Silica-supported 1,3-dibromo-5,5-dimethylhydantoin (DBH) as a useful reagent for microwave-assisted aromatization of 1,3,5-trisubstituted pyrazolines under solvent-free conditions

Article abstract of DOI:10.1055/s-2004-829149

1,3,5-Trisubstituted pyrazolines are rapidly and conveniently oxidized to their corresponding pyrazoles by 1,3-dibromo-5,5-dimethylhydantoin (DBH) under microwave irradiation and solvent-free conditions. The presence of silica gel as a supporting agent is

Full text of DOI:10.1055/s-2004-829149

1
744
SHORT PAPER
Silica-Supported 1,3-Dibromo-5,5-dimethylhydantoin (DBH) as a Useful
Reagent for Microwave-Assisted Aromatization of 1,3,5-Trisubstituted
Pyrazolines under Solvent-Free Conditions
M
D
icrowave-Assist
a
e
d
A
romati
v
zation of 1,3,
o
5-Trisubstitu
o
ted Pyrazoli
dn es Azarifar,* Mohammad Ali Zolfigol, Behrooz Maleki
Chemistry Department, School of Science, Bu-Ali Sina University, Postal code 65174, Hamadan, Iran
E-mail: azarifar27@yahoo.com
Received 16 March 2004
been previously reported, we report herein a facile micro-
wave-accelerated oxidation of pyrazolines to pyrazoles by
,3-dibromo-5,5-dimethylhydantoin (DBH) under sol-
Abstract: 1,3,5-Trisubstituted pyrazolines are rapidly and conve-
niently oxidized to their corresponding pyrazoles by 1,3-dibromo-
1
5
,5-dimethylhydantoin (DBH) under microwave irradiation and
solvent-free conditions. The presence of silica gel as a supporting vent-free condition using silica gel.
agent is shown to be effective in reducing the reaction times and in-
Our objective in this work focussed on some interesting
creasing the yields.
features such as (a) the rapid reaction rates, higher yields
and cleaner reaction conditions and (b) solvent-free con-
ditions which seems to be a highly useful technique, espe-
cially it has many industrial advantages including reduced
Key words: pyrazolines,
1,3-dibromo-5,5-dimethylhydantoin
(DBH), aromatization, solid-surface, microwave irradiation
pollution, low costs, simplicity in processing and han-
Microwave irradiation is an unconventional energy
source, which has recently become of considerable inter-
est in organic chemistry. During the last decade, a number
of publications and reviews have advocated the advantag-
es and versatility of microwave irradiation in easy and
high yielding oxidation of organic compounds. This novel
method is therefore a fast growing and clean practice in
organic synthesis which has several advantages over clas-
sical thermal conditions, including increased reaction
1b,14
dling.
The reaction of 1,3,5-trisubstituted pyrazolines
with DBH using silica gel under microwave irradiation af-
forded pyrazoles with no side products (Scheme 1). The
reaction was first optimized for the substrate 1a (Table 1).
R1
R1
R2
R2
Silica-Supported DBH
microwave
N
N
N
N
Ph
Ph
1
rates, simplicity and high reaction yields. The use of sup-
1
a–l
2a–l
ported reagents has gained popularity because of the im-
proved selectivity, reactivity and associated ease of
Scheme 1
Table 1 Optimization of Silica Gel for Substrate 1a (1 mmol)
2
manipulation. Since only the polar reagents adsorbed on
the surfaces of various supporting mineral absorb micro-
wave energy, a variety of reagents supported on such sur-
faces can be utilized for the enhancement of organic SiO
reactions using a simple microwave (MW) oven. Solvent-
(g)
Time (min)
Yield (%)
2
0
.01
5
2
3
80
90
84
free organic synthesis seems to be highly useful tech-
nique, especially when inorganic solid supports are used.3 0.02
The oxidation of 1,3,5-trisubstituted pyrazolines to pyra-
zoles is biologically very important, since many pyrazole
derivatives possess analgesic, anti-inflammatory, anti-
pyretic, antiarrhythmic, muscle relaxant, psychoanaleptic,
0
.03
The results obtained from the conversion of various 1,3,5-
trisubstituted pyrazolines to their corresponding pyrazoles
are recorded in Tables 2 and 3.
4
antidiabetic and antibacterial activities. 1,3,5-Trisubsti-
tuted pyrazolines can be easily prepared from phenylhy-
5
drazine and chalcone derivatives. Therefore, oxidative In conclusion, solvent-free microwave-assisted thermoly-
aromatization of pyrazolines by oxidizing reagents should sis proved to be a rapid oxidation of pyrazolines to pyra-
provide an efficient method for the preparation of pyra- zoles when compared with conventional solution phase or
zole derivatives. Although a variety of reagents such as heterogeneous reactions. The results indicated that the
6
7
8
Zr(NO ) , Pd/C, Co(II) and oxygen, iodobenzene diac- presence of silica gel support in the reaction can increase
3
4
9
10
11
etate,
lead
tetraacetate,
MnO2,
potassium the efficiency of the oxidant in reducing the reaction times
1
2
13
permanganate and N-bromsuccinimide (NBS) have and improving the yields.
SYNTHESIS 2004, No. 11, pp 1744–1746
x
x.
x
x
.
2
0
0
4
IR spectra were recorded using a Shimadzu 435-U-04 spectropho-
tometer (KBr pellets) and NMR spectra were obtained using 90
MHz Jeol FT NMR spectrometer.
Advanced online publication: 13.07.2004
DOI: 10.1055/s-2004-829149; Art ID: Z05404SS
Georg Thieme Verlag Stuttgart · New York
©

SHORT PAPER
Microwave-Assisted Aromatization of 1,3,5-Trisubstituted Pyrazolines
1745
Table 2 Substrates 1a–l and their Corresponding Pyrazoles 2a–l
Oxidation of 1,3,5-Substituted Pyrazolines 1 with DBH; Gener-
al Procedure
Substrate Product
R1
R2
A mixture of DBH (the molar ratios of DBH to substrate 1a–l are
given in Table 3) and the substrate 1a–l (1 mmol), was thoroughly
mixed with 70–230 mesh silica gel (8 mg per mmol of the reagent)
and the mixture was placed in an alumina bath inside a MW oven
and irradiated (900 W) for 1–5 min in the solid state. After complete
conversion of the substrate as indicated by TLC, the mixture was
quenched with an aq NaHCO solution and extracted with Et O. The
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
2a
2b
2c
2d
2e
2f
2-naphthyl
Ph
2-CH C H
3
6
4
Ph
3-CH C H
4-CH C H
3
6
4
3
6
4
4
4
3
2
4-OCH C H
2-CH C H
organic layer washed with H O, dried and evaporated to give the
2
3
6
4
4
4
4
3
6
products 2a–l.
4-OCH C H
3-CH C H
3 6
3
6
2
a
4-OCH C H
Ph
4-ClC H
4
3
6
Yield: 324 mg (90%); yellow solid; mp 151–152 °C.
–
1
g
h
i
2g
2h
2i
4-OCH C H
IR (KBr): 1589, 1494, 964 cm .
3
6
6
1
H NMR (90 MHz, CDCl ): d = 2.22 (s, 3 H), 6.80 (s, 1 H), 7.16–
3
2-naphthyl
2-naphthyl
2-naphthyl
3-CH C H
3-CH C H
3 6
4
8
.27 (m, 16 H).
4-ClC H
13
6
4
4
C NMR (90 MHz, CDCl ): d = 19.49 (CH ), 96.51 (C in pyra-
3 3 4
zole), 95.12 (C in pyrazole), 149.28 (C=N), 142.5, 138.92, 137.71,
5
j
2j
2-ClC H
6
1
1
33.21, 131.92 (Carom), 120.86, 123.44, 124.56, 125.54, 126.23,
27.05, 127.69, 128.05, 128.46, 129.21, 129.95, 130.57 (CHarom).
k
l
2k
2l
4-N(CH ) C H
3 2 6 4
3
6
4
4-OCH C H
2-ClC H
4
2b
Yield: 242 mg (82%); yellow solid; mp 136–138 °C (Lit. mp 138–
39 °C).
3
6
4
6
9
1
Table 3 Microwave-Assisted Aromatization of 1,3,5-Trisubstituted
–
1
Pyrazolines by Silica-Supported DBH under Solvent-Free Condi-
IR (KBr): 1582, 1491, 964 cm .
a
tions
1
H NMR (90 MHz, CDCl ): d = 6.93 (s, 1 H), 7.21–7.93 (m, 15 H).
3
Substrate Productb Reagent/Substratec Time (min) Yield (%)d
13
C NMR (90 MHz, CDCl ): d = 95.44 (C in pyrazole), 90.79 (C
5
3
4
in pyrazole), 150.08 (C=N), 142.08, 138.80, 135.99 (Carom), 121.21,
26.06, 128.06, 128.42, 128.71, 129.26, 129.86, 130.16, 131.99
Carom).
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
2a
2b
2c
2d
2e
2f
2.5
2.25
3.75
3. 5
3
11 (2)
9 (1)
70 (90)
70 (82)
64 (76)
74 (86)
62 (75)
76 (90)
62 (74)
70 (88)
68 (84)
74 (90)
70 (86)
68 (88)
1
(
2
c
12 (4)
15 (4)
13 (4)
9 (1)
Yield: 246 mg (76%); yellow solid; mp 95–98 °C.
IR (KBr): 1589, 1493 cm–1.
1
H NMR (90 MHz, CDCl ): d = 2.20 (s, 6 H), 7.02 (s, 1 H), 7.25–
3
7
.61 (m, 13 H).
3.5
4
1
3
C NMR (90 MHz, CDCl ): d = 21.35 (2 CH ), 114.11 (C in pyra-
3
3
4
zole), 111.61 (C in pyrazole), 149.99 (C=N), 142.30, 138.134,
g
h
i
2g
2h
2i
10 (3)
15 (5)
10 (4)
8 (3)
5
1
33.21, 131.89 (Carom), 120.34, 122.97, 125.21, 126.31, 126.92,
3.75
3.75
3.5
3.25
3.5
127.71, 128.22, 129.32, 130.12 (CHarom).
2
d
Yield: 293 mg (86%); yellow solid; mp 70–72 °C.
j
2j
–
1
IR (KBr): 1600, 1500 cm .
k
l
2k
2l
8 (5)
1
H NMR (90 MHz, CDCl ): d = 2.19 (s, 3 H), 3.75 (s, 3 H) 6.72 (s,
3
1
H), 7.05–7.83 (m, 13 H).
1
8 (2)
1
3
C NMR (90 MHz, CDCl ): d = 19.19 (CH ), 55.08 (OCH ),
a
3
3
3
The reaction time and yields obtained using silica gel are shown in
parentheses.
Products were characterized by IR, H NMR and by direct compari-
1
1
1
13.42 (C in pyrazole), 115.68 (C in pyrazole), 150.86 (C=N),
60.92, 142.22, 140.06, 133.63, 130.12 (Carom), 121.53, 122.12,
23.42, 125.14, 126.12, 127.28, 128.39, 129.20, 129.82 (CHarom).
4
5
b
1
son with authentic materials.
c
Molar ratio.
Isolated yields.
2
e
d
Yield: 254 mg (75%); yellow solid; mp 84–86 °C.
–
1
IR (KBr): 1589, 1494 cm .
1
CAUTION!
H NMR (90 MHz, CDCl ): d = 2.23 (s, 3 H), 3.85 (s, 3 H) 6.84 (s,
3
In view of the hazards associated with an active oxidant (DBH) due
caution is recommended for its use at elevated temperatures; the lo-
calized temperature can be much higher than the bulk temperature
of the bath in the microwave oven and we suggest the oven to be op-
erated at a lower power and shorter reaction time.
1 H), 7.06–7.85 (m, 13 H).
1
3
C NMR (90 MHz, CDCl ): d = 21.09 (CH ), 55.30 (OCH ),
3
3
3
1
1
1
15.12 (C in pyrazole), 112.45 (C in pyrazole), 150.96 (C=N),
60.16, 146.87, 145.30, 139.87, 137.12 (Carom), 123.12, 125.64,
26.12, 127.24, 127.92, 128.87, 129.12, 130.99, 131.42 (CHarom).
4
5
Synthesis 2004, No. 11, 1744–1746 © Thieme Stuttgart · New York

1
746
D. Azarifar et al.
SHORT PAPER
1
3
2
f
C NMR (90 MHz, CDCl ): d = 19.47 (CH ), 42.10 [2 C,
3
3
Yield: 294 mg (90%); yellow solid; mp 75–77 °C.
N(CH ) ], 111.34 (C in pyrazole), 106.82 (C in pyrazole), 151.22
3 2 4 5
–
1
(C=N), 165.09, 144.21, 142.17, 136.42, 132.12 (Carom), 124.32,
25.10, 126.06, 127.12, 127.99, 128.09, 128.92, 129.82, 130.12
(CHarom).
IR (KBr): 1645, 1594 cm .
1
1
H NMR (90 MHz, CDCl ): d = 3.76 (s, 3 H) 6.48 (s, 1 H), 6.95–
3
7
.78 (m, 14 H).
1
3
2l
C NMR (90 MHz, CDCl ): d = 56.25 (OCH ), 111.85 (C in pyra-
3
3
4
Yield: 317 mg (88%); yellow solid; mp 63–65 °C.
zole), 106.42 (C in pyrazole), 148.30 (C=N), 158.13, 136.36,
5
1
1
32.18, 131.02 (Carom), 122.60, 127.21, 127.94, 128.62, 129.04,
29.79, 130.15, 130.73 (CHarom).
IR (KBr): 1590,1490 cm–1.
1
H NMR (90 MHz, CDCl ): d = 3.78 (s, 3 H), 6.87 (s, 1 H), 6.97–
3
7
.85 (m, 13 H).
2
g
1
3
Yield: 266 mg (74%); yellow solid; mp 101–103 °C.
C NMR (90 MHz, CDCl ): d = 54.97 (OCH ), 112.42 (C in pyra-
3
3
4
–
1
zole), 110.02 (C in pyrazole), 149.46 (C=N), 161.12, 144.87,
5
IR (KBr): 1612, 1500, 964 cm .
1
39.14, 131.22, 130.72 (Carom), 120.23, 121.82, 124.42, 126.96,
1
H NMR (90 MHz, CDCl ): d = 3.87 (s, 3 H) 6.98 (s, 1 H), 7.26–
3
127.04, 128.79, 128.86, 129.20, 129.94 (CHarom).
7
.91 (m, 13 H).
1
3
C NMR (90 MHz, CDCl ): d = 54.92 (OCH ), 114.12 (C in pyra-
3
3
4
References
zole), 111.42 (C in pyrazole), 150.09 (C=N), 159.91, 144.69,
5
1
1
40.95, 132.08, 130.51 (Carom), 120.53, 121.96, 124.92, 126.82,
27.04, 128.79, 129.26 (CHarom).
(1) (a) Caddick, S. Tetrahedron 1995, 52, 1403. (b) Varma, R.
S. Green Chem. 1999, 1, 43. (c) Majetich, M.; Hicks, R. J.
Microwave Power Electromagn. Energy 1995, 30, 27.
2
h
(d) Gupta, R.; Gupta, A. K.; Paul, S.; Kachroo, P. Ind. J.
Yield: 317 mg (88%); yellow solid; mp 75–78 °C.
Chem. 1995, 34B, 151.
–
1
IR (KBr): 1651,1596 cm .
(2) (a) Mckillop, A.; Young, D. W. Synthesis 1979, 401.
(
(
b) Mckillop, A.; Young, D. W. Synthesis 1979, 481.
c) Posner, G. H. Angew. Chem., Int. Ed. Engl. 1978, 17,
1
H NMR (90 MHz, CDCl ): d = 2.51 (s, 3 H), 7.07 (s, 1 H), 7.37–
3
8
.50 (m, 16 H).
487; Angew. Chem. 1978, 90, 527. (d) Balogh, M.; Laszlo,
1
3
C NMR (90 MHz, CDCl ): d = 21.47 (CH ), 97.12 (C in pyra-
P. Organic Chemistry Using Clays; Springer Verlag: Berlin,
1993. (e) Clark, J. H. Catalysis of Organic Reactions by
Supported Inorganic Reagents; VCH: Weinheim, 1994.
(3) (a) Caddick, S. Tetrahedron 1995, 51, 10403. (b) Strauss,
C. R.; Trainor, R. W. Aust. J. Chem. 1995, 48, 1665.
(c) Marreto-Terrero, A. L.; Loupy, A. Synlett 1996, 245.
(d) Varma, R. S. In Microwave-Assisted Reactions under
Solvent-Free Dry Conditions in Microwaves, Theory and
Application in Material Processing IV, Vol. 80; Clark, D.;
Sutton, W.; Lewis, D., Eds.; American Ceramic Society,
Ceramic Transactions: New York, 1997, 357–365.
3
3
4
zole), 95.96 (C in pyrazole), 150.09 (C=N), 145.07, 142.80,
1
1
5
38.93, 134.47, 131.24 (Carom), 122.86, 123.04, 123.062, 125.09,
26.14, 127.09, 127.86, 129.18, 129.94, 130.06 (CHarom).
2
i
Yield: 320 mg (84%); yellow solid; mp 130–133 °C.
–
1
IR (KBr): 1600,1500 cm .
1
H NMR (90 MHz, CDCl ): d = 7.03 (s, 1 H), 7.25–8.29 (m, 16 H).
3
1
3
C NMR (90 MHz, CDCl ): d = 116.46 (C in pyrazole), 112.11
3
4
(
1
1
C in pyrazole), 150.08 (C=N), 144.43, 139.12, 133.18, 132.08,
30.42 (Carom), 123.31, 124.11, 126.33, 126.92, 127.12, 127.42,
27.95, 128.42, 129.12, 129.98 (CHarom).
(4) (a) Takabata, E.; Kodama, R.; Tanaka, Y.; Dohmori, R.;
Tachizawa, H.; Naita, T. Chem. Pharm. Bull. 1979, 16,
1900. (b) Parmar, S. S.; Pandy, B. R.; Dwivedi, C.;
5
Harbison, R. D. J. Pharm. Sci. 1974, 63, 1152.
2
j
(5) (a) Azarifar, D.; Shaebanzadeh, M. Moleclues 2002, 7, 885.
(b) Azarifar, D.; Ghasemnejad, H. Molecules 2003, 8, 642.
Yield: 343 mg (90%); yellow solid; mp 72–75 °C.
(
6) Sabita, G.; Reddy, G. S. K.; Reddy, C. S.; Fatima, N.; Yadav,
–
1
IR (KBr): 1599, 1491, 968 cm .
J. S. Synthesis 2003, 1267.
1
H NMR (90 MHz, CDCl ): d = 7.00 (s, 1 H), 7.30–8.51 (m, 16 H).
(7) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002,
4, 3955.
(
(
3
1
3
C NMR (90 MHz, CDCl ): d = 115.32 (C in pyrazole), 110.80
C in pyrazole), 151.82 (C=N), 136.08, 134.77, 134.26, 133.24,
32.12 (Carom), 123.88, 125.05, 125.58, 126.23, 126.80, 127.19,
27.74, 128.12, 128.52, 129.12, 129.91, 130.61 (CHarom).
3
4
8) Shah, J. N.; Shah, C. K. J. Org. Chem. 1978, 43, 1266.
9) Singh, S. P.; Kumar, D.; Prakash, O.; Kapoor, R. P. Synth.
Commun. 1997, 27, 2683.
(
5
1
1
(
10) Gladstone, W. A. F.; Norman, R. O. C. J. Chem. Soc., Chem.
Commun. 1966, 1536.
2
k
(
(
(
11) Bhatnager, I.; George, M. V. Tetrahedron 1968, 24, 1293.
12) Smith, L. I.; Howard, K. L. J. Am. Chem. Soc. 1943, 65, 159.
13) Ried, W.; Lantzsch, R. Chem. Ber. 1969, 102, 378.
(14) (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
(b) Krchnak, V.; Holladay, M. W. Chem. Rev. 2002, 102, 61.
Yield: 304 mg (86%); yellow solid; mp 67–70 °C.
–
1
IR (KBr): 1590, 1520, 980 cm .
1
H NMR (90 MHz, CDCl ): d = 2.43 (s, 3 H), 2.87 (s, 6 H) 7.00 (s,
3
1
H), 7.24–7.74 (m, 13 H).
Synthesis 2004, No. 11, 1744–1746 © Thieme Stuttgart · New York