Convenient Approach to 3,4-Diarylisoxazoles Based on the Suzuki Cross-Coupling Reaction

Article abstract of DOI:10.1002/1615-4169(200212)344:10<1146::AID-ADSC1146>3.0.CO;2-1

The Suzuki cross-coupling reaction was found effective for rapid access to a series of 3,4-diarylisoxazoles of pharmacological interest. The efficiency of this approach was demonstrated by the synthesis of the highly potent COX-2-selective inhibitor, 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide (valdecoxib), and its analogues. Thus, the coupling reaction between (3-aryl-5-methyl-4-isoxazolyl)boronic acids, prepared in situ from the corresponding bromides using triisopropyl borate, and aryl bromides containing a 4-sulfonamide or 4-methylsulfonyl group under the standard conditions [Pd(PPh₃)₄, Na₂CO₃, EtOH-H₂O, reflux] yielded the target 3,4-diarylisoxazoles in good yields.

Full text of DOI:10.1002/1615-4169(200212)344:10<1146::AID-ADSC1146>3.0.CO;2-1

FULL PAPERS
Convenient Approach to 3,4-Diarylisoxazoles Based
on the Suzuki Cross-Coupling Reaction
J. S. Dileep Kumar,a, b ManKit M. Ho,a Jennifer M. Leung,a Tatsushi Toyokunia, c,*
a
Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology,
UCLA School of Medicine, Los Angeles, California 90095-1770, USA
Present address: Department of Psychiatry/Neuroscience, NYSPI/Columbia University, 1051 Riverside Drive,
b
New York, NY 10032, USA
Correspondence address: LA Tech Center, Department of Molecular and Medical Pharmacology,
c
UCLA School of Medicine, 6140 Bristol Parkway, Culver City, CA 90320, USA
Fax: ( ‡ 1)-310-670-8428, e-mail: ttoyokuni@mednet.ucla.edu
Received: June 25, 2002; Accepted: September 1, 2002
Abstract: The Suzuki cross-coupling reaction was corresponding bromides using triisopropyl borate,
found effective for rapid access to a series of 3,4- and aryl bromides containing a 4-sulfonamide or 4-
diarylisoxazoles of pharmacological interest. The methylsulfonyl group under the standard conditions
efficiency of this approach was demonstrated by the [Pd(PPh3)4, Na2CO3, EtOH-H2O, reflux] yielded the
synthesis of the highly potent COX-2-selective in- target 3,4-diarylisoxazoles in good yields.
hibitor, 4-(5-methyl-3-phenyl-4-isoxazolyl)benzene-
sulfonamide (valdecoxib), and its analogues. Thus,
the coupling reaction between (3-aryl-5-methyl-4- Keywords: COX-2 inhibitors; cross-coupling; 3,4-
isoxazolyl)boronic acids, prepared in situ from the diarylisoxazoles; heterocycles; Suzuki reaction
Introduction
availability of proper starting compounds containing
two aryl groups on adjacent carbons.[10] Krogsgaard-
A 3,4-diarylisoxazole scaffold has frequently been in- Larsen et al.[11] have recently reported the synthesis of 4-
corporated into the pharmacophore design for a wide aryl-3-isoxazolols by palladium-catalyzed cross-cou-
range of pharmaceutical agents. Some examples include pling reactions between O-protected 4-iodo-3-isoxazo-
non-steroidal anti-inflammatory drugs (NSAIDs),[1] lols and arylboronic acids. We have therefore inves-
proteins kinase inhibitors,[2] hypertensive agents[3] and tigated the feasibility of the Suzuki cross-coupling
estrogen receptor modulators.[4] The discovery of cyclo- reaction[12] for the direct arylation of the 4-position
oxygenase-2 (COX-2) in the beginning of the last of 3-arylisoxazoles, thus forming 3,4-diarylisoxazoles
decade has set off a race to develop selective COX-2 particularly 1 and its analogues. Such an approach is
inhibitors.[5] Selective COX-2 inhibitors are potential of particular interest in light of its amenability to
anti-inflammatory drugs with reduced side effects as synthesize 3,4-diarylisoxazoles by combinatorial meth-
compared to NSAIDs which are non-selective COX-1/ ods.[13]
COX-2 inhibitors.[6] From the evaluation of numerous
compounds, diarylheterocycles and diarylcarbocycles
with a 4-sulfonamide or 4-methylsulfonyl group in one
of the phenyl rings have been identified as the
O
O
pharmacophore for selective COX-2 inhibition.[5] Re-
cently, several diarylheterocycles comprised of the 3,4-
diarylisoxazole ring have shown extremely high COX-2
selectivity and potency, represented by 4-(5-methyl-
3-phenyl-4-isoxazolyl)benzenesulfonamide (valdecox-
ib)[7] (1) and 3-(4-methylsulfonylphenyl)-4-phenyl-5-
trifluoromethylisoxazole[8] (2) (Figure 1).
S
H3C
N
O
N
O
CH3
H2N
S
CF3
O
O
Valdecoxib (1)
2
Although several methods are available for the
synthesis of substituted isoxazoles,[9] selective methods
Figure 1. Highly potent COX-2-selective inhibitors com-
to 3,4-diarylisoxazoles are limited and depend on the prised of a 3,4-diarylisoxazole scaffold.
1146
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/02/34410-1146 1151 $ 17.50-.50/0
Adv. Synth. Catal. 2002, 344, No. 10

Approach to 3,4-Diarylisoxazoles Based on the Suzuki Cross-Coupling Reaction
FULL PAPERS
Results and Discussion
isfactory; the expected coupling reaction was preceded by
competitive protodeboronation. The two electron-with-
The 3-aryl-5-methylisoxazole 5[14]/7 was prepared from drawing groups on 13 might facilitate base-catalyzed
the known oxime 3[15]/4[15] according to the standard deboronation.[19] Interestingly, the 4,4'-dimethoxytrityl
procedure,[9] which involved generation of the 1,4- (DMT) group, used for the sulfonamide protection, was
dilithium salt and subsequent condensation with lost during the cross-coupling reaction.
EtOAc followed by dehydration (Scheme 1). Electro-
The coupling reaction was next investigated with the
philic bromination of 5/7 occurred predominantly at the (3-aryl-4-isoxazolyl)boronic acid 9/10 and aryl bromides
4-position of the isoxazole ring[16] affording 6[17]/8. A containing a 4-sulfonamide or 4-methylsulfonyl group[20]
sequence of metallation and treatment with triisopropyl under identical conditions as above (Table 2). In this
borate transformed 6/8 into the boronic acid 9/10.
way valdecoxib (1) as well as its known analogues 22[7a]
The Suzuki cross-coupling reaction was firstinvestigated and 23[7a] and new analogues 16, 24 and 25 were
using 6/8 and commercially available arylboronic acid 11/ synthesized in good yields simply by variation of
12 in aqueous EtOH using Na2CO3 as base and Pd(PPh3)4 coupling partners. In contrast to the arylboronic acid
(~3 mol %) as catalyst (Table 1). The reaction proceeded 13, the two electron-withdrawing groups on the aryl
efficiently leading to the formation of the desired 3,4- bromide 18 affected favorably the cross-coupling
diarylisoxazole 14/15 in good yield. However, the attempt reaction (i.e., the syntheses of 16 and 24).[21] The poor
to prepare the valdecoxib analogue 16 by the coupling yield of 21 might be ascribed to the possibility that
reaction of 6 and the arylboronic acid 13[18] was unsat- the vicinal nitro and sulfonamide groups on the aryl
bromide 19 were acting as a bidentate chelating ligand
for Pd, thus interfering with the catalytic cycle.[22] The
direct heteroarylation of 10 with commercially available
5-bromopyrimidine (26) was also successful affording 27
in good yield (Scheme 2).
R1
R
R
N
N
a
c
NOH
CH3
O
O
HO
R2
B
CH3
CH3
HO
3 R = H
4 R = F
Table 2. Suzuki cross-coupling reaction of (4-isoxazolyl)-
boronic acids and aryl bromides.
5 R1 = R2 = H
9 R = H
10 R = F
b
b
6 R1 = H, R2 = Br
7 R1 = F, R2 = H
8 R1 = F, R2 = Br
R3
Br
N
Scheme 1. Conditions: (a) (1) BuLi (~2 equiv.), THF,
À 40 8C, 30 min, (2) EtOAc, À 40 8C ! rt, 2 h, (3) H2SO4,
80 8C, 2 h (5: 46%; 7: 42%); (b) Br2, CCl4, 0 8C ! rt, 2 h
(6: 80%; 8: 70%); (c) (1) BuLi, THF, À 78 8C, 30 min, (2)
(i-PrO)3B, À 78 8C ! rt, 2h.
[a]
O
+
9/10
R1
S
R1
R2
CH3
S
O
R2
O
O
O
17–20
1, 16, 21–25
Table 1. Suzuki cross-coupling reaction of 4-bromoisoxazoles
and arylboronic acids.
4-Isoxazolyl- R1
boronic acid
R2
R3 Aryl bromide Product Yield [%][b]
R3
H
F
NH2
NH2
H
H
H
H
F
9
17
18
19
20
17
18
20
1
70
75
30
50
60
55
50
HO
OH
B
9
16
21
22
23
24
25
N
NO2 NH2
9
[a]
O
+
6/8
R1
R2
9
H
H
F
CH3
NH2
NH2
CH3
R1
10
10
10
CH3
R2
F
H
F
11–13
14–16
[a]
[b]
Pd(PPh3)4 (~3 mol %), Na2CO3, EtOH-H2O, reflux, 12 h.
Isolated yields based on aryl bromides and not optimized.
R1 R2
R3
4-Bromo-
isoxazole
Arylboronic
acid
Product
Yield [%][b]
6
8
6
H
H
F
F
H
F
11
14
15
60
65
F
H
12
Br
SO2NHX
H
13 (X = DMT[c]
)
16 (X = H) 10[d]
N
[a]
O
+
10
N
N
60%
[a]
[b]
Pd(PPh3)4 (~3 mol %), Na2CO3, EtOH-H2O, reflux, 12 h.
Isolated yields based on 4-bromoisoxazoles and not
optimized.
N
CH3
26
N
[c]
[d]
27
DMTˆ 4,4'-dimethoxytrityl.
2-Fluorobenzenesulfonamide was isolated as the major
product.
Scheme 2. Conditions: (a) Pd(PPh3)4 (~3 mol %), Na2CO3,
EtOH-H2O, reflux, 12 h.
Adv. Synth. Catal. 2002, 344, 1146 1151
1147

J. S. Dileep Kumar et al.
FULL PAPERS
Conclusions
5-Methyl-3-phenylisoxazole[14] (5) was similarly synthesized
from acetophenone oxime[15] (3) (2.7 g, 20.0 mmol) in 46%
overall yield. The intermediate 5-hydroxy-5-methyl-3-phenyl-
The Suzuki cross-coupling reaction has proven effective
for the synthesis of 3,4-diarylisoxazoles. This approach
could allow for the rapid construction of a library of
functionalized 3,4-diarylisoxazoles. Investigations along
this line, further optimization of the coupling conditions
and pharmacological evaluation of new valdecoxib
analogues are currently in progress.
1
2-isoxazoline was characterized by H NMR and HREIMS:
1H NMR (CDCl3): d ˆ 1.78 (s, 3H), 3.24 and 3.37 (AB q, 2H,
J ˆ 17 Hz), 3.63 (br s, 1H), 7.35 7.45 (m, 3H), 7.60 7.65 (m,
2H); HREIMS: calcd. for C10H11NO2: 177.0790; found:
177.0790.
Representative Procedure for the Bromination
of 5 and 7:4-Bromo-3-(4-fluorophenyl)-5-methyl-
isoxazole (8)
Experimental Section
A 10% (v/v) solution of Br2 in CCl4 (40 mL) was added
dropwise to a solution of 7 (885 mg, 5.0 mmol) in CCl4 (15 mL)
at 0 8C over a period of 1 h. The mixture was allowed to warm
to room temperature for 2 h. The mixture was then diluted with
10% (wt/wt) aqueous NaOH and the product was extracted
with CH2Cl2. The combined organic extracts were dried over
anhydrous MgSO4 and concentrated to dryness. Flash column
chromatography with hexanes-EtOAc (95:5, v/v) afforded 8 as
a colorless solid; yield: 900 mg (70%). 1H NMR (CDCl3): d ˆ
2.50 (s, 3H), 7.18 (br t, 2H, J ˆ 8.5 Hz), 7.80 7.90 (br dd, 2H,
J ˆ 8.5, 5.5 Hz); 19F NMR (CDCl3): d ˆ 76.56 (s); HREIMS:
calcd. for C10H8BrFNO: 255.9787; found: 255.9773.
General
THF and CH2Cl2 were distilled from sodium benzophenone
ketyl and CaH2, respectively, under a positive pressure of dry
argon. The Suzuki cross-coupling reaction and the reactions
1
below 0 8C were carried out under an argon atmosphere. H
and 19F{1H} NMR spectra were recorded on a Bruker AM360
in CDCl3 or CD3OD with TMS (for 1H) and CFCl3 (for 19F) as
internal standards. LRMS and HRMS were obtained on a VG
ZAB-SE (for FABMS) and a VG 70VSE (Autospec) (for
EIMS). Flash column chromatography was performed on ICN
silica gel 60 (0.032 - 0.063 mm). The purity ( > 98%) of the
products was checked by their 1H NMR spectra.[23]
4-Bromo-5-methyl-3-phenylisoxazole[17] (6) was similarly
synthesized from 5 (2.0 g, 12.6 mmol) in 80% yield.
Representative Procedure for the Synthesis of 3-Aryl-
5-methylisoxazoles 5 and 7:3-(4-Fluorophenyl)-5-
methylisoxazole (7)
Preparation of Arylboronic Acids 9 and 10
A solution of the corresponding bromide (i.e., 6 and 8)
(1 mmol) in THF (5 mL) was treated with a 2.5 M solution of
BuLi in hexanes (1.2 equiv.) at À 78 8C for 30 min. A solution
of triisopropyl borate (2 mL, 8.6 equiv.) in THF (5 mL) was
then added dropwise over a period of 20 min. The resulting
mixture was allowed to warm to room temperature over a
period of 2 h. The reaction was quenched by addition of brine
and the product was extracted with EtOAc. The combined
organic extracts were dried over anhydrous MgSO4 and
concentrated to dryness. The crude product was used directly
in the Suzuki cross-coupling reaction without further purifica-
tion and characterization.
A solution of 4'-fluoroacetophenone oxime[15] (4) (3.16 g,
20.7 mmol) in THF (20 mL) was treated with a 2.5 M solution
of BuLi in hexanes (17.6 mL, 44.0 mmol) at À 40 8C for
30 min. A solution of EtOAc (4.0 mL, 40.9 mmol) in THF
(6 mL) was then added dropwise over a period of 20 min. The
resulting mixture was allowed to warm to room temperature
for 2 h. The reaction mixture was diluted with EtOAc (50 mL)
and H2O (50 mL). The organic layer was separated, washed
with brine, dried over anhydrous MgSO4 and concentrated to
dryness. Flash column chromatography with hexanes-EtOAc
(4:1, v/v) afforded 3-(4-fluorophenyl)-5-hydroxy-5-methyl-2-
1
isoxazoline as a colorless solid; yield: 2.50 g (63%). H NMR
(CDCl3): d ˆ 1.77 (s, 3H), 3.22 and 3.33 (AB q, 2H, J ˆ 17 Hz),
7.07 (br t, 2H, J ˆ 8.5 Hz), 7.62 (br dd, 2H, J ˆ 8.5, 5.5 Hz). The
product was used in the next step without further character-
ization.
Preparation of the Arylboronic Acid 13
A solution of 4,4'-dimethoxytrityl chloride (1.1 g, 3.3 mmol) in
CH2Cl2 (20 mL) was added dropwise to a solution of 4-bromo-
2-fluorobenzenesulfonamide[20] (18) (760 mg, 3.0 mmol) and
Et3N (0.7 mL, 5.5 mmol) in CH2Cl2-THF (20 mL, 1:1, v/v) with
stirring at 0 8C. The resulting mixture was allowed to warm to
room temperature for 1 h. The reaction mixture was then
concentrated to dryness. Flash column chromatography with
hexanes-EtOAc (4:1, v/v) afforded 4-bromo-N-(4,4'-dime-
thoxytrityl)-2-fluorobenzenesulfonamide as a pale yellow solid;
yield: 1.67 g (95%). 1H NMR (CDCl3): d ˆ 3.75 (s, 6H), 5.91 (br
s, 1H), 6.65 (br d, 4H, J ˆ 8.5 Hz), 6.74 (t, 1H, J ˆ 8.0 Hz), 6.97
(br d, 1H, J ˆ 8.5 Hz), 7.10 7.35 (m, 8H), 7.42 (br d, 2H, J ˆ
7.5 Hz); 19F NMR: d ˆ 77.39 (s); HREIMS: calcd. for
C27H23BrFNO4S: 555.0515; found: 555.0513.
A mixture of the product thus obtained (2.0 g, 10.4 mmol)
and concentrated H2SO4 (30 mL) was heated at 80 8C for 2 h.
After cooling to room temperature, the mixture was poured
slowly into crushed ice and the product was extracted with
EtOAc. The combined organic extracts were dried over
anhydrous MgSO4 and concentrated to dryness. Flash column
chromatography with hexanes-EtOAc (9:1, v/v) gave 7 as a
colorless solid; yield 1.23 g (67%; 42% overall yield). 1H NMR
(CDCl3): d ˆ 2.48 (s, 3H), 6.26 (s, 1H), 7.13 (br t, 2H, J ˆ
8.5 Hz), 7.77 (br dd, 2H, J ˆ 8.5, 5.5 Hz); 19F NMR (CDCl3):
d 75.81 (s); HREIMS: calcd. for C10H8FNO: 177.0590; found:
177.0587.
1148
Adv. Synth. Catal. 2002, 344, 1146 1151

Approach to 3,4-Diarylisoxazoles Based on the Suzuki Cross-Coupling Reaction
FULL PAPERS
A solution of the bromide thus obtained (230 mg, 0.4 mmol)
in THF (10 mL) was treated with a 2.5 M solution of BuLi in
hexanes (0.44 mL, 1.1 mmol) at À 78 8C for 30 min. A solution
of triisopropyl borate (1.0 mL, 4.3 mmol) in THF (5 mL) was
then added dropwise and the mixture was allowed to warm to
room temperature over a period of 2 h. The reaction was
quenched by addition of saturated aqueous NH4Cl and the
product was extracted with EtOAc. The combined organic
extracts were washed with brine, dried over anhydrous MgSO4
and concentrated to dryness. The residue was subjected to
flash column chromatography using two sequential eluants,
i.e., hexanes-EtOAc (4:1, v/v) and then hexanes-EtOAc
(2:3, v/v).
ature, the mixture was diluted with brine and extracted with
EtOAc. The combined organic extracts were dried over
anhydrous MgSO4 and concentrated to dryness. Flash column
chromatography with hexanes-EtOAc (7:3, v/v) gave two
fractions.
The first fraction yielded 2-fluorobenzensulfonamide as a
white powder; yield: 33 mg. 1H NMR (CD3OD): d ˆ 7.29 (br q,
2H, J ˆ 8 Hz), 7.61 (br q, 1H, J ˆ 10 Hz), 7.86 (br t, 1H, J ˆ
7.5 Hz); 19F NMR (CD3OD): d ˆ 77.86 (s); HREIMS: calcd. for
C6H6FNO2S: 175.0103; found: 175.0108.
The second fraction afforded 16 as a colorless solid; yield:
7 mg (10% based on 6). The successful synthesis of 16 and its
physical data are given below.
The first eluant furnished N-(4,4'-dimethoxytrityl)-2-fluoro-
benzenesulfonamide as a pale yellow solid; yield: 100 mg
(51%). 1H NMR (CDCl3): d ˆ 3.73 (s, 6H), 5.92 (br s, 1H), 6.64
(br d, 4H, J ˆ 9 Hz), 6.83 (br t, 1H, J ˆ 7.5 Hz), 6,88 (br t, 1H,
J ˆ 7.5 Hz), 6.96 (br d, 1H, J ˆ 7.5 Hz), 7.15 7.35 (m, 8H), 7.42
Representative Procedure for the Suzuki Cross-
Coupling Reaction of 4-Isoxazolylboronic Acids and
(br d, 2H, J ˆ 7 Hz); 19F NMR (CDCl3): d ˆ 74.98 (s); Aryl/Heteroaryl Bromides:2-Fluoro-4-(5-methyl-3-
‡
LREIMS: m/z ˆ 477 (M ), 303 (4,4'-dimethoxytrityl).
phenyl-4-isoxazolyl)benzenesulfonamide (16)
The second eluant gave 13 as a pale yellow solid; yield:
120 mg (56%). 19F NMR (CDCl3): d ˆ 76.13 (s); LREIMS: m/
z ˆ 303 (4,4'-dimethoxytrityl). This product was used in the Su-
zuki cross-coupling reaction without further characterization.
A mixture of 9 (prepared using 1 mmol of 6 as de-
scribed above), 4-bromo-2-fluorobenzenesulfonamide[20] (18)
(150 mg, 0.59 mmol), Pd(PPh3)4 (20 mg, 0.017 mmol), EtOH
(6 mL) and 2 M aqueous Na2CO3 (1 mL) was refluxed for 12 h.
After cooling to room temperature, the mixture was diluted
with brine and extracted with EtOAc. The combined organic
extracts were dried over anhydrous MgSO4 and concentrated
to dryness. Flash column chromatography with hexanes-
EtOAc (3:2, v/v) afforded 16 as a colorless solid; yield:
Representative Procedure for the Suzuki Cross-
Coupling Reaction of 4-Bromoisoxazoles and
Arylboronic Acids:3-(4-Fluorophenyl)-5-methyl-4-
phenylisoxazole (15)
1
147 mg (75% based on 18). H NMR (CD3OD): d ˆ 2.47 (s,
3H), 7.07 7.15 (m, 2H), 7.30 7.45 (m, 5H), 7.83 (br t, 1H, J ˆ
7.5 Hz); 19F NMR (CD3OD): d ˆ 78.69 (s); HREIMS: calcd. for
C16H13FN2O3S: 332.0630; found: 332.0623.
A mixture of 8 (90 mg, 0.35 mmol), phenylboronic acid 12
(60 mg, 0.50 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol), EtOH
(6 mL) and 2 M aqueous Na2CO3 (1 mL) was refluxed for 12 h.
After cooling to room temperature, the mixture was diluted
with brine and extracted with EtOAc. The combined organic
extracts were dried over anhydrous MgSO4 and concentrated
to dryness. Flash column chromatography with hexanes-
EtOAc (7:3, v/v) afforded 15 as a colorless solid; yield: 58 mg
(65% based on 8). 1H NMR (CD3OD): d ˆ 2.39 (s, 3H), 7.03 (br
t, 2H, J ˆ 8.5 Hz), 7.15 (br dd, 2H, J ˆ 7.5, 1.5 Hz), 7.30 7.40
(m, 5H); 19F NMR (CD3OD): d ˆ 77.21 (s); HREIMS: calcd.
for C16H12FNO: 253.0903; found: 253.0904.
4-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonamide
(Valdecoxib)[7] (1) was similarly synthesized from 9 (prepared
from 1 mmol of 6) and 4-bromobenzenesulfonamide[20] (17)
(140 mg, 0.59 mmol) using Pd(PPh3)4 (20 mg, 0.017 mmol) as a
colorless solid; yield: 70% based on 17.
4-(5-Methyl-3-phenyl-4-isoxazolyl)-2-nitrobenzenesulfon-
amide (21) was similarly synthesized from 9 (prepared from
1 mmol of 6) and 4-bromo-2-nitrobenzenesulfonamide (19)
(165 mg, 0.59 mmol) using Pd(PPh3)4 (20 mg, 0.017 mmol) as a
1
colorless solid; yield: 30% based on 19. H NMR (CD3OD):
4-(4-Fluorophenyl)-5-methyl-3-phenylisoxazole (14) was
similarly synthesized from 6 (90 mg, 0.38 mmol) and 4-
fluorophenylboronic acid (11) (80 mg, 0.57 mmol) using
Pd(PPh3)4 (15 mg, 0.013 mmol) as a colorless solid; yield:
60% based on 6.1H NMR (CDCl3): d ˆ 2.35 (s. 3H), 6.97 (br t,
2H, J ˆ 8.5 Hz), 7.00 7.10 (m, 2H), 7.20 7.35 (m, 5H);
19F NMR (CDCl3): d ˆ 72.71 (s); HREIMS: calcd. for
C16H12FNO: 253.0903; found: 253.0907.
d ˆ 2.49 (s, 3H), 7.30 7.50 (m, 5H), 7.56 (dd, 1H, J ˆ 8.5,
1.8 Hz), 7.67 (d, 1H, J ˆ 1.8 Hz), 8.06 (d, 1H, J ˆ 8.5 Hz);
HREIMS: calcd. for C16H13N3O5S: 359.0576; found: 359.0572.
5-Methyl-4-[4-(methylsulfonyl)phenyl]-3-phenylisoxazole[7a]
(22) was similarly synthesized from 9 (prepared from 1 mmol
of 6) and 1-bromo-4-(methylsulfonyl)benzene (20) (140 mg,
0.60 mmol) using Pd(PPh3)4 (20 mg, 0.017 mmol) as a colorless
solid; yield: 50% based on 20.
4-[3-(4-Fluorophenyl)-5-methyl-4-isoxazolyl]benzenesulfon-
amide[7a] (23) was similarly synthesized from 10 (prepared from
1 mmol of 8) and 17 (140 mg, 0.59 mmol) using Pd(PPh3)4
(20 mg, 0.017 mmol) as a colorless solid; yield: 60% based on
17.
2-Fluoro-4-[3-(4-fluorophenyl)-5-methyl-4-isoxazolyl]ben-
zenesulfonamide (24) was similarly synthesized from 10
(prepared from 1 mmol of 8) and 18 (150 mg, 0.59 mmol)
using Pd(PPh3)4 (20 mg, 0.017 mmol) as a colorless solid; yield:
55% based on 18. 1H NMR (CDCl3): d ˆ 2.43 (s, 3H), 5.05 (br s,
2H), 6.90 7.05 (m, 4H), 7.31 (br dd, 2H, J ˆ 8.5, 5.5 Hz), 7.86
Attempt to Synthesize 2-Fluoro-4-(5-methyl-3-phenyl-
4-isoxazolyl)benzenesulfonamide (16) by the Suzuki
Cross-Coupling Reaction of 6 and 13
A mixture of 6 (52 mg, 0.22 mmol), 13 [190 mg, prepared using
0.6 mmol of 4-bromo-N-(4,4'-dimethoxytrityl)-2-fluorobenze-
nesulfonamide as described above], Pd(PPh3)4 (10 mg,
0.0086 mmol), EtOH (6 mL) and 2 M aqueous Na2CO3
(1 mL) was refluxed for 12 h. After cooling to room temper-
Adv. Synth. Catal. 2002, 344, 1146 1151
1149

J. S. Dileep Kumar et al.
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(t, 1H, J ˆ 8.0 Hz); 19F NMR (CDCl3): d ˆ 76.20 (s), 76.42 (s);
HREIMS: calcd. for C16H12F2N2O3S: 350.0537; found:
350.0541.
A. F. Shaffer, Y. Y. Zhang, B. S. Zweifel, K. Seibert, J.
Med. Chem. 2000, 43, 775 777.
[8] A. G. Habeeb, P. N. P. Rao, E. E. Knaus, Drug Dev. Res.
2000, 51, 273 286.
[9] P. Gr¸nanger, P. Vita-Finzi, in The Chemistry of Hetero-
cyclic Compounds, Vol. 49 (Eds.: E. C. Taylor, A.
Weissberger), John Wiley & Sons, New York, 1991,
pp. 125 264; for more recent methods, see: A. R.
Katritzky, M. Wang, S. Zhang, M. V. Voronkov, P. J.
Steel, J. Org. Chem. 2001, 66, 6787 6791, and references
cited therein.
3-(4-Fluorophenyl)-5-methyl-4-[4-(methylsulfonyl)phenyl]-
isoxazole (25) was similarly synthesized from 10 (prepared
from 1 mmol of 8) and 20 (140 mg, 0.60 mmol) using Pd(PPh3)4
(20 mg, 0.017 mmol) as a colorless solid; yield: 50% based on
20. 1H NMR (CD3OD): d ˆ 2.49 (s, 3H), 3.14 (s, 3H), 7.12 (br t,
2H, J ˆ 8.5 Hz), 7.40 (br dd, 2H, J ˆ 8.5, 5.5 Hz), 7.46 (br d, 2H,
J ˆ 8 Hz), 7.97 (br d, 2H, J ˆ 8 Hz); 19F NMR (CD3OD): d ˆ
75.92; HREIMS: calcd. for C17H14FNO3S: 331.0678; found:
331.0671.
3-(4-Fluorophenyl)-5-methyl-4-(5-pyrimidinyl)isoxazole (27)
was similarly synthesized from 10 (prepared from 1 mmol of 8)
and 5-bromopyrimidine (26) (95 mg, 0.60 mmol) using
Pd(PPh3)4 (20 mg, 0.017 mmol) as a colorless solid; yield:
60% based on 26. 1H NMR (CDCl3): d ˆ 2.46 (s, 3H), 7.01 (br t,
2H, J ˆ 8.5 Hz), 7.30 (br dd, 2H, J ˆ 8.5, 5.5 Hz), 8.51 (s, 2H),
9.15 (s, 1H); 19F NMR (CDCl3): d ˆ 76.38; HREIMS: calcd. for
C114H10FN3O: 255.0808; found: 255.0805.
[10] For example, the syntheses by Talley et al. (Ref.[7]) and
by Habeeb et al. (Ref.[8]) started from the 1,2-diaryl-
ethanone and 3,4-diaryl-3-buten-2-one derivatives, respec-
tively. Most of these starting compounds are not com-
mercially available and thereby need to be synthesized.
[11] H. Kromann, F. A. Sl˘k, T. N. Johansen, P. Krogsgaard-
Larsen, Tetrahedron 2001, 57, 2195 2201.
[12] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457
2483; b) A. Suzuki, J. Organometal. Chem. 1999, 576,
147 168; c) H. Grˆger, J. Prakt. Chem. 2000, 342, 334
339; d) R. E. Sammelson, M. J. Kurth, Chem. Rev. 2001,
101, 137 202; e) S. R. Chemler, D. Trauner, S. J. Dani-
shefsky, Angew. Chem. Int. Ed. 2001, 40, 4544 4568.
[13] Combinatorial approaches to isoxazoles have been
reported. However, these methods are not suitable for
the selective and rapid synthesis of 3,4-diarylsioxazoles.
See: a) A. L. Marzinzik, E. R. Felder, Molecules 1997, 2,
17 30; b) B. B. Shankar, D. Y. Yang, S. Girton, A. K.
Ganguly, Tetrahedron Lett. 1998, 39, 2447 2448; c) D.-
M. Shen, M. Shu, K. T. Chapman, Org. Lett. 2000, 2,
2789 2792.
[14] The compound 5 has been synthesized by different
methods. For example, see: a) M. Yokoyama, K. Tsuji,
M. Kushida, J. Chem. Soc. Perkin Trans. 1 1986, 67 72;
b) O. Moriya, Y. Urata, T. Endo, J. Chem. Soc. Chem.
Commun. 1991, 884 885; c) W. H. Bunnelle, P. R.
Singam, B. A. Narayanan, C. W. Bradshaw, J. S. Liou,
Synthesis 1997, 439 442.
[15] The oximes 3 and 4 were prepared from acetophenone
and 4'-fluoroacetophenone, respectively, see: B. J. Greg-
ory, R. B. Moodie, K. Schofield, J. Chem. Soc. B 1970,
338 346.
[16] Bromination of the isoxazole ring is known to occur
predominantly at the 4-position, see Ref.[9] pp. 337 340.
[17] S. D. Sokolov, T. N. Egorova, Khim. Geterotsikl. Soedin.
1974, 1697 1698; Chem. Abstr. 1974, 82, 97965.
[18] The boronic acid 13 was prepared from 18 by 4,4'-
dimethoxytritylation, followed by a sequence of metal-
lation and boration, and used without extensive charac-
terization (see Experimental Section).
[19] It is reported that arylboronic acids bearing electron-
withdrawing groups are prone to deboronation with
base, see: S. Saito, S. Oh-tani, N. Miyaura, J. Org. Chem.
1997, 62, 8024 8030, and references cited therein.
[20] The aryl bromides 17 and 20 are commercially available.
Other aryl bromides are known; for 18, see: D. Cheshire,
M. Stocks (Astra Pharmaceuticals Ltd.), WO 0018730,
2000; Chem. Abstr. 2000, 132, 265088; for 19, see: D. F.
Acknowledgements
This work was supported by a research grant from the National
Institutes of Health (CA86306). J.S.D.K. was supported by a
fellowship through the Norton Simon Fund at UCLA.
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Approach to 3,4-Diarylisoxazoles Based on the Suzuki Cross-Coupling Reaction
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[22] Heteroatoms which coordinate to transition metals are
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1
[23] Copies of the H NMR and 19F NMR spectra are avail-
able upon request.
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