Silica-supported synthesis of some 1,3,5-trisubstituted 2-pyrazolines under solvent-free and microwave irradiation conditions

Article abstract of DOI:10.1002/jhet.5570420125

A simple method for the synthesis of 2-pyrazolines is described which occurs on silica surface under solvent-free conditions within 110-180 sec using microwave irradiation. The results obtained indicate that the use of silica gel as a support in pyrazolin

Full text of DOI:10.1002/jhet.5570420125

Jan-Feb 2005
157
Silica-Supported Synthesis of some 1,3,5-Trisubstituted 2-Pyrazolines
under Solvent-free and Microwave Irradiation Conditions
*
Davood Azarifar and Behrooz Maleki
Chemistry Department, School of Science, Bu-Ali-Sina University, Postal code 65174, Hamadan, Iran
E-mail:azarifar@basu.ac.ir
Received June 15, 2004
A simple method for the synthesis of 2-pyrazolines is described which occurs on silica surface under sol-
vent-free conditions within 110-180 sec using microwave irradiation. The results obtained indicate that the
use of silica gel as a support in pyrazoline formation reactions can have a profound effect on reaction rates
and yields and cause cleaner reaction conditions.
J. Heterocyclic Chem., 42, 157 (2005).
Variously substituted pyrazolines and their derivatives
The results obtained (Tables 1 and 2) indicate that the
use of silica gel support can increase both the reaction rates
and yields and cause cleaner reaction conditions.
are important constituents that often exist in biologically
active natural products [1]. They also serve as synthetic
compounds of medicinal importance as analgesic, anti-
inflammatory, antipyretic, anti-arrhythmic, tranquiliz-
ing, muscle relaxant, psycho analeptic agents [2].
Among them, 1,3,5-trisubstituted 2-pyrazolines can be
conveniently prepared from chalcone derivatives and
hydrazines via hydrazone intermediates which undergo
an easy cyclization to afford 2-pyrazolines [3,4].
Pyrazolines have played a crucial part in five-membered
heterocyclic chemistry and also utilized as valuable syn-
thetic precursors in organic synthesis [5].
Scheme 1
As it is evident from the literature [6], in recent years a
significant portion of research in heterocyclic chemistry
has been devoted to aryl-substituted pyrazolines. We
have recently reported on the synthesis of some newly
3,5-dinaphthylated 2-pyrazolines, which efficiently
acted against a variety of test organisms [7]. The increas-
ingly reported ability of different supporting agents in
improving the selectivity and reactivity of organic reac-
tions [8] has prompted us to examine the pyrazoline for-
mation under supporting conditions. Regarding that only
polar reagents activated on the surfaces of various min-
erals can absorb microwave energy, a variety of reagents
supported on such surfaces have been used to enhance
the organic reactions using a simple microwave (MW)
oven. On the other hand, solvent-free reactions seem to
be highly useful and environmentally friendly technique
in organic synthesis, especially when inorganic solid
supports are used [9].
Here, we report an extremely facile and environmen-
tally friendly method for the preparation of 1,3,5-trisub-
stituted 2-pyrazolines. We first prepared the intermediate
chalcones 3a-l from aldol condensation reactions
between ketones and aldehydes according to the litera-
ture [7]. These chalcones subsequently undergo a rapid
cyclization with phenyl hydrazine under solvent-free
and silica-supported conditions using microwave irradi-
ation to afford 1,3,5-trisubstituted 2-pyrazolines 4a-l
quantitatively in 110-180 sec (Scheme1).
Table 1
Substrates used in Silica-supported Synthesis of
1,3,5-Substituted 2-Pyrazolines
Substrate
Product
Ar
Ar
2
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
2-Naphthyl
Ph
4-MeC H
4-MeOC H
4-MeOC H
4-MeOC H
4-MeOC H
3-MeC H
2-MeC H
6
4
Ph
3-MeC H
6
4
6
4
4
4
3-MeC H
6
4
4
4
4
6
2-MeC H
6
6
Ph
6
4-ClC H
6
6
4
4-ClC H
6
4
6
4
2-Naphthyl
2-Naphthyl
2-Naphthyl
3-MeC H
6 4
3j
3k
3l
4j
4k
4l
4-ClC H
6 4
2-ClC H
6
4
4
4-MeOC H
2-ClC H
6
6
4
EXPERIMENTAL
All melting points were determined on a Büchi 530 melting
1
13
point apparatus, and reported uncorrected. The H-nmr and C-
nmr spectra were recorded for deuteriochloroform solution using
tetramethylsilane as the internal standard on a Jeol FX (at 90
MHz) spectrometer at ambient temperature. ir spectra were
recorded on a Shimadzu 435u-04 instrument using KBr pellets.
Mass spectra were recorded on a GCMS-QP1100EX at Shahid
Beheshti university, Tehran, Iran. The CHN analysis were carried
out in Iranian Petroleum Research Center (Ray city, Tehran).

158
D. Azarifar and B. Maleki
Vol. 42
Table 2
1,3,5-Trisubstituted 2-Pyrazolines Produced Under Solvent-free (I) and Solvent-free/Silica-supported Conditions (II)
using Microwave Irradiation
Substrate
Product [a]
IrradiationTime (sec)
Yield [b] (%)
I (II)
MP (°C)
I
II
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
150
140
200
240
240
190
210
180
200
190
160
190
120
130
150
170
170
160
180
140
160
150
110
150
49(60)
58(80)
38(74)
48(60)
46(64)
40(85)
38(62)
40(54)
40(69)
58(78)
40(74)
40(64)
169-171
129-131
124-126
112-114
88-90
134-136
110-112
105-107
152-154
160-162
124-126
148-150
3j
3k
3l
4j
4k
4l
1
13
[a] Products 4b, 4f, 4g and 4j are known which were characterized by ir, H-nmr, C-nmr and by direct comparison with
literature values. [b] Isolated Yields calculated on the basis of the chalcones 3a-l.
General procedure for Microwave-assisted Preparation of 1,3,5-
Trisubstituted 2-Pyrazoline Derivatives 4a-l.
13
CHAr ), 7.12-7.57 (m, 13H, Ar). C-nmr (CDCl ): δ= 77.10
2
3
(CDCl ), 21.42 (2Me), 42.14 (CH ), 64.30 (CHAr ), 149.68
3
2
2
(C=N), 142.5, 138.92, 137.71, 133.21, 131.92 (C, arom), 130.12,
129.12, 128.64, 127.10, 124.98, 123.12, 121.12, 114.04, 113.33
(CH, arom).
A mixture of chalcone 3a-l (2 mmol) and phenyl hydrazine
reagent (2.4 mmol) was thoroughly mixed with 70-230 mesh sil-
ica gel (1g). The resulting mixture was placed in an alumina bath
inside a MW oven (900 watts) and irradiated for 110-180 sec in
the solid state. After complete conversion of the substrate as indi-
Anal. Calcd. for C
H N : C, 84.66; H, 6.75; N, 8.59. Found:
23 22 2
C, 84.92; H, 6.78; N, 8.62.
cated by TLC, the product was extracted with Et O and the
2
5-(m-Methylphenyl)-3-(p-methoxyphenyl)-1-phenyl-2-pyrazo-
line (4d).
extract was filtered to remove the solid materials. The filtrate was
then evaporated to leave a solid residue which was recrystallized
from ethanol and the crystals were chromatographed on silica gel
using acetone/petroleum ether (1:5) to obtain highly pure prod-
ucts 4a-l as indicated below.
Compound 4d was obtained in 60% yield; mp 112-114˚
(recrystallization from ethanol); ir (KBr): 3022, 2838, 1597,
-1
1
1498, 1114, 748 cm ; H-nmr (CDCl ): δ= 2.17 (s, 3H, Me),
3
2.97 (dd, 1H, CHH ), 3.66 (m, 4H, CH H, OMe), 4.96 (dd, 1H,
A
B
5-(o-Methylphenyl)-3-(2-naphthyl)-1-phenyl-2-pyrazoline (4a).
13
CHAr ), 6.71-7.47 (m, 13H, Ar). C-nmr (CDCl ): δ= 77.10
2
3
(CDCl ), 21.09 (Me), 43.85 (CH ), 55.29 (OMe), 64.30
Compound 4a was obtained in 60% yield; mp 169-171˚
3
2
(CHAr ), 146.87 (C=N), 160.14, 145.30, 139.87, 137.12, 133.44
(recrystallization from ethanol); ir (KBr): 3021, 2879, 1596,
2
-1
1
(C, arom), 130.12, 129.67, 128.87, 127.24, 125.86, 125.64,
128.78, 114.04, 113.33 (CH, arom).
1499, 1140, 740 cm ; H-nmr (CDCl ): δ= 2.39 (s, 3H, Me),
3
3.05 (dd, 1H, CHH ), 3.81 (dd, 1H, CH H), 5.3 (dd, 1H,
A
B
13
Anal. Calcd. for C H ON : C, 80.70; H, 6.43; N, 8.19.
CHAr ), 6.69-8.01 (m, 16H, Ar). C-nmr (CDCl ): δ= 77.10
23 22 2
2
3
Found: C, 80.45; H, 6.46; N, 8.22.
(CDCl ), 19.47(Me), 41.74 (CH ), 61.68 (CHAr ), 146.67
3
2
2
(C=N), 144.68, 140.08, 133.83, 133.36, 130.94 (C, arom),
129.01, 128.18, 127.38, 126.91, 126.37, 125.62, 124.98,
123.561, 119.19, 113.26 (CH, arom). ms: m/z 42, 77, 91, 101,
118, 125, 127, 153, 167, 244, 271, 362.
5-(o-Methylphenyl)-3-(p-methoxyphenyl)-1-phenyl-2-pyrazo-
line (4e).
Compound 4e was obtained in 64% yield; mp 88-90˚ (recrys-
tallization from ethanol); ir (KBr): 3041, 2933, 1652, 1597,
Anal. Calcd. for C
H N : C, 86.19; H, 6.08; N, 7.73. Found:
26 22 2
-1 1
1182, 761 cm ; H-nmr (CDCl ): δ= 2.37 (s, 3H, Me), 2.91 (dd,
3
C, 86.0; H, 6.10; N, 7.76.
1H, CHH ), 3.72 (m, 4H, CH H, OMe), 5.21 (dd, 1H, CHAr ),
A
B
2
13
1,3,5-Triphenyl-2-pyrazoline (4b).
6.85-7.91 (m, 13H, Ar). C-nmr (CDCl ): δ= 77.10 (CDCl ),
3
3
21.98 (Me), 44.35 (CH ), 56.48 (OMe), 64.90 (CHAr ), 148.82
2
2
Compound 4b was obtained in 80% yield; mp 129-131˚
(recrystallization from ethanol) (Lit. [10] mp 130-132°).
(C=N), 159.94, 144.42, 140.14, 136.14, 132.68 (C, arom),
130.42, 129.24, 128.76, 126.32, 124.98, 123.68, 121.62, 114.04,
112.48 (CH, arom).
5-(m-Methylphenyl)-3-(p-methylphenyl)-1-phenyl-2-pyrazoline
(4c).
Anal. Calcd. for C
H ON : C, 80.70; H, 6.43; N, 8.19.
23 22 2
Found: C, 80.58; H, 6.40; N, 8.23.
Compound 4c was obtained in 74% yield; mp 124-126˚
3-(p-Methoxyphenyl)-1,5-(diphenyl)-2-pyrazoline (4f).
(recrystallization from ethanol); ir (KBr): 3030, 2917, 1597,
-1
1
1499, 1131, 743 cm ; H-nmr (CDCl ): δ= 2.33 (s, 6H, 2Me),
Compound 4f was obtained in 85% yield; mp 134-136˚
3
3.12 (dd, 1H, CHH ), 3.70 (dd, 1H, CH H), 5.19 (dd, 1H,
(recrystallization from ethanol) (Lit. [11] mp 135-137˚).
A
B

Jan-Feb 2005
Silica-Supported Synthesis of some 1,3,5-Trisubstituted 2-Pyrazolines
159
5-(p-Chlorophenyl)-3-(p-methoxyphenyl)-1-phenyl-2-pyrazoline
(4g).
54.98 (OMe), 63.44 (CHAr ), 146.87 (C=N), 159.90, 144.69,
142.06, 140.93, 135.76 (C, arom), 130.50, 129.20, 127.04, 126.92,
124.92, 121.96, 120.53, 118.73, 113.71 (CH, arom).
2
Compound 4g was obtained in 62% yield; mp 110-112˚
(recrystallization from ethanol) (Lit. [11] mp 115-117˚).
Anal. Calcd. for C
H ON Cl: C, 72.83; H, 5.24; N, 7.72.
22 19 2
Found: C, 72.52; H, 5.27; N, 7.69.
5-(p-Chlorophenyl)-3-(m-Methylphenyl)-1-phenyl-2-pyrazoline
(4h).
REFERENCES AND NOTES
Compound 4h was obtained in 54% yield; mp 105-107˚ (recrys-
tallization from ethanol); ir (KBr): 3032, 2918, 1633, 1597, 1116,
rd
[1a] T. L. Gilchrist, Heterocyclic Chemistry, 3 ed.; Addison-
Wesley Longman, Ltd.; England, (1998). [b] D. Lednicer, Strategies for
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[2a] E. Takabata, R. Kodama, Y. Tanaka, R. Dohmori, H.
Tachizawa and T. Naito, Chem. Pharm. Bull., 16, 1900 (1979); [b] S. S.
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1152 (1974); [c] N. Soni, K. Pande, R. Kalsi, T. K. Gupta, S. S. Parmer
and J. P. Barthwal, Res. Commun. Chem. Pathol. Pharmacol. 56, 129
(1987).
-1
1
822 cm ; H-nmr (CDCl ): δ= 2.42 (s, 3H, Me), 2.75 (dd, 1H,
3
CHH ), 3.12 (dd, 1H, CH H), 5.17 (dd, 1H, CHAr ), 6.69-7.46
A
B
2
13
(m, 13H, Ar). C-nmr (CDCl ): δ= 77.10 (CDCl ), 21.44 (Me),
3
3
42.387 (CH ), 62.12 (CHAr ), 150.62 (C=N), 142.5, 138.92,
2
2
137.71, 133.21, 131.92 (C, arom), 130.57, 129.95, 129.21, 128.05,
127.69, 126.23, 124.56, 113.12, 112.10 (CH, arom).
Anal. Calcd. for C
H N Cl: C, 76.19; H, 5.48; N, 8.08.
22 19 2
Found: C, 76.53; H, 5.50; N, 8.12.
[3a] H. G. Garge and J. Chandraprakash, J. Pharm. Sci. 14, 649
(1971); [b] L. Khnor, Ber. Dtsch. Chem. Ges., 26, 100 (1893); [c] V. G.
Thakare and K. N. Wadodkar, Ind. Chem. Sect., 25, 610 (1986); [d] M. D.
Ankhiwala and M. V. Hathi, J. Ind. Chem. Soc., 71, 587 (1994).
[4a] K. Vounauwers and A. Muller, Ber. Dtsch. Chem. Ges., 41,
4230 (1908); [b] A. Baker and V. S. Butt, J. Chem. Soc., 2142 (1949).
[5a] Yu. V. Tomilovi, G. P. Okonnishnikova, E. V. Shulishov and
O. M. Nefedov, Russ. Chem. Bt., 44, 2114 (1995); [b] E. I. Klimova, M.
Marcos, T. B. Klimova, A. T. Ceeilio, A. T. Ruben and R. R. Lena, J.
Organomet. Chem., 106, 585 (1999); [c] D. Bhaskar reddy, A. Padmaja,
P. V. Ramana reddy and B. Seenaiah, Sulfur Lett., 16, 227 (1993). [d] V.
Padmavathi, R. P. Sumathi, B. N. Chandrasekhar and D. Bhaskar reddy, J.
Chem. Res. 610 (1999).
5-(m-Methylphenyl)-3-(2-naphthyl)-1-phenyl-2-pyrazoline (4i).
Compound 4i was obtained in 69% yield; mp 152-154˚
(recrystallization from ethanol); ir (KBr): 2925, 2856, 1598,
-1
1
1495, 1104, 754 cm ; H-nmr (CDCl ): δ= 2.38 (s, 3H, Me),
3
3.33 (dd, 1H, CHH ), 3.92 (dd, 1H, CH H), 5.27 (dd, 1H,
A
B
13
CHAr ), 6.87-8.20 (m, 16H, Ar). C-nmr (CDCl ): δ= 77.10
2
3
(CDCl ), 21.47 (Me), 43.59 (CH ), 64.80 (CHAr ), 147.14
3
2
2
(C=N), 145.07, 142.80, 138.93, 133.47, 130.59 (C, arom),
128.98, 128.42, 128.18, 127.86, 126.46, 125.09, 123.62, 123.04,
119.28, 113.66 (CH, arom).
Anal. Calcd. for C
H N : C, 86.19; H, 6.08; N, 7.73. Found:
26 22 2
[6a] V. B. Kadu and A. G. Dashi, Orient. J. Chem., 13, 285 (1997);
[b] A. O. Abdelhamid, H. F. Zohdi, M. M. Sallam and N. A. Ahmed,
Molecules 5, 967 (2000); [c] K. Rurack, J. L. Bricks, B. Schultz, M.
Maus, G. Reck and U. Resch-Genger, J. Phys. Chem., 104, 6171 (2000);
[d] F. M. Guerra, M. R. Mish and E. M. Carreira, Org. Lett., 2, 4265
(2000); [e] G. Moltena and L. Garanti, Heterocycles 55, 1573 (2001). [f]
J. S. Yadav, B. V. S. Reddy and V. Geetha, Syn. Lett., 3, 513 (2002); [g] S.
Wang, B. Shi, Y. Li, Q. Wang and R. Huang, Synth. Commun., 33, 1449
(2003); [h] Y. Chen, Y. Lam and Y. H. Lai, Org. Lett., 5, 1067 (2003).
[7a] D. Azarifar and M. Shaebanzadeh, Molecules 7, 885 (2002);
[b] D. Azarifar and H. Ghasemnejad, Molecules 8, 642 (2003).
[8a] A. McKillop and D. W. Young, Synthesis 401-422 and 481-
500 (1979); [b] G. H. Posner, Angew. Chem., 90, 527 (1978), Angew.
Chem. Int. Ed. Engl. 17, 487 (1978); [c] M. Balogh and P. Laszlo,
Organic Chemistry Using Clays, Springer-Verlag, Berlin, 1993; [d] J. H.
Clark. Catalysis of Organic Reactions by Supported Inorganic Reagents,
VCH Publishers, Inc; New York 1994.
C, 85.92; H, 6.05; N, 7.75.
5-(p-Chlorophenyl)-3-(2-naphthyl)-1-phenyl-2-pyrazoline (4j).
Compound 4j was obtained in 78% yield; mp 160-162˚
11
(recrystallization from ethanol) (Lit. 156-158˚).
5-(o-Chlorophenyl)-3-(2-naphthyl)-1-phenyl-2-pyrazoline (4k).
Compound 4k was obtained in 74% yield; mp 124-126°
(recrystallization from ethanol); ir (KBr): 3054, 1598, 1496,
-1
1
1146, 750 cm ; H-nmr (CDCl ): δ= 3.14 (dd, 1H, CHH ), 4.11
3
A
(dd, 1H, CH H), 5.58 (dd, 1H, CHAr ), 6.73-8.03 (m, 16H, Ar).
B
2
13
C-nmr (CDCl ): δ= 77.10 (CDCl ), 42.11 (CH ), 63.24
3
3
2
(CHAr ), 149.46 (C=N), 144.24, 138.90, 137.98, 135.11, 133.12,
2
131.09 (C, arom), 130.00, 129.26, 128.84, 127.14, 125.84,
125.18, 123.12, 121.01, 118.24, 113.16, 112.04 (CH, arom).
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and R. W. Trainor, Aust. J. Chem., 48, 1665 (1995); [c] A. L. Marrero-
Terrero and A. Loupy, Synlett 245 (1996); [d] R. S. Varma, “Microwave-
Assisted Reactions under Solivent-Free ‘Dry’ Conditions” in
Microwaves: Theory and Application in Material Processng IV Clark, D.
Sutton and W. Lewis, Eds; American Ceramic Society, Ceramic
Transactions 1997, pp 357-65.
[10] F. Mary and F. Louis, "Reagent for Organic Synthesis" 2, 322
(1969).
[11] Shahabi, A. Ms.C. thesis; University of Bu-Ali-Sina: Iran,
(2000).
Anal. Calcd. for C
Found: C, 78.72; H, 4.95; N, 7.36.
H N Cl: C, 78.43; H, 4.97; N, 7.32.
25 19 2
5-(o-Chlorophenyl)-3-(p-methoxyphenyl)-1-phenyl-2-pyrazoline
(4l).
Compound 4l was obtained in 64% yield; mp 148-150˚ (recrys-
tallization from ethanol); ir (KBr): 2933, 2835, 1597, 1497, 1122,
-1 1
747 cm ; H-nmr (CDCl ): δ= 3.11 (dd, 1H, CHH ), 3.85 (m, 3H,
3
A
OMe), 5.16 (s, 1H, CH H), 5.62 (dd, 1H, CHAr ), 6.91-7.67 (m,
B
2
13
13H, Ar). C-nmr (CDCl ): δ= 77.10 (CDCl ), 41.38 (CH ),
3
3
2