Iron(III) phthalocyanine chloride-catalyzed oxidation-aromatization of α,β-unsaturated ketones with hydrazine hydrate: Synthesis of 3,5-disubstituted 1H-pyrazoles

Article abstract of DOI:10.1016/S1872-2067(15)61043-9

We have developed an iron(III) phthalocyanine chloride-catalyzed oxidation-aromatization of α,β-unsaturated ketones with hydrazine hydrate. Various 3,5-disubstituted 1H-pyrazoles were obtained in good to excellent yields. This method offers several advantages, including room-temperature conditions, short reaction time, high yields, simple work-up procedure, and use of air as an oxidant. The catalyst can be recovered and reused five times without loss of activity.

Full text of DOI:10.1016/S1872-2067(15)61043-9

Chinese Journal of Catalysis 37 (2016) 571–578
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
Iron(III) phthalocyanine chloride‐catalyzed
oxidation–aromatization of α,β‐unsaturated ketones with
hydrazine hydrate: Synthesis of 3,5‐disubstituted 1H‐pyrazoles
Junlong Zhao*, Jun Qiu, Xiaofeng Gou, Chengwen Hua, Bang Chen
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials Science, Northwest
University, Xi’an 710069, Shaanxi, China
A R T I C L E I N F O
A B S T R A C T
Article history:
We have developed an iron(III) phthalocyanine chloride‐catalyzed oxidation–aromatization of
α,β‐unsaturated ketones with hydrazine hydrate. Various 3,5‐disubstituted 1H‐pyrazoles were
obtained in good to excellent yields. This method offers several advantages, including room‐tem‐
perature conditions, short reaction time, high yields, simple work‐up procedure, and use of air as an
oxidant. The catalyst can be recovered and reused five times without loss of activity.
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Received 12 November 2015
Accepted 13 January 2016
Published 5 April 2016
Keywords:
Iron(III) phthalocyanine chloride
Aromatization
Published by Elsevier B.V. All rights reserved.
Pyrazole
Michael addition
Recyclable catalyst
Green chemistry
1. Introduction
polymerization reactions [14–17]. These heterocycles have also
attracted much interest because of their technological impacts,
Nitrogen heterocycles, which are widely known, are im‐
portant scaffolds in many biological molecules and pharmaceu‐
tical products. Pyrazole derivatives have been extensively used
as the core structures of biologically active compounds, e.g.,
anti‐inflammatory [1], antitumor [2], antibacterial, [3] and an‐
algesic [4] compounds. They are also vital building blocks in
many pharmaceuticals and natural products [5–7], e.g.,
celecoxib, mavacoxib, rimonabant, and MK‐0893 [8] (a potent
glucagon receptor inhibitor, Fig. 1).
e.g., as ultraviolet stabilizers, photoprotecting agents, and en‐
ergetic materials [18–22]. However, although some natural
products containing pyrazole ring systems are known, they are
not widespread [23–27].
Because of the importance of pyrazole derivatives, signifi‐
cant efforts have been devoted to developing new methods for
their synthesis. Pyrazoles are generally synthesized by (1) re‐
acting hydrazines with 1,3‐dicarbonyl compounds/unsaturated
hydrocarbons [28–34], (2) 1,3‐dipolar cycloaddition of diazo‐
alkanes with alkenes or alkynes [35–42], (3) reacting
α,β‐unsaturated carbonyl with hydrazines [43–46], and various
other strategies [47–53]. However, these methods often re‐
Pyrazoles are also used as building blocks in synthetic or‐
ganic chemistry, versatile, pluripotent ligands in coordination
chemistry [9–13], and in transition‐metal cross‐coupling and
* Corresponding author. Tel: +86‐29‐88302687; E‐mail: zhaojunlong327@163.com
This work was supported by the Industrial Research Project of Shaanxi Science and Technology Department (2014K08‐29), Science and Technology
Plan Project of Xi’an (CXY1511(7)), and Scientific Research Foundation of Northwest University.
DOI: 10.1016/S1872‐2067(15)61043‐9 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 37, No. 4, April 2016

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Junlong Zhao et al. / Chinese Journal of Catalysis 37 (2016) 571–578
Scheme 1. Preparation of 3,5‐disubstituted 1H‐pyrazoles.
tive to TMS. High‐resolution electrospray ionization mass
spectrometry (HRMS (ESI)) was performed using a Bruker
micrOTOF‐QII instrument.
2.2. General procedure for synthesis of α,β‐unsaturated ketones
An aqueous solution of sodium hydroxide (20%, 5 mL) was
slowly added to a stirred solution of ketones (1 mmol) and
aldehydes (1 mmol) in ethanol (5 mL). The mixture was stirred
at room temperature for 1 h and then poured into water (20
mL). The obtained solid was removed by filtration and washed
with ice water and ethanol to nature. The crude product was
purified by recrystallization from ethanol.
Fig. 1. Structures of some pharmacologically important pyrazoles.
2.3. General procedure for synthesis of 3,5‐disubstituted
1H‐pyrazoles from α,β‐unsaturated ketones and hydrazine
hydrate
quire harsh reaction conditions (stoichiometric strong base,
high reaction temperature), precious‐metal catalysts, and stoi‐
chiometric and environmentally unfriendly oxidants. The in‐
troduction of simple and efficient methods for the synthesis of
pyrazole derivatives under mild and environmentally benign
conditions is therefore needed.
For many years, phthalocyanines (Pcs) have been exten‐
sively studied because of their macrocyclic 18π‐electron con‐
jugated ring systems [54]. Metallophthalocyanine complexes
(MPcs), which are structurally similar to metal porphyrins, are
easily accessible and more stable to degradation than porphy‐
rins [55–57]; they have been extensively used to catalyze vari‐
ous organic reactions [58–65]. Because MPcs are insoluble in
common organic solvents, they can be easily separated from
reaction mixtures by filtration and reused without further
treatment. MPcs therefore behave like heterogeneous catalysts,
without having the inherent disadvantage of leaching com‐
monly associated with heterogeneous and heterogenized ho‐
mogeneous catalysts.
α,β‐Unsaturated ketones (0.5 mmol), hydrazine hydrate (1.5
mmol, 3 equiv.), iron(III) phthalocyanine chloride (5 mol%),
K2CO3 (0.5 mmol, 1 equiv.), and ethanol (3.0 mL) were added
successively to a dry round‐bottomed flask. The mixture was
stirred at room temperature for 3 h under air. When the reac‐
tion was complete, as indicated by thin‐layer chromatography,
the reaction mixture was washed with saturated NaCl aqueous
solution (2 × 10 mL) and extracted with ethyl acetate (2 × 10
mL); the organic layers were combined. After drying with an‐
hydrous Na2SO4 and evaporation under reduced pressure, the
crude product was purified by column chromatography on
silica gel using petroleum ether:ethyl acetate (4:1) as the eluent
to afford 3,5‐disubstituted 1H‐pyrazoles.
2.4. Spectroscopic data of products
1
Here, we report an efficient and heterogeneous method for
the synthesis of 3,5‐disubstituted 1H‐pyrazoles under mild
reaction conditions, using iron(III) phthalocyanine chloride as a
recyclable catalyst (Scheme 1). The experimental procedure is
simple and clean and uses environmentally friendly solvents,
and the products are obtained in high yields.
3,5‐Diphenyl‐1H‐pyrazole (2a). White solid, yield: 89%; H
NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 7.2 Hz, 4H), 7.39–7.30 (m,
6H), 6.82 (s, 1H); 13C NMR (100 MHz, CDCl3) δ: 148.7, 131.2,
128.8, 128.1, 125.6, 100.0; HRMS (ESI) m/z calcd. for C15H12N2
[M + H]+: 221.1073, found: 221.1073.
3‐Phenyl‐5‐(p‐tolyl)‐1H‐pyrazole (2b). White solid, yield:
84%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.29 (s, 1H), 7.85–7.71
(m, 4H), 7.44 (d, J = 6.8 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.12 (s,
1H), 2.33 (s, 3H); 13C NMR (100 MHz, DMSO‐d6) δ: 151.5, 143.1,
137.6, 129.8, 129.3, 128.2, 127.7, 126.0, 125.6, 125.6, 99.7, 21.3;
HRMS (ESI) m/z calcd. for C16H14N2 [M + H]+: 235.1230, found:
235.1238.
5‐(4‐Nitrophenyl)‐3‐phenyl‐1H‐pyrazole (2c). Yellow solid,
yield: 84%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.72 (s, 1H), 8.29
(d, J = 8.0 Hz, 2H), 8.13 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 6.8 Hz,
2H), 7.49–7.39 (m, 4H); 13C NMR (100 MHz, DMSO‐d6) δ: 149.8,
146.9, 144.5, 140.5, 129.5, 129.4, 128.9, 126.3, 125.7, 124.6,
2. Experimental
2.1. Materials and characterization
All reagents were purchased from commercial suppliers and
were used without further purification. Nuclear magnetic res‐
onance (NMR) spectra were recorded at room temperature
with a 400 MHz spectrometer (1H at 400 MHz, 13C at 100 MHz),
using DMSO‐d6 or CDCl3 as the solvent with tetramethylsilane
(TMS) as the internal standard; chemical shifts are quoted rela‐

Junlong Zhao et al. / Chinese Journal of Catalysis 37 (2016) 571–578
573
101.5; HRMS (ESI) m/z calcd. for C15H11N3O2 [M + H]+:
253.1149.
266.0924, found: 266.0917.
5‐(4‐Chlorophenyl)‐3‐(p‐tolyl)‐1H‐pyrazole (2l). White sol‐
id, yield: 95%; 1H NMR (400 MHz, CDCl3) δ: 7.69 (d, J = 7.8 Hz,
2H), 7.54 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.26–7.22
(m, 2H), 6.78 (s, 1H), 2.39 (s, 3H); 13C NMR (100 MHz,
DMSO‐d6) δ: 150.6, 144.2, 138.1, 133.1, 132.3, 130.0, 129.1,
127.2, 126.9, 125.5, 99.8, 21.3; HRMS (ESI) m/z calcd. for
C16H13N2Cl [M + H]+: 269.0840, found: 269.0840.
5‐(3‐Nitrophenyl)‐3‐phenyl‐1H‐pyrazole (2d). White solid,
1
yield: 87%; H NMR (400 MHz, CDCl3) 8.60 (s, 1H), 8.16–8.11
(m, 2H), 7.64 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H),
7.43–7.36 (m, 3H), 6.92 (s, 1H); 13C NMR (100 MHz, DMSO‐d6)
δ: 149.8, 148.8, 144.4, 135.8, 131.8, 130.8, 129.5, 129.2, 128.8,
125.6, 122.5, 119.7, 100.9; HRMS (ESI) m/z calcd. for
C15H11N3O2 [M + H]+: 266.0924, found: 266.0923.
5‐(2,4‐Dichlorophenyl)‐3‐phenyl‐1H‐pyrazole (2e). White
solid, yield: 86%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.43 (s, 1H),
7.87 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.4 Hz, 5H), 7.34 (t, J = 7.2 Hz,
1H), 7.21 (s, 1H); 13C NMR (100 MHz, DMSO‐d6) δ: 148.4, 143.5,
133.5, 132.4, 131.9, 130.1, 129.4.08, 128.5, 128.0, 125.9, 125.7,
125.4, 103.7; HRMS (ESI) m/z calcd. for C15H10Cl2N2 [M + H]+:
289.0294, found: 289.0302.
5‐(4‐Nitrophenyl)‐3‐(p‐tolyl)‐1H‐pyrazole (2m). Pale yel‐
1
low solid, yield: 89%; H NMR (400 MHz, CDCl3) δ: 13.65 (s,
1H), 8.30 (d, J = 8.4 Hz, 2H), 8.13 (d, J = 8.4 Hz, 2H), 7.72 (d, J =
7.6 Hz, 2H), 7.37 (s, 1H), 7.31 (d, J = 7.6 Hz, 2H), 2.35 (s, 3H); 13
C
NMR (100 MHz, DMSO‐d6) δ: 154.5, 151.6, 149.3, 145.3, 143.1,
134.8, 131.4, 131.0, 130.3, 129.4, 105.9, 26.1; HRMS (ESI) m/z
calcd. for C16H13N3O2 [M + H]+: 280.1081, found: 280.1082.
5‐(Thiophen‐2‐yl)‐3‐(p‐tolyl)‐1H‐pyrazole (2n). Pale yellow
solid, yield: 85%; 1H NMR (400 MHz, CDCl3) δ: 7.52 (d, J = 8.0
Hz, 2H), 7.24 (s, 1H), 7.20 (d, J = 4.8 Hz, 1H), 7.11 (d, J = 7.6 Hz,
2H), 6.99–6.97 (m, 1H), 6.62 (s, 1H); 13C NMR (100 MHz, CDCl3)
δ: 138.2, 135.3, 131.3, 130.7, 129.5, 127.5, 127.1, 125.4, 124.5,
123.9, 99.5, 21.3; HRMS (ESI) m/z calcd. for C14H12N2S [M + H]+:
241.0794, found: 241.0809.
5‐(Furan‐2‐yl)‐3‐(p‐tolyl)‐1H‐pyrazole (2o). White solid,
yield: 81%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.34 (s, 1H),
7.79–7.68 (m, 3H), 7.29–7.24 (m, 2H), 6.92 (s, 1H), 6.84–6.58
(m, 2H), 2.33 (s, 3H); 13C NMR (100 MHz, DMSO‐d6) δ: 142.8,
137.8, 132.0, 130.7, 129.9, 129.1, 125.6, 125.1, 112.1, 106.3
99.2, 21.3; HRMS (ESI) m/z calcd. for C14H13N3O [M + H]+:
225.1022, found: 225.1034.
5‐(4‐Methoxyphenyl)‐3‐(p‐tolyl)‐1H‐pyrazole (2p). White
solid, yield: 86%; 1H NMR (400 MHz, CDCl3) δ: 7.58 (dd, J = 16.6
Hz, 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H),
6.67 (s, 1H), 3.80 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 159.3, 148.6, 148.2, 137.4, 129.3, 128.7, 126.9, 125.5,
124.2, 114.0, 98.8, 55.1, 21.3; HRMS (ESI) m/z calcd. for
C17H16N2O [M + H]+: 265.1335, found: 265.1340.
3‐(4‐Chlorophenyl)‐5‐(4‐methoxyphenyl)‐1H‐pyrazole (2q).
White solid, yield: 89%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.30
(s, 1H), 7.81 (d, J = 44.0 Hz, 4H), 7.50 (s, 2H), 7.12 (s, 1H), 7.03
(s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, DMSO‐d6) δ: 159.6,
150.5, 144.0, 133.1, 132.5, 129.2, 127.2, 127.0, 122.4, 114.7,
99.5, 55.6; HRMS (ESI) m/z calcd. for C16H13N2OCl [M + H]+:
285.0789, found: 285.0782.
5‐(4‐Chlorophenyl)‐3‐phenyl‐1H‐pyrazole (2f). White solid,
yield: 90%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.44 (s, 1H), 7.85
(d, J = 19.7 Hz, 4H), 7.48 (s, 4H), 7.36 (s, 1H), 7.23 (s, 1H); 13
C
NMR (100 MHz, DMSO‐d6) δ: 151.9, 150.7, 144.0, 142.7, 133.0,
132.4, 129.4, 129.2, 128.7, 128.1, 127.3, 125.6, 100.3; HRMS
(ESI) m/z calcd. for C15H11ClN2 [M + H]+: 255.0684, found:
255.0696.
5‐(3‐Bromophenyl)‐3‐phenyl‐1H‐pyrazole (2g). White solid,
yield: 91%; 1H NMR (400 MHz, CDCl3) δ: 7.80 (s, 1H), 7.60 (dd, J
= 10.2 Hz, 4.4Hz, 3H), 7.37 (dd, J = 8.0 Hz, 0.8 Hz, 1H), 7.32–7.25
(m, 3H), 7.13 (t, J = 7.9 Hz, 1H), 6.74 (s, 1H); 13C NMR (100 MHz,
DMSO‐d6) δ: 150.3, 144.1, 136.5, 131.3, 130.6, 129.5, 129.2,
128.7, 128.0, 125.6, 124.5, 122.7, 100.6; HRMS (ESI) m/z calcd.
for C15H11BrN2 [M + H]+: 299.0178, found: 299.0156.
5‐(4‐Methoxyphenyl)‐3‐phenyl‐1H‐pyrazole (2h). White
solid, yield: 93%; 1H NMR (400 MHz, CDCl3) δ: 7.69 (d, J = 7.0
Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.36–7.25 (m, 3H), 6.85 (d, J =
8.8 Hz, 2H), 6.71 (s, 1H), 3.80 (s, 3H); 13C NMR (100 MHz,
DMSO‐d6) δ: 159.6, 151.6, 143.8, 129.4, 129.1, 128.5, 127.9,
126.9, 125.5, 114.9, 99.2, 55.6; HRMS (ESI) m/z calcd. for
C16H14N2O [M + H]+: 251.1179, found: 251.1188.
3‐Phenyl‐5‐(thiophen‐2‐yl)‐1H‐pyrazole (2i). White solid,
1
yield: 83%; H NMR (400 MHz, CDCl3) δ: 7.68–7.66 (m, 2H),
7.43 (t, J = 7.4 Hz, 2H), 7.40–7.32 (m, 2H), 7.29 (d, J = 5.0 Hz,
1H), 7.08 (dd, J = 5.0 Hz, 3.6 Hz, 1H), 6.75 (s, 1H); 13C NMR (100
MHz, DMSO‐d6) δ: 147.4, 143.9, 137.4, 129.5, 129.1, 128.8,
128.1, 125.6, 125.1, 124.2, 99.9; HRMS (ESI) m/z calcd. for
C13H10N2S [M + H]+: 227.0637, found: 227.0646.
3,5‐Bis(4‐chlorophenyl)‐1H‐pyrazole (2r). White solid,
yield: 91%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.51 (s, 1H), 7.85
(d, J = 8.0 Hz, 4H), 7.53 (d, J = 8.0 Hz, 4H), 7.28 (s, 1H); 13C NMR
(100 MHz, DMSO‐d6) δ: 150.8, 142.9, 132.8, 129.4, 127.3, 100.6;
HRMS (ESI) m/z calcd. for C15H10N2Cl2 [M + H]+: 289.0294,
found: 289.0294.
1
3,5‐Di‐p‐tolyl‐1H‐pyrazole (2j). White solid, yield: 92%; H
NMR (400 MHz, DMSO‐d6) δ: 13.23 (s, 1H), 7.72 (dd, J = 24.5 Hz,
6.2 Hz, 4H), 7.29–7.24 (m, 4H), 7.08 (s, 1H), 2.33 (s, 6H); 13C
NMR (100 MHz, DMSO‐d6) δ: 151.7, 143.7, 138.0, 137.0, 131.4,
130.0, 129.6, 127.1, 125.5, 99.4, 21.3; HRMS (ESI) m/z calcd. for
C17H16N2 [M + H]+: 249.1386, found: 249.1394.
5‐(2‐Fluorophenyl)‐3‐(p‐tolyl)‐1H‐pyrazole (2k). Pale yel‐
low solid, yield: 88%; 1H NMR (400 MHz, DMSO‐d6) δ: 13.43 (d,
J = 66.9 Hz, 1H), 8.07–7.64 (m, 3H), 7.51–7.21 (m, 5H), 7.02 (s,
1H), 2.34 (s, 3H); 13C NMR (100 MHz, DMSO‐d6) δ: 159.4 (d, 1JCF
= 257 Hz), 151.7, 146.2, 143.9, 137.8, 129.9, 128.5, 126.9, 125.6,
125.2, 121.7, 116.7 (d, 2JCF = 22 Hz), 102.6 (d, 4JCF = 22 Hz), 21.3;
HRMS (ESI) m/z calcd. for C16H13N3F [M + H]+: 253.1136, found:
3‐(Naphthalen‐2‐yl)‐5‐(p‐tolyl)‐1H‐pyrazole (2s). White
1
solid, yield: 87%; H NMR (400 MHz, CDCl3) δ: 8.20 (s, 1H),
7.89–7.83 (m, 4H), 7.63 (d, J = 8.0 Hz, 2H), 7.49–7.48 (m, 2H),
7.23 (s, 2H), 6.95 (s, 1H), 2.39 (s, 3H); 13C NMR (100 MHz,
DMSO‐d6) δ: 151.6, 144.1, 138.0, 137.2, 133.6, 132.9, 131.7,
130.0, 128.6, 128.4, 128.1, 126.9, 126.3, 125.5, 124.2, 123.9,
100.0, 21.3; HRMS (ESI) m/z calcd. for C20H16N2 [M + H]+:
285.1386, found: 285.1392.

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Junlong Zhao et al. / Chinese Journal of Catalysis 37 (2016) 571–578
3‐(o‐Tolyl)‐5‐(p‐tolyl)‐1H‐pyrazole (2t). White solid, yield:
ble 1. Initially, the reaction of chalcone (1a) with hydrazine
hydrate was performed in the absence of an iron catalyst in
ethanol at reflux temperature for 3 h in air. The desired product
2a was obtained in only 18% yield (Table 1, entry 1). When 5
mol% Fe(III)Cl–Pc was added, the yield improved to 43% (Ta‐
ble 1, entry 2). Next, we screened various iron catalysts using
air as the oxidant in the model reaction (Table 1, entries 2–6).
The highest yield of the desired product was obtained using
Fe(III)Cl–Pc (Table 1, entry 2) and was therefore used for fur‐
ther studies. The addition of K2CO3 (1.0 equiv.) to this system
substantially improved the product yield to 93% (Table 1, en‐
try 7). It is suggested that the base assisted the transformation
by serving as a proton shuttle [46]. Other additives, namely
NaOH, K3PO4, and Et3N, were also screened, but K2CO3 was
found to be the most suitable (Table 1, entries 7–10). Other
solvents, namely 1,4‐dioxane, tetrahydrofuran (THF) and
CH3CN, were used instead of ethanol under these conditions;
ethanol was the best solvent (Table 1, entries 11–13). An ex‐
cellent yield was obtained even at room temperature (Table 1,
entry 14). Lowering the amount of hydrazine hydrate to 2.0
equiv. significantly affected the reaction outcome, affording 2a
in 71% yield (Table 1, entry 15); however, a further reduction
to 1.5 equiv. of hydrazine hydrate gave 2a in only 48% yield
(Table 1, entry 16). Increasing the amount of Fe(III)Cl–Pc did
not improve the yield (Table 1, entry 17). The reaction was also
performed under nitrogen; the desired product was not
formed, indicating that oxygen is necessary for this reaction
(Table 1, entry 18). Based on all these experiments, the opti‐
85%; 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J = 8.0 Hz, 2H), 7.43
(d, J = 7.6 Hz, 1H), 7.25–7.15 (m, 5H), 6.65 (s, 1H), 2.43 (s, 3H),
2.36 (s, 3H); 13C NMR (400 MHz, CDCl3) δ: 149.3, 147.1, 137.8,
136.1, 130.9, 130.8, 129.5, 129.2, 129.0, 128.4, 126.0, 125.6,
102.8, 21.3, 20.9; HRMS (ESI) m/z calcd. for C17H16N2 [M + H]+:
249.1386, found: 249.1388.
5‐(4‐Methoxyphenyl)‐3‐methyl‐1H‐pyrazole (2u). Yellow
oil, yield: 82%; 1H NMR (400 MHz, CDCl3) δ: 7.62 (d, J = 8.4 Hz,
2H), 6.91 (d, J = 8.8 Hz, 2H), 6.27 (s, 1H), 3.82 (s, 3H), 2.31 (s,
3H); 13C NMR (400 MHz, CDCl3) δ: 159.5, 149.4, 143.4, 126.9,
125.0, 114.1, 101.6 55.3, 11.8; HRMS (ESI) m/z calcd. for
C11H12N2O [M + H]+: 189.1022, found: 189.1026.
3‐Hydrazinyl‐1,3‐diphenylpropan‐1‐one (I). Yellow oil; 1H
NMR (400 MHz, CDCl3) δ: 7.99–7.92 (m, 2H), 7.58 (m, 1H),
7.50–7.42 (m, 5H), 7.40–7.36 (m, 3H), 7.32–7.30 (m, 1H), 5.35
(t, J = 6.0 Hz, 1H), 3.38 (d, J = 1.2 Hz, 1H), 3.37 (s, 1H); 13C NMR
(400 MHz, CDCl3) δ: 200.2, 143.0, 136.6, 133.7, 128.7, 128.6,
128.2, 127.7, 125.8, 70.1, 47.4; HRMS (ESI) m/z calcd. for
C15H16N2O [M + H]+: 241.1335, found: 241.1338.
3. Results and discussion
The optimum reaction conditions were determined using
the reaction of chalcone (1a) with hydrazine hydrate as a mod‐
el. A series of experiments were performed to study the effects
of various reaction parameters such as the catalyst, solvent,
additives, and temperature; the results are summarized in Ta‐
mum reaction conditions were identified as
5 mol%
Fe(III)Cl–Pc and K2CO3 (1 equiv.) in ethanol at room tempera‐
ture for 3 h.
Table 1
Optimization of reaction conditions for synthesis of 3,5‐disubstituted
1H‐pyrazole 2a.
The substrate scope was investigated under the optimized
conditions, and the generality of the reaction was examined
using diversely substituted α,β‐unsaturated ketones and hy‐
drazine hydrate; the corresponding 3,5‐disubstituted
1H‐pyrazoles were obtained in reasonably high yields. The
results are summarized in Table 2. The reactions went
smoothly using α,β‐unsaturated ketones with various aromatic
substituents. The presence of electron‐withdrawing or
‐donating groups at the ortho, meta, or para positions of the
benzene rings of various α,β‐unsaturated ketones had no sig‐
nificant impact on the reaction, and the ketones were conven‐
iently transformed to their corresponding 3,5‐disubstituted
1H‐pyrazoles in excellent yields.
After the reaction was complete, the catalyst was separated
from the reaction mixture by filtration and reused in subse‐
quent experiments (up to four cycles). The data in Table 3 show
that the product yields were comparable to those obtained with
the fresh catalyst, indicating that the catalyst does not lose its
activity and can be recycled without further treatment.
We investigated the mechanism of the reaction of
α,β‐unsaturated ketones with hydrazine hydrate. We per‐
formed the reaction under nitrogen (Table 1, entry 18). The
target product, 2a, was not detected, but a new compound,
namely intermediate I, was isolated. 1H and 13C NMR spectros‐
copies, and HRMS (ESI) showed that I is formed by Michael
addition of chalcone with hydrazine hydrate. Next, we added
Entry
1
2
3
4
5
6
7
8
Catalyst
—
FeSO4∙7H2O
FeCl3∙6H2O
Fe(III)Cl–Pc
Fe2O3
Fe(NO3)3∙9H2O
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Fe(III)Cl–Pc
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Dioxane
THF
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
Base
—
—
—
—
Yielda (%)
18
22
25
43
31
22
93
80
82
54
75
58
33
90
71
48
87
—
—
K2CO3
NaOH
K3PO4
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
13
14b
15b,c
16b,d
17b,e
18b,f
0
Reaction conditions: 1a (0.5 mmol), hydrazine hydrate (1.5 mmol),
catalyst (5 mol%), solvent (3.0 mL), additive (1.0 equiv.), under an air
atmosphere, at refluxing temperature for 3 h.
a
b
c
Isolated yield. Room temperature. Hydrazine hydrate (1.0 mmol).
d Hydrazine hydrate (0.75 mmol). e Catalyst (10 mol%).
f Under nitrogen atmosphere.

Junlong Zhao et al. / Chinese Journal of Catalysis 37 (2016) 571–578
575
Table 2
Reaction scope and versatility.
Entry
1
Product
Yielda (%)
89
Entry
12
Product
Yielda (%)
95
NH
N
NO2
2
3
84
84
13
14
89
85
2m
4
5
6
7
8
9
87
86
90
91
93
83
15
16
17
18
19
20
81
86
89
91
87
85
10
11
92
88
21
82
Reaction conditions: 1 (0.5 mmol), hydrazine hydrate (1.5 mmol), catalyst (5 mol%), ethanol (3.0 mL), K2CO3 (1.0 equiv.), room temperature, under
an air atmosphere, 3 h. a Isolated yield.
intermediate I to the reaction mixture under general condi‐
tions; a high yield of 2a was obtained (Scheme 2).
The mechanism shown in Scheme 3 is proposed based on
our experimental observations and literature reports [66–69].
First, the chalcone reacts with hydrazine hydrate via a Michael
addition to form intermediate I, followed by dehydration ring
closure to give pyrazoline II. Catalyst A combines with oxygen
to form complex B. In the next step, complex B combines with
another catalyst, 1, followed by oxidative cleavage to give C.
Finally, pyrazoline oxidation by compound C forms product 2a,
and catalyst A is regenerated by reductive elimination of a wa‐
ter molecule, to close the catalytic cycle.

576
Junlong Zhao et al. / Chinese Journal of Catalysis 37 (2016) 571–578
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4. Conclusions
We have developed a simple, highly efficient, and environ‐
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Air is used as the oxidant, which makes the transformation
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Junlong Zhao et al. / Chinese Journal of Catalysis 37 (2016) 571–578
577
Graphical Abstract
Chin. J. Catal., 2016, 37: 571–578 doi: 10.1016/S1872‐2067(15)61043‐9
Iron(III) phthalocyanine chloride‐catalyzed
oxidation–aromatization of α,β‐unsaturated ketones with
hydrazine hydrate: Synthesis of 3,5‐disubstituted 1H‐pyrazoles
Junlong Zhao*, Jun Qiu, Xiaofeng Gou, Chengwen Hua, Bang Chen
Northwest University
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