Synthesis of pyrazolones and pyrazoles via Pd-catalyzed aerobic oxidative dehydrogenation

Article abstract of DOI:10.1016/j.tetlet.2019.03.063

A palladium-catalyzed oxidative dehydrogenation reaction in the presence of AMS and base to synthesize pyrazolones and pyrazoles was identified. This method can be utilized to a wide range of substrates, operates under mild react conditions and can give high yields. We believe it could be used as an alternative protocol for the classical dehydrogenation reactions.

Full text of DOI:10.1016/j.tetlet.2019.03.063

Accepted Manuscript
Synthesis of Pyrazolones and Pyrazoles via Pd-Catalyzed Aerobic Oxidative
Dehydrogenation
Ye-Fu Zhu, Bo-Le Wei, Jiao-Jiao Wei, Wen-Qiong Wang, Wei-Bin Song, Li-
Jiang Xuan
PII:
S0040-4039(19)30291-6
https://doi.org/10.1016/j.tetlet.2019.03.063
TETL 50704
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 January 2019
12 March 2019
26 March 2019
Please cite this article as: Zhu, Y-F., Wei, B-L., Wei, J-J., Wang, W-Q., Song, W-B., Xuan, L-J., Synthesis of
Pyrazolones and Pyrazoles via Pd-Catalyzed Aerobic Oxidative Dehydrogenation, Tetrahedron Letters (2019), doi:
https://doi.org/10.1016/j.tetlet.2019.03.063
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Synthesis of Pyrazolones and Pyrazoles via
Pd-Catalyzed Aerobic Oxidative Dehydrogenation
Ye-Fu Zhua,b, Bo-Le Weia,b, Jiao-Jiao Weia,b, Wen-Qiong Wanga, Wei-Bin Songa,
Li-Jiang Xuana,*
Affiliation
aState Key Laboratory of Drug Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 501 Haike Road, Zhangjiang
Hi-Tech Park, Shanghai 201203, PR China.
bUniversity of Chinese Academy of Sciences, No. 19A Yuquan Road,
Beijing 100049, PR China.
*Corresponding to: Li-Jiang Xuan; Tel: +86-21-20231968, Fax:
+86-21-20231968, E-mail address: ljxuan@simm.ac.cn.

Abstract
A palladium-catalyzed oxidative dehydrogenation reaction in the presence of AMS
and base to synthesize pyrazolones and pyrazoles was identified. This method can be
utilized to a wide range of substrate, operates under mild react conditions and can
give high yields. We believe it could be used as an alternative protocol for the
classical dehydrogenation reactions.
Key words: Pd(OAc)2, dehydrogenation, pyrazolones, pyrazoles
Introduction
Pyrazolone and pyrazole subunits are commonly found motifs in pharmaceutical
molecules [1-4], such as the neuroprotective agent Edaravone (A) [5], COX-2
inhibitor Celecoxib (B) with a pyrazole core [6], prostaglandin G/H synthase 2
inhibitor Antipyrine (C) [7] and thrombopoietin receptor (TpoR) agonist Eltrombopag
(D) with a pyrazolone core [8, 9] (Figure 1). Accordingly, the constructions of
pyrazolones and pyrazoles have always been synthetically attractive.
Figure 1. Bioactive drugs containing pyrazolone or pyrazole moieties
At present, one common method for preparing pyrazolone derivatives depends on
the acid-catalyzed condensation reaction between hydrazines and β-dicarbonyl
compounds [10-12]. However, several shortcomings prevented it becoming an
appealing protocol. For example, it is not easy to get a high yield due to the

generation of side products [13, 14]. In addition, some β-dicarbonyl derivatives can
not be synthesized easily when using this method. Besides, the pyrazole units
synthesized by arylhydrazones via FeBr3/O2 mediated C-H activation/C-N bond
formation reactions have been reported recently [15]. However, this condition
required oxygen environment and usage of corrosive FeBr3. Therefore, the
development of efficient catalyst for constructing pyrazolone and pyrazole units is
still highly desirable.
Recently, it has been reported that Pd-catalyzed oxidative methods have been
applied to synthesize arene derivatives from unsaturated six-membered ring
derivatives, such as cyclohexenes or cyclohexanones [16-18]. However, substrates
have to react in the absence of ligands and O2 atmosphere which is not very easy to
operate. We would like to report a new strategy by Pd-catalyzed oxidative
dehydrogenation to synthesize corresponding pyrazolone and pyrazole products, using
easily accessible starting materials and obtaining good yields (Figure 2).
Figure 2. Synthesis of Pyrazolones and Pyrazoles
In the preliminary study, 1a was used in our initial evaluation of oxidative

dehydrogenation conditions with additives at different loadings (Table 1, entry1-9)
[19]. Additionally, we selected air atmosphere for regenerating Pd2+ in the catalyst
cycle and used MgSO4 as an initial additive. As it was expected using MgSO4 gave a
slight improvement, presumably by serving as drying agent and providing better
mixing between the solvent and the air. (entry 2, 43%). However, only a little
improvement appeared on the yield after increasing the amount of MgSO4 (entry 3,
47%). Obviously, a significant improvement of the yield of Edaravone was observed
when changed MgSO4 with K2CO3 (entry 5, 67%). Besides, when we increased the
dosage of K2CO3, a notable improvement was observed and this kind of alkaline
additive led to a high product yield (entry 6, 92%). Moreover, these conditions were
successfully implemented on a larger scale for 10 mmol. We tried other different
alkaline additives, and not surprisingly, observed similar good results (entry 7, 83%).
It is worth mentioning that the stronger alkaline sodium hydroxide did not give any
improvement (entry 8-9).
Table 1. Optimization of Reaction Conditionsa,b
entry
additive (mol%)
-
yield(%)
1
2
3
4
5
6
7
8
9
25
43
47
MgSO4(20%)
MgSO4(40%)
Silica gel(100-200) (40%) 41
K2CO3(20%)
K2CO3(40%)
Et3N(40%)
67
92
83
53
54
NaOH(20%)
NaOH(40%)
aA typical procedure: A mixture of 0.5 mmol of 1a, 5 mol% of Pd(OAc)2, additive (mol%) and 20

mol% of AMS in 1 mL of dry chlorobenzene is vigorously stirred at 110℃ for 6 h under air
atmosphere. bIsolated yields of Edaravone (2a) represent the average of two runs.
Under optimized conditions, we evaluated various phenylpyrazolidines with
different substituent groups.
Table 2. Dehydrogenation of Various Phenylpyrazolidines to the Corresponding
Derivativesa,b
aReaction conditions: Substrate 1 (0.5 mmol), Pd(OAc)2 (5 mol%), AMS (20 mol%), K2CO3 (0.2
mmol), PhCl (1 mL), 110 °C, 6 h. bIsolated yields. cReaction time 12 h.
The oxidative dehydrogenation of substrates with alkyl and alkoxyl groups on the
aryl moiety proceeded smoothly and gave excellent yields (2b-2e, 91%-97%).
Meanwhile, substrates bearing a halogen atom (F/Cl/Br) or ester group (2f-2j) at
different positions were also well tolerated and yielded oxidation products which
would be useful synthons for modification. Besides, the substrate with an
electron-withdrawing group (CF3, 2k) was also obtained in good yield and the

substrate with 3, 5-CF3 produced corresponding product with an acceptable yield with
prolonging reaction time. In all cases, the C-C oxidation product was not observed.
Next, substrates 2m-2q were used to explore the influence of the pyrazolidine
substituent. When cyclopropyl or tert-butyl pyrazolidine was used, corresponding
C-N oxidative dehydrogenation products was obtained in good yields (2m, 2n).
Moreover, aryl-substituted pyrazolidines were also successfully dehydrogenated to the
corresponding products with good yield (2o-2q). And it is worth mentioning that the
oxidation of 1-phenyl-3-pyrazolidine analog proceeded smoothly and gave excellent
yield by C-C oxidation (2r, 93%).
In addition, this method can also be applied to the construction of a pyrazole
scaffold and a variety of substrates derived from α, β-unsaturated ketones and
phenylhydrazine derivatives were surveyed to prepare different starting materials of
corresponding hydrazones.
Table 3. Synthesis of Trisubstituted Pyrazolesa,b
aReaction conditions: Substrate 3 (0.5 mmol), Pd(OAc)2 (5 mol%), AMS (20 mol%), K2CO3 (0.2
mmol), PhCl (1 mL), 110 °C. 9 h. bIsolated yields. cReaction time 12 h.
As is shown in table 3, both electron-donating groups (Me, MeO; 4a-4c, 83-91%)
and electron-withdrawing groups (SO2NH2, 3-Cl, 4-Cl; 4d-4f) substituted hydrazones

could proceed smoothly and afforded the corresponding dehydrogenated pyrazole
products in good yields. Particularly, the o,m,p-substituted hydrazone gave a slightly
poorer yield of the corresponding product possibly due to the steric hindrance (4g).
Moreover, as we expected, the CF3 substituded hydrazone was smoothly
dehydrogenated under the optimized condition for 12 h to afford the desired product
Celecoxib with 83% yield (4h). Obviously, this simple method can give high yields
and could be used as an alternative protocol for the synthesis of Celecoxib.
Conclusion
In summary, a novel, ligand free and easily accessible approach was developed for
preparing a variety of pyrazolones and pyrazoles, utilizing the Pd-catalyzed oxidative
dehydrogenation in the presence of AMS as a cocatalyst. Using of inexpensive,
commercially available starting materials, simple operation as well as the good to
excellent product yield are among the major advantages of this methodology.
Experimental Section
General methods and materials
All chemicals used in this work were purchased from commercial sources. 1H and
13C NMR spectra were recorded on a Bruker NMR spectrometer with CDCl3, CD3OD
and pyridine-d5 as the solvent and TMS as an internal standard. HRESIMS was
measured on an Agilent G6224A TOF spectrometer. TLC was performed on precoated
silica gel GF254 plates (Qingdao Marine Chemical Factory). And the column
chromatography was performed on Al2O3 (100−200 mesh, Meryer Chemical
Technology Co. Ltd) with dichloromethane/methanol (or petroleum ether/ethyl
acetate) as eluent.
Typical procedure for preparing substrates:
Benzotriazole (1 mmol), propionyl chloride (1 mmol) and dry DCM were added in
a dry flask. The reaction mixture was stirred at room temperature for overnight. The

reaction mixture was washed with saturated salt solution twice and separated by
silicagel column (mobile phase: petroleum ether and ethyl acetate) to give pure
compound (1A). 1A (0.8 mmol), phenylhydrazine (1.0 mmol) and Et3N (0.2 mmol)
was added to THF, the reaction mixture was heated to reflux overnight. The mixture
was extracted with EtOAc, purified by column chromatography on Al2O3 to get the
pure product.
Typical procedure for Pd-Catalyzed Oxidative Reactions:
1a (0.5 mmol), Pd(OAc)2 (5 mol%), AMS (20 mol%), K2CO3 (0.4 equiv.), and dry
chlorobenzene (1 mL) were added in a test tube. The reaction mixture was allowed to
stir vigorously at 110 °C for 6 h. After cooling at room temperature, the mixture was
concentrated and the residue was purified by column chromatography on Al2O3
(mobile phase: dichloromethane/methanol or petroleum ether/ethyl acetate) to afford
the pure product.
Acknowledgements
We gratefully acknowledge grants from the State Key Laboratory of Drug Research
(SIMM1601ZZ-03) and the National Natural Science Foundation of China (No.
81602995 and 21702219).
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Graphical abstract

Highlights
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We reported a new and high-yield simple method to prepare pyrazolones and pyrazoles.
The reaction was catalyzed by Pd(OAc)2 and proceeded in the presence of AMS and base.
Cheap and common base K2CO3 was found as the best choice in this reaction.
Both aromatic and aliphatic groups can be applied well in the reaction.