Metal-Free Synthesis of Pyrazoles from 1,3-Diarylpropenes and Hydrazines via Multiple Inter-/Intramolecular C–H Aminations

Article abstract of DOI:10.1002/adsc.201700196

A facile and metal-free access to pyrazoles from 1,3-diarylpropenes and hydrazines via multiple inter-/intramolecular C-H aminations was described. Under the neutral and mild 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) oxidative conditions, various disubstituted pyrazoles were synthesized in moderate to excellent yields. This method provides a pot- and step-economic strategy for the construction of pyrazoles, especially those for drug discovery. (Figure presented.).

Full text of DOI:10.1002/adsc.201700196

Title: Metal-Free Synthesis of Pyrazoles from 1,3-Diarylpropenes and
Hydrazines via Multiple Inter-/Intramolecular C-H Aminations
Authors: Li Tang, Minyang Ma, Qi Zhang, Huan Luo, Tao Wang, and
Yonghai Chai
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700196
Link to VoR: http://dx.doi.org/10.1002/adsc.201700196

10.1002/adsc.201700196
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free Synthesis of Pyrazoles from 1,3-Diarylpropenes and
Hydrazines via Multiple Inter-/Intramolecular C-H Aminations
Li Tang,a Minyan Ma,a Qi Zhang,a* Huan Luo,a Tao Wang,a and Yonghai Chaib*
a
School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an, Shaanxi 710119, P. R. China
Phone: (+86)29-81530783; Fax: (+86)29-81530727; Email: qiqizhang@snnu.edu.cn
Key Laboratory of Applied Surface and Colloid Chemistry, MOE, Shaanxi Normal University, Xi'an, Shaanxi 710119,
b
P. R. China
Phone: (+86)29-81530783; Fax: (+86)29-81530727; Email: ychai@snnu.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######.((Please
delete if not appropriate))
Abstract. A facile and metal-free access to pyrazoles from
1,3-diarylpropenes and hydrazines via multiple inter-
/intramolecular C-H aminations was described. Under the
neutral and mild DDQ-oxidative conditions, various di-
substituted pyrazoles were synthesized in moderate to
excellent yields. This method provides a pot- and step-
economy strategy for the construction of pyrazoles,
especially those for drug discovery.
Keywords: Pyrazoles; Multiple C-H aminations; Metal-
free conditions; DDQ; Cascade reaction
cascade reaction of the hydrazone formation and the
C−H bond amination for the preparation of pyrazones
from unsaturated aldehydes/ketones.[6j] These above-
mentioned accesses to pyrazoles were only involved
one-time intramolecular C(sp2)-H amination.
However, to the best of our knowledge, the
construction of pyrazoles directly from hydrazines
and simple hydrocarbon compounds, such as 1,3-
diarylpropenes, via multiple inter-/intramolecular
oxidative C-H aminations has not been reported yet.
We envisioned that with the treatment of a suitable
oxidant, an oxidative cross-coupling of 1,3-
Introduction
As one of the most important heterocyclic
compounds, pyrazoles have been found to possess an
extensive range of pharmacological activities[1] such
as analgesic, anticancer, anti-inflammatory, etc, and
thus play a significant role in drug discovery. Some
pyrazole-containing drugs, such as Celebrex[2],
Sildenafil[3] and Rimonabant[4], are already booming
in the market. Consequently, numerous strategies for
constructing pyrazole rings have been developed,[5,6]
and new facile and green synthetic approaches,
especially for drug industry, still continue to be
pursued.
diarylpropene
1
with nucleophilic hydrazine
NH2NHR1 could occur, providing amination product
3 through an intermolecular C(sp3)N bond formation.
Due to the high atom efficiency and environmental
benignancy, direct C-H bond amination[7-9] has
become a powerful tool for C-N bond formation.
Employing this strategy, diverse N-containing
structural frameworks, including pyrazoles, are
assembled. The Rao[6s]
,
Bao[6r], Jiang[6p]
,
and
Punniyamurthy[6e] groups have reported the
intramolecular oxidative C-H bond amination of
vinyl hydrazones for pyrazoles synthesis under the
catalysis of Ru(II)[6s], Fe(III)[6r], Cu(II) [6p], and V(IV)
[6e], respectively. Recently, the Aggarwal [6u], Zhu[6i],
Desai[6t], and Tanimori[6d] groups have also
accomplished this transformation by using PhI(OAc)2
[6u,6i], DDQ[6t], and Oxone[6d], respectively, as the
oxidant in absence of additives. Additionally, in 2014,
Zhang and co-workers demonstrated an I2-mediated
1
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10.1002/adsc.201700196
Advanced Synthesis & Catalysis
Scheme 1. Our work: synthesis of pyrazoles from 1,3-
diarylpropenes and hydrazines
9
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
FeCl3 DCE
CuCl DCE
CuBr DCE
40
40
40
40
40
40
40
40
40
40
75
10
11
12
13
14
15
16
17
79
76
76
59
74
64
42
65
18
CuI
DCE
When the oxidant was excess, 3 would undergo a
further oxidation to yield vinyl hydrazone 4. The NH
moiety in 4 could then serve as a N-donor in the
following intramolecular amination of vinyl C-H
bond, forming the desired pyrazole ring (Scheme 1).
This oxidative protocol, permitting multiple direct C-
H bond functionalization in one pot, features great
step efficiency and mild metal-free conditions.
CuCl2 DCE
-
-
DCM
CHCl3
CCl4
-
-
CH3NO2
Toluene
18
a)
Unless otherwise noted, all reactions were carried out
with 1a (0.3 mmol), TsNHNH2 (1.4 equiv), oxidant (5
equiv), and catalyst (0.2 equiv) in solvent (3 mL) for 30
b)
min under Ar atmosphere. Yields are given for isolated
c)
Results and Discussion
products. 4 Equivalences of DDQ were used and the
d)
isolated yield was 70%. 3 Equivalences of DDQ were
To test the possibility of our hypothesis, we initially
used and the isolated yield was 49%.
chose
(E)-1,3-diphenylpropene
1a
and
p-
toluenesulfonyl hydrazide (NH2NHTs) as the model
substrates and DDQ as the oxidant (Table 1).
Gratifying, in the presence of 5 equiv of DDQ in
With the optimal conditions in hand, we
subsequently explored the substrate scope of the new
method by using different diaryl-substituted propenes,
and the results are illustrated in Scheme 2. A variety
of symmetric 1,3-diarylpropenes were found to be
compatible with this approach and were easily
converted into the corresponding pyrazoles in
moderate to excellent yields (up to 93%). Generally,
1,3-diarylpropenes with substituents in ortho position
of the aryl ring led to relatively worse outcomes (2d,
2g and 2k, 44%-79%) than those with substituents in
para and/or meta position (2b, 2c, 2e, 2f, 2i, 2j, 2h
and 2n, 47%-93%), indicating that the steric
hindrance from the ortho-substitute on the aryl ring
has big effect on the cascade reaction. Meanwhile,
the electronic effect also impacts this transformation.
Substrates bearing electron-donating groups on the
aryl ring resulted in higher yields while substrates
bearing electron-withdrawing groups resulted in
lower yields. It may be ascribed to the fact that the
substituents of the aryl ring with different electronic
nature have influence on the stability of the proposed
allyl cation intermediate generated by the oxidation
of propene 1. Concretely, the electronic donating
substituents can stabilize this intermediate while the
electronic withdrawing substituent may destabilize it.
Polycyclic aromatic and heteroaromatic substituted
propenes were proved to be also well tolerated under
the optimal conditions and furnished the expected
pyrazoles in moderate to good yields (2o, 2p).
o
DCE at 80 C, the cascade reaction of 1a with
NH2NHTs performed well, giving the expected 3,5-
diphenyl-1-tosylpyrazole 2a in 53% yield after 30
min (Table 1, entry 1). A subsequent investigation on
the effect of temperature showed the best result could
be achieved at 40 oC (Table 1, entries 2-4). It has also
been found that reducing the amount of DDQ resulted
in the decrease of the reaction yield (Table 1, entry 3,
c) and d)). Further studies revealed other commonly
used oxidants, such as BQ, TBHP, and PhI(OAc)2,
could not promote this one-pot transformation (Table
1, entries 5-7). We also attempted to introduce some
iron (II)/(III) or copper (I)/(II) salt catalysts into the
reaction system, but none of them had beneficial
effect on the tandem process (Table 1, entries 8-13).
Reaction in other solvents did not lead to any
improvement in the yield as well (Table 1, entries 14-
18). After detailed screenings mentioned above, the
optimal reaction conditions were finalized with the
use of 1a (0.3 mmol), NH2NHTs (1.4 equiv) and
o
DDQ (5 equiv) in DCE (3 mL) at 40 C for 30 min
(Table 1, entry 3).
Asymmetrically substituted propenes were next
employed in this transformation (Scheme 3). Under
the optimal condition, the cascade reaction of
propenes bearing two different aryl rings still
proceeded smoothly, and the corresponding products
were obtained in good yields as a mixture of two
regioisomers with a varying regioisomeric ratio
(2q/2q’-2u/2u’). The structures of the isomers were
Table 1. Optimization of reaction condition from 1a with
NH2NHTsa)
Entry Oxidant
Cat.
Solv.
Temp. Yield
(oC)
80
60
40
20
40
40
40
40
(%)b)
53
1
2
3
4
5
6
7
8
DDQ
-
-
-
-
-
-
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DDQ
67
80
64
N.D.
N.D.
N.D.
73
DDQc),d)
DDQ
1
determined by comparing the H NMR spectroscopy
with that of the single isomer (see the Supporting
Information for details). The regioisomerism
probably results from the nucleophilic attack of
NH2NHTs at both - and '-positions of the allyl
BQ
TBHP
PhI(OAc)2
DDQ
FeCl2 DCE
2
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10.1002/adsc.201700196
Advanced Synthesis & Catalysis
cation intermediate. Notably, both the electronic
effect and the steric effect play important roles in the
regioselectivity. When the difference in the electronic
nature between the two aryl rings of the propene was
big, higher regioselectivity was observed (2s/2s’
1.4:1, 2t/2t’ 1.5:1 vs. 2q/2q’ 1:1.1, 2r/2r’ 1.1:1). This
is presumably because the positive charge in the allyl
cation intermediate is more distributed on the carbon
adjacent to the relatively electrion-richer aryl ring,
and thus the final pyrazole product, which is
generated from the nucleophilic attack of NH2NHTs
to this carbon, followed by the oxidation and
cyclization, is more. Moreover, the greater the
difference in electronic nature between the two aryl
groups, the more uneven the distribution of the
positive charge at - and '-positions of the allyl
cation, and as a result, the higher the regioselectivity
of the two pyrazole products. Asymmetric substrate
with a bulky aryl ring in one side also led to an
enhanced regioselectivity of this transformation
(2u/2u’ 1.9:1 vs. 2q/2q’ 1:1.1), which probably
attributes that the NH2NHTs tends to attack the less
bulky side of the asymmetric allyl cation. In addition,
same results were achieved by using either (E)-1-(4-
fluorophenyl)-3-
phenylpropene
or
(E)-3-(4-
fluorophenyl)-1-phenyl propene as the substrate,
which again lent proof that an allyl cation
intermediate was involved in the reaction process
(2r/2r’c),d)). However, compound 1v and 1w couldn’t
undergo the oxidative reaction to produce the
anticipated pyrazoles, revealing that this method is
not suitable for mono-aryl substituted propenes (2v,
2w). The reason may be that for di-aryl substituted
propene, the allyl cation intermediate can form a
bigger conjugated system with two aryl groups which
may lower the overall energy of the cation and
increase the stability, while for mono-aryl substituted
propene, the key intermediate, mono-aryl substituted
allyl cation, can only be stabilized by one aryl group
so that it is not stable enough to be generated under
the standard condition.
a)
Unless otherwise noted, all reactions were carried out with 1 (0.3 mmol), TsNHNH2 (1.4 equiv), and DDQ (5 equiv) in
DCE (3 mL) for 30 min under Ar atmosphere. b) Yields are given for isolated product.
Scheme 2 Synthesis of pyrazoles 2 from symmetrically 1,3-disubstituted propenes 1a),b)
3
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10.1002/adsc.201700196
Advanced Synthesis & Catalysis
group, afforded the pyrazolyl acetic acid 6 in 86%
yield. By the treatment of (COCl)2, 6 was converted
into the corresponding chloride, which was then
reacted with 4-aminobenzenesulfonamide to provide
the desired target molecule 7, a potential anti-
inflammatory agent.
o
Scheme 4 Reagents and conditions: a. DDQ/DCE, 40 C,
30 min, 80%; b. Mg/MeOH, rt, 3 h, 95%; c. i) ethyl
bromoacetate/K2CO3/MeCN, reflux, 2 h; ii) NaOH/H2O, rt,
o
4 h, 86%; d. i) (COCl)2/DMF/DCM, 0 C-rt, 3 h; ii) 4-
o
aminobenzenesulfonamide/pyridine/acetone, 0 C-rt, 9 h,
83%.
We also conducted a series of experiments to gain
some insight into the reaction mechanism. Treatment
of 1a and NH2NHTs with 1.05 equiv of DDQ gave
the cross-coupling product 3a in 87% yield (eqn 1).
The DDQ-promoted oxidation of 3a also performed
well and afforded hydrazone 4a in 84% yield
(calculated based on the amount of DDQ) (eqn 2). In
the presence of 1.5 equiv of DDQ, 4a could directly
form the final pyrazole 2a, irrespective of the
stereochemistry of the CN double bond in the
hydrazone (eqn 3). It should also be noted that in the
absence of DDQ, no reaction was happened and the
starting material 4a was recovered quantitatively (eqn
4). Furthermore, under the same condition, diphenyl
hydrazone 8 could be also converted into the
amination product 9 (eqn 5). The outcomes of these
three experiments (eqn 3-5) suggest that the
formation of pyrazoles is probably unlike to undergo
a Michael addition and subsequent aromatization.
Inclusion of TEMPO (2,2,6,6-tetramethylpiperidine-
N-oxyl), a radical inhibitor, as the additive had
extremely deleterious effect on the pyrazole
formation (eqn 6, the yield of 2a decreased from 74%
to 6% with the recovery of 4a in 18% yield), which
implies that a SET process might be involved in the
transformation of 4a to 2a.[11].
a)
Unless otherwise noted, all reactions were carried out
with 1 (0.3 mmol), TsNHNH2 (1.4 equiv), and DDQ (5
equiv) in DCE (3 mL) for 30 min under Ar atmosphere.
b)
Yields are given for isolated products, and the ratio of 2/2’
is determined by 1H NMR of the crude reaction mixtures. c)
(E)-1-(4-Fluorophenyl)-3-phenylpropene was used as the
substrate.
used as the substrate.
d)
(E)-3-(4-Fluorophenyl)-1-phenylpropene was
Scheme 3. Synthesis of pyrazoles 2 and 2’ from
asymmetrically 1,3-disubstituted propenes 1a),b)
To further demonstrate the application of this
transformation in the synthesis of drug-aimed
molecules, a pyrazole derivative 7, which shows good
anti-inflammatory activity[10], was chosen as the
synthetic target. Using our method, the key pyrazole
ring was readily constructed, giving 2a in 80% yield.
Then, under the condition of Mg/MeOH/rt, 3 h, the
Ts group on 2a was clearly cleaved to furnish the
unprotected pyrazole 5. Coupling of 5 with ethyl
bromoacetate, followed by the hydrolysis of the ester
4
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10.1002/adsc.201700196
Advanced Synthesis & Catalysis
propene 1 with DDQ generates the allyl radical A,
which can undergo the second SET oxidation to
produce the allyl cation B.[12] Next, the nucleophilic
NH2NHTs attacks the intermediate B to give rise to
the C-N bond coupling product 3 and 3’. By the DDQ
oxidative system, the hydrazine 3 is further oxidized
to the corresponding hydrazone 4. A SET process
between
4 and DDQ generates the nitrogen
radicals[9c,13] C with (E)-configuration of the CN
double bond and C’ with (Z)-configuration of the CN
double bond. C and C’ can tautomerize to each other
via the carbon radical C’’, which may be the reason
why the stereochemistry of the hydrazono group
doesn't affect the formation of the target pyrazole.
The intermediate C then undergoes an intramolecular
radical addition to yield a 5-membered cyclic radical
D, which goes through a fast single-electron transfer
(forming E) and a subsequent β-H elimination to
form the final product, pyrazole 2. For asymmetric
substrates, the regioisomer 2’ can be produced by the
same procedure via the allyl hydrazine 3’.
In light of the above findings and the
literatures[9,12,13], a possible mechanism of the
oxidative cascade reaction was proposed in Scheme 5.
First, a single-electron-transfer (SET) oxidation of the
Scheme 5. Proposed mechanism
only provides a promising method to prepare versatile
pyrazole compounds, especially those aiming to
employ in drug research, but also offer a novel
strategy to functionalize hydrocarbon molecules by
one-pot multiple inter-/intramolecular C-N bond
formations.
Conclusion
In summary, we have demonstrated a facile protocol
for multiple amination of simple hydrocarbon
molecules. Various 3,5-disubstituted pyrazoles were
installed efficiently via the cascade intermolecular
C(sp3)-N bond formation, oxidation and C(sp2)-N
bond formation under neutral and mild DDQ-
oxidative conditions. This metal-free protocol not
Experimental Section
General Information
5
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10.1002/adsc.201700196
Advanced Synthesis & Catalysis
1H NMR and 13C NMR spectra were recorded in CDCl3 or
7.30–7.21 (m, 7H), 7.15 (d, J = 7.6 Hz, 1H), 6.43 (s, 1H),
2.46 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 155.6, 146.4, 145.3, 138.2, 136.6, 135.0,
131.2, 131.0, 130.3, 129.8, 129.6 (2C), 129.5, 129.4, 128.8,
128.2, 125.8, 125.0, 111.7, 21.6, 21.4, 20.2; HR-MS (ESI):
m/z = 425.1294, calcd. for [C24H22N2O2S+Na]+: 425.1300.
DMSO-d6 on a Bruker Avance 400 instrument. Chemical
shifts (δ) are referenced to internal TMS, DMSO-d6 or
CDCl3. High-resolution mass spectra were recorded on a
Bruker axis Impact mass spectrometer. Melting points were
determined by using a Stuart Scientific SMP10 instrument
and are uncorrected. IR spectra were recorded in the ATR
3,5-Bis(4-methoxylphenyl)-1-tosylpyrazole (2e): White
mode on
a Nicolet 6700 FTIR Thermo Scientific
o
solid; Yield: 85% (111 mg); mp: 131–133 C. IR (KBr): ν
spectrometer; only the more significant peaks are reported.
Unless otherwise noted, all reagents and solvents were
obtained commercially and used as received without
further purification. Dichloromethane (CH2Cl2), 1,2-
dichloroethane (CH2ClCH2Cl), and toluene were dried and
distilled from calcium hydride under argon. Reactions were
monitored by TLC on glass-backed plates coated with a 0.2
mm thickness of silica gel 60 F254; chromatograms were
visualized by UV radiation (254 nm) or by staining with
phosphomolybdic acid, 2,4-dinitrophenylhydrazine and
KMnO4. Flash column chromatography was performed on
300-400 mesh silica gel.
= 3424, 3051, 2926, 2844, 1610, 1497, 1385, 1253, 1183,
1
1022, 832, 739 cm−1; H NMR (400 MHz, CDCl3): δ =
7.77 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.38 (d, J
= 7.6 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 6.96–6.91 (m, 4H),
6.49 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.34 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 160.5, 160.4, 155.1, 149.5,
145.0, 141.6, 134.9, 131.2, 129.5, 127.9, 127.8, 124.0,
121.8, 114.0, 113.2, 109.0, 55.2, 21.6; HR-MS (ESI): m/z
= 457.1202, calcd. for [C24H22N2O4S+Na]+: 457.1198.
3,5-Bis(3-methoxylphenyl)-1-tosylpyrazole
(2f):
Colorless oil; Yield: 81% (106 mg). IR (KBr): ν = 3428,
3058, 2930, 2836, 1587, 1470, 1376, 1256, 1174, 750, 665
cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.4 Hz,
2H), 7.39 (d, J = 8.0 Hz, 2H), 7.36–7.29 (m, 2H), 7.20 (d, J
= 8.0 Hz, 2H), 7.03–6.99 (m, 3H), 6.92 (dd, J = 1.6 Hz, 8.2
Hz, 1H), 6.59 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 2.36 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 159.8, 158.8, 154.9,
149.1, 145.3, 134.8, 132.6, 130.7, 129.7, 129.6, 128.8,
128.0, 122.3, 119.0, 115.5, 115.2, 115.1, 111.6, 109.6,
55.34, 55.31, 21.6; HR-MS (ESI): m/z = 457.1207, calcd.
for [C24H22N2O4S+Na]+: 457.1198.
General procedure for the synthesis of
substituted pyrazoles (2a-2w)
To a flame-dried 10 mL Schlenk tube under Ar was added
alkene (0.3 mmol, 1.0 equiv), hydrazide (0.42 mmol, 1.4
equiv), DDQ (1.5 mmol, 5 equiv), and dry DCE (3 mL).
The reaction mixture was then stirred at 40 oC and
monitored by TLC. After the reaction was completed
(about 30 min), the resulting mixture was filtered and
poured into saturated aqueous NaHCO3 (3 mL), which was
extracted with ethyl acetate (3 × 15 mL). The combined
organic phase was washed with water (3 × 5 mL) and brine
(5 mL), dried over anhydrous MgSO4, filtered, and
evaporated in vacuo. The resulting residue was purified by
flash column chromatography on silica gel to afford the
desired products.
3,5-Bis(2-methoxylphenyl)-1-tosylpyrazole (2g): White
o
solid; Yield: 79% (103 mg); mp: 161–162 C. IR (KBr): ν
= 3470, 2926, 2844, 1634, 1458, 1376, 1248, 1108, 750,
660 cm−1; 1H NMR (400 MHz, CDCl3): δ = 8.08 (d, J = 8.0
Hz, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.46–7.42 (m, 1H), 7.33–
7.28 (m, 1H), 7.23–7.20 (m, 3H), 7.02–6.87 (m, 5H), 3.81
(s, 3H), 3.73 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 157.9, 157.2, 152.3, 144.8, 143.8, 135.4, 131.1,
130.9, 130.1, 129.3, 129.2, 128.1, 120.7, 120.4, 119.7,
119.5, 112.9, 111.2, 110.5, 55.2, 55.3, 21.5; HR-MS (ESI):
m/z = 457.1187, calcd. for [C24H22N2O4S+Na]+: 457.1198.
3,5-Diphenyl-1-tosylpyrazole (2a)[6i]: White solid; Yield:
o
80% (90 mg); mp: 121–123 C. IR (KBr): ν = 3419, 3051,
2954, 2920, 2844, 1447, 1377, 1175, 1105, 755, 667 cm−1;
1H NMR (400 MHz, CDCl3): δ = 7.84 (dd, J = 7.8, 1.6 Hz,
2H), 7.63 (d, J = 8.4 Hz, 2H), 7.47–7.37 (m, 8H), 7.20 (d, J
= 8.4 Hz, 2H), 6.61 (s, 1H), 2.36 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 155.1, 149.4, 145.2, 134.8, 131.3, 129.9,
129.54, 129.50, 129.4, 129.2, 128.6, 127.9, 127.7, 126.4,
109.4, 21.6; HR-MS (ESI): m/z = 397.0981, calcd. for
[C22H18O2N2S+Na]+: 397.0987.
3,5-Bis(3,4-dimethylphenyl)-1-tosylpyrazole (2h): White
o
solid; Yield: 85% (110 mg); mp: 110–111 C. IR (KBr): ν
= 3424, 3058, 2963, 2844, 1551, 1381, 1190, 1116, 875,
1
1022, 809, 665 cm−1; H NMR (400 MHz, CDCl3): δ =
7.65 (s, 1H), 7.62 (d, J = 5.6 Hz, 2H), 7.53 (d, J = 5.2 Hz,
1H), 7.21–7.13 (m, 6H), 6.53 (s, 1H), 2.32 (s, 6H), 2.30 (s,
3H), 2.28 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 155.4, 149.7, 144.9, 137.9, 137.8, 136.8, 135.8,
134.9, 130.9, 129.8, 129.4, 129.0, 128.8, 127.8, 127.4,
127.3, 127.0, 123.8, 109.3, 21.5, 19.6, 19.59 (2C), 19.55;
3,5-Bis(4-methylphenyl)-1-tosylpyrazole (2b): White
o
solid; Yield: 93% (112 mg); mp: 128–130 C. IR (KBr): ν
= 3445, 3042, 2920, 2858, 1596, 1497, 1381, 1194, 945,
809, 668 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J
= 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.4 Hz,
2H), 7.26–7.18 (m, 6H), 6.55 (s, 1H), 2.44 (s, 3H), 2.37(s,
3H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 155.3,
149.7, 145.1, 139.4, 139.3, 135.0, 129.8, 129.5, 129.3,
128.6, 128.5, 128.1, 126.7, 126.3, 109.3, 21.6, 21.4, 21.3;
HR-MS (ESI): m/z
=
453.1618, calcd. for
[C26H26O2N2S+Na]+: 453.1613.
3,5-Bis(4-fluorophenyl)-1-tosylpyrazole (2i): Pale yellow
solid; Yield: 75% (92 mg); mp: 153–154 oC. IR (KBr): ν =
3439, 3062, 2926, 1602, 1501, 1385, 1183, 809, 660 cm−1;
1H NMR (400 MHz, CDCl3): δ = 7.82–7.78 (m, 2H), 7.62
(d, J = 8.4 Hz, 2H), 7.43–7.39 (m, 2H), 7.22 (d, J = 8.0 Hz,
2H), 7.15–7.05 (m, 4H), 6.55 (s, 1H), 2.36 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 163.4 (d, JC-F = 248.6 Hz),
163.3 (d, JC-F = 247.5 Hz), 154.1, 148.3, 145.5, 134.6,
131.8(d, JC-F = 8.3 Hz), 129.6, 128.2 (d, JC-F = 8.3 Hz),
127.9, 127.4, (d, JC-F = 3.3 Hz), 125.4 (d, JC-F = 3.4 Hz),
115.6 (d, JC-F = 21.6 Hz), 114.9 (d, JC-F = 21.8 Hz), 109.3,
HR-MS (ESI): m/z
=
425.1294, calcd. for
[C24H22N2O2S+Na]+: 425.1300.
3,5-Bis(3-methylphenyl)-1-tosylpyrazole (2c): White
solid; Yield: 79% (95 mg); mp: 132–133 oC. IR (KBr): ν =
3428, 3034, 2918, 1605, 1377, 1184, 1114, 781, 667 cm−1;
1H NMR (400 MHz, CDCl3): δ = 7.71 (s, 1H), 7.62 (t, J =
8.0 Hz, 3H), 7.35–7.18 (m, 8H), 6.58 (s, 1H), 2.41 (s, 3H),
2.39 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
= 155.2, 149.5, 145.1, 138.3, 137.4, 135.0, 131.2, 130.6,
130.1, 130.0, 129.5, 128.5, 128.0, 127.6, 127.03, 127.01
(2C), 123.6, 109.5, 21.6, 21.34, 21.32; HR-MS (ESI): m/z
= 425.1298, calcd. for [C24H22N2O2S+Na]+: 425.1300.
21.6; HR-MS (ESI): m/z
= 433.0801, calcd. for
[C22H16N2O2SF2+Na]+: 433.0798.
3,5-Bis(3-fluorophenyl)-1-tosylpyrazole (2j): Colorless
oil; Yield: 47% (61 mg). IR (KBr): ν = 3430, 3058, 2918,
3,5-Bis(2-methylphenyl)-1-tosylpyrazole (2d): White
solid; Yield: 68% (82 mg); mp: 121–122 oC. IR (KBr): ν =
3419, 3051, 2928, 2832, 1631, 1377, 1184, 1123, 754, 666
cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.4 Hz,
2H), 7.55 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H),
1
1587, 1462, 1385, 1186, 870, 735 cm−1; H NMR (400
MHz, CDCl3): δ = 7.67 (d, J = 8.4 Hz, 2H), 7.60–7.55 (m,
2H), 7.45–7.35 (m, 2H), 7.27–7.24 (m, 3H), 7.22–7.05 (m,
3H), 6.60 (s, 1H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 163.0 (d, JC-F = 244.6 Hz), 161.9 (d, JC-F
=
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700196
Advanced Synthesis & Catalysis
245.4 Hz), 153.8 (d, JC-F = 2.8 Hz), 147.8 (d, JC-F = 2.4 Hz), MS (ESI): m/z = 497.1309, calcd. for [C30H22N2O2S+Na]+:
145.7, 134.6, 133.3 (d, JC-F = 8.1 Hz), 131.2 (d, JC-F = 8.7 497.1300.
Hz), 130.3 (d, JC-F = 8.1 Hz), 129.8, 129.4 (d, JC-F = 8.3
Hz), 128.1, 125.9, (d, JC-F = 3.2 Hz), 122.1 (d, JC-F = 2.9
3,5-Di-2-thienyl-1-tosylpyrazole (2p): Pale Yellow solid;
Yield: 57% (66 mg); mp: 154–156 oC. IR (KBr): ν = 3420,
3109, 2922, 2852, 1583, 1381, 1183, 1116, 809, 699 cm−1;
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 8.4 Hz, 2H),
7.47 (d, J = 4.8 Hz, 1H), 7.40 (dd, J = 5.8, 4.0 Hz, 2H),
7.34 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.15–
Hz), 117.0 (d, JC-F = 22.7 Hz), 116.5 (d, JC-F = 20.8 Hz),
116.2 (d, JC-F = 21.1 Hz), 113.3 (d, JC-F = 22.8 Hz), 109.5,
21.6; HR-MS (ESI): m/z
= 433.0796, calcd. for
[C22H16N2O2SF2+Na]+: 433.0798.
3,5-Bis(2-fluorophenyl)-1-tosylpyrazole (2k): Colorless 7.13 (m, 1H), 7.06–7.04 (m, 1H), 6.58 (s, 1H), 2.37 (s, 3H);
oil; Yield: 44% (54 mg). IR (KBr): ν = 3439, 3055, 2926, 13C NMR (100 MHz, CDCl3): δ = 150.2, 145.4, 141.6,
1
2852, 1595, 1385, 1186, 1120, 812, 657 cm−1; H NMR 134.5, 134.1, 131.0, 129.7, 128.2, 128.1, 128.0, 127.5,
(400 MHz, CDCl3): δ = 8.09 (td, J = 7.6, 1.6 Hz, 1H), 7.77 127.3, 126.8, 126.2, 110.5, 21.6; HR-MS (ESI): m/z =
(d, J = 8.4 Hz, 2H), 7.51–7.46 (m, 1H), 7.40–7.31 (m, 2H), 409.0115, calcd. for [C18H14N2O2S3+Na]+: 409.0115.
7.28–7.16 (m, 5H), 7.10 (dd, J = 11.0, 8.4 Hz, 1H), 6.82 (d,
J = 4.0 Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz,
Mixture
of
5-(4-methylphenyl)-3-phenyl-1-tosyl
pyrazole (2q)[14] and 3-(4-methylphenyl)-5-phenyl-1-
CDCl3): δ = 160.6 (d, JC-F = 249.3 Hz), 160.2 (d, JC-F
=
tosylpyrazole (2q’)[14]: White solid; Yield: 79% (92 mg,
2q:2q’ = 1:1.1); 2q: H NMR (400 MHz, CDCl3): δ =
248.4 Hz), 150.1, 145.5, 141.6 (d, JC-F = 2.3 Hz), 134.7,
131.9 (d, JC-F = 2.0 Hz), 131.6 (d, JC-F = 8.1 Hz), 130.7 (d,
JC-F = 8.5 Hz), 129.8, 129.1 (d, JC-F = 3.1 Hz), 128.3, 124.4
1
7.85–7.83 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.43–7.34 (m,
5H), 7.25 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H),
6.58(s, 1H), 2.44 (s, 3H), 2.36 (s, 3H); 2q’:1H NMR (400
MHz, CDCl3): δ = 7.74 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 8.0
Hz, 2H), 7.45–7.36 (m, 5H), 7.26–7.18 (m, 4H), 6.58(s,
1H), 2.35 (s, 6H); Mixture of 2q and 2q’: IR (KBr): ν =
3443, 3060, 2922, 2867, 1595, 1489, 1376, 1183, 1113,
(d, JC-F = 3.4 Hz), 123.6 (d, JC-F = 3.6 Hz), 119.3 (d, JC-F
=
11.6 Hz), 118.0 (d, JC-F = 16.0 Hz), 116.0 (d, JC-F = 21.9
Hz), 115.5 (d, JC-F = 21.3 Hz), 112.8 (d, JC-F = 10.4 Hz),
21.7; HR-MS (ESI): m/z
= 433.0801, calcd. for
[C22H16N2O2SF2+Na]+: 433.0798.
3,5-Bis(4-chlorophenyl)-1-tosylpyrazole (2l): Pale yellow 809, 665 cm−1; 13C NMR (100 MHz, CDCl3): δ = 155.2,
solid; Yield: 63% (84 mg); mp: 146–147 oC. IR (KBr): ν = 155.1, 149.6, 149.4, 145.2, 145.1, 139.4, 139.2, 134.9,
3432, 3062, 2918, 1602, 1478, 1381, 1178, 1098, 809, 657 134.8, 131.3, 129.9, 129.8, 129.6, 129.5 (3C), 129.32,
cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.77 (d, J = 8.4 Hz, 129.30, 129.2, 128.6, 128.5, 127.93, 127.90, 127.7, 126.6,
2H), 7.63 (d, J = 8.4 Hz, 2H), 7.44–7.37 (m, 6H), 7.24 (d, J 126.4, 126.3, 109.4, 109.2, 21.6 (2C), 21.4, 21.3; HR-MS
= 8.0 Hz, 2H), 6.57 (s, 1H), 2.38 (s, 3H); 13C NMR (100 (ESI): m/z = 411.1146, calcd. for [C23H20N2O2S+Na]+:
MHz, CDCl3): δ = 154.0, 148.2, 145.6, 135.8, 135.3, 134.6, 411.1143.
131.2, 129.74, 129.70, 128.9, 128.2, 128.0, 127.8, 127.7,
109.4, 21.7; HR-MS (ESI): m/z = 465.0216, calcd. for
Mixture of 5-(4-fluorophenyl)-3-phenyl-1-tosylpyrazole
[C22H16N2O2SCl2+Na]+: 465.0207.
(2r)[14] and 3-(4-fluorophenyl)-5-phenyl-1- tosylpyrazole
(2r’)[14]: Pale yellow solid; Yield: 75% (88 mg, 2r:2r’ =
1
3,5-Bis(4-bromophenyl)-1-tosylpyrazole (2m): White 1.1:1); 2r: H NMR (400 MHz, CDCl3) δ = 7.84 (dd, J =
o
solid; Yield: 62% (101 mg); mp: 168–170 C. IR (KBr): ν 8.0, 1.6 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.45–7.36 (m,
= 3439, 3062, 2922, 1595, 1479, 1381, 1174, 1116, 1007, 5H), 7.22 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 6.60
809, 660 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J (s, 1H), 2.37 (s, 3H); 2r’: 1H NMR (400 MHz, CDCl3): δ =
= 8.4 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 7.84–7.79 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.48–7.34 (m,
2H), 7.53 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.23 5H), 7.20 (d, J = 8.0 Hz, 2H), 7.07 (J = 8.8 Hz, 2H), 6.55 (s,
(d, J = 8.0 Hz, 2H), 6.57 (s, 1 H), 2.38 (s, 3H); 13C NMR 1H), 2.35 (s, 3H); Mixture of 2r and 2r’: IR (KBr): ν =
(100 MHz, CDCl3): δ = 154.0, 148.2, 145.6, 135.8, 135.3, 3432, 3062, 2926, 1602, 1489, 1381, 1225, 1183, 1116,
134.6, 131.2, 129.74, 129.70, 128.9, 128.2, 128.0, 127.8, 816, 665 cm−1; 13C NMR (100 MHz, CDCl3): δ = 164.4 (d,
127.7, 109.4, 21.7; HR-MS (ESI): m/z = 554.9194, calcd. JC-F = 248.4 Hz), 163.4 (d, JC-F = 249.5 Hz), 155.1, 154.1,
for [C22H16N2O2SBr2+Na] +: 554.9197.
149.4, 148.2, 145.4 (d, JC-F = 5.7 Hz), 134.7 (d, JC-F = 4.4
Hz), 131.9, 131.8, 131.1, 129.9, 129.61, 129.58, 129.42,
129.38, 129.3, 128.6, 128.25, 128.17, 128.0, 127.9, 127.7,
127.5 (d, JC-F = 3.1 Hz), 126.3, 125.5 (d, JC-F = 3.3 Hz),
115.6 (d, JC-F = 21.6 Hz), 114.9 (d, JC-F = 21.7 Hz), 109.5,
109.2, 21.6 (2C); HR-MS (ESI): m/z = 415.0896, calcd. for
[C22H17N2O2SF+Na]+: 415.0892.
3,5-Bis(3-fluoro-4-methylphenyl)-1-tosylpyrazole (2n):
o
Pale yellow solid; Yield: 75% (99 mg); mp 78–79 C. IR
(KBr): ν = 3428, 3066, 2926, 1622, 1470, 1381, 1128, 809,
754, 660 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J
= 8.0 Hz, 2H), 7.50–7.46 (m, 2H), 7.27–7.18 (m, 4H),
7.15–7.08 (m, 2H), 6.54 (s, 1H), 2.37 (s, 3H), 2.36 (s, 3H),
2.28 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 161.4 (d, Mixture of 5-(4-fluorophenyl)-3-(4-methylphenyl)-1-
JC-F = 243.3 Hz), 160.4 (d, J = 244.0 Hz,), 154.1 (d, JC-F
=
tosylpyrazole
(2s)
and
3-(4-fluorophenyl)-5-(4-
2.5 Hz), 148.2 (d, JC-F = 2.1 Hz), 145.5, 134.7, 131.6 (d, JC- methylphenyl)-1-tosylpyrazole (2s’): Pale yellow solid;
1
= 5.3 Hz), 130.8 (d, JC-F = 5.5 Hz), 130.8 (d, JC-F = 9.3 Yield: 85% (104 mg, 2s:2s’ = 1.4:1); 2s: H NMR (400
F
Hz), 129.7, 128.5 (d, JC-F = 8.5 Hz), 128.0, 126.4 (d, JC-F
=
MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.8
16.9 Hz), 126.1 (d, JC-F = 17.3 Hz), 125.5 (d, JC-F = 3.4 Hz, 2H), 7.44 (dd, J = 8.5, 5.4 Hz, 2H), 7.26–7.18 (m, 4H),
Hz), 121.8 (d, JC-F = 3.3 Hz), 116.5 (d, JC-F = 23.9 Hz), 7.12 (t, J = 8.6 Hz, 2H), 6.56 (s, 1H), 2.36 (s, 3H), 2.35 (s,
1
112.8 (d, J = 23.8 Hz), 109.3, 21.6, 14.5 (d, JC-F = 3.4 Hz), 3H); 2s’: H NMR (400 MHz, CDCl3): δ = 7.83–7.79 (m,
14.4 (d, JC-F =3.4 Hz); HR-MS (ESI): m/z = 461.1116, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.25
calcd. for [C24H20N2O2SF2+Na]+: 461.1111.
(d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.10–7.06 (m,
2H), 6.52 (s, 1H), 2.44 (s, 3H), 2.36 (s, 3H); Mixture of 2s
and 2s’: IR (KBr): ν = 3436, 3059, 2922, 1607, 1501, 1381,
1186, 1123, 816, 668 cm−1; 13C NMR (100 MHz, CDCl3): δ
= 163.4 (d, JC-F = 248.2 Hz), 163.3 (d, JC-F = 247.1 Hz),
155.3, 154.1, 149.7, 148.2, 145.3, 145.2, 139.5, 139.4,
134.8, 134.7, 131.8 (d, JC-F = 8.4 Hz), 129.8, 129.58,
129.55, 129.3, 128.5, 128.3, 128.2 (d, JC-F = 8.3 Hz), 128.0,
127.9, 127.6 (d, JC-F = 3.2 Hz), 126.5, 126.3, 125.6 (d, JC-F
= 3.5 Hz), 115.6 (d, JC-F = 21.6 Hz), 114.9 (d, JC-F = 21.8
Hz), 109.5, 109.0, 21.56, 21.55, 21.4, 21.3; HR-MS (ESI):
m/z = 429.1052, calcd. for [C23H19N2O2SF+Na]+: 429.1049.
3,5-Di-2-naphthalenyl-1-tosylpyrazole (2o): White solid;
Yield: 85% (121 mg); mp: 201–202 oC. IR (KBr): ν = 3405,
3045, 2930, 2860, 1595, 1381, 1186, 1113, 816, 754 cm−1;
1H NMR (400 MHz, CDCl3): δ =8.30 (s, 1H), 8.04 (dd, J =
8.6, 1.6 Hz, 1H), 7.92–7.87 (m, 6H), 7.84–7.82 (m, 1H),
7.65–7.61 (m, 3H), 7.59–7.53 (m, 2H), 7.50–7.46 (m, 2H),
7.17 (d, J = 8.0 Hz, 2H), 6.82 (s, 1H), 2.33(s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 155.3, 149.6, 145.3, 134.9,
133.8, 133.5, 133.2, 132.5, 129.6 129.2, 128.7, 128.43,
128.36, 128.3, 128.0, 127.84, 127.75, 127.6, 127.3, 127.1,
127.0, 126.6 (2C), 126.4, 125.8, 124.0, 110.0, 21.6; HR-
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201700196
Advanced Synthesis & Catalysis
Mixture of 3-(4-methoxyphenyl)-5-(4-methylphenyl)-1- 13C NMR (100 MHz, DMSO) δ = 169.6, 149.8, 145.3,
tosylpyrazole (2t) and 5-(4-methoxyphenyl)-3-(4- 132.9, 129.9, 128.9, 128.8, 128.6, 128.3, 127.7, 125.2,
methylphenyl)-1-tosylpyrazole (2t’): Pale yellow solid; 103.6, 51.5; HR-MS (ESI): m/z = 279.1141, calcd. for
1
Yield: 80% (100 mg, 2t:2t’ = 1.5:1); 2t: H NMR (400 [C17H14O2N2+H]+: 279.1134.
MHz, CDCl3): δ = 7.77 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.4
Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H),
N-[4-(Aminosulfonyl)phenyl]-3,5-diphenyl-1H-pyrazole
-1-acetamide (7)[10]: A solution of (COCl)2 (51 μL, 0.6
mmol) in dry CH2Cl2 (0.5 mL) was added dropwise to a
stirred solution of 6 (116.9 mg, 0.42 mmol) in dry CH2Cl2
7.19 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.51 (s,
1
1H), 3.83 (s, 3H), 2.44 (s, 3H), 2.36 (s, 3H); 2t’: H NMR
(400 MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz, 2H), 7.60 (d, J
= 7.2 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.24–7.17 (m, 4H),
6.96 (d, J = 8.4 Hz, 2H), 6.53 (s, 1H), 3.88 (s, 3H), 2.37 (s,
3H), 2.36 (s, 3H); Mixture of 2t and 2t’: IR (KBr): ν =
3437, 2920, 2841, 1613, 1491, 1429, 1386, 1245, 1167,
816, 675 cm−1; 13C NMR (100 MHz, CDCl3): δ 160.48,
160.47, 155.4, 155.1, 149.7, 149.5, 145.1, 145.0, 139.4,
139.3, 134.91, 134.89, 131.3, 129.8, 129.5 (2C), 129.3,
128.6, 128.5, 128.0, 127.9, 127.8, 126.7, 126.3, 124.0,
121.8, 114.0, 113.2, 109.2, 109.2, 55.3(2C), 21.6 (2C), 21.4,
o
(10 mL) under Ar at 0 C, then DMF (5 μL) was added.
After addition, the reaction mixture was stirred at rt for 3 h,
then CH2Cl2 was evaporated. The resulting residue was
dissolved in dry Et2O (20 mL), filtered, and the filtrate was
evaporated in vacuo. Then, a solution of this crude product
in dry acetone (4 mL) was added dropwise to a stirred
solution of 4-aminobenzenesulfonamide (51.7 mg, 0.3
mmol) and pyridine (50 μL, 0.6 mmol) in dry acetone (3
mL) under Ar at 0 oC. The reaction mixture was stirred at rt
for 9 h, then H2O (5 mL) was added. 1 mol/L HCl solution
was dropped to the resulting solution until the solution
became acidic. White precipitation was formed. This
21.3; HR-MS (ESI): m/z
= 441.1251, calcd. for
[C24H22N2O3S+Na]+: 441.1249.
Mixture of 3-(4-methoxyphenyl)-5-(2-methylphenyl)-1- precipitation was filtered, washed by cold water, and dried
tosylpyrazole (2u) and 5-(4-methoxyphenyl)-3-(2- to afford the desired product 7. White solid; Yield: 83%
methylphenyl)-1-tosylpyrazole (2u’): Colorless oil; (107.6 mg); mp: 246–247 oC. (KBr): ν = 3620, 3335, 3268,
1
Yield: 72% (87 mg, 2u:2u’ = 1.9:1); 2u: H NMR (400 2954, 2918, 1745, 1694, 1529, 1340, 1152, 828, 771 cm−1;
MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.6 1H NMR (600 MHz, DMSO) δ = 10.73 (s, 1H), 7.85 (d, J =
Hz, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.29–7.21 (m, 6H), 7.08 7.7 Hz, 2H), 7.79–7.74 (m, 4H), 7.61 (d, J = 7.4 Hz, 2H),
(d, J = 7.2 Hz, 1H), 6.52 (s, 1H), 2.37 (s, 6H), 2.16 (s, 3H); 7.52 (t, J = 7.5 Hz, 2H), 7.46 (t, J = 7.3 Hz, 1H), 7.42 (t, J
1
2u’: H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.4 Hz, = 7.6 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.28 (s, 2H), 6.94 (s,
2H), 7.48 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 1H), 5.07 (s, 2H); 13C NMR (150 MHz, DMSO) δ = 166.3,
7.27–7.19 (m, 7H), 6.45 (s, 1H), 2.44 (s, 3H), 2.39 (s, 6H); 150.0, 145.8, 141.3, 138.8, 132.9, 130.0, 128.84, 128.76,
Mixture of 2u and 2u’: IR (KBr): ν = 3439, 2918, 2852, 128.6, 128.5, 127.7, 126.8, 125.2, 118.9, 103.4, 52.9; HR-
1641, 1451, 1382, 1178, 1116, 812, 657 cm−1; 13C NMR MS (ESI): m/z = 455.1154, calcd. for [C23H20O2N4S+Na]+:
(100 MHz, CDCl3): δ = 156.0, 154.9, 148.7, 147.4, 145.20, 455.1154.
145.18, 139.4, 139.2, 138.2, 136.6, 135.0, 134.9, 131.1,
130.9, 130.2, 129.80, 129.78, 129.6 (2C), 129.51, 129.50,
2-(1,3-Diphenylallyl)hydrazide-p-toluenesulfonic acid
(3a)[17]: To a flame-dried 10 mL Schlenk tube under Ar
was added 1a (58.2 mg, 0.3 mmol), NH2NHTs (78.1 mg,
0.42 mmol), DDQ (75.5 mg, 0.315 mmol), and dry DCE (3
129.4, 129.3, 128.7, 128.6 128.5, 128.1, 128.0, 126.6,
126.3, 125.8, 124.9, 112.0, 108.9, 21.61(2C), 21.4, 21.3,
21.2, 20.1; HR-MS (ESI): m/z = 425.1294, calcd. for
[C24H22N2O2S+Na]+: 425.1300.
o
mL). The reaction mixture was stirred at 40 C under Ar
atmosphere and monitored by TLC. After the reaction was
3,5-Diphenyl-1H-pyrazole (5)[15]: To a flame-dried 25 mL completed (about 2 h), the resulting mixture was poured
Schlenk tube under Ar was added pyrazole 2a (561.7mg, into saturated aqueous NaHCO3 (3 mL), which was
1.5 mmol), Mg (360.0 mg, 15 mmol), and dry MeOH (9 extracted with ethyl acetate (3 × 15 mL). The combined
mL). The reaction mixture was stirred at rt under Ar, and organic phase was washed with water (3 × 5 mL) and brine
monitored by TLC. After the reaction was completed (5 mL), dried over anhydrous MgSO4, filtered, and
(about 3 h), the resulting mixture was poured into saturated evaporated in vacuo. The resulting residue was purified by
aqueous NH4Cl (20 mL), which was extracted with ethyl flash column chromatography on silica gel (PE/EA 3/1) to
acetate (3 × 50 mL). The combined organic phase was afford the product 3a. White solid; Yield: 87% (99 mg);
o
washed with water (3 × 20 mL) and brine (20 mL), dried mp: 119–120 C. IR (KBr): ν = 3249, 3027, 2922, 1595,
over anhydrous Na2SO4, filtered, and evaporated in vacuo. 1489, 1323, 1159, 1089, 1022, 750, 696 cm−1; H NMR
1
The resulting residue was purified by flash column (400 MHz, DMSO-d6): δ = 8.69 (s, 1H), 7.72 (d, J = 8.0
chromatography on silica gel (PE/EA 4/1) to afford the Hz, 2H), 7.39–7.30 (m, 10H), 7.25–7.20 (m, 2H), 6.43 (d, J
product 5. White solid; Yield: 95% (313.5 mg); mp: 161– = 15.6 Hz, 1H), 6.20 (dd, J = 16.0, 8.0 Hz, 1H), 5.00 (brs,
162 oC. 1H NMR (400 MHz, CDCl3) δ = 8.90 (s, 1H), 7.73 1H), 4.47 (d, J = 8.0 Hz, 1H), 2.37 (s, 3H); 13C NMR (100
–7.71 (m, 4H), 7.41–7.33 (m, 6H), 6.84 (s, 1H); 13C NMR MHz, DMSO-d6): δ = 142.7, 141.3, 136.6 (2C), 130.9,
(100 MHz, CDCl3) δ = 148.6, 131.1, 128.8, 128.2, 125.6, 130.7, 129.3, 128.5, 128.2, 127.61, 127.57, 127.4, 127.1,
100.1.
126.2, 66.9, 20.1; HR-MS (ESI): m/z = 401.1294, calcd.
for [C22H22N2O2S+Na]+: 401.1300.
2-(3,5-Diphenyl-1H-pyrazol-1-yl) acetic acid (6)[16]
:
Ethyl bromoacetate (133 μL, 1.2 mmol) was added N′-((E)-1,3-Diphenylallylidene)-4-methylbenzene-
dropwise to a stirred solution of 5 (220.3 mg, 1 mmol) and sulfonohydrazide (4a)[18]: To a flame-dried 10 mL Schlenk
K2CO3 (290.2 mg, 2.1 mmol) in dry CH3CN (10 mL) under tube under Ar was added 3a (189.2 mg, 0.5 mmol), DDQ
Ar. After addition, the reaction mixture was refluxed for 2 (56.7 mg, 0.25 mmol), and dry DCE (3 mL). The reaction
h, and then the solvent was evaporated in vacuo. A solution mixture was stirred at 40 oC under Ar atmosphere and
of NaOH (600 mg, 15 mmol) in H2O (5 mL) was added to monitored by TLC. After the reaction was completed
the crude product. The reaction mixture was stirred at rt, (about 40 min), the resulting mixture was poured into
and monitored by TLC. After the reaction was completed saturated aqueous NaHCO3 (3 mL), which was extracted
(about 4 h), the resulting mixture was extracted with with ethyl acetate (3 × 15 mL). The combined organic
CH2Cl2 (2 × 10 mL). Then, 2 mol/L HCl solution was phase was washed with water (3 × 5 mL) and brine (5 mL),
added to the aqueous phase until the solution became acidic. dried over anhydrous MgSO4, filtered, and evaporated in
White precipitation was formed. This precipitation was vacuo. The resulting residue was purified by column
filtered, washed by cold water, and dried to afford the chromatography on silica gel (PE/EA 6/1) to afford the
desired product 6. White solid; Yield: 83% (239.3 mg); product. (More polar, 21%, 22 mg); Pale yellow solid; mp:
o
mp: 147–148 oC. (KBr): ν = 3410, 2917, 2711, 2521, 1744, 147–149 C. IR (KBr): ν = 3209, 3060, 2911, 1587, 1447,
1
1
1464, 1368, 1218, 1004, 758, 688 cm−1; H NMR (400 1323, 1159, 1079, 1018, 750, 685 cm−1; H NMR (400
MHz, DMSO) δ = 13.18 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), MHz, CDCl3): δ = 7.82 (d, J = 8.0 Hz, 2H), 7.54–7.52 (m,
7.52 (d, J = 3.9 Hz, 4H), 7.49–7.47 (m, 1H), 7.43 (t, J = 7.5 3H), 7.47 (s, 1H), 7.35–7.25 (m, 7H), 7.11–7.07 (m, 3H),
Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 6.92 (s, 1H), 4.96 (s, 2H); 6.26 (d, J = 16.4 Hz, 1H), 2.44 (s, 3H); 13C NMR (100
8
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10.1002/adsc.201700196
Advanced Synthesis & Catalysis
MHz, CDCl3): δ = 156.1, 144.2, 137.6, 135.8, 135.5,
130.10, 130.07, 129.8, 129.7, 128.8, 128.7, 128.2, 128.1,
127.8, 127.0, 21.6; HR-MS (ESI): m/z = 399.1132, calcd.
for [C22H20N2O2S+Na]+: 399.1143.
K. Makino, H. S. Kim, Y. Kurasawa, J. Hetercyclic.
Chem. 1999, 36, 321-332; c) S. Fustero, M. Sanchez-
Rosello, P. Barrio, A. Simon-Fuentes, Chem. Rev. 2011,
111, 6984-7034; d) S. Dadiboyena, A. Nefzi, Eur. J.
Med. Chem. 2011, 46, 5258-5275; e) Y. L. Janin, Chem.
Rev. 2012, 112, 3924-3958; f) M. Li, B.-X. Zhao, Eur. J.
Med. Chem. 2014, 85, 311-340; g) L. Pizzuti, A. G.
Barschak, F. M. Stefanello, M. D. Farias, C. Lencina,
M. Roesch-Ely, W. Cunico, S. Moura, C. M. P. Pereira,
Curr. Org. Chem. 2014, 18, 115-126; h) S. Kumari, S.
Paliwal, R. Chauhan, Synthetic Commun. 2014, 44,
1521-1578; i) P. Chauhan, S. Mahajan, D. Enders,
Chem. Commun. 2015, 51, 12890-12907; and
references cited therein.
(Less polar, 63%, 65 mg); Pale yellow solid; mp: 127–129
oC; 1H NMR (400 MHz, CDCl3): δ = 8.19 (s, 1H), 7.94 (d,
J = 8.0 Hz, 2H), 7.49–7.45 (m, 4H), 7.40–7.33 (m, 8H),
6.95 (d, J = 16.4 Hz, 1H), 6.82 (d, J = 16.4 Hz, 1H), 2.44
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 154.3, 144.2,
141.7, 136.3, 135.3, 134.9, 129.8, 129.7, 129.6, 128.9,
128.7, 128.24, 128.17, 127.4, 116.7, 21.6.; HR-MS (ESI):
m/z = 399.1135, calcd. for [C22H20N2O2S+Na]+: 399.1140.
1,3-Diphenyl-1H-indazole (9)[6q]: To a flame-dried 10 mL
Schlenk tube under Ar was added hydrazone 8 (81.7 mg,
0.3 mmol), DDQ (102.1 mg, 0.45 mmol), and dry DCE (3
o
mL). The reaction mixture was stirred at 40 C under Ar
atmosphere and monitored by TLC. After the reaction was
completed (about 40 min), the resulting mixture was
poured into saturated aqueous NaHCO3 (3 mL), which was
extracted with ethyl acetate (3 × 15 mL). The combined
organic phase was washed with water (3 × 5 mL) and brine
(5 mL), dried over anhydrous MgSO4, filtered, and
evaporated in vacuo. The resulting residue was purified by
flash column chromatography on silica gel (PE/EA 20/1) to
afford the product 7. White solid; Yield: 42% (47 mg); mp:
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X. Li, L. He, H. Chen, W. Wu, H. Jiang, J. Org. Chem.
2013, 78, 3636-3646; q) L. Hao, J.-J. Hong, J. Zhu, Z.-
P. Zhan, Chem.-Eur. J. 2013, 19, 5715-5720; r) T.
Zhang, W. Bao, J. Org. Chem. 2013, 78, 1317-1322; s)
J. Hu, S. Chen, Y. Sun, J. Yang, Y. Rao, Org. Lett.
2012, 14, 5030-5033; t) V. G. Desai, P. C. Satardekar, S.
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39, 2169-2177.
o
109–111 C. IR (KBr): ν = 3209, 3060, 2911, 1587, 1447,
1
1323, 1159, 1079, 1018, 750, 685 cm−1; H NMR (400
MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0
Hz, 2H), 7.80 (t, J = 7.4 Hz, 3H), 7.54 (dd, J = 16.0, 8.0
Hz, 4H), 7.45 (dd, J = 17.4, 8.0 Hz, 2H), 7.38 (t, J = 7.6
Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ = 146.1, 140.3, 140.1, 133.2, 129.5, 128.8,
128.3, 127.8, 127.1, 126.7, 123.1, 123.0, 121.9, 121.6,
110.7; HR-MS (ESI): m/z
= 293.1052, calcd. for
[C19H14N2+Na]+: 293.1055.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21302119, 21471093). We also
thank Dr. Hui Huang for helpful discussion.
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Advanced Synthesis & Catalysis
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FULL PAPER
Metal-Free Synthesis of Pyrazoles from 1,3-
Diarylpropenes and Hydrazines via Multiple Inter-
/Intramolecular C-H Aminations
Adv. Synth. Catal. Year, Volume, Page – Page
Li Tang,a Minyan Ma,a Qi Zhang,a* Huan Luo,a
Tao Wang,a and Yonghai Chaib*
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