Copper-catalyzed cross-coupling of sulfonamides with aryl iodides and bromides facilitated by amino acid ligands

Article abstract of DOI:10.1016/j.tetlet.2005.08.149

A highly general, convenient, and inexpensive catalyst system was developed for the N-arylation of sulfonamides with aryl iodides or bromides by using 5-20 mol % of CuI as catalyst, 20 mol % of N-methylglycine (for aryl iodides) or N,N-dimethylglycine (for aryl bromides) as ligand, and K₃PO ₄ as base.

Full text of DOI:10.1016/j.tetlet.2005.08.149

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7295–7298
Copper-catalyzed cross-coupling of sulfonamides with
aryl iodides and bromides facilitated by amino acid ligands
Wei Deng, Lei Liu,* Chen Zhang, Min Liu and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
Received 18 July 2005; revised 30 August 2005; accepted 30 August 2005
Available online 13 September 2005
Abstract—A highly general, convenient, and inexpensive catalyst system was developed for the N-arylation of sulfonamides with
aryl iodides or bromides by using 5–20 mol % of CuI as catalyst, 20 mol % of N-methylglycine (for aryl iodides) or N,N-dimethyl-
glycine (for aryl bromides) as ligand, and K3PO4 as base.
Ó 2005 Elsevier Ltd. All rights reserved.
Transition metal catalyzed cross-coupling of sulfon-
amides with aryl halides provides a straightforward
route to N-arylsulfonamides. This reaction has recently
received considerable attention because a large number
of pharmaceutically active compounds (e.g., class III
antiarrhythmic agents, non-nucleotide reverse transcript-
ase inhibitors, non-peptidic vasopressin V1a receptor
antagonists, and HIV-1 protease inhibitors) contain an
aryl sulfonamide.1 Up to now catalysts based on two
transition metals have been examined for the N-aryla-
tion of sulfonamides. The first one is Pd, which often re-
quires the use of expensive, unstable, and poisonous
phosphine ligands.2 The second one is Cu, which is more
likely to be used for large scale synthesis because Cu cat-
alysts can often work with relatively cheap nitrogen-cen-
tered ligands.3,4
more, in a related work, Lam et al. reported the synthe-
sis of N-arylsulfonamides through the copper-catalyzed
N-arylation of sulfonamides with arylboronic acids.7
Ma et al.8 and we9 have recently found that simple
amino acids can serve as ligands for Cu(I)-catalyzed
cross-couplings between aryl halides and diverse nucleo-
philes. These catalytic reactions are advantageous not
only because of their high yields, but also because of
the following desirable properties of amino acids. (1)
Amino acid is cheap and safe to use. (2) The amino acid
ligand is easy to remove after the reaction because it is
highly soluble in water. (3) Amino acid waste is rela-
tively environmentally benign. (4) There are a large
number of different amino acids. Most of them are chiral
and we may use them as ligands in the synthesis of
atropisomeric coupling products. To date the Cu(I)/
amino acid catalysts have been successfully utilized for
the cross-coupling of aryl halides with amides, carba-
mates, amines, amino acids, N-heterocycles, sulfinic
acids, alkynes, and azides.8,9 To expand the scope of
the Cu(I)/amino acid-catalyzed reactions, herein we
report our recent application of amino acid ligands to
Cu-catalyzed N-arylation of sulfonamides.
In 2003, He and Wu systematically studied the CuI-cat-
alyzed N-arylation of sulfonamides with a number of
aryl bromides and iodides for the first time.5 No ligand
was utilized in their study but the synthesis required the
use of microwave heating. Although the arylation can be
finished relatively rapidly in the microwave oven (2–4 h),
the yields of the couplings are mostly modest (54–90%).
Later Steinhuebel et al. reported the Cu2O-catalyzed N-
arylation of sulfonamides under normal heating condi-
tions.6 N-Methyl-2-pyrrolidone was used as solvent
and 2,20-bipyridine was utilized as the ligand. The yields
of their couplings ranged from 35% to 93%. Further-
During the course of our study, we have screened many
different combinations of amino acid ligands, bases,
solvents, and reaction temperatures in order to maxi-
mize the cross-coupling yield. The best ligand turns
out to be N-methylglycine, which is a non-expensive
and readily available compound. The most suitable
base is K3PO4 and the best solvent is DMF.9 In order
to test the applicability of the new procedure, we have
*
Corresponding authors. Fax: +86 551 3606689; e-mail addresses:
leiliu@ustc.edu; qxguo@ustc.edu.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.149

7296
W. Deng et al. / Tetrahedron Letters 46 (2005) 7295–7298
Table 1. Yields of the CuI/N-methylglycine-catalyzed coupling reac-
tions between aryl iodides and sulfonamides10
Table 1 (continued)
Entry
Aryl iodide
Sulfonamide
Isolated
yield (%)
O
S
O
S
R'
NH
R'
N
Ar
+
Ar
I
R
R
O
S
O
OCH3
I
O
O
17
76
H3C
NH2
Entry
1
Aryl iodide
Sulfonamide
Isolated
yield (%)
OCH3
I
O
S
O
O
S
O
18
19
20
55
NH2
95
94
H3C
NH2
I
OCH3
I
O
S
O
CH3
NH
O
S
O
Trace
60
2
3
4
NH2
I
I
I
OCH3
I
O
S
O
O
S
O
CH3
NH
H3C
NH2
82
99
O
S
O
H3C
H3C
NH2
examined a few different combinations of aryl iodides
and sulfonamides (see Table 1). It is found that when
iodobenzene, ethyl 4-iodobenzoate and methyl 3-
iodobenzoate are used as aryl iodide, the yields of the
cross-coupling reactions range from 82% to 99% (entries
1–12). Compared to the previous catalytic systems
(where yields = 54–90% or 35–93%),5,6 the present cata-
lytic system is clearly advantageous because it gives sig-
nificantly higher reaction yields. Nonetheless, we found
that when 2-iodotoluene or 2-iodoanisole is used as aryl
iodide, the yields of the cross-couplings become much
lower (entries 13–20), due to steric hindrance of the 2-
methyl or 2-methoxy group. Furthermore, in the cross-
coupling of 2-iodotoluene or 2-iodoanisole with N-
methylbenzenesulfonamide (entries 15 and 19), only
trace amount of product was obtained.
O
S
O
5
6
99
99
NH2
EtOOC
EtOOC
I
O
S
O
NH2
I
I
I
O
S
O
CH3
NH
7
98
95
99
99
99
EtOOC
O
S
O
8
H3C
H3C
NH2
EtOOC
I
O
S
O
9
NH2
Having successfully dealt with aryl iodides, we next try
to optimize a procedure for the cross-coupling between
sulfonamides and aryl bromides. Again, we have
screened different combinations of amino acid ligands,
bases, solvents, and reaction temperatures in order to
maximize the cross-coupling yield. Interestingly, we
found that N,N-dimethylglycine is a more suitable li-
gand than N-methylglycine for aryl bromide.11 Using
the optimized procedure, we have examined the cross-
coupling between a number of different sulfomides and
aryl bromides (see Table 2). We found that the yields
of the cross-couplings mostly range from 80% to 99%.
The cross-coupling reaction proceeds well with aryl bro-
mides with both electron-withdrawing groups (e.g., 4-
bromoacetophenone) and electron-donating groups
(e.g., 4-bromoanisole). The lowest yield (68%) is ob-
tained for the cross-coupling between 4-bromoanisole
and N-methylbenzenesulfonamide (entry 11), where the
steric hindrance of the N-methyl group may exert signifi-
cant negative effects.
COOCH3
I
I
O
S
O
10
11
NH2
COOCH3
O
S
O
CH3
NH
COOCH3
COOCH3
I
O
S
O
12
13
99
50
H3C
H3C
NH2
CH3
O
S
O
NH2
I
CH3
I
O
S
O
14
15
16
56
NH2
CH3
I
O
S
O
CH3
NH
At present the mechanism of the Cu(I)-catalyzed cross-
coupling reaction is not completely clear yet.12 Nonethe-
less, the results from the present study are consistent
with the mechanism in which a four-coordinated Cu(III)
intermediate is involved (Scheme 1).12 According to the
mechanism, the role of the amino acid ligand in the reac-
Trace
80
CH3
I
O
S
O
H3C
NH2

W. Deng et al. / Tetrahedron Letters 46 (2005) 7295–7298
7297
Table 2. Yields of the CuI/N,N-dimethylglycine-catalyzed coupling
reactions between aryl bromides and sulfonamides
O
R2
O
S
R1
O
HX
N
H
O
S
O
S
R'
NH
R'
N
O
O
+
Ar Br
R
R
Ligand exchange
Ar
O
O
NH
(III)Cu
Entry
1
Aryl bromide
Sulfonamide
Isolated
yield (%)
R1
O
NH
(III)Cu
Ar
O
X
N
Ar
O
S
O
O
S
99
95
82
99
91
96
99
89
85
75
68
80
95
91
90
96
H3C
NH2
Br
Br
R2
Oxidative addition
Reductive elimination
O
S
O
2
NH2
O
R2
O
O
S
Ar-X
O
NH
(I)Cu
R1
N
O
S
CH3
NH
3
Br
Ar
O
Scheme 1.
O
S
O
4
H3C
H3C
NH2
Br
nitrogen that participates in the coupling, because in
the Cu(III) complex sulfonamide nitrogen is anionic
(therefore more reactive) whereas the NH group of the
amino acid ligand is neutral.
O
S
O
5
NH2
NH2
NH2
H3C
Br
Br
Br
Br
O
6
S
NH2
H3C
O
In summary, we reported a novel Cu(I)-catalyzed N-aryl-
ation reaction of sulfonamides with aryl bromides and
iodides facilitated by amino acid ligands. Compared to
the previous results,2,5,6 the present coupling reaction
gives significantly higher yields and, at the same time,
it is considerably less expensive and more environmen-
tally benign. The present study provides further evidence
that Cu(I)/amino acid is a powerful catalyst system for
C-heteroatom cross-coupling reactions.8,9 We wish that
the cross-coupling reaction reported here would find
application for the preparation of pharmaceutically
important N-aryl sulfonamides.
O
S
CH3
NH
7
H3C
O
O
S
O
8
H3C
H3C
NH2
H3C
O
S
O
9
H3CO
H3CO
H3CO
Br
O
10
11
12
13
14
15
16
S
NH2
Br
Br
Br
O
O
S
CH3
NH
Acknowledgments
O
O
S
O
This research was supported by the NSFC (Nos.
20332020 and 20472079).
H3C
H3C
NH2
H3CO
O
O
S
O
Br
References and notes
O
O
O
O
1. Very recent examples: (a) Natarajan, A.; Guo, Y.;
Harbinski, F.; Fan, Y.-H.; Chen, H.; Luus, L.; Diercks,
J.; Aktas, H.; Chorev, M.; Halperin, J. A. J. Med. Chem.
2004, 47, 4980; (b) Koehler, N. K. U.; Yang, C.-Y.;
Varady, J.; Lu, Y.; Wu, X.-W.; Liu, M.; Yin, D.; Bartels,
M.; Xu, B.-Y.; Roller, P. P.; Long, Y.-Q.; Li, P.; Kattah,
M.; Cohn, M. L.; Moran, K.; Tilley, E.; Richert, J. R.;
Wang, S. J. Med. Chem. 2004, 47, 4989; (c) Cole, D. C.;
Lennox, W. J.; Lombardi, S.; Ellingboe, J. W.; Bernotas,
R. C.; Tawa, G. J.; Mazandarani, H.; Smith, D. L.;
Zhang, G.; Coupet, J.; Schechter, L. E. J. Med. Chem.
2005, 48, 353; (d) Banerjee, M.; Poddar, A.; Mitra, G.;
Surolia, A.; Owa, T.; Bhattacharyya, B. J. Med. Chem.
2005, 48, 547.
S
NH2
Br
Br
Br
O
O
S
CH3
NH
O
O
S
H3C
NH2
O
tion is either to promote the oxidative addition of aryl
halide to the Cu(I) species or to stabilize the Cu(III)
intermediate. The mechanism also explains why it is
not the amino group of amino acid ligand (e.g., the
N–H group of N-methylglycine) but the sulfonamide
2. (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
4043; (b) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett.
2003, 5, 4373; (c) Alcaraz, L.; Bennion, C.; Morris, J.;
Meghani, P.; Thom, S. M. Org. Lett. 2004, 6, 2705.

7298
W. Deng et al. / Tetrahedron Letters 46 (2005) 7295–7298
3. Reviews: (a) Deng, W.; Liu, L.; Guo, Q. X. Chin. J. Org.
9. (a) Deng, W.; Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X.
Synlett 2004, 1254; (b) Deng, W.; Wang, Y.-F.; Zou, Y.;
Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004, 45, 2311.
10. Typical procedures for the CuI/amino acid-catalyzed
sulfonamide arylation reactions of aryl iodides are as
follows. An oven-dried, three-necked flask is charged with
CuI (47.6 mg, 0.25 mmol, 5.0 mol %), sulfonamides (6.0
mmol), N-methylglycine ligand (1.0 mmol, 20 mol %), and
K3PO4 (2.65 g, 12.5 mmol). The flask is evacuated and
backfilled with nitrogen. Then aryl iodide (5.0 mmol) and
DMF (10.0 ml) are added under nitrogen. The reaction
mixture is stirred under 100 °C for 24 h. The resulting
suspension is cooled to room temperature and the solvent
was removed. The residue is filtered through a 2–3 cm pad
of silica gel with the help of 100 ml of ethyl acetate. The
filtrate is concentrated and the residue is purified by
chromatography to afford pure product.
11. Typical procedures for the CuI/amino acid-catalyzed
sulfonamide arylation reactions of aryl bromides are as
follows. An oven-dried, three-necked flask is charged with
CuI (190.4 mg, 1.00 mmol, 20.0 mol %), sulfonamides
(6.0 mmol), N,N-dimethylglycine (1.0 mmol, 20 mol %),
and K3PO4 (2.65 g, 12.5 mmol). The flask is evacuated and
backfilled with nitrogen. Then aryl iodide (5.0 mmol) and
DMF (10.0 ml) are added under nitrogen. The reaction
mixture is refluxed for 48 h. The resulting suspension is
cooled to room temperature and the solvent was removed.
The residue is filtered through a 2–3 cm pad of silica gel
with the help of 100 ml of ethyl acetate. The filtrate is
concentrated and the residue is purified by chromatogra-
phy to afford pure product.
Chem. 2004, 24, 150; (b) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400; (c) Kunz, K.;
Scholz, U.; Ganzer, D. Synlett 2003, 2428.
4. For recent examples of Cu-catalyzed cross-couplings, see:
(a) Fang, Y.; Li, C. Chem. Commun. 2005, 3574; (b) Xu,
L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2005,
61, 6553; (c) Wang, P.-S.; Liang, C.-K.; Leung, M.-K.
Tetrahedron 2005, 61, 2931; (d) Hu, T.; Li, C. Org. Lett.
2005, 7, 2035; (e) Bates, C. G.; Saejueng, P.; Doherty, M.
Q.; Venkataraman, D. Org. Lett. 2004, 6, 5005; (f) Patil,
N. M.; Kelkar, A. A.; Nabi, Z.; Chaudhari, R. V. Chem.
Commun. 2004, 2368; (g) Antilla, J. C.; Baskin, J. M.;
Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578.
5. He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385.
6. Steinhuebel, D.; Palucki, M.; Askin, D.; Dolling, U.
Tetrahedron Lett. 2004, 45, 3305.
7. Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415.
8. (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am.
Chem. Soc. 1998, 120, 12459; (b) Ma, D.; Xia, C.; Jiang, J.;
Zhang, J. Org. Lett. 2001, 3, 2189; (c) Ma, D.; Xia, C.
Org. Lett. 2001, 3, 2583; (d) Ma, D.; Xia, C.; Jiang, J.;
Zhang, J.; Tang, W. J. Org. Chem. 2001, 68, 442; (e) Ma,
D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453; (f) Ma, D.;
Cai, Q. Org. Lett. 2003, 5, 3799; (g) Ma, D.; Cai, Q.
Synlett 2004, 128; (h) Pan, X.; Cai, Q.; Ma, D. Org. Lett.
2004, 6, 1809; (i) Ma, D.; Liu, F. Chem. Commun. 2004,
1934; (j) Zhu, W.; Ma, D. Chem. Commun. 2004, 888; (k)
Zhu, W.; Ma, D. J. Org. Chem. 2005, 70, 2696; (l) Zhang,
H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164; (m) Cai,
Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis
2005, 496.
12. (a) Cohen, T.; Cristea, I. J. Am. Chem. Soc. 1976, 98, 748;
(b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2002,
4, 4309.