An easy direct arylation of 5-pyrazolones

Article abstract of DOI:10.3762/bjoc.9.240

A mild, efficient and catalytic ligand-free method for the direct arylation of 5-pyrazolones by Pd-catalyzed C-H bond activation is reported. The process smoothly proceeds and yields are moderate to excellent.

Full text of DOI:10.3762/bjoc.9.240

An easy direct arylation of 5-pyrazolones
Hao Gong1, Yiwen Yang1,2, Zechao Wang1 and Chunxiang Kuang*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2033–2039.
1Department of Chemistry, Tongji University, Siping Road 1239,
Shanghai 200092, China, 2College of Biological, Chemical Sciences
and Engineering, Jiaxing University, Jiaxing 314001,China and 3Key
Laboratory of Yangtze River Water Environment, Ministry of
Education, Shanghai 200092, China
doi:10.3762/bjoc.9.240
Received: 14 July 2013
Accepted: 13 September 2013
Published: 08 October 2013
Email:
Associate Editor: M. Rueping
Chunxiang Kuang* - kuangcx@tongji.edu.cn.
© 2013 Gong et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
arylation; aryl halide; C–H bond activation; Pd(OAc)2; pyrazolone
Abstract
A mild, efficient and catalytic ligand-free method for the direct arylation of 5-pyrazolones by Pd-catalyzed C–H bond activation is
reported. The process smoothly proceeds and yields are moderate to excellent.
Introduction
5-Pyrazolones are attracting considerable research interest The reaction of pyrazolones with arylboronic acids is an attrac-
because of their unique chemical properties and their structures tive approach for the synthesis of arylpyrazolone [15,16].
that facilitate their application as biological and pharmaceutical However, it often needs pre-formation of halo-pyrazolones.
intermediates and products [1-3]. Over the years, many of the Transition metal-catalyzed direct arylation of (hetero)arenes has
biological activities of pyrazolones such as their antipyretic, emerged over the past few years as a rapidly growing field of
analgesic [4,5], anti-inflammatory [6,7], antitumor [8,9], syntheses [17-26]. The direct arylation of pyrazolones by using
antiviral, antibacterial [10], and herbicidal [11] properties have aryl halides offers a cleaner and more efficient method of
been discovered and investigated. Pyrazolones are also potent meeting such goals and rare examples of such transformations
inhibitors of telomerase, cyclooxygenase isoenzymes, platelet have been described [15].
tromboxane synthesis, and prostanoid synthesis in humans
[12,13]. Recently, pharmacologists have developed a novel In this paper, we report a convenient and catalytic ligand-free
class-II c-met inhibitor, whose structural unit is a pyrazolone synthesis of a series of 4-aryl-5-pyrazolones 3 from 5-pyra-
ring [14]. The great medicinal significance and broad applica- zolones 1 and aryl halides 2 (Scheme 1). The direct arylation of
tions of pyrazolones prompted us to synthesize a new series of 5-pyrazolones by Pd-catalyzed C–H bond activation was
heterocyclic compounds containing the pyrazolone moiety.
utilized.
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Beilstein J. Org. Chem. 2013, 9, 2033–2039.
continued to optimize reaction conditions to further improve the
chemical yield.
When 1a reacted with 2a in the presence of K2CO3 as a base in
acetonitrile (90 °C, 12 h), the desired product 3a was generated
in 43% yield (Table 1, entry 2). Changing K2CO3 to Cs2CO3,
Na2CO3 and DBU (1,8-diazabicyclo(5.4.0)undec-7-ene),
decreased the yield to 35%, 27% and 0%, respectively (Table 1,
entry 3–5). Changing K2CO3 to K3PO4, the yield was increased
to 49% (Table 1, entry 6). When Ph3P as a catalytic ligand was
Scheme 1: Direct arylation of 5-pyrazolones.
Results and Discussion
We commenced this study by performing the direct arylation of added to the reaction, the yield decreased to 42% (Table 1,
phenazone (1a) in the presence of 2 equiv of iodobenzene (2a), entry 7). Reducing the dosage of Pd(OAc)2 to 0.05 equiv and
10 mol % of Pd(OAc)2 as a catalyst in acetonitrile in a sealed 0.02 equiv, respectively, decreased the yield to 40% and 32%
tube. The results are shown in Table 1. Gratifyingly, a 45% (Table 1, entries 8–9). Several solvents were examined under
yield of the desired product 3a was achieved after stirring for the conditions of entry 1. When the solvent was changed to
12 h at 90 °C. Encouraged by this preliminary result, we THF, DCE, dioxane, and benzene, the yields decreased to trace,
Table 1: Optimization of the synthesis of 3aa.
entry
additive (2 equiv)
catalyst (0.1 equiv)
solvent
T (°C)
yield of 3ab
1
none
Pd(OAc)2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
90
90
90
90
90
90
90
90
90
90
90
90
90
25
60
120
90
90
90
90
90
90
90
90
45
43
35
27
0
2
K2CO3
Cs2CO3
Na2CO3
DBU
Pd(OAc)2
3
Pd(OAc)2
4
Pd(OAc)2
5
Pd(OAc)2
6
K3PO4
Ph3P (0.25 equiv)
none
Pd(OAc)2
49
42
40
32
traces
31
0
7
Pd(OAc)2
8
Pd(OAc)2 (0.05 equiv)
Pd(OAc)2 (0.02 equiv)
Pd(OAc)2
9
none
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
none
none
Pd(OAc)2
DCE
none
Pd(OAc)2
dioxane
benzene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
none
Pd(OAc)2
22
0
none
Pd(OAc)2
none
Pd(OAc)2
31
35
55
5
none
Pd(OAc)2
O2(1atm)
K2S2O8
benzoquinone
Cu(OAc)2
Ag2CO3
none
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
0
Pd(OAc)2
25
80
0
Pd(OAc)2
FeCl3 (0.3 equiv)
Cu(OAc)2 (0.2 equiv)
none
none
0
none
0
aReaction conditions: 1.0 equiv of 1a and 2.0 equiv of 2a were stirred for 12 h. bIsolated yield.
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Beilstein J. Org. Chem. 2013, 9, 2033–2039.
31%, 0% and 22%, respectively (Table 1, entries 10–13). Other 90 °C, air atmosphere, 1:2 molar ratio of 1a to 2a, and 12 h
reaction parameters such as temperature and oxidants were also reaction time.
screened. When the reaction temperatures were 25 °C, 60 °C,
and 120 °C, the yields decreased to 0%, 31% and 35%, respect- Under the optimized conditions (Table 1, entry 10), the scope of
ively (Table 1, entries 14–16). When the reaction was under aryl halides was examined and the results are summarized in
oxygen (1 atm) in a sealed tube and oxygen was used as an Table 2. The reactions of aryl halides 2 with phenyl moieties
oxidant, product 3a was obtained in 55% yield (Table 1, entry carrying either an electron-donating group such as methyl (2d
17). Changing the oxidant to K2S2O8, benzoquinone and and 2i), ethyloxy (2e) or an electron-withdrawing substituent
Cu(OAc)2 decreased the yield to 5%, 0% and 25%, respective- such as methoxycarbonyl (2c and 2g), trifluoromethyl (2f) or
ly (Table 1, entries 18–20). When Ag2CO3 was added to the formyl (2h) proceeded smoothly with moderate to good yields
reaction, the yield increased to 80% (Table 1, entry 21). (Table 2, entries 3–10). When the phenyl moiety of the aryl
Different catalysts were also examined. When Cu(OAc)2 or halides 2 carried an electron-donating group, higher yields were
FeCl3 was used as a catalyst, or no catalyst was used in the obtained (Table 2, entries 4, 5, 9). On the other hand, an elec-
reaction, product 3a was not obtained (Table 1, entries 22–24). tron-withdrawing group on the phenyl moiety of the aryl halides
Ultimately, the optimal reaction conditions were determined to (2c, 2f, 2g and 2h) provided 4-aryl-5-pyrazolones 3 in rela-
be 0.1 equiv Pd(OAc)2 catalyst, 2.0 equiv Ag2CO3, acetonitrile, tively low yields (Table 2, entries 3, 6–8). Entries 1 and 2 show
Table 2: Synthesis of 4-aryl- 5-pyrazolones 3.
entry
1
Ar–X
product
yield of 3 (%)a
80
2a
3a
3a
2
3
67
71
2b
2c
3b
4
81
2d
3c
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Beilstein J. Org. Chem. 2013, 9, 2033–2039.
Table 2: Synthesis of 4-aryl- 5-pyrazolones 3. (continued)
5
84
2e
3d
6
71
2f
3e
7
78
2g
3f
8
70
2h
3g
9
82
2i
3h
10
64
2j
3i
aIsolated yield.
that the yield of products was lower when using aryl bromide were generated smoothly in moderate to good yields. When the
than when using aryl iodide, and 2-bromopyridine also provided phenyl moiety of pyrazolones 1 carried an electron-donating
3i in moderate yield (Table 2, entry 10).
substituent such as methoxy (1b) and methyl (1c), the reactions
provided pyrazolones 3 in high yields (Table 3, entries 1, 2). On
Next, we investigated the scope of 5-pyrazolone 1 substrates. the other hand, when pyrazolones 1 carried an electron-with-
Table 3 shows that in most cases, the desired pyrazolones 3 drawing substituent such as nitro (1f) and halogens (1g, 1i and
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Beilstein J. Org. Chem. 2013, 9, 2033–2039.
Table 3: Synthesis of 4-phenyl-5-pyrazolones 3.
entry
5-pyrazolone
product
yield of 3 (%)a
1
87
1b
3j
2
83
1c
1d
1e
3k
3l
3
4
53
66
3m
5
51
1f
3n
6
69
1g
3o
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Beilstein J. Org. Chem. 2013, 9, 2033–2039.
Table 3: Synthesis of 4-phenyl-5-pyrazolones 3. (continued)
7
41
1h
3p
8
62
1i
3q
9
47
1j
3r
10
71
1k
3s
11
59
1l
3t
aIsolated yield.
1k) in the aromatic portion, relatively low yields were obtained Conclusion
(Table 3, entries 5, 6, 8, 10). Compared with 5-pyrazolones In summary, we developed a mild, simple and efficient method
containing a butyl or a phenyl substituent on the 3-position of for the direct arylation of 5-pyrazolones by Pd-catalyzed
the heterocycle (1d and 1e), the methyl (1a) on the same pos- C–H bond activation. This approach resulted in the
ition resulted in a higher yield (Table 3, entries 3 and 4). The construction of 4-aryl-5-pyrazolones, which are important hete-
cause might be the steric hindrance of phenyl or butyl. The rocyclic compounds used in medicinal and biological research.
same trend could be seen from 1g to 1l (cf. 3o, 3q and 3s with The investigations on the reaction mechanism are still in
3p, 3r and 3t) (Table 3, entries 6–11).
progress.
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Beilstein J. Org. Chem. 2013, 9, 2033–2039.
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Supporting Information
Supporting Information File 1
Experimental details and characterization data for all
compounds.
15.Guckian, K.; Carter, M. B.; Lin, E. Y.-S.; Choi, M.; Sun, L.;
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Acknowledgements
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The present work was supported by the Natural Science Foun-
dation of China (No. 21272174), the Key Projects of Shanghai
in Biomedicine (No. 08431902700), and the Scientific Research
Foundation of the State Education Ministry for Returned Over-
seas Chinese Scholars. We would also like to thank the Center
for Instrumental Analysis, Tongji University, China.
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