Oxidative aromatization of 1,3,5-trisubstituted pyrazolines using hydrogen tetrachloroaurate as catalyst under an oxygen atmosphere

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Oxidative Aromatization of 1,3,5-
Trisubstituted Pyrazolines Using
Hydrogen Tetrachloroaurate as Catalyst
Under an Oxygen Atmosphere
Yunkui Liu a , Dajie Mao a , Shaojie Lou a , Jianqing Qian a & Zhen-
Yuan Xu a
a State Key Laboratory Breeding Base of Green Chemistry-Synthesis
Technology , Zhejiang University of Technology , Hangzhou, P. R.
China
Published online: 01 Jun 2009.
To cite this article: Yunkui Liu , Dajie Mao , Shaojie Lou , Jianqing Qian & Zhen-Yuan Xu (2009)
Oxidative Aromatization of 1,3,5-Trisubstituted Pyrazolines Using Hydrogen Tetrachloroaurate as
Catalyst Under an Oxygen Atmosphere, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 41:3, 237-242, DOI: 10.1080/00304940902956119
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Organic Preparations and Procedures International, 41:237–242, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304940902956119
Oxidative Aromatization of 1,3,5-Trisubstituted
Pyrazolines Using Hydrogen Tetrachloroaurate
as Catalyst Under an Oxygen Atmosphere
Yunkui Liu, Dajie Mao, Shaojie Lou, Jianqing Qian,
and Zhen-Yuan Xu
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology,
Zhejiang University of Technology Hangzhou, P. R. China
Today gold is without a doubt the “star metal” in chemistry because of the focus of
attention on gold-catalyzed organic transformations in recent years.1–7 Among various new
transformations catalyzed by gold, those involving nucleophilic additions to C-C multiple
bonds (alkynes, alkenes or allenes)8–10 and catalytic C-H bond functionalization11,12, have
been studied intensively. In contrast, gold-catalyzed oxidation chemistry, in particular
gold as heterogeneous and/or homogeneous catalyst for selective oxidation reactions with
economic and environmentally benign oxidants, such as dioxygen or hydrogen peroxide, has
been less developed.13 Thus far, representative oxidation transformations are mainly limited
in oxidation of monoxide,14–16 alcohols,17–24 amines25,26 and sulfides,27,28 epoxidations of
olefins,29 oxidative cleavage of carbon-carbon multiple bonds,30,31 etc. Therefore, it is still
desirable to extend gold-catalyzed oxidation chemistry.
1,3,5-trisubstituted pyrazoles are one class of important compounds because heterocy-
cles containing pyrazole moieties often exhibit valuable biological and medicinal activities,
such as analgestic, anti-inflammatory, antipyretic, anti-arrhythmic, psychoanaleptic, antidi-
abetic and antibacterial ones.32–37 Generally, oxidative aromatization of 1,3,5-trisubstituted
pyrazolines which could be easily prepared from the condensation of chalcones with
arylhydrazines,38 is the most widely used protocol for synthesis of 1,3,5-trisubstituted
pyrazole derivatives. To date, a variety of oxidants have been used for the purpose, e.g.
zirconium (IV) nitrate,39 lead (IV) tetraacetate,40 silver (I) nitrate,41 bismuth (III) nitrate,42
manganese (IV) dioxide,43 potassium permanganate,44 mercury (II) oxide,45 iodobenzene
diacetate,46 sodium nitrite and sodium nitrate in acetic acid,47 trichloroisocyanuric acid,48
4-(p-chloro)phenyl-1,3,4-triazole-3,5-dione,49 Pd/C,50 iodine pentoxide or iodic acid,51 ac-
tivated carbon/oxygen system,52 and N-hydroxyphthalimide (NHPI)/cobalt acetate/oxygen
sytem,53 etc. However, these processes have one or more limitations including high catalyst
Received January 2, 2009; in final form March 20, 2009.
Address correspondence to Zhen-Yuan Xu, State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou, 310014, P. R.
China. E-mail: greensyn@zjut.edu.cn
237

238
Xu et al.
1
2
.
1
2
HAuCl4 4H2O (1 mol%)
R
R
R
R
O2 (balloon)
HOAc, 50 °C, 2-4 hr.
N
N
N
N
Ph
Ph
2
1
a) R1 = C6H5, R2 = C6H5, b) R1 = C6H5, R2 = 4-CH3C6H4, c) R1 = C6H5, R2 = 4-CH3OC6H4,
d) R1 = C6H5, R2 = 4-ClC6H4, e) C6H5, R2 = 4-BrC6H4, f) R1 = C6H5, R2 = 4-NO2C6H4,
g) R1 = C6H5, R2 = 2,4-Cl2C6H3, h) R1 = C6H5, R2 = 2-furyl, i) R1 = 4-ClC6H4, R2 = C6H5,
j) R1 = 4-ClC6H4, R2 = 4-ClC6H4, k) R1 = 4-BrC6H4, R2 = C6H5, l) R1 = 4-BrC6H4, R2 = 4-ClC6H4,
m) R1 = 4-CH3C6H4, R2 = 4-ClC6H4
Figure 1
loading, or using stoichiometric, even excess amounts of oxidants (other than dioxygen)
relative to the substrates, long reaction times, high temperature, troublesome for disposal
problems, and using toxic reagents. As part of our continued effort in synthesis of useful
heterocycles,54 we now report an efficient oxidative aromatization of 1,3,5-trisubstituted
pyrazolines to the corresponding pyrazoles in good to excellent yields by using only
1 mol% of hydrogen tetrachloroaurate as catalyst under oxygen atmosphere.
Initially, 1,3,5-trisubstituted pyrazoline 1a was chosen as a model substrate for opti-
mization of the reaction conditions (Figure 1, Table 1). The reaction hardly occurs in the
Table 1
Optimization of Reaction Conditionsa
Catalyst
(0.01 mmol)
Temperature
(◦C)
Time
(hrs)
Yield
(%)b
Entry
Solvent
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
THF
1
2
3
4
5
6
7
8
9
10
11
12
13
14
none
50
50
50
50
50
40
50
50
50
50
50
50
50
50
2
2
2
2
2
2
2
2
4
4
4
4
4
4
<5
55
70
83
95
83c
91
87
85
84
70
50
38
16
AuCl
NaAuCl4·2H2O
AuCl3
HAuCl4·4H2O (3)
3
3
3
3
3
3
3
3
3
EtOH
ClCH2CH2Cl
Toluene
CH3CN
DMF
CH2Cl2
Acetone
a) Carried out on 1 mmol scale of 1a in the presence of catalyst in 2 mL solvent under oxygen
atmosphere (balloon).
b) Isolated yield.
c) 30% Aqueous H2O2 solution (2 mmol) was used as oxidant.

Aromatization of 1,3,5-Trisubstituted Pyrazolines
239
absence of a gold catalyst (Entry 1). Treatment of 1a with 1 mol% of AuCl at 50◦C for 2 h
in HOAc under an oxygen atmosphere gave the aromatized product 2a in 55% yield (Entry
2). Under the catalysis of NaAuCl4·2H2O and AuCl3, the yield of 2a was improved to be
70% and 83%, respectively (Entries 3, 4). HAuCl4·4H2O proved to be the ideal catalyst
for conducting this reaction, giving 2a in 95% yield when employed in HOAc at 50◦C for
2 h under an oxygen atmosphere (Entry 5). The yield of 2a decreased to 83% when 30%
aqueous H2O2 solution was used as oxidant catalyzed by HAuCl4·4H2O (Entry 6). The
reaction was successful in THF, EtOH, toluene and 1,2-dichloroethane, which gave 2a in
good yields (Entries 7–10, 84%–91%); while CH3OH, CH3CN, CH2Cl2 and acetone are
not good choice (Entries 11–14).
With optimized conditions in hand, we next turned our attention to examine the scope
of the reaction and the results are presented in Table 2. Various substituted pyrazolines
were tested to establish its generality and efficiency, and all reactions proceeded smoothly
under similar conditions. The experimental results showed that there is not much difference
between substituent containing electron-donating and electron-withdrawing functionalities
on R1 and R2 with respect to reaction times and yields of products. The present reaction
conditions tolerate several functionalities such as halogen, nitro, methoxy and ether groups.
In summary, we have described an efficient protocol for oxidative aromatization of
1,3,5-trisubstituted pyrazolines to the corresponding pyrazoles by using only 1 mol% of
HAuCl4·4H2O as catalyst under oxygen atmosphere. The advantages of the method are
lower catalyst loading, good to excellent yields, mild reaction conditions, and simple
operational procedures.
Experimental Section
Melting points are uncorrected. 1H NMR and 13C NMR spectra were obtained on a Bruker
AVANCE III 500 (500 MHz) instrument in CDCl3 using TMS as internal standard. Chemical
shifts (δ) are expressed in ppm and coupling constants J are given in Hz. Mass spectra were
obtained on a HP 5989B mass spectrometer. Elemental analyses were performed on an
EA-1110 instrument. TLC analyses were performed on Merck silica gel 60 F254. GC-
MS analyses were performed with an Agilent 6890N GC system equipped with a 5973N
mass-selective detector. All gold catalysts were purchased from Aldrich.
General Procedure
A two-necked flask (25 mL) was charged with 1,3,5-trisubstituted pyrazolines 1 (1.0 mmol),
HAuCl4·4H2O (4.0 mg, 0.01 mmol) and HOAc (2 mL). Then the flask was fitted with a
balloon filled with dioxygen and the reaction mixture heated to 50◦C and stirred for
2–4 h under oxygen atmosphere. Upon complete consumption of 1 monitored by TLC
and GC-MS analyses, the resulting mixture was filtered to remove the gold catalyst, the
filtrate was poured into saturated NaHCO3 solution (10 mL) and extracted with ethyl acetate
(40 mL × 3). The organic layer was dried over anhydrous MgSO4. After evaporation of
solvent under vacuum and the residue was purified by chromatography using hexane/ethyl
acetate (15:1) as eluent. All the products are isolated as white or light yellow solids.
The HAuCl4·4H2O/HOAc catalyst system could be directly reused at least for two
cycles with similar activity and chemoselectivity after product 2 had been extracted with
ether from the reaction mixture.28

240
Xu et al.
Table 2
Yields, mps., Elemental Analysis and Spectral Data of Compounds 2
Elemental Analysis
mp.
(◦C)
(lit. mp.)
MS
m/z
(M+)
(Found)
Yield
Cmpd (%)
1H NMR
(δ)
13N NMR
(δ)
C
H
N
2a50
2b55
2c50
95 139.1–140.0 7.93 (d, 2H, J = 8.5 Hz), 7.94–7.92
(141–142) (m, 13H), 6.82 (s, 1H)
97 114.5–115.6 7.81 (d, 2H, J = 8.0 Hz), 7.38–7.23
(116–117) (m, 12H), 6.79 (s, 1H), 2.38 (s, 3H)
296
310
326
—
—
—
—
—
—
—
—
—
98
79.0–79.8 7.93 (d, 2H, J = 8.0 Hz), 7.43–7.18
(79–80)
(m, 10H), 6.83 (d, 2H, J = 8.5 Hz),
6.76 (s, 1H), 3.79 (s, 3H)
2d50
2e47
2f50
87 114.4–115.2 7.85 (d, 2H, J = 8.5 Hz), 7.40–7.25
(114–115) (m, 12H), 6.79 (s, 1H)
89 128.7–129.6 7.77 (d, 2H, J = 8.0 Hz), 7.34–7.19
(126–128) (m, 12H), 6.75 (s, 1H)
330
374
341
—
—
—
—
—
—
—
—
—
77 142.1–142.9 8.25 (d, 2H, J = 8.5 Hz), 8.05 (d, 2H,
(142–144)
J = 8.5 Hz), 7.44–7.31 (m, 10H),
6.89 (s, 1H)
2g
85
75.9–76.5 7.92 (d, 2H, J = 9.0 Hz), 7.42–7.22 151.89, 139.99, 364 69.05 3.86 7.67
(m, 11H), 6.80 (s, 1H)
139.95, 135.60,
134.80, 132.85,
129.98, 129.02,
128.93, 128.76,
128.21, 127.41,
127.28, 125.88,
124.13, 107.06
(69.23) (3.84) (7.70)
2h
81 108.2–109.3 7.90 (d, 2H, J = 8.5 Hz), 7.48–7.38 152.03, 144.47, 286 79.70 4.93 9.78
(m, 9H), 6.97 (s, 1H), 6.31 142.60, 140.31, (79.86) (4.96) (9.74)
(d, 1H, J = 4.0 Hz), 5.96 (d, 1H, 135.79, 132.83,
J = 3.5 Hz)
129.14, 128.70,
128.47, 128.12,
126.04, 125.87,
111.31, 108.96,
103.41
2i56
2j39
2k46
93 134.6–135.4 7.85 (d, 2H, J = 8.0 Hz), 7.40–7.25
330
364
374
—
—
—
—
—
—
—
—
—
(137–140)
(m, 12H), 6.79 (s, 1H)
92 141.4–141.9 7.82 (d, 2H, J = 8.0 Hz), 7.39–7.17
(140–141) (m, 11H), 6.76 (s, 1H)
94 160.5–161.5 7.79 (d, 2H, J = 8.5 Hz), 7.55
(156–157)
(d, 2H, J = 8.5 Hz), 7.36–7.25
(m, 10H), 6.79 (s, 1H)
2l
91 131.1–132.1 7.80 (d, 2H, J = 8.5 Hz), 7.54
150.97, 143.40, 410 61.56 3.44 6.84
(d, 2H, J = 8.5 Hz), 7.38–7.16
139.76, 134.53,
131.85, 131.82,
129.95, 129.13,
128.85, 128.79,
127.85, 127.34,
125.30, 122.06,
105.18
(61.42) (3.41) (6.88)
(m, 9H), 6.77 (s, 1H)
2m
92 109.5–110.4 7.80 (d, 2H, J = 8.0 Hz), 7.35–
152.18, 143.10, 344 76.63 4.97 8.12
(76.79) (4.92) (8.16)
7.18 (m, 11H), 6.77 (s, 1H), 2.38 139.94, 137.94,
(s, 3H)
134.34, 130.05,
129.98, 129.42,
129.08, 128.79,
127.63, 125.74,
125.36, 105.18,
21.37

Aromatization of 1,3,5-Trisubstituted Pyrazolines
Acknowledgements
241
We are grateful to the Natural Science Foundation of Zhejiang Province (No. Y407168) and
the Opening Foundation of Zhejiang Provincial Top Key Discipline for financial support.
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