Efficient synthesis of 1,3-diaryl-4-halo-1 H-pyrazoles from 3-arylsydnones and 2-aryl-1,1-dihalo-1-alkenes

Article abstract of DOI:10.3762/bjoc.7.195

An efficient synthesis of 1,3-diaryl-4-halo-1H-pyrazoles was achieved. The synthesis involves the [3 + 2] dipolar cycloaddition of 3-arylsydnones and 2-aryl-1,1-dihalo-1-alkenes. The process proceeds smoothly in moderate to excellent yields. 1,3-Diaryl-4-

Full text of DOI:10.3762/bjoc.7.195

Efficient synthesis of 1,3-diaryl-4-halo-1H-pyrazoles
from 3-arylsydnones and 2-aryl-1,1-dihalo-1-alkenes
Yiwen Yang1,2, Chunxiang Kuang*1, Hui Jin1, Qing Yang3
and Zhongkui Zhang1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1656–1662.
1Department of Chemistry, Tongji University, Siping Road 1239,
Shanghai 200092, China, 2College of Biological, Chemical Sciences
and Engineering, Jiaxing University, Jiaxing 314001, China and
3Department of Biochemistry, School of Life Sciences, Fudan
University, Handan Road 220, Shanghai 200433, China
doi:10.3762/bjoc.7.195
Received: 06 October 2011
Accepted: 10 November 2011
Published: 12 December 2011
Email:
Associate Editor: B. Stoltz
Yiwen Yang - yangyiwen1002@126.com; Chunxiang Kuang* -
kuangcx@tongji.edu.cn; Qing Yang - yangqing68@fudan.edu.cn
© 2011 Yang et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
C–H bond activation; cycloaddition; dihaloalkenes; pyrazole;
sydnones
Abstract
An efficient synthesis of 1,3-diaryl-4-halo-1H-pyrazoles was achieved. The synthesis involves the [3 + 2] dipolar cycloaddition of
3-arylsydnones and 2-aryl-1,1-dihalo-1-alkenes. The process proceeds smoothly in moderate to excellent yields. 1,3-Diaryl-4-halo-
1H-pyrazoles are found to be important intermediates that can easily be converted into 1,2,5-triaryl-substituted pyrazoles via
Pd-catalyzed C–H bond activation.
Introduction
Over the past decade, pyrazoles as key motifs in biologically [8]. As pesticides, they are used as insecticides [9] and fungi-
active compounds have received increasing attention from the cides [10], and as well as antiviral [11] and antibacterial agents
synthetic community. Diazoles can be employed as a central [12]. Pyrazoles are gaining interest as ligands for transition
building block in the synthesis of compound libraries in the metals, and in the field of materials chemistry [13,14].
pharmaceutical [1] and agrochemical [2] industries. Pyrazole
and its derivatives are an important class of heterocyclic com- Pyrazole and its derivatives can be synthesized by several
pounds. As medicines, many of them display anti-inflammatory methods [15]. The most common approach is based on the con-
[3], antimicrobial [3], antiplatelet [4], antiallergenic [5], anti- densation of hydrazines with 1,3-dicarbonyl compounds or their
fungal [6], MAP Kinase inhibitor [7], and anticancer activities equivalents. However, the 1,3-dipolar cycloaddition offers a
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more convenient synthetic route. Sydnones are easily acces- smoothly to generate the desired product 3a in 72% yield.
sible aromatic compounds and versatile synthetic intermediates. Changing the base to K2CO3 decreased the yield to 54%. When
They can be used as unusual, alternative cycloaddition Et3N, DBU, or no base was used, product 3a was not obtained
substrates for pyrazole synthesis [16,17]. These dipolar com- (Table 1, entries 1–5). Changing the solvent to DMSO and
pounds are readily prepared in two steps from N-functionalized DMF led to traces of 3a or no product, respectively (Table 1,
amino acids, and are readily stored and handled. Methods have entries 6–7). Various molar ratios of 1a to 2a were also studied.
been disclosed for the [3 + 2] dipolar cycloaddition of sydnones When the molar ratio of 1a to 2a was 1:1, the yield (48%) was
with alkenyl silanes [18] and stannanes [18], alkenyl arenes much lower than that obtained with a ratio of 1:2 (72%)
[19], 1,3-dienes [20,21], α,β-unsaturated esters [19,22] and (Table 1, entries 1 and 8). Changing the quantity of Cs2CO3 to
nitriles [23], phosphane oxides [24] or with alkynyl silanes [18], 2.0 equiv decreased the yield to 56%, but increasing the amount
stannanes [18,25,26], arenes [27,28], esters [29-33], boronic of Cs2CO3 to 4.5 equiv led to only a slightly higher yield (73%)
esters [34,35]. However, the cycloaddition of sydnones with (Table 1, entries 9 and 10).
1,1-dihaloalkenes is unknown, as is the direct formation of
4-halopyrazoles through the [3 + 2] dipolar cycloaddition of The effects of the reaction temperature on the formation of 3a
sydnones.
were also remarkable. At 120 °C and 90 °C, the yields were
decreased to 63% and 31%, respectively (Table 1, entries
In the present study, a convenient and efficient synthesis of a 12–13). At 160 °C, product 3a was formed in 80% yield
series of new 1,3-diaryl-4-halo-1H-pyrazoles 3 in moderate to (Table 1, entry 11). Ultimately, the optimal reaction conditions
excellent yields is reported. The route employed involves 1,3- were determined as 1:2 molar ratio of 1a to 2a, 3.0 equiv
dipolar cycloaddition between 3-arylsydnones 1 and 2-aryl-1,1- Cs2CO3 base, xylene solvent, 160 °C, and 16 h in the dark
dihalo-1-alkenes 2 (Scheme 1). 1,3-Diaryl-4-halo-1H-pyrazoles (Table 1, entry 11).
were found to be important intermediates that could easily be
converted into 1,2,4-triaryl- or 1,2,5-triaryl-substituted pyra- Under the optimized conditions, a series of 3-arylsydnones 1
zoles via a Pd-catalyzed C–C coupling reaction. To the best of and 2-aryl-1,1-dihalo-1-alkenes 2 substrates were examined.
our knowledge, this synthesis of 1,3-diaryl-4-halo-1H-pyra- Table 2 shows that in most cases, the desired pyrazoles 3 were
zoles has not yet been reported.
smoothly generated in high yields (Table 2, entries 1, 4, 5, and
7–9). In cases with the aromatic portion of 3-arylsydnones 1
carrying either an electron-withdrawing group, such as in chlo-
Results and Discussion
To determine the optimal reaction conditions, 3-phenylsydnone rine 1d, or an electron-donating substituent, as in methyl 1b and
(1a) and 1-(2,2-dibromovinyl)-4-nitrobenzene (2a) were used as methoxyl 1c, the reactions all proceeded smoothly in moderate
the model substrates. A mixture of 1a, 2a, Cs2CO3 and xylene to excellent yields. Higher yields were obtained when the
was then stirred in the dark in a sealed tube maintained at aromatic portion of 3-arylsydnones 1 carried an electron-
140 °C in an oil bath. After 16 h, the product 3a was isolated in donating group. The presence of a strong electron-donating
72% yield.
group in the aromatic portion of 3-arylsydnones 1c greatly
increased the reaction yield (Table 2, entries 7–9). On the other
The effects of different bases, molar ratios of 1a to 2a, solvents, hand, the presence of an electron-withdrawing substituent on
and temperatures on the formation of 3a were investigated. The the aromatic portion of 3-arylsydnones 1d lead to the reactions
optimization of the 1,3-dipolar cycloaddition process between providing pyrazoles 3 in relatively low yields (Table 2, entries
1a and 2a is summarized in Table 1. Several bases were exam- 10–12). The effects of 2-aryl-1,1-dihalo-1-alkenes 2 on the for-
ined. When 1a reacted with 2a in the presence of Cs2CO3 as a mation of pyrazoles 3 were also remarkable. In the cases of the
base in xylene (140 °C, 16 h) in the dark, the reaction proceeded aromatic portion of 2-aryl-1,1-dihalo-1-alkenes 2 carrying nitryl
Scheme 1: Access to 1,3-diaryl-4-halo-1H-pyrazoles from 3-arylsydnones and 2-aryl-1,1-dihalo-1-alkenes.
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Table 1: Screening for optimal reaction conditions.a
entry
base (3 equiv)
solvent
T (°C)
yield of 3a (%)b
1
2
Cs2CO3
K2CO3
Et3N
xylene
xylene
xylene
xylene
xylene
DMSO
DMF
140
140
140
140
140
140
140
140
140
140
160
120
90
72
54
0
3
4
DBU
0
5
none
0
6
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
trace
0
7
8c
9d
10e
11
12
13
xylene
xylene
xylene
xylene
xylene
xylene
48
56
73
80
63
31
aReaction conditions: 1.0 equiv of 1a and 2.0 equiv of 2a were stirred in the dark for 16 h. bIsolated yield. c1.0 equiv of 1a and 1.0 equiv of 2a. d2.0
equiv of Cs2CO3. e4.5 equiv of Cs2CO3.
Table 2: Synthesis of 1,3-diaryl-4-halo-1H-pyrazoles 3.a
yield of
3 (%)b
entry
sydnones 1
1,1-dihaloalkenes 2
pyrazoles 3
1
80
1a
1a
1a
2a
2b
2c
3a
3b
3c
2
3
65
56
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Beilstein J. Org. Chem. 2011, 7, 1656–1662.
Table 2: Synthesis of 1,3-diaryl-4-halo-1H-pyrazoles 3.a (continued)
4
84
1b
1b
1b
1c
1c
1c
1d
1d
1d
2a
2b
2c
2a
2b
2c
2a
2b
2c
3d
5
6
73
3e
63
3f
7
92
3g
8
75
3h
9
72
3i
10
11
12
66
3j
49
3k
41
3l
aReaction conditions: A mixture of 1 (0.3 mmol), 2 (0.6 mmol), and Cs2CO3 (0.9 mmol) was stirred in 3 mL of xylene in a sealed tube at 160 °C for
16 h in the dark. bIsolated yield.
2a or cyano 2c groups all reactions proceeded smoothly in 8, 10 and 11). Generally speaking, where present the electron-
moderate to excellent yields. However, the stronger electron- donating groups of the substrates 1 exhibited stronger electron-
withdrawing nitryl group provided pyrazoles 3 in relatively high donating effects, relative to substrates 2, leading to higher
yields. Under the same conditions, the reactivity of 1-(2,2- yields. We also used 1-(2,2-dibromovinyl)-4-methylbenzene
dibromovinyl)-4-nitrobenzene 2a was higher than that of 1-(2,2- (2d) as a dipolarophile to react with 3-phenylsydnone. In the
dichlorovinyl)-4-nitrobenzene 2b (Table 2, entries 1, 2, 4, 5, 7, process, two isomers, 4-bromo-1-phenyl-3-p-tolyl-1H-pyrazole
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Beilstein J. Org. Chem. 2011, 7, 1656–1662.
(3m) and 3-bromo-1-phenyl-4-p-tolyl-1H-pyrazole (3n) were two halogen atoms on the alkenes is possibly the key factor.
found, and they were generated in 35% and 17% yields, respec- Thus a plausible mechanism for the synthesis of pyrazoles 3
tively. The experimental results indicate that the electron- could be as follows (Scheme 2): Initially, a haloalkyne is
donating group, i.e., methyl on the aromatic portion of 2-aryl- obtained by the elimination of a hydrogen halide from 2-aryl-
1,1-dihalo-1-alkenes, reduced the yields and regioselectivity of 1,1-dihalo-1-alkenes 2 with Cs2CO3 as a base [36]. Then,
the reaction. Products 3 (except 3m and 3n) were generated haloalkyne reacts with 3-arylsydnone 1 in a 1,3-dipolar cyclo-
with excellent regiocontrol. It may be that the large substituent addition reaction. Finally, CO2 is lost [18,34] and pyrazole 3 is
(aryl) on the alkyne and the strong electron-withdrawing group, generated.
i.e., nitryl or cyano, are of great benefit to the regioselectivity of
the reaction.
The polysubstituted pyrazoles 3 were characterized by NMR,
IR and HRMS. The structure of pyrazole 3g was further
confirmed by single-crystal X-ray diffraction studies (Figure 1).
Figure 1: Crystal structure of pyrazole 3g.
In order to elucidate the probable reaction mechanism, a mix-
Scheme 2: Proposed mechanism for the synthesis of 3.
ture of 1a, 2a and xylene was stirred in the dark at 160 °C. After
16 h, no product was found. The results indicate that it was
difficult for 2-aryl-1,1-dihalo-1-alkenes to react with 3-aryl- Subsequently, the arylation reaction of pyrazoles 3 with iodo-
sydnone in the absence of a base. The steric hindrance of the benzene or phenylboronic acid was investigated (Scheme 3).
Scheme 3: Arylation reactions of pyrazoles (3) with iodobenzene or phenylboronic acid.
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The work was supported by the Natural Science Foundation of
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