A convenient synthesis of 5-alkylthio-3,4-diarylisoxazoles by palladium-catalyzed coupling reactions

Article abstract of DOI:10.1002/jhet.5570440227

(Chemical Equation Presented) Palladium-catalyzed coupling reaction was found effective for rapid access to pharmacologically interesting 3,4-diarylisoxazoles derivatives as selective COX-2 inhibitors. Thus, the coupling reaction between 5-alkylthio-3-ary

Full text of DOI:10.1002/jhet.5570440227

Mar-Apr 2007
449
A Convenient Synthesis of 5-Alkylthio-3,4-diarylisoxazoles by
Palladium-Catalyzed Coupling Reactions.
Roozbeh Eskandaria, Latifeh Navidpoura, Mohsen Aminia, Hamed Shafaroodib,
Abbas Shafiee*,a
aDepartment of Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center,
Tehran University of Medical Sciences,
Tehran 14174, Iran. ashafiee@ams.ac.ir
bDepartment of Pharmacology, Tehran Medical Unit, Islamic Azad University, Tehran, Iran
Received March 7, 2006
H3CO2S
H3CO2S
R'
Pd (PPh3)4 (3 mol%)
Na2CO3 (2M)
I
(HO)2B
+
N
N
DME, reflux
R'
SR
O
SR
O
Palladium-catalyzed coupling reaction was found effective for rapid access to pharmacologically
interesting 3,4-diarylisoxazoles derivatives as selective COX-2 inhibitors. Thus, the coupling reaction
between 5-alkylthio-3-aryl-4-iodoisoxazoles and arylboronic acids afforded the target 5-alkylthio-3,4-
diarylisoxazoles in good yields.
J. Heterocyclic Chem., 44, 449 (2007).
A 3,4-diarylisoxazole scaffold has frequently been
incorporated into the pharmacophore design for a wide
range of pharmaceutical agents [1]. Some examples
include non-steroidal anti-inflammatory drugs (NSAIDs)
[2], protein kinase inhibitors [3] and hypertensive agents
[4]. The discovery of cyclooxygenase-2 (COX-2) enzyme
in the beginning of the last decade has set off a race to
develop selective COX-2 inhibitors [5]. Selective COX-2
inhibitors are potential anti-inflammatory drugs with
reduced side effects as compared to NSAIDs which are
non-selective COX-1/COX-2 inhibitors [6].
H3CO2S
SO2NH2
N
N
CF3
CH3
O
O
(2)
Valdecoxib (1)
H3CO2S
R'
From the evaluation of numerous compounds, diaryl
heterocycles and diaryl carbocyles with a 4-sulfonamide
or 4-methylsulfonyl group in one of the phenyl rings have
been identified as the pharmacophore for selective COX-2
inhibition [5]. Several diaryl isoxazole rings have shown
extremely high COX-2 selectivity and potency,
represented by 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene-
sulfonamide, Valdecoxib, (Bextra ®) (1) [7] and 3-(4-
methylsulfonylphenyl)-4-phenyl-5-trifluromethyl-
N
SR
O
12, R: -CH3
R': F
13-17, R: -CH2CH3 R':H, F, Br, CH3, C2H5
Representative examples and designed 3,4-diarylisoxazoles
as COX-2 selective inhibitors.
Figure 1
isoxazole (2) [8] (Figure 1).
Whereas small lipophilic central ring substitutent (Me,
CF3) frequently enhances, or is often a requirement for
COX-2 selectivity [9], modification of them to find a new
ligand with improved properties is desirable.
Although several methods are available for the
synthesis of substituted isoxazoles [10], no selective
method to 5-alkylthio-3,4-diarylisoxazole is available in
the literature. Krogsgaard Larsen et al. [11] have recently
reported the synthesis of 4-arylisoxazololes by palladium-
catalyzed cross-coupling reactions between O-protected
4-iodo-3-isoxazololes and arylboronic acids. We have
therefore investigated the feasibility of the Suzuki cross-
coupling reaction for arylation of the 4-position of
5-alkylthio-3-aryl-4-iodoisoxazoles, in order to prepare
5-alkylthio-3,4-diarylisoxazoles 12-17. The synthetic
reactions used for the synthesis of 5-alkylthio-4-aryl-3-(4-
methylsulfonylphenyl)isoxazoles 12-17 are outlined in
Schemes 1-3.
5-Alkylthio-4-(4-methylsulfonylphenyl)isoxazoles 8/9 are
key intermediates for the production of the desired
compounds 12-17. The latter was prepared from ꢀ-
oxoketene dithioacetals. The ꢀ-oxoketene dithioacetal 4/5

450
R. Eskandari, L. Navidpour, M. Amini, H. Shafaroodi, A. Shafiee
Vol 44
was prepared from the known 4-methylsulfonylaceto-
phenone 3 [12] according to the standard procedure [13,14]
which involved treatment of 3 with NaH in benzene and
subsequent addition of CS2 and alkyl iodide (Scheme 1).
methylthio isomer) suggesting that the alkylthio group is
adjacent to the ring O-atom [15,16].
Iodination of C4 position of isoxazoles is
accomplished through the addition of iodine
monochloride in aqueous acetic acid solution [17]. The
polar medium induces heterolytic dissociation of ICl to
produce I+ species [18].
The activity of I+ species is so high that it could be used
for successful iodination of 8/9 at 20 °C, higher iodination
temperature of these substrates lead to mixture of higher
oxidized form of alkylthio group.
Each iodinated isoxazole prepared was characterized by
ir, 1H nmr and ms. The location of iodine was confirmed
by both the absence of the strong isoxazole C-H stretch at
ca. 3145-3149 cm-1 in the ir and the singlet for the C4
proton in the 1H nmr.
Compounds 10/11 are proper intermediates for
organometallic cross-coupling reaction. Since boronic
acids can tolerate a wide range of functional groups such
as alkylthio, aromatic cross-coupling can be obtained in
the presence of palladium catalyst with iodo derivatives
[19, 20].
Scheme 1
H3CO2S
H3CO2S
a
b
SR
SR
O
O
4, R: -CH3
5, R: -CH2CH3
3
H3CO2S
H3CO2S
SR
SR
SR
N
N
O
OH
6, R: -CH3
7, R: -CH2CH3
8, R: -CH3
9, R: -CH2CH3
Reagents and conditions: (a) NaH, benzene, 0 ºC, 2 hours, then CS2, alkyl
iodide, below 45 ºC, 24 hours; (b) NH2OH.HCl, Ba(OH)2, reflux, 4 hours.
The reaction of hydroxylamine hydrochloride with ꢀ-
oxoketene dithioacetal afforded highly regioselective 5-
alkylthioisoxazole. In this case ring closure performed by
using hydroxylamine hydrochloride and barium hydroxide
in boiling ethanol (pH = 5-9) via in-situ oxime 6/7
formation [15].
Many parameters have been studied such as base, the
solvent and the ionic additives for the improvement of
Suzuki coupling reaction. It is important to note that
influence of these parameters depend on the nature of the
substrate [21].
The Suzuki cross-coupling reaction between 10/11 and
commercially available arylboronic acids was performed
in a mixture of dimethoxyethane (DME) and aqueous
solution of Na2CO3 as base and Pd(PPh3)4 as catalyst
(Table1) [11].
A clear distinction of regioselectivity of above reaction
could be made by means of mass spectral fragmentation.
The
3-(4-methylsulfonylphenyl)-5-alkylthioisoxazole
showed characteristic peaks due to loss of –SR and
–COSR fragment (M-47 and M-75 in the case of 5-
Table 1
Suzuki cross-coupling of 5-alkythio-4-iodo-3-(4-methylsulfonylphenyl)isoxazole and
arylboronic acids and their anti-inflammatory activity.
H3CO2S
R'
N
SR
O
Compound
R
R´
Yield
Mp
(°C)
AI activitya
% inhibition
at 3 h
(%)
% inhibition
at 5 h
12
13
CH3
F
H
94
88
92
81
80
85
135-137
178-180
120-121
152-154
147-149
126-128
84.5 ± 1.1
84.2 ± 6.05
83.3 ± 1.3
n.t.b
63.3 ± 3.3
76.6 ± 12.3
82.5 ± 1.83
n.t.
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
14
15
F
Br
16
17
CH3
CH2CH3
74.6 ± 5.7
75.7 ± 3.7
70.53 ± 4.7
70.0 ± 6.4
63.0 ± 6.24
50.0 ± 2.5
celecoxib
a Inhibitory activity on carrageenan-induced rat paw edema. The results are expressed as mean ± SEM (n = 4-6) following a
50 mg/kg oral dose of the test compound. b not tested.

Mar-Apr 2007
A Convenient Synthesis of 5-Alkylthio-3,4-diarylisoxazoles
451
1-(4-Methylsulfonylphenyl)-3,3-bis-methylthio-propenone
(4). To an ice chilled solution of 4-methylsulfonylaceto-
phenone 3 [12] (19.8 g, 0.1 mole) in dry benzene (150 ml) was
added sodium hydride (8.0 g of a 60% in mineral oil, 0.2 mole).
Carbon disulfide (12.0 g, 0.15 mole) and methyl iodide (42.6 g,
0.3 mole) were added cautiously to the cold solution. N,N-
Dimethylacetamide (5 ml) was added dropwise while the
mixture was kept below 45º. After stirring for 24 hours at room
temperature, a small amount of crushed ice was added to the
heterogenous solution to consume any unreacted NaH. The
solvent was removed under reduced pressure, and the residue
was partitioned between water and dichloromethane. The
organic layer was washed with water, dried (Na2SO4), filtered
and evaporated to afford an oily residue which was crystallized
from ethanol to give 4 (24.2 g, 80%) as a yellow crystal, mp
174-176º; ir (potassium bromide): 1147, 1306 (SO2CH3), 1685
Scheme 2
H3CO2S
H3CO2S
I
N
N
SR
O
SR
O
10, R: -CH3
11, R: -CH2CH3
8, R: -CH3
9, R: -CH2CH3
Reagents and condition: ICl, HOAc, H2O, 20 ºC, 2 hours.
Scheme 3
H3CO2S
H3CO2S
R'
1
(C=O) cm-1; H nmr (deuteriochloroform): ꢀ 2.57 (s, 3H), 2.60
(s, 3H), 3.08 (s, 3H), 6.71 (s, 1H), 8.23 (d, J = 8.8 Hz, 2H), 8.07
(d, J = 8.8 Hz, 2H); ms: m/z 302 (M+, 32), 287 (92), 241 (9), 198
(32), 183 (100), 121 (74). Anal. Calcd. for C12H14O3S3: C, 47.66;
H, 4.67. Found: C, 47.51; H, 4.80.
(HO)2B
I
+
R'
N
N
SR
O
O
SR
1-(4-Methylsulfonylphenyl)-3,3-bis-ethylthiopropenone
(5). Compound 5 (26.4 g, 80%) was prepared following the
procedure described for 4 as an orange crystal, mp 147-148°; ir
(potassium bromide): 1151, 1307 (SO2CH3), 1610 (CO) cm-1; 1H
nmr (deuteriochloroform): ꢀ 1.41 (t, J = 7.2 Hz, 3H), 1.46 (t, J =
7.2 Hz, 3H), 3.08 (s, 3H), 3.10 (q, J = 7.2 Hz, 2H), 3.12 (q, J =
7.2 Hz, 2H), 6.75 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 8.06 (d, J =
8.4, 2H); ms: m/z 330 (M+, 18), 301 (100), 273 (4), 241 (15),
183 (34), 121 (7). Anal. Calcd. for C14H18O3S3: C, 50.88; H,
5.49. Found: C, 50.69; H, 5.63.
12, R: -CH3
10, R: -CH3
11, R: -CH2CH3
R': F
13-17, R: -CH2CH3
R':H, F, Br, CH3, C2H5
Reagents and condition: Pd(PPh3)4 (3 mol%), DME, reflux, 12 hours,
aqueous Na2CO3 (2 M).
The reaction proceeded efficiently leading to formation
of desired 5-alkylthio-4-aryl-3-(4-methylsulfonylphen-
yl)isoxazoles in good yields (Table1). These results have
paved the way for the synthesis of analogues of the 5-
alkylthio-3,4-diarylisoxazoles.
3-(4-Methylsulfonylphenyl)-5-methylthioisoxazole (8). To a
stirred suspension of Ba(OH)2.8H2O (151.2 g, 0.48 mole) in
EtOH (250 ml) was added hydroxylamine hydrochloride (22.4
g, 0.32 mole), followed by the addition of ꢁ-oxoketene
dithioacetal (4). The mixture was refluxed with stirring for 4
hours and then the solvent was removed under reduced pressure.
The residue was poured into ice/cold water (1500 ml) and this
mixture was acidified with diluted AcOH (5%, 120 ml). The
isoxazole was filtered and passed through a neutral alumina
column using EtOAc as solvent. The residue crystallized from
EtOAc/hexane gave 8 (11.2 g, 52%) as a yellow crystal, mp
142-143º; ir (potassium bromide): 1155, 1309 (SO2CH3), 1539
In vivo pharmacological evaluation of compounds 12-
14, 16 and 17 was carried out to assess their potential
anti-inflammatory activity. Qualitative structure-activity
relationship data, acquired using the anti-inflammatory rat
paw edema assay [22], showed this group of C-5 alkylthio
substituted 3,4-diarylisoxazoles exhibits anti-inflam-
matory activity with excellent activity range. In this
regards, these compounds reduced inflammation by 75-
85% and 63-82% at 3 and 5 h post drug administration,
respectively, relative to the reference drug celecoxib (70
and 50% reduction in inflammation at 3 and 5 h drug
administration, respectively), administered at the same
dose (see Table 1).
1
(C=N, isoxazole), 3149 (H4) cm-1; H nmr (deuteriochloroform):
ꢀ 2.66 (s, 3H), 3.10 (s, 3H), 6.44 (s, 1H), 7.98 (d, J = 8.4 Hz,
2H), 8.05 (d, J = 8.4 Hz, 2H). ms: m/z 269 (M+, 22), 222 (100),
194 (4), 143 (16). Anal. Calcd. for C11H11NO3S2: C, 49.05; H,
4.12; N, 5.20. Found: C, 49.23; H, 4.01; N, 5.37.
5-Ethylthio-3-(4-methylsulfonylphenyl)isoxazole (9).
Compound 9 (11.3 g, 50%) was prepared following the
procedure described for 8 as a yellow crystal, mp 112-113º; ir
(potassium bromide): 1148, 1299 (SO2CH3), 1537 (C=N,
EXPERIMENTAL
1
isoxazole), 3145 (H4) cm-1; H nmr (deuteriochloroform): ꢀ 1.44
(t, J = 7.2 Hz, 3H), 3.10 (s, 3H), 3.18 (q, J = 7.2 Hz, 2H), 6.52
(s, 1H), 7.98 (d, J = 6.8 Hz, 2H), 8.05 (d, J = 6.8 Hz, 2H); ms:
m/z 283 (M+, 75), 222 (100), 194 (5), 143 (52), 132 (24), 115
(11). Anal. Calcd. for C12H13NO3S2: C, 50.86; H, 4.62; N, 4.94.
Found: C, 50.71; H, 4.78; N, 4.77.
4-Iodo-3-(4-methylsulfonylphenyl)-5-methylthioisoxazole
(10). To a solution of 8 (38 mmoles) in AcOH (150 ml) and
water (180 ml) was added iodine monochloride (9.29 g, 57.2
mmoles). The solution was stirred for 24 hours at 20º and then
Melting points were determined with a Reichert-Jung hot-
stage microscope and are uncorrected. 1H nmr (400 MHz)
spectra were recorded on a Varian Utility plus 400 spectrometer
using deuteriochloroform or DMSO-d6 as solvent. Chemical
shifts (ꢀ) are reported in ppm relative to TMS as internal
standard. Infrared spectra were acquired on a Nicolet Magna
550-FT spectrometer. Mass spectra were obtained with a
Finnigan Mat TSQ-70 spectrometer. Elemental microanalyses
were within ± 0.4% of the theoretical values for C, H and N.

452
R. Eskandari, L. Navidpour, M. Amini, H. Shafaroodi, A. Shafiee
Vol 44
was added to 75 ml solution of Na2SO3 (10%), the precipitate
was filtered off and redissolved in acetone (120 ml). The solvent
was removed under reduced pressure and the residue was
crystallized from diethyl ether to give 10 (12.0 g, 80%) as a
white crystal, mp 157-160º (decomp.); ir (potassium bromide):
1153, 1308 (SO2CH3), 1503 (C=N, isoxazole) cm-1; 1H nmr
(deuteriochloroform): ꢀ 2.74 (s, 3H), 3.12 (s, 3H), 8.02 (d, J = 8
Hz, 2H), 8.08 (d, J = 8 Hz, 2H); ms: m/z 395 (M+, 34), 348
(100), 268 (10), 221 (85), 206 (37), 158 (33), 114 (20). Anal.
Calcd. for C11H10INO3S2: C, 33.43; H, 2.55; N, 3.54. Found: C,
33.60; H, 2.37; N, 3.66.
(2:20:80) afforded 14 (33.0 mg, 92%) as a white crystal, mp
120-121º; ir (potassium bromide): 1153, 1312 (SO2CH3), 1557
(C=N, isoxazole) cm-1; 1H nmr (deuteriochloroform): ꢀ 1.40 (t, J
= 7.2 Hz, 3H), 3.08 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 7.07-7.12
(m, 2H, H-Ar), 7.16-7.19 (m, 2H, H-Ar), 7.65 (d, J = 8.4 Hz,
2H), 7.94 (d, J = 8.4 Hz, 2H); ms: m/z 377 (M+, 57), 316 (100),
288 (38), 208 (18), 199 (41), 139 (17). Anal. Calcd. for
C18H16FNO3S2: C, 57.28; H, 4.27; N, 3.71. Found: C, 57.42; H,
4.10; N, 3.55.
4-(Bromophenyl)-5-ethylthio-3-(4-methylsulfonylphenyl)-
isoxazole (15). From 11 (40.5 mg, 0.1 mmole) following the
general procedure (in this case reflux continued for 36 hours),
flash chromatography AcOH-EtOAc-hexane (1:50:50) afforded
15 (35.5 mg, 81%) as a pale yellow crystal, mp 152-154º; ir
(potassium bromide): 1153, 1317 (SO2CH3), 1557 (C=N,
isoxazole) cm-1; 1H nmr (deuterio- chloroform): ꢀ 1.40 (t, J = 7.2
Hz, 3H), 3.08 (s, 3H), 3.25 (q, J = 7.2 Hz, 2H), 7.07 (dd, J =
8.0 Hz, 2H), 7.58 (t, J = 8.4 Hz, 4H), 7.95 (d, J = 8.0 Hz, 2H);
ms: m/z 439 (M+, 57), 437 (63), 378 (79), 376 (77), 350 (30),
348 (28), 300 (14), 201 (18), 199 (100), 190(17). Anal. Calcd.
for C18H16BrNO3S2: C, 49.32; H, 3.68; N, 3.20. Found: C, 49.50;
H, 3.51; N, 3.33.
5-Ethylthio-4-iodo-3-(4-methylsulfonylphenyl)isoxazole
(11). Compound 11 (11.0 g, 71%) was prepared following the
procedure described for 10 as a pale yellow crystal, mp 116-
118º; ir (potassium bromide): 1145, 1305 (SO2CH3), 1506 (C=N,
1
isoxazole) cm-1; H nmr (deuteriochloroform): ꢀ 1.47 (t, J = 7.2
Hz, 3H), 3.12 (s, 3H), 3.24 (q, J = 7.2 Hz, 2H), 8.02 (d, J = 8.4
Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H); ms: m/z 409 (M+, 34), 348
(100), 282 (14), 254 (13), 221 (84), 206 (26), 158 (23). Anal.
Calcd. for C12H12INO3S2: C, 35.22; H, 2.96; N, 3.42. Found: C,
35.10; H, 2.79; N, 3.61.
General procedure for Palladium-catalyzed Suzuki
coupling of 5-alkythio-4-iodo-3-(4-methylsulfonylphenyl)-
isoxazole (12-17). To a solution of 5-alkythio-4-iodo-3-(4-
methylsulfonylphenyl)isoxazole (10 and 11, 0.1 mmole) in DME
(5 ml) was added Pd(PPh3)4 (3.5 mg, 0.003 mmole). The
resulting solution was allowed to stir for 5 minutes and then to
this solution was added a 2 M aqueous solution of Na2CO3 (1
ml) and boronic acid (1.2 mmoles). The reaction was refluxed
for 12 hours. The mixture was cooled to room temperature and
was extracted with diethyl ether (5 ml). The organic phase was
washed with brine (5 ml), NaOH (2 M, 2ꢀ5 ml), brine (5 ml)
and dried (Na2SO4). The solvent was removed under reduced
pressure and the product was purified by flash chromatography
on silica gel using appropriate solvent.
5-Ethylthio-3-(4-methylsulfonylphenyl)-4-p-tolyl isoxazole
(16). From 11 (40.5 mg, 0.1 mmole) following the general
procedure,
flash
chromatography
AcOH-EtOAc-hexane
(2:20:80) afforded 16 (30.0 mg, 80%) as a white crystal, mp
147-149º, ir (potassium bromide): 1148, 1317 (SO2CH3), 1547
(C=N, isoxazole) cm-1; 1H nmr (deuteriochloroform): ꢀ 1.39 (t, J
= 7.6 Hz, 3H), 2.39 (s, 3H), 3.07 (s, 3H), 3.13 (q, J = 7.6 Hz,
2H), 7.07 (d, J = 8 Hz, 2H), 7.20 (d, J = 8 Hz, 2H), 7.67 (d, J =
8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H). ms: m/z 373 (M+, 44), 312
(96), 284 (55), 199 (100),135 (20). Anal. Calcd. for
C19H19NO3S2: C, 61.10; H, 5.13; N, 3.75. Found: C, 61.22; 5.22;
N, 3.55.
5-Ethylthio-4-(4-ethylphenyl)-3-(4-methylsulfonylphenyl)-
isoxazole (17). From 11 (40.5 g, 0.1 mmole) following the
general procedure, flash chromatography AcOH-EtOAc-hexane
(2:20:80) afforded 17 (33 mg, 85%) as a white crystal, mp 126-
128º; ir (potassium bromide): 1153, 1317 (SO2CH3), 1552 (C=N,
4-(4-Fluorophenyl)-3-(4-methylsulfonylphenyl)-5-methyl-
thioisoxazole (12). From 10 (39.5 mg, 0.1 mmole) following
the general procedure, flash chromatography AcOH-EtOAc-
hexane (1:25:75) afforded 12 (34.2 g, 94%) as a white crystal,
mp 135-137º; ir (potassium bromide): 1148, 1312 (SO2CH3),
1
isoxazole) cm-1; H nmr (deuteriochloroform): ꢀ 1.27 (t, J = 7.6
1
1557 (C=N, isoxazole) cm-1; H nmr (deuteriochloroform): ꢀ
Hz, 3H), 1.39 (t, J = 7.2 Hz, 3H), 2.69 (q, J = 7.6 Hz, 2H), 3.07
(s, 3H), 3.14 (q, J = 7.2 Hz, 2H), 7.10 (d, J = 8 Hz, 2H), 7.22 (d,
J = 8 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H);
ms: m/z 387 (M+, 29), 326 (61), 298 (35), 199 (100), 149 (19),
117 (29). Anal. Calcd. for C20H21NO3S2: C, 61.99; H, 5.46; N,
3.61. Found: C, 62.18; H, 5.30; N, 3.79.
2.66 (s, 3H), 3.08 (s, 3H), 7.10 (t, J = 8.8 Hz, 2H), 7.18 (dt, J =
2.4, 8.8 Hz, 2H), 7.64 (dd, J = 1.6, 6.4 Hz, 2H), 7.94(dd, J = 1.6,
6.4 Hz, 2H); ms: m/z 363 (M+, 69), 316 (100), 288 (64), 225
(36), 208 (52), 199 (75), 139 (38), 107 (73), 75 (74). Anal.
Calcd. for C17H14FNO3S2: C, 56.18; H, 3.88; N, 3.85. Found: C,
56.38; H, 4.02; N, 3.69.
Anti-inflammatory Assay. The test compounds were
evaluated using in vivo rat carrageenan-induced foot paw edema
model reported previously [22].
5-Ethylthio-3-(4-methylsulfonylphenyl)-4-phenylisoxazole
(13). From 11 (40.5 mg, 0.1 mmole) following the general
procedure,
flash
chromatography
AcOH-EtOAc-hexane
Acknowledgment. This research was supported by grants
from the research council of Tehran University of Medical
Sciences and Iran National Science Foundation (INSF).
(2:20:80) afforded 13 (31.6 mg, 88%) as a white crystal, mp
178-180º; ir (potassium bromide): 1143, 1312 (SO2CH3), 1542
(C=N, isoxazole) cm-1; 1H nmr (deuteriochloroform): ꢀ 1.40 (t, J
= 7.6 Hz, 3H), 3.07 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 7.18-7.21
(m, 2H), 7.38-7.40 (m, 3H), 7.66 (d, J = 8.4 Hz, 2H), 7.92 (d, J =
8.4 Hz, 2H). ms: m/z 359 (M+, 29), 298 (100), 270 (34), 207
(11), 199 (37), 190 (12), 121 (16), 89 (45). Anal. Calcd. for
C18H17NO3S2: C, 60.14; H, 4.77; N, 3.90. Found: C, 60.01; H,
4.89; N, 3.71.
REFERENCES
[1] J. S. Dileep Kumar, M. M. Ho, J. M. Leung and T. Toyokuni,
Adv. Synth. Catal., 344, 1146 (2002).
[2a] R.G. Micetich, C.-C. Shaw and R. B. Rastogi, Eur. Pat. Appl.
26928 (1981); Chem. Abstr., 95, 115518d (1981); [b] Y. Hagiwara, M.
Tanaka, A. Kajitani and S. Yasumoto, Jpn. Kokai Tokkyo Koho JP
03220180 (1991); Chem. Abstr., 116, 128944s(1992).
5-Ethylthio-4-(flurophenyl)-3-(4-methylsulfonylphenyl)is-
oxazole (14). From 11 (40.5 g, 1 mmole) following the general
procedure,
flash
chromatography
AcOH-EtOAc-hexane

Mar-Apr 2007
A Convenient Synthesis of 5-Alkylthio-3,4-diarylisoxazoles
453
[10] A. R. Kartizky, M. Wang, S. Zhang, M. V. Voronkov and P.
J. Steel, J. Org. Chem., 66, 6787 (2001).
[11] H. Kormann, F. A. Slok, T. N. Johansen and P. Krogsgaard-
Larsen, Tetrahedron, 57, 2195 (2001).
[12] M. Therien, J. Y. Gauthier, Y. Leblanc, S. Leger, H. Perrier,
P. Prasit and Z. Wang, Syntheis, 12, 1778 (2001).
[13] K. T. Potts, M. J. Cipullo, P. Ralli and G. Theodoridis, J.
Org. Chem., 47, 3028 (1982).
[14a] H. Junjappa, H. Ila and C. V. Askan, Tetrahedron, 456, 5423
(1990); [b] R. K. Dieter, Tetrahedron, 42, 3029 (1986).
[15] M. L. Purkayastha, H. Ila and H. Junjappa, Synthesis, 1989,
20-24.
[3a] N. Minami, M. Sato, K. Hasumi, N. Yamamoto, K. Keino, T.
Matsui, A. Kaneda, S. Ota, N. Saito, S. Sato, A. Asadori, S. Doi, M.
Kobayashi, J. Sato and S. Asano, Jpn. Kokai Tokkyo Koho JP
2000086657 (2000); Chem. Abstr., 132, 251139r (2000); [b] J. Green, G.
Bemis, A.-L. Grillot, M. Ledeboer, F. Salituro, E. Harrington, H. Gao,
C. Baker, J. Cao and M. Hale, WO 0112621 (2001); Chem. Abstr., 134,
178569r (2001).
[4] G. Dannhardt, P. Dominiak and S. Laufer, Arzneim.-Forsch.,
43, 441 (1993).
[5] G. Dannhardt and W. Kiefer, Eur. J. Med. Chem., 36, 109
(2001).
[6] C. A. Rouzer and L. J. Marnett, Chem. Rev., 103, 2239
(2003).
[16] T. Nishiwaki, Tetrahedron, 25, 747 (1969).
[17] S. M. Hubig, W. Jung and J. K. Kochi, J. Org. Chem., 59, 6233
(1994).
[18] F. Fairbrother, J. Chem. Soc., 847 (1936).
[19] A. R. Martin and Y. Yang, Acta Chem. Scand., 47, 221 (1993).
[20] W. J. Thompson and J. Gaudino, J. Org. Chem., 49, 5237 (1984).
[21a] J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire,
Chem. Rev., 102, 1359 (2002); [b] N. Miyaura and A. Suzuki, Chem.
Rev., 95, 2457 (1995); [c] S. P. Stanforth, Tetrahedron, 54, 263 (1998).
[22] C. A. Winter, E. A. Risley and G. W. Nuss, Proc. Soc. Exp.
Biol. Med. 111, 544 (1962).
[7a] J. J. Talley, US Pat. 5859257 (1999); Chem. Abstr., 130,
110269e (1999); [b] J. J. Talley, D. L. Brown, J. S. Carter, M. J.
Graneto, C. M. Koboldt, J. L. Masferrer, W. E. Perkins, R. S. Rogers, A.
F. Shaffer, Y. Y. Zhang, B. S. Zweifel and K. Seibert, J. Med. Chem.,
43, 775 (2000).
[8] A. G. Habeeb, P. N. P. Rao and E. E. Kanus, Drug. Dev.
Res., 51, 273 (2002).
[9] W. F. Hood, J. K. Gierse, P. C. Isakson, J. R. Kiefer, R.G.
Kurumbail, k. Siebert and J. B. Monahan, Mol. Pharmacol., 63, 870
(2003).