Divergent Synthesis of 1H-Indazoles and 1H-Pyrazoles from Hydrazones via Iodine-Mediated Intramolecular Aryl and sp3 C–H Amination

Article abstract of DOI:10.1002/adsc.201700824

A divergent intramolecular C–H amination of hydrazones has been developed employing molecular iodine (I₂) as the sole oxidant. The required hydrazone substrates were readily obtained by condensation of hydrazines with the corresponding ketones.

Full text of DOI:10.1002/adsc.201700824

Title: Divergent Synthesis of 1H-Indazoles and 1H-Pyrazoles from
Hydrazones via Iodine-Mediated Intramolecular Aryl and sp3 C
−H Amination
Authors: Wei Wei, Zhen Wang, Xikang Yang, Wenquan Yu, and
Junbiao Chang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700824
Link to VoR: http://dx.doi.org/10.1002/adsc.201700824

10.1002/adsc.201700824
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Divergent Synthesis of 1H-Indazoles and 1H-Pyrazoles from
Hydrazones via Iodine-Mediated Intramolecular Aryl and sp3 C−H
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, China
Fax: +86-(0)371-6778-1588; Phone: +86-(0)371-6778-1788; E-mail: wenquan_yu@zzu.edu.cn;
changjunbiao@zzu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A divergent intramolecular C−H amination of hydrazones were transformed into 1H-pyrazole products
hydrazones has been developed employing molecular in a reaction involving sp3 C−H amination. This synthetic
iodine (I2) as the sole oxidant. The required hydrazone methodology does not involve transition metals, and is
substrates were readily obtained by condensation of operationally simple, providing facile access to indazole
hydrazines with the corresponding ketones. In the presence and pyrazole derivatives in an efficient and scalable
of potassium iodide, I2-mediated oxidative cyclization of fashion.
diaryl and tert-butyl aryl ketone hydrazones produced 1H- Keywords: iodine; C−H amination; 1H-indazole; 1H-
indazoles via direct aryl C−H amination. Under similar pyrazole; hydrazone
reaction conditions, primary and secondary alkyl ketone
attention in recent years owing to its advantages, such
as the rich source of hydrocarbons, high step
efficiency and atom economy. Previously, we
established several C‒H amination reactions
employing molecular iodine as the sole oxidant under
transition-metal-free conditions to produce hetero-
cycles, such as, pyrazoles,[13] triazolopyridines,[14] and
benzimidazoles.[15] As a continuation of this work, we
describe in this paper I2-mediated cyclization
reactions of readily accessible hydrazones for
synthesis of 1H-indazoles and 1H-pyrazoles via
intramolecular aryl and sp3 C−H amination reactions,
respectively.
Introduction
N-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] including anti-
inflammatory[2] and antimicrobial drugs,[3] kinase
inhibitors,[4] and anti-HIV agents.[5] Derivatives of
these N-heterocyclic compounds also find widespread
applications in agricultural chemistry[6] and material
science[7] and consequently, considerable research
efforts have been devoted to their synthesis.[1b-e,
8]
Recently, several approaches involving intra-
molecular C−H 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
elegant methods, but they have drawbacks, such as
limited substrate scopes or low yields due to the
relative instability of hydrazone substrates. Thus it is
important to develop simpler and more efficient
approaches, especially those that could lead to either
of these heterocyclic frameworks.
Carbon−nitrogen (C−N) bond formation is one of
the most fundamental and important reactions in
organic synthesis. In earlier decades, transition metal-
catalyzed coupling reactions, especially Buchwald-
Hartwig amination,[11] have become powerful and
reliable 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
Results and Discussion
The required hydrazone substrates can be readily
obtained by the condensation of hydrazines with the
corresponding ketones. The I2/KI-mediated oxidative
cyclization of 1a using K2CO3 as the base in 1,2-
dichloroethane (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
accelerates the conversion rate and results in a
slightly improved yield (entry 2). Further screening
of a series of commonly used solvents (entries 3−8)
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 product 2a with a higher yield (entry 3)
than under reflux (entry 4). Replacement of K2CO3
1
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10.1002/adsc.201700824
Advanced Synthesis & Catalysis
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
produces 2a with a significantly improved yield
(entry 10). The reaction can also be conveniently
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 C−H amination reactions, and in the
absence of KI, the yield of the product was slightly
reduced (entry 12).
hydrolysis can be observed by TLC. In light of the
low stability of the 4-methoxy substituted hydrazone
(1d), this intermediate was not isolated. Upon the
completion of the first-step condensation, the solvent
was removed and the resulting 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−k, and 2n) in good
yields.[16] The relatively low yield of N-tert-butyl
indazole 2p could be due to the poor stability of the
corresponding intermediate (1p).
Table 1. Optimization of the Reaction Conditions for 1H-
Indazole Synthesisa
entry
1
base
additive
KI
solvent
DCE
temp
rt
time/h yieldb
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
NaOAc
KOAc
NaOAc
1
0.5
0.5
0.5
1.5
1
38%
45%
61%
44%
53%
43%
trace
trace
52%
85%d
59%
79%
2
KI
DCE
reflux
rt
3
KI
toluene
toluene
1,4-dioxane
DMF
4
KI
reflux
refluxc
100 ºCc
80 ºCc
100 ºC
rt
5
KI
6
KI
7
KI
DMSO
DMSO
toluene
toluene
toluene
toluene
1
8
KI
0.5
3
9
KI
10
11
12
KI
KI
refluxc
reflux
reflux
4
4
−
2
aOptimal reaction conditions (entry 10): 1a (0.5 mmol), I2
(1 mmol), KI (1.05 mmol), NaOAc (2.25 mmol), toluene,
b
c
reflux. Isolated yields are given. The conversion rate is
d
slow at lower temperatures. The yields for both 0.5 and 6
mmol scale.
Scheme 1. Substrate scope of the R3 group for indazole
synthesis. Optimal reaction conditions: 1 (0.5 mmol), I2 (1
mmol), KI (1.05 mmol), NaOAc (2.25 mmol), toluene,
Having established the optimal reaction conditions,
we examined the substrate scope of the reaction. A
variety of hydrazones were then subjected to the
above oxidative cyclization conditions (Scheme 1).
The present synthetic method is compatible with both
electron-donating groups (EDGs) and electron-
withdrawing groups (EWGs) - R3 on the N-phenyl
ring (2a−o). Generally, substrates bearing EWGs
(2e−o) produce the corresponding products in higher
yields than EDG-substituted compounds (2b−d) do.
This could be because the presence of EWGs can
increase the stability of the hydrazone substrates,
diminishing the hydrolysis side reactions. During the
cyclization of hydrazones bearing EDGs, the
corresponding diaryl ketone by-products, formed by
a
reflux (isolated yields are given). The reaction is carried
out without isolation of the hydrazone substrates.
bChlorobenzene is used as the solvent.
Hydrazones derived from substituted diphenyl
ketones can also be cyclized successfully, forming
the corresponding 1H-indazoles (2q−z) (Scheme 2),
with the p-methoxyphenyl compound giving the best
yield (2r). Good regioselectivity is observed in the
cyclization of substrates from unsymmetrical diaryl
ketones (2v−z). The presence of EDGs favors the
2
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10.1002/adsc.201700824
Advanced Synthesis & Catalysis
cyclization process, with methoxy substitution giving
the best selectivity (2w).
relatively lower yields for pyrazole synthesis due to
the formation of corresponding ketones and some
other byproducts 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 crystallography.[19] The isobutyl-
containing substrate (1ah) is converted into a 4,5-
dimethylpyrazole product (3ah) via a 1,2-methyl
migration process. A plausible mechanism for this
transformation is proposed in Scheme 3C.
Table 2. Substrate scope of R2 group for pyrazole
synthesisa
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),
a
toluene, reflux (isolated yields are given). Chlorobenzene
b
was used as the solvent. The ratios were determined by
1HNMR.
Encouraged by the successful cyclization of diaryl
ketone hydrazones, we continued to explore the
substrate scope, replacing the aromatic R2 group with
aliphatic groups. Considering that EWGs can increase
the stability of hydrazones and the para-nitrophenyl
(PNP) group can be removed[17] for further
derivatization, 4-nitrohydrazine 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 cyclization conditions, but the reaction of
methyl ketone 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
(3ac−ah) (Table 2) instead were formed in moderate
to good yields in place of the indazoles. This reaction
involves sp3 C−H amination (see Scheme 3B). The
aOptimal reaction conditions: 1 (0.5 mmol), I2 (1 mmol),
b
NaOAc (2.25 mmol), toluene, reflux. Isolated yields are
c
given. The reaction resulted in the dihydropyrazole G as
the major product which was further converted into 3ac by
DDQ (see the Experimental Section). dChlorobenzene was
used as the solvent.
Tentative mechanisms for these I2-mediated C−H
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
concomitant electrocyclic ring closure to give
intermediate B. Finally, subsequent deprotonation by
base affords the 1H-indazole framework 2a. In the
case of the hydrazone 1ac, the resulting iodide
3
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10.1002/adsc.201700824
Advanced Synthesis & Catalysis
General Information. 1H 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 tetramethylsilane (TMS) as an
internal standard. The peak patterns are indicated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; dd, doublet of doublets, td, triplet of doublets.
The coupling constants (J) are reported in Hertz (Hz).
Melting points were determined on a micromelting point
apparatus without corrections. High-resolution mass
spectra (HRMS) were obtained on a Q-TOF Mass
Spectrometer equipped with an electrospray ion source
(ESI), operated in the positive mode. Flash column
chromatography was performed over silica gel 200–300
mesh, and the eluent was a mixture of CH2Cl2/petroleum
ether (PE) or EtOAc/PE.
intermediate C may undergo β-elimination to produce,
after tautomerization,
a
vinyl hydrazone E.
results in
Intramolecular cycloadditon of
E
dihydropyrazoles F and G. The intermediate G was
1
been isolated and characterized by HNMR and MS
(see the Experimental Section). Further oxidative
aromatization of the dihydropyrazole(s) affords the
pyrazole product 3ad. For the reaction 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. Subsequent
deprotonation of J by base leads to the 4,5-dimethyl
pyrazole 3ah.
General Procedure A for the Preparation of Hydrazone
Substrates 1. A mixture of a ketone (3 mmol), the
corresponding hydrazine (3.6 mmol, or 4.5 mmol of
hydrazine hydrochloride, and AcOH (174 µL, 3 mmol; or
295 mg, 3.6 mmol of NaOAc) in EtOH (5 mL) was heated
to reflux until TLC indicated the disappearance of the
ketone (12−24 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 the
synthesis of 2h, 2j−k, 2n, 2aa) was stirred at room
temperature for 10 min, then treated with the hydrazone
substrate 1 (0.5 mmol) and NaOAc (185 mg, 2.25 mmol)
in sequence, and finally heated to reflux. If the reaction
was not complete within 4 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 × 10 mL). The combined organic layer was washed with
brine (10 mL), dried over anhydrous Na2SO4, and
concentrated. The given residue was purified by column
chromatography through silica gel to afford the 1H-
indazole 2.
1,3-Diphenyl-1H-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,
Scheme 3. Proposed Mechanism for the I2-Mediated C−H
Amination Reactions
1
mp 96-98 ºC (lit.[20] mp 95-98 ºC); H NMR (400 MHz,
CDCl3): δ 8.08 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 7.2 Hz,
2H), 7.79 (t, J = 8.0 Hz, 3H), 7.54 (dd, J = 15.2, 7.6 Hz,
4H), 7.44 (dd, J = 15.6, 8.0 Hz, 2H), 7.36 (t, J = 7.6 Hz,
1H), 7.28 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 146.1, 140.4, 140.2, 133.3, 129.5, 128.9, 128.3,
127.8, 127.1, 126.7, 123.2, 123.0, 122.0, 121.6, 110.7;
HRMS (m/z) [M + H]+ calcd for C19H15N2 271.1230, found
271.1231.
Conclusion
In summary, the intramolecular C−H amination
reactions 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 C−H amination. Oxidative
cyclization of primary and secondary alkyl ketone
substrates affords the corresponding 1H-pyrazole
products in a process involving sp3 C−H amination.
This transition-metal free synthetic approach to
indazoles and pyrazoles is operationally simple and
broadly applicable to a variety of easily accessible
hydrazone substrates. The reaction can be
conveniently conducted on a gram scale.
3-Phenyl-1-(p-tolyl)-1H-indazole (2b). 2 h (1 mmol of
I2); eluent: CH2Cl2/PE 20:80; yield: 125 mg, 88%; white
1
solid, mp 92-93 ºC (lit.[9d] mp 88-90 ºC); H NMR (400
MHz, CDCl3): δ 8.07 (d, J = 8.4 Hz, 1H), 8.05-8.03 (m,
2H), 7.73 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H),
7.52 (t, J = 7.2 Hz, 2H), 7.45-7.40 (m, 2H), 7.34 (d, J = 8.4
Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 2.43 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for
C20H17N2 285.1386, found 285.1388.
1-(4-Isopropylphenyl)-3-phenyl-1H-indazole (2c). 2 h (1
mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 129 mg, 83%;
1
colorless oil; H NMR (400 MHz, CDCl3): δ 8.08 (d, J =
8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz,
1H), 7.69 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H),
7.46-7.39 (m, 4H), 7.27 (t, J = 8.0 Hz, 1H), 3.05-2.95 (m,
Experimental Section
4
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10.1002/adsc.201700824
Advanced Synthesis & Catalysis
1H), 1.31 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz,
CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for C22H21N2 313.1699,
found 313.1691.
1-(4-Nitrophenyl)-3-phenyl-1H-indazole (2j). 10 h (2
mmol of I2); eluent: CH2Cl2/PE 25:75; yield: 157 mg, 99%;
1
yellow solid, mp 162-163 ºC (lit.[9a] mp 160-162 ºC); H
NMR (400 MHz, CDCl3): δ 8.39 (d, J = 9.2 Hz, 2H), 8.09
(d, J = 8.0 Hz, 1H), 8.04-8.01 (m, 4H), 7.87 (d, J = 8.4 Hz,
1H), 7.57-7.53 (m, 3H), 7.50-7.46 (m, 1H), 7.36 (t, J = 7.6
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd
for C19H14N3O2 316.1081, found 316.1083.
1-(4-Methoxyphenyl)-3-phenyl-1H-indazole (2d). After
the condensation of diphenyl ketone (0.5 mmol) and
hydrazine salt (0.9 mmol), prepared according to General
Procedure A was complete, the reaction mixture was
concentrated and the resulting crude hydrazone (1d) was
directly subjected to the General Procedure B. 2 h (1.5
mmol of I2); eluent: CH2Cl2/PE 35:65; yield: 110 mg, 73%;
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): δ 8.10 (d,
J = 8.4 Hz, 1H), 8.05 (d, J = 7.6 Hz, 2H), 7.63-7.58 (m,
2H), 7.52 (d, J = 7.6 Hz, 2H), 7.46-7.41 (m, 4H), 7.31-7.26
(m, 2H); 13C NMR (100 MHz, CDCl3): δ 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; HRMS
(m/z) [M + H]+ calcd for C19H14ClN2 305.0840, found
305.0850.
1
white solid, mp 128-129 ºC (lit.[9b] mp 129-131 ºC); H
NMR (400 MHz, CDCl3): δ 8.07 (d, J = 8.0 Hz, 1H), 8.05-
8.03 (m, 2H), 7.68-7.65 (m, 3H), 7.52 (t, J = 7.6 Hz, 2H),
7.44-7.40 (m, 2H), 7.26 (m, 1H, overlapped with the peak
of chloroform), 7.08-7.04 (m, 2H), 3.87 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for
C20H17N2O 301.1335, found 301.1337.
1-(3-Chlorophenyl)-3-phenyl-1H-indazole (2l).[9c] 6 h
(1.5 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 131 mg,
86%; colorless oil.; 1H NMR (400 MHz, CDCl3): δ 8.07 (d,
J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.84 (s, 1H),
7.77 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.53 (t, J
= 8.0 Hz, 2H), 7.49-7.42 (m, 3H), 7.33-7.24 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+
calcd for C19H14ClN2 305.0840, found 305.0849.
1-(4-Fluorophenyl)-3-phenyl-1H-indazole (2e).[9c] 6 h (1
mmol of I2); eluent: CH2Cl2/PE 25:75; yield: 137 mg, 95%;
1
white solid, mp 114-115 ºC; H NMR (400 MHz, CDCl3):
δ 8.08 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.76-
7.72 (m, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.53 (t, J = 7.2 Hz,
2H), 7.47-7.41 (m, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.26-7.21
(m, 2H, overlapped with the peak of chloroform); 13C
NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+
calcd for C19H14FN2 289.1136, found 289.1131.
1-(2,4-Dichlorophenyl)-3-phenyl-1H-indazole (2m).[9b]
10 h (2 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 169
1
mg, 99%; colorless oil; H NMR (400 MHz, CDCl3): δ
1-(4-Chlorophenyl)-3-phenyl-1H-indazole (2f).[9c] 5 h (1
8.09 (d, J = 8.0 Hz, 1H), 8.04-8.02 (m, 2H), 7.63 (d, J =
2.0 Hz, 1H), 7.54-7.50 (m, 3H), 7.46-7.41 (m, 3H), 7.30 (t,
J = 7.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H, overlapped with
the peak of chloroform); 13C NMR (100 MHz, CDCl3): δ
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; HRMS (m/z) [M + Na]+ calcd for C19H12Cl2N2Na
361.0270, found 361.0270.
mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 148 mg, 97%;
1
white solid, mp 121-122 ºC; H NMR (400 MHz, CDCl3):
δ 8.08 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.76-
7.72 (m, 3H), 7.75-7.42 (m, 6H), 7.29 (d, J = 7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for
C19H14ClN2 305.0840; found 305.0847.
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 95-98 ºC; 1H NMR (400 MHz,
CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 8.04-8.02 (m, 2H), 7.62
(d, J = 2.4 Hz, 1H), 7.53 (t, J = 8.4 Hz, 3H), 7.47-7.40 (m,
3H), 7.32-7.27 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
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; HRMS (m/z) [M + H]+ calcd for C19H13Cl2N2
339.0450, found 339.0442.
1-(4-Bromophenyl)-3-phenyl-1H-indazole (2g).[21] 5 h (1
mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 167 mg, 96%;
1
white solid, mp 123-124 ºC; H NMR (400 MHz, CDCl3):
δ 8.07 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 7.2 Hz, 2H), 7.73-
7.63 (m, 5H), 7.52 (t, J = 7.6 Hz, 2H), 7.47-7.41 (m, 2H),
7.28 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
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; HRMS
(m/z) [M + H]+ calcd for C19H14BrN2 349.0335, found
349.0331.
3-Phenyl-1-(2,4,6-trichlorophenyl)-1H-indazole (2o).[9c]
4-(3-Phenyl-1H-indazol-1-yl)benzonitrile (2h).[9c] 8 h
12 h (2 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 185
1
(1.5 mmol of I2); eluent: EtOAc/PE 15:85; yield: 130 mg,
mg, 99%; colorless oil; H NMR (400 MHz, CDCl3): δ
1
88%; white solid, mp 161-163 ºC; H NMR (400 MHz,
8.11 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.55-
7.51 (m, 4H), 7.47-7.42 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H),
7.11 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ
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; HRMS
(m/z) [M + H]+ calcd for C19H12Cl3N2 373.0061, found
373.0052.
CDCl3): δ 8.09 (d, J = 8.4 Hz, 1H), 8.03-7.97 (m, 4H),
7.85-7.81 (m, 3H), 7.57-7.45 (m, 4H), 7.35 (t, J = 7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+
calcd for C20H14N3 296.1182, found 296.1175.
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 137-139 ºC; 1H NMR
(400 MHz, CDCl3): δ 8.10 (d, J = 8.0 Hz, 1H), 8.04-8.02
(m, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.82 (t, J = 9.2 Hz, 3H),
7.56-7.44 (m, 4H), 7.33 (t, J = 7.6 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for C20H14F3N2
339.1104, found 339.1104.
1-(Tert-butyl)-3-phenyl-1H-indazole (2p). After the
condensation 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
1
104-106 ºC; H NMR (400 MHz, CDCl3): δ 8.02 (d, J =
8.4 Hz, 1H), 7.98-7.96 (m, 2H), 7.72 (d, J = 8.8 Hz, 1H),
7.48 (t, J = 8.0 Hz, 2H), 7.38-7.32 (m, 2H), 7.19-7.15 (m,
1H), 1.83 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 141.9,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700824
Advanced Synthesis & Catalysis
139.6, 134.2, 128.7, 127.6, 127.5, 125.2, 123.3, 121.5,
120.4, 112.4, 59.8, 29.8; HRMS (m/z) [M + H]+ calcd for
C17H19N2 251.1543, found 251.1547.
121.3,110.7, 21.4; HRMS (m/z) [M + H]+ calcd for
C20H17N2 285.1386; found 285.1382.
6-Methoxy-1,3-diphenyl-1H-indazole (2w). 2 h (1 mmol
6-Methyl-1-phenyl-3-(p-tolyl)-1H-indazole (2q). 2 h (1
of I2); eluent: CH2Cl2/PE 33:67; yield: 120 mg, 80%; white
1
mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 117 mg, 79%;
solid, mp 137-139 ºC (lit.[10a] mp 138-140 ºC); H NMR
1
white solid, mp 90-92 ºC (lit.[9b] mp 88-90 ºC); H NMR
(400 MHz, CDCl3): δ 8.02-8.00 (m, 2H), 7.93 (d, J = 8.8
Hz, 1H), 7.78 (d, J = 6.8 Hz, 2H), 7.58-7.50 (m, 4H), 7.44-
7.36 (m, 2H), 7.12 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.88 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+
calcd for C20H17N2O 301.1335; found 301.1344.
(400 MHz, CDCl3): δ 7.94-7.91 (m, 3H), 7.78 (d, J = 7.6
Hz, 2H), 7.56-7.52 (m, 3H), 7.37-7.31 (m, 3H), 7.10 (d, J
= 8.4 Hz, 1H), 2.51 (s, 3H), 2.43 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for
C21H19N2 299.1543, found 299.1534.
3-(4-Fluorophenyl)-1-phenyl-1H-indazole (2x) and 6-
fluoro-1,3-diphenyl-1H-indazole (2xʹ).[9c] 2 h (1 mmol of
I2); eluent: CH2Cl2/PE 25:75; yield: 119 mg, 83% (2x:2x'
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 135-136 ºC (lit.[9a] mp 132-
1
1
= 80:20 by H NMR); white solid, mp 96-98 ºC; H NMR
134 ºC); 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.8 Hz, (400 MHz, CDCl3): δ 8.02-7.97 (m, 3H), 7.79-7.73 (m,
2H), 7.89 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H),
7.54 (t, J = 8.0 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.10 (d, J
= 2.0 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.91 (dd, J = 8.8,
2.0 Hz, 1H), 3.87 (s, 6H); 13C NMR (100 MHz, CDCl3): δ
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;
HRMS (m/z) [M + H]+ calcd for C21H19N2O2 331.1441;
found 331.1441.
2.8H), 7.56-7.50 (m, 2.4H), 7.46-7.35 (m, 2.2H), 7.28 (t, J
= 8.0 Hz, 0.8H), 7.23-7.19 (m, 1.6H, overlapped with the
peak of chloroform), 7.03 (td, J = 8.8, 2.0 Hz, 0.2H); 13C
NMR (100 MHz, CDCl3): 2x: δ 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, 121.4, 116.0, 115.8, 110.8; 2xʹ: δ 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);
HRMS (m/z) [M + H]+ calcd for C19H14FN2 289.1136;
found 289.1138.
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 137-138 ºC (lit.[10a] mp 135-137 ºC);
1H NMR (400 MHz, CDCl3): δ 7.98-7.93 (m, 3H), 7.73 (d,
J = 7.6 Hz, 2H), 7.56 (t, J = 7.6 Hz, 2H), 7.42-7.37 (m,
2H), 7.22 (t, J = 8.8 Hz, 2H), 7.05 (td, J = 8.8, 2.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): δ 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
3-(4-Chlorophenyl)-1-phenyl-1H-indazole (2y) and 6-
chloro-1,3-diphenyl-1H-indazole (2yʹ).[9a] 4 h (1 mmol of
I2); eluent: CH2Cl2/PE 25:75; yield: 122 mg, 80% (2y:2y'
1
1
= 85:15 by H NMR); white solid, mp 114-117 ºC; H
NMR (CDCl3, 400 MHz): δ 8.03-7.96 (m, 3H), 7.78-7.73
(m, 3H), 7.57-7.44 (m, 5H), 7.40-7.36 (m, 1H), 7.29 (d, J =
7.2 Hz, 0.85H), 7.25-7.22 (m, 0.15H, overlapped with the
peak of chloroform); 13C NMR (100 MHz, CDCl3): 2y: δ
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; 2yʹ: δ
146.2, 140.8, 139.6, 133.7, 132.7, 129.6, 128.6, 127.8,
127.2, 122.6, 121.7, 110.5; HRMS (m/z) [M + H]+ calcd
for C19H14ClN2 305.0840; found 305.0831.
(d, JC-F = 21.6 Hz), 111.8 (d, JC-F = 25.7 Hz), 96.7 (d, JC-F
=
26.9 Hz); HRMS (m/z) [M + H]+ calcd for C19H13F2N2
307.1041; found 307.1046.
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 153-154 ºC (lit.[10a] mp 150-151 ºC);
1H NMR (400 MHz, CDCl3): δ 7.94-7.90 (m, 3H), 7.74-
7.71 (m, 3H), 7.56 (t, J = 8.4 Hz, 2H), 7.49 (d, J = 8.8 Hz,
2H), 7.41 (t, J = 7.6 Hz, 1H), 7.26-7.23 (m, 1H, overlapped
with the peak of chloroform); 13C NMR (100 MHz,
CDCl3): δ 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;
HRMS (m/z) [M + H]+ calcd for C19H13Cl2N2 339.0450;
found 339.0455.
3-(4-Bromophenyl)-1-phenyl-1H-indazole (2z)[10a] and
6-bromo-1,3-diphenyl-1H-indazole (2zʹ). 4 h (1 mmol of
I2); eluent: CH2Cl2/PE 25:75; yield: 138 mg, 79% (2z:2z' =
1
80:20 by 1H NMR); white solid, mp 147-150 ºC; H NMR
(CDCl3, 400 MHz): δ 8.03 (d, J = 8.0 Hz, 0.8H), 7.99-7.93
(m, 0.4H), 7.93-7.91 (m, 2H), 7.78-7.73 (m, 2.8H), 7.65-
7.63 (m, 1.6H), 7.57-7.50 (m, 2.4H), 7.47-7.43 (m, 1H),
7.39-7.35 (m, 1.2H), 7.31-7.29 (m, 0.8H); 13C NMR (100
MHz, CDCl3): 2z: δ 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; 2zʹ: δ 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; HRMS (m/z) [M + H]+ calcd for C19H13BrN2
349.0335; found 349.0331.
6-Bromo-3-(4-bromophenyl)-1-phenyl-1H-indazole (2u).
5 h (1 mmol of I2); eluent: CH2Cl2/PE 20:80; yield: 169 mg,
1
79%; white solid, mp 152-154 ºC; H NMR (400 MHz,
CDCl3): δ 7.92 (d, J = 1.2 Hz, 1H), 7.87-7.85 (m, 3H),
7.73-7.71 (m, 2H), 7.66-7.63 (m, 2H), 7.57 (t, J = 8.0 Hz,
2H), 7.43-7.37 (m, 2H); 13C NMR (100 MHz, CDCl3): δ
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; HRMS
(m/z) [M + Na]+ calcd for C19H12Br2N2Na 448.9259, found
448.9233.
3-(Tert-butyl)-1-(4-nitrophenyl)-1H-indazole (2aa).[22]
10 h (2 mmol of I2); eluent: CH2Cl2/PE 40:60; yield: 147
1
mg, 99%; yellow solid, mp 128-130 ºC; H NMR (400
MHz, CDCl3): δ 8.38 (d, J = 9.2 Hz, 2H), 7.99-7.95 (m,
3H), 7.84 (d, J = 8.8 Hz, 1H), 7.50-7.46 (m, 1H), 7.29-7.25
(m, 1H), 1.59 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
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; HRMS (m/z) [M + H]+
calcd for C17H18N3O2 296.1394, found 296.1389.
6-Methyl-1,3-diphenyl-1H-indazole (2v) and 1-phenyl-
3-(p-tolyl)-1H-indazole (2vʹ).[9b] 2 h (1 mmol of I2);
eluent: CH2Cl2/PE 25:75; yield: 116 mg, 82% (2v:2v' =
1
77:23 by 1H NMR); white solid, mp 114-116 ºC; H NMR
(400 MHz, CDCl3): δ 8.08-8.02 (m, 1.77H), 7.96-7.93 (m,
1.23H), 7.80-7.76 (m, 2.23H), 7.56-7.50 (m, 4.31H), 7.46-
7.32 (m, 2.46H), 7.27 (t, J = 8.0 Hz, 0.23H), 7.11 (d, J =
8.4 Hz, 0.77H), 2.51 (s, 2.31H), 2.43 (s, 0.69H); 13C NMR
(100 MHz, CDCl3): 2v: δ 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; 2vʹ: δ 146.2, 140.33, 140.2,
138.2, 130.4, 127.69, 127.1, 123.2, 123.0, 121.8, 121.7,
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 °C 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 × 10 mL).
The combined organic layer was dried over anhydrous
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700824
Advanced Synthesis & Catalysis
Na2SO4, concentrated, and then purified through column
chromatography through silica gel to afford 1H-indazole
2jʹ.[9c] Eluent: EtOAc/PE 16:84; yield: 77 mg, 79%; light-
brown solid, mp 102-103 ºC; 1H NMR (400 MHz, CDCl3):
δ 11.64 (br, s, 1H), 8.02 (dd, J = 8.0, 0.8 Hz, 3H), 7.54 (t, J
= 7.6 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.36-7.33 (m, 1H),
7.25-7.19 (m, 2H, overlapped with the peak of
chloroform); 13C NMR (100 MHz, CDCl3): δ 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) [M + H]+ calcd for C13H11N2 195, found
195.
28.8, 27.0, 22.7, 14.1; HRMS (m/z) [M + H]+ calcd for
C24H30N3O2 392.2333, found 392.2320.
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 150-152 ºC; 1H
NMR (400 MHz, CDCl3): δ 8.31 (d, J = 9.2 Hz, 2H), 7.83-
7.79 (m, 4H), 7.46-7.42 (m, 2H), 7.38-7.34 (m, 1H); 2.88-
2.86 (m, 2H), 2.81-2.79 (m, 2H), 1.90-1.85 (m, 4H); 13C
NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for C19H18N3O2
320.1394, found 320.1393.
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
toluene (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 × 10
mL). The combined organic layer was washed with brine
(10 mL), dried over anhydrous Na2SO4, and concentrated.
The given residue was purified by column chromatography
through silica gel to afford the 1H-pyrazole 3.
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 114-116 ºC; 1H NMR
(400 MHz, CDCl3): δ 8.33 (d, J = 9.2 Hz, 2H), 7.76-7.71
(m, 4H), 7.47-7.31 (m, 2H), 7.39-7.36 (m, 1H), 2.42 (s,
3H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 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; HRMS (m/z) [M + H]+ calcd for
C17H16N3O2 294.1237, found 294.1234.
Acknowledgements
1-(4-Nitrophenyl)-3-phenyl-1H-pyrazole
(3ac).
According to the General Procedure C for 2 h (1 mmol of
I2), the dihydropyrazole G was formed as the major
product [eluent: CH2Cl2/PE 50:50, yellow soild; 1H NMR
(400 MHz, CDCl3): δ 8.15 (d, J = 9.2 Hz, 2H), 7.75-7.74
(m, 2H), 7.43-7.38 (m, 3H), 7.03 (d, J = 9.2 Hz, 2H), 3.96
(t, J = 10.4 Hz, 2H), 3.35 (t, J = 10.4 Hz, 2H); MS (m/z)
[M + H]+ calcd for C15H14N3O2 268, found 268]. A solution
of the crude intermediate G above in toluene (5 mL) was
treated with DDQ (0.25 mmol) and refluxed for 1 h to
afford pyrazole 3ac. Eluent: CH2Cl2/PE 33:67; yield: 66
mg, 50% (from the hydrazone); yellow solid, mp 168-170
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
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Gaikwad, A. D. Chapolikar, C. G. Devkate, K. D.
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Med. Chem. 2015, 90, 707-731; c) A. Schmidt, A.
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1
ºC (lit.[23] mp 170-173 ºC); H NMR (400 MHz, CDCl3): δ
8.33 (d, J = 9.2 Hz, 2H), 8.04 (d, J = 2.8 Hz, 1H), 7.94-
7.91 (m, 4H), 7.47-7.44 (m, 2H), 7.40-7.36 (m, 1H), 6.86
(d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 154.5,
145.2, 144.4, 132.2, 128.83, 128.79, 128.3, 126.0, 125.4,
118.3, 106.9; HRMS (m/z) [M + H]+ calcd for C15H12N3O2
266.0924, found 266.0925.
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 119-121 ºC (lit.[24] mp 124-125
1
ºC); H NMR (400 MHz, CDCl3): δ 8.34 (d, J = 8.8 Hz,
2H), 7.85 (d, J = 7.2 Hz, 2H), 7.77 (d, J = 9.2 Hz, 2H),
7.44-7.40 (m, 2H), 7.36-7.33 (m, 1H), 6.59 (s, 1H), 2.50 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 152.9, 145.9, 145.0,
140.6, 132.6, 128.7, 128.4, 125.9, 124.8, 123.8, 106.6,
13.4; HRMS (m/z) [M + H]+ calcd for C16H14N3O2
280.1081, found 280.1077.
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5-Ethyl-1-(4-nitrophenyl)-3-phenyl-1H-pyrazole
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1
yield: 108 mg, 74%; yellow solid, mp 110-111 ºC; H
NMR (400 MHz, CDCl3): δ 8.35 (d, J = 9.2 Hz, 2H), 7.88-
7.86 (m, 2H), 7.75 (d, J = 9.2 Hz, 2H), 7.44-7.41 (m, 2H),
7.37-7.33 (m, 1H), 6.63 (s, 1H), 2.83 (q, J = 14.8, 7.2 Hz,
2H), 1.34 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 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; HRMS (m/z) [M +
H]+ calcd for C17H16N3O2 294.1237, found 294.1239.
[3] a) X. Li, S. Chu, V. A. Feher, M. Khalili, Z. Nie, S.
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84%; yellow solid, mp 76-77 ºC; H NMR (400 MHz,
CDCl3): δ 8.36 (d, J = 8.8 Hz, 2H), 7.88-7.85 (m, 2H), 7.74
(d, J = 9.2 Hz, 2H), 7.44-7.40 (m, 2H), 7.36-7.33 (m, 1H),
6.62 (s, 1H), 2.77 (t, J = 7.6 Hz, 2H), 1.73-1.66 (m, 2H),
1.39-1.26 (m, 12H), 0.89-0.86 (m, 3H); 13C NMR (100
MHz, CDCl3): δ 152.9, 146.1, 145.8, 145.2, 132.6, 128.7,
128.4, 125.8, 124.7, 124.6, 104.8, 31.9, 29.4, 29.3, 29.2,
7
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10.1002/adsc.201700824
Advanced Synthesis & Catalysis
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8
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10.1002/adsc.201700824
Advanced Synthesis & Catalysis
FULL PAPER
Divergent Synthesis of 1H-Indazoles and 1H-
Pyrazoles from Hydrazones via Iodine-Mediated
Intramolecular Aryl and sp3 C−H Amination
Adv. Synth. Catal. Year, Volume, Page – Page
Wei Wei, Zhen Wang, Xikang Yang, Wenquan
Yu,* and Junbiao Chang*
9
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