Microwave enhanced green synthesis of 2-pyrazolines, isoxazolines and cyclohexenones

Article abstract of DOI:10.14233/ajchem.2013.15070

Hydroxy chalcones undergo simple cyclizations with phenylhydrazine to afford 2-pyrazolines under microwave irradiation in the presence of glacial AcOH as cyclizing agent, also undergo simple cyclizations with hydroxylamine to afford 2-isoxazolines under m

Full text of DOI:10.14233/ajchem.2013.15070

Asian Journal of Chemistry; Vol. 25, No. 11 (2013), 6427-6433
http://dx.doi.org/10.14233/ajchem.2013.15070
Microwave Enhanced Green Synthesis of 2-Pyrazolines, Isoxazolines and Cyclohexenones
1,*
2
1
ABDULLAH S. AL-BOGAMI , HAMAD Z. ALKHATHLAN and TAMER S. SALEH
1Department of Chemistry, Faculty of Science, King Abdulaziz University, North Jeddah, P.O. Box 80203, Jeddah 21589, Saudi Arabia
2Department of Chemistry, Faculty of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
*Corresponding author: Fax: +966 2 6400376; Tel: +966 5 54433416; E-mail: chem_org@hotmail.com
(Received: 31 December 2012;
Accepted: 11 May 2013)
AJC-13486
Hydroxy chalcones undergo simple cyclizations with phenylhydrazine to afford 2-pyrazolines under microwave irradiation in the presence
of glacial AcOH as cyclizing agent, also undergo simple cyclizations with hydroxylamine to afford 2-isoxazolines under microwave
irradiation in the presence of KOH, and new cyclohexenone derivatives. Some valuable intermediates in the synthesis of fused heterocycles,
have been prepared through K2CO3 which activate the cyclocondensation of hydroxychalcones with ethyl acetoacetate. The obtained results
indicate that the microwave irradiation give shorter reaction times and cleaner reactions for synthesis of biologically important compounds.
Key Words: 2-Pyrazolines, 2-Isoxazolines, Cyclohexenone, Hydroxy Chalcone, Microwave Irradiation.
acid ester to give ethoxycarbonyl cyclohexenone derivatives pre-
sumably through Micheal addition followed by condensation
of the terminal methyl group with the carbonyl function of the
adduct.Although several chalcones underwent this reaction but
suffer from by products, low yield and longer reaction time23.
Microwave has increasingly been used in organic synthesis
in last three decades. Compared with traditional methods, this
method is more convenient and easily controlled. A large
number of microwave reactions can be carried out in higher
yield, shorter reaction time or milder conditions24.
INTRODUCTION
The chemistry of chalcones has generated intensive scien-
tific studies throughout the world. Especially interest has been
focused on the synthesis and biodynamic activities of chalcones.
Chalcone bears a very good synthon so that variety of
novel heterocycles with good pharmaceutical profile can be
designed. In which chalcones are used to synthesize several
derivatives like pyrazolines, isoxazoles, pyridine, pyrimidine,
and many fused heterocyclic ring, also used for synthesis of
cyclohexnone systems1-4.
From all of the facts stated above and in continuation of
our interest in utilizing green chemistry tools in synthesis of
heterocyclic compounds25-28, herein we wish to report a study
the possibility of the reaction of different hydroxy chalcones
with phenylhydrazines, hydroxylamines and ethyl acetoacetate
under microwave irradiation as a green protocol.
Numerous pyrazoline type compounds and isoxazoles
have been found to possess useful bioactivity, e.g., antimicro-
bial5, central nervous system6 and immunosuppressive7.
Among the various pyrazoline isomers, 2-pyrazolines and 3,4-
disubstituted isoxazoles appear to be the most frequently
investigated compounds. As a consequence, a large number
of 2-pyrazolines and 3,4-disubstituted isoxazoles have been
described in the chemical literature, using different synthetic
methods for their preparation. A popular procedure is based
on the reaction of α,β-unsaturated carbonyl compounds with
hydrazines and hydroxyl amine respectively8-20. However, there
are always some problems due to long reaction time, low yield
or environmental concerns.
EXPERIMENTAL
Melting points are uncorrected and were determined on
Gallenkamp-melting point apparatus. NMR spectra were
recorded on JEOL ECP 400 (400 MHz) in CDCl3 and expressed
as δ in ppm. Mass spectra were recorded on Shimadzu QP-
5050A GC/MS system. Microwave experiments were carried
out using CEM MARS synthatorTM microwave apparatus. TLC
was performed on (TLC plates silica gel 60F245 pre-coated 20
× 20 cm layer thickness 0.25 mm).
A careful survey of literature reveals that cyclohexenone
moiety constitutes an important structural feature in several
biologically active heterocyclic compounds21,22
.
Microwave experiments were carried out using CEM
MARS synthatorTM microwave apparatus with temperature
control for microwave experiments using IR sensor.
One of the most important reported methods for the syn-
thesis of cyclohexenone that chalcones react with acetoacetic

6428 Al-Bogami et al.
Asian J. Chem.
Synthesis of pyrazoline derivatives: Phenylhydrazine
reagent (3 mmol) was added dropwise to a stirring solution of
the chalcones 1a-j (1 mmol) in glacial AcOH (10 mL). The
mixtures in open vessel subjected to microwave heating (300
W) for suitable time 7-12 min. The progress of the reaction
was monitored by TLC upon completion of the reaction, the
reaction mixture after cooling poured into crushed ice water
(30 mL) and the reaction mixture was left to stay at 2-3 ºC
overnight. The separated solid was collected by filtration and
recrystallized from absolute.
5.65 (1H, dd, J = 12.00, 7.00 Hz, 1H), 6.82-7.48 (m, 11H, Ar'
H), 10.24 (s, 1H, D2O exchangable, OH). 13C NMR: δ 20.13,
40.29, 59.76, 113.10, 116.53, 116.67, 119.98, 128.68, 128.85,
129.91, 130.10, 131.81, 132.77, 133.53, 138.22, 143.76,
150.82, 154.62. MS: m/z 396.
5-(2',4'-Dichlorophenyl)-3-(2''-hydroxy-5''-methoxy-
phenyl)-1-phenyl-2-pyrazoline (3g)29: m.p. 120-122 ºC, 1H
NMR (400 MHz, CDCl3): δ 3.12 (dd, J = 16.88, 7.32 Hz, 1H),
3.76 (s, 3H, OMe), 4.06 (dd, J = 17.60, 12.50Hz, 1H), 5.59
(1H, dd, J = 12.50, 7.36 Hz, 1H), 6.86-7.49 (m, 11H, Ar' H),
10.26 (s, 1H, D2O exchangable, OH). 13C NMR: δ 42.33, 56.01,
59.81, 112.00, 113.17, 116.65, 117.32, 120.40, 128.18, 128.40,
129.42, 129.80, 137.34, 143.39, 149.80, 151.43, 152.60. MS:
m/z 412.
3-(2'-Hydroxyphenyl)-1,5-diphenyl-2-pyrazoline
(3a)29: m.p. 160-162 ºC, 1H NMR (400 MHz, CDCl3): δ 3.28
(dd, J = 16.88, 7.32 Hz, 1H) 3.99 (dd, J = 16.81, 12.44Hz,
1H), 5.23 (1H, dd, J = 12.50, 7.32 Hz, 1H), 6.95-7.36 (m,
14H, Ar' H), 10.8 (s, 1H, D2O exchangable, OH). 13C NMR: δ
44.07, 63.45, 113.43, 116.42, 116.70, 119.47, 120.02, 125.99,
127.23, 127.96, 129.21, 129.37, 130.52, 141.99, 144.11,
149.68. 157.28. MS: m/z 314.
3-(5'-Bromo-2'hydroxyphenyl)-5-(2'',4''-dichloro-
phenyl)-1-phenyl-2-pyrazoline (3h)29: m.p. 128-129 ºC, 1H
NMR (400 MHz, CDCl3): δ 3.14 (dd, J = 17.60, 7.32 Hz, 1H),
4.08 (dd, J = 16.84, 12.50 Hz, 1H), 5.59 (1H, dd, J = 12.50,
7.36 Hz, 1H), 6.87-7.26 (m, 11H, Ar' H), 10.64 (s, 1H, D2O
exchangable, OH). 13C NMR: δ 42.12, 49.92, 111.28, 113.23,
117.97, 118.57, 120.72, 128.19, 128.26, 129.47, 129.55,
130.05, 133.22, 134.49, 137.00, 143.09, 148.72, 156.22. MS:
m/z 462.
5-(4'-Chlorophenyl)-3-(2''-hydroxy-6''methoxy-
phenyl)-1-phenyl-2-pyrazoline (3b)29: m.p. 158-159 ºC, 1H
NMR (400 MHz, CDCl3): δ 3.46 (dd, J = 18.00, 7.32 Hz, 1H),
3.76 (s, 3H, OMe), 4.18 (dd, J = 18.32, 12.4Hz, 1H), 5.11
(1H, dd, J = 12.50, 8.08 Hz, 1H), 7.17-7.81 (m, 12H, Ar' H),
11.83 (s, 1H, D2O exchangable, OH). 13C NMR: δ 48.09, 55.54,
62.72, 101.77, 106.35, 110.11, 113.35, 119.99, 127.48, 129.24,
119.45, 130.67, 133.48, 141.08, 144.10, 149.78, 158.57,
159.23. MS: m/z 378.
5-(3',5'-Dichloro-2'-hydroxyphenyl)-5-(2'',4''-dichloro-
1
phenyl)-1-phenyl-2-pyrazoline (3i)29: m.p. 203-204 ºC, H
NMR (400 MHz, CDCl3): δ 3.14 (dd, J = 17.60, 7.36 Hz, 1H),
4.07 (dd, J = 16.80, 12.50Hz, 1H), 5.65 (1H, dd, J = 12.50, 7.32
Hz, 1H), 6.87-7.49 (m, 10H, Ar' H), 11.82 (s, 1H, D2O
exchangable, OH). 13C NMR: δ 42.00, 60.14, 113.32, 118.14,
121.09, 122.35, 124.21, 125.11, 128.24, 129.53, 130.13, 130.22,
134.64, 136.68, 142.70, 148.11, 151.57. MS: m/z 452.
5-(4'-Chlorophenyl)-3-(2''-hydroxyphenyl)-1-phenyl-
1
2-pyrazoline (3c)29: m.p. 138-140 ºC, H NMR (400 MHz,
CDCl3): δ 3.24 (dd, J = 17.50, 7.32 Hz, 1H), 4.02 (dd, J =
16.84, 12.5Hz, 1H), 5.22 (1H, dd, J = 12.50, 8.08 Hz, 1H),
6.92-7.34 (m, 13H, Ar' H), 11.22 (s, 1H, D2O exchangable,
OH). 13C NMR: δ 43.97, 62.85, 113.48, 116.23, 116.77,
119.53, 120.29, 125.11, 127.23, 127.44, 129.04, 129.27,
129.58, 130.69, 133.75, 140.47, 143.92, 149.73, 157.28. MS:
m/z 348.
5-(5'-Chloro-2'-hydroxyphenyl)-5-(2'',4''-dichloro-
1
phenyl)-1-phenyl-2-pyrazoline (3j)29: m.p. 129-131 ºC, H
NMR (400 MHz, CDCl3): δ 3.13 (dd, J = 16.90, 7.32 Hz, 1H),
4.07 (dd, J = 17.60, 12.44 Hz, 1H), 5.58 (1H, dd, J = 12.50,
7.32 Hz, 1H), 6.85-7.24 (m, 11H, Ar' H), 11.62 (s, 1H, D2O
exchangable, OH). 13C NMR: δ 42.12, 59.91, 113.23, 117.36,
118.11, 120.71, 124.28, 126.28, 128.19, 128.27, 129.47,
130.05, 130.36, 132.55, 134.48, 137.02, 143.12, 148.83,
155.74. MS: m/z 417.
3-(2'-Hydroxyphenyl)-5-(3'',4'',5''-trimethoxyphenyl)-
1
1-phenyl-2-pyrazoline (3d): m.p. 97-99 ºC, H NMR (400
MHz, CDCl3): δ 3.28 (dd, J = 16.88, 8.80 Hz, 1H), 3.82 (s,
9H, OMe), 3.98 (dd, J = 18.0, 12.44 Hz, 1H), 5.12 (1H, dd,
J = 12.44, 8.80 Hz, 1H), 6.65-7.25 (m, 11H, Ar' H), 11.83 (s,
1H, D2O exchangable, OH). 13C NMR: δ 44.25, 56.28, 60.95,
102.49, 113.62, 116.33, 116.74, 119.51, 120.33, 127.28,
129.21, 129.29, 129.68, 130.56, 137.38, 137.86, 144.57,
150.03, 154.03,157.32,. MS: m/z 404.
Synthesis of isoxazoline derivatives: To a mixture of
2-hydroxychalcone (0.29 mmol) and hydroxylamine hydro-
chloride (1.45 mmol) in absolute ethanol (5 mL) a three drops
of KOH solution (10 g in 20 mL of water) was added. The
reaction mixture was subjected to microwave irradiation (300
W) for 6-10 min. as monitored by TLC. Then pour the reaction
mixture on ice-water mixture, the resulting precipitate was
washed with distilled water and dried. The resulting crude was
crystallized from absolute ethanol to obtained white crystalline
product.
5-(3',5'-Dichloro-2'-hydroxyphenyl)-5-(3'',4'',5''-
trimethoxyphenyl)-1-phenyl-2-pyrazoline (3e): m.p. 153-
155 ºC, 1H NMR (400 MHz, CDCl3): δ 3.13 (dd, J = 16.88,
7.32 Hz, 1H), 3.81 (s, 9H, OMe), 4.07 (dd, J = 17.60, 12.44Hz,
1H), 5.57 (1H, dd, J = 12.50, 7.32 Hz, 1H), 6.48-7.22 (m, 9H,
Ar' H), 11.44 (s, 1H, D2O exchangable, OH). 13C NMR: δ
43.78, 56.28, 60.95, 102.40, 113.71, 118.37, 120.97, 122.22,
124.14, 125.08, 129.32, 129.69, 137.04, 137.59, 143.61,
147.91, 151.58, 154.11 MS: m/z 472.
3-(2'-Hydroxy phenyl)-5-(3'',4'',5''-trimethoxy-
phe-nyl)-2-isoxazoline (7a)30: m.p. 129-130 ºC, 1H NMR (400
MHz, CDCl3): δ 3.47 (dd, J = 16.16, 8.08 Hz, 1H), 3.87 (s,
9H, 3OMe), 3.95 (dd, J = 19.6, 11.00 Hz, 1H), 5.67 (1H, dd,
J = 11.60, 8.08 Hz, 1H), 6.65 (s, 2H, Ar' H), 6.92-7.28 (m,
4H, Ar' H), 9.81 (s, 1H, D2O exchangable, OH). 13C NMR: δ
43.53, 56.10, 60.96, 81.68, 101.70, 117.06, 118.57, 122.41,
132.62, 135.27, 153.76, 156.08, 158.38. MS: m/z 329.
5-(2',4'-Dichlorophenyl)-3-(2''-hydroxy-5''-
methylphenyl)-1-phenyl-2-pyrazoline (3f)29: m.p. 146-148
ºC, 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H, Me), 3.30 (dd,
J = 17.60, 8.80 Hz, 1H), 4.17 (dd, J = 17.60, 12.50 Hz, 1H),

Vol. 25, No. 11 (2013)
Microwave Enhanced Green Synthesis of 2-Pyrazolines, Isoxazolines and Cyclohexenones 6429
3-(5'-Chloro-2'-hydroxyphenyl)-5-(3'',4'',5''-trimeth-
oxyphenyl)-2-isoxazoline (7b)30: m.p. 144-145 ºC, 1H NMR
(400 MHz, CDCl3): δ 3.44 (dd, J = 16.90, 8.08 Hz, 1H), 3.89
(s, 9H, 3OMe), 3.91 (dd, J = 17.6, 11.60 Hz, 1H), 5.69 (1H,
dd, J = 11.60, 8.80 Hz, 1H), 6.59 (s, 2H, Ar'H), 6.89-7.48 (m,
3H, Ar' H), 9.61 (s, 1H, D2O exchangable, OH). 13C NMR: δ
43.19, 56.21, 60.15, 81.95, 102.73, 115.06, 118.57, 124.33,
127.78, 131.62, 135.27, 153.76, 156.08, 157.51. MS: m/z 363.
3-(3',5'-dichloro-2'-hydroxyphenyl)-5-(3'',4'',5''-trime-
thoxyphenyl)-1-phenyl--2-isoxazoline (7c)30: m.p. 133-136
ºC, 1H NMR (400 MHz, CDCl3): δ 3.42 (dd, J = 16.77, 8.08
Hz, 1H), 3.90 (s, 9H, 3OMe), 3.92 (dd, J = 17.8, 7.04 Hz,
1H), 5.67 (1H, dd, J = 11.20, 8.80 Hz, 1H), 6.54 (s, 2H,Ar'H),
7.19 (s, 1H, Ar'H), 7.48 (s, 1H, Ar' H), 10.01 (s, 1H, D2O
exchangable, OH). 13C NMR: δ 43.66, 56.1, 61.35, 81.70,
103.25, 121.22, 126.47, 128.55, 134.56, 134.91, 137.84,
149.87, 152.58, 156.99. MS: m/z 398.
Anal. calcd. for C21H19ClO4: C, 68.02; H, 5.16. Found: C 68.25,
H 5.01.
Ethyl-4-(2'-hydroxyphenyl)-2-oxo-6-(3',4',5'-trimeth-
oxyphenyl)-cyclohex-3-en-1-carboxylate (10c): Yield: 77 %,
m.p. 84-85 ºC, IR (KBr, νmax, cm-1): 1662 (C=O ketone), 1743
(C=O ester), 3312 (OH). 1H NMR (400 MHz, CDCl3): δ 1.07
(t, 3H, J = 6.9 Hz, Me Ester), 3.04 (m, 1H, H6), 3.12 (1H, dd,
Jtrans = 3.30 Hz, Jcis =17.4 Hz, H1), 3.80-3.82 (m, 1H, H5),
3.86 (s, 9H, 3OMe), 4.08 (q, J = 6.9 Hz, CH2 Ester), 6.56 (s,
2H, Ar'H), 6.72 (s, 1H, Hvinyl), 6.92-7.31 (m, 4H, Ar' H), 7.99
(s, 1H, D2O exchangable, OH). 13C NMR: δ 14.18, 37.73,
44.80, 55.49, 56.21, 60.93, 61.12, 102.47, 104.30, 106.74,
117.52, 124.83, 129.90, 137.07, 137.15, 153.39, 156.82,
158.77, 162.42, 169.66, 196.38. MS: m/z 426. Anal. calcd.
for C24H26O7: C, 67.59; H, 6.15. Found: C 67.84, H 5.95.
Ethyl 4-(2'-hydroxy-4'-methoxyphenyl)- 2-oxo-6-
(3',4',5'-trimethoxyphenyl)-cyclohex-3-en-1-carboxylate
(10d): Yield: 86 %, m.p. 172-174 ºC, IR (KBr, νmax, cm-1):
1660 (C=O ketone), 1741 (C=O ester), 3322 (OH). 1H NMR
(400 MHz, CDCl3): δ 1.06 (t, 3H, J = 6.8 Hz, Me Ester), 3.03
(m, 1H, H6), 3.11 (1H, dd, Jtrans = 6.30 Hz, Jcis =17.4 Hz, H1)
3.75-3.83 (m, 1H, H5), 3.86 (s, 12H, 4OMe), 4.07 (q, J = 6.8
Hz, CH2 Ester), 6.44 (s, 2H, Ar'H), 6.50 (s, 1H, Hvinyl), 6.99-
7.31 (m, 3H, Ar' H), 8.01 (s, 1H, D2O exchangable, OH). 13C
NMR: δ 14.12, 26.10, 34.98, 55.81, 56.10, 61.30, 63.78,
102.11, 103.55, 106.88, 107.64, 126.01, 127.58, 136.11,
142.30, 151.24, 152.11, 156.41, 161.00, 169.58, 197.11. MS:
m/z 456. Anal. calcd. for C25H28O8: C, 65.78; H, 6.18. Found:
C 66.01, H 6.02.
3-(5'-Chloro-2'-hydroxyphenyl)-5-(2'',4''-dichloro-
phenyl)-2-isoxazoline (7d)30: m.p. 112-116 ºC, 1H NMR (400
MHz, CDCl3): δ 3.29 (dd, J = 16.84, 6.60 Hz, 1H), 3.99 (dd,
J = 16.9, 11.76 Hz, 1H), 5.98 (1H, dd, J = 11.00, 7.32 Hz,
1H), 6.95-7.38 (m, 6H, Ar' H), 9.98 (s, 1H, D2O exchangable,
OH). 13C NMR: δ 43.10, 81.70, 116.25, 119.21, 125.56,
126.13, 129.56, 131.57, 133.56, 133.87, 134.16, 136.78,
156.22, 158.20. MS: m/z 342.
Synthesis of cyclohexenone derivatives: Hydroxy
chalcone analogue 8 (2.2 mmol) and ethyl acetoacetate 2 (2.9
mmol) were mixed in dichloromethane (5 mL) then K2CO3
(6.6 mmol) was added the evaporate under vaccum the solvent,
the remaiang residue was taken and subjected to microwave
irradiation for 6 min. as monitered by TLC. The reaction
mixture was then taken in dichloromethane to get ride of K2CO3
then the reaction product separated as a solid after evapora-
tion of dichloromethane under vacuum, which was filtered
off and recrystallized from absolute ethanol.
RESULTS AND DISCUSSION
We report in our earlier paper that some Aldol reactions
between 2-hydroxyacetophenone derivatives and benzalde-
hydes in the presence of KOH/MeOH to give chalcones28, it
has been found that undergo a rapid cyclization with phenyl-
hydrazine in the presence of glacial AcOH under microwave
irradiation at (300 W) to yield 2-pyrazolines in 4-12 min. The
results of the study are summarized in Table-1.
Ethyl 4-(2'-hydroxyphenyl)-2-oxo-6-phenyl-cyclohex-
3-en-1-carboxylate (10a): Yield: 85 %, m.p. 152-154 ºC, IR
(KBr, νmax, cm-1): 1660 (C=O ketone), 1740 (C=O ester), 3310
(OH). 1H NMR (400 MHz, CDCl3): δ 1.07 (t, 3H, J = 6.8 Hz,
Me Ester), 3.05 (d, J = 5.88 Hz, 1H, H6), 3.15 (1H, dd, Jtrans
=
R3
O
5.60 Hz, Jcis =17.4 Hz, H1) 3.81-3.83 (m, 1H, H5), 4.08 (q,
J = 6.8 Hz, CH2 Ester), 6.74 (s, 1H, Hvinyl), 7.21-7.31 (m, 9H,
Ar' H), 7.77 (s, 1H, D2O exchangable, OH). 13C NMR: δ 13.99,
37.72, 44.61, 59.83, 61.09, 116.91, 120.70, 126.75, 127.39,
127.49, 128.64, 128.83, 131.13, 141.10, 153.97, 159.33,
169.59, 195.43. MS: m/z 336. Anal. calcd. for C21H20O4: C,
74.98; H, 5.99. Found: C 74.76, H 6.08.
R4
R3
R2
N
N
NHNH2
R4
R5
R6
R2
R5
R6
MW, 300W
AcOH
OH
+
OH
R1
R7
R1
R7
1a-j
2
3a-j
1,3
a
b
c
d
e
f
g
h
H
Br
H
Cl
H
Cl
H
I
J
H
Cl
H
Cl
H
Cl
H
Ethyl 4-(2'-hydroxyphenyl)-2-oxo-6-(4'-chlorophenyl)-
cyclohex-3-en-1-carboxylate (10b): Yield: 91 %, m.p. 173-
175 ºC, IR (KBr, νmax, cm-1): 1667 (C=O ketone), 1740 (C=O
ester), 3322 (OH). 1H NMR (400 MHz, CDCl3): δ 1.08 (t, 3H,
J = 6.9 Hz, Me Ester), 3.03 (d, J = 6.60 Hz, 1H, H6), 3.11
(1H, dd, Jtrans= 6.30 Hz, Jcis =17.4 Hz, H1) 3.78-3.81 (m, 1H,
H5), 4.08 (q, J = 6.9 Hz, CH2 Ester), 6.70 (s, 1H, Hvinyl), 6.73
-7.31 (m, 8H, Ar' H), 7.98 (s, 1H, D2O exchangable, OH). 13C
NMR: δ 14.09, 37.53, 43.96, 59.66, 61.32, 76.78, 77.10,
116.92, 120.77, 126.66, 128.70, 128.78, 129.04, 131.31,
133.28, 139.58, 154.10, 159.28, 169.46, 195.20. MS: m/z 370.
R1
R2
R3
R4
R5
R6
R7
H
H
H
H
H
H
H
H
H
OMe
H
H
Cl
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
Cl
H
H
Me
H
Cl
H
H
H
H
Cl
H
Cl
H
Cl
Cl
H
Cl
H
OMe OMe
OMe OMe
OMe OMe
Cl
H
Cl
H
Scheme-I: Microwave assisted synthesis of 2-pyrazolines
The heterocyclic products were characterized on the
1
basis of their H NMR, 13C NMR and MS spectral analysis
(cf. experimental part).

6430 Al-Bogami et al.
Asian J. Chem.
TABLE-1
SYNTHESIS OF PYRAZOLINE FROM 2-HYDROXYCHALCONES
Entry
Substrate
Product
Yield (%)
Time (min)
O
N
N
90
5
1
OH
OH
1a
3a
OMe
O
OMe
N
N
88
82
94
9
4
8
2
3
4
OH
1b
O
OH
Cl
Cl
3b
N
N
OH
OH
Cl
Cl
1c
3c
O
N
N
OMe
OMe
OMe
OMe
OH
OH
1d
OMe
3d
OMe
O
Cl
N
N
OMe
91
9
5
Cl
OMe
OH
Cl
OMe
OH
OMe
1e
OMe
3e
Cl
OMe
O
Me
N
N
84
10
6
Me
Cl
Cl
Cl
Cl
OH
OH
1f
3f

Vol. 25, No. 11 (2013)
Entry
Microwave Enhanced Green Synthesis of 2-Pyrazolines, Isoxazolines and Cyclohexenones 6431
Product Yield (%) Time (min)
Substrate
O
MeO
N
N
7
90
12
MeO
Cl
Cl
Cl
Cl
OH
OH
1g
3g
O
Br
Cl
Cl
Cl
Cl
N
N
8
9
87
8
Br
OH
Cl
OH
Cl
1h
3h
O
Cl
Cl
N
N
OH
9
Cl
83
Cl
Cl
1i
OH
Cl
3i
Cl
10
O
Cl
Cl
N
N
OH
10
Cl
81
Cl
1j
OH
Cl
3j
On the other hand, the ring closure reaction of chalcone
a-d and hydroxylamine hydrochloride (5) occurred under
microwave irradiation in the presence of potassium hydroxide
to afford the isoxazoline derivatives 6a-d (Scheme-II).
A possible mechanism for this reaction, proposed based
on our experimental results together with some literature data
for the cyclization reaction of chalcone, is that it is realized in
two steps; first nucleophilic attack of the carbonyl group by
the NH2 moiety occurs, which is followed by oxime formation
(adduct 6) and then intramolecular cyclization lead to the five
member ring products 7a-d (Scheme-II).
OH
O
N
R2
R2
R3
R3
R4
R5
MW, 300W
R4
R5
OH
NH2OH.HCl
OH
+
KOH-EtOH
R1
R1
R6
R6
4
5
6
R3
4,7
A
B
C
Cl
Cl
H
OMe
OMe
OMe
D
H
Cl
Cl
H
N
O
R4
R5
R2
R1
R2
R3
R4
R5
R6
H
H
H
H
Cl
H
OMe
OMe
OMe
OH
The reactions were performed using α,β-unsaturated
carbonyl compounds with diverse substituents. The results of
the experiments are summarized in Table-2.
R6
OMe
OMe
OMe
R1
Cl
H
7a-d
Also, the reaction of chalcones and their heterocyclic
analogs with ethyl acetoacetate is known to lead to three structu-
rally diverse types of compounds, depending on the experimental
conditions employed: pyrylium salts31, Michael addition
Scheme-II: Microwave assisted synthesis of isoxazolines
products32 and cyclohexenone derivatives33. The catalyst plays
a key role in directing the reaction to different end products.

6432 Al-Bogami et al.
Asian J. Chem.
TABLE-2
SYNTHESIS OF ISOXAZOLINES FROM 2-HYDROXYCHALCONES
Entry
Substrate
Product
Yield (%)
Time (min)
O
N
O
OMe
OMe
OMe
OMe
1
82
6
OH
OH
7a
OMe
4a
OMe
O
N
O
Cl
Cl
OMe
OMe
2
88
8
OH
OH
OMe
OMe
7b
OMe
4b
OMe
O
N
O
Cl
Cl
OMe
OMe
OMe
OMe
3
80
9
OH
4c
O
OH
Cl
7c
Cl
OMe
Cl
OMe
Cl
Cl
N
O
Cl
4
77
10
OH
OH
Cl
Cl
4d
7d
R
O
3
O
CH
3
A strong Lewis acid such as boron trifluoride etherate gene-
rates pyrylium cations from the reaction of chalcones and
acetoacetic acid esters, but basic catalysts would turn the
intermediate.
R
R
O
2
3
R
R
4
O
O
R
R
COOC
H
5
2
1
2
R
R
5
6
MW, 300W
CO
R
4
R
OH
1
OC
H
5
+
K
2
2
3
OH
6
min.
R
5
7
R
R
6
7
8
Michael addition product into cyclohexenones through
the intramolecular cyclocondensation of the methyl group
originating from acetoacetic acid ester and the ketone function
of the initial chalcone. Thus, in the presence of a base, chalcone
analogs 8a-f and ethyl acetoacetate produce cyclohexenones
10a-f by means of an intermediate Michael adduct 9 in 6 min,
as outlined in Scheme-III.
9
-H
O
2
8,10
R1
A
B
H
H
H
H
H
Cl
H
c
d
R
6
R
R
R
7
5
H
H
H
H
H
H
H
H
H
H
H
OMe
H
R2
4
∗
R3
H
C OOC
H
5
∗
2
R
3
The cyclocondensation of ethyl acetoacetate with
chalcones 8 leads to the generation of two chiral centers at C1
and C6 in the structure of cyclohexenones 10. As the explored
reaction is not stereoselective, both configuration of the chiral
carbon atoms are expected to be noticed in the synthesized
cyclohexenones 10, which would result in a mixture of diaste-
reomers. No attempt to separate the diastereomeric cyclo-
hexenones 10 has been undertaken and the cyclocondensation
R4
H
R
2
1
O
R5
OMe
OMe
OMe
OMe
OMe
OMe
R
OH
R6
R7
10a-d
Scheme-III: Microwave assisted synthesis of cyclohexenones
products have been characterized in the form of the mixture
originated from the synthesis. Structural analysis of the newly

Vol. 25, No. 11 (2013)
Microwave Enhanced Green Synthesis of 2-Pyrazolines, Isoxazolines and Cyclohexenones 6433
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investigations. The IR spectra of these compounds revealed a
sharp strong absorption band above 1700 cm-1 that can be
correlated with the presence of the ester function in the struc-
ture of cyclohexenones 10. Furthermore, another sharp strong
absorption band was noticed at approximately 1660 cm-1 and
was assigned to the carbonyl group conjugated with a carbon-
carbon double bond. In addition to a broad absorption band in
region 3500-3200 cm-1 due to hydroxyl group. No other
absorption band could be evidenced in the region of the IR
spectrum associated with the stretching vibrations of the
carbonyl group, thus excluding the intermediate Michael
adduct having an extra carbonyl group. The 1H NMR spectra
substantiated the results of the IR analysis. The characteristic
signals of an ethyl ester moiety (a triplet at chemical shift values
of about 1 ppm and a quartet at δ values above 4 ppm)
confirmed the presence of the ester group in the structure of
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skeleton usually appears as a multiplet immediately below 3
ppm, when the signals due to this proton shift to higher δ
values and single with the peaks attributed to the proton at C1.
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to the neighboring C6 proton and owing to the possible cis-
trans geometry on the other hand. The two diastereotopic
protons at C5 of the cyclohexenone ring are represented in the
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1
ppm. The characteristic signal in the H NMR spectra of
compounds 10 is however the singlet of the vinylic proton in
the position 3 of the cyclohexenone ring, that occurs at
approximately 6.5 ppm and confirms that the intramolecular
cyclocondensation subsequent to the Michael addition
actually took place.
In conclusion, we develop a facile synthesis of pyrazoline,
isoxazoline and cyclohexanone derivatives utilizing hydroxy
chalcone derivatives under microwave irradiations which give
high yield in short reaction time.
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