Efficient ligand-free, copper-catalyzed N-arylation of sulfonamides

Article abstract of DOI:10.1055/s-0030-1259925

An efficient and convenient protocol has been developed for the N-arylation of sulfonamides with differently substituted aryl iodides using ligand-free copper iodide to afford the arylated products in good to excellent yields (up to 91%). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1259925

LETTER
837
Efficient Ligand-Free, Copper-Catalyzed N-Arylation of Sulfonamides
C
opper-Catalyzed
o
N
-Arylation
n
of Sulfonam
g
ides -Chua Teo,* Fui-Fong Yong
Natural Sciences and Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore
637616, Singapore
E-mail: yongchua.teo@nie.edu.sg
Received 28 October 2010
of copper catalysts and assisting ligands under mostly in-
Abstract: An efficient and convenient protocol has been developed
ert conditions.18
for the N-arylation of sulfonamides with differently substituted aryl
iodides using ligand-free copper iodide to afford the arylated prod-
ucts in good to excellent yields (up to 91%).
Based on these precedents, there is still a need to develop
economical protocols that provide efficient synthesis of
arylated sulfonamide and to widen the substrate scope un-
der practical reaction conditions. As part of our interest in
ligand-free, copper catalysis and development of sustain-
able strategy for the synthesis of N-arylsulfonamides, we
decided to use copper salts as cheap and readily available
catalyst for this reaction. In this paper, we report an effi-
cient cross-coupling of sulfonamides with a wide variety
of aryl iodides using air-stable, ligand-free CuI as the cat-
alyst and DMF as the solvent. It is noteworthy that these
reactions can be performed without protection from air or
moisture.
Key words: ligand-free, copper, sulfonamides, N-arylation
N-Arylsulfonamides constitute an important class of com-
pound which are prevalent in many pharmaceuticals and
bioactive compounds. In particular, they have been re-
ported to possess biological activities associated with
class III antiarrhythmic agents,1 nonpeptidic vasopressin
VIa receptor antagonists,2 translation initiation inhibi-
tors,3 and HIV-1 protease inhibitors.4 As such, significant
efforts have been channeled to the development of new
and sustainable protocols for the preparation of such com-
pounds.
Copper-catalyzed N-arylation of amines5 (Ullmann con-
densation) and amides6 has emerged as powerful methods
for the formation of C–N bond. In recent years, these re-
actions are usually carried out in the presence of a suitable
mono- or bidentate ligand such as phosphines,7 diols,8
diketone,9 amino acids,10 1,10-phenanthroline deriva-
tives,11 oxalyldihydrazone,12 salicylamides,13 and
phosphoramidite14 to significantly increase the yield of
the product, broaden the substrate scope and also to
achieve milder reaction conditions. In addition, room-
temperature Ullmann arylation reactions have also been
documented recently.15
In our initial study, p-toluenesulfonamide and iodoben-
zene were used as model substrates for optimizing the re-
action conditions. The experiments were carried out with
5 mol% of copper salt and Cs2CO3 as base in DMF at
130 °C (Table 1). It is interesting to note that several cop-
per salts proved applicable for this coupling reaction fur-
nishing the N-phenyltolylsulfonamide in yields ranging
from 46–86% with copper(I) iodide being the best catalyst
(Table 1, entries 1–6). A control experiment was also car-
ried out to confirm that no product was obtained in the ab-
sence of the copper source (Table 1, entry 7). Next, we
probed the solvent effect and found out that DMF was the
best solvent and proved to be critical for the success of this
ligand-free system. Only a trace amount of the products
was detected with the use of water, toluene, and acetoni-
trile as solvents (Table 1, entries 8–10). The influence of
bases on the yield of the N-arylated product was also in-
vestigated. It was found that Cs2CO3 was the most effec-
tive base, while the use of other bases such as K3PO4,
K2CO3, and KOH resulted in much lower yields (Table 1,
entries 11-13). In summary, the optimal conditions for the
N-arylation of p-toluenesulfonamide was achieved using
a combination of CuI (5 mol%) and Cs2CO3 (2 equiv),
stirred in DMF at 130 °C for 24 hours.
Although significant progress has been achieved for the
aforementioned reactions, however, the copper-catalyzed,
cross-coupling reactions using sulfonamides as nitrogen
nucleophiles are limited and still remained as a challenge
among the synthetic community. The cross-coupling of
sulfonamides with aryl boronic acids was first demon-
strated using Cu(OAc)2 as catalyst.16 He and Wu reported
the assembly of N-arylsulfonamides through the ligand-
free, copper-catalyzed arylation of sulfonamides using
microwave heating.17 This method required the use of mi-
crowave heating at 195 °C which limited its practicality.
Recently, the N-arylation of sulfonamides with aryl and
heteroaryl halides was also achieved using a combination
The generality of this methodology was further extended
to the coupling of p-toluenesulfonamide with aryl halides.
The results are shown in Table 2. The corresponding ary-
lated sulfonamides were obtained in good to excellent
yields for substrates with varying types of substitution on
the aryl halides. A range of functional groups such as me-
thyl, methoxy, halo (Cl, Br and F), trifluoromethyl, nitro,
and ester was tolerated by the system. No significant elec-
tronic and steric effects were observed for the meta- and
SYNLETT 2011, No. 6, pp 0837–0843
x
x.
x
x.
2
0
1
1
Advanced online publication: 16.03.2011
DOI: 10.1055/s-0030-1259925; Art ID: D28910ST
© Georg Thieme Verlag Stuttgart · New York

838
Y.-C. Teo, F. F. Yong
LETTER
para-substituted substrates (Table 2, entries 4–12). How-
ever, a steric effect for the ortho-substituted aryl iodides
was observed for the 2-methoxy group but not with the 2-
chloro functionality (Table 2, entries 2 and 3). The proto-
col was limited only to aryl iodides as evident by the low
yields obtained for the bromo counterparts (Table 2, en-
tries 13 and 14).
Table 1 Optimization Studies of Ligand-Free Cross-Coupling of
p-Toluenesulfonamide and Iodobenzenea
O
S
NH2
O
[Cu] (5 mol%)
base
1
+
I
O
S
NH
solvent, 130 °C
air, 24 h
O
Next, we tested the scope of this catalytic system by react-
ing differently substituted sulfonamides with selected aryl
iodides. The results are shown in Table 3. In general, the
corresponding N-arylated sulfonamides were obtained in
good and excellent yields using 10 mol% of catalyst load-
ing (Table 3, entries 1–14). No significant electronic and
steric effects were observed for the electron-donating and
electron-withdrawing substituted sulfonamides. As ex-
pected, neutral and meta-substituted electron-rich/elec-
tron-deficient aryl iodides were excellent electrophilic
counterparts for these coupling reactions.
3
2
Entry
1
[Cu] source Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
toluene
H2O
Yield (%)b
Cu
Cs2CO3
52
82
63
80
46
86
0
2
CuO
Cu2O
CuCl
CuBr
CuI
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
KOH
3
4
In summary, we have developed a versatile and operation-
ally simple ligand-free, CuI-catalyzed cross-coupling pro-
tocol for the arylation of various sulfonamides with aryl
iodides.19 In most instances, the N-arylated derivatives
were obtained in good to excellent yields. The use of
ligands for metal-catalyzed reactions very often incur
costs both in time and material, with many ligands being
more expensive than the metal used. We believe that this
ligand-free coupling strategy is an attractive alternative to
access various N-arylsulfonamides. Exploration into ap-
plications of this ligand-free copper catalytic system to
other cross-coupling is ongoing.
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
trace
0
9
10
11
12
13
trace
36
39
58
DMF
DMF
DMF
K3PO4
a Unless otherwise shown, the reaction was carried out with p-tolu-
enesulfonamide (1.47 mmol), iodobenzene (2.21 mmol), base (2.94
mmol), Cu source (5 mol%) in solvent (0.75 mL) at 130 °C for 24 h.
b Isolated yield after column chromatography.
Table 2 CuI-Catalyzed N-Arylation of p-Toluenesulfonamide with Aryl Halidesa
CuI (5 mol%)
Cs2CO3
O
S
O
S
NH2
+
NH
X
DMF, 130 °C
air, 24 h
R
O
O
2
1
R
3a–k
Entry
1
ArX
Product
Yield (%)b
86
O
S
NH
NH
O
I
3a
3b
O
S
MeO
OMe
2
25
O
I
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LETTER
Copper-Catalyzed N-Arylation of Sulfonamides
839
Table 2 CuI-Catalyzed N-Arylation of p-Toluenesulfonamide with Aryl Halidesa (continued)
CuI (5 mol%)
Cs2CO3
O
S
O
S
NH2
+
NH
X
DMF, 130 °C
air, 24 h
R
O
O
2
1
R
3a–k
Entry
3
ArX
Product
Yield (%)b
72
O
S
Cl
NH
NH
NH
NH
NH
NH
Cl
O
I
I
3c
3d
3e
3f
O
S
4
5
6
7
76
65
73
63
O
O
S
Cl
O
I
I
I
I
Cl
O
S
CF3
O
CF3
O
S
NO2
O
NO2
3g
O
S
O
8
9
74
80
OMe
OMe
3h
3i
O
S
NH
O
I
F
F
O
S
NH
O
10
42
I
Cl
Cl
3j
Synlett 2011, No. 6, 837–843 © Thieme Stuttgart · New York

840
Y.-C. Teo, F. F. Yong
LETTER
Table 2 CuI-Catalyzed N-Arylation of p-Toluenesulfonamide with Aryl Halidesa (continued)
CuI (5 mol%)
Cs2CO3
O
S
O
S
NH2
+
NH
X
DMF, 130 °C
air, 24 h
R
O
O
2
1
R
3a–k
Entry
11
ArX
Product
Yield (%)b
O
S
NH
O
52c
I
Br
Br
3k
O
S
NH
O
12
70
I
CF3
CF3
3l
O
S
NH
NH
13
14
16
14
O
Br
Br
3a
O
S
OMe
O
OMe
a Reaction conditions: p-toluenesulfonamide (1.47 mmol), aryl halides (2.21 mmol), Cs2CO3 (2.94 mmol), CuI (5 mol%) in DMF (0.75 ml) at
130 °C for 24 h.
b Isolated yield after column chromatography.
c Product contains 15% of the regioisomer.
Table 3 CuI-Catalyzed N-Arylation of Sulfonamides with Selected Aryl Halidesa
CuI (10 mol%)
O
S
O
S
Cs2CO3
Ar2I
Ar1
NH
Ar2
Ar1
NH2
+
DMF, 130 °C
Air, 24 h
O
O
4a–n
Entry
1
Ar1SO2NH2
Ar2X
Product
Yield (%)b
86
O
S
NH
NH
O
S
O
NH2
I
O
4a
4b
O
S
O
S
2
71
O
NH2
I
O
Synlett 2011, No. 6, 837–843 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed N-Arylation of Sulfonamides
841
Table 3 CuI-Catalyzed N-Arylation of Sulfonamides with Selected Aryl Halidesa (continued)
CuI (10 mol%)
O
S
O
S
Cs2CO3
Ar2I
Ar1
NH
Ar2
Ar1
NH2
+
DMF, 130 °C
Air, 24 h
O
O
4a–n
Entry
3
Ar1SO2NH2
Ar2X
Product
Yield (%)b
82
O
S
Cl
NH
O
S
O
NH2
I
I
Cl
O
4c
O
S
NH
NH
NH
91
O
S
4
5
6
O
77c
NH2
NH2
NH2
O
4d
4e
O
S
O
S
84
86
O
I
O
O
S
Cl
O
S
O
I
I
Cl
O
4f
O
S
O
S
NH
NH
NH
7
8
76
80
88
73
NH2
NH2
NH2
O
O
4g
4h
O
S
O
S
O
I
O
O
S
O
S
Cl
9
O
I
I
Cl
O
4i
O
S
O
S
F
NH
10
F
F
NH2
O
O
4j
O
S
O
S
F
NH
NH2
11
83
O
I
O
4k
Synlett 2011, No. 6, 837–843 © Thieme Stuttgart · New York

842
Y.-C. Teo, F. F. Yong
LETTER
Table 3 CuI-Catalyzed N-Arylation of Sulfonamides with Selected Aryl Halidesa (continued)
CuI (10 mol%)
O
S
O
S
Cs2CO3
Ar2I
Ar1
NH
Ar2
Ar1
NH2
+
DMF, 130 °C
Air, 24 h
O
O
4a–n
Entry
12
Ar1SO2NH2
Ar2X
Product
Yield (%)b
80
O
S
O
S
Cl
F
NH
F
NH2
O
I
I
Cl
O
4l
O
F3C
S
NH
NH
O
S
13
14
71
82
O
F3C
NH2
O
4m
O
S
Cl
F3C
O
S
O
F3C
NH2
I
Cl
O
4n
a Unless otherwise shown, the reaction was carried out with p-toluenesulfonamide (1.47 mmol), aryl iodides (2.21 mmol), Cs2CO3 (2.94 mmol),
CuI (10 mol%) in DMF (0.75 mL) at 130 °C for 24 h.
b Isolated yield after column chromatography.
c The reaction was performed with CuI (5 mol%).
C. Synthesis 2007, 3519. (f) Sreedhar, B.; Venkanna, G. T.;
Kumar, K. B. S.; Balasubrahmanyam, V. Synthesis 2008,
Supporting Information for this article is available online at
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http://www.thieme-connect.com/ejournals/toc/synlett.
2008, 10, 341. (h) Jammi, S.; Sakthivel, S.; Rout, L.;
Mukherjee, T.; Mandal, S.; Mitra, R.; Saha, R.;
Punniyamurthy, T. J. Org. Chem. 2009, 74, 1971.
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Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311. (b) Chen,
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Acknowledgment
We thank the National Institute of Education and Nanyang Techno-
logical University for their generous financial support.
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Synlett 2011, No. 6, 837–843 © Thieme Stuttgart · New York

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Copper-Catalyzed N-Arylation of Sulfonamides
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(19) Representative Procedure for N-Arylation of
Sulfonamides
A mixture of CuI (Sigma-Aldrich, 99.99%, 0.0735 mmol)
and Cs2CO3 (2.94 mmol) was dissolved in DMF (0.75 mL).
Then, aryl halide (2.21 mmol) and sulfonamide (1.47 mmol)
were added to this reaction vial, and a screw cap was fitted
to it. The reaction mixture was stirred under air in a closed
system at 135 °C for 24 h, then the heterogeneous mixture
was cooled to r.t. and diluted with CH2Cl2. The resulting
solution was directly filtered through a pad of Celite. The
combined organic extracts were dried with anhyd Na2SO4,
and the solvent was removed under reduced pressure. The
crude product was purified by silica gel column chroma-
tography to afford the N-arylated product. The identity and
purity of the products was confirmed by 1H NMR and 13
NMR spectroscopic analysis. Following the general
procedure using p-toluenesulfonamide (1.47 mmol) and
iodobenzene (2.94 mmol) provided 314 mg (86%) of the
coupling product 3a as a yellowish solid after purification by
flash chromatography (hexane–EtOAc, 85:15) of the crude
oil. 1H NMR (400 MHz, CDCl3): d = 7.70 (d, J = 8.3 Hz, 2
H), 7.22–7.18 (m, 4 H), 7.11–7.06 (m, 3 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 143.8, 136.7, 136.0, 129.6,
129.2, 127.3, 125.1, 121.3, 21.5. Anal. Calcd for
C
C13H13NO2S: C, 63.13; H, 5.30; N, 5.66; S, 12.97. Found: C,
62.68; H, 5.29; N, 5.53; S, 12.72.
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