A convergent route to 5-(arylsulfanyl)-6-sulfonamido-3-benzofuranones

Article abstract of DOI:10.1055/s-2000-6396

A procedure for the synthesis of 5-(arylsulfanyl)-2,3-dihydro-6- sulfonamido-3-benzofuranones (1) via 5-bromo-3-methoxy-6-nitrobenzofuran (4) as a common advanced synthetic intermediate has been developed. The key step consists of a regioselective nucleophilic aromatic substitution of the bromine atom of 4 by an aryl or heteroarylthiol.

Full text of DOI:10.1055/s-2000-6396

PAPER
721
A Convergent Route to 5-(Arylsulfanyl)-6-sulfonamido-3-benzofuranones
Joan Bosch,*a Tomàs Roca,a Juan-Lorenzo Catena,a Carles Farrerons,b Ignasi Miquelb
a Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, E-08028-Barcelona, Spain
Fax +34(93)4021896; E-mail: jbosch@farmacia.far.ub.es
b R&D Centre, Labs. SALVAT, S.A., E-08950 Esplugues de Ll., Barcelona, Spain
Received 30 November 1999; revised 31 January 2000
With these difficulties in mind, we have developed a flex-
ible and efficient route to substituted 3-benzofuranones 1
from a common advanced synthetic intermediate, namely
5-bromo-6-nitrobenzofuran (4), formed in high yield by a
Abstract: A procedure for the synthesis of 5-(arylsulfanyl)-2,3-di-
hydro-6-sulfonamido-3-benzofuranones (1) via 5-bromo-3-meth-
oxy-6-nitrobenzofuran (4) as a common advanced synthetic
intermediate has been developed. The key step consists of a regiose-
lective nucleophilic aromatic substitution of the bromine atom of 4 Perkin-type cyclization.8 The synthesis starts from 4-ami-
no-5-bromo-2-methoxybenzoic acid (5)9 and is outlined in
by an aryl or heteroarylthiol.
Scheme 2. The crucial step is the nucleophilic aromatic
substitution of the bromine atom of 4 by an arylthiol. Sub-
sequent manipulation of the nitro substituent and the enol
ether functionality provides a variety of 5-(arylsulfanyl)-
6-sulfonamido-3-benzofuranones 1.
Key words: nucleophilic aromatic substitutions, heterocycles, ben-
zofuranones, sulfonamides, drugs
5-(Arylsulfanyl)-6-sulfonamidobenzofuran-3-ones
11
have been shown to be selective cyclooxygenase-2 (COX-
2) inhibitors,2 with a high antiinflammatory activity but
lacking the undesirable side effects of most traditional
nonsteroidal antiinflammatory drugs. There are relatively
few methods for the preparation of 3-benzofuranones.3
Among them, the intramolecular Friedel-Crafts acylation
of aryloxyacetic acid derivatives,4 a useful method for
the cyclization of arylpropionic acids (2, X = CH2) to the
corresponding 1-indanones 3,5,6 seemed a priori to be a
suitable method for the preparation of the target 3-benzo-
furanones 1. However, negligible or poor yields (0-10%)
were obtained in this cyclization for several substrates 2
(X = O), probably due to the easy decarbonylation7 of the
starting aryloxyacetic acid derivatives. Furthermore, this
route suffers from an additional synthetic drawback since
the arylsulfanyl substituent at position 5 is introduced in
the initial steps of the synthesis therefore, for each specific
compound 1, a complete synthetic sequence has to be de-
veloped.
Acid 5 was converted in 61% overall yield to diacid 6 in a
five step sequence consisting of diazotization with in situ
treatment of the diazonium salt with sodium nitrite in the
presence of copper powder, cleavage of the methoxy
group, esterification, alkylation of the phenolic hydroxy
group with ethyl bromoacetate, and finally alkaline hy-
drolysis of the resulting diester. The closure of the benzo-
furan ring was accomplished by treatment of diacid 6 with
a mixture of acetic acid, acetic anhydride and sodium ac-
etate to afford 3-acetoxybenzofuran 7 in 71% yield. Acid-
catalyzed methanolysis of 7 afforded the key intermediate
4 in 85% yield.
Reaction of 4 with a variety of arylthiols10 under basic
conditions gave the corresponding benzofurans 8 in ac-
ceptable to good yields (Scheme 2, Table 1).
OR
Br
Br
Br
CO2H
CO2H
OMe
vi
i-v
O
O2N
OCH2CO2H
H2N
O2N
vii
6
5
7 R= Ac
4 R= Me
Ar
O
X
S
Cl
Ar
S
OMe
Ar
S
O
Ar SH
viii
MeSO2NH
ix
2
O
O2N
O
RHN
8
9 R= H
Ar
S
x
O
1 R= MeSO2
1 X= O
3 X= CH2
Reagents and conditions: i) HBF4/NaNO2, 0°C, then Cu/NaNO2,
0°C, 75%; ii) 48% HBr/AcOH/Ac2O, D, 97%; iii) MeOH/concd
H2SO4, D, 85%; iv) BrCH2CO2Et/K2CO3/acetone, D, 98%; v) 1:1:1 2
N KOH/MeOH/dioxane, r.t., 99%; vi) AcOH/Ac2O/AcONa, D, 71%;
vii) 10:1 MeOH/35% HCl, D, 85%; viii) t-BuOK/t-BuOH, reflux, see
Table 1; ix) Fe/NH4Cl, 2:1 EtOH/H2O, D, 82-96%; x) MsCl/Et3N/
CH2Cl2, r.t., then 1:10 1 N KOH/THF, r.t., then 1:10 1 N KOH/EtOH,
45°C, 46-68%
X
MeSO2NH
this work
OMe
Br
+
Ar
SH
O
O2N
4
Scheme 2
Scheme 1
Synthesis 2000, No. 5, 721–725 ISSN 0039-7881 © Thieme Stuttgart · New York

722
J. Bosch et al.
PAPER
Table 1 5-(Arylsulfanyl)benzofurans 8 Prepared from the Com-
mon Intermediate 4
expressed in Hertz and signals are quoted as follows: s, singlet; d,
doublet; dd, doublet of a doublet; t, triplet; td, triplet of doublets; q,
quartet; m, multiplet; br s, broad singlet. Analytical TLC was car-
ried out on Merck silica gel 60 F254 plates, and the spots were locat-
ed with UV light. Flash chromatography was carried out on silica
gel (silica gel 60, SDS, 0.04-0.06 mm). Drying of organic extracts
during the work-up of reactions was performed over anhyd Na2SO4.
Evaporation of the solvents was accomplished under reduced pres-
sure with a rotatory evaporator. Microanalyses were performed on
a Carlo Erba 1106 analyzer by Centro de Investigación y Desarrollo
(CSIC), Barcelona.
Product
Aryl
Yield (%)
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
2-thiazolyl
70
50
60
35
52
54
21
28
30
67
56
71
28
30
59
40
38
37
18
56
61
50
56
61
62
4-methyl-2-thiazolyl
4-ethyl-2-thiazolyl
4-isopropyl-2-thiazolyl
1-methyl-2-imidazolyl
2-benzothiazolyl
3,5-dichloro-2-pyridyl
3-(trifluoromethyl)-2-pyridyl
5-(trifluoromethyl)-2-pyridyl
phenyl
3-fluorophenyl
4-fluorophenyl
2-fluorophenyl
3-chlorophenyl
4-Bromo-2-carboxy-5-nitrophenoxyacetic Acid (6)
Aq 4 M NaNO2 solution (140 mL) was added dropwise to an ice-
cooled solution of 59 (68.7 g, 279 mmol) in 20% HBF4 (350 mL).
The resulting mixture was stirred at 0 ºC for 30 min, and then was
added dropwise to a suspension of Cu powder (84.3 g, 1.32 mol)
and NaNO2 (253 g, 3.6 mol) in H2O (380 mL). After stirring for 3 h
at r.t. the mixture was filtered through Celite and the cake was
washed with EtOAc (200 mL) and 2 N HCl (50 mL). The organic
phase was successively washed with 2 N HCl (2 × 50 mL) and brine
(2 × 75 mL), dried, filtered, and concentrated to give 5-bromo-2-
methoxy-4-nitrobenzoic acid as a brown solid; yield: 58.4 g (75%).
4-chlorophenyl
3,4-dichlorophenyl
2,5-dichlorophenyl
2,3-dichlorophenyl
2-bromophenyl
2-chloro-4-fluorophenyl
2-(trifluoromethyl)phenyl
4-(trifluoromethyl)phenyl
4-(trifluoromethoxy)phenyl
2-ethylphenyl
8t
A solution of the above acid (36 g, 130 mmol) in AcOH (45 mL),
Ac2O (40 mL) and 48% HBr (100 mL) was refluxed for 6 h. After
addition of cold H2O (350 mL), the mixture was extracted with
EtOAc (3 × 150 mL). The organic extracts were dried, filtered, and
concentrated to give 5-bromo-2-hydroxy-4-nitrobenzoic acid as a
brown solid; yield: 33.2 g (97%).
8u
8v
8w
8x
8y
2-isopropylphenyl
A solution of this acid (33.2 g, 127 mmol) in MeOH (200 mL) and
concd H2SO4 (15 mL) was refluxed for 24 h. After cooling to 5 ºC,
H2O (200 mL) was added, and the resulting orange solid was crys-
tallized from MeOH; yield: 29.8 g (85%).
The reaction was general and worked well with diversely
substituted phenyl and heteroarylthiols. The enol ether
function present in 4 ensures that the SNAr process occurs
on the carbon atom linked to bromine. In contrast, at-
tempts to displace the bromine atom from the 3-benzo-
furanone formed by hydrolysis of 4 resulted in the
substitution of the nitro group due to the activation exert-
ed by the carbonyl group at the para position. Finally,
treatment of 8 with iron powder in aqueous ethanol under
slightly acidic conditions brought about both reduction of
the nitro group and hydrolysis of the enol ether function to
give the aminobenzofuranones 9 in 82-96% yield
(Scheme 2, Table 2). Sulfonylation with excess methane-
sulfonyl chloride, followed by two successive controlled
alkaline hydrolytic steps from the resulting N,N,O-
tris(methylsulfonyl) derivative provided the target 2,3-di-
hydro-3-benzofuranones 1 in 46-68% yield (Table 3).
A
suspension of the above methyl ester (24.9 g, 90.2 mmol),
K2CO3 (18.7 g, 135.3 mmol) and ethyl bromoacetate (12.6 mL,
108.2 mmol) in acetone (400 mL) was refluxed for 12 h. The inor-
ganic salts were filtered off, and the filtrate was concentrated in vac-
uo. Then, a solution of the crude product in EtOAc (300 mL) was
successively washed with saturated Na2CO3 (3 × 100 mL) and brine
(200 mL), dried, filtered, and concentrated to give ethyl-4-bromo-
2-(methoxycarbonyl)-5-nitrophenoxyacetate as an orange solid;
yield: 32 g (98%).
A solution of the above diester (32 g, 88.7 mmol) in a 1:1:1 mixture
of 2 N KOH/MeOH/dioxane (500 mL) was stirred at r.t. for 18 h.
The mixture was acidified with 2 N HCl and extracted with CH2Cl2
(3 × 250 mL). The organic extracts were dried, filtered, and con-
centrated to give diacid 6 as a brown solid; mp 200-202 °C; yield:
28.1 g (99%).
1H NMR (300 MHz, CDCl3): d = 4.76 (s, 2 H), 7.39 (s, 1 H), 8.23
(s, 1 H).
In conclusion, an efficient and convergent procedure for
the preparation of pharmacologically valuable 5-(arylsul-
13C NMR (75 MHz, CDCl3): d = 66.9, 106.2, 111.5, 125.5, 138.5,
151.9, 156.4, 164.7, 169.6.
fanyl)-2,3-dihydro-6-sulfonamido-3-benzofuranones
1
Anal. calcd for C9H6BrNO7 (320.9): C, 33.96; H, 1.88; N, 4.36.
Found: C, 33.65; H, 1.53; N, 4.63.
via a common advanced intermediate 4 has been devel-
oped. Taking advantage of both the activation at C-5 to-
wards the nucleophilic attack and the functionalization of
C-6, this intermediate may also provide a synthetic entry
to a variety of diversely 5-substituted and 5,6-disubstitut-
ed 3-benzofuranones.
3- Acetoxy-5-bromo-6-nitrobenzofuran (7)
A
solution of 6 (28.1 g, 87.6 mmol) and AcONa (11.4 g,
130.7 mmol) in AcOH (20 mL) and Ac2O (110 mL) was refluxed
for 4 h. After cooling to 5 °C, H2O (100 mL) was added, and the
brown solid was filtered; mp 109-111 °C; yield: 18.9 g (71%).
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H), 7.92 (s, 1 H), 8.03
Melting points were determined in a capillary tube and are uncor-
rected. NMR spectra were recorded on a Varian Gemini spectrom-
eter at 300 MHz (1H) and 75 MHz (13C). Coupling constants are
(s, 1 H), 8.26 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.6, 108.1, 110.2, 124.3, 125.8,
133.1, 138.7, 146.4, 149.4, 166.8.
Synthesis 2000, No. 5, 721–725 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convergent Route to 5-(Arylsulfanyl)-6-sulfonamido-3-benzofuranones
723
Anal. calcd for C10H6BrNO5 (300.1): C, 40.02; H, 2.01; N, 4.67.
Found: C, 39.75; H, 2.39; N, 4.30.
After stirring at reflux temperature for 4 h, the mixture was filtered
and the filtrate was concentrated to dryness. The residue was dis-
solved in EtOAc, and the organic phase washed with saturated
aqueous Na2CO3, dried, filtered, and concentrated to give the corre-
sponding benzofuranones 9a-y in 82-96% yield (Table 2).
5-Bromo-3-methoxy-6-nitrobenzofuran (4)
A solution of 7 (38 g, 126.6 mmol) in MeOH (250 mL) and 35%
HCl (25 mL) was refluxed for 6 h. The MeOH was evaporated, H2O
(100 mL) was added, and the orange precipitate was collected by fil-
tration. Yield: 29.3 g (85%). An analytical sample was crystallized
from hexane/CH2Cl2 (3:1), mp 160-161 °C.
1H NMR (300 MHz, CDCl3): d = 3.91 (s, 3 H), 7.46 (s, 1 H), 7.93
(s, 1 H), 7.97 (s, 1 H).
5-(Arylsulfanyl)-2,3-dihydro-6-(methylsulfonamido)-3-benzo-
furanones 1; General Procedure
A solution of MeSO2Cl (1.0 mL, 13.2 mmol) in CH2Cl2 (25 mL)
was added dropwise to a solution of 9a-y (4.0 mmol) and Et3N
(4.5 mL, 32 mmol) in CH2Cl2 (75 mL). The mixture was stirred at
r.t. for 3 h, and then was concentrated to dryness. The residue was
dissolved in EtOAc (75 mL), and the organic phase was successive-
ly washed with 1 N HCl (3 × 50 mL) and brine (200 mL), dried, fil-
tered, and concentrated to give the corresponding crude N,N,O-
tris(methylsulfonyl) derivative, which was dissolved in a 1:10 mix-
ture of 1 N KOH/THF (90 mL). The resulting solution was stirred
at r.t. for 5 h. Then, H2O (30 mL) was added, and the mixture was
acidified with 2 N HCl and extracted with EtOAc. The organic ex-
tract was dried, filtered, and concentrated. A solution of the result-
ing crude N,O-bis(methylsulfonyl) derivative in a 1:10 mixture of
1N KOH/MeOH (50 mL) was stirred at 45 °C for 1.5 h. Then, cold
H2O (30 mL) was added, and the mixture was acidified with 2N HCl
and extracted with EtOAc. The organic extract was successively
washed with 5% aq NaHCO3 solution and brine, dried, filtered, and
concentrated to give the target benzofuranones 1 in a 46-68% yield
(Table 3).
13C NMR (75 MHz, CDCl3): d = 58.5, 107.3, 110.1, 124.6, 126.2,
129.6, 144.1, 150.8, 175.4.
Anal. calcd for C9H6BrNO4 (272.0): C, 39.73; H, 2.22; N, 5.15.
Found: C, 40.01; H, 2.40; N, 5.21.
5-(Arylsulfanyl)-3-methoxy-6-nitrobenzofurans 8; General
Procedure
t-BuOK (20 mmol) and an appropriate arylthiol10 (25 mmol) were
added to a solution of 4 (10 mmol) in t-BuOH (110 mL). After stir-
ring at reflux temperature for 72 h, the solution was concentrated to
dryness. The solid residue was dissolved in sat. aq Na2CO3 solution,
and the aqueous solution was extracted with EtOAc. The organic
extracts were dried, filtered, and concentrated to give the corre-
sponding 5-(arylsulfanyl)benzofurans 8a-y (Tables 1 and 2), which
were purified by flash chromatography (hexane/CH2Cl2).
6-Amino-5-(arylsulfanyl)-2,3-dihydro-3-benzofuranones 9;
General Procedure
NH4Cl (3.80 mmol) and Fe powder (17 mmol) were added to a so-
lution of 8a-y (3.50 mmol) in a 2:1 mixture of EtOH/H2O (30 mL).
Table 2 Spectroscopic Data of Selected Benzofurans 8 and Benzofuranones 9
Producta
1H NMR (300 MHz, CDCl3), d, J (Hz)
13C NMR (75 MHz, CDCl3), d
8a
3.84 (s, 3 H), 7.41 (s, 1 H), 7.44 (s, 1 H), 7.55 (d, 1 H, J = 3.4),
7.99 (d, 1 H, J = 3.2), 8.28 (s, 1 H)
58.4, 109.9, 110.1, 120.2, 124.5, 126.8, 127.4, 130.1,
144.5, 144.9, 150.9, 159.8
8b
8c
8d
8e
9a
9b
9c
9d
9e
2.54 (s, 3 H), 3.84 (s, 3 H), 7.11 (s, 1 H), 7.39 (s, 1 H), 7.44
(s, 1 H), 8.25 (s, 1 H)
17.3, 58.4, 109.7, 111.4, 119.3, 119.8, 126.8, 128.1,
130.1, 144.4, 150.7, 155.3, 158.2
1.34 (t, 3 H, J = 7.6), 2.89 (q, 2 H, J = 7.6), 3.84 (s, 3 H), 7.11
(s, 1 H), 7.40 (s, 1 H), 7.44 (s, 1 H), 8.26 (s, 1 H)
13.3, 24.9, 58.3, 109.7, 117.9, 119.6, 126.8, 128.2, 130.1,
144.3, 150.6, 158.1, 161.5
1.36 (d, 6 H, J = 6.9), 3.19 (m, 1 H), 3.84 (s, 3 H), 7.09 (s,
1 H), 7.43 (s, 1 H), 7.44 (s, 1 H), 8.27 (s, 1 H)
22.1, 31.0, 58.3, 109.6, 116.7, 119.4, 126.7, 128.2, 130.0,
144.3, 150.5, 158.1, 166.0
3.67 (s, 3 H), 3.81 (s, 3 H), 6.67 (s, 1 H), 7.21 (s, 1 H), 7.34
(s, 1 H), 7.42 (s, 1 H), 8.33 (s, 1 H)
33.9, 58.3, 110.0, 117.2, 124.5, 127.2, 129.7, 130.3,
131.0, 137.1, 142.8, 144.2, 150.2
4.62 (s, 2 H), 5.40 (br s, 2 H), 6.38 (s, 1 H), 7.20 (d, 1 H, J =
3.2), 7.65 (d, 1 H, J = 3.2), 7.94 (s, 1 H)
75.6, 96.0, 109.2, 112.8, 120.3, 134.8, 143.4, 156.5,
176.5, 195.7
2.39 (s, 3 H), 4.63 (s, 2 H), 5.26 (br s, 2 H), 6.37 (s, 1 H), 6.74
(s, 1 H), 7.95 (s, 1 H)
17.2, 75.6, 96.0, 109.3, 112.9, 114.8, 135.0, 153.9, 156.5,
176.5, 195.7
1.25 (t, 3 H, J = 7.5), 2.73 (q, 2 H, J = 7.5), 4.62 (s, 2 H), 5.43
(br s, 2 H), 6.39 (s, 1 H), 6.74 (s, 1 H), 7.92 (s, 1 H)
13.0, 24.8, 75.5, 95.9, 109.2, 112.6, 113.4, 134.8, 156.6,
160.0, 164.8, 176.3, 195.7
1.27 (d, 6 H, J = 6.8), 3.01 (m, 1 H), 4.62 (s, 2 H), 5.43 (br s,
2 H), 6.38 (s, 1 H), 6.72 (s, 1 H), 7.93 (s, 1 H)
22.0, 30.9, 75.5, 95.9, 109.4, 112.4, 112.7, 134.8, 156.5,
164.5 164.7, 176.4, 195.7
3.74 (s, 3 H), 4.56 (s, 2 H), 5.80 (br s, 2 H), 6.23 (s, 1 H), 6.97
(s, 1 H), 7.04 (s, 1 H), 7.84 (s, 1 H)
34.1, 75.5, 95.8, 109.9, 111.7, 123.8, 129.1, 132.2, 137.6,
157.5, 175.9, 196.0
a All new compounds gave satisfactory elemental analyses: C 0.12, H 0.15, N 0.11.
Synthesis 2000, No. 5, 721–725 ISSN 0039-7881 © Thieme Stuttgart · New York

724
J. Bosch et al.
PAPER
Table 3 Characteristic Physical and Spectroscopic Data of Benzofuranones 1
Producta mp (ºC) 1H NMR (300 MHz, CDCl3), d, J (Hz)
13C NMR (75 MHz, CDCl3), d, J (Hz)
1a
1b
1c
171-172
177-178
146-147
3.10 (s, 3 H), 4.70 (s, 2 H), 7.33 (d, 1 H, J = 3.4), 7.54 (s, 40.2, 75.8, 102.5, 114.3, 117.3, 121.9, 133.6, 143.7, 147.8,
1 H), 7.71 (d, 1 H, J = 3.4), 8.06 (s, 1 H), 8.82 (br s, 1 H) 161.7, 176.1, 196.5
2.40 (s, 3 H), 3.10 (s, 3 H), 4.70 (s, 2 H), 6.85 (s, 1 H), 7.54 17.1, 40.2, 75.8, 102.5, 114.7, 116.5, 117.2, 133.4, 147.9,
(s, 1 H), 8.05 (s, 1 H), 9.10 (br s, 1 H)
154.3, 160.5, 176.1, 196.6
1.28 (t, 3 H, J = 7.5), 2.75 (q, 2 H, J = 7.5), 3.10 (s, 3 H), 13.1, 24.8, 40.3, 75.8, 102.8, 115.0, 115.4, 117.2, 133.3,
4.69 (s, 2 H), 6.86 (s, 1 H), 7.53 (s, 1 H), 8.05 (s, 1 H), 9.29 147.9, 176.0, 196.6
(br s, 1 H)
1d
138-139
1.27 (d, 6 H, J = 6.8), 3.03 (m, 1 H), 3.10 (s, 3 H), 4.70 (s, 22.1, 30.9, 40.4, 75.8, 103.2, 114.5, 115.4, 117.3, 133.1,
2 H), 6.86 (s, 1 H), 7.53 (s, 1 H), 8.05 (s, 1 H), 9.49 (br s, 148.0, 160.5, 165.1, 176.0, 196.7
1 H)
b
1e
1f
-
3.15 (s, 3 H), 3.80 (s, 3 H), 4.66 (s, 2 H), 6.99 (s, 1 H), 7.10 34.1, 40.5, 75.7, 104.3, 115.2, 116.9, 123.7, 129.0, 131.5,
(s, 1 H), 7.51 (s, 1 H), 7.96 (s, 1 H)
138.3, 148.9, 175.7, 197.0
157-158
3.01 (s, 3 H), 4.72 (s, 2 H), 7.32 (td, 1 H, J1= 1.5, J2 = 7.3, 40.2, 75.9, 101.9, 112.1, 117.3, 121.1, 122.1, 125.2, 126.6,
J3 = 7.9), 7.42 (td, 1 H, J1= 1.5, J2 = 7.2, J3 = 8.2), 7.57 (s, 134.4, 135.5, 147.8, 153.3, 164.9, 176.6, 196.3
1 H), 7.70 (d, 1 H, J = 7.8), 7.80 (d, 1 H, J = 7.8), 8.07 (s,
1 H), 8.37 (br s, 2H)
1g
1h
129-131
181-183
3.07 (s, 3 H), 4.69 (s, 2 H), 7.51 (s, 1 H), 7.67 (s, 1 H), 7.79 40.0, 75.8, 101.2, 111.5, 117.2, 129.4, 129.6, 134.5, 136.5,
(s, 1 H), 7.90 (s, 1 H), 8.10 (s, 1 H)
146.2, 148.3, 152.9, 176.1, 196.5
3.10 (s, 3 H), 4.69 (s, 2 H), 7.25 (dd, 1 H, J1= 4.6, J2 = 7.9), 40.0, 75.7, 101.9, 112.7, 117.2, 120.8, 122.9 (q, J = 271.9),
7.53 (s, 1 H), 7.95 (d, 1 H, J = 8.1), 7.96 (s, 1 H), 8.31 (br 124.9 (q, J = 33.8), 134.5, 135.3 (q, J = 5.2), 148.6, 151.9,
s, 1 H), 8.42 (d, 1 H, J = 3.6)
155.7, 176.1, 196.5
1i
171-173
3.12 (s, 3 H), 4.72 (s, 2 H), 7.27 (d, 1 H, J = 9.3), 7.54 (s, 40.1, 75.8, 101.5, 111.7, 117.3, 121.2, 123.1 (q, J = 270.5),
1 H), 7.79 (dd, 1 H, J1= 2.1, J2 = 8.4), 7.91 (s, 1 H), 8.12 124.3 (q, J = 32.8), 134.1 (q, J = 3.1), 134.4, 146.7 (q, J =
(s, 1 H), 8.58 (br s, 1 H)
4.2), 148.1, 161.9, 176.1, 196.4
1j
163-165
140-142
2.79 (s, 3 H), 4.68 (s, 2 H), 7.10 (d, 2 H, J = 7.5), 7.23 (m, 39.6, 75.7, 101.2, 115.1, 117.1, 127.2, 127.8, 129.5, 133.9,
3 H), 7.46 (s, 1 H), 8.00 (br s, 2 H) 134.6, 147.1, 175.7, 196.2
1k
2.94 (s, 3 H), 4.72 (s, 2 H), 6.70 (d, 1 H, J = 7.2), 6.89 (m, 39.9, 75.7, 101.1, 113.3, 113.9 (d, J = 24), 114.0 (d, J =
2 H), 7.25 (m, 1 H), 7.49 (s, 1 H), 7.97 (br s, 1 H), 8.01 (s, 20.8), 117.2, 122.6 (d, J = 3.8), 130.9 (d, J = 8.5), 134.4,
1 H)
137.2 (d, J = 7.4), 147.2, 163.1 (d, J = 248.7), 175.9, 196.4
1l
100-102
146-148
2.91 (s, 3 H), 4.71 (s, 2 H), 7.02 (t, 2 H, J = 8.1), 7.14 (dd, 39.9, 75.7, 101.0, 115.3, 116.7 (d, J = 21), 117.0, 129.5,
2 H, J1= 4.8, J2 = 8.1), 7.45 (s, 1 H), 8.02 (br s, 2 H)
130.1 (d, J = 8.2), 133.6, 146.8, 161.9 (d, J = 246.8), 175.6,
196.5
1m
3.01 (s, 3 H), 4.68 (s, 2 H), 7.09 (m, 3 H), 7.28 (m, 1 H), 39.8, 75.6, 100.6, 114.1, 116.2 (d, J = 21), 117.0, 121.5 (d,
7.45 (s, 1 H), 8.00 (s, 1 H), 8.10 (br s, 1 H)
J = 17.5), 125.0, 129.8 (d, J = 7.7), 131.1, 133.9, 147.0,
160.4 (d, J = 244.6), 175.5, 196.4
1n
1o
1p
1q
87-89
2.94 (s, 3 H), 4.73 (s, 2 H), 7.00 (d, 1 H, J = 2.4), 7.19 (m, 39.9, 75.7, 101.1, 113.3, 117.3, 125.2, 126.5, 127.2, 130.5,
3 H), 7.50 (s, 1 H), 7.94 (br s, 1 H), 8.02 (s, 1 H) 134.4, 135.5, 136.7, 147.1, 176.0, 196.4
150-152
141-143
190-192
2.96 (s, 3 H), 4.73 (s, 2 H), 7.06 (d, 2 H, J= 10.2), 7.27 (d, 39.9, 75.7, 100.9, 114.1, 117.1, 128.7, 129.6, 133.1, 134.1,
2 H, J = 9.5), 7.49 (s, 1 H), 8.00 (br s, 1 H), 8.03 (s, 1 H) 146.9, 175.8, 196.5
3.01 (s, 3 H), 4.71 (s, 2 H), 6.90 (d, 1 H, J= 8.1), 7.08 (s, 1 40.1, 75.8, 101.1, 112.8, 117.3, 126.1, 128.2, 131.1, 133.7,
H), 7.32 (d, 1 H, J = 8.4), 7.46 (s, 1 H), 7.97 (s, 1 H)
134.4, 134.9, 147.1, 176.0, 196.5
3.05 (s, 3 H), 4.75 (s, 2 H), 6.52 (d, 1 H, J = 2.4), 7.13 (dd, 40.1, 75.9, 101.1, 111.6, 117.6, 126.2, 127.7, 130.1, 131.1,
1 H, J1= 2.4, J2 = 8.4), 7.34 (d, 1 H, J = 8.4), 7.55 (s, 1 H), 133.6, 134.8, 136.0, 147.3, 176.1, 196.2,
7.87 (br s, 1 H), 8.00 (s, 1 H)
1r
156−158
3.07 (s, 3 H), 4.73 (s, 2 H), 6.48 (dd, 1 H, J1= 1.2, J2 = 7.9), 40.2, 75.8, 100.9, 112.1, 117.4, 124.4, 127.7, 128.1, 129.7,
7.04 (t, 1 H, J1 = 7.9, J2 = 8.2), 7.30 (dd, 1 H, J1= 1.2, J2 = 134.0, 134.8, 136.7, 147.4, 175.9, 196.1
8.2), 7.51 (s, 1 H), 7.95 (br s, 1 H), 7.98 (s, 1 H)
Synthesis 2000, No. 5, 721–725 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A Convergent Route to 5-(Arylsulfanyl)-6-sulfonamido-3-benzofuranones
725
Table 3 (continued)
Producta mp (ºC)
1H NMR (300 MHz, CDCl3), d, J (Hz)
13C NMR (75 MHz, CDCl3), d, J (Hz)
1s
187-189
2.98 (s, 3 H), 4.71 (s, 2 H), 6.54 (dd, 1 H, J1= 1.5, J2 = 7.8), 40.0, 75.7, 101.1, 113.7, 117.4, 122.0, 127.4, 128.0, 128.2,
7.07 (td, 1 H, J1= 1.8, J2 = 7.3, J3 = 7.8), 7.15 (td, 1 H, J1= 133.4, 134.5, 136.0, 147.3, 175.9, 196.4
1.5, J2 = 7.5, J3 = 7.8), 7.50 (s, 1 H), 7.57 (dd, 1 H, J1= 1.5,
J2 = 7.8), 7.97 (br s, 1 H), 8.01 (s, 1 H)
1t
160-162
172-173
130-132
3.04 (s, 3 H), 4.71 (s, 2 H), 6.84 (m, 2 H), 7.18 (dd, 1 H, 40.1, 75.7, 100.9, 113.6, 115.3 (d, J = 21.5), 117.3, 117.9
J1= 2.7, J2 = 8.4), 7.47 (s, 1 H), 7.98 (s, 1 H), 8.02 (br s, (d, J = 25.2), 129.1, 129.9 (d, J = 8.5), 133.9 (d, J = 10.0),
1 H)
134.1, 147.1, 161.5 (d, J = 250.2), 175.8, 196.3
1u
1v
2.93 (s, 3 H), 4.74 (s, 2 H), 6.92 (d, 1 H, J = 9), 7.36 (m, 39.9, 75.7, 101.3, 113.4, 117.2, 123.5 (q, J = 327), 127.1
2 H), 7.50 (s, 1 H), 7.72 (d, 1 H, J = 8.7), 7.96 (br s, 1 H), (q, J = 5.4), 127.2, 128.4 (q, J = 36.8), 128.9, 132.5, 134.2,
8.04 (s, 1 H)
134.7, 147.2, 176.0, 196.4
2.93 (s, 3 H), 4.72 (s, 2 H), 7.13 (d, 2 H, J= 7.8), 7.49 (s, 40.1, 75.8, 101.0, 112.4, 117.3, 123.8 (q, J = 270.5), 126.3
1 H), 7.51 (d, 2 H, J = 7.8), 7.97 (s, 1 H), 8.01 (s, 1 H)
(q, J = 3.9), 126.5, 138.9 (q, J = 32.8), 134.6, 139.9, 147.3,
176.0, 196.3
1w
1x
152-153
134-136
2.94 (s, 3 H), 4.72 (s, 2 H), 7.14 (s, 2 H), 7.48 (s, 1 H), 8.00 39.9, 75.7, 101.0, 114.0, 117.2, 120.2 (q, J = 254.2), 122.1,
(br s, 1 H), 8.02 (s, 1 H) 128.8, 133.3, 134.2, 147.0, 148.1, 175.8, 196.4
1.30 (t, 3 H, J = 7.5), 2.82 (s, 3 H), 2.84 (q, 2 H, J = 7.5), 14.4, 26.7, 39.6, 75.7, 101.2, 114.9, 117.3, 126.8, 126.9,
4.70 (s, 2 H), 6.66 (dd, 1 H, J1= 0.9, J2 = 7.9), 7.03 (td,
1 H, J1= 1.5, J2 = 7.8, J3= 7.8), 7.15 (td, 1 H, J1= 0.9, J2 =
7.5, J3= 7.5), 7.23 (dd, 1 H, J1= 1.5, J2 = 7.6), 7.49 (s, 1 H),
7.87 (br s, 1 H), 7.96 (s, 1 H)
127.1, 129.1, 133.2, 133.9, 142.3, 147.0, 175.7, 196.6
1y
188-190
1.31 (d, 6 H, J = 6.9), 2.79 (s, 3 H), 3.46 (m, 1 H), 4.70 (s, 23.2, 30.5, 39.6, 75.7, 101.2, 115.3, 117.3, 126.2, 126.8,
2 H), 6.66 (dd, 1 H, J1= 0.9, J2 = 7.9), 7.01 (td, 1 H, J1= 1.5, 127.0, 129.3, 132.6, 133.8, 147.0, 175.7, 196.6
J2 = 7.8, J3= 7.8), 7.19 (td, 1 H, J1= 0.9, J2 = 7.5, J3= 7.5),
7.32 (dd, 1 H, J1= 1.5, J2 = 7.6), 7.49 (s, 1 H), 7.85 (br s,
1H), 7.97 (s, 1 H)
a All new compounds gave satisfactory elemental analyses: C 0.37, H 0.25, N 0.39.
b Decomposes above 120ºC.
Acknowledgement
Chabot, M.; Tzimas, M.; Webb, E.; Breton, J.; Griswold, D. J.
Med. Chem. 1996, 39, 5035.
(b) Metwally, M.; Darwish, Y.; El-Hussini, M.; Amer, F. J.
Indian. Chem. Soc. 1988, 65, 54.
This work was supported by the CICYT (Spain)-European Comis-
sion (project 2FD97-0450). Thanks are also due to the Comissionat
per Universitats i Recerca (Generalitat de Catalunya) for Grant
1997SGR-00018.
(5) (a) House, H. O.; Hudson, C. B. J. Org. Chem. 1970, 35, 647.
(b) House, H. O.; McDaniel, W. C. J. Org. Chem. 1977, 42,
2155.
(6) In our case, Friedel-Crafts cyclization of 2 (X = CH2,
Ar = 2,4-difluorophenyl) to the corresponding indanone 3,
which has the same substitution pattern as 1, proceeded in
70% yield.
(7) For precedents see: Palmer, M.; McVie, G. J. Chem. Soc. (B)
1968, 745.
References
(1) (a) Farrerons, C.; Bosch, J.; Lagunas, C.; Casadevall, C.;
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(2) For a review on selective COX-2 inhibitors, see: Beuck, M.
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(10) 4-Alkyl-2-mercaptothiazoles were prepared as described in
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Synthesis 2000, No. 5, 721–725 ISSN 0039-7881 © Thieme Stuttgart · New York