I2-mediated oxidative C-N bond formation for metal-free one-pot synthesis of di-, tri-, and tetrasubstituted pyrazoles from α,β-unsaturated aldehydes/ketones and hydrazines

Article abstract of DOI:10.1021/jo501844x

An I₂-mediated metal-free oxidative C-N bond formation methodology has been established for the regioselective pyrazole synthesis. This practical and eco-friendly one-pot protocol requires no isolation of the less stable intermediates hydrazone

Full text of DOI:10.1021/jo501844x

Article
pubs.acs.org/joc
I2‑Mediated Oxidative C−N Bond Formation for Metal-Free One-Pot
Synthesis of Di‑, Tri‑, and Tetrasubstituted Pyrazoles from α,β-
Unsaturated Aldehydes/Ketones and Hydrazines
Xinting Zhang, Jinfeng Kang, Pengfei Niu, Jie Wu, Wenquan Yu,* and Junbiao Chang*
College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan Province 450001, China
S
* Supporting Information
ABSTRACT: An I2-mediated metal-free oxidative C−N bond
formation methodology has been established for the regiose-
lective pyrazole synthesis. This practical and eco-friendly one-pot
protocol requires no isolation of the less stable intermediates
hydrazones and provides a facile access to a variety of di-, tri-, and
tetrasubstituted (aryl, alkyl, and/or vinyl) pyrazoles from readily
available α,β-unsaturated aldehydes/ketones and hydrazine salts.
tuted pyrazoles have also been applied in agrochemistry11 and
1. INTRODUCTION
The intramolecular C−N bond formation via oxidation of C−
H and N−H bonds is a valuable tool for the construction of a
as ligands for cross-coupling reactions.12 Consequently, a
variety of methodologies have been developed for the
preparation of pyrazole derivatives.13 Among them, two general
nitrogen-containing heterocycle ring system (Scheme 1). It has
and classical pyrazole synthesis strategies are cyclocondensation
of 1,3-dicarbonyl compounds with hydrazines and 1,3-dipolar
cycloaddition of dipolarophiles with appropriate dipoles. For
Scheme 1. Oxidation and Coupling Strategies for the
Intramolecular C−N Bond Formation
the cyclocondensation, when substituted hydrazines and 1,3-
dicarbonyl substrates are used, the corresponding pyrazoles are
formed as mixtures of two regioisomers. 1,3-Dipolar cyclo-
addition reaction could afford substituted pyrazoles with better
regioselectivity, which, however, needs to use dangerous
reagents (e.g., diazo compounds). Besides the above two
strategies, another straightforward approach to construct the
pyrazole ring is from hydrazones 4, the advantages of which
advantages, such as (1) direct functionalization of C−H bonds
include that (1) no regioisomers will be form during the
with NHR groups without preactivation of the reaction centers;
reaction,2a−e and (2) the required substrates could be readily
(2) facilitative preparation of structurally diverse substrates; and
prepared via condensation of a variety of easily accessible α,β-
(3) no generation of the unwanted stoichiometric amounts of
byproducts derived from the leaving groups (LGs) in substrates
for the classic coupling reaction. Therefore, this synthetic
strategy has drawn considerable attention from organic
unsaturated carbonyl compounds 2 and hydrazines 3. Oxidative
cyclization of hydrazones 4 by hypervalent iodine(III)2a or
DDQ2b could provide substituted pyrazoles 1. Recently, this
transformation was also achieved by transition-metal-catalyzed
chemists and resulted in the discovery of numerous new
aerobic oxidation (eq 1).2c−e However, there are still limitations
synthetic methods for the preparation of indoles/carbazoles,1
pyrazoles/indazoles,2 benzoimidazole,3 and other nitrogen-
containing heterocycles.4 Many recent developments in the
literature, however, require the use of hypervalent iodine,1a,b,2a,4
iodobenzene/oxidants,2f,3 and DDQ,2b or via transition-metal-
catalyzed aerobic oxidative cyclization.1c,d,2c−e In this paper, we
developed a molecular iodine-mediated metal-free method-
ology for the oxidative intramolecular C−N bond formation to
synthesize pyrazole derivatives.
Pyrazole, a five-membered heterocycle with two adjacent
nitrogen atoms, is an important structural motif, which widely
exists in natural products5 and synthetic biologically active
compounds,6 such as cyclooxygenase-2 (Cox-2),7 protein
kinase,8 and HIV-1 reverse transcriptase9 inhibitors, as well as
antibacterial and antifungal compounds.10 Moreover, substi-
Received: August 9, 2014
© XXXX American Chemical Society
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a
Table 1. Optimization of the Reaction Conditions for the Synthesis of Pyrazole 1a
b
entry
substrates
equiv of I2
solvent
temp
yield
c
1
4a
1.2
1.2
1.5
1.2
1.5
2.0
DMSO
EtOH
EtOH
EtOH
EtOH
EtOH
100 °C
reflux
reflux
reflux
reflux
trace
67%
80%
62%
82%
78%
2
4a
d
3
2a + 3a
2a + 3a
2a + 3a
2a + 3a
e
4
e
5
e
6
reflux
a
b
Optimal reaction conditions (entry 5): 2a (0.5 mmol), 3a (0.75 mmol), I2 (0.75 mmol), EtOH, reflux, 1 h. Isolated yields after silica gel column
c
d
chromatography. The reaction was carried out in the presence of K2CO3 (3 equiv). First, a mixture of 2a and 3a in EtOH was stirred at rt for 1 h,
then treated with I2, and heated to reflux for 1 h. A reaction mixture of 2a, 3a, and I2 in EtOH was directly heated to reflux for 1 h.
e
associated with these methods, such as limited substrate scope
and unsatisfactory overall yields due to the low stability of the
intermediates hydrazones 4. Thus, more general and efficient
procedures for pyrazole synthesis are still highly desirable.
Previously, we have successfully developed a facile 1,3,4-
oxadiazole synthesis protocol through I2-mediated oxidative
intramolecular C−O bond formation strategy.14 As a part of
our continuing research on the oxidative C−X (X = O, N, etc.)
bond construction, herein, we report a practical and
regioselective one-pot pyrazole synthesis methodology via the
oxidative annulation of α,β-unsaturated aldehydes/ketones and
hydrazines (eq 2).
dehyde (2a) were subjected to the above reaction conditions,
which afforded the corresponding 1,5-disubstituted pyrazoles
(1a−f, entries 1−6) in 64−92% yield. The structure of 1-(4-
cyanophenyl)-substituted pyrazole 1e was further confirmed by
X-ray crystallography (See Supporting Information). Cinna-
maldehydes bearing both electron-donating (EDG) and
electron-withdrawing (EWG) groups on the benzene ring
(2g,h) were converted to the desired products (1g,h, entries 7
and 8) in 74% and 79% yields via the reaction with p-
tolylhydrazine hydrochloride (3a). In addition, this method-
ology is compatible with both cinnamaldehyde with a
substituent on the carbon−carbon double bond (2i) and
crotonaldehyde (2j). The low yield of pyrazole 1j might be due
to the poor stability of the condensation intermediate 4j (which
decomposed quickly on the TLC plate).
2. RESULTS AND DISCUSSION
Initially, we investigated the transformation from isolated
hydrozone 4a to pyrazole 1a under the oxidative cyclization
conditions for 1,3,4-oxadiazole synthesis described in our
previous work.14a However, only a trace amount of the pyrazole
1a was formed (indicated by TLC, entry 1, Table 1). After the
screening of a series of laboratory commonly used solvents, we
found that this conversion proceeded well in ethanol at
refluxing temperature in the absence of base (entry 2). As the
condensation of cinnamaldehyde (2a) and p-tolylhydrazine
hydrochloride (3a) was also carried out in ethanol, we
continued to optimize the reaction conditions by using crude
hydrazone 4a formed in ethanol without isolation from the
reaction system. After the first-step condensation was complete
(1 h at room temperature), the reaction mixture was directly
treated with molecular iodine (1.5 equiv) and then heated to
reflux for another hour, which provided the desired pyrazole 1a
in 80% yield (entry 3). In further optimization of the reaction
procedure, a mixture of 2a and 3a in the presence of molecular
iodine (1.5 equiv) in ethanol was directly heated to reflux. To
our delight, the reaction was also complete within 1 h and
afforded the product in equally good yield (82%, entry 5).
However, either increasing or decreasing the amount of iodine
affected the yield of pyrazole 1a (entry 4 or 6).
In light of these encouraging results, we initiated further
investigation of this one-pot protocol with α,β-unsaturated
ketones15 (Table 3). It is noteworthy to mention that the
condensation products of these enones and hydrazines are
relatively less stable (decomposing in silica gel column, usually
purified through recrystallization), which will decrease the
overall efficiency of pyrazole synthesis via step-by-step reaction.
Under the optimal oxidative annulation conditions, a series of
chalcones (2k and 2q−v) and the corresponding arylhydrazine
salts were directly converted into 1,3,5-trisubstituted pyrazoles
(1k−v) in good yields, without separation of the corresponding
intermediates hydrazones. The structure of 1-(4-chlorophenyl)-
substituted pyrazole 1m was further confirmed by X-ray
crystallography (See Supporting Information). This method-
ology worked well with both EDG (2k and 2r) and EWG (2s−
u) substituted chalcones, as well as the one containing furyl
group (2v). Moreover, 1,3,4,5-tetrasubstituted pyrazole 1w
could be prepared via the reaction of enone 2w and p-
tolylhydrazine hydrochloride (3a). While, the brominated
chalcone 2x led to 1,4,5-trisubstituted pyrazole 1k, with the
bromine reduced to hydrogen under the cyclization con-
ditions.16 Interestingly, the reaction of chalcones (2k and 2s)
and tert-butylhydrazine salt (3y) gave the de-tert-butyl products
(1y and 1z) in 69−75% yield (Scheme 2). The de-tert-
butylation process might be promoted by hydroiodide (HI)
formed during the reaction (Scheme 3).
With the optimal one-pot reaction conditions (1.0 equiv of 2,
1.5 equiv of 3, and 1.5 equiv of iodine in ethanol at refluxing
temperature) in hand, we sought to probe the scope and
generality of this method for pyrazole synthesis (Table 2). A
series of substituted arylhydrazine salts (3a−f) and cinnamal-
B
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a b
,
Table 2. Scope of α,β-Unsaturated Aldehydes 2 and Hydrazines 3
a
b
Optimal reaction conditions: 2 (0.5 mmol), 3 (0.75 mmol), I2 (0.75 mmol), EtOH, reflux, 1 h; Isolated yields after silica gel column
chromatography.
cyclization conditions, all of these α,β-unsaturated ketones
(2aa−af) were also converted to the desired pyrazoles (1aa−
af) in 67−92% yield via the reaction with p-tolylhydrazine
hydrochloride (3a). It is worth to notice that substrates with
tert-butyl (2ad) and vinyl (2af) substituents gave the desired
pyrazoles in better yields than substrates 2aa−ac and 1ae did.
This could be owing to the higher stability of the corresponding
intermediates, hydrazones 4ad and 4af, which could be
converted into pyrazoles 1ad and 1af more efficiently with
less byproducts formed.
Scheme 2. Synthesis of 3,5-Disubstituted Pyrazoles (1y and
1z) Using tert-Butylhydrazine Hydrochloride (3y)
To further explore the substrate scope, we replaced the
phenyl moiety in chalcone 2k with aliphatic or vinyl
substituents (R3, Table 4). Under the optimal one-pot oxidative
A plausible reaction mechanism for the formation of pyrazole
1 is proposed. As shown in Scheme 3, the oxidative iodination
C
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a b
,
Table 3. Scope of α,β-Unsaturated Ketones 2 and Hydrazines 3
a
b
Optimal reaction conditions: 2 (0.5 mmol), 3 (1 mmol), I2 (1 mmol), EtOH, reflux, 1 h. Isolated yields after silica gel column chromatography.
D
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Article
acid (Scheme 4).17 It was then subjected to the standard I2-
mediated reaction conditions, which also afforded pyrazole 1k
Scheme 3. Proposed Mechanism for the Formation of
Pyrazole 1
Scheme 4. Synthesis of Pyrazole 1k via Pyrazoline 5k
of hydrazone 4 generates an iodide intermediate A.
Consequently, intemediate B is formed via an SN2′-type
cyclization of compound A, with a new C−N bond formed.
Finally, the subsequent deprotonation affords the pyrazole
framework 1. Furthermore, another possible intermediate
pyrazoline 5k was synthesized via the cyclocondensation of
chalcone 2k and hydrazine 3a in the presence of conc. sulfuric
in 90% yield; however, the conversion rate is quite slow (over
36 h). This result suggested that the oxidative aromatization of
pyrazoline 5k pathway is unlikely to be involved in this one-pot
oxidative annulation reaction.18
a b
,
Table 4. Scope of R3 on α,β-Unsaturated Ketones 2
a
b
Optimal reaction conditions: 2 (0.5 mmol), 3 (1 mmol), I2 (1 mmol), EtOH, reflux, 1 h. Isolated yields after silica gel column chromatography.
E
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3. CONCLUSIONS
Article
ethyl acetate (20 mL × 3). The combined organic layer was dried over
anhydrous sodium sulfate, concentrated, and purified through silica gel
column chromatography (EA/PE 0:100−3:97) to afford the desired
ketone 2aa as a yellow oil (509 mg, 65%).
In summary, we have established an efficient and eco-friendly
methodology for regioselective pyrazole synthesis through I2-
mediated oxidative intramolecular C−N bond formation. This
practical one-pot protocol is metal-free and requires no
isolation of the less stable intermediates hydrazones. Under
the optimal reaction conditions, a variety of di-, tri-, and
tetrasubstituted (aryl, alkyl, and/or vinyl) pyrazole derivatives
were prepared from a broad substrate scope of readily available
α,β-unsaturated carbonyl compounds (both aldehydes and
ketones) and hydrazine salts.
4.2.4. Preparation of Ketones 2ab−ad and 2af.22 To a stirred
solution of 4-methyl benzaldehyde (1.73 g, 14.4 mmol) and methyl
tert-butyl ketone (1.20 g, 12.0 mmol) in ethanol (40 mL) at 0 °C was
treated with 10% NaOH (1 mL) slowly over 30 min. After addition,
the reaction was stirred at 0 °C for several hours and then allowed to
warm up to room temperature (overnight, TLC indicated the
conversion was complete). The solvent was removed by evaporation,
and the residue was treated with water (40 mL) and extracted with
ethyl acetate (30 mL × 3). The combined organic layer was dried over
anhydrous sodium sulfate, concentrated, and purified through silica gel
column chromatography (EA/PE 1:99) to afford the desired ketone
2ad as a white solid (2.14 g, 88%). Similarly, ketones 2ab, 2ac, and 2af
were prepared using methyl ethyl ketone, methyl isopropyl ketone,
and acetone, respectively.
4. EXPERIMENTAL SECTION
4.1. 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;
quint, quintet; sext, sextet; m, multiplet; dd, doublet of doublets; dt,
doublet of triplets. The coupling constants (J) are reported in hertz
(Hz). Melting points were determined on a micromelting point
apparatus without corrections. Flash column chromatography was
performed over silica gel 200−300 mesh, and the eluent was a mixture
of ethyl acetate (EA) and petroleum ether (PE). High-resolution mass
spectra (HRMS-ESI) were obtained on a Q-TOF mass spectrometer.
Ethanol was refluxed with magnesium and iodine, followed by
distillation, before being used for the synthesis of pyrazoles 1. All the
α,β-unsaturated aldehydes (2a and 2g−j) were purchased from
commercial sources and were used without further purification. All the
α,β-unsaturated ketones (2k, 2q−x, and 2aa−af) were prepared as
follows.
4.2.5. Preparation of Ketone 2ae.23 A reaction mixture of the 4-
methyl benzaldehyde (1.22 g, 10 mmol) and 2-heptanone (3.57g, 31.3
mmol) in 3 M NaOH (12 mL) was heated to reflux for 16 h (TLC
indicated the conversion was complete). The cooled mixture was
diluted with water (24 mL) and extracted with ethyl ether (20 mL ×
3). The combined organic layer was dried over anhydrous sodium
sulfate, concentrated, and purified through silica gel column
chromatography (EA/PE 5:95) to afford the desired ketone 2ae as a
white solid (1.95 g, 90%).
4.3. Synthesis of Pyrazoles 1. 4.3.1. General Procedure. To a
stirred solution of α,β-unsaturated aldehydes/ketones 2 (0.50 mmol)
and hydrazine HCl salts 3 (0.75 mmol when 2 was aldehyde; 1 mmol
when 2 was ketone) in ethanol (10 mL) was added molecular iodine
(0.75 mmol when 2 was aldehyde; 1 mmol when 2 was ketone), and
then the reaction was heated to reflux for 1 h under a nitrogen
atmosphere. The reaction mixture was concentrated, quenched with
5% Na2S2O3, and then extracted with ethyl acetate (15 mL × 3). The
combined organic layer was dried over anhydrous sodium sulfate,
concentrated, and purified through silica gel column chromatography
using a mixture of EA and PE as eluent to afford the corresponding
pyrazoles 1.
4.2. Preparation of α,β-Unsaturated Ketones 2. 4.2.1. Prep-
aration of Ketones 2k and 2q−w (General Procedure A).19 To a
stirred solution of acetophenone (10 mmol) in methanol (5 mL) was
added dropwise a solution of sodium hydroxide (13 mmol) in
methanol (10 mL). Fifteen minutes later, the resulting mixture was
further treated with substituted benzaldehydes (10 mmol) and stirred
at room temperature (for the preparation of 2w, the reaction was
heated to reflux) until the conversion was complete (disappearance of
acetophenone, monitored by TLC). The solvent was removed by
evaporation, and the residue was treated with water (40 mL) and
extracted with ethyl acetate (30 mL × 3). The combined organic layer
was dried over anhydrous sodium sulfate, concentrated, and purified
through silica gel column chromatography using a mixture of EA and
PE as eluent to afford the corresponding α,β-unsaturated ketones in
38−95% yield.
5-Phenyl-1-(p-tolyl)-1H-pyrazole (1a).24 Yield: 96 mg, 82%; white
solid, mp 74−76 °C; Rf = 0.40 (EA/PE 10:90); H NMR (400 MHz,
CDCl3) δ 7.70 (d, J = 2.0 Hz, 1H), 7.30−7.28 (m, 3H), 7.25−7.22 (m,
2H, overlaps with the peak of chloroform), 7.19−7.11 (m, 4H), 6.49
(d, J = 2.0 Hz, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
142.8, 140.0, 137.7, 137.2, 130.7, 129.4, 128.7, 128.4, 128.0, 125.0,
107.5, 21.0; HRMS (m/z) (M + H) calcd for C16H15N2 235.1230,
found 235.1232.
1
1,5-Diphenyl-1H-pyrazole (1b).25 Yield: 70 mg, 64%; yellow oil; Rf
= 0.52 (EA/PE 10:90); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 1.6
Hz, 1H), 7.34−7.21 (m, 10H, overlaps with the peak of chloroform),
6.51 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 143.0, 140.3,
140.1, 130.6, 128.9, 128.7, 128.4, 128.2, 127.4, 125.2, 107.8; HRMS
(m/z) (M + H) calcd for C15H13N2 221.1073, found 221.1076.
1-(4-Chlorophenyl)-5-phenyl-1H-pyrazole (1c).26 Yield: 104 mg,
82%; yellow semisolid; Rf = 0.45 (EA/PE 5:95); 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J = 1.6 Hz, 1H), 7.33−7.28 (m, 5H), 7.25−7.21 (m,
4H, overlaps with the peak of chloroform), 6.50 (d, J = 1.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 143.0, 140.6, 138.6, 133.0, 130.3,
129.0, 128.7, 128.6, 128.4, 126.2, 108.2; HRMS (m/z) (M + H) calcd
for C15H12ClN2 255.0683, found 255.0686.
4.2.2. Preparation of Ketone 2x.20 To a solution of chalcone 2k
(222 mg, 1.0 mmol) in dry dichloromethane (3 mL) at 0 °C was
added bromine (192 mg, 1.2 mmol) dropwise. The obtained orange
solution was stirred for 1 h at room temperature and then quenched
with an ammonium chloride solution (1 M, 5 mL). It was extracted
with dichloromethane (5 mL × 2), and the combined organic layer
was dried over anhydrous sodium sulfate and concentrated. The
resulting residue was redissolved in chloroform (3 mL) and then
treated with triethylamine (172 mg, 1.7 mmol). The obtained mixture
was stirred overnight at room temperature. After the conversion was
complete (monitored by TLC), it was quenched with 5% HCl solution
(5 mL) and extracted with dichloromethane (5 mL × 2). The
combined organic layer was dried over anhydrous sodium sulfate,
concentrated, and purified through silica gel column chromatography
(EA/PE 0:100−3:97) to afford the desired ketone 2x as a colorless oil
(232 mg, 77%).
5-Phenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole (1d).25 Yield:
130 mg, 90%; white solid, mp 51−53 °C; Rf = 0.42 (EA/PE 5:95); 1H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.4
Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.36−7.33 (m, 3H), 7.25−7.23 (m,
2H, overlaps with the peak of chloroform), 6.53 (d, J = 2.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 143.8, 142.8, 141.1, 130.2, 129.0 (q,
JC−F = 32.6 Hz), 128.8, 128.7, 128.6, 126.0 (q, JC−F = 3.8 Hz), 124.8,
123.8 (d, JC−F = 270.6 Hz), 108.8; HRMS (m/z) (M + H) calcd for
C16H12F3N2 289.0947, found 289.0950.
4.2.3. Preparation of Ketone 2aa.21 A solution of 4-methyl
benzaldehyde (600 mg, 5 mmol) in acetone (10 mL) and water (1
mL) was heated to reflux and then treated with 10% NaOH (1 mL)
slowly. After addition, the reaction mixture was stirred for 6 h at room
temperature (TLC indicated the conversion was complete) and
acidified with 1 M HCl to pH = 2. The product was extracted with
F
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4-(5-Phenyl-1H-pyrazol-1-yl)benzonitrile (1e). Yield: 113 mg,
92%; white solid, mp 82−83 °C; Rf = 0.29 (EA/PE 10:90); 1H
NMR (400 MHz, CDCl3) δ 7.77(d, J = 1.6 Hz, 1H), 7.61 (dt, J = 8.8,
2.0 Hz, 2H), 7.43 (dt, J = 8.8, 2.0 Hz, 2H), 7.39−7.34 (m, 3H), 7.25−
7.22 (m, 2H), 6.54 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 143.4, 143.3, 141.5, 132.9, 130.0, 128.9, 128.81, 128.78, 124.9, 118.2,
110.5, 109.3; HRMS (m/z) (M + H) calcd for C16H12N3 246.1026,
found 246.1030.
7.37−7.33 (m, 1H), 7.17 (s, 4H), 6.80 (s, 1H), 2.38 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 152.6, 144.7, 142.9, 138.8, 132.7, 129.4, 129.0,
128.68, 128.65, 128.2, 127.3, 126.0 (q, JC−F = 4.0 Hz), 125.8, 124.8,
123.9 (d, JC−F = 270.8 Hz), 106.0, 21.3; HRMS (m/z) (M + H) calcd
for C23H18F3N2 379.1417, found 379.1425.
4-(3-Phenyl-5-(p-tolyl)-1H-pyrazol-1-yl)benzonitrile (1o). Yield:
150 mg, 93%; white solid, mp 150−152 °C; Rf = 0.56 (EA/PE
1
15:85); H NMR (400 MHz, CDCl3) δ 7.91−7.89 (m, 2H), 7.62−
1-(2,4-Dichlorophenyl)-5-phenyl-1H-pyrazole (1f).26 Yield: 123
7.59 (m, 2H), 7.51−7.42 (m, 4H), 7.38−7.34 (m, 1H), 7.20−7.15 (m,
4H), 6.80 (s, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
153.0, 144.8, 143.5, 139.1, 132.8, 132.4, 129.5, 128.7, 128.65, 128.4,
127.1, 125.9, 124.8, 118.4, 110.2, 106.6, 21.3; HRMS (m/z) (M + H)
calcd for C23H18N3 336.1495, found 336.1503.
1
mg, 85%; white solid, mp 60−62 °C; Rf = 0.48 (EA/PE 10:90); H
NMR (400 MHz, CDCl3) δ 7.77 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 2.0
Hz, 1H), 7.35−7.26 (m, 5H), 7.20−7.17 (m, 2H), 6.55 (d, J = 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 145.0, 141.0, 136.8, 135.3,
133.1, 130.6, 130.2, 129.8, 128.5, 128.4, 127.9, 127.8, 106.6; HRMS
(m/z) (M + H) calcd for C15H11Cl2N2 289.0294, found 289.0297.
5-(4-Methoxyphenyl)-1-(p-tolyl)-1H-pyrazole (1g). Yield: 98 mg,
1-(2,4-Dichlorophenyl)-3-phenyl-5-(p-tolyl)-1H-pyrazole (1p).
Yield: 180 mg, 95%; white solid, mp 136−138 °C; Rf = 0.55 (EA/
1
PE 8:92); H NMR (400 MHz, CDCl3) δ 7.90−7.88 (m, 2H), 7.45−
1
7.40 (m, 4H), 7.36−7.31 (m, 2H), 7.13−7.08 (m, 4H), 6.82 (s, 1H),
2.32(s, 3H). 13C NMR (100 MHz, CDCl3) δ 152.7, 146.4, 138.5,
137.0, 135.3, 133.3, 132.8, 130.8, 130.2, 129.3, 128.6, 128.1, 127.83,
127.75, 126.9, 125.9, 103.6, 21.2; HRMS (m/z) (M + H) calcd for
C22H17Cl2N2 379.0763, found 379.0767.
74%; yellow syrup; Rf = 0.46 (EA/PE 15:85); H NMR (400 MHz,
CDCl3) δ 7.68 (d, J = 2.0 Hz, 1H), 7.19−7.12 (m, 6H), 6.84−6.80 (m,
2H), 6.43 (d, J = 2.0 Hz, 1H), 3.79 (s, 3H), 2.35 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 159.4, 142.7, 140.0, 137.8, 137.1, 130.0, 129.4,
125.0, 123.1, 113.8, 107.0, 55.2, 21.1; HRMS (m/z) (M + H) calcd for
C17H17N2O 265.1335, found 265.1343.
3,5-Diphenyl-1-(p-tolyl)-1H-pyrazole (1q).28 Yield: 147 mg, 95%;
white solid, mp 106−108 °C; Rf = 0.50 (EA/PE 7:93); 1H NMR (400
MHz, CDCl3) δ 7.93−7.91 (m, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.34−
7.23 (m, 8H, overlaps with the peak of chloroform), 7.14 (d, J = 8.0
Hz, 2H), 6.81 (s, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
151.7, 144.2, 137.7, 137.3, 133.1, 130.7, 129.5, 128.7, 128.6, 128.4,
128.2, 127.9, 125.8, 125.1, 104.9, 21.1; HRMS (m/z) (M + H) calcd
for C22H19N2 311.1543, found 311.1545.
5-(4-Bromophenyl)-1-(p-tolyl)-1H-pyrazole (1h). Yield: 123 mg,
1
79%; white solid, mp 115−117 °C; Rf = 0.36 (EA/PE 10:90); H
NMR (400 MHz, CDCl3) δ 7.70 (d, J = 2.0 Hz, 1H), 7.43−7.41 (m,
2H), 7.15 (s, 4H), 7.11−7.07 (m, 2H), 6.49 (d, J = 2.0 Hz, 1H), 2.37
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 141.7, 140.1, 137.6, 137.4,
131.6, 130.2, 129.59, 129.55, 125.0, 122.3, 107.6, 21.1; HRMS (m/z)
(M + H) calcd for C16H14BrN2 313.0335, found 313.0339.
5-(4-Methoxyphenyl)-3-phenyl-1-(p-tolyl)-1H-pyrazole (1r). Yield:
153 mg, 90%; white solid, mp 41−43 °C; Rf = 0.42 (EA/PE 10:90);
1H NMR (400 MHz, CDCl3) δ 7.92−7.90 (m, 2H), 7.43−7.39 (m,
2H), 7.32(t, J = 7.2 Hz, 1H), 7.26−7.24 (m, 2H, overlaps with the
peak of chloroform), 7.21−7.19 (m, 2H), 7.15−7.13 (m, 2H), 6.86−
6.83 (m, 2H), 6.75 (s, 1H), 3.81 (s, 3H), 2.36 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.5, 151.6, 144.1, 137.8, 137.2, 133.2, 130.0, 129.4,
128.6, 127.8, 125.7, 125.1, 123.1, 113.8, 104.4, 55.2, 21.1; HRMS (m/
z) (M + H) calcd for C23H21N2O 341.1648, found 341.1652.
5-(4-Chlorophenyl)-3-phenyl-1-(p-tolyl)-1H-pyrazole (1s). Yield:
153 mg, 89%; white solid, mp 126−127 °C; Rf = 0.48 (EA/PE 7:93);
1H NMR (400 MHz, CDCl3) δ 7.91−7.89 (m, 2H), 7.42 (t, J = 7.6
Hz, 2H), 7.35−7.27 (m, 3H), 7.24−7.15 (m, 6H), 6.79 (s, 1H), 2.37
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.8, 143.0, 137.6, 137.5,
134.2, 132.9, 129.9, 129.6, 129.1, 128.7, 128.6, 128.0, 125.7, 125.2,
105.0, 21.1; HRMS (m/z) (M + H) calcd for C22H18ClN2 345.1153,
found 345.1158.
4-Methyl-5-phenyl-1-(p-tolyl)-1H-pyrazole (1i). Yield: 95 mg,
77%; yellow syrup; Rf = 0.40 (EA/PE 10:90); H NMR (400 MHz,
1
CDCl3) δ 7.58 (s, 1H), 7.35−7.29 (m, 3H), 7.18−7.15 (m, 2H),
7.11−7.04 (m, 4H), 2.30 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 140.8, 139.7, 137.9, 136.5, 130.7, 129.8, 129.2, 128.4, 127.9,
124.5, 116.1, 21.0, 9.2; HRMS (m/z) (M + H) calcd for C17H17N2
249.1386, found 249.1395.
5-Methyl-1-(p-tolyl)-1H-pyrazole (1j).27 Yield: 40 mg, 23% (1
1
mmol scale); white semisolid; Rf = 0.58 (EA/PE 10:90); H NMR
(400 MHz, CDCl3) δ 7.75 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz,
2H), 7.21 (d, J = 8.4 Hz, 2H), 6.21 (d, J = 2.4 Hz, 1H), 2.37(s, 3H),
2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.2, 138.0, 135.6,
129.8, 127.3, 118.8, 107.1, 20.8, 13.7; HRMS (m/z) (M +H) calcd for
C11H13N2 173.1073, found 173.1077.
3-Phenyl-1,5-di-p-tolyl-1H-pyrazole (1k). Yield: 147 mg, 91%;
1
white solid, mp 91−93 °C; Rf = 0.48 (EA/PE 7:93); H NMR (400
MHz, CDCl3) δ 7.92−7.90 (m, 2H), 7.43−7.39 (m, 2H), 7.34−7.30
(m, 1H), 7.26−7.24 (m, 2H, overlaps with the peak of chloroform),
7.18−7.10 (m, 6H), 6.77 (s, 1H), 2.35 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 151.6, 144.3, 138.1, 137.8, 137.2, 133.2, 129.4,
129.1, 128.56, 128.55, 127.8, 127.7, 125.8, 125.1, 104.7, 21.3, 21.1;
HRMS (m/z) (M + H) calcd for C23H21N2 325.1699, found 325.1706.
1,3-Diphenyl-5-(p-tolyl)-1H-pyrazole (1l).2e Yield: 132 mg, 85%;
white solid, mp 110−112 °C; Rf = 0.55 (EA/PE 8:92); 1H NMR (400
MHz, CDCl3) δ 7.93−7.91 (m, 2H), 7.44−7.27 (m, 8H), 7.17−7.10
(m, 4H), 6.79 (s, 1H), 2.34 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
151.9, 144.4, 140.2, 138.2, 133.1, 129.2, 128.9, 128.59, 128.58, 127.9,
127.7, 127.3, 125.8, 125.3, 104.9, 21.3; HRMS (m/z) (M + H) calcd
for C22H19N2 311.1543, found 311.1550.
5-(2-Fluorophenyl)-3-phenyl-1-(p-tolyl)-1H-pyrazole (1t). Yield:
1
153 mg, 93%; white semisolid; Rf = 0.42 (EA/PE 7:93); H NMR
(400 MHz, CDCl3) δ 7.93−7.91 (m, 2H), 7.42 (t, J = 8.0 Hz, 2H),
7.35−7.30 (m, 2H), 7.25−7.21 (m, 3H, overlaps with the peak of
chloroform), 7.13−7.04 (m, 4H), 6.86 (s, 1H), 2.33 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 159.4 (d, JC−F = 249 Hz), 151.8, 137.9,
137.8, 137.2, 133.0, 131.3 (d, JC−F = 2.4 Hz), 130.4 (d, JC−F = 8.1 Hz),
129.4, 128.6, 127.9, 125.8, 124.2, 124.1 (d, JC−F = 3.7 Hz), 118.9 (d,
JC−F = 14.6 Hz), 116.1 (d, JC−F = 21.6 Hz), 106.5 (d, JC−F = 2.0 Hz),
21.0; HRMS (m/z) (M + H) calcd for C22H18FN2 329.1448, found
329.1452.
5-(3-Nitrophenyl)-3-phenyl-1-(p-tolyl)-1H-pyrazole (1u). Yield:
167 mg, 94%; white solid, mp 141−143 °C; Rf = 0.38 (EA/PE
10:90); 1H NMR (400 MHz, CDCl3) δ 8.20 (t, J = 2.0 Hz, 1H), 8.17−
8.14 (m, 1H), 7.93−7.90 (m, 2H), 7.52−7.50 (m, 1H), 7.47−7.41 (m,
3H), 7.37−7.33 (m, 1H), 7.24−7.16 (m, 4H), 6.92 (s, 1H), 2.37 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 152.0, 148.2, 141.7, 138.2,
137.0, 134.3, 132.6, 132.2, 129.8, 129.4, 128.7, 128.2, 125.8, 125.3,
123.3, 122.8, 105.5, 21.1; HRMS (m/z) (M + H) calcd for
C22H18N3O2 356.1394, found 356.1402.
1-(4-Chlorophenyl)-3-phenyl-5-(p-tolyl)-1H-pyrazole (1m). Yield:
155 mg, 90%; white solid, mp 129−130 °C; Rf = 0.55 (EA/PE 7:93);
1H NMR (400 MHz, CDCl3) δ 7.91−7.89 (m, 2H), 7.44−7.41 (m,
2H), 7.36−7.31 (m, 5H), 7.15 (t, J = 9.2 Hz, 4H), 6.78 (s, 1H), 2.37
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.2, 144.5, 138.7, 138.5,
132.9, 129.3, 129.0, 128.63, 128.60, 128.1, 127.4, 126.3, 125.8, 105.3,
21.3; HRMS (m/z) (M + H) calcd for C22H18ClN2 345.1153, found
345.1160.
5-(Furan-2-yl)-3-phenyl-1-(p-tolyl)-1H-pyrazole (1v). Yield: 111
3-Phenyl-5-(p-tolyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole
1
(1n). Yield: 181 mg, 96%; white solid, mp 121−122 °C; Rf = 0.60
mg, 74%; white semisolid; Rf = 0.44 (EA/PE 7:93); H NMR (400
1
(EA/PE 5:95); H NMR (400 MHz, CDCl3) δ 7.92−7.90 (m, 2H),
MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 2H), 7.43−7.24 (m, 8H, overlaps
with the peak of chloroform), 6.97 (s, 1H), 6.33 (q, J = 2.0 Hz, 1H),
7.59 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.45−7.41 (m, 2H),
G
dx.doi.org/10.1021/jo501844x | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5.96 (d, J = 3.2 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
151.8, 144.6, 142.4, 138.6, 137.8, 135.8, 132.9, 129.7, 128.6, 128.0,
125.9, 125.8, 111.2, 108.7, 103.0, 21.2; HRMS (m/z) (M + Na) calcd
for C20H16N2ONa 323.1155, found 323.1161.
4.4. Synthesis of Pyrazoles 1k via Pyrazoline 5k. A solution of
chalcone 2k (222 mg, 1 mmol) and hydrazine HCl salts 3a (476 mg, 3
mmol) in methanol (10 mL) was treated with conc. sulfuric acid (1
mL) slowly and then heated to reflux for 24 h.17 After it cooled to
room temperature, the reaction mixture was neutralized with saturated
aq. sodium bicarbonate and extracted with ethyl acetate (15 mL × 3).
The combined organic layer was dried over anhydrous sodium sulfate,
concentrated, and purified through silica gel column chromatography
using a mixture of EA and PE (5:95) as eluent to afford pyrazoline 5k
as a light-yellow solid (261 mg, 80%). mp 117−118 °C; Rf = 0.67
4-Methyl-3-phenyl-1,5-di-p-tolyl-1H-pyrazole (1w). Yield: 115
mg, 68%; white solid, mp 115−116 °C; Rf = 0.45 (EA/PE 7:93);
1H NMR (400 MHz, CDCl3) δ 7.82−7.79 (m, 2H), 7.44 (t, J = 7.6
Hz, 2H), 7.36−7.32 (m, 1H), 7.19−7.06 (m, 8H), 2.37 (s, 3H), 2.31
(s, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.9, 141.4,
137.9, 136.4, 134.0, 129.9, 129.2, 129.1, 128.3, 127.9, 127.8, 127.4,
124.6, 113.7, 21.3, 21.0, 10.2; HRMS (m/z) (M + H) calcd for
C24H23N2 339.1856, found 339.1858.
1
(EA/PE 5:95); H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz,
2H), 7.34 (t, J = 7.6 Hz, 2H), 7.29−7.26 (m, 1H, overlapped with the
peak of chloroform), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H),
6.97 (t, J = 9.2 Hz, 4H), 5.16 (dd, J = 12.4, 7.6 Hz, 1H), 3.74 (dd, J =
17.2, 12.4 Hz, 1H), 3.06 (dd, J = 17.2, 7.6 Hz, 1H), 2.29 (s, 3H), 2.21
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.3, 142.9, 139.8, 137.2,
133.0, 129.8, 129.5, 128.6, 128.4, 128.3, 125.9, 125.7, 113.6, 64.7, 43.7,
21.2, 20.6. MS (m/z) (M +H) calcd for C23H23N2 327, found 327.
To a stirred solution of pyrazoline 5k (163 mg, 0.5 mmol) in
ethanol (10 mL) was added molecular iodine (1 mmol), and then the
reaction was heated to reflux under a nitrogen atmosphere until TLC
indicated that the conversion was complete (36 h). The reaction
mixture was concentrated, quenched with sat. 5% Na2S2O3, and then
extracted with ethyl acetate (15 mL × 3). The combined organic layer
was dried over anhydrous sodium sulfate, concentrated, and purified
through silica gel column chromatography using a mixture of EA and
PE as eluent to afford pyrazole 1k as a white solid (146 mg, 90%).
3-Phenyl-5-(p-tolyl)-1H-pyrazole (1y).13e Yield: 88 mg, 75%; white
1
solid, mp 174−176 °C; Rf = 0.55 (EA/PE 30:70); H NMR (400
MHz, DMSO-d6) δ 13.26 (s, 1H), 7.80 (d, J = 7.6 Hz, 2H), 7.69 (d, J
= 8.0 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.22
(d, J = 7.6 Hz, 2H), 7.09 (s, 1H), 2.29 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 137.5, 129.8, 129.2, 128.1, 125.50, 125.45, 99.7, 21.2;
HRMS (m/z) (M + H) calcd for C16H15N2 235.1230, found 235.1233.
5-(4-Chlorophenyl)-3-phenyl-1H-pyrazole (1z). Yield: 88 mg, 69%;
1
white solid, mp 212−214 °C; Rf = 0.65 (EA/PE 30:70); H NMR
(400 MHz, DMSO-d6) δ 13.42 (s, 1H), 7.84−7.78 (m, 4H), 7.48−
7.40 (m, 4H), 7.32−7.31 (m, 1H), 7.19 (s, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 132.6, 129.3, 129.2, 128.4, 127.2, 125.5, 100.3; HRMS
(m/z) (M + H) calcd for C15H12ClN2 255.0684, found 255.0691.
3-Methyl-1,5-di-p-tolyl-1H-pyrazole (1aa). Yield: 105 mg, 80%;
1
white solid, mp 46−48 °C; Rf = 0.40 (EA/PE 10:90); H NMR (400
MHz, CDCl3) δ 7.16−7.14 (m, 2H), 7.12−7.07 (m, 6H), 6.26 (s, 1H),
2.37 (s, 3H), 2.335 (s, 3H), 2.328 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 149.0, 143.7, 137.9, 137.6, 136.9, 129.4, 129.0, 128.4, 127.8,
125.0, 107.2, 21.2, 21.0, 13.5; HRMS (m/z) (M + H) calcd for
C18H19N2 263.1543, found 263.1547.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of pyrazoles 1, and
crystallographic data of pyrazoles 1e and 1m in CIF (CCDC
1016873−1016874). This material is available free of charge via
the Internet at http://pubs.acs.org.
3-Ethyl-1,5-di-p-tolyl-1H-pyrazole (1ab). Yield: 98 mg, 71%; white
1
solid, mp 56−58 °C; Rf = 0.50 (EA/PE 10:90); H NMR (400 MHz,
CDCl3) δ 7.17−7.06 (m, 8H), 6.29 (s, 1H), 2.75 (q, J = 7.6 Hz, 2H),
2.32 (d, J = 2.4 Hz, 6H), 1.33 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 155.1, 143.5, 137.81, 137.76, 136.8, 129.4, 129.0,
128.5, 128.0, 125.0, 105.7, 21.5, 21.2, 21.0, 13.9; HRMS (m/z) (M +
H) calcd for C19H21N2 277.1699, found 277.1702.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: changjunbiao@zzu.edu.cn (J.C.).
*E-mail: wenquan_yu@zzu.edu.cn (W.Y.).
■
3-Isopropyl-1,5-di-p-tolyl-1H-pyrazole (1ac). Yield: 103 mg, 71%;
1
white solid, mp 76−78 °C; Rf = 0.46 (EA/PE 5:95); H NMR (400
MHz, CDCl3) δ 7.18−7.15 (m, 2H), 7.12−7.06 (m, 6H), 6.29 (s, 1H),
3.08 (heptet, J = 6.8 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 1.34 (d, J =
6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 159.6, 143.2, 137.9,
137.7, 136.7, 129.3, 129.0, 128.5, 128.1, 125.0, 104.2, 27.9, 22.9, 21.2,
21.0; HRMS (m/z) (M + H) calcd for C20H23N2 291.1856, found
291.1859.
3-(tert-Butyl)-1,5-di-p-tolyl-1H-pyrazole (1ad). Yield: 140 mg,
92%; white solid, mp 106−108 °C; Rf = 0.67 (EA/PE 5:95); 1H
NMR (400 MHz, CDCl3) δ 7.19−7.16 (m, 2H), 7.12−7.06 (m, 6H),
6.31 (s, 1H), 2.32 (s, 6H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 162.2, 142.9, 138.1, 137.6, 136.6, 129.3, 129.0, 128.5, 128.3, 125.1,
104.1, 32.2, 30.6, 21.2, 21.0; HRMS (m/z) (M + H) calcd for
C21H25N2 305.2012, found 305.2021.
3-Pentyl-1,5-di-p-tolyl-1H-pyrazole (1ae). Yield: 107 mg, 67%;
yellow syrup; Rf = 0.50 (EA/PE 5:95); 1H NMR (400 MHz, CDCl3) δ
7.17−7.15 (m, 2H), 7.12−7.06 (m, 6H), 6.27 (s, 1H), 2.70 (t, J = 8.0
Hz, 2H), 2.33 (d, J = 2.4 Hz, 6H), 1.73 (quint, J = 7.6 Hz, 2H), 1.43−
1.35 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 154.0, 143.4, 137.9, 137.7, 136.7, 129.3, 129.0, 128.4, 128.1, 125.0,
106.1, 31.8, 29.4, 28.3, 22.5, 21.2, 21.0, 14.1; HRMS (m/z) (M + H)
calcd for C22H27N2 319.2169, found 319.2173.
(E)-3-(4-Methylstyryl)-1,5-di-p-tolyl-1H-pyrazole (1af). Yield: 160
mg, 88%; white solid, mp 174−176 °C; Rf = 0.50 (EA/PE 10:90); 1H
NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 2H), 7.21−7.09 (m,
12H), 6.67 (s, 1H), 2.35 (s, 6H), 2.34(s, 3H); 13C NMR (100 MHz,
CDCl3) δ 151.0, 144.1, 138.1, 137.7, 137.5, 137.1, 134.4, 130.3,
129.43, 129.36, 129.1, 128.5, 127.6, 126.4, 125.0, 119.6, 104.4, 21.3,
21.1; HRMS (m/z) (M + H) calcd for C26H25N2 365.2012, found
365.2019.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21172202, 81302637, and 81330075) and the China
Postdoctoral Science Foundation (Nos. 2013M530341 and
2014T70690) for financial support.
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I
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