An efficient one-pot synthesis of 3,5-diaryl-4-bromopyrazoles by 1,3-dipolar cycloaddition of in situ generated diazo compounds and 1-bromoalk-1-ynes

Article abstract of DOI:10.1055/s-0032-1317992

A simple, highly efficient, one-pot synthesis of 3,5-di-aryl-4- bromopyrazoles via 1,3-dipolar cycloaddition of diazo compounds and alkynyl bromides has been developed. The diazo compounds and alkynyl bromides were generated in situ from tosylhydrazones and gem-dibromoalkenes, respectively. When ketone-derived hydrazones were used, 3,5-diaryl-4-bromo-3H-pyrazoles were obtained and the isomerization products 3,5-diaryl-4-bromo-1H-pyrazoles were formed when using aldehyde-derived hydrazones. The reaction system exhibited high regioselectivity and good functional group tolerance. Both electron-rich and electron-deficient-substituents on the aromatic ring of the hydrazones or the gem-dibromoalkenes gave desired products in moderate to good yields (67-86%). Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0032-1317992

PAPER
▌413
paper
An Efficient One-Pot Synthesis of 3,5-Diaryl-4-bromopyrazoles by 1,3-Dipolar
Cycloaddition of In Situ Generated Diazo Compounds and 1-Bromoalk-1-ynes
One-Pot Synthesis of 3,5-Diaryl-4-bromopyrazoles
Qiang Sha, Yunyang Wei*
School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, P. R. of China
Fax +86(25)84317078; E-mail: ywei@mail.njust.edu.cn
Received: 08.11.2012; Accepted after revision: 13.12.2012
thetic protocols have been developed to expand the scope
Abstract: A simple, highly efficient, one-pot synthesis of 3,5-di-
of this type of reaction.9
aryl-4-bromopyrazoles via 1,3-dipolar cycloaddition of diazo com-
pounds and alkynyl bromides has been developed. The diazo
compounds and alkynyl bromides were generated in situ from tosyl-
hydrazones and gem-dibromoalkenes, respectively. When ketone-
derived hydrazones were used, 3,5-diaryl-4-bromo-3H-pyrazoles
were obtained and the isomerization products 3,5-diaryl-4-bromo-
1H-pyrazoles were formed when using aldehyde-derived hydra-
zones. The reaction system exhibited high regioselectivity and good
functional group tolerance. Both electron-rich and electron-
deficient substituents on the aromatic ring of the hydrazones or the
gem-dibromoalkenes gave desired products in moderate to good
yields (67–86%).
To the best of our knowledge, most reported syntheses of
pyrazoles use aldehyde-derived tosylhydrazones and ter-
minal alkynes. Reports on the cycloaddition between di-
azo compounds and alkynyl halides are rare. Field and
Atherton reported a cycloaddition reaction between bro-
moacetylene and trifluorodiazoethane; the reaction was
not fully regioselective and gave a mixture of isomers.10
Hanamoto and co-workers reported a one-pot preparation
of 4-fluoro-5-(tributylstannyl)-1H-pyrazole via 1,3-dipo-
lar cycloaddition between diazomethane and fluoro(tribu-
tylstannyl)acetylene generated in situ.11 The reaction
between iodoalkynes and diazomethane reported in 1988
by Dzhuraev et al. led to 3-iodopyrazoles in 91–93%
yields.12 All of these reactions used only aldehyde-derived
hydrazones or the corresponding diazo compounds.
Key words: cycloaddition, diazo compounds, hydrazones, pyr-
azoles, gem-dibromoalkenes
Pyrazoles and their derivatives have important applica-
tions in the pharmaceutical and agricultural industries due
to their diverse bioactivity.1 Thus, they have attracted
much attention and many methods have been developed
for their synthesis2 and chemical structural modifica-
tions.3
gem-Dibromoalkenes are used as an alkynyl donor in or-
ganic reactions.13 Generating alkynyl bromides from gem-
dibromoalkenes in situ is an easy and economic way for
the preparation of alkynyl bromides, which are usually
malodorous and expensive.
Among these, the most practical method is the condensa-
tion of hydrazines with 1,3-diketones or their derivatives.4
However, the reactions often give undesired isomers as
major products. Another important method is the 1,3-di-
polar cycloaddition of diazo compounds to triple bonds,5
however diazo compounds without an electron-withdraw-
ing group are usually unstable and thus difficult to han-
dle.6 These factors significantly limit the scope of these
reactions.
The preparation of 3,5-diaryl-4-bromopyrazoles by tradi-
tional methods requires two steps, synthesis of 3,5-diaryl-
pyrazoles first and bromination of the pyrazoles using N-
bromosuccinimide14 or bromine15 in a separate step or
through the condensation of hydrazine hydrate with 2-
bromo-substituted 1,3-diarylpropane-1,3-diones.16 How-
ever these methods can only be used to synthesize 3,5-di-
aryl-4-bromo-1H-pyrazoles. In this article, we would like
to report a novel, one-pot 1,3-dipolar cycloaddition reac-
tion between diazo compounds and alkynyl bromides. The
diazo compounds are generated in situ from ketone- or
aldehyde-derived tosylhydrazones and the alkynyl bro-
mides are generated in situ from gem-dibromoalkenes.
The reaction was carried out in tetrahydrofuran in the
presence of sodium hydroxide under mild conditions (80
°C, 10 h) and gave the corresponding products in moder-
ate to good yields. Of the two possible regioisomers, 3 and
4, isomer 3 was obtained with high regioselectivity. It was
found that if the diazo compound was generated in situ
from an aldehyde-derived tosylhydrazone 1 (R1 = H), the
isolated product is 5, which was formed through the isom-
erization of the initially formed addition product 3
(Scheme 1). Both of isomer 3 and 5 can be used as inter-
mediates toward the synthesis of other important com-
pounds.17 In particular, they are of special interest,
In 2003, Aggarwal et al. prepared 1H-pyrazoles by 1,3-di-
polar cycloaddition reactions of diazo compounds gener-
ated in situ from aldehyde-derived tosylhydrazones.7 The
reaction was carried out in acetonitrile with sodium hy-
droxide as the base and took 48 hours to go to completion;
in most cases moderate yields of the products were ob-
tained. Recently, Chen and co-workers improved the reac-
tion by using a stronger base, sodium ethoxide, instead of
sodium hydroxide and carried out the reaction in toluene
instead of acetonitrile in a one-pot procedure.8 The meth-
od of generating diazo compounds in situ has been widely
used in organic synthesis in recent years, and many syn-
SYNTHESIS 2013, 45, 0413–0420
Advanced online publication: 09.01.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317992; Art ID: SS-2012-H0875-OP
© Georg Thieme Verlag Stuttgart · New York

414
Q. Sha, Y. Wei
PAPER
N–
N+
N
N
N
N
N
R3
Br NaOH
THF
N+
–
R1
Br
+
R1
+
R1
R2
R1
R2
R3
R2
R2
R3
Br
3
4 (trace)
in situ
in situ
Br
R1 = H
NNHTs
Br
H
R3
N
N
R1
R2
R3
2
1
R2
Br
5
Scheme 1 1,3-Dipolar cycloaddition between substituted tosylhydrazones and gem-dibromoethenes
because the halogen atom provides an opportunity for fur- was found to be most suitable (entries 6–8). Finally the re-
ther functionalization to form a variety of C–C, C–X action temperature and time were investigated and it was
(X = N, O, S, etc.) bonds.
found that reaction at 80 °C for 10 hours gave the highest
yield of 3aa (entries 9–12). Using these conditions for the
reaction of tosylhydrazone 1a and 1-(2-bromoethy-
nyl)benzene, the yield of 3aa also increased to 84%
(Scheme 2, conditions B).
We initiated our studies by examining the reaction of ace-
tophenone tosylhydrazone (1a) with 1-(2-bromoethy-
nyl)benzene in dioxane with lithium tert-butoxide as the
base (Scheme 2, conditions A). To our delight, the reac-
tion proceeded with high regioselectivity and gave prod-
uct 3aa in 65% yield.
Table 1 Optimization of the Reaction Conditionsa
NNHTs
N
N
Br
N
NNHTs
Br
N
+
Br
Br
+
3aa
1a
2a
Br
1a
3aa
Entry
Base
Solvent
Temp (°C) Time (h) Yieldb (%)
Scheme 2 The reaction of acetophenone tosylhydrazone (1a) with 1-
(2-bromoethynyl)benzene: Conditions A: 1a (0.3 mmol), 1-(2-bro-
moethynyl)benzene (0.3 mmol), LiOt-Bu (3 equiv), dioxane (3 mL),
110 °C, 10 h (65%). Conditions B: 1a (0.3 mmol), 1-(2-bromoethy-
nyl)benzene (0.3 mmol), NaOH (3 equiv), THF (3 mL), 80 °C, 10 h
(84%)
1
2
K2CO3
LiOt-Bu
KOt-Bu
NaOH
Cs2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
–
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
THF
110
110
110
110
110
110
110
110
80
12
12
12
12
12
12
12
12
12
12
10
8
trace
59
3
42
4
72
Inspired by these results, we decided to replace alkynyl
bromides by using inexpensive and easy prepared gem-di-
bromoalkenes. For the optimization of the reaction condi-
tions, the cycloaddition between acetophenone
tosylhydrazone (1a) and (2,2-dibromovinyl)benzene (2a)
was selected as a model reaction (Table 1). The desired
product 3aa was obtained in 59% yield in dioxane with
lithium tert-butoxide as the base (entry 2). Following this
encouraging result, further optimization of the reaction
conditions was performed. A series of bases, including
potassium tert-butoxide, potassium carbonate, cesium
carbonate, and sodium hydroxide, were screened first.
With potassium tert-butoxide as the base instead of lithi-
um tert-butoxide, the yield of 3aa decreased from 59% to
42% (entry 3). When the reaction was carried out using
potassium or cesium carbonate as the base, only trace
amounts of 3aa were detected (entries 1 and 5). Without
the presence of a base, no reaction took place (entry 13).
However, when sodium hydroxide was used, the yield of
the product increased to 72% (entry 4). A range of sol-
vents including toluene, tetrahydrofuran, 1,2-dichloroeth-
ane, and dioxane were then screened, and tetrahydrofuran
5
trace
55
6
7
85
8
DCE
trace
86
9
THF
10
11
12
13
THF
60
52
THF
80
85
THF
80
70
THF
80
10
NR
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), base (3 equiv),
solvent (3 mL), under air.
b Isolated yields.
With the optimized conditions in hand, the scope of this
cycloaddition reaction was investigated (Table 2). When
ketone-derived hydrazones were used, both electron-
neutral 2a and electron-rich 2b gem-dibromoalkenes gave
Synthesis 2013, 45, 413–420
© Georg Thieme Verlag Stuttgart · New York

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One-Pot Synthesis of 3,5-Diaryl-4-bromopyrazoles
415
the desired products in good yields. For electron-deficient Tosylhydrazones 1 were prepared via condensation of to-
gem-dibromoalkenes, the type of electron-withdrawing sylhydrazine and the corresponding aldehydes or ketones.
group on the aromatic ring was important. Substrate bear- If the tosylhydrazones 1 can be generated in situ, the pro-
ing a weak electron-withdrawing group on the aromatic cedure may simplified further. Therefore, we tried the cy-
ring, such as chloro-substituted 2d, still gave a high prod- cloaddition reaction with (2,2-dibromovinyl)benzene
uct yield. Substrates bearing strong electron-withdrawing (2a), tosylhydrazine, and acetophenone (6a) as the start-
groups on the aromatic ring, such as nitro-substituted 2c ing materials. Unfortunately, the desired product 3aa was
and 2h, gave much lower product yields. However, the obtained in only 23% yield. Compared with the reaction
yield of product increased to 84% when the reaction was of using hydrazones directly, the only difference is the
carried out in dioxane with lithium tert-butoxide as the generation of one equivalent of water during the conden-
base. Heteroaromatic gem-dibromoalkenes 2e–g were sation of the tosylhydrazine with a ketone or aldehyde to
also tested in the reaction and gave good yields. The reac- form the tosylhydrazone. Hence 4 Å molecular sieves
tion also proceeded well with different tosylhydrazones were added to the reaction mixture to remove the in situ
1b–e. Then the use of the aldehyde hydrazones 1e–h was formed water. To our delight, the tandem reaction with
examined, and isomerized products 5 were obtained in (2,2-dibromovinyl)benzene (2a), tosylhydrazine, and ace-
good yields. Various functional groups of the hydrazones tophenone (6a) proceeded well and cycloaddition product
and gem-dibromoalkenes were also investigated. The aro- 3aa was obtained in 76% yield (Table 3, entry 1). Then
matic moiety tolerated electron-donating as well as elec- electron-rich and electron-deficient ketones 6b and 6c
tron-withdrawing groups (entries 12–18).
Table 2 1,3-Dipolar Cycloaddition between a Variety of Substituted Tosylhydrazones and gem-Dibromoethenesa
H
N
N
N
NNHTs
N
R3
NaOH
THF
Br
R3
R3
R1
or
+
R2
R1
R2
R2
Br
Br
Br
1
2
3
5
Entry
Hydrazone
R1
R2
gem-Dibromoalkene R3
Product
Yieldb (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1e
1e
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
2b
2c
2d
2e
2f
Ph
3aa
3ab
3ac
3ad
3ae
3af
85
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
2-pyridyl
2-furyl
2-thienyl
2-O2NC6H4
Ph
76
3
42 (84b)
82
4
5
75
6
86
7
2g
2h
2a
2a
2a
2a
2b
2c
2d
2a
2a
2a
3ag
3ah
3ba
3ca
3da
5ea
5eb
5ec
5ed
5fa
81
8
48 (80c)
81
9
4-MeOC6H4
Ph
10
11
12
13
14
15
16
17
18
Ph
83
4-NCC6H4
Ph
Me
H
Ph
73
Ph
76
Ph
H
4-MeOC6H4
4-O2NC6H4
4-ClC6H4
Ph
75
Ph
H
79
Ph
H
80
4-ClC6H4
4-Me2NC6H4
4-MeOC6H4
H
67
1g
1h
H
Ph
5ga
5ha
78
H
Ph
81
a Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), NaOH (0.9 mmol), THF (3 mL), 80 °C, 10 h.
b Isolated yield.
c Reaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), LiOt-Bu (0.9 mmol), dioxane (3 mL), 110 °C, 4 h.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 413–420

416
Q. Sha, Y. Wei
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Table 3 The Tandem Reaction of Carbonyl Compounds with gem-Dibromoalkenesa
(1) TsNHNH2, THF, 4 Å MS, 80 °C, 1.5 h
N
N
O
Br
, NaOH, 80 °C, 10 h
(2)
Br
R
Br
NNHTs
R
6
3
R
Br
Br
TsNHNH2
2a
1
Entry
Ketone
R
Product
Yieldb (%)
1
2
3
6a
6b
6c
H
3aa
3ba
3da
76 (23c)
78
OMe
CN
72
a Reaction conditions: ketone 6 (0.3 mmol), TsNHNH2 (0.3 mmol), 4 Å MS (0.1 g), (2,2-dibromovinyl)benzene (2a) (0.3 mmol), NaOH (0.9
mmol), THF (3 mL), 80 °C.
b Isolated yields.
c Without the use of 4 Å MS.
were used, and the yields of products were also good (en-
tries 2 and 3).
Theoretically, the reaction may give two products, 3 and
4 (Scheme 1). In order to make sure of the exact structure
of the product, product 3ac was selected as an example.
Firstly, the structure of 3ac was determined by 2D NMR
HMBC techniques. It was found from the HMBC spec-
trum that there was correlation between H1 and Ca (desig-
nation as shown in Figure 1) and no correlation between
H1 and Cb (for HMBC and NOESY spectra see the Sup-
porting Information). If the product is another isomer 4ac,
there must be correlation between H1 and Cb, because
these two atoms are three bonds apart (Figure 1). Then,
the structure was further examined by the NOESY exper-
iment. It was found that there were NOE correlations
between H1 and H2 and no NOE correlations between H1
and H3 (Figure 1). The distance of H2, H3, and H4 to H1
in isomer 4ac was then calculated according to Gaussian
Figure 2 The calculated distance of hydrogen atoms of isomer 4ac.
Computations were performed according to Gaussian 03 package us-
ing the B3LYP method. The optimizations were performed without
03 package using the B3LYP method. Obviously, the dis- any symmetry restrictions using the default convergence criteria in
the programs. The optimized structure was characterized to be true lo-
cal energy minima on the potential energy surfaces without imaginary
frequencies.
tance of H1 to H3 (3.888 Å) is shorter than 5 Å (Figure 2).
So if the product is the isomer 4ac, there must be NOE
correlations between H1 and H3. All the above discussion
supported the structure of the product as isomer 3ac.
NMR spectra of 5ea synthesized by the literature method
were exactly the same as our sample (see the Supporting
Information). We found that the 13C spectra of 5ea dif-
fered widely when using different solvents (see Figure 3
and the Supporting Information) as reported in litera-
ture.18 When using DMSO-d6, ten signals were present in
the 13C spectrum. However when using CDCl3, only six
signals were present. From the 13C spectra, we drew the
conclusion that there is fast tautomerism of 5ea in CDCl3
and slow tautomerism in DMSO-d6.
Br
a
N
N
N
b
N
NO2
b
a
1
Me
Me
1
H3
Br
H
2H
2H
3
NO2
H4
3ac
isomer (4ac)
H4
Figure 1 The structure of 3ac and its potential isomer
In summary, a simple, highly efficient, and regioselective
procedure for the synthesis of 3,5-diaryl-4-bromopyr-
azoles via the reaction of hydrazones and gem-dibro-
moalkenes was developed. The diazo compounds and 1-
Among the eighteen products, only 5ea has been previ-
ously reported in literature. This could also give the evi-
dence for the structure of the products. We synthesized
5ea according to the literature method.8,14 The 1H and 13C
Synthesis 2013, 45, 413–420
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One-Pot Synthesis of 3,5-Diaryl-4-bromopyrazoles
417
1H NMR (500 MHz, CDCl3): δ = 7.47 (s, 1 H), 7.61 (d, J = 8.5 Hz,
2 H), 8.15 (d, J = 8.5 Hz, 2 H).
1-Chloro-4-(2,2-dibromovinyl)benzene (2d)20
Light green solid; yield: 2.23 g (76%); mp 35–36 °C.
1H NMR (500 MHz, CDCl3): δ = 7.34 (d, J = 8.5 Hz, 2 H), 7.43 (s,
1 H), 7.47 (d, J = 8.5 Hz, 2 H).
4-Bromo-3-methyl-3,5-diphenyl-3H-pyrazole (3aa) by Cycload-
dition of Acetophenone Tosylhydrazone (1a) with 1-(2-Bromo-
ethynyl)benzene
A Schlenk tube with a magnetic stirrer bar charged with hydrazone
1a (0.3 mmol), 1-(2-bromoethynyl)benzene (0.3 mmol), NaOH (0.9
mmol), and THF (3 mL). The system was heated at 80 °C with stir-
ring for 10 h, The mixture was then allowed to cool to r.t., and di-
luted with EtOAc (20 mL), and washed with brine (15 mL), H2O (15
mL), and then the organic layer was dried (Na2SO4). After concen-
trated in vacuo, the crude product was purified by column chroma-
tography; yield: 78.7 mg (84%).
Figure 3 The different 13C spectra of 5ea
bromoalk-1-ynes were both generated in situ. The reac-
tion may also be carried out in a tandem manner starting
from a 1-bromoalk-1-yne, tosylhydrazine, and a ketone or
aldehyde. The reaction system exhibits tolerance with var-
ious functional groups not only on the aromatic ring of the
hydrazones but also on the aromatic ring of the gem-di-
bromoalkenes, and gives 3,5-diaryl-4-bromo-3H-pyr-
azoles or 3,5-diaryl-4-bromo-1H-pyrazoles with high
regioselectivity and in good yields (67–86%). The struc-
ture of the product was determined by HMBC spectra and
NOESY experiments. Studies on further applications of
this methodology are now in progress.
4-Bromo-3-methyl-3,5-diphenyl-3H-pyrazole (3aa) by Cycload-
dition of Acetophenone Tosylhydrazone (1a) with 1-(2-Bromo-
vinyl)benzene (2a); Typical Procedure
A Schlenk tube with a magnetic stir bar charged with hydrazone 1a
(0.3 mmol), 1-(2-bromovinyl)benzene (2a, 0.3 mmol), NaOH (0.9
mmol), and THF (3 mL). The system was heated at 80 °C with stir-
ring for 10 h, The mixture was then allowed to cool to r.t., and di-
luted with EtOAc (20 mL), and washed with brine (15 mL) and H2O
(15 mL). The organic layer was dried (Na2SO4) and concentrated in
vacuo, and the crude product was purified by column chromatogra-
phy; yield: 79.6 mg (85%).
4-Bromo-3-methyl-3,5-diphenyl-3H-pyrazole (3aa) by One-Pot
Cycloaddition of Acetophenone (6a) with 1-(2-Bromovinyl)ben-
zene (2a); Typical Procedure
A Schlenk tube with a magnetic stir bar charged with acetophenone
(6a, 0.036 g, 0.3 mmol), TsNHNH2 (0.056 g, 0.3 mmol), 4 Å MS
(0.1 g), and THF (3 mL). The system was heated at 80 °C with stir-
ring for 1.5 h, then NaOH (0.036 g, 0.9 mmol) and 1-(2,2-dibro-
movinyl)benzene (2a, 0.078 g, 0.3 mmol) were added, the mixture
was heated at 80 °C with stirring for 10 h. The mixture was then al-
lowed to cool to r.t., and diluted EtOAc (20 mL) and washed with
brine (15 mL) and H2O (15 mL). The organic layer was dried
(Na2SO4) and concentrated in vacuo, and the crude product was pu-
rified by column chromatography; yield: 71.2 mg (76%).
All solvents were distilled prior to use. 1,4-Dioxane, toluene, and
THF were dried over Na, DCE was dried over CaH2, other chemi-
cals (AR grade) were obtained from commercial sources and were
used without further purification. Petroleum ether (PE) refers to the
fraction bp 60–90 °C. The progress of the reactions was monitored
by TLC (silica gel, Polygram SILG/UV 254 plates). Column chro-
matography was performed on Silicycle silica gel (200–300 mesh).
Melting points were obtained using a Yamato melting point appara-
1
tus Model MP-21 and are uncorrected. H and 13C NMR spectra
were obtained using a Bruker DRX 500 (500 MHz) spectrometer in
CDCl3 or DMSO-d6 with TMS as the internal standard.
4-Bromo-3-methyl-3,5-diphenyl-3H-pyrazole (3aa)
Yellow solid; yield: 79.6 mg (85%); mp 47–50 °C; Rf = 0.55 (PE–
EtOAc, 10:1).
Tosylhydrazones 1; General Procedure19
A soln of pure TsNHNH2 (1.72 g, 10 mmol) in MeOH (10 mL) was
stirred at 60 °C until the TsNHNH2 was completely dissolved. Then
carbonyl compounds (10.5 mmol) were added dropwise slowly to
the mixture, and it was then refluxed for 2 h. The mixture was al-
lowed to cool to r.t.; the crude products were obtained as solid pre-
cipitates. The precipitates were washed with cold petroleum ether
then dried to give the pure products. The general yield was ~80%.
1H NMR (500 MHz, CDCl3): δ = 8.38 (d, J = 7.5 Hz, 2 H), 7.57–
7.49 (m, 3 H), 7.39–7.36 (m, 3 H), 7.22 (dd, J = 7.9, 1.9 Hz, 2 H),
1.91 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 149.47, 136.67, 133.01, 129.78,
129.69, 128.99, 128.75, 128.38, 128.05, 126.25, 100.81, 19.69.
GC-MS (EI, 70 eV): m/z = 311.9.
(Dibromovinyl)benzene (2a); Typical Procedure20
Anal. Calcd for C16H13BrN2 (312.03): C, 61.36; H, 4.18; N, 8.94.
Found: C, 61.52; H, 4.21; N, 8.89.
To a stirred mixture of benzaldehyde (1.06 g, 10 mmol), CBr4 (6.6
g, 20 mmol), and CH2Cl2 (25 mL) at 0 °C was added Ph3P (10.5 g,
40 mmol) in portions over 15 min; the resulting brown-colored soln
was stirred at 0 °C for 2 h. The reaction was quenched with petro-
leum ether (100 mL), the precipitate was filtered through silica gel
pad, and the filtrate was evaporated. The crude product was further
purified by column chromatography (silica gel, 1% EtOAc–PE) to
give 2a as a yellow liquid; yield: 2.27 g (87%).
4-Bromo-5-(4-methoxyphenyl)-3-methyl-3-phenyl-3H-pyr-
azole (3ab)
Yellow solid; yield: 78.0 mg (76%); mp 84–87 °C; Rf = 0.37 (PE–
EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 8.36 (d, J = 7.5 Hz, 2 H), 7.39–
7.35 (m, 3 H), 7.22 (d, J = 7.5 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H),
3.90 (s, 3 H), 1.89 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 160.69, 149.29, 134.04, 133.44,
129.69, 129.03, 128.72, 126.37, 122.49, 114.28, 100.63, 55.50,
19.86.
1-(2,2-Dibromovinyl)-4-methoxybenzene (2b)20
White solid; yield: 2.84 g (98%); mp 37–38 °C.
1-(2,2-Dibromovinyl)-4-nitrobenzene (2c)20
Yellow solid; yield: 2.68 g (88%); mp 93–94 °C.
© Georg Thieme Verlag Stuttgart · New York
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418
Q. Sha, Y. Wei
PAPER
GC-MS (EI, 70 eV): m/z = 341.9.
4-Bromo-3-methyl-5-(2-nitrophenyl)-3-phenyl-3H-pyrazole
(3ah)
Anal. Calcd for C17H15BrN2O (342.04): C, 59.49; H, 4.41; N, 8.16.
Found: C, 59.56; H, 4.43; N, 8.09.
Gray solid; yield: 85.7 mg (80%); mp 133–136 °C; Rf = 0.19 (PE–
EtOAc, 10:1).
4-Bromo-3-methyl-5-(4-nitrophenyl)-3-phenyl-3H-pyrazole
1H NMR (500 MHz, CDCl3): δ = 8.23–8.21 (m, 1 H), 7.80–7.77 (m,
1 H), 7.75–7.73 (m, 1 H), 7.70–7.67 (m, 1 H), 7.44–7.38 (m, 3 H),
7.31–7.27 (m, 2 H), 1.92 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 149.64, 148.61, 140.38, 133.58,
132.40, 132.17, 130.78, 129.25, 129.07, 126.45, 125.37, 125.25,
100.43, 19.26.
(3ac)
Yellow solid; yield: 89.9 mg (84%); mp 154–157 °C; Rf = 0.34
(PE–EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 8.56 (d, J = 8.5 Hz, 2 H), 8.37 (d,
J = 8.5 Hz, 2 H), 7.40–7.37 (m, 3 H), 7.19–7.17 (m, 2 H), 1.91 (s, 3
H).
GC-MS (EI, 70 eV): m/z = 356.9.
13C NMR (125 MHz, CDCl3): δ = 148.00, 147.47, 141.04, 135.84,
132.31, 129.18, 129.08, 128.81, 126.17, 123.99, 101.88, 19.76.
Anal. Calcd for C16H12BrN3O2 (357.01): C, 53.65; H, 3.38; N,
11.73. Found: C, 53.58; H, 3.39; N, 11.80.
GC-MS (EI, 70 eV): m/z = 356.8.
4-Bromo-3-(4-methoxyphenyl)-3-methyl-5-phenyl-3H-pyr-
azole (3ba)
Yellow liquid; yield: 83.1 mg (81%); Rf = 0.40 (PE–EtOAc, 10:1).
Anal. Calcd for C16H12BrN3O2 (357.01): C, 53.65; H, 3.38; N,
11.73. Found: C, 54.54; H, 3.46; N, 11.82.
4-Bromo-5-(4-chlorophenyl)-3-methyl-3-phenyl-3H-pyrazole
(3ad)
1H NMR (500 MHz, CDCl3): δ = 8.39 (d, J = 7 Hz, 2 H), 7.55 (t,
J = 7.5 Hz, 2 H), 7.50 (t, J = 7 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 2 H),
6.91 (d, J = 9 Hz, 2 H), 3.81 (s, 3 H), 1.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 159.85, 149.16, 136.98, 129.84,
129.68, 128.77, 128.03, 127.56, 114.38, 100.52, 55.34, 19.76.
Yellow liquid; yield: 85.1 mg (82%); Rf = 0.62 (PE–EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 8.34–8.33 (m, 2 H), 7.53–7.53 (m,
2 H), 7.39–7.37 (m, 3 H), 7.22–7.20 (m, 2 H), 1.90 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 148.45, 137.12, 135.66, 132.82,
129.32, 129.20, 129.05, 128.84, 128.25, 126.22, 101.10, 19.72.
GC-MS (EI, 70 eV): m/z = 341.8.
Anal. Calcd for C17H15BrN2O (342.04): C, 59.49; H, 4.41; N, 8.16.
Found: C, 59.53; H, 4.46; N, 8.11.
GC-MS (EI, 70 eV): m/z = 345.8.
Anal. Calcd for C16H12BrClN2 (345.99): C, 55.28; H, 3.48; N, 8.06.
Found: C, 55.41; H, 3.45; N, 7.93.
4-Bromo-3-ethyl-3,5-diphenyl-3H-pyrazole (3ca)
Yellow solid; yield: 81.2 mg (83%); mp 50–53 °C; Rf = 0.55 (PE–
EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 8.40–8.38 (m, 2 H), 7.58–7.55 (m,
2 H), 7.53–7.50 (m, 1 H), 7.39–7.36 (m, 3 H), 7.32–7.30 (m, 2 H),
3.01–2.94 (m, 1 H), 2.37–2.30 (m, 1 H), 0.71 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 150.55, 134.92, 133.63, 129.89,
129.79, 129.07, 128.86, 128.73, 128.21, 126.64, 104.22, 27.48,
7.50.
4-Bromo-3-methyl-3-phenyl-5-(2-pyridyl)-3H-pyrazole (3ae)
Brown liquid; yield: 70.4 mg (75%); Rf = 0.22 (PE–EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 8.84–8.82 (m, 1 H), 8.41 (d, J = 8
Hz, 1 H), 7.91–7.88 (m, 1 H), 7.42–7.34 (m, 4 H), 7.23–7.21 (m, 2
H), 1.91 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 149.94, 149.26, 149.20, 141.23,
137.15, 132.72, 129.12, 128.93, 126.41, 124.13, 123.94, 101.40,
19.81.
GC-MS (EI, 70 eV): m/z = 325.9.
GC-MS (EI, 70 eV): m/z = 312.8.
Anal. Calcd for C17H15BrN2 (326.04): C, 62.40; H, 4.62; N, 8.56.
Found: C, 62.56; H, 4.54; N, 8.49.
Anal. Calcd for C15H12BrN3 (313.02): C, 57.34; H, 3.85; N, 13.37.
Found: C, 57.44; H, 3.91; N, 13.33.
4-(4-Bromo-3-methyl-5-phenyl-3H-pyrazol-3-yl)benzonitrile
(3da)
4-Bromo-5-(2-furyl)-3-methyl-3-phenyl-3H-pyrazole (3af)
Brown liquid; yield: 77.9 mg (86%); Rf = 0.55 (PE–EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 7.68–7.67 (m, 1 H), 7.39–7.33 (m,
4 H), 7.23–7.20 (m, 2 H), 6.64–6.63 (m, 1 H), 1.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 145.82, 144.20, 143.52, 133.06,
Yellow solid; yield: 73.8 mg (73%); mp 45–47 °C; Rf = 0.22 (PE–
EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 8.37–8.34 (m, 2 H), 7.68–7.67 (m,
2 H), 7.55–7.51 (m, 3 H), 7.35–7.33 (m, 2 H), 1.90 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 150.43, 138.50, 135.14, 12.86,
130.20, 129.36, 128.98, 128.20, 127.31, 118.37, 112.37, 100.25,
19.90.
132.27, 129.00, 128.76, 126.28, 112.74, 111.86, 100.51, 19.91.
GC-MS (EI, 70 eV): m/z = 301.8.
Anal. Calcd for C14H11BrN2O (302.01): C, 55.47; H, 3.66; N, 9.24.
Found: C, 55.53; H, 3.71; N, 9.27.
GC-MS (EI, 70 eV): m/z = 336.8.
Anal. Calcd for C17H12BrN3 (337.02): C, 60.37; H, 3.58; N, 12.42.
Found: C, 60.46; H, 3.62; N, 12.33.
4-Bromo-3-methyl-3-phenyl-5-(2-thienyl)-3H-pyrazole (3ag)
Gray solid; yield: 77.3 mg (81%); mp 115–117 °C; Rf = 0.54 (PE–
EtOAc, 10:1).
1H NMR (500 MHz, CDCl3): δ = 8.20 (d, J = 3.5 Hz, 1 H), 7.58–
7.56 (m, 1 H), 7.40–7.36 (m, 3 H), 7.27–7.23 (m, 3 H), 1.91 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 146.47, 133.37, 132.33, 129.11,
4-Bromo-3,5-diphenyl-1H-pyrazole (5ea)
White solid; yield: 67.9 mg (76%); mp 207–208 °C (Lit.14 199–200
°C, Lit.15 195 °C); Rf = 0.38 (PE–EtOAc, 3:1).
1H NMR (500 MHz, CDCl3): δ = 7.79–7.78 (m, 4 H), 7.45–7.41 (m,
6 H), 5.16 (s, 1 H).
1H NMR (500 MHz, DMSO-d6): δ = 13.75 (s, 1 H), 7.85–7.76 (m,
4 H), 7.55–7.41 (m, 6 H).
128.86, 128.23, 127.92, 126.39, 100.89, 20.11.
GC-MS (EI, 70 eV): m/z = 317.8.
13C NMR (125 MHz, CDCl3): δ = 146.45, 129.39, 129.12, 128.63,
128.01, 91.74.
Anal. Calcd for C14H11BrN2S (317.98): C, 52.68; H, 3.47; N, 8.78.
Found: C, 52.59; H, 3.55; N, 8.91.
13C NMR (125 MHz, DMSO-d6): δ = 149.43, 141.53, 133.01,
129.54, 129.40, 128.96, 128.83, 128.63, 128.12.
Synthesis 2013, 45, 413–420
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of 3,5-Diaryl-4-bromopyrazoles
419
GC-MS (EI, 70 eV): m/z = 298.0.
Anal. Calcd for C11H16BrN3 (341.05): C, 59.66; H, 4.71; N, 12.28.
Found: C, 59.54; H, 4.73; N, 12.17.
Anal. Calcd for C15H11BrN2 (298.01): C, 60.22, H, 3.71, N, 9.36.
Found: C, 60.31; H, 3.68; N, 9.29.
4-Bromo-3-(4-methoxyphenyl)-5-phenyl-1H-pyrazole (5ha)
White solid; yield: 79.7 mg (81%); mp 205–208 °C; Rf = 0.24 (PE–
EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 13.67 (s, 1 H), 7.84–7.77 (m,
4 H), 7.50–7.42 (m, 3 H), 7.07 (d, J = 7 Hz, 2 H), 3.80 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 160.05, 149.11, 141.44,
133.09, 131.99, 129.49, 129.11, 128.09, 121.16, 114.63, 89.75,
55.76.
4-Bromo-5-(4-methoxyphenyl)-3-phenyl-1H-pyrazole (5eb)
White solid; yield: 73.8 mg (75%); mp 204–207 °C; Rf = 0.22 (PE–
EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 13.63 (s, 1 H), 7.85–7.70 (m,
4 H), 7.53–7.41 (m, 3 H), 7.09–7.05 (m, 2 H), 3.81 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 160.29, 159.72, 149.29,
141.45, 133.13, 129.41, 128.94, 128.56, 128.08, 125.46, 121.16,
114.84, 114.41, 89.85, 89.61, 55.82.
GC-MS (EI, 70 eV): m/z = 328.0.
GC-MS (EI, 70 eV): m/z = 328.0.
Anal. Calcd for C16H13BrN2O (328.02): C, 58.38; H, 3.98, N, 8.51.
Found: C, 58.51; H, 4.01; N, 3.89.
Anal. Calcd for C16H13BrN2O (328.02): C, 58.38; H, 3.98; N, 8.51.
Found: C, 58.51; H, 4.01; N, 3.89.
Acknowledgment
4-Bromo-5-(4-nitrophenyl)-3-phenyl-1H-pyrazole (5ec)
Yellow solid; yield: 81.3 mg (79%); mp 221–224 °C; Rf = 0.30
(PE–EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 14.06 (s, 1 H), 8.37–8.31 (m,
We are grateful to Nanjing University of Science and Technology
for financial support. We thank Dr. Cai-chao Ye for calculating the
distance of hydrogen atoms of isomer 4ac. We also thank Professor
Lu-de Lu and Associate Professor Xiao-dong Wu for helping us to
analyze the NMR spectra and perform NMR experiments.
2 H), 8.17–8.05 (m, 2 H), 7.83–7.74 (m, 2 H), 7.55–7.48 (m, 3 H).
13C NMR (125 MHz, DMSO-d6): δ = 150.08, 149.46, 147.73,
147.37, 147.18, 142.34, 139.39, 134.91, 132.58, 129.76, 129.42,
128.99, 128.65, 128.26, 126.38, 125.76, 124.58, 124.30, 90.75.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
GC-MS (EI, 70 eV): m/z = 343.0.
m
tgioSrantnugIifoop
r
itmnatr
Anal. Calcd for C15H10BrN3O2 (343.00): C, 52.35; H, 2.93; N,
12.21. Found: C, 52.44; H, 2.99; N, 12.08.
References
4-Bromo-5-(4-chlorophenyl)-3-phenyl-1H-pyrazole (5ed)
White solid; yield: 79.7 mg (80%); mp 226–230 °C; Rf = 0.43 (PE–
EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 13.83 (s, 1 H), 7.88–7.76 (m,
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4 H), 7.61–7.48 (m, 5 H).
13C NMR (125 MHz, DMSO-d6): δ = 149.59, 148.23, 141.80,
140.43, 134.32, 133.40, 132.87, 131.84, 129.68, 129.41, 129.08,
128.68, 127.64, 127.36, 125.69, 90.18.
GC-MS (EI, 70 eV): m/z = 332.0.
Anal. Calcd for C15H10BrClN2 (331.97): C, 54.00; H, 3.02; N, 8.40.
Found: C, 53.87; H, 3.08; N, 8.43.
4-Bromo-3-(4-chlorophenyl)-5-phenyl-1H-pyrazole (5fa)
White solid; yield: 66.7 mg (67%); mp 210–213 °C; Rf = 0.40 (PE–
EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 13.83 (s, 1 H), 7.89–7.74 (m,
4 H), 7.64–7.42 (m, 5 H).
13C NMR (125 MHz, DMSO-d6): δ = 149.47, 148.13, 141.71,
140.34, 134.21, 133.30, 131.73, 129.77, 129.35, 129.01, 128.57,
128.08, 127.52.
GC-MS (EI, 70 eV): m/z = 332. 0.
Anal. Calcd for C15H10BrClN2 (331.97): C, 54.00; H, 3.02; N, 8.40.
Found: C, 53.89; H, 3.07; N, 8.47.
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4-(4-Bromo-5-phenyl-1H-pyrazol-3-yl)-N,N-dimethylaniline
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Yellow solid; yield: 79.8 mg (78%); mp 196–200 °C; Rf = 0.23
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(PE–EtOAc, 3:1).
1H NMR (500 MHz, DMSO-d6): δ = 13.49 (s, 1 H), 7.86–7.64 (m,
4 H), 7.48–7.40 (m, 3 H), 6.815 (d, J = 8 Hz, 2 H), 2.94 (s, 6 H).
13C NMR (125 MHz, DMSO-d6): δ = 150.92, 149.07, 141.93,
133.21, 129.29, 128.82, 128.69, 128.39, 127.96, 115.92, 112.40,
88.68, 60.25.
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GC-MS (EI, 70 eV): m/z = 341.1.
© Georg Thieme Verlag Stuttgart · New York
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PAPER
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