CH amination.

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Scheme 3. Proposed mechanisms for the I2-mediated CH amination reactions.
This transition metal-free synthetic approach to inda-
zoles and pyrazoles is operationally simple and broad-
ly applicable to a variety of easily accessible hydra-
zone substrates. The reaction can be conveniently
conducted on a gram scale.
Experimental Section
General Information
1 the synthesis of 2h, 2jk, 2n, 2aa) was stirred at room tem-
H and 13C NMR spectra were recorded on a 400 MHz
(100 MHz for 13C NMR) spectrometer. Chemical shift
values are given in ppm (parts per million) with tetramethyl-
silane (TMS) as an internal standard. The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quar-
tet; m, multiplet; dd, doublet of doublets, td, triplet of dou-
blets. The coupling constants (J) are reported in Hertz (Hz).
Melting points were determined on a micromelting point ap-
paratus without correction. High-resolution mass spectra
(HR-MS) were obtained on a Q-TOF Mass Spectrometer
equipped with an electrospray ion source (ESI), operated in
the positive mode. Flash column chromatography was per-
formed over silica gel 200300 mesh, and the eluent was a
mixture of CH2Cl2/petroleum ether (PE) or EtOAc/PE.
General Procedure A for the Preparation of
Hydrazone Substrates 1
A mixture of a ketone (3 mmol), the corresponding hydra-
zine (3.6 mmol, or 4.5 mmol of hydrazine hydrochloride),
and AcOH (174 mL, 3 mmol; or 295 mg, 3.6 mmol of
Adv. Synth. Catal. 2017, 359, 3378 3387
NaOAc) in EtOH (5 mL) was heated to reflux until TLC in-
dicated the disappearance of the ketone (1224 h). Then the
solvent was removed under the reduced pressure, and the
resulting residue was purified through silica gel column
chromatography to provide the hydrazone substrate 1.
General Procedure B for the Synthesis of 1H-
Indazoles 2
A mixture of I2 (254 mg, 1 mmol) and KI (174 mg,
1.05 mmol) in toluene (5 mL; chlorobenzene was used for
perature for 10 min, then treated with the hydrazone sub-
strate 1 (0.5 mmol) and NaOAc (185 mg, 2.25 mmol) in se-
quence, and finally heated to reflux. If the reaction was not
complete within 4 h with more than 1/4 of substrate 1 re-
maining (monitored by TLC), another portion of iodine (0.5
or 1 mmol, with 1 or 2 mmol of NaOAc) was added. Upon
completion of the reaction, it was quenched with 5%
Na2S2O3 (10 mL), and then extracted with CH2Cl2 (4 X
10 mL). The combined organic layer was washed with brine
(10 mL), dried over anhydrous Na2SO4, and concentrated.
The residue was purified by column chromatography
through silica gel to afford the 1H-indazole 2.
1,3-Diphenyl-1 H-indazole (2a): For 0.5 mmol scale: 4 h
[1 mmol of I2 was used; yield: 115 mg (85%)]; for 6 mmol
scale: 6 h [12 mmol of I2 was used; yield: 1.385 g (85%)];
eluent: CH2Cl2/petroleum ether (PE) 15:85; white solid; mp
9698 8C (lit.[20] mp 9598 8C); 1H NMR (400 MHz, CDCl3):
d = 8.08 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 7.2 Hz, 2 H), 7.79 (t,
J = 8.0 Hz, 3 H), 7.54 (dd, J = 15.2, 7.6 Hz, 4 H), 7.44 (dd, J =
15.6, 8.0 Hz, 2 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.28 (t, J = 7.6 Hz,
1 H); 13C NMR (100 MHz, CDCl3): d = 146.1, 140.4, 140.2,
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133.3, 129.5, 128.9, 128.3, 127.8, 127.1, 126.7, 123.2, 123.0,
122.0, 121.6, 110.7; HR-MS: m/z = 271.1231 [M + H]+, calcd.
for C19H15N2 : 271.1230.
3-Phenyl-1-(p-tolyl)-1H-indazole (2b): 2 h (1 mmol of I2);
eluent: CH2Cl2/PE 20:80; yield: 125 mg (88%); white solid;
mp 9293 8C (lit.[9d] mp 8890 8C); 1H NMR (400 MHz,
CDCl3): d = 8.07 (d, J = 8.4 Hz, 1 H), 8.058.03 (m, 2 H), 7.73
(d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.4 Hz, 2 H), 7.52 (t, J =
7.2 Hz, 2 H), 7.457.40 (m, 2 H), 7.34 (d, J = 8.4 Hz, 2 H),
7.27 (t, J = 7.6 Hz, 1 H), 2.43 (s, 3 H); 13C NMR (100 MHz,
CDCl3): d = 145.8, 140.4, 137.7, 136.6, 133.4, 130.0, 128.8,
128.2, 127.8, 127.0, 123.1, 123.0, 121.8, 121.6, 110.7, 21.1;
HR-MS: m/z = 285.1388 [M + H]+, calcd. for C20H17N2 :
285.1386.
1-(4-Isopropylphenyl)-3-phenyl-1H-indazole (2c): 2h
(1 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 129 mg
(83%); colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.08
(d, J = 8.4 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 2 H), 7.75 (d, J =
8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 2 H), 7.52 (t, J = 7.6 Hz,
2 H), 7.467.39 (m, 4 H), 7.27 (t, J = 8.0 Hz, 1 H), 3.052.95
(m, 1 H), 1.31 (d, J = 6.8 Hz, 6 H); 13C NMR (100 MHz,
CDCl3): d = 147.7, 145.7, 140.4, 137.9, 133.4, 128.8, 128.2,
127.8, 127.4, 126.9, 123.2, 123.0, 121.8, 121.5, 110.8, 33.9,
24.1; HR-MS: m/z = 313.1691 [M + H]+, calcd. for C22H21N2 :
313.1699.
1-(4-Methoxyphenyl)-3-phenyl-1H-indazole (2d): After
the condensation of diphenyl ketone (0.5 mmol) and hydra-
zine salt (0.9 mmol), prepared according to General Proce-
dure A was complete, the reaction mixture was concentrated
and the resulting crude hydrazone (1d) was directly subject-
ed to the General Procedure B: 2 h (1.5 mmol of I2); eluent:
CH2Cl2/PE 35:65; yield: 110 mg (73%); white solid; mp
128129 8C (lit.[9b] mp 129131 8C); 1H NMR (400 MHz,
CDCl3): d = 8.07 (d, J = 8.0 Hz, 1 H), 8.058.03 (m, 2 H),
7.687.65 (m, 3 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.447.40 (m,
2 H), 7.26 (m, 1 H, overlapped with the peak of chloroform),
7.087.04 (m, 2 H), 3.87 (s, 3 H); 13C NMR (100 MHz,
CDCl3): d = 158.5, 145.6, 140.6, 133.4, 133.3, 128.9, 128.2,
127.8, 126.9, 124.9, 122.7, 121.7, 121.5, 114.7, 110.5, 55.6;
HR-MS: m/z = 301.1337 [M + H]+, calcd. for C20H17N2O:
301.1335.
1-(4-Fluorophenyl)-3-phenyl-1H-indazole (2e):[9c] 6h
(1 mmol of I2); eluent: CH2Cl2/PE 25:75; yield: 137 mg
(95%); white solid; mp 114115 8C; 1H NMR (400 MHz,
CDCl3): d = 8.08 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.2 Hz, 2 H),
7.767.72 (m, 2 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.53 (t, J =
7.2 Hz, 2 H), 7.477.41 (m, 2 H), 7.28 (t, J = 7.6 Hz, 1 H),
7.267.21 (m, 2 H, overlapped with the peak of chloroform);
13
C NMR (100 MHz, CDCl3): d = 161.2 (d, JC,F = 245.0 Hz),
146.2, 140.5, 136.3 (d, JC,F = 2.9 Hz), 133.1, 128.9, 128.4,
127.8, 127.3, 124.9 (d, JC,F = 8.3 Hz), 123.0, 122.0, 121.7, 116.4
(d, JC,F = 22.9 Hz), 110.4; HR-MS: m/z = 289.1131 [M + H]+,
calcd. for C19H14FN2 : 289.1136..
1-(4-Chlorophenyl)-3-phenyl-1H-indazole (2f):[9c] 5h
(1 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 148 mg
(97%); white solid; mp 121122 8C; 1H NMR (400 MHz,
CDCl3): d = 8.08 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.2 Hz, 2 H),
7.767.72 (m, 3 H), 7.757.42 (m, 6 H), 7.29 (d, J = 7.6 Hz,
1 H); 13C NMR (100 MHz, CDCl3): d = 146.5, 140.2, 138.7,
133.0, 132.1, 129.6, 128.9, 128.5, 127.8, 127.4, 124.0, 123.3,
122.2, 121.8, 110.5; HR-MS: m/z = 305.0847 [M + H]+, calcd.
for C19H14ClN2 : 305.0840.
Adv. Synth. Catal. 2017, 359, 3378 3387
1-(4-Bromophenyl)-3-phenyl-1H-indazole (2g):[21] 5h
(1 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 167 mg
(96%); white solid; mp 123124 8C; 1H NMR (400 MHz,
CDCl3): d = 8.07 (d, J = 8.4 Hz, 1 H), 8.01 (d, J = 7.2 Hz, 2 H),
7.737.63 (m, 5 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.477.41 (m,
2 H), 7.28 (t, J = 7.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3):
d = 146.6, 140.2, 139.3, 133.0, 132.6, 128.9, 128.5, 127.8, 127.4,
124.2, 123.4, 122.2, 121.8, 119.8, 110.5; HR-MS: m/z =
349.0331 [M + H]+, calcd. for C19H14BrN2 : 349.0335.
4-(3-Phenyl-1H-indazol-1-yl)benzonitrile (2h):[9c] 8h
(1.5 mmol of I2); eluent: EtOAc/PE 15:85; yield: 130 mg
(88%); white solid; mp 161163 8C; 1H NMR (400 MHz,
CDCl3): d = 8.09 (d, J = 8.4 Hz, 1 H), 8.037.97 (m, 4 H),
7.857.81 (m, 3 H), 7.577.45 (m, 4 H), 7.35 (t, J = 7.6 Hz,
1 H); 13C NMR (100 MHz, CDCl3): d = 147.9, 143.8, 140.0,
133.6, 132.5, 129.0, 128.9, 128.0, 127.9, 124.1, 122.9, 122.1,
122.0, 118.6, 110.7, 109.2; HR-MS: m/z = 296.1175 [M + H]+,
calcd. for C20H14N3 : 296.1182.
3-Phenyl-1-[4-(trifluoromethyl)phenyl]-1H-indazole
(2i):[9b] 10 h (2 mmol of I2); eluent: CH2Cl2/PE 20:80; yield:
160 mg (95%); white solid; mp 137139 8C; 1H NMR
(400 MHz, CDCl3): d = 8.10 (d, J = 8.0 Hz, 1 H), 8.048.02
(m, 2 H), 7.97 (d, J = 8.4 Hz, 2 H), 7.82 (t, J = 9.2 Hz, 3 H),
7.567.44 (m, 4 H), 7.33 (t, J = 7.6 Hz, 1 H); 13C NMR
(100 MHz, CDCl3): d = 147.3, 143.1, 140.2, 132.8, 128.9,
128.7, 128.1 (q, JC,F = 32.6 Hz), 127.9, 127.7, 126.7 (q, JC,F =
3.7 Hz), 124.0 (q, JC,F = 270.3 Hz), 123.8, 122.5, 122.2, 122.0,
110.6; HR-MS: m/z = 339.1104 [M + H]+, calcd. for
C20H14F3N2 : 339.1104.
1-(4-Nitrophenyl)-3-phenyl-1H-indazole (2j): 10 h
(2 mmol of I2); eluent: CH2Cl2/PE 25:75; yield: 157 mg
(99%); yellow solid; mp 162163 8C (lit.[9a] mp 160162 8C);
1
H NMR (400 MHz, CDCl3): d = 8.39 (d, J = 9.2 Hz, 2 H),
8.09 (d, J = 8.0 Hz, 1 H), 8.048.01 (m, 4 H), 7.87 (d, J =
8.4 Hz, 1 H), 7.577.53 (m, 3 H), 7.507.46 (m, 1 H), 7.36 (t,
J = 7.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3): d = 148.3,
145.4, 144.9, 140.1, 132.3, 129.0, 128.2, 127.9, 125.3, 124.3,
123.1, 122.2, 121.4, 110.9; HR-MS: m/z = 316.1083 [M + H]+,
calcd. for C19H14N3O2 : 316.1081.
1-(2-Chlorophenyl)-3-phenyl-1H-indazole (2k):[10b] 10 h
(2 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 149 mg
(98%); colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.10
(d, J = 8.4 Hz, 1 H), 8.05 (d, J = 7.6 Hz, 2 H), 7.637.58 (m,
2 H), 7.52 (d, J = 7.6 Hz, 2 H), 7.467.41 (m, 4 H), 7.317.26
(m, 2 H); 13C NMR (100 MHz, CDCl3): d = 146.5, 141.9,
137.1, 133.2, 131.7, 130.8, 129.9, 129.8, 128.9, 128.4, 127.82,
127.76, 127.0, 122.2, 121.8, 121.5, 110.9; HR-MS: m/z =
305.0850 [M + H]+, calcd. for C19H14ClN2 : 305.0840.
1-(3-Chlorophenyl)-3-phenyl-1H-indazole (2l):[9c] 6h
(1.5 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 131 mg
(86%); colorless oil.; 1H NMR (400 MHz, CDCl3): d = 8.07
(d, J = 8.0 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 2 H), 7.84 (s, 1 H),
7.77 (d, J = 8.8 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.53 (t, J =
8.0 Hz, 2 H), 7.497.42 (m, 3 H), 7.337.24 (m, 2 H);
13
C NMR (100 MHz, CDCl3): d = 146.8, 141.3, 140.2, 135.2,
132.9, 130.4, 128.9, 128.6, 127.9, 127.5, 126.6, 123.5, 122.9,
122.3, 121.8, 120.6, 110.6; HR-MS: m/z = 305.0849 [M + H]+,
calcd. for C19H14ClN2 : 305.0840.
1-(2,4-Dichlorophenyl)-3-phenyl-1H-indazole (2m):[9b]
10 h (2 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 169 mg
(99%); colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.09
(d, J = 8.0 Hz, 1 H), 8.048.02 (m, 2 H), 7.63 (d, J = 2.0 Hz,
3383 V 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 FULL PAPERS asc.wiley-vch.de
1 H), 7.547.50 (m, 3 H), 7.467.41 (m, 3 H), 7.30 (t, J =
7.2 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H, overlapped with the
peak of chloroform); 13C NMR (100 MHz, CDCl3): d =
146.9, 141.9, 135.9, 135.1, 133.0, 132.4, 130.6, 130.5, 128.9,
128.5, 128.1, 127.8, 127.2, 122.3, 122.0, 121.6, 110.7; HR-MS:
m/z = 361.0270 [M + Na]+, calcd. for C19H12Cl2N2Na:
361.0270.
1-(2,5-Dichlorophenyl)-3-phenyl-1H-indazole (2n): 10 h
(2 mmol of I2); eluent: CH2Cl2/PE 15:75; yield: 169 mg
(99%); white solid; mp 9598 8C; 1H NMR (400 MHz,
CDCl3): d = 8.09 (d, J = 8.4 Hz, 1 H), 8.048.02 (m, 2 H), 7.62
(d, J = 2.4 Hz, 1 H), 7.53 (t, J = 8.4 Hz, 3 H), 7.477.40 (m,
3 H), 7.327.27 (m, 2 H); 13C NMR (100 MHz, CDCl3): d =
147.1, 141.7, 138.1, 133.3, 132.9, 131.6, 129.9, 129.8, 129.7,
128.9, 128.6, 127.8, 127.3, 122.4, 122.1, 121.6, 110.9; HR-MS:
m/z = 339.0442 [M + H]+, calcd. for C19H13Cl2N2 : 339.0450.
3-Phenyl-1-(2,4,6-trichlorophenyl)-1H-indazole (2o):[9c]
12 h (2 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 185 mg
(99%); colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.11
(d, J = 8.4 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 2 H), 7.557.51 (m,
4 H), 7.477.42 (m, 2 H), 7.31 (t, J = 7.6 Hz, 1 H), 7.11 (d, J =
8.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3): d = 147.2, 141.9,
136.5, 136.1, 133.7, 132.9, 129.0, 128.9, 128.6, 127.9, 127.5,
122.1, 122.0, 121.7, 109.8; HR-MS: m/z = 373.0052 [M + H]+,
calcd. for C19H12Cl3N2 : 373.0061.
1-(tert-Butyl)-3-phenyl-1H-indazole (2p): After the con-
densation of diphenyl ketone (2 mmol) and hydrazine salt
(3.6 mmol) according to General Procedure A was complete,
the reaction mixture was concentrated and the resulting
crude hydrazone (1p) was directly subjected to the General
Procedure B: 1 h (6 mmol of I2); eluent: CH2Cl2/PE 25:75;
yield: 121 mg (24%); white solid; mp 104106 8C; 1H NMR
(400 MHz, CDCl3): d = 8.02 (d, J = 8.4 Hz, 1 H), 7.987.96
(m, 2 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 2 H),
7.387.32 (m, 2 H), 7.197.15 (m, 1 H), 1.83 (s, 9 H);
13
C NMR (100 MHz, CDCl3): d = 141.9, 139.6, 134.2, 128.7,
127.6, 127.5, 125.2, 123.3, 121.5, 120.4, 112.4, 59.8, 29.8; HR-
MS: m/z = 251.1547 [M + H]+, calcd. for C17H19N2 : 251.1543.
6-Methyl-1-phenyl-3-(p-tolyl)-1H-indazole (2q): 2h
(1 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 117 mg
(79%); white solid; mp 9092 8C (lit.[9b] mp 8890 8C);
1
H NMR (400 MHz, CDCl3): d = 7.947.91 (m, 3 H), 7.78 (d,
J = 7.6 Hz, 2 H), 7.567.52 (m, 3 H), 7.377.31 (m, 3 H), 7.10
(d, J = 8.4 Hz, 1 H), 2.51 (s, 3 H), 2.43 (s, 3 H); 13C NMR
(100 MHz, CDCl3): d = 146.0, 140.9, 140.3, 138.1, 137.5,
130.5, 129.5, 129.4, 127.6, 126.5, 124.0, 123.1, 121.4, 121.3,
110.1, 22.1, 21.4; HR-MS: m/z = 299.1534 [M + H]+, calcd.
for C21H19N2 : 299.1543.
6-Methoxy-3-(4-methoxyphenyl)-1-phenyl-1H-indazole
(2r): 2 h (1 mmol of I2); eluent: CH2Cl2/PE 40:60; yield:
142 mg (86%); white solid; mp 135136 8C (lit.[9a] mp 132
134 8C); 1H NMR (400 MHz, CDCl3): d = 7.94 (d, J = 8.8 Hz,
2 H), 7.89 (d, J = 8.8 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.54
(t, J = 8.0 Hz, 2 H), 7.36 (t, J = 7.2 Hz, 1 H), 7.10 (d, J =
2.0 Hz, 1 H), 7.04 (d, J = 8.8 Hz, 2 H), 6.91 (dd, J = 8.8,
2.0 Hz, 1 H), 3.87 (s, 6 H); 13C NMR (100 MHz, CDCl3): d =
159.9, 159.8, 146.0, 141.6, 140.3, 129.5, 128.9, 126.5, 125.9,
123.0, 122.4, 117.8, 114.3, 113.3, 91.9, 55.6, 55.4; HR-MS: m/
z = 331.1441 [M + H]+, calcd. for C21H19N2O2 : 331.1441.
6-Fluoro-3-(4-fluorophenyl)-1-phenyl-1H-indazole (2s):
2 h (1 mmol of I2); eluent: CH2Cl2/PE 25:75; yield: 129 mg
(84%); white solid; mp 137138 8C (lit.[10a] mp 135137 8C);
Adv. Synth. Catal. 2017, 359, 3378 3387
1
H NMR (400 MHz, CDCl3): d = 7.987.93 (m, 3 H), 7.73 (d,
J = 7.6 Hz, 2 H), 7.56 (t, J = 7.6 Hz, 2 H), 7.427.37 (m, 2 H),
7.22 (t, J = 8.8 Hz, 2 H), 7.05 (td, J = 8.8, 2.0 Hz, 1 H);
13
C NMR (100 MHz, CDCl3): d = 163.0 (d, JC,F = 246.6 Hz),
162.7 (d, JC,F = 244.7 Hz), 145.4, 140.7 (d, JC,F = 12.2 Hz),
139.7, 129.6, 129.4 (d, JC,F = 8.3 Hz), 128.9 (d, JC,F = 3.4 Hz),
127.1, 122.9, 122.8 (d, JC,F = 11.0 Hz), 119.8, 115.9 (d, JC,F =
21.6 Hz), 111.8 (d, JC,F = 25.7 Hz), 96.7 (d, JC,F = 26.9 Hz);
HR-MS: m/z = 307.1046 [M + H]+, calcd. for C19H13F2N2 :
307.1041.
6-Chloro-3-(4-chlorophenyl)-1-phenyl-1H-indazole (2t):
7 h (1 mmol of I2); eluent: CH2Cl2/PE 15:85; yield: 124 mg
(73%); white solid; mp 153154 8C (lit.[10a] mp 150151 8C);
1
H NMR (400 MHz, CDCl3): d = 7.947.90 (m, 3 H), 7.74
7.71 (m, 3 H), 7.56 (t, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.8 Hz,
2 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.267.23 (m, 1 H, overlapped
with the peak of chloroform); 13C NMR (100 MHz, CDCl3):
d = 145.0, 140.8, 139.5, 134.5, 133.8, 131.2, 129.7, 129.2, 128.9,
127.3, 123.2, 123.1, 122.2, 121.4, 110.6; HR-MS: m/z =
339.0455 [M + H]+, calcd. for C19H13Cl2N2 : 339.0450.
6-Bromo-3-(4-bromophenyl)-1-phenyl-1H-indazole (2u):
5 h (1 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 169 mg
(79%); white solid; mp 152154 8C; 1H NMR (400 MHz,
CDCl3): d = 7.92 (d, J = 1.2 Hz, 1 H), 7.877.85 (m, 3 H),
7.737.71 (m, 2 H), 7.667.63 (m, 2 H), 7.57 (t, J = 8.0 Hz,
2 H), 7.437.37 (m, 2 H); 13C NMR (100 MHz, CDCl3): d =
145.1, 141.2, 139.4, 132.1, 131.6, 129.7, 129.1, 127.4, 125.7,
123.2, 122.7, 122.4, 121.8, 121.7, 113.7; HR-MS: m/z =
448.9233 [M + Na]+, calcd. for C19H12Br2N2Na: 448.9259.
6-Methyl-1,3-diphenyl-1H-indazole (2v) and 1-phenyl-3-
(p-tolyl)-1H-indazole (2v):[9b] 2 h (1 mmol of I2); eluent:
CH2Cl2/PE 25:75; yield: 116 mg (82%; 2v:2v = 77:23 by
1
H NMR); white solid; mp 114116 8C; 1H NMR (400 MHz,
CDCl3): d = 8.088.02 (m, 1.77 H), 7.967.93 (m, 1.23 H),
7.807.76 (m, 2.23 H), 7.567.50 (m, 4.31 H), 7.467.32 (m,
2.46 H), 7.27 (t, J = 8.0 Hz, 0.23 H), 7.11 (d, J = 8.4 Hz,
0.77 H), 2.51 (s, 2.31 H), 2.43 (s, 0.69 H); 13C NMR
(100 MHz, CDCl3): 2v: d = 145.9, 141.0, 140.25, 137.5, 133.4,
129.6, 129.5, 128.8, 128.2, 127.72, 126.6, 124.1, 123.1, 121.2,
110.2, 22.1; 2v: d = 146.2, 140.33, 140.2, 138.2, 130.4, 127.69,
127.1, 123.2, 123.0, 121.8, 121.7, 121.3,110.7, 21.4; HR-MS:
m/z = 285.1382 [M + H]+, calcd. for C20H17N2 : 285.1386.
6-Methoxy-1,3-diphenyl-1H-indazole (2w). 2 h (1 mmol of
I2); eluent: CH2Cl2/PE 33:67; yield: 120 mg (80%); white
solid; mp 137139 8C (lit.[10a] mp 138140 8C); 1H NMR
(400 MHz, CDCl3): d = 8.028.00 (m, 2 H), 7.93 (d, J =
8.8 Hz, 1 H), 7.78 (d, J = 6.8 Hz, 2 H), 7.587.50 (m, 4 H),
7.447.36 (m, 2 H), 7.12 (s, 1 H), 6.94 (d, J = 8.8 Hz, 1 H),
3.88 (s, 3 H); 13C NMR (100 MHz, CDCl3): d = 160.0, 146.1,
141.7, 140.2, 133.3, 129.5, 128.8, 128.3, 127.7, 126.7, 123.1,
122.4, 117.8, 113.6, 92.0. 55.6; HR-MS: m/z = 301.1344 [M +
H]+, calcd. for C20H17N2O: 301.1335.
3-(4-Fluorophenyl)-1-phenyl-1H-indazole (2x) and 6-
fluoro-1,3-diphenyl-1H-indazole (2x):[9c] 2 h (1 mmol of I2);
eluent: CH2Cl2/PE 25:75; yield: 119 mg (83%; 2x:2x = 80:20
by 1H NMR); white solid; mp 9698 8C; 1H NMR (400 MHz,
CDCl3): d = 8.027.97 (m, 3 H), 7.797.73 (m, 2.8 H), 7.56
7.50 (m, 2.4 H), 7.467.35 (m, 2.2 H), 7.28 (t, J = 8.0 Hz,
0.8 H), 7.237.19 (m, 1.6 H, overlapped with the peak of
chloroform), 7.03 (td, J = 8.8, 2.0 Hz, 0.2 H); 13C NMR
(100 MHz, CDCl3): 2x: d = 162.9 (d, JC,F = 246.1 Hz), 145.2,
140.4, 140.1, 129.6, 129.5, 129.4, 127.2, 126.8, 123.0, 122.1,
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 FULL PAPERS asc.wiley-vch.de
121.4, 116.0, 115.8, 110.8; 2x: d = 162.7 (d, JC,F = 244.4 Hz),
146.4, 140.7 (d, JC,F = 12.3 Hz), 139.8, 132.8, 128.9, 128.6,
127.8, 127.0, 123.1, 123.0, 122.9, 120.0, 111.6 (d, JC,F =
25.6 Hz), 96.6 (d, JC,F = 27.0 Hz); HR-MS: m/z = 289.1138
[M + H]+, calcd. for C19H14FN2 : 289.1136.
3-(4-Chlorophenyl)-1-phenyl-1H-indazole (2y) and 6-
chloro-1,3-diphenyl-1H-indazole (2y):[9a] 4 h (1 mmol of I2);
eluent: CH2Cl2/PE 25:75; yield: 122 mg (80%; 2y:2y = 85:15
by 1H NMR); white solid; mp 114117 8C; 1H NMR (CDCl3,
400 MHz): d = 8.037.96 (m, 3 H), 7.787.73 (m, 3 H), 7.57
7.44 (m, 5 H), 7.407.36 (m, 1 H), 7.29 (d, J = 7.2 Hz, 0.85 H),
7.257.22 (m, 0.15 H, overlapped with the peak of chloro-
form); 13C NMR (100 MHz, CDCl3): 2y: d = 144.9, 140.4,
140.0, 134.2, 131.8, 129.5, 129.1, 128.9, 127.3, 126.9, 123.1,
122.9, 122.2, 121.3, 110.8; 2y: d = 146.2, 140.8, 139.6, 133.7,
132.7, 129.6, 128.6, 127.8, 127.2, 122.6, 121.7, 110.5; HR-MS:
m/z = 305.0831 [M + H]+, calcd. for C19H14ClN2 : 305.0840.
3-(4-Bromophenyl)-1-phenyl-1H-indazole (2z)[10a] and 6-
bromo-1,3-diphenyl-1H-indazole (2z): 4 h (1 mmol of I2);
eluent: CH2Cl2/PE 25:75; yield: 138 mg (79%; 2z:2z = 80:20
by 1H NMR); white solid; mp 147150 8C; 1H NMR (CDCl3,
400 MHz): d = 8.03 (d, J = 8.0 Hz, 0.8 H), 7.997.93 (m,
0.4 H), 7.937.91 (m, 2 H), 7.787.73 (m, 2.8 H), 7.657.63
(m, 1.6 H), 7.577.50 (m, 2.4 H), 7.477.43 (m, 1 H), 7.39
7.35 (m, 1.2 H), 7.317.29 (m, 0.8 H); 13C NMR (100 MHz,
CDCl3): 2z: d = 144.9, 140.4, 140.0, 132.2, 132.0, 129.5, 129.2,
127.3, 126.9, 123.08, 122.9, 122.4, 122.2, 121.3, 110.9; 2z: d =
146.3, 141.1, 139.6, 132.6, 129.6, 129.0, 128.6, 127.8, 127.2,
125.5, 123.14, 122.8, 122.0, 121.7, 113.6; HR-MS: m/z =
349.0331 [M + H]+, calcd. for C19H13BrN2 : 349.0335.
3-(tert-Butyl)-1-(4-nitrophenyl)-1H-indazole (2aa):[22] 10 h
(2 mmol of I2); eluent: CH2Cl2/PE 40:60; yield: 147 mg
(99%); yellow solid; mp 128130 8C; 1H NMR (400 MHz,
CDCl3): d = 8.38 (d, J = 9.2 Hz, 2 H), 7.997.95 (m, 3 H), 7.84
(d, J = 8.8 Hz, 1 H), 7.507.46 (m, 1 H), 7.297.25 (m, 1 H),
1.59 (s, 9 H); 13C NMR (100 MHz, CDCl3): d = 157.3, 145.7,
144.4, 140.1, 127.5, 125.3, 124.1, 123.0, 121.7, 120.9, 110.8,
34.1, 29.8; HR-MS: m/z = 296.1389 [M + H]+, calcd. for
C17H18N3O2 : 296.1394.
Cleavage of the 4-Nitrophenyl Group for the
Synthesis of 1H-Indazole (2j)
A solution of indazole 2j (157 mg, 0.5 mmol) in DMSO
(5 mL) was treated with NaOEt (102 mg, 1.5 mmol) and
stirred at 120 8C under a nitrogen atmosphere for 2 h. Upon
completion of the reaction, the solution was cooled to room
temperature, quenched with brine (10 mL), and extracted
with CH2Cl2 (4 X 10 mL). The combined organic layer was
dried over anhydrous Na2SO4, concentrated, and then the
residue was purified by column chromatography through
silica gel (eluent: EtOAc/PE 16:84) to afford 1H-indazole
2j;[9c] ; yield: 77 mg (79%); light-brown solid; mp 102
103 8C. 1H NMR (400 MHz, CDCl3): d = 11.64 (br, s, 1 H),
8.02 (dd, J = 8.0, 0.8 Hz, 3 H), 7.54 (t, J = 7.6 Hz, 2 H), 7.45
(t, J = 7.6 Hz, 1 H), 7.367.33 (m, 1 H), 7.257.19 (m, 2 H,
overlapped with the peak of chloroform); 13C NMR
(100 MHz, CDCl3): d = 145.7, 141.7, 133.5, 129.0, 128.2,
127.7, 126.8, 121.3, 121.1, 120.9, 110.3; MS: m/z = 195 [M +
H]+, calcd. for C13H11N2 : 195.
Adv. Synth. Catal. 2017, 359, 3378 3387
General Procedure C for the Synthesis of 1H-
Pyrazoles 3
A mixture of the hydrazone substrate 1 (0.5 mmol), I2
(254 mg, 1 mmol) and NaOAc (185 mg, 2.25 mmol) in tolu-
ene (5 mL; chlorobenzene was used for the synthesis of 3ag)
was heated to reflux. If the reaction was not complete
within 2 h with more than 1/4 of substrate 1 remaining
(monitored by TLC), another portion of iodine (0.5 or
1 mmol, with 1 or 2 mmol of NaOAc) was added. Upon
completion of the reaction, it was quenched with 5%
Na2S2O3 (10 mL), and then extracted with CH2Cl2 (4 X
10 mL). The combined organic layer was washed with brine
(10 mL), dried over anhydrous Na2SO4, and concentrated.
The residue was purified by column chromatography
through silica gel to afford the 1H-pyrazole 3.
1-(4-Nitrophenyl)-3-phenyl-1H-pyrazole (3ac): According
to the General Procedure C for 2 h (1 mmol of I2), the dihy-
dropyrazole G was formed as the major product [eluent:
CH2Cl2/PE 50:50, yellow solid; 1H NMR (400 MHz, CDCl3):
d = 8.15 (d, J = 9.2 Hz, 2 H), 7.757.74 (m, 2 H), 7.437.38 (m,
3 H), 7.03 (d, J = 9.2 Hz, 2 H), 3.96 (t, J = 10.4 Hz, 2 H), 3.35
(t, J = 10.4 Hz, 2 H); MS: m/z = 268 [M + H]+, calcd. for
C15H14N3O2 : 268.
A solution of the crude intermediate G from above in tol-
uene (5 mL) was treated with DDQ (0.25 mmol) and re-
fluxed for 1 h to afford pyrazole 3ac. Eluent: CH2Cl2/PE
33:67; yield: 66 mg (50%, from the hydrazone); yellow
solid; mp 168170 8C (lit.[23] mp 170173 8C); 1H NMR
(400 MHz, CDCl3): d = 8.33 (d, J = 9.2 Hz, 2 H), 8.04 (d, J =
2.8 Hz, 1 H), 7.947.91 (m, 4 H), 7.477.44 (m, 2 H), 7.40
7.36 (m, 1 H), 6.86 (d, J = 2.4 Hz, 1 H); 13C NMR (100 MHz,
CDCl3): d 154.5, 145.2, 144.4, 132.2, 128.83, 128.79, 128.3,
126.0, 125.4, 118.3, 106.9; HR-MS: m/z = 266.0925 [M + H]+,
calcd. for C15H12N3O2 : 266.0924.
5-Methyl-1-(4-nitrophenyl)-3-phenyl-1H-pyrazole (3ad):
3 h (1.5 mmol of I2); eluent: CH2Cl2/PE 50:50; yield: 106 mg
(76%); yellow solid; mp 119121 8C (lit.[24] mp 124125 8C);
1
H NMR (400 MHz, CDCl3): d = 8.34 (d, J = 8.8 Hz, 2 H),
7.85 (d, J = 7.2 Hz, 2 H), 7.77 (d, J = 9.2 Hz, 2 H), 7.447.40
(m, 2 H), 7.367.33 (m, 1 H), 6.59 (s, 1 H), 2.50 (s, 3 H);
13
C NMR (100 MHz, CDCl3): d = 152.9, 145.9, 145.0, 140.6,
132.6, 128.7, 128.4, 125.9, 124.8, 123.8, 106.6, 13.4; HR-MS:
m/z = 280.1077 [M + H]+, calcd. for C16H14N3O2 : 280.1081.
5-Ethyl-1-(4-nitrophenyl)-3-phenyl-1H-pyrazole (3ae):[25]
3 h (1.5 mmol of I2); eluent: CH2Cl2/PE 50:50; yield: 108 mg
(74%); yellow solid; mp 110111 8C; 1H NMR (400 MHz,
CDCl3): d = 8.35 (d, J = 9.2 Hz, 2 H), 7.887.86 (m, 2 H), 7.75
(d, J = 9.2 Hz, 2 H), 7.447.41 (m, 2 H), 7.377.33 (m, 1 H),
6.63 (s, 1 H), 2.83 (q, J = 14.8, 7.2 Hz, 2 H), 1.34 (t, J =
7.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3): d = 153.0, 147.1,
146.0, 145.2, 132.6, 128.7, 128.4, 125.8, 124.7, 124.4, 104.4,
20.6, 13.1; HR-MS (m/z) [M + H]+ calcd for C17H16N3O2
294.1237, found 294.1239.
1-(4-Nitrophenyl)-5-nonyl-3-phenyl-1H-pyrazole (3af): 6 h
(2 mmol of I2); eluent: CH2Cl2/PE 60:40; yield: 165 mg
(84%); yellow solid; mp 7677 8C; 1H NMR (400 MHz,
CDCl3): d = 8.36 (d, J = 8.8 Hz, 2 H), 7.887.85 (m, 2 H), 7.74
(d, J = 9.2 Hz, 2 H), 7.447.40 (m, 2 H), 7.367.33 (m, 1 H),
6.62 (s, 1 H), 2.77 (t, J = 7.6 Hz, 2 H), 1.731.66 (m, 2 H),
1.391.26 (m, 12 H), 0.890.86 (m, 3 H); 13C NMR (100 MHz,
CDCl3): d = 152.9, 146.1, 145.8, 145.2, 132.6, 128.7, 128.4,
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 FULL PAPERS asc.wiley-vch.de
125.8, 124.7, 124.6, 104.8, 31.9, 29.4, 29.3, 29.2, 28.8, 27.0,
22.7, 14.1; HR-MS: m/z = 392.2320 [M + H]+, calcd. for
C24H30N3O2 : 392.2333.
1-(4-Nitrophenyl)-3-phenyl-4,5,6,7-tetrahydro-1H-indazole
(3ag): 6 h (2 mmol of I2); eluent: CH2Cl2/PE 50:50; yield:
80 mg (50%); yellow solid; mp 150152 8C; 1H NMR
(400 MHz, CDCl3): d = 8.31 (d, J = 9.2 Hz, 2 H), 7.837.79
(m, 4 H), 7.467.42 (m, 2 H), 7.387.34 (m, 1 H); 2.882.86
(m, 2 H), 2.812.79 (m, 2 H), 1.901.85 (m, 4 H); 13C NMR
(100 MHz, CDCl3): d = 151.0, 145.1, 140.2, 133.3, 128.6,
128.1, 127.1, 124.9, 121.9, 117.8, 24.9, 22.8, 22.7, 22.6; HR-
MS: m/z = 320.1393 [M + H]+, calcd. for C19H18N3O2 :
320.1394.
4,5-Dimethyl-1-(4-nitrophenyl)-3-phenyl-1H-pyrazole
(3ah): 4 h (1.5 mmol of I2); eluent: CH2Cl2/PE 50:50; yield:
81 mg (55%); yellow solid; mp 114116 8C; 1H NMR
(400 MHz, CDCl3): d = 8.33 (d, J = 9.2 Hz, 2 H), 7.767.71
(m, 4 H), 7.477.31 (m, 2 H), 7.397.36 (m, 1 H), 2.42 (s, 3 H),
2.22 (s, 3 H); 13C NMR (100 MHz, CDCl3): d = 152.6, 145.7,
145.2, 137.4, 133.4, 128.6, 128.0, 127.9, 124.8, 123.9, 115.0,
11.8, 9.7; HR-MS: m/z = 294.1234 [M + H]+, calcd. for
C17H16N3O2 : 294.1237.
Acknowledgements
We thank the Outstanding Young Talent Research Fund of
Zhengzhou University (No. 1521316004) and the National
Natural Science Foundation of China (Nos. 81330075 and
81302637) for financial support.
References
[1] a) J. Elguero, in: Comprehensive Heterocyclic Chemis-
try, Vol. 5, (Eds.: A. R. Katritzky, C. W. Rees), Perga-
mon, New York, 1984, pp 167303; b) D. D. Gaikwad,
A. D. Chapolikar, C. G. Devkate, K. D. Warad, A. P.
Tayade, R. P. Pawar, A. J. Domb, Eur. J. Med. Chem.
2015, 90, 707731; c) A. Schmidt, A. Beutler, B. Snovy-
dovych, Eur. J. Org. Chem. 2008, 40734095; d) A.
Schmidt, A. Dreger, Curr. Org. Chem. 2011, 15, 1423
1463; e) A. A. Bekhit, A. Hymete, A. E. A. Bekhit, A.
Damtew, H. Y. Aboul-Enein, Mini-Rev. Med. Chem.
2010, 10, 10141033.
[2] a) T. D. Penning, J. J. Talley, S. R. Bertenshaw, J. S.
Carter, P. W. Collins, S. Docter, M. J. Graneto, L. F.
Lee, J. W. Malecha, J. M. Miyashiro, R. S. Rogers, D. J.
Rogier, S. S. Yu, G. D. Anderson, E. G. Burton, J. N.
Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins,
K. Seibert, A. W. Veenhuizen, Y. Y. Zhang, P. C. Isak-
son, J. Med. Chem. 1997, 40, 13471365; b) A. A.
Bekhit, T. Abdel-Aziem, Bioorg. Med. Chem. 2004, 12,
19351945.
[3] a) X. Li, S. Chu, V. A. Feher, M. Khalili, Z. Nie, S.
Margosiak, V. Nikulin, J. Levin, K. G. Sprankle, M. E.
Tedder, R. Almassy, K. Appelt, K. M. Yager, J. Med.
Chem. 2003, 46, 56635673; b) A. Tanitame, Y. Oyama-
da, K. Ofuji, M. Fujimoto, N. Iwai, Y. Hiyama, K.
Suzuki, H. Ito, H. Terauchi, M. Kawasaki, K. Nagai, M.
Wachi, J. Yamagishi, J. Med. Chem. 2004, 47, 3693
3696; c) T. S. Haque, S. Tadesse, J. Marcinkeviciene,
Adv. Synth. Catal. 2017, 359, 3378 3387
M. J. Rogers, C. Sizemore, L. M. Kopcho, K. Amsler,
L. D. Ecret, D. L. Zhan, F. Hobbs, A. Slee, G. L. Train-
or, A. M. Stern, R. A. Copel, A. P. Combs, J. Med.
Chem. 2002, 45, 46694678.
[4] a) K. B. Goodman, H. Cui, S. E. Dowdell, D. E. Gaita-
nopoulos, R. L. Ivy, C. A. Sehon, R. A. Stavenger,
G. Z. Wang, A. Q. Viet, W. Xu, G. Ye, S. F. Semus, C.
Evans, H. E. Fries, L. J. Jolivette, R. B. Kirkpatrick, E.
Dul, S. S. Khandekar, T. Yi, D. K. Jung, L. L. Wright,
G. K. Smith, D. J. Behm, R. Bentley, C. P. Doe, E. Hu,
D. Lee, J. Med. Chem. 2007, 50, 69; b) E. Barile, S. K.
De, C. B. Carlson, V. Chen, C. Knutzen, M. Riel-
Mehan, L. Yang, R. Dahl, G. Chiang, M. Pellecchia, J.
Med. Chem. 2010, 53, 83688375; c) P. G. Wyatt, A. J.
Woodhead, V. Berdini, J. A. Boulstridge, M. G. Carr,
D. M. Cross, D. J. Davis, L. A. Devine, T. R. Early,
R. E. Feltell, E. J. Lewis, R. L. McMenamin, E. F. Nav-
arro, M. A. OQBrien, M. OQReilly, M. Reule, G. Saxty,
L. C. A. Seavers, D.-M. Smith, M. S. Squires, G. Trewar-
tha, M. T. Walker, A. J.-A. Woolford, J. Med. Chem.
2008, 51, 49864999; d) J. Regan, A. Capolino, P. F. Ci-
rillo, T. Gilmore, A. G. Graham, E. Hickey, R. R. Kroe,
J. Madwed, M. Moriak, R. Nelson, C. A. Pargellis, A.
Swinamer, C. Torcellini, M. Tsang, N. Moss, J. Med.
Chem. 2003, 46, 46764686.
[5] L. H. Jones, G. Allan, O. Barba, C. Burt, R. Corbau, T.
Dupont, T. Knchel, S. Irving, D. S. Middleton, C. E.
Mowbray, M. Perros, H. Ringrose, N. A. Swain, R.
Webster, M. Westby, C. Phillips, J. Med. Chem. 2009,
52, 12191223.
[6] a) G. P. Lahm, T. M. Stevenson, T. P. Selby, J. H. Freu-
denberger, D. Cordova, L. Flexner, C. A. Bellin, C. M.
Dubas, B. K. Smith, K. A. Hughes, J. G. Hollingshaus,
C. E. Clark, E. A. Benner, Bioorg. Med. Chem. Lett.
2007, 17, 62746279; b) P. Caboni, R. E. Sammelson,
J. E. Casida, J. Agric. Food Chem. 2003, 51, 70557061.
[7] a) K. W. Fan, J. J. Roberts, P. J. Martens, M. H. Stenzel,
A. M. Granville, J. Mater. Chem. B 2015, 3, 74577465;
b) P. Yin, L. A. Mitchell, D. A. Parrish, J. M. Shreeve,
Chem. Asian J. 2017, 12, 378384.
[8] a) S. Fustero, M. S#nchez-Roselll, P. Barrio, A. Simln-
Fuentes, Chem. Rev. 2011, 111, 69847034; b) S. Dadi-
boyena, A. Nefzi, Eur. J. Med. Chem. 2011, 46, 5258
5275.
[9] a) T. Zhang, W. Bao, J. Org. Chem. 2013, 78, 1317
1322; b) X. Li, L. He, H. Chen, W. Wu, H. Jiang, J.
Org. Chem. 2013, 78, 36363646; c) J. Hu, H. Xu, P.
Nie, X. Xie, Z. Nie, Y. Rao, Chem. Eur. J. 2014, 20,
39323938; d) J. Yu, J. W. Lim, S. Y. Kim, J. Kim, J. N.
Kim, Tetrahedron Lett. 2015, 56, 14321436.
[10] a) M. Kashiwa, M. Sonoda, S. Tanimori, Eur. J. Org.
Chem. 2014, 47204723; b) Z. Zhang, Y. Huang, G.
Huang, G. Zhang, Q. Liu, J. Heterocycl. Chem. 2017,
54, 24262433.
[11] a) J. P. Wolfe, S. Wagaw, J.-F. Marcoux, S. L. Buchwald,
Acc. Chem. Res. 1998, 31, 805818; b) J. F. Hartwig,
Angew. Chem. 1998, 110, 21542177; Angew. Chem. Int.
Ed. 1998, 37, 20462067.
[12] a) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117,
92479301; b) P. Subramanian, G. C. Rudolf, K. P. Ka-
liappan, Chem. Asian J. 2016, 11, 168192; c) J. Jiao, K.
Murakami, K. Itami, ACS Catal. 2016, 6, 610633;
3386 V 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
 FULL PAPERS asc.wiley-vch.de

d) S. H. Cho, J. Y. Kim, J. Kwak, S. Chang, Chem. Soc. tained free of charge from The Cambridge
Rev. 2011, 40, 50685083; e) F. Collet, R. H. Dodd, P. Crystallographic Data Centre via
Dauban, Chem. Commun. 2009, 50615074. www.ccdc.cam.ac.uk/data_request/cif.
[13] X. Zhang, J. Kang, P. Niu, J. Wu, W. Yu, J. Chang, J. [20] C. Spiteri, S. Keeling, J. E. Moses, Org. Lett. 2010, 12,
Org. Chem. 2014, 79, 1017010178. 33683371.
[14] E. Li, Z. Hu, L. Song, W. Yu, J. Chang, Chem. Eur. J. [21] D. Liang, Q. Zhu, Asian J. Org. Chem. 2015, 4, 4245.
2016, 22, 1102211027. [22] M. Barrejln, M. J. Glmez-Escalonilla, J. L. G. Fierro, P.
[15] Z. Lv, J. Liu, W. Wei, J. Wu, W. Yu, J. Chang, Adv. Prieto, J. R. Carrillo, A. M. Rodr&guez, G. Abell#n,
Synth. Catal. 2016, 358, 27592766. M. C. Llpez-Escalante, M. Gab#s, J. T. Llpez-Navar-
[16] The conversion rate can also be accelerated by using a rete, F. Langa, Phys. Chem. Chem. Phys. 2016, 18,
combination of catalytic iodine, NBS (1.5 equiv.); how- 2958229590.
ever, the yields were significantly decreased. For exam- [23] D. L. Browne, J. B. Taylor, A. Plant, J. P. A. Harrity, J.
ple, I2/NBS-mediated cyclization of 1j produced prod- Org. Chem. 2010, 75, 984987.
uct 2j in only 45 % yield. [24] I. Bouabdallah, R. Touzani, I. Zidane, A. Ramdani, S.
[17] Taking indazole 2j as an example, the removal of the p- Radi, ARKIVOC (Gainesville, FL, U.S.A.) 2006, 138
nitrophenyl group by NaOEt in DMSO at 120 8C af- 144.
fords the unprotected 1H-indazole 2j in 79% yield. [25] X.-J. Wang, J. Tan, K. Grozinger, R. Betageri, T. Kir-
[18] Y.-P. Zhu, Z. Fei, M.-C. Liu, F.-C. Jia, A.-X. Wu, Org.
rane, J. R. Proudfoot, Tetrahedron Lett. 2000, 41, 5321
Lett. 2013, 15, 378381.
5324.
[19] CCDC 1558444 (3ae) contains the supplementary crys-
tallographic data for this paper. These data can be ob-

Adv. Synth. Catal. 2017, 359, 3378 3387 3387 V 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim