Short Articles
Table 1. Optimization of the Reaction Conditionsa)
O
O
N-Alkylation of Sulfonamides
with Alcohols by Tf2O
S
cat.
HO
N
SO2NH2
+
OH
1a
2a
3a
Temp.
/°C
Time
/h
Yield
Ting Ting Yu,1 Lan-Jun Qi,1 Dong-Mei Cui,*1
Chen Zhang,*2 and Yan Zhao3
Entry
Cat. (mol %) Solvent
/%b)
1
2
3
4
5
6
7
8
9
10
11
12
13
Tf2O (20)
Tf2O (20)
Tf2O (10)
Tf2O (20)
Tf2O (20)
TfOH (20)
H2SO4 (20)
AgOTf (20)
AlCl3 (20)
ZnCl2 (20)
Tf2O (20)
Tf2O (20)
Tf2O (20)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
DMF
120
120
120
90
120
120
120
120
120
120
120
120
120
32
48
48
48
24
57
23
51
45
44
48
48
48
73
96
78
60
89
33
17
0
0
0
68
0
0
1College of Pharmaceutical Science, Zhejiang University
of Technology, Hangzhou 310014, P. R. China
2School of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, P. R. China
3School of Pharmaceutical Sciences, Jiamusi University,
Jiamusi 154007, P. R. China
E-mail: cuidongmei@zjut.edu.cn
Received: January 6, 2015; Accepted: January 21, 2015;
Web Released: January 28, 2015
DMSO
a) The reactions were performed with 1a (2 mmol), 2a
(3 mmol), and catalyst (10-20 mol %) in solvent (3 mL) at
120 °C. b) Isolated yields.
N-sulfonylpyrrolidines and N-alkyl sulfonamides were
efficiently prepared via alkylation of sulfonamides with 1,4-
diols or alcohols by Tf2O. The reaction occurred under mild
reaction conditions in moderate to high yields and tolerated
aryl and aliphatic sulfonamides.
derivative 3a in 96% yield (Table 1, Entry 2). We observed
that the formation of 3a was related to the amount of Tf2O, the
reaction time, and the temperature: decreasing the amount of
Tf2O to 10 mol %, or reaction time to 32 h, or lowering the
reaction temperature to 90 °C resulted in a slightly lower yield
(Table 1, Entries 1-4). Brønsted acids and Lewis acids were
also examined as catalysts for the reaction between 1a and 2a.
Other proton acid catalysts, such as TfOH or H2SO4, were
utilized to afford 3a at a lower yield and the reaction did not
proceed in the presence of AgOTf, AlCl3, or ZnCl2 (Table 1,
Entries 6-10). Different solvents were screened, the reaction
with xylene also gave a modest yield and no reaction occurred
in polar aprotic solvents such as DMSO and DMF (Table 1,
Entries 12 and 13).
With the optimized reaction conditions determined, the
substrate scope was further examined. As shown in Table 2, we
first examined the reactions of sulfonamides bearing various
functional groups on the aromatic ring. Similar to the case of
1a, reactions of o-toluenesulfonamide and benzenesulfonamide
afforded the desired products 3b and 3c in 53% and 81%
yields, respectively (Table 2, Entries 2 and 3). The N-alkylation
of benzenesulfonamides containing a halide atom, such as
chloro, bromo, and iodo gave the corresponding products 3d-3f
in 46-92% yields (Table 2, Entries 4-6). In the case of p-
hydroxybenzenesulfonamide, the corresponding product 3g
was obtained in 28% yield (Table 2, Entry 7). The coupling
was also applied to aliphatic sulfonamides, such as methane-
sulfonamide, affording the desired product 3h in 64% yield
(Table 2, Entry 8). To evaluate further the scope of the reac-
tion, the N-alkylation of 1a with a variety of diols 2b-2d was
examined. Reactions with butane-1,4-diol bearing methyl or
benzyl groups at 1 or 3 position produced the correspond-
ing pyrrolidine products in good yields (Table 2, Entries 9 and
10). When pentane-1,5-diol (2d) was used as substrate, the
Sulfonamides have been extensively used as antibacterials,
diuretics, anticonvulsants, hypoglycemics, and HIV protease
inhibitors. N-Sulfonylpyrrolidine derivatives constitute the
essential core of many structural entities with enhanced bio-
logical activity.1-4 The most common method reported in the
literature for synthesis of these compounds typically proceeds
via reaction of the corresponding pyrrolidines with sulfonyl
chlorides. Although several other synthetic methods have also
been reported, such as the intramolecular reductive N-alkyl-
ation of amide esters,5 intramolecular substitution reactions of
aryl(sulfonyl)amino groups,6 the conversion of the p-toluene-
sulfonate salt of pyrrolidine,7 the gold-catalyzed intramolecular
N-alkylation of sulfonamides,8 sulfamination of γ-amino-
alkenes,9 nucleophilic ring closure of 1,4-diol derivatives,10
N-alkylation of sulfonamides with alcohol,11 the condensation
of methyl sulfinate with pyrrolidine and following oxidation.12
Despite these advantages, several drawbacks remain associated
with such reactions, including the use of transition metals and
generating unwanted side-products. Thus, development of new
methods for their synthesis is still needed. Recently, we have
developed the N-alkylation of sulfonamides using cyclic and
acyclic ethers as alkyl sources.13 Herein, we report the N-
alkylation of sulfonamides with alcohols by trifluoromethane-
sulfonic anhydride (Tf2O) under mild reaction conditions.
First, we examined the reaction of p-toluenesulfonamide
(1a) with butane-1,4-diol (2a) to synthesize 1-[(4-methylphen-
yl)sulfonyl]pyrrolidine (3a) under various conditions. The
results are summarized in Table 1. Reacting 1a with 2a in the
presence of Tf2O (20 mol %) at 120 °C in toluene for 48 h
afforded the corresponding alkylation product pyrrolidine
© 2015 The Chemical Society of Japan