Copper-catalyzed N-arylation of sulfonamides with boronic acids in water under ligand-free and aerobic conditions

Article abstract of DOI:10.1055/s-0033-1340475

An efficient and novel method for the copper-catalyzed arylation of sulfonamides in water under ligand-free conditions is reported. The significant advantages of this methodology are high yields, simple workup procedure, and elimination of toxic materials

Full text of DOI:10.1055/s-0033-1340475

LETTER
▌505
lCettoerpper-Catalyzed N-Arylation of Sulfonamides with Boronic Acids in Water
under Ligand-Free and Aerobic Conditions
N-Arylation of Sulfonamides
Mahmoud Nasrollahzadeh,*a Ali Ehsani,a Mehdi Mahamb
a
Department of Chemistry, Faculty of Science, University of Qom, PO Box 3716146611, Qom, Iran
Fax +98(25)32850953; E-mail: mahmoudnasr81@gmail.com
b
Department of Chemistry, Aliabad Katoul Branch, Islamic Azad University, Aliabad Katoul, Iran
Received: 05.10.2013; Accepted after revision: 23.11.2013
required a prolonged reaction time (2–4 h of microwave
Abstract: An efficient and novel method for the copper-catalyzed
irradiation at 195 °C) and the yields of products were
modest (54–90%).
arylation of sulfonamides in water under ligand-free conditions is
reported. The significant advantages of this methodology are high
yields, simple workup procedure, and elimination of toxic materi-
als.
In continuation of our efforts to develop environmentally
friendly synthetic methodologies,5 we now wish to report
Key words: arylation, arylboronic acid, ligand-free, copper, sul-
fonamide, water
the copper-catalyzed arylation of sulfonamides with aryl-
boronic acids in water under ligand-free and aerobic con-
ditions (Scheme 1).
Sulfonamides are a common substructure present in many
pharmaceuticals and bioactive compounds such as β-
secretase inhibitors for Alzheimer’s disease,1a,b dipeptidyl
peptidase IV inhibitors for diabetes,1c insulin-like growth
factor receptor (IGF-IR) inhibitors for cancer,1d HCV
NS5B polymerase inhibitors for acute hepatitis and chron-
ic liver disease,1e and as antibacterial agents.1f
Cu(OAc)2⋅H2O
R1SO2NHR2
ArBH(OH)2
+
R1SO2NR2Ar
K2CO3, H2O, reflux
Scheme 1
For optimization of the reaction conditions, we chose the
reaction of p-toluenesulfonamide with phenylboronic acid
in water in the presence of 0.2 mmol of Cu(OAc)2·H2O as
the model reaction to examine the effects of the base. As
shown in Table 1, the reaction was influenced significant-
ly by the base employed, and the best result was obtained
with K2CO3 (Table 1, entry 1). The optimum conditions
were found to be 1.0 mmol of phenylboronic acid, 1.0
mmol of p-toluenesulfonamide, 0.2 mmol of
Cu(OAc)2·H2O, and 1 mmol of K2CO3 in H2O (12 mL).
Increasing the amount of copper salt showed no substan-
tial improvement in the yield.
The vast majority of sulfonamides are prepared via the re-
action of sulfonyl chlorides with excess ammonia or pri-
mary or secondary amines. However, this methodology,
when applied to pharmaceutical manufacturing, suffers
from the limitation that both the sulfonyl chloride and ar-
omatic amine are genotoxic alerting structures, bearing a
very low (ppm level) threshold of residual tolerance in ac-
tive pharmaceutical ingredients (API) according to regu-
latory guidelines.2 An alternate route to N-aryl
sulfonamides is the transition-metal-catalyzed coupling of
aryl halides or pseudohalides with primary sulfonamides.
Among various methods for the arylation of sulfon-
Table 1 Model Reaction in the Synthesis of p-Toluenesulfonamidea
amides, palladium catalysts in the presence of phosphine Entry
Cu(OAc)2 (mmol) Base
Time (h) Yield (%)b
ligands have been widely investigated,3 while less expen-
1
0.2
0.2
0.2
0.2
0.2
0.2
0.5
0.1
K2CO3
2
2
2
2
3
2
2
3
94
86
75
82
45
31
92
52
sive copper catalysts have received scant attention. How-
ever, traditional copper-catalyzed reactions require the
use of stoichiometric amounts of copper catalysts, harsh
reaction conditions, and, often, use of toxic polar solvents
2
Cs2CO3
Na2CO3
KOAc
Et3N
3
and this limits therefore large-scale applications in indus-
4
try.4a–f Thus, it is desirable to develop a convenient and
5
simple method for the copper-catalyzed arylation of sul-
fonamides in water under ligand-free conditions.
6
7
8
NaF
In 2003, He and Wu studied the copper iodide catalyzed
N-arylation of sulfonamides with aryl halides under mi-
crowave irradiation in N-methylpyrrolidinone.4g Al-
though no ligand was used in their study, the synthesis
K2CO3
K2CO3
a Reaction conditions: Cu(OAc)2·H2O (0.2 mmol), phenylboronic
acid (1.0 mmol), p-toluenesulfonamide (1.0 mmol), base (1.3 mmol),
H2O (12 mL), reflux conditions.
SYNLETT 2014, 25, 0505–0508
Advanced online publication: 10.01.2014
b Isolated yields.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340475; Art ID: ST-2013-D0940-L
© Georg Thieme Verlag Stuttgart · New York

506
M. Nasrollahzadeh et al.
LETTER
Next, using the optimized procedure, a variety of arylbo- entries 15 and 16) are also effective nucleophiles. It is ev-
ronic acids possessing both electron-releasing and elec- ident that this method is reasonably general and can be ap-
tron-withdrawing groups was employed (Table 2). The plied to several kinds of arylboronic acids. In all cases the
nature of the substituent on the benzene ring did not affect reaction gives the corresponding sulfonamides in good to
the reaction time, and the yields were excellent in all ex- excellent yields under the reaction conditions. However,
amples. Apart from arylboronic acids we also tested 3- this type of N-arylation does not seem to work with 2-sub-
pyridinylboronic acid and 3-thienylboronic acid as het- stituted phenylboronic acids. For example, treatment of
eroaryl boronic acids (Table 2, entries 8–10). In addition benzenesulfonamide with 2-bromophenylboronic acid in
to primary arylsulfonamides, secondary arylsulfonamides the presence of Cu(OAc)2·H2O and potassium carbonate
(Table 2, entry 13) and aliphatic sulfonamides (Table 2, provided very little product even after ten hours.
Table 2 Formation of Sulfonamides via Copper-Catalyzed Arylation of Various Arylboronic Acidsa
Entry
Substrate
Arylboronic acid
Time (h)
Yield (%)b
95
mp (°C) (reported)ref.
111–113 (111–112)6a
O
S
1
2
NH2
NH2
B(OH)2
O
O
S
2
3
3
3
91
92
117–119 (117–119)6b
88–90 (88–89)6c
B(OH)2
O
O
S
B(OH)2
NH2
O
O
F3C
B(OH)2
S
NH2
4
5
6
2
3
3
94
88
87
102–104 (102–103)6d
113–114 (114)6e
O
O
S
NH2
NH2
MeO
B(OH)2
O
O
S
115–117 (117)6d
B(OH)2
B(OH)2
O
O
S
NH2
7
3
89
94–96 (94–95.5)6f
O
F3C
O
S
B(OH)2
8
9
2
2
8
89
88
65
190–191 (188.1–189.1)6g
191–193 (190.5–191.5)6h
105–107 (105–106)6i
NH2
O
O
N
B(OH)2
B(OH)2
S
NH2
O
N
S
O
S
NH2
10
O
OMe
O
S
11
10
12
87–89 (88–89)6j
NH2
B(OH)2
O
O
NH2
B(OH)2
B(OH)2
S
12
13
10
5
0
–
O
O
S
80
108–110 (110)4b
NHMe
O
Synlett 2014, 25, 505–508
© Georg Thieme Verlag Stuttgart · New York

LETTER
N-Arylation of Sulfonamides
507
Table 2 Formation of Sulfonamides via Copper-Catalyzed Arylation of Various Arylboronic Acidsa (continued)
Entry
14
Substrate
Arylboronic acid
Time (h)
10
Yield (%)b
trace
mp (°C) (reported)ref.
OMe
O
S
–
NHMe
B(OH)2
O
B(OH)2
B(OH)2
15
16
MeSO2NH2
MeSO2NH2
4
80
0
93–97 (93–97)4b
10
–
a Reaction conditions: Cu(OAc)2·H2O (0.2 mmol), arylboronic acid (1.0 mmol), sulfonamide (1.0 mmol), base (1.3 mmol), H2O (12 mL), reflux
conditions.
b Yields are after workup.
Table 3 shows the application of different reagents in the
N-arylation of p-toluenesulfonamide and benzenesulfon-
General Procedure for the Copper-Catalyzed Arylation of Sul-
fonamides with Arylboronic Acids
amide. The present method offers several notable fea-
To a mixture of copper salt (0.2 mmol) and arylboronic acid (1.0
tures, compared with other work on the N-arylation of
mmol) in H2O (6 mL), base (1.3 mmol), sulfonamide (1.0 mmol),
and H2O (12 mL) were added, and the mixture was vigorously
sulfonamides, including avoidance of harsh reaction con-
ditions, nongreen solvents and ligands; wide substrate
stirred for the appropriate times under reflux conditions. After com-
scope and generality – especially for arylboronic acids
containing electron-withdrawing groups – higher yields,
shorter reaction time, and milder conditions.
pletion (as monitored by TLC), the reaction mixture was cooled to
r.t. The resulting product was filtered and purified by recrystalliza-
tion using EtOAc and n-hexane to afford the N-arylated product. All
anlytical data are consistent with those reported in the literature.2b,6
In summary, a novel, simple method has been developed
for the copper-catalyzed arylation of sulfonamides in wa-
ter under ligand-free conditions. The significant advan-
tages of this methodology are high yields, simple workup
procedure, elimination of toxic organic solvents, and ex-
pensive, unstable, and poisonous ligands.
Acknowledgment
We gratefully acknowledge the University of Qom for the support
of this work.
Table 3 Comparison Present Methodology with other Reported Methods in the N-Arylation of Different Sulfonamides
Entry
Sulfonamide
Conditions
Yielda (%)ref.
1
2
p-TolSO2NH2
p-TolSO2NH2
p-TolSO2NH2
p-TolSO2NH2
p-TolSO2NH2
PhSO2NH2
CuI (0.25 mmol, 5.0 mol%), PhI, NMG,b K3PO4, DMF, N2, 100 °C, 24 h
CuI (10 mol%), PhBr, MW, K2CO3, NMP,c 195 °C, 3 h
954b
704g
3
CuI (20 mol%), PhI, N,N′-DMEDA,d KF/Al2O3, dioxane, Ar, 100–110 °C, 9 h
CuI (10 mol%), PhBr, Cs2CO3, DMF, air, 130 °C, 24 h
937
4
168
5
Cu(OAc)2·H2O (20 mol%), PhB(OH)2, K2CO3, H2O, reflux, 2 h
CuI (0.25 mmol, 5.0 mol%), PhI, NMG,b K3PO4, DMF, N2, 100 °C, 24 h
CuI (10 mol%), PhI, MW, K2CO3, NMP,c 195 °C, 3 h
94this work
944b
6
7
PhSO2NH2
904g
8
PhSO2NH2
CuI (20 mol%), PhI, N,N′-DMEDA,d KF/Al2O3, dioxane, Ar, 100–110 °C, 9 h
CuI (10 mol%), PhI, Cs2CO3, DMF, air, 130 °C, 24 h
917
9
PhSO2NH2
868
10
11
PhSO2NH2
Cu(OAc)2·H2O (10 mol%), PhB(OH)2, [bmim][BF4], 70 °C, 6 h
Cu(OAc)2·H2O (20 mol%), PhB(OH)2, K2CO3, H2O, reflux, 2 h
309
PhSO2NH2
94this work
a Yields are after workup.
b N-Methylglycine as ligand.
c N-Methylpyrrolidinone.
d N,N′-Dimethylethylenediamine as ligand.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 505–508

508
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LETTER
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