A novel one-pot approach to oxidative aromatization and bromination of pyrazolidin-3-one with HBr-H2O2 system

Article abstract of DOI:10.1515/hc-2018-0046

An efficient and green one-pot method for the oxidative aromatization and bromination of pyrazolidin-3-ones under mild conditions with a HBr-H₂O₂ system was developed. A mechanism was proposed.

Full text of DOI:10.1515/hc-2018-0046

Heterocycl. Commun. 2018; aop
Shanguang Yang, Jingjing Liu, Zhudan Jin, Wei Tian, Hao Sun and Mingliang Wang*
A novel one-pot approach to oxidative aromatization
and bromination of pyrazolidin-3-one with HBr-H O
2
2
system
https://doi.org/10.1515/hc-2018-0046
to 4-bromopyrazolol from pyrazolidinone have been
reported. Traditionally, there are two steps in the syn-
thesis of 4-bromopyrazolol from pyrazolidinone [7, 11, 12]
that involve aromatization of pyrazolidin-3-ones to give
pyrazol-3-ols and bromination of pyrazol-3-ols [7]. This
protocol requires the use of a transition-metal catalyst,
extremely toxic liquid bromine, a long reaction time,
Received March 19, 2018; accepted March 27, 2018
Abstract: An efficient and green one-pot method for the
oxidative aromatization and bromination of pyrazolidin-
3
-ones under mild conditions with a HBr-H O system was
2 2
developed. A mechanism was proposed.
Keywords: aromatization; bromination; bromopyrazol; multi-step manipulations and the final yield is only mod-
hydrogen bromide; hydrogen peroxide; one-pot; oxida- erate. In recent years, brominations with safe bromination
tive; pyrazolidin-3-one.
reagents and green co-oxidants have received growing
attention because of their greenness and high efficiency
24]. Herein, we report a novel one-pot, metal-free, atom-
[
economic and highly effective method for the preparation
of 4-bromopyrazol-3-ol from pyrazolidin-3-one using a
HBr-H O system under mild conditions.
Introduction
Pyrazole derivatives attract attention due to their excel-
lent pharmacological properties [1–4]. Halogenated pyra-
zolols [5, 6], especially 4-bromo derivatives, are precursors
2
2
for the synthesis of functionalized pyrazoles [7–9], such as Results and discussion
pharmaceuticals [10], multifunctional materials [11, 12],
fused- [13] and spiro-heterocyclic compounds [14]. Various The starting compounds 1 (Scheme 1) were commer-
protocols for the synthesis of brominated pyrazolols have cially available or easily prepared according to previ-
been reported. However, bromination of pyrazolols with ously published procedures [7, 11, 12, 19–23]. Initially,
Br in acetic acid is carried out under harsh conditions 1-(4-chlorophenyl)-pyrazolidin-3-one (1a) was treated with
2
and requires careful manipulation [15]. Efforts have been various amounts of hydrogen peroxide and hydrobromic
made by Ahmed et al. [16] to use the photolysis of N-bro- acid using various solvents. It was found that the use of dif-
mosuccinimide as the source of bromine [16]. Due to the ferent solvents including carbon tetrachloride, chloroform,
formation of the coupling by-products, bromopyrazolols dichloromethane, methanol and N,N-dimethylformamide
are afforded in low yields. Although N-bromobenzamide had little effect on the outcome, affording the yield of the
[
17] and dibromoisocyanuric acid [18] have also been product 2a in the range from 72% to 90%. Nevertheless,
explored as mild brominating agents for pyrazolols, these the highest yield of 90% was obtained for the reaction
approaches have met with limited success.
conducted in chloroform. Under optimized conditions, the
Recently, pyrazolidinones have been reported as sub- synthesis of 2a was conducted in chloroform at 60°C using
strates for the synthesis of pyrazolols [7, 11, 12, 19–23]. 3 equivalents of H O and 1 equivalent of HBr.
Unfortunately, few efficient methods for direct access
2
2
Decreasing the amount of hydrogen peroxide to 1
equivalent or 2 equivalents resulted in a decrease of the
yield of the product 2a. On the other hand, an increase
in the amount of hydrogen peroxide from 3 equivalents to
*
Corresponding author: Mingliang Wang, School of Chemistry
and Chemical Engineering, Southeast University, Nanjing 211189,
P. R. China, e-mail: wangmlchem@seu.edu.cn. http://orcid.
org/0000-0002-3934-6100
4
equivalents did not affect the yield. With the optimized
reaction conditions for 2a, a wide range of 4-bromo-3-hy-
droxypyrazolidines were synthesized (Scheme 1). The
reaction proceeds well with pyrazolidin-3-ones containing
a phenyl group, a substituted phenyl group or a pyridinyl
Shanguang Yang, Jingjing Liu, Zhudan Jin, Wei Tian and Hao
Sun: School of Chemistry and Chemical Engineering, Southeast
University, Nanjing 211189, P. R. China
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2
ꢀꢀꢀꢀꢁꢀS. Yang et al.: Aromatization and bromination of pyrazolidin-3-one
R1
OH
R1
H
N
N
N
1 eq. HBr, 3 eq. H O
2
2
1 eq. HBr, 3 eq. H O
N
N
2
2
OH
Cl
N
+
2a (90%)
2a (0%)
O
30 min
CHCl , 60°C, 30 min
R2
R2
3
1a
4 (0%)
Br
2a–l
1
1
eq. HBr, 3 eq. H O
2
2
4
(trace)
+
1
1
1
2
2
2
2
a: R = 4-Cl-C H
2e: R = 3-Cl-pyridin-2-yl
2i: R = Ph
3 eq. TEMPO, 30 min
6
4
2
R2 = H
R2 = Ph
R = H
1
1
2j: R1 = Ph
b: R = Ph
2f: R = 4-Cl-C H
Scheme 3ꢀ
6
4
2
2
2
R = H
R
= Me
R
= Me
1
1
1
c: R = 4-F-C H
2g: R =4-Cl-C H
2k: R = 4-Me-C H
6
4
6
4
6
4
2
2
2
R = H
R
= Ph
R
= Me
1
1
1
d: R = 4-Me-C H
2h: R = 4-Cl-C H
2l: R = H
+
+
6
4
6
4
2HBr
H O
2H O
Br2
2
2
2
2
2
2
R = H
R
= MeO
R
= Me
H O
2
2
Scheme 1ꢀ
Br
1
H O
2
2
group. With an increase in the electron-donating capa-
bility of the substituent at the 5-position of pyrazolidin-
HBr
H
N
O
3
-ones (MeOꢀ>ꢀCH ꢀ>ꢀH), the efficiency of the reaction is
R1
N
I
3
2
HBr
CH
increased in the same order.
R2
Interestingly, when the reaction with 5 equivalents of
HBr was carried out for 3 h (Scheme 2), the correspond-
ing dibrominated products 3b,j were obtained accompa-
nied by the corresponding monobrominated products 2b,j
in moderate yields. However, in the case of compound 1i
Br2
N
OH
R1
N
OH
II
N
Br
R1
N
C
III R2
R2
Br
only monobrominated product 2i was acquired in high Scheme 4ꢀ
yield. For further confirmation of the structure of the
series, a single crystal of 3j was obtained and subjected to
X-ray diffraction analysis (Figure 1).
reaction under optimized conditions was performed
To gain access to the mechanism, the experiments in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
were carried out as shown in Scheme 3. When the (TEMPO) as a radical scavenger, only a trace amount of
1
-(4-chlorophenyl)-1H-pyrazol-3-ol (4) was detected, sug-
gesting a radical pathway. This finding and previous
reports [25–27], are consistent with the mechanism sug-
gested in Scheme 4. First, compound 1 undergoes a reac-
tion with a bromine radical to generate the corresponding
radical intermediate I, which is subsequently converted
to the substituted pyrazol-3-ol II by oxidation with
molecular bromine. Then, in the presence of the bromine
radical, the corresponding radical species III is generated
from the intermediate compound II. Finally, the reaction
of the intermediate product III with the bromide radical
furnishes the observed 4-bromopyrazol-3-ol 2.
H
N
O
N
OH
5
eq. HBr, 8 eq. H
CCl , ∆, 3 h
2 2
O
N
Br
N
+
2b,j,i
4
Br
R
b,j,i
R
1
3b,j,i
b: R = H; 3b (50%), 2b (35%)
j: R = Me; 3j (58%), 2j (33%)
i: R = Ph; 3i (0%), 2i (89%)
Scheme 2ꢀ
Conclusions
A green and efficient protocol to prepare substituted
4-bromo-pyrazol-3-ols 2 from pyrazolidin-3-ones 1 under
mild conditions in excellent yields was described. The
corresponding dibromination products 3b,j were also
obtained in moderate yields under harsh conditions.
Figure 1ꢀMolecular structure of 3j with atom labeling.
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S. Yang et al.: Aromatization and bromination of pyrazolidin-3-oneꢂꢁꢀꢀꢀꢂ3
4
-Bromo-5-methyl-1-(4-chlorophenyl)-1H-pyrazol-3-ol
Experimental
1
(
2f)ꢁYellow solid; mp 221–223°C; yield 92%; H NMR: δ 10.80 (s, 1H,
OH), 7.55 (m, 2H, Ar), 7.51 (m, 2H, Ar), 2.28 (s, 3H, CH ); IR: 3455, 2978,
3
1
Proton nuclear magnetic resonance ( H NMR) spectra were obtained
on a Bruker spectrometer operating at 600 MHz with dimethyl
−1
+
1
617, 1545, 1510, 1393, 1102 cm ; MS: m/z 288.2 [(Mꢀ+ꢀ1) , 81%]. Anal.
Calcd for C H BrClN O: C, 41.77; H, 2.80; N, 9.74. Found: C, 41.61; H,
1
0
8
2
sulfoxide-d as solvent and tetramethylsilane as internal standard.
6
2.93; N, 9.89.
Infrared (IR) spectra were obtained using KBr disks on a Bomem
Michelson Series Fourier-transform infrared spectrometer. The mass
spectrometry (MS) data were recorded with an Agilent 7890A-5975C
instrument. Melting points were obtained on an X-4 microscope elec-
trothermal apparatus (Taike, China) and are uncorrected. Elemental
analyses were carried out on a Vario EL III analyzer. Spectral data
for compounds 2b, 3b and 4 are virtually identical with the reported
values [9, 20, 28].
4
-Bromo-5-phenyl-1-(4-chlorophenyl)-1H-pyrazol-3-ol (2g)ꢁWhite
1
solid; mp 253–255°C; yield 94%; H NMR: δ 11.07 (s, 1H, OH), 7.43 (m,
3
H, Ar), 7.39 (d, Jꢀ=ꢀ9 Hz, 2H, Ar), 7.30 (m, 2H, Ar), 7.21 (d, Jꢀ=ꢀ9 Hz, 2H,
−1
+
Ar); IR: 3462, 2973, 1552, 1496, 1331, 1075 cm ; MS: m/z 350.3 [(Mꢀ+ꢀ1) ,
100%]. Anal. Calcd for C H BrClN O: C, 51.53; H, 2.88; N, 8.01. Found:
15 10 2
C, 51.34; H, 3.06; N, 8.22.
4
-Bromo-5-methoxy-1-(4-chlorophenyl)-1H-pyrazol-3-ol
1
(
2h)ꢁYellow solid; mp 228–230°C; yield 95%; H NMR: δ 11.37 (s, 1H,
OH), 7.65 (m, 2H, Ar), 7.38 (m, 2H, Ar), 3.74 (s, 3H, OCH ); IR: 3452,
Synthesis of 4-bromopyrazol-3-ones 2a–l
3
−1
2
961, 1632, 1560, 1503, 1402, 1314, 1207, 1054 cm ; MS: m/z 300.4
+
[
(Mꢀ+ꢀ1) , 100%]. Anal. Calcd for C H BrClN O : C, 39.57; H, 2.66; N,
1
0
8
2
2
A mixture of 1a–l (0.01 mol) in CHCl (10 mL) and 40% hydrobromic
3
9.23. Found: C, 39.48; H, 2.79; N, 9.38.
acid (40%, 0.01 mol) was stirred at 60°C and treated dropwise for
1
0 min with an aqueous solution of H O (30%, 0.03 mol), and stirring
2 2
4
-Bromo-1,5-diphenyl-1H-pyrazol-3-ol (2i)ꢁYellow solid; mp 242–
was continued for an additional 20 min. The resultant precipitate of
a–l was filtered off and crystallized from ethanol. The filtrate was
1
2
44°C; yield 93%; H NMR: δ 10.98 (s, 1H, OH), 7.41 (m, 3H, Ar), 7.29
2
(
m, 5H, Ar), 7.14 (d, Jꢀ=ꢀ8 Hz, 2H, Ar); IR: 3453, 2965, 1624, 1541, 1444,
concentrated and the residue was subjected to silica gel chromato-
graphy eluting with ethyl acetate/petroleum ether (10:1) to give an
additional amount of 2a–l.
−1
+
1
335, 1252, 1085 cm ; MS: m/z 314.1 [(Mꢀ+ꢀ1) , 100%]. Anal. Calcd for
C H BrN O: C, 57.16; H, 3.52; N, 8.89. Found: C, 57.37; H, 3.38; N, 8.71.
1
5
11
2
4
-Bromo-5-methyl-1-phenyl-1H-pyrazol-3-ol (2j)ꢁWhite solid; mp
4
-Bromo-1-(4-chlorophenyl)-1H-pyrazole-3-ol (2a)ꢁWhite solid;
1
2
18–220°C; yield 91%; H NMR: δ 10.71 (s, 1H, OH), 7.49 (m, 4H, Ar),
1
mp 192–194°C; yield 90%; H NMR: δ 11.13 (s, 1H, OH), 8.58 (s, 1H, CH),
7
.36 (t, Jꢀ=ꢀ7 Hz, 1H, Ar), 2.27 (s, 3H, CH ); IR: 3450, 2969, 1623, 1549,
3
+
7
.71 (d, Jꢀ=ꢀ9 Hz, 2H, Ar), 7.51 (d, Jꢀ=ꢀ9 Hz, 2H, Ar); IR: 3440, 2971, 1617,
−1
1
496, 1409, 1328, 1270, 1103 cm ; MS: m/z 254.1 [(Mꢀ+ꢀ1) , 100%]. Anal.
−1
+
1
563, 1494, 1392, 1306, 1105 cm ; MS: m/z 274.3 [(Mꢀ+ꢀ1) , 100%]. Anal.
Calcd for C H BrN O: C, 47.46; H, 3.58; N, 11.07. Found: C, 47.63; H,
1
0
9
2
Calcd for C H BrClN O: C, 39.52; H, 2.21; N, 10.24. Found: C, 39.81; H,
9
6
2
3.81; N, 10.86.
2
.03; N, 10.02.
4
-Bromo-5-methyl-1-(4-methylphenyl)-1H-pyrazol-3-ol
4
-Bromo-1-phenyl-1H-pyrazole-3-ol (2b)ꢁYellow solid; mp 188–
1
(
2k)ꢁWhite solid; mp 232–234°C; yield 92%; H NMR: δ 10.64 (s,
1
1
90°C; yield 91%; H NMR: δ 11.02 (s, 1H, OH), 8.54 (s, 1H, CH), 7.69 (d,
1
H, OH), 7.35–7.28 (m, 4H, Ar), 2.35 (s, 3H, CH ), 2.24 (s, 3H, CH );
3
3
Jꢀ=ꢀ8 Hz, 2H, Ar), 7.45 (t, Jꢀ=ꢀ8 Hz, 2H, Ar), 7.23 (t, Jꢀ=ꢀ8 Hz, 1H, Ar); IR: 3449,
−1
IR: 3452, 2974, 1627, 1553, 1515, 1406, 1323, 1257, 1103 cm ; MS: m/z
−1
+
2927, 1620, 1550, 1493, 1309, 1102 cm ; MS: m/z 240.1 [(Mꢀ+ꢀ1) , 100%].
+
2
1
66.1 [(Mꢀ+ꢀ1) , 100%]. Anal. Calcd for C H BrN O: C, 49.46; H, 4.15; N,
0.49. Found: C, 49.63; H, 4.36; N, 10.06.
1
1
11
2
4
-Bromo-1-(4-fluorophenyl)-1H-pyrazole-3-ol (2c)ꢁWhite solid;
1
mp 219–221°C; yield 89%; H NMR: δ 11.01 (s, 1H, OH), 8.51 (s, 1H, CH),
4
-Bromo-5-methyl-1H-pyrazol-3-ol (2l)ꢁWhite solid; mp 192–
7
.70 (m, 2H, Ar), 7.30 (t, Jꢀ=ꢀ9 Hz, 2H, Ar); IR: 3451, 2971, 1622, 1568,
1
1
94°C; yield 85%; H NMR: δ 2.09 (s, 3H, CH); IR: 2060–3270, 1587,
−1
+
1
519, 1404, 1311, 1240, 1087 cm ; MS: m/z 258.1 [(Mꢀ+ꢀ1) , 100%]. Anal.
−1
+
1
253, 1172, 1053 cm ; MS: m/z 176.9659 [(Mꢀ+ꢀ1) , 100%). Anal. Calcd for
Calcd for C H BrFN O: C, 42.05; H, 2.35; N, 10.90. Found: C, 42.22; H,
9
6
2
C H BrN O: C, 27.14; H, 2.85; N, 15.83. Found: C, 27.26; H, 2.96; N, 15.66.
4
5
2
2
.21; N, 10.68.
4
-Bromo-1-(4-methylphenyl)-1H-pyrazole-3-ol (2d)ꢁYellow solid;
Synthesis of 4-bromo-1-(4-bromophenyl)pyrazol-
-ones 3b,j
1
mp 183–185°C; yield 92%; H NMR: δ 10.93 (s, 1H, OH), 8.47 (s, 1H, CH),
3
7
.56 (d, Jꢀ=ꢀ8 Hz, 2H, Ar), 7.24 (d, Jꢀ=ꢀ8 Hz, 2H, Ar), 2.31 (s, 3H, CH ); IR:
3
+
−1
3
454, 2964, 1625, 1548, 1381, 1327, 1082 cm ; MS: m/z 254.2 [(Mꢀ+ꢀ1) ,
1
00%]. Anal. Calcd for C H BrN O: C, 47.46; H, 3.58; N, 11.07. Found: A mixture of 1b,j (0.01 mol), CCl (10 mL) and hydrobromic acid (40%,
10
9
2
4
C, 47.31; H, 3.73; N, 10.88.
0.05 mol) was stirred, heated under reflux and treated dropwise with
an aqueous solution of H O (30%, 0.08 mol) for 3 h. After concentra-
2
2
4
-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-3-ol (2e)ꢁYellow tion under reduced pressure, the residue was chromatographed on
1
solid; mp 233–235°C; yield 91%; H NMR: δ 11.48 (s, 1H, OH), 8.49 silica gel eluting with ethyl acetate/petroleum ether (10:1) to give 3b,j.
(
(
1
s, 1H, CH), 7.98 (d, Jꢀ=ꢀ8 Hz, 1H, Ar), 7.60 (d, Jꢀ=ꢀ8 Hz, 1H, Ar), 7.37
d, Jꢀ=ꢀ8 Hz, 1H, Ar); IR: 3451, 2965, 1626, 1582, 1444, 1389, 1305, 4-Bromo-1-(4-bromophenyl)-1H-pyrazole-3-ol (3b)ꢁYellow solid;
−1
+
1
261, 1068 cm ; MS: m/z 273.1 [(Mꢀ+ꢀ1) , 100%]. Anal. Calcd for mp 199–201°C; yield 50%; H NMR: δ 11.17 (s, 1H, OH), 8.62 (s, 1H, CH),
C H BrClN O: C, 35.00; H, 1.84; N, 15.31. Found: C, 34.83; H, 2.02; 7.69 (m, 4H, Ar); IR: 3458, 2962, 1624, 1556, 1494, 1390, 1302, 1209,
8
5
3
−1
+
N, 15.50.
1048 cm ; MS: m/z 318.9 [(Mꢀ+ꢀ1) , 100%].
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4
ꢀꢀꢀꢀꢁꢀS. Yang et al.: Aromatization and bromination of pyrazolidin-3-one
4
-Bromo-5-methyl-1-(4-bromophenyl)-1H-pyrazol-3-ol
3-hydroxyisoxazole-containing glutamate receptor ligands
based on the 3-hydroxypyrazole-moiety: design, synthesis and
pharmacological characterization. Neurochem. Res. 2014, 39,
1895–1905.
1
(
3j)ꢁWhite solid; mp 243–245°C; yield 58%; H NMR: δ 10.82 (s, 1H,
OH), 7.68 (d, Jꢀ=ꢀ9 Hz, 2H, Ar), 7.45 (d, Jꢀ=ꢀ9 Hz, 2H, Ar), 2.28 (s, 3H,
CH ); IR: 3446, 2971, 1628, 1547, 1510, 1395, 1322, 1261, 1108 cm ; MS:
−1
3
+
m/z 330.3 [(Mꢀ+ꢀ1) , 100%]. Anal. Calcd for C H Br N O: C, 36.18; H, [11] Arbačiauskienė, E.; Kazlauskas, K.; Miasojedovas, A.;
10
8
2
2
2
.43; N, 8.44. Found: C, 36.33; H, 2.61; N, 8.28.
Juršėnas, S.; Jankauskas, V.; Holzer, W.; Getautis, V.; Šačkus, A.
Multifunctional polyconjugated molecules with carbazolyl and
pyrazolyl moieties for optoelectronic applications. Synth. Met.
2010, 160, 490–498.
1
-(4-Chlorophenyl)-1H-pyrazol-3-ol (4)ꢁWhite solid; mp 189–
1
1
91°C; H NMR: δ 10.32 (s, 1H, OH), 8.24 (d, Jꢀ=ꢀ3 Hz, 1H, CH), 7.70 (d,
Jꢀ=ꢀ9 Hz, 2H, Ar), 7.48 (d, Jꢀ=ꢀ9 Hz, 2H, Ar), 5.84 (d, Jꢀ=ꢀ3 Hz, 1H, CH); IR: [12] Arbačiauskienė, E.; Kazlauskas, K.; Miasojedovas, A.;
−1
3
438, 2976, 1630, 1545, 1489, 1382, 1245, 1057, 945, 757 cm ; MS: m/z
Juršėnas, S.; Jankauskas, V.; Holzer, W.; Getautis, V.;
Šačkus, A. Pyrazolyl-substituted polyconjugated molecules
for optoelectronic applications. Dyes Pigments 2010, 85,
+
1
95.7 [(Mꢀ+ꢀ1) , 100%].
7
9–85.
Acknowledgment: This project is supported by the Prior-
ity Academic Program Development of the Jiangsu higher
education institutions (1107047002).
[
13] Chande, M. S.; Bhandari, J. D.; Joshi, V. R. Investigation on
the reaction of 4-anilino-5-mercapto-s-triazoles with pyra-
zolines and barbituric Acids. Indian J. Chem. B 1993, 32B,
1
218–1228.
[
[
14] El-Saraf, G. A.; El-Sayed, A. M.; El-Saghier, A. M. One-pot PTC
synthesis of polyfused pyrazoles. Heteroat. Chem. 2003, 14,
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synthetic protocol for oxidation of alkyl-arenes into ketones
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