A new synthesis of 3-(sulfonamido)benzofurans through an acid-promoted cascade reaction of N-(2,2-dichloro-2-phenylethylidene)arenesulfonamides with para-substituted phenols

Article abstract of DOI:10.1002/ejoc.201100362

2-Phenyl-3-(sulfonamido)benzofurans are produced in a cascade reaction of N-(2,2-dichloro-2-phenylethylidene)arenesulfonamides with para-substituted phenols in the presence of the superacid H₂SO₄/P ₄O₁₀ system. A convenient synthetic approach to 2-aryl-3-(sulfonamido)benzofurans through a cascade reaction of available N-(2,2-dichloro-2-phenylethylidene)arenesulfonamides withpara-substituted phenols in the presence of the superacid H₂SO₄/P ₄O₁₀ system was developed.

Full text of DOI:10.1002/ejoc.201100362

FULL PAPER
DOI: 10.1002/ejoc.201100362
A New Synthesis of 3-(Sulfonamido)benzofurans through an Acid-Promoted
Cascade Reaction of N-(2,2-Dichloro-2-phenylethylidene)arenesulfonamides
with para-Substituted Phenols
Igor B. Rozentsveig,*[a] Gulnur N. Rozentsveig,[a] Valeriy Yu. Serykh,[a]
Kirill A. Chernyshev,[a] and Galina G. Levkovskaya[a]
Keywords: Cyclization / Heterocycles / Imines / Phenols / Sulfonamides / Superacidic systems
2-Phenyl-3-(sulfonamido)benzofurans are produced in a cas-
sulfonamides with para-substituted phenols in the presence
cade reaction of N-(2,2-dichloro-2-phenylethylidene)arene-
of the superacid H2SO4/P4O10 system.
cols are the application of moisture-sensitive reagents and
catalysts (in some cases), or the use of expensive starting
compounds. Furthermore, some of the methods are labori-
ous and comprise multi-step procedures, and the target
products are typically formed in only moderate yields.
Polyhaloaldimines exhibit high electrophilicity due to the
strongly electron-withdrawing substituents. The ability of
polyhalogenated N-sulfonylaldimines to react with various
nucleophiles has been used for the design of a wide range
of acyclic and heterocyclic sulfonamide derivatives.[11]
Sulfonylimines 1 are important representatives of acti-
vated imines containing electron-deficient azomethine
groups. An effective synthetic protocol for obtaining these
promising reagents has been developed on the basis of radi-
cal reactions of N,N-dichlorosulfonamides with phenyl-
acetylene[12] (Scheme 1). Thus, sulfonylimines of type 1 are
available for application in synthetic practice.
Introduction
Benzofuran rings are important structural subunits in
modern heterocyclic chemistry.[1] A wide range of natural
compounds contain such moieties,[2] and numerous biolo-
gically active benzofurans are known to exert anti-inflam-
matory, anti-arrhythmic, haemostatic, anti-bacterial, fungi-
cidal, anti-viral, anti-tumor, and anti-oxidant activities.[3]
Some of them are promising drugs against Parkinson’s[3e]
and Alzheimer’s disease.[3f]
Among various functionally substituted benzofuran de-
rivatives, 3-amino- and 3-amido-substituted benzofurans
are important due to their anti-tumor[4a] and anti-asthmat-
ic[4b–4d] activities. 3-Aminobenzofurans are often used as
key reagents in the synthesis of acyclic amino deriva-
tives[4b–4d] or annulated heterocycles,[5] and are of interest
for structural investigations.[6] Thus, these compounds are
promising drugs and useful scaffolds for organic synthesis.
Consequently, further development of known methods and
elaboration of new protocols for 3-aminobenzofuran syn-
thesis represent an urgent challenge.
Synthetic approaches to 3-amino- and 3-amido-substi-
tuted benzofurans are based on the reactions of ortho-hy-
droxybenzonitriles.[7] Three-component reactions of acetyl-
enes with ortho-hydroxybenzaldehydes and amines in the
presence of copper salts[8] or arylglyoxals, phenols and para-
toluenesulfonamide, in the presence of Hf(OTf)4, TiCl4, or
InCl3 are also known.[9] In addition, the synthesis of 2,3-
bis(arylamino)benzofurans by reaction of 2-[(arylimino)-
methyl]phenols with aryl isocyanides catalyzed by BF3 has
been reported.[10] Among the disadvantages of these proto-
Scheme 1. Synthesis of imines 1 from N,N-dichlorosulfonamides
and phenylacetylene.
Results and Discussion
Having studied C-amidoalkylation of aromatics with
imines 1, we found that the reaction with para-substituted
phenols 2 in the presence of strong acids unexpectedly re-
sulted in the formation of 2-phenyl-3-(sulfonamido)benzo-
furans 3. Preliminarily, a range of Lewis and Brønsted acids
were screened as catalysts in the model reaction of imine 1a
with p-chlorophenol (2a; Scheme 2).
[a] A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch
of the Russian Academy of Sciences,
1, Favorsky st., 664033 Irkutsk, Russia
Fax: +7-3952-419346
E-mail: i_roz@irioch.irk.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100362.
Eur. J. Org. Chem. 2011, 4415–4421
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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I. B. Rozentsveig et al.
FULL PAPER
Table 1. Screening of Lewis and Brønsted acids in the reactions of imine 1a with p-chlorophenol (2a).[a]
Entry
Catalyst
Amount
Time [h]
Product
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
–
–
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
10 mol-%
50 mol-%
1 equiv.
5
5
10
10
5
5
5
5
5
5
5
4aa
4aa
4aa
4aa
4aa
4aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
3aa
4aa
4aa
75[b]
83[b]
67[b]
82[b]
78[b]
53[b]
37
41
47
43
50
AlCl3
BF3·Et2O
TsOH
3-NBSA[c]
MeSO3H
[d]
H2SO4[d]
H2SO4[d]
H2SO4[d]
H2SO4
2 equiv.
oleum (20% free SO3)
2 equiv. based on MW 98.08
10 mol-%/10 mol-%
50 mol-%/50 mol-%
1 equiv./1 equiv
50 mol-%
[d]
H2SO4/P4O10
H2SO4/P4O10
H2SO4/P4O10
5
5
5
5
32
46
59
77
[d]
[d]
P4O10
P4O10
1 equiv.
5
75
[a] The reaction was carried out with p-chlorophenol (2a; 1 equiv.) by stirring in CCl4 at room temp. [b] Semiaminal 5 and 4-chlorobenz-
enesulfonamide were formed as an admixture (identified by NMR spectroscopy). Compound 4aa was quantitatively transformed into
semiaminal 5 by addition of water or by standing in humid air (Scheme 3). [c] 3-Nitrobenzenesulfonic acid. [d] H2SO4 (96%) was used.
hydroxy group in phenol 2, which is followed by spontane-
ous heterocyclization of the intermediate [2,2-dichloro-1-(2-
hydroxyphenyl)-2-phenylethyl]amide B through the OH and
CCl moieties. Subsequent aromatization of the bicyclic in-
termediate C as a result of HCl elimination gives 3. The
cyclization and dehydrochlorination steps occur easily,
probably due to the effect of the benzene ring (benzylic po-
sition of the reaction centre), the intramolecular character
of the substitution, and the formation of a thermodynami-
cally stable heteroaromatic structure.
Scheme 2. Reaction of imine 1a with p-chlorophenol 2a.
4-Chloro-N-(5-chloro-2-phenylbenzofuran-3-yl)benzene-
sulfonamide (3aa) was found to be formed in the presence
of a strong Brønsted acid (Table 1). Maximal yield was
achieved with an H2SO4/P4O10 mixture (Table 1, Entry 14).
Under these conditions, the process was accompanied by
the formation of 4-chlorobenzenesulfonamide (ca. 15%
yield). In the absence of a catalyst or in the presence of
Lewis acids or sulfonic acids (Table 1, Entries 1–6), benzo-
furan 3aa was not produced, and the reaction afforded a
mixture of nucleophilic addition product 4aa, semiaminal
5, and 4-chlorobenzenesulfonamide (Schemes 2 and 3).
Scheme 4. Possible mechanism of the benzofuran 3 formation.
It is logical to suppose that the mixture of H2SO4 and
P4O10 can work as a superacid system that assists the gener-
ation of carbocation A. We did not find any literature data
on the protonating ability and superacidic properties of
Scheme 3. Hydrolysis of 4a.
H2SO4/P4O10 mixtures, but the application of P4O10 in the
preparation of a binary superacid medium has been men-
The corresponding semiaminal, 4-chloro-N-(2,2- tioned.[13] P4O10 evidently plays the role of a conjugate base,
dichloro-1-hydroxy-2-phenylethyl)benzenesulfonamide (5), similar to free SO3 in oleum (Hammett’s function[14] H0 for
was produced by hydrolysis of compound 4aa (Scheme 3).
H2SO4 = –12, H0 for oleum Յ –12.24), promoting the for-
The formation of substituted benzofurans 3 apparently mation of a superacid medium. It can also be presumed
proceeds through a reaction cascade (Scheme 4): C-Amido- that SO3 is produced in situ in the equilibrium between
alkylation by amidoalkyl cation A takes place ortho to the H2SO4 and P4O10.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4415–4421

A New Synthesis of 3-(Sulfonamido)benzofurans
The application of phenol (2i) under the reaction condi-
tions did not generate benzofurans, but selectively led to the
formation of the para-substituted C-amidoalkylated deriva-
tive 4-chloro-N-[2,2-dichloro-1-(4-hydroxyphenyl)-2-phen-
ylethyl]benzenesulfonamide (6; Scheme 5). However, p-
halophenols 2a–c as well as p-nitrophenol (2d), and 2,4-
dichloro- and 2,4-dibromophenols (2e and 2f) smoothly de-
livered the corresponding benzofurans 3 in moderate to
good yields (Table 2). p-Cresol (2g) gave benzofuran 3ag in
poor yield, and no benzofuran was obtained from the p-
tert-butylphenol 2h, probably because of the tendency of
alkylphenols to produce sulfonated and protonated species
under the reaction conditions.
Scheme 6. Reaction between chloralimine 1d and p-chlorophenol
(2a).
furan derivatives requires either more severe conditions or
the assistance of a base; these approaches are the subject of
our future investigations.
The structures of the compounds obtained were deduced
1
1
from their H and 13C NMR spectroscopic data. The H
and 13C NMR signals of benzofurans 3 and sulfonamide 7
were assigned by using 13C-HSQC, 13C-HMBC, and
NOESY experiments.
To establish the benzofuran structure HMBC 1H–13C
techniques were used, which were optimized for 13C–1H
spin–spin coupling constants of 10 Hz, which are typical
for carbon and proton atoms separated by three bonds
(Figure 1). In the HMBC 1H–13C spectra of benzofurans 3,
cross-peaks between the signals of the proton of the NH
group and the carbon atom C-2 of the benzofuran ring were
observed. The same C-2 atom has cross-peaks with the
ortho-protons of the benzene ring. This can be observed
only when the sulfonamide group and the benzene ring are
bonded to different carbon atoms of the furan moiety.
Moreover, cross-peaks between the C-3 atom and the 5-H
proton can be seen in the HMBC spectra, which is in agree-
ment with the proposed structure.
Scheme 5. Reaction between imine 1a and phenol (2i).
Table 2. Acid-promoted synthesis of benzofurans 3 from imines 1
and phenols 2 in the presence of an H2SO4/P4O10 mixture.[a]
Entry Imine
Ar
Phenol
R
RЈ Benzofuran 3 Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1c
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2a
2b
2c
2d
2a
Cl
Br
F
NO2
Cl Cl
Br Br
Me
tBu
H
Cl
Br
H
H
H
H
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3ba
3bb
3bc
3bd
3ca
59
46
67
58
83
78
23
0
H
H
H
H
H
H
H
H
0[b]
71
30
44
60
68
Ph
Ph
Ph
F
NO2
Cl
4-MeC6H4
Figure 1. Main HMBC 1H–13C (3JCH) correlations for benzofurans
3.
[a] For reaction conditions, see the Experimental Section. [b] Com-
pound 6 was isolated as the only product (see Scheme 5).
The structure of C-amidoalkylated chlorophenol deriva-
tive 7 was assigned by application of 1H–1H 2D homo-
nuclear NOESY experiments (Figure 2). A cross-peak be-
tween the proton of the CHCCl3 fragment and the 6-H pro-
ton of the phenol ring was observed in the spectrum of
sulfonamide 7, as were cross-peaks between the 3-H proton
and both the 4-H and OH protons.
When chloralimines were used instead of imines 1a and
1b in the reaction with para-substituted phenols, the process
stopped at the stage of the C-amidoalkylated product, and
no benzofurans were formed. For instance, the reaction of
4-chloro-N-(2,2,2-trichloroethylidene)benzenesulfonamide
(1d) with p-chlorophenol (2a) resulted in the formation of
4-chloro-N-[2,2,2-trichloro-1-(5-chloro-2-hydroxyphenyl)-
ethyl]benzenesulfonamide (7) as a final product (Scheme 6).
It was shown[15] that saturation of a melt of p-cresol and
chloral hydrate with hydrogen chloride led to the formation
of 4-methyl-2-(2,2,2-trichloro-1-hydroxyethyl)phenol, which
gave no heterocycles in the presence of H2SO4, similar to
trichloroethylsulfonamide 7. Heterocyclization[15] to the
corresponding 2,3-dihydrobenzofuran-3-ol derivative was
accomplished by treatment with aqueous potassium hy-
droxide. Clearly, the trichloromethyl group is less reactive
Figure 2. Main NOESY correlations for sulfonamide 7.
The structure of sulfonamide 7 indirectly confirms the
than the dichloro(phenyl)methyl moiety. Therefore, hetero- formation of the benzofuran ring through C-amidoalkyl-
cyclization of trichloroethylamides of type 7 to give benzo- ation ortho to the OH group of the phenol.
Eur. J. Org. Chem. 2011, 4415–4421
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4417

I. B. Rozentsveig et al.
FULL PAPER
(AAЈBBЈ, 2 H, Ho, 4-ClC6H4), 7.61 (d, 3J = 8.7 Hz, 1 H, 7-H), 7.91
(m, 2 H, Ho, C6H5), 10.25 (s, 1 H, NH) ppm. 13C NMR ([D6]-
DMSO, 100.61 MHz): δ = 112.7 (C-3), 113.2 (C-7), 118.6 (C-4),
125.1 (C-6), 126.2 (Cm, C6H5), 127.8 (C-5), 128.0 (Ci, C6H5), 128.6
(Co, C6H5), 128.6 (C-3a), 128.8 (Co, 4-ClC6H4), 129.3 (Cm, 4-
ClC6H4), 129.5 (Cp, C6H5), 138.3 (Cp, 4-ClC6H4), 138.7 (Ci, 4-
ClC6H4), 150.6 (C-7a), 152.5 (C-2) ppm. C20H13Cl2NO3S (418.29):
calcd. C 57.43, H 3.13, Cl 16.95, N 3.35, S 7.66; found C 57.35, H
3.18, Cl 17.06, N 3.48, S 7.76.
Conclusions
An experimentally straightforward protocol for the syn-
thesis of 2-phenyl-3-(sulfonamido)benzofuran by using an
acid-assisted reaction of N-(2,2-dichloro-2-phenylethylid-
ene)sulfonamides with para-substituted phenols was devel-
oped. The advantages of the above method are the availabil-
ity of starting reagents (dichlorosulfonamides, phenylacetyl-
ene, and phenols), good yields of the target benzofuran de-
rivatives, and the possibility of accessing benzofurans con-
taining substituents in the annulated benzene ring. The re-
action is likely to be applied with a range of polyhalogen-
ated imines so that the substituent at position 2 of the
annulated furan ring can be varied. The method presented
herein and the known three-component approach[9] to ben-
zofurans with similar structures, complement each other.
The latter method[9] allows 2-aryl-3-(sulfonamido)benzo-
furans to be generated that are either unsubstituted or that
include bulky substituents; however, these approaches re-
quire the use of more expensive reagents and catalysts (aryl-
glyoxals, indium or hafnium salts).[9]
N-(5-Bromo-2-phenylbenzofuran-3-yl)-4-chlorobenzenesulfonamide
(3ab): Colorless solid; m.p. 207–208 °C; yield 2.13 g (46%). IR
(KBr): ν = 1164, 1337 (SO ), 3227 (NH) cm–1. 1H NMR ([D6]-
˜
2
DMSO, 400.13 MHz): δ = 6.86 (d, 4J = 1.6 Hz, 1 H, 4-H), 7.43
(dd, 3J = 8.6, 4J = 1.6 Hz, 1 H, 6-H), 7.43 (m, 3 H, Hm, Hp, C6H5),
7.49 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4), 7.57 (d, J = 8.6 Hz, 1 H, 7-
3
H), 7.62 (AAЈBBЈ, 2 H, Ho, 4-ClC6H4), 7.93 (m, 2 H, Ho, C6H5),
10.22 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 100.61 MHz): δ
= 112.6 (C-3), 113.6 (C-7), 115.6 (C-4), 121.6 (C-6), 126.2 (Cm,
C6H5), 127.7 (C-5), 128.0 (Ci, C6H5), 128.6 (Co, C6H5), 128.8 (Cp,
4-ClC6H4), 129.0 (C-3a), 129.3 (Cm, 4-ClC6H4), 129.5 (Cp, C6H5),
138.3 (Cp, 4-ClC6H4), 138.8 (Ci, 4-ClC6H4), 150.9 (C-7a), 152.2 (C-
2) ppm. C20H13BrClNO3S (462.74): calcd. C 51.91, H 2.83, N 3.03,
S 6.93; found C 52.01, H 2.86, N 3.12, S 6.84.
In addition, the synthesis of C-amidotrichloroethylated
phenol 7 has been demonstrated. Compounds of the type 7
are promising reagents that can be used to obtain further
3-amino-2-chloro- and 3-amino-2-hydroxybenzofurans.
The structures of compounds 3–7 were established by
NMR spectroscopy and confirmed by IR spectroscopy and
elemental analysis (see Experimental Section).
4-Chloro-N-(5-fluoro-2-phenylbenzofuran-3-yl)benzenesulfonamide
(3ac): Colorless needles; m.p. 175–176 °C; yield 2.69 g (67%). IR
(KBr): ν = 1165, 1337 (SO ), 3261 (NH) cm–1. 1H NMR ([D6]-
˜
2
4
3
DMSO, 400.13 MHz): δ = 6.69 (dd, J = 2.6, JHF = 8.7 Hz, 1 H,
3
4
3
4-H), 7.15 (m, J = 9.0, J = 2.6, JH,F = 9.2 Hz, 1 H, 6-H), 7.38
(m, 3 H, Hm, Hp, C6H5), 7.43 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4), 7.61
(AAЈBBЈ, 2 H, Ho, 4-ClC6H4), 7.62 (d, 3J = 9.0 Hz, 1 H, 7-H), 7.84
(m, 2 H, Ho, C6H5), 10.25 (s, 1 H, NH) ppm. 13C NMR ([D6]-
2
DMSO, 100.61 MHz): δ = 104.7 (d, JC,F = 26.4 Hz, C-4), 112.8
Experimental Section
3
2
(d, JC,F = 9.5 Hz, C-7), 112.8 (d, JC,F = 26.8 Hz, C-6), 113.4 (d,
4JC,F = 4.0 Hz, C-3), 126.1 (Cm, C6H5), 128.2 (Ci, C6H5), 128.2 (d,
3JC,F = 10.6 Hz, C-3a), 128.4 (Co, C6H5), 128.7 (Co, 4-ClC6H4),
General Remarks: 1H, 13C, and 19F NMR spectra were recorded
with a Bruker DPX 400 MHz spectrometer (1H, 400.13 MHz; 13C,
100.61 MHz; 19F, 376.50 MHz) in a 5 mm broadband probe at
25 °C in DMSO, with HMDS as an internal standard. Spectral
assignments of the 1H and 13C NMR spectra of compounds 1–7
are based on the results of 13C-HSQC, 13C-HMBC, and NOESY
experiments. Settings for the HMBC experiments were the follow-
ing: pulse length 6 μs (1H), 13 μs (13C); spectral width 800 Hz (1H),
7 kHz (13C); acquisition time 1.3 s; relaxation delay 2 s; digital reso-
lution 0.5 Hz; accumulation time 2 h. Settings for the HSQC ex-
periments were the following: pulse length 6 μs (1H), 13 μs (15N);
spectral width 800 Hz (1H), 7 kHz (13C); acquisition time 0.7 s; re-
laxation delay, 2.5 s; digital resolution 1 Hz; accumulation time 4 h.
IR spectra were recorded with a Bruker IFS spectrophotometer.
Elemental analyses were obtained with a Thermo Finnigan Flash
series1112 EA analyzer.
129.2 (Cm, 4-ClC6H4), 129.3 (Cp, C6H5), 137.9 (Cp, 4-ClC6H4),
1
138.9 (Ci, 4-ClC6H4), 148.4 (C-7a), 152.5 (C-2), 158.5 (d, JC,F
=
237.7 Hz, C-5) ppm. 19F NMR ([D6]DMSO, 376.50 MHz): δ =
119.93 ppm. C20H13ClFNO3S (401.84): calcd. C 59.78, H 3.26, N
3.49, S 7.98; found C 59.56, H 3.35, N 3.61, S 8.08.
4-Chloro-N-(5-nitro-2-phenylbenzofuran-3-yl)benzenesulfonamide
(3ad): Colorless needles; m.p. 235–236 °C; yield 2.49 g (58%). IR
(KBr): ν = 1171, 1338 (SO ), 1357, 1515 (NO ), 3262 (NH) cm–1.
˜
2
2
1H NMR ([D6]DMSO, 400.13 MHz): δ = 7.46 (m, 3 H, Hm, Hp,
C6H5), 7.46 (AAЈBBЈ, 2 H, 4-ClC6H4), 7.94 (m, 2 H, Ho, C6H5),
7.64 (AAЈBBЈ, 2 H, 4-ClC6H4), 7.69 (d, 4J = 1.7 Hz, 1 H, 4-H),
3
4
3
8.18 (dd, J = 8.8, J = 1.7 Hz, 1 H, 6-H), 7.84 (d, J = 8.8 Hz, 1
H, 7-H), 10.44 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
100.61 MHz): δ = 112.7 (C-7), 113.2 (C-3), 115.7 (C-4), 120.8 (C-
6), 126.4 (Cm, C6H5), 127.5 (C-3a), 127.5 (Ci, C6H5), 128.7 (Co,
C6H5), 128.8 (Co, 4-ClC6H5), 129.4 (Cm, 4-ClC6H5), 130.0 (Cp,
C6H5), 138.5 (Cp, 4-ClC6H5), 138.5 (Ci, 4-ClC6H5), 143.7 (C-5),
154.0 (C-2), 154.8 (C-7a) ppm. C20H14ClN2O5S (429.85): calcd. C
55.88, H 3.28, Cl 8.25, N 6.52, S 7.46; found C 55.95, H 3.31, Cl
8.36, N 6.39, S 7.35.
General Procedure for the Synthesis of N-(2-Phenylbenzofuran-3-yl)-
arenesulfonamides (3): para-Substituted phenol (10 mmol) was
added to a stirred mixture of imine 1a,b (10 mmol), P4O10 (1 mmol,
0.28 g), and H2SO4 (96%, 0.55 mL, ca. 10 mmol) in CCl4 (10 mL).
The reaction mass was stirred for 5 h and mixed with water
(100 mL). The precipitate was filtered off, dried, and recrystallized
from CHCl3 to give the final benzofuran 3.
4-Chloro-N-(5,7-dichloro-2-phenylbenzofuran-3-yl)benzenesulfon-
4-Chloro-N-(5-chloro-2-phenylbenzofuran-3-yl)benzenesulfonamide amide (3ae): Colorless needles; m.p. 221–222 °C; yield 3.75 g (83%).
1
(3aa): Colorless needles; m.p. 194–196 °C; yield 2.47 g (59%). IR
IR (KBr): ν = 1169, 1379 (SO ), 3296 (NH) cm–1. H NMR ([D ]-
˜
2 6
(KBr): ν = 1165, 1337 (SO ), 3275 (NH) cm–1. 1H NMR ([D6]-
DMSO, 400.13 MHz): δ = 6.76 (d, 4J = 1.3 Hz, 1 H, 6-H), 7.45 (m,
˜
2
DMSO, 400.13 MHz): δ = 6.79 (d, 4J = 2.2 Hz, 1 H, 4-H), 7.30 3 H, Hm, Hp, C6H5), 7.46 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4), 7.56 (d,
(dd, 3J = 8.7, 4J = 2.2 Hz, 1 H, 6-H), 7.41 (m, 2 H, Hm, C6H5), 4J = 1.3 Hz, 1 H, 4-H), 7.62 (AAЈBBЈ, 2 H, Ho, 4-ClC6H4), 7.90
7.42 (m, 1 H, Hp, C6H5), 7.47 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4), 7.63
4418
(m, 2 H, Ho, C6H5), 10.36 (s, 1 H, NH) ppm. 13C NMR ([D6]-
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4415–4421

A New Synthesis of 3-(Sulfonamido)benzofurans
DMSO, 100.61 MHz): δ = 113.3 (C-7), 116.7 (C-3), 117.9 (C-4), C6H5SO2), 133.2 (Cp, C6H5SO2), 140.2 (Ci, C6H5SO2), 150.8 (C-
124.7 (C-6), 126.4 (Cm, C6H5), 127.5 (Ci, C6H5), 128.3 (C-3a), 128.8 7a), 152.1 (C-2) ppm. C20H14BrNO3S (428.30): calcd. C 56.09, H
(Co, 4-ClC6H4), 129.0 (Co, C6H5), 129.4 (Cm, 4-ClC6H4), 129.9 (C- 3.29, N 3.27, S 7.49; found C 56.15, H 3.32, N 3.35, S 7.57.
5), 130.0 (Cp, C6H5), 138.5 (Cp, 4-ClC6H4), 138.5 (Ci, 4-ClC6H4),
N-(5-Fluoro-2-phenylbenzofuran-3-yl)benzenesulfonamide
(3bc):
146.4 (C-7a), 153.4 (C-2) ppm. C20H11Cl3NO3S (451.73): calcd. C
53.18, H 2.45, Cl 23.54, N 3.10, S 7.10; found C 53.25, H 2.50, Cl
23.45, N 3.06, S 7.02.
Colorless needles; m.p. 192–194 °C; yield 1.62 g (44%). IR (KBr):
ν = 1165, 1337 (SO ), 3265 (NH) cm–1. 1H NMR ([D6]DMSO,
˜
2
400.13 MHz): δ = 6.74 (dd, 4J = 2.7, JH,F = 8.7 Hz, 1 H, 4-H),
3
3
4
3
4-Chloro-N-(5,7-dibromo-2-phenylbenzofuran-3-yl)benzenesulfon- 7.10 (m, J = 9.1, J = 2.7, JH,F = 9.3 Hz, 1 H, 6-H), 7.43 (m, 3
amide (3af): Colorless needles; m.p. 235–236 °C; yield 4.23 g (78%). H, Hm, Hp, C6H5), 7.44 (m, 2 H, Hm, C6H5SO2), 7.59 (d, 3J =
IR (KBr): ν = 1164, 1336 (SO ), 3263 (NH) cm–1. H NMR ([D ]- 9.1 Hz, 1 H, 7-H), 7.59 (m, 1 H, Hp, C6H5SO2), 7.70 (m, 2 H, Ho,
1
˜
2
6
DMSO, 400.13 MHz): δ = 6.89 (d, 4J = 1.3 Hz, 1 H, 6-H), 7.42 C6H5SO2), 7.95 (m, 2 H, Ho, C6H5), 10.16 (s, 1 H, NH) ppm. 13C
2
(m, 3 H, Hm, Hp, C6H5), 7.45 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4), 7.63 NMR ([D6]DMSO, 100.61 MHz): δ = 104.7 (d, JC,F = 26.5 Hz,
3
2
(AAЈBBЈ, 2 H, Ho, 4-ClC6H4), 7.68 (d, 4J = 1.3 Hz, 1 H, 4-H), 7.92
C-4), 112.7 (d, JC,F = 9.6 Hz, C-7), 112.7 (d, JC,F = 26.2 Hz, C-
4
(m, 2 H, Ho, C6H5), 10.36 (s, 1 H, NH) ppm. 13C NMR ([D6]-
6), 113.5 (d, JC,F = 4.1 Hz, C-3), 126.1 (Cm, C6H5), 126.8 (Cm,
DMSO, 100.61 MHz): δ = 104.7 (C-7), 113.1 (C-4), 115.9 (C-3), C6H5SO2), 128.1 (d, 3JC,F = 10.7 Hz, C-3a), 128.3 (Ci, C6H5), 128.5
121.3 (C-6), 126.3 (Cm, C6H5), 127.5 (Ci, C6H5), 128.7 (Co, 4- (Co, C6H5), 129.1 (Co, C6H5SO2), 129.4 (Cp, C6H5), 133.0 (Cp,
ClC6H4), 128.9 (Co, C6H5), 129.4 (Cm, 4-ClC6H4), 129.5 (C-5),
129.9 (C-3a), 130.0 (Cp, C6H5), 138.5 (Cp, 4-ClC6H4), 138.5 (Ci, 4- (d, JC,F
C6H5SO2), 140.3 (Ci, C6H5SO2), 148.5 (C-7a), 152.5 (C-2), 158.4
1
=
237.7 Hz, C-5) ppm. 19F NMR ([D6]DMSO,
ClC6H4), 148.1 (C-7a), 153.2 (C-2) ppm. C20H12Br2ClNO3S
(541.64): calcd. C 44.35, H 2.23, N 2.59, S 5.92; found C 44.48, H
2.29, N 2.54, S 6.01.
376.50 MHz): δ = 120.06 ppm. C20H14FNO3S (367.39): calcd. C
65.38, H 3.84, N 3.81, S 8.73; found C 65.31, H 3.88, N 3.90, S
9.02.
4-Chloro-N-(5-methyl-2-phenyl-1-benzofuran-3-yl)benzenesulfon- N-(5-Nitro-2-phenylbenzofuran-3-yl)benzenesulfonamide (3bd): Col-
amide (3ag): Colorless needles; m.p. 189–191 °C; yield 0.91 g
orless needles; m.p. 247–249 °C; yield 2.36 g (60%). IR (KBr): ν =
˜
(23%). IR (KBr): ν = 1170, 1380 (SO ), 3300 (NH) cm–1. 1H NMR
1169, 1341 (SO2), 1355, 1514 (NO2), 3259 (NH) cm–1. 1H NMR
˜
2
([D6]DMSO, 400.13 MHz): δ = 2.24 (s, 3 H, CH3), 6.54 (d, 4J =
([D6]DMSO, 400.13 MHz): δ = 7.48 (m, 3 H, Hm, Hp, C6H5), 7.48
3
4
4
1.6 Hz, 1 H, 4-H), 7.10 (dd, J = 8.4, J = 1.6 Hz, 1 H, 6-H), 7.40
(m, 2 H, Hm, C6H5SO2), 7.57 (m, 1 H, Hp, C6H5SO2), 7.69 (d, J
(m, 2 H, Hm, C6H5), 7.41 (m, 1 H, Hp, C6H5), 7.44 (d, 3J = 8.4 Hz, = 2.3 Hz, 1 H, 4-H), 7.72 (m, 2 H, Ho, C6H5SO2), 7.85 (d, 3J =
3
4
1 H, 7-H), 7.48 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4), 7.62 (AAЈBBЈ, 2
9.1 Hz, 1 H, 7-H), 8.03 (m, 2 H, Ho, C6H5), 8.18 (dd, J = 9.1, J
H, Ho, 4-ClC6H4), 7.91 (m, 2 H, Ho, C6H5), 10.12 (s, 1 H, NH) = 2.3 Hz, 1 H, 6-H), 10.32 (s, 1 H, NH) ppm. 13C NMR ([D6]-
ppm. 13C NMR ([D6]DMSO, 100.61 MHz): δ = 20.6 (CH3), 110.9
(C-7), 112.8 (C-3), 118.9 (C-4), 125.9 (Cm, C6H5), 126.3 (C-6), 127.1
(C-5), 128.4 (Co, C6H5), 128.6 (C-3a), 128.8 (Co, 4-ClC6H4), 128.9
DMSO, 100.61 MHz): δ = 113.9 (C-7), 114.8 (C-3), 116.3 (C-4),
121.3 (C-6), 126.9 (Cm, C6H5), 127.4 (Cm, C6H5SO2), 128.1 (C-3a),
128.3 (Ci, C6H5), 129.2 (Co, C6H5), 129.8 (Co, C6H5SO2), 130.5 (Cp,
(Ci, C6H5), 129.2 (Cm, 4-ClC6H4), 132.0 (Cp, C6H5), 137.9 (Cp, 4- C6H5), 133.8 (Cp, C6H5SO2), 140.6 (Ci, C6H5SO2), 144.2 (C-5),
ClC6H4), 139.2 (Ci, 4-ClC6H4), 150.5 (C-7a), 151.0 (C-2) ppm.
C21H16ClNO3S (397.88): calcd. C 63.39, H 4.05, N 3.52, Cl 8.91,
S 8.06; found C 63.35, H 4.02, N 3.58, Cl 8.84, S 7.98.
154.2 (C-2), 155.3 (C-7a) ppm. C20H14N2O5S (394.40): calcd. C
60.91, H 3.58, N 7.10, S 8.13; found C 60.87, H 3.53, N 7.15, S
8.19.
N-(5-Chloro-2-phenylbenzofuran-3-yl)benzenesulfonamide
(3ba): N-(5-Chloro-2-phenylbenzofuran-3-yl)-4-methylbenzenesulfonamide
Colorless needles; m.p. 191–192 °C; yield 2.73 g (71%). IR (KBr):
(3ca): Colorless needles; m.p. 187–189 °C; yield 2.71 g (68%). IR
ν = 1163, 1332 (SO ), 3258 (NH) cm–1. 1H NMR ([D6]DMSO,
(KBr): ν = 1161, 1333 (SO ), 3265 (NH) cm–1. 1H NMR ([D6]-
˜
˜
2
2
4
3
400.13 MHz): δ = 6.66 (d, J = 1.5 Hz, 1 H, 4-H), 7.26 (dd, J = DMSO, 400.13 MHz): δ = 2.34 (s, 3 H, CH3), 7.24 (AAЈBBЈ, 2 H,
8.8, J = 1.5 Hz, 1 H, 6-H), 7.42 (m, 2 H, Hm, C6H5), 7.44 (m, 1 Hm, 4-CH3C6H4), 7.26 (dd, J = 8.6, J = 2.1 Hz, 1 H, 6-H), 7.44
4
3
4
3
H, Hp, C6H5), 7.47 (m, 2 H, Hm, C6H5SO2), 7.59 (d, J = 8.8 Hz,
1 H, 7-H), 7.59 (m, 1 H, Hp, C6H5SO2), 7.69 (m, 2 H, Ho,
C6H5SO2), 7.96 (m, 2 H, Ho, C6H5), 10.28 (s, 1 H, NH) ppm. 13C
NMR ([D6]DMSO, 100.61 MHz): δ = 113.6 (C-3), 113.6 (C-7),
119.3 (C-4), 125.6 (C-6), 126.7 (Cm, C6H5), 127.4 (C-5), 127.4 (Cm,
(m, 3 H, Hm, Hp, C6H5), 7.54 (AAЈBBЈ, 2 H, Ho, 4-CH3C6H4), 7.60
4
3
(m, 2 H, Ho, C6H5), 6.55 (d, J = 2.1 Hz, 1 H, 4-H), 7.60 (d, J =
8.6 Hz, 1 H, 7-H), 9.93 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
100.61 MHz): δ = 20.9 (CH3), 113.0 (C-7), 113.1 (C-3), 118.7 (C-
4), 124.9 (C-6), 126.2 (Cm, C6H5), 127.0 (Cm, 4-CH3C6H4), 127.6
C6H5SO2), 128.2 (Ci, C6H5), 128.7 (C-3a), 129.1 (Co, C6H5), 129.7 (C-5), 128.2 (Ci, C6H5), 128.5 (C-3a), 128.5 (Co, C6H5), 129.4 (Cp,
(Co, C6H5SO2), 130.1 (Cp, C6H5), 133.7 (Cp, C6H5SO2), 140.9 (Ci, C6H5), 129.6 (Co, 4-CH3C6H4), 137.2 (Cp, 4-CH3C6H4), 143.7 (Ci,
C6H5SO2), 151.0 (C-7a), 152.8 (C-2) ppm. C20H14ClNO3S (383.85):
calcd. C 62.58, H 3.68, Cl 9.24, N 3.65, S 8.35; found C 62.53, H
3.71, Cl 9.36, N 3.59, S 8.39.
4-CH3C6H4), 150.4 (C-7a), 152.4 (C-2) ppm. C21H16ClNO3S
(397.88): calcd. C 63.39, H 4.05, Cl 8.91, N 3.52, S 8.06; found C
63.31, H 4.08, Cl 9.01, N 3.61, S 8.14.
N-(5-Bromo-2-phenylbenzofuran-3-yl)benzenesulfonamide
(3bb): Synthesis of 4-Chloro-N-[2,2-dichloro-1-(4-chlorophenoxy)-2-phen-
Colorless needles; m.p. 197–198 °C; yield 1.28 g (30%). IR (KBr):
ylethyl]benzenesulfonamide (4aa) and 4-Chloro-N-(2,2-dichloro-1-
hydroxy-2-phenylethyl)benzenesulfonamide (5): 4-Chloro-N-(2,2-
ν = 1163, 1331 (SO ), 3259 (NH) cm–1. 1H NMR ([D6]DMSO,
˜
2
4
3
400.13 MHz): δ = 6.77 (d, J = 1.7 Hz, 1 H, 4-H), 7.39 (dd, J = dichloro-2-phenylethylidene)benzenesulfonamide (1a; 10 mmol,
8.8, 4J = 1.7 Hz, 1 H, 6-H), 7.45 (m, 3 H, Hm, Hp, C6H5), 7.45 (m, 3.63 g) and 4-chlorophenol (2a; 10 mmol, 1.29 g) were stirred in
2 H, Hm, C6H5SO2), 7.55 (d, 3J = 8.8 Hz, 1 H, 7-H), 7.62 (m, 1 H, CCl4 (10 mL) for 5 h at room temp., either in the absence of a
Hp, C6H5SO2), 7.69 (m, 2 H, Ho, C6H5SO2), 7.97 (m, 2 H, Ho,
C6H5), 10.12 (s,
H, NH) ppm. 13C NMR ([D6]DMSO, Entries 1–6 and 15–16). The reaction mass was kept in the cold for
100.61 MHz): δ = 112.7 (C-3), 113.5 (C-7), 115.6 (C-4), 121.7 (C- 12 h, then the precipitate of compound 4aa was filtered off and
catalyst or in the presence of Lewis or Brønsted acids (Table 1,
1
6), 126.1 (Cm, C6H5), 126.9 (Cm, C6H5SO2), 127.7 (C-5), 128.1 (Ci,
C6H5), 128.5 (Co, C6H5), 129.0 (C-3a), 129.2 (Cp, C6H5), 129.2 (Co,
recrystallized from CHCl3. Upon standing in humid air or in water,
compound 4aa was quantitatively converted into compound 5.
Eur. J. Org. Chem. 2011, 4415–4421
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4419

I. B. Rozentsveig et al.
FULL PAPER
Compound 5 was also obtained in quantitative yield by exposing
imine 1a to humid air for 20 h.
C14H10Cl5NO3S (449.56): calcd. C 37.40, H 2.24, Cl 39.43, N 3.12,
S 7.13; found C 37.31, H 2.20, Cl 39.48, N 3.06, S 7.26.
4-Chloro-N-[2,2-dichloro-1-(4-chlorophenoxy)-2-phenylethyl]benz-
enesulfonamide (4aa): Colorless moisture-sensitive solid; m.p. 111–
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of the products obtained.
113 °C; yield without a catalyst (Table 1, Entry 1): 3.68 g (74%).
1
IR (KBr): ν = 1170, 1340 (SO ), 3290 (NH) cm–1. H NMR ([D ]-
˜
2
6
DMSO, 400.13 MHz): δ = 5.32 (d, 3J = 10.1 Hz, 1 H, CHCCl2),
7.18 (AAЈBBЈ, 2 H, Ho, C6H4O), 7.04 (AAЈBBЈ, 2 H, Hm, C6H4O),
7.30 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4), 7.42 (m, 3 H, Ho, Hp, C6H5),
7.49 (AAЈBBЈ, 2 H, Ho, 4-ClC6H4), 7.81 (m, 2 H, Hm, C6H5), 8.52
(d, 3J = 10.1 Hz, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
100.61 MHz): δ = 86.0 (CHCCl2), 96.9 (CCl2), 114.5 (Co, C6H4O),
125.9 (Cm, C6H4O), 127.4 (Cm, C6H5), 127.8 (Co, C6H5), 128.2 (Co,
4-ClC6H4), 128.7 (Cm, 4-ClC6H4), 129.6 (Cp, C6H5), 136.9 (Ci,
C6H5), 138.3 (Cp, 4-ClC6H4), 140.3 (Ci, 4-ClC6H4), 145.1 (Cp,
C6H4O), 154.3 (Ci, C6H4O) ppm.
[1]
[2]
a) B. A. Keay, P. W. Dibble, Comprehensive Heterocyclic Chem-
istry II, Pergamon Press, Oxford, 1996, p. 395–436; b) B. H.
Lipshutz, Chem. Rev. 1986, 86, 795–819; c) D. M. X. Donelly,
M. J. Meegan, Comprehensive Heterocyclic Chemistry IV, Per-
gamon Press, New York, 1984, p. 657–712; d) C. W. Bird,
G. W. H. Cheeseman, Comprehensive Heterocyclic Chemistry
IV, Pergamon Press, New York, 1984, p. 89–147.
a) T. Yuan, S.-P. Yang, H.-Y. Zhang, S.-G. Liao, W. Wang, Y.
Wu, X.-C. Tang, J.-M. Yue, J. Asian Nat. Prod. Res. 2009, 11,
243–249; b) C. C. Hughes, D. Trauner, Angew. Chem. 2002, 41,
1569–1572; c) D. E. Fuerst, B. M. Stoltz, J. L. Wood, Org. Lett.
2000, 2, 3521–3523; d) J. Boukouvalas, M. Pouliot, J. Rob-
ichaud, S. MacNeil, V. Snieckus, Org. Lett. 2006, 8, 3597–3599;
e) F. Marion, D. E. Williams, B. O. Patrick, I. Hollander, R.
Mallon, S. C. Kim, D. M. Roll, L. Feldberg, R. V. Soest, R. J.
Andersen, Org. Lett. 2006, 8, 321–324; f) G. E. Schneiders, R. J.
Stevenson, J. Org. Chem. 1979, 44, 4710–4711; g) K.-S. Huang,
M. Lin, G.-F. Cheng, Phytochemisty 2001, 58, 357–362; h) O.
Shirota, V. Pathak, S. Sekita, M. Stake, Y. Nagashima, Y. Hi-
rayama, Y. Hakamata, T. Haysahi, J. Nat. Prod. 2003, 66,
1128–1133; i) Y. Okamoto, M. Ojika, Y. Sakagami, Tetrahedron
Lett. 1999, 40, 507–510; j) Y. Okamoto, M. Ojika, S. Suzuki,
M. Murakami, Y. Sakagami, Bioorg. Med. Chem. 2001, 9, 179–
183; k) D. M. X. Donnelly, T. O’Cridain, M. O’Sullivan, J.
Chem. Soc., Chem. Commun. 1981, 1254–1255.
4-Chloro-N-(2,2-dichloro-1-hydroxy-2-phenylethyl)benzenesulfon-
amide (5): Colorless needles; m.p. 86–88 °C; yield 3.73 g (98%). IR
1
(KBr): ν = 1170, 1340 (SO ), 3270 (NH), 3460 (OH) cm–1. H
˜
2
NMR ([D6]DMSO, 400.13 MHz): δ = 5.37 (d, 3J = 9.3 Hz, 1 H,
CH), 7.24 (br. s, 1 H, OH), 7.41 (m, 2 H, Ho, C6H5), 7.42 (m, 1 H,
Hp, C6H5), 7.58, 7.80 (AAЈBBЈ, 4 H, 4-ClC6H4), 7.91 (m, 2 H, Hm,
C6H5), 8.58 (d, 3J = 9.3 Hz, 1 H, NH) ppm. 13C NMR ([D6]DMSO,
100.61 MHz): δ = 84.7 (CHCCl2), 95.5 (CCl2), 127.9 (Co, C6H5),
128.6 (Cm, C6H5), 129.2 (Co, 4-ClC6H4), 129.4 (Cm, 4-ClC6H4),
129.7 (Cp, C6H5), 137.5 (Ci, C6H5), 139.7 (Ci, 4-ClC6H4), 141.3 (Cp,
4-ClC6H4) ppm. C14H12Cl3NO3S (380.67): calcd. C 44.17, H 3.18,
Cl 27.94, N 3.68, S 8.42; found C 45.13, H 3.25, Cl 27.42, N 3.61,
S 8.58.
[3]
Synthesis of 4-Chloro-N-[2,2-dichloro-1-(4-hydroxyphenyl)-2-phenyl-
ethyl]benzenesulfonamide (6): Compound 6 was obtained from
imine 1a and phenol (2i) under the conditions used for the synthesis
of benzofurans 3. Colorless solid; m.p. 157–159 °C; yield 4.34 g
a) R. E. Ziegert, J. Toräng, K. Knepper, S. Bräse, J. Comb.
Chem. 2005, 7, 147–169; b) R. Fleischer, M. Wiese, J. Med.
Chem. 2003, 46, 4988–5004; c) J. J. Marugán, C. Manthey, B.
Anaclerio, L. Lafrance, T. Lu, T. Markotan, K. A. Leonard,
C. Crysler, E. Eisennagel, M. Dasgupta, B. Tomczuk, J. Med.
Chem. 2005, 48, 926–934; d) S. Butini, S. Gemma, G. Campi-
ani, S. Franceschini, F. Trotta, M. Borriello, N. Ceres, S. Ros,
S. S. Coccone, M. Bernetti, M. D. Angelis, M. Brindisi, V.
Nacci, I. Fiorini, E. Novellino, A. Cagnotto, T. Mennini, K.
Sandager-Nielsen, J. T. Andreasen, J. Scheel-Kruger, J. D.
Mikkelsen, C. Fattorusso, J. Med. Chem. 2009, 52, 151–159; e)
O. Saku, M. Saki, M. Kurokawa, K. Ikeda, T. Takizawa, N.
Uesaka, Bioorg. Med. Chem. Lett. 2010, 20, 1090–1093; f) S.
Rizzo, C. Riviare, L. Piazzi, A. Bisi, S. Gobbi, M. Bartolini, V.
Andrisano, F. Morroni, A. Tarozzi, J.-P. Monti, A. Rampa, J.
Med. Chem. 2008, 51, 2883–2886; g) S. Boyle, S. Guard, M.
Higginbottom, D. C. Horwell, W. Howson, A. T. McKnight,
K. Martin, M. C. Pritchard, J. O’Toole, J. Raphy, D. C. Rees,
E. Roberts, K. J. Watling, G. N. Woodruff, J. Hughes, Bioorg.
Med. Chem. 1994, 2, 357–370; h) R. Kiyama, T. Homna, K.
Hayashi, M. Ogawa, M. Hara, M. Fujimoto, T. Fujishita, J.
Med. Chem. 1995, 38, 2728–2741; i) S. Yoo, S.-H. Kim, S.-H.
Lee, N.-J. Kim, D.-W. Lee, Bioorg. Med. Chem. 2000, 8, 2311–
2316; j) J. Gubun, H. de Vogelaer, H. Inion, C. Houben, J. Luc-
chetti, J. Mahaux, G. Rosseels, M. Peiren, M. Clinat, P. Polster,
P. Chatelain, J. Med. Chem. 1993, 36, 1425–1433; k) A. E. Ko-
zikowsky, WO 010008, 2006 (Chem. Abstr. 2006, 144, 164278);
l) K. A. Ohemeng, M. A. Apollina, V. N. Nguyen, C. F.
Schwender, M. Singer, M. Steber, J. Araseli, D. Argentieri, W.
Hageman, J. Med. Chem. 1994, 37, 3663–3667.
(95%). IR (KBr): ν = 1170, 1340 (SO ), 3160 (NH), 3340 (OH)
˜
2
cm–1. 1H NMR ([D6]DMSO, 400.13 MHz): δ = 5.06 (d, 3J =
10.7 Hz, 1 H, CHCCl2), 6.32 (AAЈBBЈ, 2 H, Hm, C6H4OH), 6.78
(AAЈBBЈ, 2 H, Ho, C6H4OH), 7.30 (AAЈBBЈ, 2 H, Hm, 4-ClC6H4),
7.33 (m, 1 H, Hp, C6H5), 7.34 (m, 2 H, Ho, C6H5), 7.47 (AAЈBBЈ,
2 H, Ho, 4-ClC6H4), 7.54 (m, 2 H, Hm, C6H5), 8.75 (d, 3J = 10.7 Hz,
1 H, NH), 9.30 (s, 1 H, OH) ppm. 13C NMR ([D6]DMSO,
100.61 MHz):
δ = 63.4 (CHCCl2), 95.8 (CCl2), 113.7 (Cm,
C6H4OH), 124.7 (Ci, C6H4OH), 127.3 (Co, C6H5), 127.9 (Cm,
C6H5), 128.3 (Co, 4-ClC6H4), 128.4 (Cm, 4-ClC6H4), 129.2 (Cp,
C6H5), 130.4 (Co, C6H4OH), 136.7 (Cp, 4-ClC6H4), 139.7 (Ci,
C6H5), 139.8 (Ci, 4-ClC6H4), 156.9 (Cp, C6H4OH) ppm.
C20H16Cl3NO3S (456.77): calcd. C 52.59, H 3.53, Cl 23.28, N 3.07,
S 7.02; found C 52.53, H 3.05, Cl 23.48, N 3.00, S 7.68.
Synthesis of 4-Chloro-N-[2,2,2-trichloro-1-(5-chloro-2-hydroxy-
phenyl)ethyl]benzenesulfonamide (7): Compound 7 was obtained
from chloralimine 1d and 4-chlorophenol (2a) by the procedure
described for benzofurans 3. Colorless solid; m.p. 199–201 °C; yield
3.92 g (87%). IR (KBr): ν = 1173, 1343 (SO ), 1583 (C=CAr), 3249
˜
2
(NH), 3520 (OH) cm–1. H NMR ([D6]DMSO, 400.13 MHz): δ =
1
3
3
5.63 (d, J = 10.7 Hz, 1 H, CHCCl3), 6.63 (d, J = 8.7 Hz, 1 H, 6-
H), 7.02 (dd, 3J = 8.7, J = 2.5 Hz, 1 H, 4-H), 7.32 (AAЈBBЈ, 2 H,
4
4
Hm, 4-ClC6H4), 7.44 (d, J = 2.5 Hz, 1 H, 6-H), 7.54 (AAЈBBЈ, 2
[4]
a) R. Romagnoli, P. G. Baraldi, T. Sarkar, M. D. Carrion, O.
Cruz-Lopez, C. L. Cara, M. Tolomeo, S. Grimaudo, A. D. Cri-
stina, M. R. Pipitone, J. Balzarini, R. Gambari, L. Ilaria, R.
Saletti, A. Brancale, E. Hamel, Bioorg. Med. Chem. 2008, 16,
8419–8426; b) K. Ando, Y. Kawamura, Y. Akai, J. Kunitomo,
T. Yokomizo, M. Yamashita, S. Ohta, T. Ohishi, Y. Ohishi, Org.
3
H, Ho, 4-ClC6H4), 9.10 (d, J = 10.7 Hz, 1 H, NH), 10.37 (s, 1 H,
OH) ppm. 13C NMR ([D6]DMSO, 100.61 MHz):
δ = 63.8
(CHCCl3), 101.6 (CCl3), 116.9 (C-3), 122.7 (C-5), 122.8 (C-1),
128.5 (C-6), 128.5 (Co, 4-ClC6H4), 129.0 (Cm, 4-ClC6H4), 129.9 (C-
4), 137.5 (Cp, 4-ClC6H4), 139.2 (Ci, 4-ClC6H4), 154.7 (C-2) ppm.
4420
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4415–4421

A New Synthesis of 3-(Sulfonamido)benzofurans
Biomol. Chem. 2008, 6, 296–307; c) K. Ando, E. Tsuji, Y. Ando,
N. Kuwata, J. Kunitomo, M. Yamashita, S. Ohta, S. Kohno, Y.
Ohishi, Org. Biomol. Chem. 2004, 2, 625–635; d) E. Tsuji, K.
Ando, J. Kunitomo, M. Yamashita, S. Ohta, S. Kohno, Y. Ohi-
shi, Org. Biomol. Chem. 2003, 1, 3139–3141.
O. V. Il’chenko, O. V. Zaremba, S. M. Kovalenko, A. A.
Sherakov, V. P. Chernykh, Synth. Commun. 2007, 37, 2559–
2568.
[8] a) N. Sakai, N. Uchida, T. Konakahara, Tetrahedron Lett.
2008, 49, 3437–3440; b) H. Li, J. Liu, B. Yan, Y. Li, Tetrahedron
Lett. 2009, 50, 2353–2357.
[9] C.-X. Chen, L. Liu, D.-P. Yang, D. Wang, Y.-J. Chen, Synlett
2005, 2047–2051.
[10] K. Kobayashi, Y. Shirai, S. Fukamachi, H. Konishi, Synthesis
2010, 666–670.
[11] G. G. Levkovskaya, T. I. Drozdova, I. B. Rozentsveig, A. N.
Mirskova, Russ. Chem. Rev. 1999, 68, 581–604.
[12] a) L. B. Krivdin, K. A. Chernyshev, G. N. Rosentsveig, I. V.
Ushakova, I. B. Rosentsveig, G. G. Levkovskaya, Magn. Reson.
Chem. 2007, 45, 980–984; b) I. B. Rozentsveig, G. N. Rozents-
veig, A. N. Mirskova, K. A. Chernyshev, L. B. Krivdin, G. G.
Levkovskaya, Russ. J. Gen. Chem. 2008, 78, 1371–1379.
[13] a) P. E. Eaton, G. R. Carlson, J. T. Lee, J. Org. Chem. 1973, 38,
4071–4073; b) N. Yonezawa, T. Hino, K. Matsuda, T. Matsuki,
D. Narushima, M. Kobayashi, T. Ikeda, J. Org. Chem. 2000,
65, 941–944; c) J.-B. Baek, L.-S. Tan, Macromolecules 2006, 39,
2794–2803.
[5]
[6] a) F. Bachechi, V. M. Coiro, M. Delfini, G. Settimj, Acta Crys-
tallogr., Sect. C: Cryst. Struct. Commun. 1988, 44, 1449–1451;
b) N. O. Iskeleli, C. Kazak, C. Kirilmis, M. Koca, Acta Cryst.
Sect. E: Struct. Rep. Online 2005, E61, o1571–o1573; c) F. Ba-
chechi, V. M. Coiro, F. Gatta, G. Settimj, M. Delfini, Acta
Crystallogr., Sect. C: Cryst. Struct. Commun. 1988, 44, 300–
303.
[7] a) K. Gewald, H. J. Jaensch, J. Prakt. Chem. 1973, 315, 779–
785; b) S. Radl, P. Hezky, P. Konvicka, I. Krejci, Collect. Czech.
Chem. Commun. 2000, 65, 1093–1108; c) K. Ando, Y. Akai, J.
Kunitomo, T. Yokomizo, H. Nakajima, T. Takeuchi, M. Yama-
shita, S. Ohta, T. Ohishi, Y. Ohishi, Org. Biomol. Chem. 2007,
5, 655–663; d) F. A. Trofimov, G. F. Lelyak, L. I. Shevchenko,
A. N. Grinev, Chem. Heterocycl. Compd. 1974, 10, 1016–1018;
e) F. A. Trofimov, G. F. Lelyak, L. I. Shevchenko, A. N. Grinev,
Chem. Heterocycl. Compd. 1975, 11, 1129–1131.
[14] G. A. Olah, G. K. S. Prakash, Á. Molnár, J. Sommer in Su-
peracid Chemistry, 2nd ed., John Wiley & Sons Inc., Hoboken,
New Jersey, 2009, pp. 47–49.
[15] M. P. Balfe, W. C. Webber, J. Chem. Soc. 1942, 718–720.
Received: March 15, 2011
Published Online: June 21, 2011
Eur. J. Org. Chem. 2011, 4415–4421
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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