Regioselective synthesis of 3,5-diaryl-4-methylisoxazoles

Article abstract of DOI:10.1007/s00706-012-0782-9

A new class of isoxazole derivatives, namely 2-(3-aryl-4-methylisoxazol-5- yl)phenols, has been efficiently synthesized through the regioselective reaction of 2-aryl-3-methylchromones with hydroxylamine. The products were characterized by spectroscopic me

Full text of DOI:10.1007/s00706-012-0782-9

Monatsh Chem (2013) 144:237–245
DOI 10.1007/s00706-012-0782-9
ORIGINAL PAPER
Regioselective synthesis of 3,5-diaryl-4-methylisoxazoles
•
Pradeep D. Lokhande Kamal Hasanzadeh
•
•
Hamid Khaledi Hapipah Mohd Ali
Received: 4 September 2011 / Accepted: 28 April 2012 / Published online: 30 May 2012
ꢀ Springer-Verlag 2012
Abstract A new class of isoxazole derivatives, namely
2-(3-aryl-4-methylisoxazol-5-yl)phenols, has been effi-
ciently synthesized through the regioselective reaction of
2-aryl-3-methylchromones with hydroxylamine. The prod-
ucts were characterized by spectroscopic methods and
X-ray crystallography.
1-phenethylpiperidine, which has been reported to exhibit
significant antipsychotic activity [8] (Fig. 1).
Several methods have been developed for the con-
struction of isoxazole rings, including the reaction of
1,3-dicarbonyl compounds with hydroxylamine [9–14],
1,3-dipolar cycloaddition [15–20], Claisen condensation of
ketoximedianions [21, 22], cyclizations of propargylic
oximes [23, 24], oxidation of isoxazolines [25–28], and a
gold-catalyzed domino reaction of alkynyloxime ethers
[29]. However, most of these methods suffer from poor
chemo- and regioselectivities, drastic reaction conditions,
expensive reagents, and low yields.
Keywords 2-(3-Aryl-4-methylisoxazol-5-yl)phenols Á
2-Aryl-3-methyl-4H-chromen-4-ones Á
Hydroxylamine hydrochloride Á Regioselectivity
Introduction
Another way to prepare isoxazoles is through the reac-
tion of chromone derivatives (such as flavones) with
hydroxylamine hydrochloride, which might be expected to
form two isomeric isoxazoles: 2-(isoxazol-5-yl)- and
2-(isoxazol-3-yl)phenols. The predominant formation of
one isomer depends on the substituents on the pyrone rings
and the reaction conditions. For instance, 2,3-unsubstituted
chromones in ethanol [30], 2-unsubstituted isoflavones
[31], and 2-hetarylchromones [32] in pyridine react with
hydroxylamine hydrochloride to give mixtures of the two
isomeric isoxazoles. On the other hand, reactions of
NH2OHÁHCl with 2-unsubstituted isoflavones in ethanol
and in the presence of N-methylmorpholine [31] and with
3-aryl-2-methylchromones in pyridine [33, 34] form only
2-(isoxazole-5-yl)phenol derivatives.
The isoxazole nucleus has been widely used as key building
block for pharmaceutical agents. Isoxazole derivatives dis-
play anti-inflammatory [1], antiviral [2, 3], and antiprotozoal
properties [4], as well as useful activities in anti-hypergly-
cemic and lipid lowering [5]. Specifically, isoxazoles bearing
methyl moieties have been shown to possess significant
pharmacological applications. For example, valdecoxib [6]
and disoxaril [7] are well-known anti-arthritis and anti-rhi-
novirus drugs with the methylisoxazole structure. Another
example is 4-[3-(4-chlorophenyl)-4-methylisoxazol-5-yl]-
P. D. Lokhande Á K. Hasanzadeh (&)
Department of Chemistry, University of Pune,
Pune 411007, India
In this paper, we wish to report the reaction of the 2-aryl-
3-methyl-4H-chromen-4-ones 4a–4j with hydroxylamine
hydrochloride in KOH/MeOH, leading to the exclusive
formation of 2-(3-aryl-4-methylisoxazol-5-yl)phenols with
excellent yields. To the best of our knowledge, there is no
previous report of the synthesis of 2-(3-aryl-4-methylisox-
azol-5-yl)phenols, and reports on the preparation of
4-methylisoxazole derivatives are very rare in the literature.
e-mail: kamalhasanzade2001@yahoo.com
P. D. Lokhande
e-mail: pdlokhande@chem.unipune.ac.in
H. Khaledi Á H. M. Ali
Department of Chemistry, University of Malaya,
50603 Kuala Lumpur, Malaysia
123

238
P. D. Lokhande et al.
Fig. 1 Some examples of
methylisoxazoles with
pharmacological activity
SO2NH2
H3C
Cl
O
CH3
6
N
O
N
Ph
N
N
O
Ph
CH3
O
N
O
Valdecoxib
Disoxaril
4-[3-(4-Chlorophenyl)-4-methyl-
isoxazol-5-yl]-1-phenethylpiperidine
Results and discussion
lower Rf value than the starting chromone. The IR spectrum
of the product shows a sharp absorption band due to O–H
1
Our approach to the synthesis of the methylisoxazoles
started from the condensation of substituted o-hydroxy-
propiophenones 1 with benzaldehydes 2 using sodium
methoxide in methanol (Scheme 1). The obtained
a-methylchalcones 3a–3j were purified and transformed
into the corresponding 2-aryl-3-methyl-4H-chromen-4-
ones 4a–4j using I2-DMSO according to our previous study
[35]. Compounds 4a–4j were then utilized for the reaction
with hydroxylamine hydrochloride to synthesize the
methylisoxazoles.
stretching at 3,526 cm-1, and its H NMR spectrum dis-
plays a D2O exchangeable broad peak at 6.24 ppm which is
assignable to the phenolic OH hydrogen. The compound is
soluble in 2N KOH solution but does not give any color
reaction with an alcoholic solution of ferric chloride. This
can be attributed to its inability to form a chelate involving
the phenol hydroxyl and the isoxazole N atom [31], which
is thus indicative of the formation of isomer 5i rather than
6i (Scheme 2). The structure of the product was further
established by single-crystal X-ray diffraction to be
2-(isoxazol-5-yl)phenol 5i. Figure 2 depicts the solid state
structure of 5i and Table 1 compiles selected bond lengths
and angles. The isoxazole ring makes dihedral angles of
38.99(6)ꢁ and 35.49(6)ꢁ with the phenol and the methoxy-
bearing phenyl rings, respectively. The hydroxyl group
makes an intramolecular hydrogen bond with the bromine
atom and an O–H…Ni hydrogen bond with the adjacent
molecule (symmetry code: i: -x ? 1, y - 1/2, -z ? 5/2).
Compound 4i was chosen as a model substrate to opti-
mize the reaction conditions. Suitable conditions for the
reaction were found to be 3 eq. KOH in refluxing metha-
nol, under which the starting chromone 4i was consumed
within 6 h. The reaction mixture was then neutralized by
dilute hydrochloric acid to give the product with an
excellent yield (92 %). TLC analysis suggested the for-
mation of only one methylisoxazole isomer, which had a
R3
Scheme 1
R4
R5
R1
R1
CHO
OH
OH
O
NaOMe/ MeOH
25-30 h, reflux
R3
R5
R2
Me
R2
Me
R4
O
3
1
2
I2 / DMSO, 110 o
15-20 min
C
1
3
5
2
4
a
: R = R = R = H, R = Cl, R = OMe
b: R1 = R3 = R5 = H, R2 = R4 = Cl
c: R1 = R2 = Cl, R3 = R4 = R5 = H
R3
d: R1 = R2 = Cl, R3 = R5 = H, R4 = OMe
e: R1 = R2 = Cl, R3 = R4 = OMe, R5 = H
f: R1 = R2 = Cl, R3 = R4 = R5 = OMe
g: R1 = R2 = R4 = Cl, R3 = R5 = H
R4
R5
R1
O
O
h: R1 = Br, R2 = Cl, R3 = R4 = R5 = H
i: R1 = Br, R2 = Cl, R3 = R5 = H, R4 = OMe
R2
Me
1
2
4
3
5
j
: R = Br, R = R = Cl, R = R = H
4
123

Regioselective synthesis of 3,5-diaryl-4-methylisoxazoles
239
R3
Scheme 2
O
OH
R2
N
R1
R4
Me
R5
R3
R4
R5
R1
1
6
O
2
3
7
8
NH2OH.HCl / MeOH
KOH (3eq), reflux
4
R2
6
Me
5
R3
O
N
O
OH
R1
4
R4
1
2
3
Me
R5
4
5
R2
5
f: R1 = R2 = Cl, R3 = R4 = R5 = OMe
a: R1 = R3 = R5 = H, R2 = Cl, R4 = OMe
b
c
d
e
: R1 = R2 = R4 = Cl, R3 = R5 = H
: R1 = R3 = R5 = H, R2 = R4 = Cl
: R1 = R2 = Cl, R3 = R4 = R5 = H
: R1 = R2 = Cl, R3 = R5 = H, R4 = OMe
: R1 = R2 = Cl, R3 = R4 = OMe, R5 = H
g
h
i
: R1 = Br, R2 = Cl, R3 = R4 = R5 = H
: R1 = Br, R2 = Cl, R3 = R5 = H, R4 = OMe
j: R1 = Br, R2 = R4 = Cl, R3 = R5 = H
Fig. 2 X-ray crystal structure
of 5i
Table 1 Selected geometric parameters for 5i
Under the same reaction conditions, various chromones
4 were then converted to the corresponding isoxazoles 5
1
with excellent yields (Scheme 2). H NMR analysis of the
˚
Interatomic distances/A
Br(1)–C(2)
Cl(1)–C(4)
O(1)–C(1)
1.889(2) O(3)–C(17)
1.746(2) N(1)–C(10)
1.352(3) C(6)–C(7)
1.363(2) C(7)–C(8)
1.405(2) C(8)–C(10)
1.367(3) C(10)–C(11)
1.428(3)
1.323(3)
1.468(3)
1.352(3)
1.431(3)
1.473(3)
products revealed that the conversion of the chromones to
the isoxazoles is accompanied by significant upfield shifts
(0.5–0.8 ppm) of C5–H, with the proton being deshielded
by the anisotropy of the carbonyl group in the chromones.
The formation of the 2-(3-aryl-4-methylisoxazol-5-
yl)phenols 5 can be considered to be the result of nucleo-
philic attack by the hydroxylamine nitrogen atom on the C2
atom of the chromones [36, 37]. Pyrone ring fission due to
the action of the base followed by recyclization of the
O(2)–C(7)
O(2)–N(1)
O(3)–C(14)
Bond angles/ꢁ
C(14)–O(3)–C(17) 117.86(18) O(2)–C(7)–C(6)
117.09(18)
C(10)–N(1)–O(2)
106.32(16) N(1)–C(10)–C(11) 119.89(19)
123

240
P. D. Lokhande et al.
Scheme 3
HO
HO
NH2
Ar
NH
O
O
O
Ar
O
H2N OH
OH
R
Ar
Me
R
R
Me
Me
O
O
OH
OH
OH
OH
O
-H2O
H
R
R
R
O
O
O
N
O
N
Me
NH
Me
Me
H
Ar
Ar
Ar
intermediate in an acidic medium leads to the formation of
the 2-(3-aryl-4-methylisoxazol-5-yl)phenols 5 (Scheme 3).
In order to synthesize the regioisomer of these trisub-
stituted isoxazoles, we attempted to prepare isoxazolines
by the reaction of a-methylchalcones 3 with hydroxyl-
amine hydrochloride in refluxing methanol or a KOH/
MeOH system, but under these conditions the chalcones
gave mixtures of products which we were unable to sepa-
rate and characterize. A similar observation has been
reported by Huang and Katzenellenbogen [38] for the
reactions of the a-methylchalcones 3 with phenylhydr-
azine.
layer chromatography (TLC) was performed on silica gel
60 PF254 plates or aluminum oxide plates from Merck
(Darmstadt, Germany). Elemental analyses were performed
on a Thermo Fisher (Waltham, MA, USA) FlashEA 1112
analyzer. The parent 5-chloro-2-hydroxypropiophenone
and 3,5-dichloro-2-hydroxypropiophenone compounds
were synthesized from p-chloro- and 2,4-dichlorophenol,
respectively, by Fries rearrangement using propionyl
chloride and AlCl3 [39]. 3-Bromo-5-chloro-2-hydro-
xypropiophenone was synthesized by the bromination of
5-chloro-2-hydroxypropiophenone using bromine in acetic
acid [39].
General procedure for the preparation of the 3-aryl-1-
(2-hydroxyaryl)-2-methylprop-2-en-1-ones 3a–3j
Conclusion
To a solution of 2-hydroxypropiophenone 1 (1.0 mmol)
and benzaldehyde 2 (1.0 mmol) in 40 cm3 methanol,
sodium methoxide (3.0 mmol) was added. The reaction
mixture was refluxed for 25–30 h. After neutralization by
dilute hydrochloric acid, the 3-aryl-1-(2-hydroxyaryl)-2-
methylprop-2-en-1-one 3 was precipitated. The solid
product was isolated by filtration and recrystallized from
methanol.
In summary, we have developed a regioselective and facile
protocol for the synthesis of the 2-(3-aryl-4-methylisox-
azol-5-yl)phenols 5a–5j through the reaction of the 2-aryl-
3-methyl-4H-chromen-4-ones 4a–4j with hydroxylamine.
The chromone substrates had themselves been easily pre-
pared via the cyclization-oxidation of a-methylchalcones.
Experimental
1-(5-Chloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)-2-
methylprop-2-en-1-one (3a, C17H15ClO3)
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded on a Varian (Palo Alto, CA, USA) VXR 300
instrument at 293 K in DMSO-d6. Chemical shift values
were recorded in d units (ppm) relative to Me4Si used as an
internal standard. Melting points were determined using a
Bu¨chi (Flawil, Switzerland) melting point apparatus.
Infrared spectra were recorded using KBr pellets on a
PerkinElmer (Waltham, MA, USA) 240C analyzer. Mass
spectra were recorded in an AE-IMS-30 spectrometer. Thin
Yield: 82 %; M.p.: 89–90 ꢁC; IR (KBr): vꢀ = 3,451, 3,061,
1
2,982, 1,678, 1,595 cm-1; H NMR (CDCl3): d = 2.26 (s,
3H), 3.88 (s, 3H), 6.96–7.01 (m, 4H), 7.44 (d, J = 9 Hz,
2H), 7.48 (dd, J1 = 8.1 Hz, J2 = 2.4 Hz, 1H), 7.61 (d,
J = 2.4 Hz, 1H), 12.12 (s, 1H) ppm; 13C NMR (CDCl3):
d = 15.4, 55.8, 114.3, 115.9, 120.1, 123.3, 127.5, 129.4,
133.4, 132.2, 133.0, 141.6, 158.7, 160.8, 205.0 ppm; MS:
m/z (%) = 302 (M?), 287, 271, 195, 160, 156, 132, 147
(100), 101, 91, 77.
123

Regioselective synthesis of 3,5-diaryl-4-methylisoxazoles
241
1-(5-Chloro-2-hydroxyphenyl)-3-(4-chlorophenyl)-2-
methylprop-2-en-1-one (3b, C16H12Cl2O2)
d = 2.31 (s, 3H), 3.93 (s, 6H), 3.94 (s, 3H), 6.70 (s, 2H),
7.04 (s, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.67 (d, J = 2.7 Hz,
1H), 12.12 (s, 1H) ppm; 13C NMR (CDCl3): d = 15.2, 56.1,
60.8, 107.4, 120.3, 123.0, 123.8, 129.8, 130.1, 134.3, 135.1,
138.6, 140.7, 153.1, 156.8, 201.9 ppm; MS: m/z (%) = 396
(M?), 361, 345, 208, 194, 193, 189 (100), 166, 72, 57.
Yield: 84 %; M.p.: 95–96 ꢁC; IR (KBr): vꢀ = 3,441, 3,056,
1
2,991, 1,681, 1,587 cm-1; H NMR (CDCl3): d = 2.29 (s,
3H), 6.98 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.38–7.45 (m,
4H), 7.50 (dd, J1 = 7.8 Hz, J2 = 1.9 Hz, 1H), 7.56 (d,
J = 1.9 Hz, 1H), 12.01 (s, 1H) ppm; 13C NMR (CDCl3):
d = 15.5, 117.1, 119.8, 123.8, 123.9, 128.8, 133.4, 133.5,
134.7, 135.1, 138.6, 141.2, 159.0, 199.7 ppm; MS: m/z
(%) = 306 (M?), 291, 195, 155, 151 (100), 123, 120, 95, 77.
3-(4-Chlorophenyl)-1-(3,5-dichloro-2-hydroxyphenyl)-2-
methylprop-2-en-1-one (3g, C16H11Cl3O2)
Yield: 78 %; M.p.: 118–119 ꢁC; IR (KBr): vꢀ = 3,441,
3,056, 2,989, 1,688, 1,591 cm-1 1H NMR (CDCl3):
;
1-(3,5-Dichloro-2-hydroxyphenyl)-2-methyl-3-
phenylprop-2-en-1-one (3c, C16H12Cl2O2)
d = 2.25 (s, 3H), 6.93 (s, 1H), 7.36–7.46 (m, 4H), 7.59
(d, J = 2.1 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 12.08 (s,
1H) ppm; 13C NMR (CDCl3): d = 15.3, 121.4, 122.6,
124.6, 128.1, 128.2, 129.8, 132.0, 135.1, 135.8, 138.4,
139.7, 161.2, 201.5 ppm; MS: m/z (%) = 340 (M?), 325,
229, 189, 161, 154, 151 (100), 133, 99, 76.
Yield: 79 %; M.p.: 139–140 ꢁC; IR (KBr): vꢀ = 3,408,
3,064, 3,024, 2,958, 1,693, 1,616, 1,577 cm-1; H NMR
1
(CDCl3): d = 2.28 (s, 3H), 7.00 (s, 1H), 7.27–7.34 (m,
5H), 7.59 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H),
12.14 (s, 1H) ppm; 13C NMR (CDCl3): d = 14.8, 120.2,
122.1, 123.5, 127.9, 128.8, 133.9, 134.3, 134.6, 135.1,
137.6, 138.5, 158.0, 198.9 ppm; MS: m/z (%) = 306 (M?),
291, 225, 188, 160, 153, 118 (100), 97, 91, 77.
1-(3-Bromo-5-chloro-2-hydroxyphenyl)-2-methyl-3-
phenylprop-2-en-1-one (3h, C16H12BrClO2)
Yield: 85 %; M.p.: 115–116 ꢁC; IR (KBr): vꢀ = 3,452,
3,043, 2,983, 1,685, 1,601 cm-1 1H NMR (CDCl3):
;
1-(3,5-Dichloro-2-hydroxyphenyl)-3-(4-methoxyphenyl)-2-
methylprop-2-en-1-one (3d, C17H14Cl2O3)
d = 2.27 (s, 3H), 7.02 (s, 1H), 7.31–7.35 (m, 5H), 7.68
(d, J = 2.7 Hz, 1H), 7.70 (d, J = 2.7 Hz, 1H), 12.10 (s,
1H) ppm; 13C NMR (CDCl3): d = 15.6, 115.9, 121.0,
124.4, 124.6, 127.3, 130.1, 132.5, 132.9, 133.2, 139.6,
141.2, 161.3, 203.4 ppm; MS: m/z (%) = 350 (M?), 335,
270, 245, 198, 117 (100), 76.
Yield: 82 %; M.p.: 108–109 ꢁC; IR (KBr): vꢀ = 3,432,
3,066, 2,980, 1,691, 1,653, 1,610 cm-1; 1H NMR (CDCl3):
d = 2.28 (s, 3H), 3.86 (s, 3H), 6.96–6.99 (m, 3H), 7.43 (d,
J = 8.7 Hz, 2H), 7.57 (d, J = 2.7 Hz, 1H), 7.62 (d,
J = 2.7 Hz, 1H), 12.06 (s, 1H) ppm; 13C NMR (CDCl3):
d = 15.1, 55.2, 114.0, 120.5, 122.8, 123.6, 127.3, 130.1,
131.6, 132.8, 134.8, 141.1, 156.7, 160.2, 201.9 ppm; MS:
m/z (%) = 336 (M?), 323, 321, 305, 229, 189, 148 (100),
133, 121, 103, 91, 77.
1-(3-Bromo-5-chloro-2-hydroxyphenyl)-3-
(4-methoxyphenyl)-2-methylprop-2-en-1-one
(3i, C17H14BrClO3)
Yield: 86 %; M.p.: 133–134 ꢁC; IR (KBr): vꢀ = 3,435,
3,043, 2,988, 1,671, 1,594 cm-1 1H NMR (CDCl3):
;
1-(3,5-Dichloro-2-hydroxyphenyl)-3-
(3,4-dimethoxyphenyl)-2-methylprop-2-en-1-one
(3e, C18H16Cl2O4)
d = 2.30 (s, 3H), 3.87 (s, 3H), 6.98-7.01 (m, 3H), 7.41
(d, J = 8.1 Hz, 2H), 7.69 (d, J = 3 Hz, 1H), 7.72 (d,
J = 3 Hz, 1H), 12.14 (s, 1H) ppm; 13C NMR (CDCl3):
d = 15.0, 55.1, 114.5, 114.9, 121.5, 123.1, 126.8, 129.3,
133.2, 133.4, 134.5, 139.8, 157.0, 161.4, 201.0 ppm; MS:
m/z (%) = 380 (M?), 365, 301, 273, 238, 233, 205, 148
(100), 101, 99, 77.
Yield: 78 %; M.p.: 128–129 ꢁC; IR (KBr): vꢀ = 3,416,
3,021, 2,986, 1,695, 1,610, 1,577 cm-1; 1H NMR (CDCl3):
d = 2.27 (s, 3H), 3.82 (s, 3H), 3.84 (s, 3H), 6.93 (d,
J = 8.4 Hz, 1H), 6.98 (s, 1H), 7.06 (d, J = 1.9 Hz, 1H),
7.21 (dd, J1 = 8.4 Hz, J2 = 1.9 Hz, 1H), 7.51 (d,
J = 2.4 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 12.29 (s, 1H)
ppm; 13C NMR (CDCl3): d = 14.8, 56.8, 58.2, 109.3,
114.7, 115.7, 120.3, 120.4, 125.0, 125.1, 127.5, 130.9,
133.4, 139.2, 151.6, 151.8, 160.3, 198.4 ppm; MS: m/z
(%) = 366 (M?), 351, 335, 218, 188, 178 (100), 163, 151,
115, 107, 91, 77.
1-(3-Bromo-5-chloro-2-hydroxyphenyl)-3-
(4-chlorophenyl)-2-methylprop-2-en-1-one
(3j, C16H11BrCl2O2)
Yield: 85 %; M.p.: 147–148 ꢁC; IR (KBr): vꢀ = 3,443,
3,029, 2,987, 1,686, 1,602, 1,522 cm-1; 1H NMR (CDCl3):
d = 2.21 (s, 3H), 6.96 (s, 1H), 7.39–7.48 (m, 4H), 7.68 (d,
J = 2.7 Hz, 1H), 7.72 (d, J = 2.7 Hz, 1H), 12.15 (s, 1H)
ppm; 13C NMR (CDCl3): d = 14.8, 116.2, 121.3, 124.5,
127.8, 128.0, 128.9, 131.8, 136.5, 136.6, 137.3, 140.7,
160.9, 202.3 ppm; MS: m/z (%) = 384 (M?), 369, 305,
241, 205, 198, 177, 150 (100), 99, 77.
1-(3,5-Dichloro-2-hydroxyphenyl)-2-methyl-3-(3,4,5-
trimethoxyphenyl)prop-2-en-1-one (3f, C19H18Cl2O5)
Yield: 87 %; M.p.: 143–144 ꢁC; IR (KBr): vꢀ = 3,436,
3,078, 2,971, 1,689, 1,614 cm-1 1H NMR (CDCl3):
;
123

242
P. D. Lokhande et al.
General procedure for synthesis of the 2-aryl-3-methyl-
4H-chromen-4-ones 4a–4j
161.8, 162.2, 178.1 ppm; MS: m/z (%) = 334 (M?), 319,
303, 227 (100), 192, 147, 93, 77, 56.
6,8-Dichloro-2-(3,4-dimethoxyphenyl)-3-methyl-4H-
chromen-4-one (4e, C18H14Cl2O4)
To a solution of 3-aryl-1-(2-hydroxyaryl)-2-methylprop-2-
en-1-one 3 (0.2 mmol) in 10 cm3 dimethyl sulfoxide was
added iodine (0.02 mmol). The reaction mixture was
heated at 110 ꢁC for 30 min. After cooling, the reaction
mixture was diluted with water and the untreated iodine
was removed by washing with a saturated solution of
sodium thiosulfate. The product was isolated by filtration
and recrystallized from ethanol.
Yield: 89 %; M.p.: 175–176 ꢁC; 1H NMR (CDCl3):
d = 2.24 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 7.01 (d,
J = 8.4 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.33 (dd,
J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 7.74 (d, J = 3 Hz, 1H),
8.12 (d, J = 3 Hz, 1H) ppm; 13C NMR (CDCl3): d = 11.6,
55.1, 56.4, 110.8, 113.7, 118.1, 118.8, 125.1, 126.9, 127.3,
129.7, 132.1, 134.3, 148.8, 149.2, 151.0, 161.8, 176.1 ppm;
MS: m/z (%) = 364 (M?), 349, 333 (100), 314, 302, 227,
187, 176, 145, 101, 63, 41.
6-Chloro-2-(4-methoxyphenyl)-3-methyl-4H-chromen-4-
one (4a, C17H13ClO3)
Yield: 94 %; M.p.: 153–154 ꢁC; IR (KBr): vꢀ = 3,067,
2,965, 1,639, 1,608, 1,511, 1,461 cm-1; 1H NMR (CDCl3):
d = 2.19 (s, 3H), 3.90 (s, 3H), 7.04 (d, J = 9 Hz, 2H), 7.42
(d, J = 8.7 Hz, 1H), 7.57–7.63 (m, 3H), 8.21 (d,
J = 2.1 Hz, 1H) ppm; 13C NMR (CDCl3): d = 11.9,
55.4, 113.8, 116.9, 119.5, 123.3, 125.1, 125.3, 130.3,
130.5, 133.4, 154.3, 161.1, 161.2, 177.7 ppm; MS: m/z
(%) = 300 (M?), 299 (100), 285, 269, 257, 222, 205, 194,
178, 146, 126, 103, 77, 63.
6,8-Dichloro-3-methyl-2-(3,4,5-trimethoxyphenyl)-4H-
chromen-4-one (4f, C19H16Cl2O5)
Yield: 95 %; M.p.: 187–188 ꢁC; IR (KBr): vꢀ = 3,071,
1
1,646, 1,595, 1,506 cm-1; H NMR (CDCl3): d = 2.24 (s,
3H), 3.93 (s, 6H), 3.95 (s, 3H), 6.94 (s, 2H), 7.71 (d,
J = 2.4 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H) ppm; 13C NMR
(CDCl3): d = 11.9, 56.3, 60.9, 106.6, 117.5, 123.8, 123.9,
127.6, 130.2, 133.1, 133.3, 140.1, 150.2, 153.1, 160.8,
177.0 ppm; MS: m/z (%) = 394 (M?), 379, 365, 363 (100),
349, 323, 321, 295, 293, 265, 249, 230, 191, 160, 148, 133,
97, 77, 63.
6-Chloro-2-(4-chlorophenyl)-3-methyl-4H-chromen-4-one
(4b, C16H10Cl2O2)
Yield: 92 %; M.p.: 198–199 ꢁC; 1H NMR (CDCl3):
d = 2.15 (s, 3H), 7.41 (d, J = 8.7 Hz, 1H), 7.51 (d,
J = 8.4 Hz, 2H), 7.58–7.62 (m, 3H), 8.21 (d, J = 2.4 Hz,
1H) ppm; 13C NMR (CDCl3): d = 11.8, 114.2, 117.1,
125.2, 126.8, 128.9, 129.1, 131.3, 131.4, 134.1, 135.6,
154.9, 160.8, 178.3 ppm; MS: m/z (%) = 304 (M?), 289,
269, 258, 224, 193, 150, 111 (10), 77, 61.
6,8-Dichloro-2-(4-chlorophenyl)-3-methyl-4H-chromen-4-
one (4g, C16H9Cl3O2)
Yield: 94 %; M.p.: 210–211 ꢁC; IR (KBr): vꢀ = 3,076,
1,651, 1,612, 1,597, 1,568, 1,498, 1,460, 1,359, 1,186,
;
1,130, 869, 783 cm-1 1H NMR (CDCl3): d = 2.19 (s,
3H), 7.52 (d, J = 9 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H),
7.71 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H) ppm;
13C NMR (CDCl3): d = 11.2, 114.1, 127.0, 128.4, 128.6,
128.7, 129.5, 129.6, 132.3, 136.5, 138.9, 153.5, 161.2,
179.3 ppm; MS: m/z (%) = 338 (M?), 323, 303, 288, 227,
187 (100), 152, 117, 98, 77.
6,8-Dichloro-3-methyl-2-phenyl-4H-chromen-4-one
(4c, C16H10Cl2O2)
Yield: 90 %; M.p.: 165–166 ꢁC; IR (KBr): vꢀ = 3,072,
1,647, 1,618, 1,597, 1,566, 1,458, 1,357, 1,182, 1,130,
;
1,078, 891, 773 cm-1 1H NMR (CDCl3): d = 2.21 (s,
3H), 7.54–7.56 (m, 3H), 7.70–7.73 (m, 3H), 8.12 (d,
J = 3 Hz, 1H) ppm; 13C NMR (CDCl3): d = 11.9, 113.5,
127.8, 128.0, 128.3, 129.4, 129.6, 129.7, 133.1, 133.4,
137.4, 151.7, 159.8, 176.5 ppm; MS: m/z (%) = 304 (M?),
289, 254, 227, 188, 153, 116 (100), 77, 43.
8-Bromo-6-chloro-3-methyl-2-phenyl-4H-chromen-4-one
(4h, C16H10BrClO2)
Yield: 94 %; M.p.: 170–171 ꢁC; IR (KBr): vꢀ = 3,070,
1,647, 1,618, 1,597, 1,562, 1,454, 1,359, 1,179, 1,130, 889,
769 cm-1; 1H NMR (CDCl3): d = 2.21 (s, 3H), 7.54–7.56
(m, 3H), 7.72–7.74 (m, 2H), 7.87 (d, J = 2.4 Hz, 1H), 8.17
(d, J = 2.4 Hz, 1H) ppm; 13C NMR (CDCl3): d = 11.6,
113.1, 116.0, 125.4, 128.5, 129.6, 129.7, 129.9, 131.7,
134.2, 137.9, 153.1, 161.8, 178.3 ppm; MS: m/z (%) = 350
([M ? 2]?), 348 (M?), 153, 115 (100), 100, 97, 77.
6,8-Dichloro-2-(4-methoxyphenyl)-3-methyl-4H-
chromen-4-one (4d, C17H12Cl2O3)
Yield: 91 %; M.p.: 168–169 ꢁC; IR (KBr): vꢀ = 3,074,
1,641, 1,610, 1,568, 1,512, 1,458, 1,356, 1,265, 1,182,
1,132, 1,026, 8,659, 777 cm-1
;
1H NMR (CDCl3):
8-Bromo-6-chloro-2-(4-methoxyphenyl)-3-methyl-4H-
chromen-4-one (4i, C17H12BrClO3)
d = 2.22 (s, 3H), 3.90 (s, 3H), 7.05 (dd, J1 = 6.9 Hz,
J2 = 1.8 Hz, 2H), 7.67–7.71 (m, 3H), 8.11 (d, J = 2.7 Hz,
1H) ppm; 13C NMR (CDCl3): d = 12.3, 55.6, 113.7, 116.4,
123.1, 127.5, 127.6, 127.9, 129.1, 131.4, 139.2, 151.6,
Yield: 93 %; M.p.: 181–182 ꢁC; IR (KBr): vꢀ = 3,076,
1,647, 1,612, 1,566, 1,510, 1,452, 1,365, 1,176, 1,124,
;
1,030, 879, 775 cm-1 1H NMR (CDCl3): d = 2.23 (s,
123

Regioselective synthesis of 3,5-diaryl-4-methylisoxazoles
243
3H), 3.90 (s, 3H), 7.06 (dd, J1 = 7.8 Hz, J2 = 2.1 Hz, 2H),
7.72 (dd, J1 = 6.6 Hz, J2 = 2.1 Hz, 2H), 7.85 (d,
J = 2.4 Hz, 1H), 8.16 (d, J = 3 Hz, 1H) ppm; 13C NMR
(CDCl3): d = 12.1, 55.6, 113.7, 113.9, 119.0, 123.1, 128.5,
128.6, 129.0, 133.2, 138.9, 153.4, 160.9, 162.2, 179.4 ppm;
MS: m/z (%) = 378 (M?), 363, 328, 299, 297, 271, 146
(100), 101, 77, 61.
2,4-Dichloro-6-(4-methyl-3-phenylisoxazol-5-yl)phenol
(5c, C16H11Cl2NO2)
Yield: 93 %; M.p.: 178–179 ꢁC; IR (KBr): vꢀ = 3,506,
3,082, 2,993, 1,624, 1,579 cm-1 1H NMR (CDCl3):
;
d = 2.19 (s, 3H), 6.35 (bs, 1H), 7.41 (d, J = 2.1 Hz,
1H), 7.48 (d, J = 2.1 Hz, 1H), 7.49–7.53 (m, 3H),
7.68–7.71 (m, 2H) ppm; 13C NMR (CDCl3): d = 8.3,
108.9, 119.3, 122.5, 123.1, 125.6, 126.3, 128.1, 129.3,
129.7, 132.1, 152.4, 160.1, 163.1 ppm; MS: m/z (%) = 319
(M?), 318, 244, 216, 199, 189, 160, 130, 104, 97, 77 (100),
63, 51.
8-Bromo-6-chloro-2-(4-chlorophenyl)-3-methyl-4H-
chromen-4-one (4j, C16H9BrCl2O2)
Yield: 95 %; M.p.: 209–210 ꢁC; 1H NMR (CDCl3):
d = 2.20 (s, 3H), 7.53 (d, J = 8.4 Hz, 2H), 7.68 (d,
J = 8.4 Hz, 2H), 7.88 (d, J = 2.7 Hz, 1H), 8.16 (d,
J = 2.4 Hz, 1H) ppm; 13C NMR (CDCl3): d = 11.4,
12.9, 119.1, 126.8, 126.9, 129.3, 129.8, 131.3, 133.1,
135.2, 137.3, 154.1, 159.6, 178.1 ppm; MS: m/z (%) = 384
([M ? 2]?), 382 (M?), 351, 347, 303, 268, 234, 206, 176,
149, 115 (100), 99, 97, 75, 62.
2,4-Dichloro-6-[3-(4-methoxyphenyl)-4-methylisoxazol-5-
yl]phenol (5d, C17H13Cl2NO3)
Yield: 93 %; M.p.: 155–156 ꢁC; IR (KBr): vꢀ = 3,520,
1
3,076, 2,972, 1,612 cm-1; H NMR (CDCl3): d = 2.40 (s,
3H), 3.89 (s, 3H), 7.06 (d, J = 9 Hz, 2H), 7.45 (d,
J = 3 Hz, 1H), 7.53 (d, J = 3 Hz, 1H), 7.66 (d,
J = 8.7 Hz, 2H), 9.95 (bs, 1H) ppm; 13C NMR (CDCl3):
d = 8.7, 56.1, 110.5, 114.1, 118.9, 121.5, 123.1, 125.8,
127.3, 127.5, 132.3, 153.5, 158.4, 159.0, 163.2 ppm; MS:
m/z (%) = 351 ([M ? 2]?), 349 (M?), 321, 306, 213, 188,
160, 135 (100), 108, 92, 77, 63.
General procedure for the synthesis of the 2-
(3-aryl-4-methylisoxazol-5-yl)phenols 5a–5j
To a solution of 2-aryl-3-methyl-4H-chromen-4-one 4
(0.01 mmol) and hydroxylamine hydrochloride (0.01 mmol)
in 50 cm3 methanol was added KOH (0.03 mmol). The
reaction mixture was refluxed for 6–7 h. After neutralizing
with dilute hydrochloric acid, the 2-(3-aryl-4-methylisoxazol-
5-yl)phenol 5 was precipitated. The solid product was isolated
by filtration and recrystallized from ethanol.
2,4-Dichloro-6-[3-(3,4-dimethoxyphenyl)-4-
methylisoxazol-5-yl]phenol (5e, C18H15Cl2NO4)
Yield: 96 %; M.p.: 179–180 ꢁC; IR (KBr): vꢀ = 3,468,
1
3,031, 2,988, 1,621 cm-1; H NMR (CDCl3): d = 2.20 (s,
3H), 3.95 (s, 6H), 6.34 (bs, 1H), 6.99 (d, J = 8.1 Hz, 1H),
7.23-7.28 (m, 2H), 7.40 (d, J = 1.8 Hz, 1H), 7.48 (d,
J = 2.4 Hz, 1H) ppm; 13C NMR (CDCl3): d = 8.9, 56.1,
58.4, 111.3, 113.8, 114.1, 119.4, 119.8, 121.3, 122.6,
123.1, 124.9, 133.8, 151.2, 152.0, 153.8, 158.1, 163.1 ppm;
MS: m/z (%) = 379 (M?), 348, 344, 329, 242, 216 (100),
199, 160, 137, 92, 76, 50.
4-Chloro-2-[3-(4-methoxyphenyl)-4-methylisoxazol-5-
yl]phenol (5a, C17H14ClNO3)
Yield: 91 %; M.p.: 207–208 ꢁC; IR (KBr): vꢀ = 3,459,
1
3,028, 2,992, 1,608 cm-1; H NMR (CDCl3): d = 2.27 (s,
3H), 3.88 (s, 3H), 6.68 (bs, 1H), 7.01–7.06 (m, 3H), 7.33
(dd, J1 = 9 Hz, J2 = 2.7 Hz, 1H), 7.42 (d, J = 2.7 Hz,
1H), 7.63 (d, J = 8.7 Hz, 2H) ppm; 13C NMR (CDCl3):
d = 8.7, 54.8, 110.3, 113.8, 116.2, 117.1, 121.3, 122.6,
128.9, 129.0, 130.5, 153.8, 159.9, 161.6, 162.9 ppm; MS:
m/z (%) = 315 (M?), 300, 284, 280, 263, 182 (100), 165,
155, 133, 128, 107, 77, 51.
2,4-Dichloro-6-[4-methyl-3-(3,4,5-trimethoxyphenyl)-
isoxazol-5-yl]phenol (5f, C19H17Cl2NO5)
Yield: 96 %; M.p.: 196–197 ꢁC; IR (KBr): vꢀ = 3,487,
3,120, 3,077, 2,989, 1,634 cm-1 1H NMR (CDCl3):
;
d = 2.19 (s, 3H), 3.92 (s, 3H), 3.93 (s, 6H), 6.29 (bs,
1H), 6.91 (s, 2H), 7.41 (d, J = 2.7 Hz, 1H), 7.49 (d,
J = 2.7 Hz, 1H) ppm; 13C NMR (CDCl3): d = 9.3, 56.2,
60.9, 105.5, 111.9, 117.2, 122.2, 124.2, 125.6, 128.5,
130.5, 139.2, 148.1, 153.4, 162.0, 163.3 ppm; MS: m/z
(%) = 409 (M?), 394, 366, 216, 206, 189 (100), 178, 162,
135, 109, 97, 66.
4-Chloro-2-[3-(4-chlorophenyl)-4-methylisoxazol-5-
yl]phenol (5b, C16H11Cl2NO2)
Yield: 96 %; M.p.: 229–230 ꢁC; IR (KBr): vꢀ = 3,478,
1
3,021, 2,991, 1,619 cm-1; H NMR (CDCl3): d = 2.25 (s,
3H), 6.58 (bs, 1H), 7.02 (d, J = 8.7 Hz, 1H), 7.34 (dd,
J1 = 8.85 Hz, J2 = 2.4 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H),
7.50 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H) ppm;
13C NMR (CDCl3): d = 8.3, 109.8, 116.2, 116.9, 122.4,
125.1, 127.5, 127.6, 128.1, 129.8, 133.8, 153.4, 159.0,
162.1 ppm; MS: m/z (%) = 319 (M?), 362, 208, 182 (100),
167, 137, 111, 97, 75, 63, 51.
2,4-Dichloro-6-[3-(4-chlorophenyl)-4-methylisoxazol-5-
yl]phenol (5g, C16H10Cl3NO2)
Yield: 95 %; M.p: 198–199 ꢁC; IR (KBr): vꢀ = 3,518,
1
3,082, 2,931, 1,599 cm-1; H NMR (CDCl3): d = 2.17 (s,
3H), 6.24 (bs, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.47 (d,
J = 2.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.65 (d,
J = 8.4 Hz, 2H) ppm; 13C NMR (CDCl3): d = 8.5,
123

244
P. D. Lokhande et al.
109.8, 118.3, 124.8, 125.9, 126.1, 126.3, 127.9, 128.3,
129.9, 132.5, 154.0, 157.9, 162.8 ppm; MS: m/z (%) = 353
(M?), 338, 318, 242, 216, 179, 137 (100), 111, 98, 75,
63, 51.
2-Bromo-4-chloro-6-[3-(4-chlorophenyl)-4-
methylisoxazol-5-yl]phenol (5j, C16H10BrCl2NO2)
Yield: 94 %; M.p.: 228–229 ꢁC; IR (KBr): vꢀ = 3,506,
1
3,045, 2,969, 1,622 cm-1; H NMR (CDCl3): d = 2.17 (s,
3H), 6.24 (bs, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.48 (d,
J = 8.7 Hz, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.65 (d,
J = 8.7 Hz, 2H) ppm; 13C NMR (CDCl3): d = 9.1,
113.0, 114.1, 117.2, 123.8, 125.6, 127.9, 128.3, 128.6,
132.1, 134.1, 154.8, 159.4, 162.8 ppm; MS: m/z (%) = 397
(M?), 382, 362, 319, 290, 260, 235, 179, 164, 137, 113,
111, 97, 75 (100), 63, 50.
2-Bromo-4-chloro-6-(4-methyl-3-phenylisoxazol-5-yl)-
phenol (5h, C16H11BrClNO2)
Yield: 94 %; M.p.: 155–156 ꢁC; IR (KBr): vꢀ = 3,497,
1
3,087, 2,989, 1,610 cm-1; H NMR (CDCl3): d = 2.19 (s,
3H), 6.35 (bs, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.49–7.53 (m,
3H), 7.62 (d, J = 2.1 Hz, 1H), 7.68–7.71 (m, 2H) ppm; 13
C
NMR (CDCl3): d = 9.1, 109.3, 113.8, 117.3, 126.4, 126.7,
127.5, 128.3, 128.9, 129.4, 132.4, 154.1, 159.8, 162.3 ppm;
MS: m/z (%) = 363 (M?), 382, 328, 286, 284, 260 (100),
205, 188, 126, 104, 77, 63, 51.
Crystallography
Diffraction data for 5i were measured with a Bruker
(Karlsruhe, Germany) SMART Apex II CCD area-detector
diffractometer (graphite-monochromated Mo-Ka radiation,
2-Bromo-4-chloro-6-[3-(4-methoxyphenyl)-4-
methylisoxazol-5-yl]phenol (5i, C17H13BrClNO3)
Yield: 92 %; M.p.: 168–169 ꢁC; IR (KBr): vꢀ = 3,526,
˚
k = 0.71073 A). The orientation matrix, unit-cell refine-
ment, and data reduction were all handled by the Apex2
software (SAINT integration, SADABS absorption cor-
rection [40]). The structure was solved using the direct
method in the program SHELXS-97 and refined by the full
matrix least-squares method on F2 with SHELXL-97 [41].
All non-hydrogen atoms were refined anisotropically. The
C-bound hydrogen atoms were placed at calculated posi-
tions, whereas the O-bound hydrogen atom, H1, was
located in a difference Fourier map and refined with an
1
3,074, 2,960, 1,612 cm-1; H NMR (CDCl3): d = 2.18 (s,
3H), 3.87 (s, 3H), 6.36 (bs, 1H), 7.03 (d, J = 8.7 Hz, 2H),
7.43 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.64
(d, J = 8.7 Hz, 2H) ppm; 13C NMR (CDCl3): d = 9.1,
55.3, 110.2, 113.7, 114.1, 118.3, 121.0, 126.8, 127.5,
127.6, 132.8, 152.7, 160.3, 162.9, 163.2 ppm; MS: m/z
(%) = 393 (M?), 362, 358, 315, 283, 286, 260, 237, 205,
133 (100), 108, 99, 63, 51.
˚
O–H distance restraint of 0.84(2) A. The molecule was
drawn using XSEED [42]. Crystal data and structural
refinement are summarized in Table 2. CCDC 842610
contains the supplementary crystallographic data for the
crystal. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: ?44 1223 336033;
or deposit@ccdc.cam.ac.uk).
Table 2 Crystal data and structural refinement for 5i
Parameter
Value
Empirical formula
Formula weight
C17H13BrClNO3
394.64
Temperature/K
100(2)
Crystal system, space group
Unit cell dimensions
Monoclinic, P 21/c
Acknowledgments The authors are thankful to Garware Research
Center, Pune, for spectral and elemental analysis. Financial support
from the University of Malaya is highly appreciated (ERGS grant no.
ER009-2011A).
˚
a/A
15.0859(6)
˚
b/A
7.7568(3)
˚
c/A
14.6543(6)
b/ꢁ
Volume/A
117.851(2)
3
˚
References
1516.19(10)
Z, density (calculated)/g cm-3
Crystal size/mm3
4, 1.729
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0.46 9 0.16 9 0.03
2.78–26.00
h range for data collection/ꢁ
Reflections collected/unique
Completeness
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To h = 26.00ꢁ: 100 %
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Final R indices [I [ 2r (I)]
R indices (all data)
1.041
R1 = 0.0249, wR2 = 0.0601
R1 = 0.0305, wR2 = 0.0624
123

Regioselective synthesis of 3,5-diaryl-4-methylisoxazoles
245
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