Sulfonylation of arenes with sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2008.06.114

In the presence of triflic anhydride, sulfonylation of arenes with sulfonamides proceeded smoothly in Cl₂CHCHCl₂ at 80-140 °C, which gave rise to the desired products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.06.114

Tetrahedron Letters 49 (2008) 5385–5388
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Tetrahedron Letters
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Sulfonylation of arenes with sulfonamides
*
Bangben Yao, Yuhong Zhang
Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of triflic anhydride, sulfonylation of arenes with sulfonamides proceeded smoothly in
Cl2CHCHCl2 at 80–140 °C, which gave rise to the desired products in good to excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 22 April 2008
Revised 24 June 2008
Accepted 27 June 2008
Available online 1 July 2008
Keywords:
Friedel–Crafts sulfonylation
Sulfonamide
Aromatics
Triflic anhydride
The aryl sulfones are common structures in valuable molecules
in fields such as pharmaceuticals, agrochemicals, and polymer sci-
ences.1 In particular, their immense utilities in medicinal chemis-
try and their unique bioactivities have attracted considerable
attention on their synthesis. For example, diaryl sulfones have
been reported to inhibit HIV-12 reverse transcriptase, and diphenyl
sulfone3 is used as an intermediate for the synthesis of 4,40-diami-
no-diphenyl sulfone (DAPSONE), which is effective for leprosy
treatment.4 The aryl sulfones can be prepared from the transition
metal-catalyzed reactions using sulfonic acids or sulfonyl chlo-
ride,5 but the pre-functionalizing such as metallization or halogen-
ations of arenas are required. A well-known process involving the
formation of new C–S bond from aromatic C–H bonds is the
Friedel–Crafts (FC) sulfonylation of various arenes, especially
electron-rich arenes.6,7 Sulfonchlorides or sulfonanhydrides are
general substrates employed in the FC sulfonylation. However, sul-
fonamides, which are much cheaper than sulfonchlorides and sul-
fonanhydrides, can be easily available by reacting sulfinic acid salts
with an electrophilic nitrogen sources such as hydroxylamine-O-
sulfonic acid, have not been explored as a substrate of FC sulfony-
lation. The stability of sulfonamides to air and moisture requires no
special caution to handle and is amenable to long-term storage. In
these respects sulfonamides have a clear advantage as the sulfonyl-
ation substrates over the sulfonchlorides and sulfonanhydrides.
Herein, we report the FC sulfonylation of arenes using sulfona-
mides in the presence of triflic anhydride.8
sulfonamide as a model reaction. A variety of Lewis acids and Br/
nsted acids were tested and the results are presented in Table 1.
The sulfone product was not observed in the presence of 2 equiv
AlCl3, 2 equiv FeCl3 (Table 1, entries 1–2). Cu(OTf)2 (20 mol %)
was fully inactive to the reaction (Table 1, entry 3). Among the var-
ious Br/nsted acids (H2SO4, CF3COOH, and CF3SO3H), a 58% yield
was obtained using triflic acid (Table 1, entries 4–6). When the
sulfonylation reaction was carried out in the presence of 1 equiv
triflic anhydride, we obtained quite satisfactory results in
Cl2CHCHCl2 at 120 °C for 12 h (Table 1, entry 7). The solvents
exerted remarkable effect on the sulfonylation reaction and low
conversions were obtained in nitrobenzene, nitromethane, and
benzenenitrile (Table 1, entries 8–10). The reaction became slower
at lower temperature and no reaction occurred at room tempera-
ture (Table 1, entries 11–12).
Due to its great activity and ready availability, Tf2O was sub-
sequently used to a range of FC sulfonylation reactions and the
results are summarized in Table 2. The sulfonylation of various
arenes furnished sulfones with good to excellent isolated yields.
The reaction of volatile benzene was performed at 80 °C due to
its lower boiling point and a 70% yield was obtained for 24 h (Table
2, entry 1). p-Xylene and mesitylene delivered excellent yields at
120 °C for 12 h (Table 2, entries 2–3), and the sulfonylation of
meta-xylene afforded exclusively the less hindered ortho-substi-
tuted product in high yield (Table 2, entry 4). These impressive
results were comparable with bismuth(III) triflate catalytic system
using sulfonchloride and sulfonanhydride and showed sulfon-
amide was a good alternative substrate for sulfones.4,9 Activated
arenes such as anisole and toluene afforded the corresponding sulf-
ones in good yields, and similar with the Lewis acid catalyzed sys-
tems, isomers were observed (Table 2, entries 5–6). When the
To examine the reactivity of sulfonamides to the FC sulfonyl-
ation, we carried out the sulfonylation of p-xylene with p-toluene-
* Corresponding author. Tel.: +86 571 87952723; fax: +86 571 87953244.
E-mail address: yhzhang@zjuem.zju.edu.cn (Y. Zhang).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.114

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B. Yao, Y. Zhang / Tetrahedron Letters 49 (2008) 5385–5388
Table 1
Sulfonylation of 4-methylbenzenesulfonamide with p-xylenea
O
O
S
Catalyst
S NH2
O
Solvent, 12 h
O
Entry
Catalyst
Solvent
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
AlCl3, 2 equiv
FeCl3, 2 equiv
Cu(OTf)2, 20 mol %
H2SO4, 1 equiv
CF3CO2H, 1 equiv
CF3SO3H, 1 equiv
(CF3SO2)2O, 1 equiv
(CF3SO2)2O, 1 equiv
(CF3SO2)2O, 1 equiv
(CF3SO2)2O, 1 equiv
(CF3SO2)2O, 1 equiv
(CF3SO2)2O, 1 equiv
CHCl2CHCl2
CHCl2CHCl2
CHCl2CHCl2
CHCl2CHCl2
CHCl2CHCl2
CHCl2CHCl2
CHCl2CHCl2
PhNO2
CH3NO2
PhCN
CHCl2CHCl2
CHCl2CHCl2
120
120
120
120
120
120
120
120
120
120
80
NR
NR
NR
Trace
NR
58
95
Trace
NR
NR
10
11
12
42
NR
rt
a
Reaction conditions: 4-methylbenzenesulfonamide 0.5 mmol (85 mg), p-xylene 1.0 mmol (106 mg), solvent 3 mL, 12 h.
Isolated yields.
b
Table 2
Sulfonylation reactions of sulfonamide catalyzed by triflic anhydridea
O
O
S
1 equiv Tf2O
S NH2
R2
R1
Cl2CHCHCl2
80-140 oC
R1
R2
O
O
Entry
1
Aryl
Arene
Product
Yieldb (%)
70
O
S
O
O
S
2
3
4
5
95
89
90
86
O
O
S
O
O
S
O
O
S
OMe
OMe
O
p:o:m =63:20:3c
O
S
O
6
7
86
83
p:o:m =68:14:4c
O
S
O
p:o=72:11c

B. Yao, Y. Zhang / Tetrahedron Letters 49 (2008) 5385–5388
5387
Table 2 (continued)
Entry
Aryl
Arene
Product
Yieldb (%)
92
O
S
8
9
O
β:α=18:74d
O
S
85
Cl
Cl
O
O
S
10
11
12
13
89
83
95
84e
Br
I
Br
I
O
O
S
O
O
S
O
O
Cl
Cl
S
O
O
O2N
S
14
15
75e
42e
O2N
O2N
O
p:o=68:7c
CH3
O
S
O2N
O
H3C
O
S
16
86f
58
S
S
O
O
O
17
H3C S NH2
H3C
S
O
O
a
Reaction conditions: sulfonamides 0.5 mmol, arene 1 mmol, triflic anhydride 0.5 mmol, CHCl2CHCl2 3 mL, 120 °C, 12 h.
Isolated yield.
Determined by GC–MS.
Determined by 1H NMR.
Reaction temperature was 140 °C.
Reaction temperature was 80 °C.
b
c
d
e
f
biphenyl was used as the substrate, the ratio of para-substituted
product was increased and only trace of the ortho-substituted iso-
mer was isolated (Table 2, entry 7), m-isomer was not observed. In
the case of naphthalene, the dynamically stable isomer was prefer-
entially generated (Table 2, entry 8). The deactivated aromatic
halides such as chlorobenzene, bromobenzene and iodobenzene,
could be easily converted to the corresponding sulfones with
excellent para-selectivity (Table 2, entries 9–11). It is important
to note that the arylsulfonamides with deactivated substitutes in
the phenyl ring such as –Cl and –NO2 could carry out the desired
FC sulfonylation reactions at higher temperature and gave in mod-
erate to good yields (Table 2, entries 13–15). 2-Thiophenyl sulfon-
OTf
R S NH2
O
Tf2O
R S NH2
O
TfO
O
1
Ar-H
TfOH
O
R S Ar
O
Ar
hydrolysis
R S NH2
O
Scheme 1. The plausible mechanism.

5388
B. Yao, Y. Zhang / Tetrahedron Letters 49 (2008) 5385–5388
O
O
S
1 equivTf2O
S NHPh
O
Cl2CHCHCl2
80 oC, 12 h
O
Isolated yield: 93%
O
O
C
1 equivTf2O
C NHPh
+
Cl2CHCHCl2
120 oC, 12 h
Isolated yield: 43%
O
O
C
1 equivTf2O
C NH2
+
Cl2CHCHCl2
120 oC, 12 h
Isolated yield: 0
Scheme 2. The acylation reactivity of N-phenyl amide.
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amide also showed good reactivity and delivered the desired sulf-
onylation product in good yield (Table 2, entry 16). The alkylsulf-
onamide was less active with respect to arylsulfonamide (Table
2, entry 17).
Because sulfonamides were used as the acylation substrates, the
sulfiminium salt intermediate 1 via a Vilsmeier-Haack process10 is
possibly formed in the presence of triflic anhydride, which should
be a potential agent for the FC sulfonylation and generates the FC
sulfonylation product 2 with arene (Scheme 1).11 The subsequent
hydrolysis gives the desired sulfone product. Concerning the inter-
mediate, 1 and 2, their stability should be enhanced by the substi-
tution of phenyl on amide and hence their reactivity should be
higher. Indeed, we found that N-phenyl-p-toluenesulfonamide
showed much higher activity to give the sulfonylation product in
93% yield at 80 °C (Scheme 2), indicating that the phenyl on the
amide facilitates the reaction. The similar results were observed
in the cases of benzamide and N-phenylbenzamide, where benz-
amide did not react with p-xylene, and a 43% yield of acylation
product was obtained for N-phenylbenzamide under the reaction
conditions (Scheme 2).
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4423–4425; (e) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Parisi, L. M. Org. Lett.
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In Comprehensive Chemical Kinetics; Banford, C. H., Tipper, C. F. H., Eds.; Elsevier:
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6808; (b) Khodaei, M. M.; Alizadeh, A.; Nazari, E. Tetahedron Lett. 2007, 48,
4199–4202; (c) Corey, E. J.; Tian, Y. Org. Lett. 2005, 7, 5535–5537.
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Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu, Q. Org. Lett. 2007, 9, 2421–
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Effenberger, F.; Huthmacher, K. Angew. Chem., Int. Ed. 1974, 13, 409–410.
12. General procedure for sulfonylation: A mixture of sulfonamides (0.5 mmol),
arenes (1 mmol), triflic anhydride (1 mmol) in 3 mL Cl2CHCHCl2 was stirred at
120 °C for 12 h. Afterward, the reaction solution was cooled to room
temperature and the solvent was removed under reduced pressure. The
further purification of the product was achieved by flash chromatography on a
silica gel column. Selected spectroscopic data: 4-(4-nitrophenyl-
sulfonyl)biphenyl. White solid; mp 187–188 °C; 1H NMR (CDCl3, 400 MHz,
TMS) 8.36 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.75
(d, J = 8.0 Hz, 2H), 7.57 (d, J = 6.8 Hz, 2H), 7.41–7.49 (m, 3H) ppm; 13C NMR
(CDCl3, 125 MHz, TMS) 150.6, 147.7, 147.4, 139.0, 138.6, 129.4, 129.2, 129.1,
128.8, 128.5, 127.6, 124.8 ppm; MS (ESI) m/z 362 (100%) [M+Na]+. HRESIMS:
m/z calcd for [M+Na]+ C18H13NSO4, 362.0457, found 362.0452.
In conclusion, we have described an unusual process of arenes
with sulfonamides to produce arylsulfones in the presence of triflic
anhydride.12 The method provides a direct process for the synthe-
sis of arylsulfones. The transformation has been shown to be high
yielding and constitutes a useful alternative to the commonly
accepted sulfonylation procedures.
Acknowledgement
This work was supported by the Natural Science Foundation of
China (No. 205710631).
References and notes
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S. H.; Levesque, J.-F.; Seto, C.; Silva, J. H.; Trimble, L. A.; Carriere, M.-C.; Denis,
D.; Greig, G.; Kargman, S.; Lamontagne, S.; Mathieu, M.-C.; Sawyer, N.; Slipetz,
D.; Abraham, W. M.; Jones, T.; McAuliffe, M.; Piechuta, H.; Nicoll-Griffith, D. A.;
Wang, Z.; Zamboni, R.; Young, R. N.; Metters, K. M. J. Med. Chem. 2007, 50, 794–
806; (b) Trost, B. M.; Shen, H. C.; Surivet, J.-P. J. Am. Chem. Soc. 2004, 126,
12565–12579; (c) Adams, C. M.; Ghosh, I.; Kishi, Y. Org. Lett. 2004, 6, 4723–
4726; (d) Artico, M.; Silvestri, R.; Pagnozzi, E.; Bruno, B.; Novellino, E.; Greco,
G.; Massa, S.; Ettorre, A.; Loi, A. G.; Scintu, F.; La Colla, P. J. Med. Chem. 2000, 43,
1886–1888; (e) Michaely, W. J.; Krattz, G. W. U.S. Patent 4,780,127, 1988;
Chem. Abstr. 1989, 111, 129017; (f) Kochi, T.; Noda, S.; Yoshimura, K.; Nozaki, K.
2-(2,5-Dimethylphenylsulfonyl)thiophene. White solid; mp 129–131 °C; 1H
NMR (CDCl3, 400 MHz, TMS) 7.98 (s, 1H), 7.685 (d, J = 3.6 Hz, 1H), 7.63 (d,
J = 4.8 Hz, 1H), 7.285 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.08 (t,
J = 4.6 Hz, 1H), 2.55 (s, 3H), 2.40 (s, 3H) ppm; 13C NMR (CDCl3, 125 MHz, TMS)
143.4, 139.5, 136.9, 135.1, 134.7, 133.5, 133.4, 132.9, 129.5, 127.6, 21.1,
20.0 ppm; MS (ESI) m/z 253 (100%) [M+H]+. HRESIMS: m/z calcd for [M+Na]+
C12H12S2O2, 275.0171, found 275.0176.