Efficient di-bromination of 5-pyrazolones and 5-hydroxypyrazoles by N-bromobenzamide

Article abstract of DOI:10.1016/j.tet.2009.09.055

An efficient and convenient method for the bromination of pyrazolones and 5-hydroxypyrazoles was developed by using N-bromobenzamide in THF at room temperature. This new method provided di-bromimated pyrazolones in excellent yields (≥90%). Crown Copyright

Full text of DOI:10.1016/j.tet.2009.09.055

Tetrahedron 65 (2009) 9592–9597
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient di-bromination of 5-pyrazolones and 5-hydroxypyrazoles
by N-bromobenzamide
Yu-Ying Huang a, Hui-Chang Lin a, Kaung-Min Cheng a, Wei-Nien Su a, Kuan-Chin Sung b,
,
Tsung-Ping Lin a, Jiann-Jyh Huang c, Shao-Kai Lin d, Fung Fuh Wong a
*
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan, ROC
b Department of Surgery, Attending Physician Neurosurgery, No. 201, Taikang Village, Liouying Township 709, Taiwan ROC
c Development Center for Biotechnology, No. 101, Lane 169, Kangning St., Xizhi City, Taipei County 221, Taiwan ROC
d Sustainable Environment Research Center, National Cheng Kung University, No. 500, Sec. 3, An-ming Rd., Tainan City 709, Taiwan ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 August 2009
Received in revised form 7 September 2009
Accepted 15 September 2009
Available online 18 September 2009
An efficient and convenient method for the bromination of pyrazolones and 5-hydroxypyrazoles was
developed by using N-bromobenzamide in THF at room temperature. This new method provided di-bro-
mimated pyrazolones in excellent yields (ꢀ90%).
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Keywords:
Bromination
N-Bromobenzamide
Pyrazolones
5-Hydroxypyrazoles
1. Introduction
N-bromobenzamide has been also reported as a mild and effective
brominating agent with unsaturated alkenes.17 They were also
Pyrazolones1 and pyrazoles2 attract attentions due to their wide
range of pharmacological proprieties.3–7 Some halogenated pyra-
zolones also displayed bioactivities, examples include 4,4-dichloro-5-
pyrazolone derivatives as a potent catalytic inhibitor of human
telomerase8 and 4,4-dibromo-5-pyrazolone as fungicide against
demonstrated to act as an oxidant agent18,19 and nitrogen source in
the asymmetric aminohydroxylationprocess.19 Herein, we report the
use of N-bromobenzamide as a safe and efficient bromination agent
for pyrazolones and 5-hydroxypyrazoles. The newly developed
method provided the corresponding di-brominated pyrazolones in
excellent yields (ꢀ90%). The reaction proceeded smoothly at room
temperature with easy manipulation. Comparing N-bromobenza-
mide and N-bromosuccinimide (NBS) as the brominating agents
toward pyrazolone reactants, we found that N-bromobenzamide can
provide more efficient reactivity than N-bromosuccinimide (NBS).
Helminthosporium oryzae,9
a-glucosidase inhibitors, and for treat-
ment of tumor metastasis, AIDS, diabetes, hyperlipidemia, autoim-
munedisease, allergy, rejectioninorgantransplant, etc.10 Pyrazolones
and pyrazoles are key starting materials for the synthesis of com-
mercial aryl/heteroaropyrazolone dye.11,12 Brominated and chlorinated
pyrazolones are also useful synthetic intermediates for synthesis of
diazo-dyes,13 fused-14 and spiro-heterocyclic compounds.15
Traditional methods for the synthesis of brominated pyrazolones
contain the use of Br2 in acetic acid,12 however, the harsher condi-
tions require manipulations with care. Ahmed et al. have treated
the pyrazolones with N-bromosuccinimide (NBS) to perform the
photochemical bromination.16 Since the reaction also provided the
mono-substituted and coupling by-products, the desired dibromo-
pyrazolines were obtained in low yields.16 Commercially available
2. Result and discussion
We first prepared 5-pyrazolone derivatives as the starting ma-
terials by tandem condensation and thermal cyclization.20
a-Keto
esters 1 were heated at reflux with equal equivalent of arylylhy-
drazines 2a–2h possessing various substituents including m-Me,
p-OMe, p-NO2 and 2,4,6,-trichloro in AcOH for 4 h. The corre-
sponding 5-pyrazolones (keto form) were obtained in good to ex-
cellent yields (75–95%, see Scheme 1, Chart 1, and Table 1).20 When
the reaction was performed under microwave radiation, the
reaction time was decreased to 10 min and the excellent yields of
the products were also obtained. Use of hydrazine, and pyridyl and
* Corresponding author. Tel.: þ886 4 2205 3366x5603; fax: þ886 4 2207 8083.
E-mail addresses: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F.F.
Wong).
0040-4020/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.055

Y.-Y. Huang et al. / Tetrahedron 65 (2009) 9592–9597
9593
X = Ph, m-Me-Ph, p-OMe-Ph,
O
O
o,p-di-NO2-Ph, 2.4.6.tri-Cl-Ph
O
Ph
NHBr
X
N
N-bromobenzamide
N
X
X
N
R
X = Aryl, Phenyl
N
O
O
O
O
3a-3h
R
X-NHNH2 (2a-2h)
AcOH, at reflux
Br
Br
R
3a-3h
R
OEt
X
N
Br
X N
O
THF
R = Me, CF3, i-Pr, Ph
1
N
N
OH
R
OH
Ph
NHBr
N-bromobenzamide
4
5a-5k
R = Me, CF3, i-Pr, Ph
X
N
N
X = H, Pyridyl, Isoquinolinyl
N
X = H, Pyridyl,
Isoquinolinyl
N
R
R
3i-3k
3i-3k
Scheme 1.
Scheme 2.
O
O
O
O
Y
Y
Y
Y
Ph
N
Ph
N
Ph
N
N
Ph
N
Y
Y
CF3
Y
Pr
Y
Ph
N
N
N
i
CH3
3a. Y = H, 5a. Y = Br
Me
3b. Y = H, 5b. Y = Br
3c. Y = H, 5c. Y = Br
3d. Y = H, 5d. Y = Br
Cl
Cl
O
O
X2
O
3f. X1 = OMe, X2 = Y = H
Y
Y
5f. X1 = OMe, X2 = H, Y = Br
Y
N
N
Cl
N
X1
N
Y
Ph
Y
Ph
N
3g.X1 = X2 = NO2, Y = H
Y
N
5g.X1 = X2 = NO2, Y = Br
Ph
3e. Y = H, 5e. Y = Br
3h. Y = H, 5h. Y = Br
5i. X = H
3i. X = H
3j. X =
OH
O
N
N
N
Br
Br
Ph
5j. X =
5k. X =
X
N
N
X
N
N
N
Ph
3k. X =
Chart 1.
reported data.13,16 By employing same conditions as shown in
Scheme 2, 5-pyrazolones 3b–3h bearing N-substituted phenyl
group including m-Me, p-OMe, o,p-di-NO2-Ph, and 2,4,6-trichloro
was successfully di-brominated to the corresponding products
5b–5h in ꢀ91% yields (see Table 2). This reaction was also appli-
cable to the 5-hydroxypyrazole (enol form) bearing N-substituted
group, such as H, pyridyl, and isoquinolinyl (compounds 3i–3k).
The desired di-brominated compounds 5i–5k were obtained in
90–93% yields. For example, compound 5j possessed characteriza-
Table 1
The results of tandem thermal condensation/cyclizationa
Hydrazines
(2a–2h)
5-Pyrazolones (3a–3h) or
5-hydroxypyrazoles (3i–3k)
Substrates
X
Compounds
R
Yields (%)
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
Me
CF3
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
91
75
95
94
88
90
82
85
96
88
86
m-Me-Ph
p-OMe-Ph
o,p-di-NO2-Ph
2,4,6,-Trichloro-Ph
H
tion absorptions at
d 42.4 ppm for gem-dibromomethylene carbon
[O]C–13C(Br)2] in pyrazolone ring and IR absorptions at 1744 cmꢁ1
for the stretching of the –C]O group. When 2-pyrrolidinone and
g-butyrolactone were allowed to react with N-bromobenzamide,
2g
2h
Pyridyl
3j
Isoquinolinyl
3k
Table 2
a
The tandem thermal condensation and cyclization in AcOH at reflux for 4 h.
The results of bromination by using N-bromobenzamide
5-Pyrazolones (3a–3h) or 5-hydroxypyrazoles (3i–3k) Brominationa (5a–5k)
isoquinolinyl hydrazines as the starting material provided the
corresponding 5-hydroxypyrazoles 3i–3k (enol form) in 86–88%
yields (see Scheme 1, Chart 1, and Table 1). The experiment results
were consistent with the reported literature.21,22 When acetyl and
isonicotinoyl hydrazines reacted with ethyl benzoylacetate (1), only
3-phenyl-1H-pyrazol-5-ol (3i) was obtained due to the instability
of the amide bond (–(C]O)–N–) in acidic condition.
The N-bromobenzamide was allowed to react with pyrazolones
for the investigation of its feasibility of di-bromination. Treatment
of 5-pyrazolone 3a with N-bromobenzamide in THF solution at
room temperature for 1 h gave 4,4-dibromo-5-pyrazolone 5a in
96% yield (see Chart 1 and Scheme 2). Compound 5a was fully
characterized by spectroscopic method and consistent with the
Compounds
X
R
Products Yields (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
Ph
Me
CF3
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
96
93
95
98
96
92
91
96
93
93
90
m-Me-Ph
p-OMe-Ph
o,p-di-NO2-Ph
2,4,6,-Trichloro-Ph
H
3j
3k
Pyridyl
Isoquinolinyl
5j
5k
a
The di-bromination of compounds 3i–3k with N-bromobenzamide in THF
solution at room temperature for 1 h.

9594
Y.-Y. Huang et al. / Tetrahedron 65 (2009) 9592–9597
N-bromobenzamide
O
O
O
X
N
N
+
O
Ph
NH2
PhCNH +
Br
O
O
6
7
R
PhCNH +
Br
X
N
Br
X
N
N
N
X = Phenyl, Aryl
O
R
R
4
3a-3h
Ph
NH2
6
O
Br
Br
R
X
N
N
5a-5k
O
Ph
NH2
OH
O
6
X = H, Pyridyl, Isoquinolinyl
X
N
Br
X
N
O
O
N
N
O
O
R
R
PhCNH +
Br
X
N
4
+
3i-3k
PhCNH +
Br
Ph
NH2
N
6
8
R
N-bromobenzamide
Scheme 3.
the reaction did not give the desired products either at room
temperature or at reflux.
and isonicotinic acid hydrazide were purchased from TCI Chemical
Co. Ethyl trifluoroacetoacetate and tert-butyl acetoacetate were
purchased from Alfa Chemical Co. Purification by gravity column
chromatography was carried out by use of Merck Reagents Silica
Gel 60 (particle size 0.063–0.200 mm, 70–230 mesh ASTM). In-
frared (IR) spectra were measured on a Bomem Michelson Series
FT-IR spectrometer. The wavenumbers reported are referenced to
the polystyrene 1601 cmꢁ1 absorption. Absorption intensities are
recorded by the following abbreviations: s, strong; m, medium; w,
weak. Proton NMR spectra were obtained on a Bruker (200 MHz)
spectrometer by use of CDCl3, CH3OD, and DMSO-d6 as the solvent.
Carbon-13 NMR spectra were obtained on a Bruker (50 MHz)
spectrometer by use of CDCl3, CH3OD, and DMSO-d6 as the solvent.
Carbon-13 chemical shifts are referenced to the center of the CDCl3
We proposed a plausible mechanism for the bromination of 5-
pyrazolones by use of N-bromobenzamide (see Scheme 3). N-Bro-
mobenzamide first underwent homolytic cleavage to form two
radical species (PhCONH$ and Br$) by photolysis in THF at room
temperature.17a The PhCONH$ radical quickly trapped a hydrogen
from the
a-position of pyrazolones or from –OH group of 5-
hydroxypyrazoles to generate benzamide 6 and the corresponding
radical intermediate 7 or 8.17c Benzamide 6 was isolated by column
chromatography and identified by 1H and 13C NMR spectroscopic
methods.17c The resultant
a-radical of 5-pyrazolone 7 or O-radical of
5-hydroxypyrazole 8 was formed and reacted with Br$ to give the
mono-brominated pyrazolone 4. In the presence of excess N-bro-
mobenzamide, the reaction proceeded to convert pyrazolones 4 to
the final di-brominated products 5a–5k. For understanding the
reaction mechanism, we added dihydroquinone to the reaction
mixture. The reaction gave benzamide 6 and quinone without the
formation of bromination adduct. We believed that the reaction
favored the radical-type mechanism since the two radical species
PhCONH$ and Br$ would be quenched by dihydroquinone. As a re-
sult, no bromination product was found.
triplet (d 77.0 ppm). Multiplicities are recorded by the following
abbreviations: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet; J, coupling constant (Hz). Elemental analyses were carried
out on a Heraeus CHN–O RAPID element analyzer.
3.2. Standard procedure for the condensation–cyclization
reaction to prepare pyrazolones 3a–3h and 5-hydroxy-
pyrazoles 3i–3k
In conclusion, we have successfully developed a brominating
method by using N-bromobenzamide to convert pyrazolone and
5-hydroxypyrazole to the corresponding 4,4-dibromo-pyrazolones
in excellent yields (ꢀ90%). We considered the bromination pro-
cedure was a safe and efficient method in the large-scale for the
preparation of 4,4-dibromo-pyrazolones.
To a neat solution containing 1,3-ketoester (1, 1.0 equiv) and
hydrazines (2a–2h,1.1 equiv) was added glacial acetic acid (2.0 mL).
The reaction mixture was heated at reflux for 2–3 h. After the re-
action was completed, the solution was diluted with Et2O (10 mL)
and stirred at ice-bath for 30 min. The resultant solid was filtrated,
washed with Et2O (10 mL), dried under vacuum for 12 h, and
recrystallized from EtOH to give pure pyrazolones 3a–3h and
5-hydroxypyrazoles 3i–3k as solids in 75–96% yield.
3. Experimental section
3.1. General procedure
3.2.1. 3-Methyl-1-phenyl-2-pyrazolin-5-one (3a)22. Mp (recrystal-
All chemicals were reagent grade and used as purchased unless
otherwise noted. All reactions were carried out under nitrogen
atmosphere and monitored by TLC. Flash column chromatography
was carried out on silica gel (230–400 mesh). Dichloromethane,
ethyl acetate, hexanes, and methanol were purchased from Mal-
linckrodt Chemical Co. The following compounds were purchased
from Acros Chemical Co: m-tolylhydrazine hydrochloride, tert-
butyl acetoacetate, ethyl isobutylacetate, phenylhydrazine, 4-
methoxyphenylhydrazine hydrochloride, and 2,4-dinitrophenyl
hydrazine. 2,4,6-Trichlorophenyl hydrazine, 2-hydrazinopyridine,
lized from ethanol) 127–129 ꢂC; 1H NMR (CDCl3, 200 MHz)
d 2.15
(s, 3H, CH3), 3.39 (s, 2H, pyrazolone-H), 7.14 (d, 1H, J¼2.2 Hz, ArH),
7.36 (dd, 2H, J¼7.8, 2.2 Hz, ArH), 7.81 (d, 2H, J¼7.8 Hz, ArH); 13C NMR
(50 MHz, CDCl3)
d
17.0, 43.1,118.9 (2ꢃCH),125.1,128.8 (2ꢃCH),137.9,
156.4,170.6; IR (KBr) 3101 (s), 2802 (m),1622 (s, C]O),1584 (s, C¼N),
1494 (m), 1412 (m), 1301 (s), 1220 (m), 1035 (m), 967 (m) cmꢁ1
.
3.2.2. 1-Phenyl-3-trifluoromethyl-2-pyrazolin-5-one (3b)22. Mp (recry-
stallized from ethanol) 194–196 ꢂC; 1H NMR (CDCl3, 200 MHz)
3.71
(s, 2H, pyrazolone-H), 6.61 (s, 1H, ArH), 7.66 (d, 2H, J¼7.8 Hz, ArH),
d

Y.-Y. Huang et al. / Tetrahedron 65 (2009) 9592–9597
9595
7.80 (d, 2H, J¼7.6 Hz, ArH); 13C NMR (50 MHz, DMSO-d6)
122.3, 127.2, 129.1, 137.7, 140.4 (q, 3JC–F¼37.6 Hz), 153.7.
d
85.6,
(KBr) 3024 (m), 2920 (m), 1601 (m), 1491 (m), 1450 (m), 1069 (m),
756 (m), 698 (m) cmꢁ1
.
3.2.3. 3-Isopropyl-1-phenyl-2-pyrazolin-5-one (3c)22. Mp (recrys-
tallized from ethanol) 101–103 ꢂC; 1H NMR (CDCl3, 200 MHz)
1.21
3.2.10. 5-Hydroxy-3-phenyl-1-(pyrid-2-yl)-1H-pyrazole (3j)11. Mp
d
(recrystallized from ethanol) 110–112 ꢂC; 1H NMR (CDCl3,
(d, 6H, J¼7.4, CH(CH3)2), 2.68–2.82 (m, 1H, CHMe2), 3.37 (s, 2H,
200 MHz) d 5.93 (s, 1H, pyrazole-H), 7.07–7.17 (m, 1H, ArH), 7.36–
pyrazolone-H), 7.14 (t, 1H, J¼7.4, ArH), 7.35 (dd, 2H, J¼8.1, 7.4 Hz,
7.41 (m, 3H, ArH), 7.82–7.87 (m, 3H, ArH), 8.00 (d, 1H, J¼7.6 Hz,
ArH), 7.84 (d, 2H, J¼8.1 Hz, ArH); 13C NMR (50 MHz, CDCl3)
d
20.1
ArH), 8.24 (d, 1H, J¼7.2 Hz, ArH); 13C NMR (50 MHz, CDCl3)
d 85.7,
(2ꢃCH3), 30.7, 39.8, 118.8 (2ꢃCH), 124.9, 128.8 (2ꢃCH), 138.2, 164.3,
170.6; IR (KBr) 3101 (s), 2802 (m), 1622 (s, C]O), 1584 (s, C¼N),
112.3, 120.0, 125.8 (2ꢃCH), 128.6 (3ꢃCH), 133.1, 140.0, 145.1, 152.6,
154.6, 157.3; IR (KBr) 3056 (m), 1624 (s, C]O), 1585 (s, C¼N), 1466
(m), 1384 (m), 1310 (m), 1203 (m), 1150 (m), 1086 (m), 1027 (m), 987
1494 (m), 1412 (m), 1301 (s), 1220 (m), 1035 (m), 967 (m) cmꢁ1
.
(m), 942 (m) cmꢁ1
.
3.2.4. 1,3-Diphenyl-2-pyrazolin-5-one(3d)22. Mp (recrystallized from
ethanol) 136–138 ꢂC; 1H NMR (CDCl3, 200 MHz)
3.82 (s, 2H,
d
3.2.11. 5-Hydroxy-3-phenyl-1-(3-isoquinolinyl)-1H-pyrazole
pyrazolone-H), 7.24 (t,1H, J¼7.6, ArH), 7.44–7.53 (m, 5H, ArH), 7.82–
(3k). Mp (recrystallized from ethanol) 147–149 ꢂC; 1H NMR (CDCl3,
7.86 (m, 2H, ArH), 8.01 (d, 2H, J¼7.6 Hz, ArH); 13C NMR (50 MHz,
200 MHz)
d 5.98 (s, 1H, pyrazole-H), 7.38–7.53 (m, 4H, ArH), 7.71–
CDCl3)
d
39.7, 119.1 (2ꢃCH), 125.3, 126.0 (2ꢃCH), 128.9 (2ꢃCH),
7.90 (m, 5H, ArH), 8.12–8.31 (m, 2H, ArH); 13C NMR (50 MHz, CDCl3)
130.7, 130.9 (2ꢃCH), 134.8, 138.1, 154.6, 170.2; IR (KBr) 3067 (m),
d
85.9, 112.1, 125.8, 125.9 (2ꢃCH), 126.0, 126.5, 127.0, 128.0, 128.6
1715 (s, C]O), 1601 (s, C]N), 1496 (m), 1383 (m), 1326 (m), 1172
(2ꢃCH), 131.1, 133.0, 140.2, 143.8, 152.9, 153.8, 157.9; IR (KBr), 3089
(m), 1615 (s, C]O), 1595 (s, C¼N), 1492 (m), 1358 (m), 1196 (m),
1002 (m), 827 (m) cmꢁ1; Anal. Calcd for C18H13N3O: C, 75.25; H,
4.56; N, 14.63. Found: C, 75.28; H, 4.57; N, 14.67.
(m), 1116 (m), 899 (m) cmꢁ1
.
3.2.5. 1-(30-Methylphenyl)-3-phenyl-2-pyrazolin-5-one (3e). Mp
(recrystallized from ethanol) 190–192 ꢂC; 1H NMR (CD3OD,
200 MHz)
d
2.27 (s, 3H, CH3), 3.30 (s, 2H, pyrazolone-H), 7.51 (d, 2H,
3.3. Standard procedure for bromination to prepare
4,4-dibromo-5-pyrazolone derivatives 5a–5k
J¼7.2, ArH), 7.54–7.59 (m, 5H, ArH), 7.82 (d, 2H, J¼7.2, ArH); 13C
NMR (50 MHz, CD3OD)
d
15.9, 126.3 (2ꢃCH), 126.6, 127.2, 128.0,
128.5, 129.2 (2ꢃCH), 131.1, 131.2, 131.5, 131.7, 136.7, 149.6, 157.4; IR
(KBr) 3293 (m), 3124 (s), 1880 (m), 1537 (s, C]N), 1472 (m), 1305
(m), 1147 (m), 982 (m), 807 (m) cmꢁ1; Anal. Calcd for C16H14N2O: C,
76.78; H, 5.64; N, 11.19. Found: C, 76.81; H, 5.62; N, 11.22.
To a solution of pyrazolones 3a–3h or 5-hydroxypyrazoles 3i–3k
(1.0 equiv) in THF (20 mL) was added N-bromobenzamide
(2.1 equiv). The reaction mixture was stirred at room temperature
for w1 h. The solution was concentrated under reduced pressure
and the resultant oil was re-dissolved in CH2Cl2 (50 mL). The so-
lution was washed with H2O (20 mLꢃ2), brine (20 mLꢃ2), and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (30% EtOAc in hexanes as
eluant) to give 4,4-dibromo-5-pyrazolones 5a–5k as solids in
90–98% yields.
3.2.6. 1-(40-Methoxyphenyl)-3-phenyl-2-pyrazolin-5-one (3f)11. Mp
(recrystallized from ethanol) 128–130 ꢂC; 1H NMR (CDCl3,
200 MHz) d 3.78 (s, 2H, pyrazolone-H), 3.79 (s, 3H, CH3), 6.90 (d, 2H,
J¼6.8 Hz, ArH), 7.40–7.44 (m, 3H, ArH), 7.73 (d, 2H, J¼7.2 Hz, ArH),
7.81 (d, 2H, J¼6.8 Hz, ArH); 13C NMR (50 MHz, CDCl3)
d 39.5, 55.5,
114.0 (2ꢃCH), 121.0 (2ꢃCH), 125.9 (2ꢃCH), 128.9 (2ꢃCH), 130.6,
130.9, 131.5, 154.5, 157.2, 170.0; IR (KBr) 2927 (m), 1709 (s, C]O),
3.3.1. 4,4-Dibromo-3-methyl-1-phenyl-2-pyrazolin-5-one (5a)13,16. Mp
1512 (s, C¼N), 1500 (m), 1248 (m), 1030 (m), 832 (m) cmꢁ1
.
(purified by column chromatography on silica gel) 80–82 ꢂC; 1H
NMR (CDCl3, 200 MHz)
d
2.42 (s, 3H, CH3), 7.21 (d, 1H, J¼2.6 Hz,
3.2.7. 1-(20,40-Dinitrophenyl)-3-phenyl-2-pyrazolin-5-one (3g). Mp
ArH), 7.39 (dd, 2H, J¼7.4, 2.6 Hz, ArH), 7.84 (d, 2H, J¼7.4 Hz, ArH); 13C
(recrystallized fromethanol)201–203 ꢂC; 1HNMR (CDCl3, 200 MHz)
NMR (CDCl3, 50 MHz) d 20.0, 41.7, 118.9, 125.0, 128.8, 138.1, 159.9,
d
3.88 (s, 2H, pyrazolone-H), 7.46–7.50 (m, 3H, ArH), 7.71 (d, 2H,
170.6; IR (KBr) 3199 (m), 2960 (m), 1706 (s, C]O), 1508 (s, C¼N),
1348 (m), 1227 (m), 972 (m), 754 (m) cmꢁ1; EIMS m/z (relative in-
tensity) 362 (Mþ2, 7), 360 (Mþ,14), 358 (Mꢁ2, 7), 281 (84), 279 (84),
265 (3), 201 (20), 200 (13),184 (3),171 (4),131 (3),105 (11), 95 (7), 92
(4), 77 (100), 65 (8), 51 (13). Anal. Calcd for C10H8Br2N2O: C, 36.18; H,
2.43; N, 8.44. Found: C, 36.22; H, 2.47; N, 8.46.
J¼7.4 Hz, ArH), 8.10 (d,1H, J¼7.8 Hz, ArH), 8.46 (dd,1H, J¼7.8, 2.4 Hz,
ArH), 8.74 (d, 1H, J¼2.4 Hz, ArH); 13C NMR (50 MHz, CDCl3)
d 38.4,
121.2, 124.9, 126.3 (2ꢃCH), 127.5, 129.2 (2ꢃCH), 129.8, 131.7, 134.3,
141.9,144.6,157.2,169.9; IR (KBr) 3302 (m), 2920 (m),1738 (s, C]O),
1612 (s, C¼N), 1514 (m), 1337 (m), 1132 (m), 998 (m), 840 (m) cmꢁ1
;
Anal. Calcd for C15H10N4O5: C, 55.22; H, 3.09; N, 17.17. Found: C,
55.18; H, 3.07; N, 17.16.
3.3.2. 4,4-Dibromo-1-phenyl-3-trifluoromethyl-2-pyrazolin-5-one
(5b). Mp (purified by column chromatography on silica gel) 119–
3.2.8. 1-(20,40,60-Trichlorophenyl)-3-phenyl-2-pyrazolin-5-one (3h). Mp
201 ꢂC; 1H NMR (CDCl3, 200 MHz)
d 7.24–7.52 (m, 3H, ArH), 7.81 (d,
(recrystallized from ethanol) 144–146 ꢂC; 1H NMR (CD3OD,
2H, J¼7.8 Hz, ArH); IR (KBr) 3391 (s), 3184 (m), 1631 (s, C]O), 1576
(s, C¼N), 1404 (m), 1113 (m), 773 (m), 704 (m), 633 (m) cmꢁ1. Anal.
Calcd for C10H5Br2F3N2O: C, 31.12; H, 1.31; N, 7.26, Found: C, 31.32;
H, 1.28; N, 7.34.
200 MHz)
d
3.28 (s, 2H, pyrazolone-H), 7.34–7.43 (m, 3H, ArH),
47.1, 125.4
7.68–7.72 (m, 4H, ArH); 13C NMR (50 MHz, CD3OD)
d
(2ꢃCH), 128.4 (2ꢃCH), 128.6 (2ꢃCH), 129.1 (2ꢃCH), 130.6, 132.1,
136.4, 152.8, 156.9, 171.0; IR (KBr) 3075 (m), 1732 (s, C]O), 1559 (s,
C¼N), 1461 (s), 1380 (m), 1157 (m), 1097 (m), 983 (m), 829 (m)
cmꢁ1; Anal. Calcd for C15H9Cl3N2O: C, 53.05; H, 2.67; N, 8.25.
Found: C, 53.08; H, 2.64; N, 8.24.
3.3.3. 4,4-Dibromo-3-isopropyl-1-phenyl-2-pyrazolin-5-one
(5c). Mp (purified by column chromatography on silica gel) 77–
79 ꢂC; 1H NMR (CDCl3, 200 MHz)
d
1.44 (d, 6H, J¼7.2 Hz, 2ꢃCH3),
3.06 (m, 1H, CHMe2), 7.23 (d, 1H, J¼7.9 Hz, ArH), 7.41 (dd, 2H, J¼7.9,
3.2.9. 5-Hydroxy-3-phenyl-1H-pyrazole (3i)22. Mp (recrystallized
3.2 Hz, ArH), 7.86 (d, 2H, J¼3.2 Hz, ArH); 13C NMR (CDCl3, 50 MHz)
from EtOH) 235–237 ꢂC; 1H NMR (DMSO-d6, 200 MHz)
d
5.88 (s,1H,
d
22.2 (2ꢃCH3), 28.6, 45.8, 118.8 (2ꢃCH), 125.9, 129.0 (2ꢃCH), 137.1,
pyrazole-H), 7.24 (d, 1H, J¼3.8 Hz, ArH), 7.34 (dd, 2H, J¼7.4, 3.8 Hz,
163.1, 165.0; IR (KBr) 3193 (m), 2935 (m), 1717 (s, C]O), 1575 (s,
C¼N),1489 (m),1283 (m), 979 (m), 802 (m), 763 (m) cmꢁ1; EIMS m/z
(relative intensity) 359 (Mþ2, 4), 358 (Mþ, 8), 357 (Mꢁ2, 4), 344 (9),
ArH), 7.61–7.65 (d, 2H, J¼7.4 Hz, ArH); 13C NMR (50 MHz, DMSO-d6)
d
87.3, 125.1 (2ꢃCH), 128.2, 129.2 (2ꢃCH), 130.9, 143.8, 161.5; IR

9596
Y.-Y. Huang et al. / Tetrahedron 65 (2009) 9592–9597
315 (4), 278 (6), 254 (8), 253 (14), 252 (8), 201 (9), 184 (5), 174 (28),
173 (32),171 (4),145 (3),130 (6),119 (4),105 (19), 91 (32), 78 (10), 77
(100), 67 (11), 64 (10), 51 (24). Anal. Calcd for C12H12Br2N2O: C,
40.03; H, 3.36; N, 7.78. Found: C, 40.06; H, 3.32; N, 7.81.
51 (25). Anal. Calcd for C15H7Br2Cl3N2O: C, 36.22; H, 1.42; N, 5.63.
Found: C, 36.45; H, 1.56; N, 5.31.
3.3.9. 4,4-Dibromo-3-phenyl-2-pyrazolin-5-one (5i). Mp 147–149 ꢂC;
1H NMR (DMSO-d6, 200 MHz)
d
7.49–7.54 (m, 3H, ArH), 8.11–8.16 (m,
3.3.4. 4,4-Dibromo-1,3-diphenyl-2-pyrazolin-5-one (5d)10. Mp (pu-
2H, ArH); 13C NMR (DMSO-d6, 50 MHz)
d
40.5, 126.3 (2ꢃCH), 127.9,
rified by column chromatography on silica gel) 128–130 ꢂC; 1H
128.3 (2ꢃCH), 130.7, 154.3, 170.5; IR (KBr) 3156 (m), 1742 (s, C]O),
1541 (m, C¼N), 1271 (m), 865 (m), 742 (m), 692 (m) cmꢁ1; EIMS m/z
(relative intensity) 320 (Mþ2, 8), 318 (Mþ,16), 316 (Mꢁ2, 8), 240 (61),
209 (7),182 (13),160 (41),129 (100),102 (86), 77 (44), 75 (46), 63 (12),
51(39). Anal. CalcdforC9H6Br2N2O:C,34.00;H,1.90;N, 8.81. Found:C,
33.97; H, 1.94; N, 8.78.
NMR (CDCl3, 200 MHz)
d
7.27 (d, 1H, J¼7.6 Hz, ArH), 7.42–7.54 (m,
5H, ArH), 7.99 (d, 2H, J¼7.8 Hz, ArH), 8.23 (d, 2H, J¼7.8 Hz, ArH); 13C
NMR (CDCl3, 50 MHz)
d
42.7, 119.1 (2ꢃCH), 126.4, 127.2 (2ꢃCH),
128.9 (2ꢃCH), 129.2 (2ꢃCH), 131.7, 137.0, 137.1, 153.5, 165.7; IR (KBr)
3391 (s), 3184 (m), 1632 (s, C]O), 1575 (s, C¼N), 1404 (m), 1112 (m),
773 (m), 704 (m) cmꢁ1; EIMS m/z (relative intensity) 397 (Mþ2, 18),
395 (Mþ, 36), 393 (Mꢁ2, 18), 338 (14), 315 (45), 263 (9), 219 (66),
241 (15), 165 (19), 154 (39), 119 (52), 95 (93), 69 (99), 55 (100);
HRMS calcd for C15H10Br2N2O 391.9160, found 391.9157.
3.3.10. 4,4-Dibromo-3-phenyl-1-(pyrid-2-yl)-2-pyrazolin-5-one
(5j). Mp (purified by column chromatography on silica gel) 180–
182 ꢂC; 1H NMR (CDCl3, 200 MHz)
d 7.16–7.27 (m, 1H, ArH), 7.43–
7.50 (m, 3H, ArH), 7.79–7.87 (m, 1H, ArH), 7.90–7.99 (m, 1H, ArH),
3.3.5. 4,4-Dibromo-1-(20-methylphenyl)-3-phenyl-2-pyrazolin-5-
8.21–8.26 (m, 2H, ArH), 8.55–8.58 (m, 1H, ArH); 13C NMR (CDCl3,
one (5e). Mp (purified by column chromatography on silica gel)
50 MHz)
d
42.4, 114.9, 122.0, 127.0, 127.5 (2ꢃCH), 127.8, 128.7
104–106 ꢂC; 1H NMR (CD3OD, 200 MHz)
d
2.23 (s, 3H, CH3), 7.47–
7.52 (m, 7H, ArH), 7.96–8.01 (m, 2H, ArH); 13C NMR (CD3OD,
50 MHz)
16.0, 126.1 (2ꢃCH), 127.0, 127.6, 128.0, 128.5, 129.0
(2ꢃCH), 131.8, 138.5, 148.9, 154.2, 165.9; IR (KBr) 3200 (s), 2929 (m),
1718 (s, C]O), 1558 (s, C¼N), 1409 (m), 1311 (m), 1268 (m), 974 (m),
864 (m), 828 (m), 812 (m), 739 (m), 690 (m) cmꢁ1; EIMS m/z (rel-
ative intensity) 395 (Mþ, 2), 320 (8), 318 (16), 316 (8), 237 (46), 209
(7), 182 (12), 160 (12), 129 (100), 102 (69), 75 (32), 51 (21); HRMS
calcd for C14H9Br2N3O 392.9112, found 392.9109.
d
(2ꢃCH), 130.6, 131.0, 131.1, 132.5, 136.6, 149.8, 157.5; IR (KBr) 3198
(s), 2959 (m), 1717 (s, C]O), 1542 (s, C¼N), 1319 (m), 1194 (m), 980
(m), 761 (m) cmꢁ1; MS m/z (relative intensity) 410 (Mþ2, 6), 408
(Mþ, 12), 406 (Mꢁ2, 6), 365 (2), 327 (74), 311 (3), 283 (7), 249 (53),
219 (10), 191 (6), 171 (6), 145 (12), 129 (36), 105 (24), 91 (100), 65
(26), 51 (16). Anal. Calcd for C16H12Br2N2O: C, 47.09; H, 2.96; N, 6.86.
Found: C, 47.13; H, 2.92; N, 6.90.
3.3.11. 4,4-Dibromo-3-phenyl-1-(3-isoquinolinyl)-2-pyrazolin-5-one
(5k). Mp (purified by column chromatography on silica gel) 131–
133 ꢂC; 1H NMR (CDCl3, 200 MHz)
d
7.38–7.58 (m, 5H, ArH) 7.70–
7.85 (m, 3H, ArH) 8.09–8.16 (m, 1H, ArH) 8.27–8.34 (m, 2H, ArH);
13C NMR (CDCl3, 50 MHz)
42.5, 113.7, 126.7, 126.9, 127.1, 127.5,
3.3.6. 4,4-Dibromo-1-(40-methoxyphenyl)-3-phenyl-2-pyrazolin-5-
d
one (5f). Mp (purified by column chromatography on silica gel)
127.6 (2ꢃCH), 128.7 (2ꢃCH), 129.1, 130.4, 131.9, 138.9, 146.8, 148.0,
154.3, 166.2; IR (KBr) 3045 (m), 2884 (m), 1751 (s, C]O), 1645 (m,
C¼N), 1503 (m), 1429 (m), 1383 (m), 1290 (m), 899 (m), 823 (m),
686 (m) cmꢁ1. Anal. Calcd for C18H11Br2N3O: C, 48.57; H, 2.49; N,
9.44. Found: C, 48.24; H, 2.64; N, 9.31.
108–110 ꢂC; 1H NMR (CDCl3, 200 MHz)
d 3.81 (s, 3H, CH3), 6.97 (d,
2H, J¼7.2 Hz, ArH), 7.48–7.51 (m, 3H, ArH), 7.85 (d, 2H, J¼7.2 Hz,
ArH), 8.19 (d, 2H, J¼7.8 Hz, ArH); 13C NMR (CDCl3, 50 MHz)
d 42.6,
55.6, 114.2 (2ꢃCH), 121.0 (2ꢃCH), 127.1 (2ꢃCH),127.3,128.8 (2ꢃCH),
130.2, 131.5, 153.4, 157.9, 165.4; IR (KBr) 3194 (s), 2959 (m), 1717 (s,
C]O), 1508 (s, C¼N), 1251 (m), 1006 (m) cmꢁ1; MS m/z (relative
intensity) 427 (Mþ2, 2), 425 (Mþ, 4), 423 (Mꢁ2, 2), 345 (99), 343
(97), 266 (82), 265 (53), 235 (14), 221 (17), 209 (6), 162 (8), 160 (15),
158 (8), 135 (48), 129 (39), 121 (30), 107 (100), 102 (17), 92 (38), 77
(66), 64 (19). Anal. Calcd for C16H12Br2N2O2: C, 45.31; H, 2.85; N,
6.61. Found: C, 45.27; H, 2.89; N, 6.57.
Acknowledgements
We are grateful to the China Medical University (CMU97–225 &
CMU97–251) and the National Science Council of Republic of China
for financial support.
References and notes
3.3.7. 4,4-Dibromo-1-(20,40-dinitrophenyl)-3-phenyl-2-pyrazolin-5-
one (5g). Mp (purified by column chromatography on silica gel)
1. (a) Golden, J. E.; Sanders, S. D.; Muller, K. M.; Bu¨rli, R. W. Tetrahedron Lett. 2008,
49, 794–798; (b) Bu¨rli, R. W.; Hu, H.; Zou, X.; Muller, K.; Golden, J.; Frohn, M.;
Adlam, M.; Plant, M. H.; Wong, M.; McElvain, M.; Regal, K.; Viswanadhan, V. N.;
Tagari, P.; Hungate, R. Bioorg. Med. Chem. Lett. 2006, 16, 3713–3718; (c) Banner, B.
L.; Bilotta, J. A.; Fotouhi, N.; Gillespie, P.; Goodnow, R. A.; Hamilton, M. M.; Haynes,
N.-E.; Kowalczyk, A.; Myers, M. P.; Pietranico-Cole, S. L; Sctto, N. R.; Thakkar, K. C.;
Tilley, J. W. U.S. Patent Appl. 2,007,049,632, 2007; (d) Tripathy, R.; Ghose, A.; Singh,
J.; Bacon, E. R.; Angeles, T. S.; Yang, S. X.; Albom, M. S.; Aimone, L. D.; Herman, J. L.;
Mallamo, J. P. Bioorg. Med. Chem. Lett. 2007, 17, 1793–1798; (e) Balestra, M.; Bunting,
H.; Chen, D.; Egle, I.; Forst, J.; Frey, J.; Isaac, M.; Ma, F.; Nugiel, D.; Slassi, A.; Steelman,
G.; Sun, G.-R.; Sundar, B.; Ukkiramapandian, R.; Urbanek, R.A.; Walsh, S. Patent Appl.
WO 2,006,071,730, 2006; (f) Pe´gurier, C.; Collart, P.; Danhaive, P.; Defays, S.; Gillard,
M.; Gilson, F.; Kogej, T.; Pasau, P.; Houtvin, N. V.; Thuyne, M. V.; van Keulen, B. Bioorg.
Med. Chem. Lett. 2007,17, 4228–4231;(g)Costa,D.;Marques, A.P.; Reis, R. L.; Lima, J. L.
C.; Fernandes, E. Free Radical Biol. Med. 2006, 40, 632–640.
182–184 ꢂC; 1H NMR (CDCl3, 200 MHz)
d 7.22–7.28 (m, 1H, ArH),
7.45–7.52 (m, 2H, ArH), 7.86 (dd, 1H, J¼7.8, 3.7 Hz, ArH), 7.97 (d,
1H, J¼7.8 Hz, ArH), 8.22–8.27 (m, 2H, ArH), 8.61 (d, 1H, J¼3.7 Hz,
ArH); 13C NMR (CDCl3, 50 MHz)
d
38.4, 121.2, 124.9, 126.3 (2ꢃCH),
127.5, 129.2 (2ꢃCH), 129.8, 131.7, 134.3, 141.9, 144.6, 157.2, 169.9; IR
(KBr) 3195 (m), 2926 (s), 1749 (s, C]O), 1510 (s, C¼N), 1339 (m),
1169 (m), 1079 (m), 892 (m), 685 (m) cmꢁ1; EIMS m/z (relative
intensity) 486 (Mþ2, 9), 484 (Mþ, 18), 482 (Mꢁ2, 9), 405 (98), 325
(89), 279 (11), 205 (17), 147 (19), 129 (100), 103 (88), 93 (29), 77
(80), 63 (22), 51 (31); HRMS calcd for C15H8Br2N4O5 481.8861,
found 481.8857.
2. (a) Ramesh Kakarla, G. L.; Gerritz, S. W. Tetrahedron Lett. 2007, 48, 4595–4599;
(b) Haddad, N.; Salvango, A.; Busacca, C. Tetrahedron Lett. 2004, 45, 5935–5937.
3. (a) Tanitam, A.; Oyamada, Y.; Ofugi, K.; Fujimoto, M.; Iwai, N.; Hiyama, Y.;
Suzuki, K.; Ito, H.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.; Yamagishi,
Junichi J. Med. Chem. 2004, 47, 3693–3696; (b) Cali, P.; Naerum, L.; Mukhija, S.;
Hjelmencrantz, A. Bioorg. Med. Chem. Lett. 2004, 14, 5997–6000.
3.3.8. 4,4-Dibromo-1-(20,40,60-trichlorophenyl)-3-phenyl-2-pyr-
azolin-5-one (5h). Mp (purified by column chromatography on
silica gel) 90–91 ꢂC; 1H NMR (CDCl3, 200 MHz)
d 7.46–7.52 (m, 5H,
ArH), 8.11–8.16 (m, 2H, ArH); IR (KBr) 3198 (m), 1749 (s, C]O), 1557
(s, C¼N), 1470 (m), 1183 (m), 1064 (m), 815 (m) cmꢁ1; EIMS m/z
(relative intensity) 502 (Mþ2, 4), 500 (Mþ, 8), 498 (Mꢁ2, 4), 419
(67), 416 (100), 391 (14), 389 (21), 387 (11), 339 (46), 303 (20), 273
(21), 221 (4), 207 (27), 179 (57), 158 (29), 129 (63), 103 (68), 75 (33),
4. (a) Tsurumi, K.; Abe, A.; Fujimura, H.; Asai, H.; Nagasaka, M.; Mikaye, H. Folia
Pharmacol. Jpn. 1976, 72, 41–52; (b) Rapposelli, S.; Lapucci, A.; Minutolo, F.;
Orlandimi, E.; Ortore, G.; Pinza, M.; Balsamo, A. Farmaco 2004, 59, 25–31; (c)
Souza, F. R.; Souza, V. T.; Ratzlaff, V.; Borges, L. P.; Oliverira, M. R.; Bonacorso, H. G.;
Zanatta, N.; Martins, M. A. P.; Mello, C. F. Eur. J. Pharmacol. 2002, 451, 141–147.
5. Al-Omran, F.; El-Khair, A. A. J. Heterocycl. Chem. 2004, 41, 327–333.

Y.-Y. Huang et al. / Tetrahedron 65 (2009) 9592–9597
9597
6. Sechi, M.; Sannia, L.; Carta, F.; Palomba, M.; Dallochio, R.; Dessi, A.;
Derudas, M.; Zawahir, Z.; Neamati, N. Antiviral Chem. Chemother. 2005, 16,
41–61.
7. Cottineau, B.; Toto, P.; Marot, C.; Pipaud, A.; Chenault, J. Bioorg. Med. Chem. Lett.
2002, 12, 2105–2108.
16. Ahmed, S. A.; Award, D. M. A.; Abdel-Wahab, Aboel-Mahab A. Chem. Commun.
2002, 1, 84–86.
17. (a) Schuetz, R. D.; Millard, F. W. J. Org. Chem. 1959, 24, 297–300; (b) Buckles, R. E.;
Prosst, W. J. J. Org. Chem. 1957, 22, 1728–1729; (c) Buckles, R. E.; Johnson, R. C.;
Probst, W. J. J. Org. Chem. 1957, 22, 55–59.
8. Kakiuchi, Y.; Sasaki, N.; Satoh-Masuoka, M.; Murofushi, H.; Murakami-Mur-
ofushi, K. Biochem. Biophys. Res. Commun. 2004, 320, 1351–1358.
9. Sarojbasinidas, A. N.; Mishra, C. R.; Mittra, A. S. J. Indian Chem. Soc. 1977, LIV,
485–487.
18. Chowdhury, K.; Banerji, K. K. J. Org. Chem. 1990, 55, 5391–5393.
19. (a) Song, C. E.; Oh, C. R.; Roh, E. J.; Lee, S.-G.; Choi, J. H. Tetrahedron: Asymmetry
1999, 10, 671–674; (b) Demko, Z. P.; Bartsch, M.; Sharpless, K. B. Org. Lett. 2000, 15,
2221–2223.
10. Fuminori, K.; Hirohiko, K. J.P. Patent Augest 10-45588, 1998.
11. Basaif, S. A.; Hassan, M. A.; Gobouri, A. A. Dyes Pigments 2007, 72, 387–391.
12. (a) Karci, F.; Ertan, N. Dyes Pigments 2002, 55, 99–108; (b) Ho, Y. W. Dyes Pig-
ments 2005, 64, 223–230.
20. (a) Wang, X.-j.; Tan, J.; Grozinger, K. Tetrahedron Lett. 2000, 41, 4713–4716;
(b) DeRuiter, J.; Carter, D. A.; Arledge, W. S.; Sullivan, P. J. J. Heterocycl. Chem.
ˇ
´
1987, 24, 149–153; (c) Brana, M. F.; Gradillas, A.; Ovalles, A. G.; Lopez, B.; Acero,
N.; Llinares, F.; Mingarro, D. M. Bioorg. Med. Chem. 2006, 14, 9–16.
13. Kirscuke, K.; Luize, G.; Schmttz, E. J. Prakt. Chem. 1984, 326, 367–373.
14. Chande, M. S.; Bhandari, J. D.; Joshi, V. R.; Joshi, V. R. India J. Chem. B. 1993, 32B,
1218–1228.
21. (a) McFerrin, C. A.; Hammer, R. P.; Fronczek, F. R.; Watkins, S. F. Acta. Crystallogr.
2006, E62, 2518–2519; (b) Kimata, A.; Nakagawa, H.; Ohyama, R.; Fukuuchi, T.;
Ohta, S.; Suzuki, T.; Miyata, N. J. Med. Chem. 2007, 50, 5053–5056.
15. El-Saraf, G. A.; El-Sayed, A. M. Heteroat. Chem. 2003, 14, 211–217.
22. Mojtahedi,M.M.;Javadpour, M.;Abaee,M. S.Utrason. SonoChem.2008,15, 828–832.