A novel and efficient solvent-free and heterogeneous method for the synthesis of primary, secondary and bis-N-acylsulfonamides using metal hydrogen sulfate catalysts

Article abstract of DOI:10.1016/j.tet.2009.06.112

Some metal hydrogen sulfates were used as acid catalysts in the N-acylation of different sulfonamides using carboxylic acid chlorides and anhydrides as acylating agents under both heterogeneous and solvent-free conditions. Al(HSO₄)₃

Full text of DOI:10.1016/j.tet.2009.06.112

Tetrahedron 65 (2009) 7696–7705
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel and efficient solvent-free and heterogeneous method for the synthesis
of primary, secondary and bis-N-acylsulfonamides using metal
hydrogen sulfate catalysts
,
b
,
a
a
a
Ahmad Reza Massah a , Beheshteh Asadi , Mahdieh Hoseinpour , Azadeh Molseghi ,
*
Roozbeh Javad Kalbasi b, Hamid Javaherian Naghash b
a Department of Chemistry, Islamic Azad University, Shahreza Branch, Shahreza, P.O. Box: 86145-311, Isfahan, Iran
b Razi Chemistry Research Center, Islamic Azad University, Shahreza Branch, Shahreza, Isfahan, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Some metal hydrogen sulfates were used as acid catalysts in the N-acylation of different sulfonamides using
carboxylic acid chlorides and anhydrides as acylating agents under both heterogeneous and solvent-free
conditions. Al(HSO4)3 and Zr(HSO4)4 were found to have the highest activity and catalyze the reactions effi-
ciently to furnish the primary N-acyl sulfonamides (RCONHSO2R0), secondary N-acylsulfonamides
(RCONR00SO2R0) and bis-N-acylsulfonamnides [RCO(SO2R0)N-R00-N(SO2R0)COR] in good to high yield. The mild
reaction conditions, inexpensive and low toxicity of catalysts and easy work-up procedure make this method
attractive.
Received 9 January 2009
Received in revised form 9 June 2009
Accepted 25 June 2009
Available online 2 July 2009
Keywords:
N-Acylation
Ó 2009 Elsevier Ltd. All rights reserved.
N-Acylsulfonamide
Aluminum hydrogen sulfate
Zirconium hydrogen sulfate
Solvent-free reactions
Heterogeneous catalysis
1. Introduction
unavailable reagents are some of the limitations of these methods.
Clearly, there is a need for development of a new, inexpensive and
N-Acylation of sulfonamides has attracted special attention in
organic synthesis because of their pharmacological importance of
the products.1 This transformation is also a useful tool for lead
optimization and lead generation.2 N-Acylsulfonamides with their
acidity make them suitable carboxylic acid proxies,3 while their
resistance to chemical and enzymatic hydrolysis renders them
amenable for use as enzyme inhibitors.
Direct condensation of a carboxylic acid with a sulfonamide in the
presence of coupling reagents, such as EDC$HCl4 and DCC in the pres-
ence of DMAP5 provides N-acylsulfonamides. Alternately, N-acylsul-
fonamide synthesis starts with the coupling of the parent sulfonamides
with carboxylic acid chloride or anhydrides using trialkylamines, pyr-
idine,1a,6 oralkali hydroxides.7 Formation of bis-acylatedbyproduct and
difficult purification of N-acylsulfonamides are the main problems of
these methods. There are a few reports mentioning this transformation
under acidic condition. Corrosion caused by the liquid acid such as
H2SO4 contamination of the waste water with acid, the high temper-
ature needed to achieve conversion8 and use of expensive or
bench top acid that can promote the above reaction in a catalytic way.
There are significant demands by the pharmaceutical industries
for new and efficient catalysts. Moreover, together with traditional
criteria, such as good activity and selectivity; these new catalysts
must include additional properties, such as low cost and environ-
mental friendliness. In addition, there is current research and general
interest in solvent-free9 and heterogeneous10 systems because of
their importance in industry and in developing technologies. Be-
tween the huge numbers of reagents, solid acidic compounds, which
are used as protic or Lewis acids, have special position in organic
chemistry.11 Among them, metal hydrogen sulfates have attracted
the attention of organic chemist during the last decade.12 In addition,
the stability, low cost, heterogeneous nature of the reactions, high
yields of the products, short reaction time, and reusability are among
other important advantages of these reagents. Aluminum and zir-
conium hydrogen sulfates, as stable materials are efficient reagents
which can be used for different functional group transformations.13
In continuation of our interest on sulfonamides and N-acylsul-
fonamides,14 herein we report an attractive method using Al(HSO4)3
and Zr(HSO4)4 as catalysts for N-acylation of different sulfonamides
with some carboxylic acid anhydride and chloride under solvent-
free and heterogeneous conditions.
* Corresponding author. Tel./fax: þ98 321 321 3095.
E-mail address: massah@iaush.ac.ir (A.R. Massah).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.112

A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
7697
Table 1
2. Results and discussion
Absorbed and desorbed pyridine molecules on the Al(HSO4)3 and Zr(HSO4)4
2.1. Catalysts characterization
Catalyst
Brønsted acidity (mmol kgꢀ1
(desorption temperature
of pyridine)
)
Lewis acidity (mmol kgꢀ1
(desorption temperature
of pyridine)
)
The FTIR spectra of the Al(HSO4)3 and Zr(HSO4)4 catalysts is
shown in Figure 1. As clearly seen in the Figure the intensity of the
peak due to OH bending mode (probably due to M–OH groups)
around 1620 cmꢀ1 is low because of loading the support with H2SO4.
Some additional peaks; asymmetric and symmetric stretching of
S]O bond at 1229–1290 and 1177 cmꢀ1, respectively, confirm the
presence of HSO4 in the structure of the catalysts. The other peaks in
the range of 750–1000 cmꢀ1 may attributed to the S–O bond.
373 K
473 K
573 K
373 K
473 K
573 K
Al(HSO4)3
Zr(HSO4)4
262.5
218.4
140.7
175
39.2
175
308
287
236.6
280
157.5
250
According to the results of Figure 2 and Table 1, it can be seen
that the acidity of Al(HSO4)3 catalyst is higher than the Zr(HSO4)4
catalyst. On the other hand, the acid sites in the Zr(HSO4)4 are more
thermally stable and it’s acidity is remaining even up to 573 K. The
amount of Brønsted acidity of Al(HSO4)3 decreases about 85% with
increase desorption temperature from 373 to 573 K. However, this
is only about 20% for Zr(HSO4)4 catalyst.
The TG-DTG and DSC curves of the various samples have been
investigated (Figs. 3 and 4). The Zr(HSO4)4 and Al(HSO4)3 sample
shows three separate weight loss steps. The first, small (around 6%,
w/w) step appearing at temperature <150 ꢁC corresponds to the
release of water (i.e., adsorbed water on the inner and outer sur-
face). The second step (about 200–250 ꢁC) can be attributed to the
H2SO4 loss from the outer surface of the catalysts (around 10%,
w/w). The third weight loss (about 250–300 ꢁC) amounts around
45% (w/w) is related to the decomposition of the catalyst and
production of SO2. The DSC curve of these catalysts shows that the
overall process is endothermic.
2.2. Optimization of the reaction conditions
In order to find the best reaction condition, the reaction was
optimized with respect to the catalyst, solvent, temperature and
reaction time. At first different metal hydrogen sulfates including;
aluminum hydrogen sulfate, zirconium hydrogen sulfate, calcium
hydrogen sulfate, cobalt hydrogen sulfate and magnesium hydrogen
sulfate were screened for N-acylation of benzenesulfonamide and
4-methyl-N-propylbenzenesulfonamide with propionyl chloride
and acetic anhydride to find the best catalyst. The results show that
the reaction in the presence of Al(HSO4)3 and Zr(HSO4)4 (5 mol % for
N-acylation of benzenesulfonamide and 10 mol % for N-acylation of
4-methyl-N-propylbenzenesulfonamide) furnished the expected
N-acylsulfonamides in good to high yields (82–93%) in 5–15 min in
CH2Cl2 and solvent-free condition. The reactions in the presence of
Figure 1. FTIR spectra of (a) Zr(HSO4)4; (b) Al(HSO4)3.
The nature of acid sites of the Zr(HSO4)4 and Al(HSO4)3 catalysts
was determined by FTIR-pyridine adsorption study (Fig. 2) and the
values are reported in Table 1. As it shown in Figure 2 Zr(HSO4)4 and
Al(HSO4)3 have a broad acid sites distribution. Absorption bands
around 1605, 1575, 1490 and 1444 cmꢀ1 characteristic of Lewis acid
sites15 can be observed for the catalysts. Also Brønsted acidity
(1540 cmꢀ1 band) is observed in these catalysts and the concen-
tration of Brønsted sites in the catalysts, especially in the Al(HSO4)3
catalyst is higher (Table 1).
Figure 2. (A) FTIR spectra of: (a) pyridine desorption on Zr(HSO4)4 at 373 K; (b) pyridine desorption on Zr(HSO4)4 at 473 K; (c) pyridine desorption on Zr(HSO4)4 at 573 K. (B) FTIR
spectra of: (a) pyridine desorption on Al(HSO4)3 at 373 K; (b) pyridine desorption on Al(HSO4)3 at 473 K; (c) pyridine desorption on Al(HSO4)3 at 573 K.

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A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
Figure 3. (A) TG-DTG curve of Al(HSO4)3, (B) DSC curve of Al(HSO4)3.
Figure 4. (A) TG-DTG curve of Zr(HSO4)4, (B) DSC curve of Zr(HSO4)4.
other catalysts required longer reaction time (25–45 min) and led to
the products in lower yields (68–70%). Notably, no product was
observed when the reaction was carried out in the absence of cat-
alyst after 10 h. Therefore, Al(HSO4)3 and Zr(HSO4)4 were chosen for
further study. To find the most suitable solvent, the reaction of
benzenesulfonamide, 4-methyl-N-propylbenzenesulfonamide and
bis-sulfonamide (1g) as examples of primary, secondary and bis-
sulfonamides with propionyl chloride and acetic anhydride were
carried out in different solvent such as CH2Cl2, CHCl3, CH3CN, THF,
n-hexane and ethyl acetate. The best results were obtained when
CH2Cl2 was used for N-acylation of primary and secondary sulfon-
amides at room temperature. In the case of bis-sulfonamide (1g),
refluxing CH3CN is the best condition for N-acylation reaction. The
best reaction conditions were collected in Table 2.
2.3. N-Acylation of primary and secondary sulfonamides
It has been found that Al(HSO4)3 and Zr(HSO4)4 efficiently cata-
lyzed the N-acylation of different primary and secondary sulfon-
amides under solvent-free and heterogeneous conditions at room
temperature (Scheme 1). Methanesulfonamide, benzenesulfonamide
O
O
S
O
O
S
O
Al(HSO4)3 or Zr(HSO4)4
CH2Cl2 or Solvent-free, r.t
R"
R'
R
N
H
R'
R
N
R=Ph, p-Tol, Me R'= H, n-Pr, n-Bu, Ph R"= Me, Et, n-Pr, i-Pr, n-Bu,n-Pent
Scheme 1. N-Acylation of primary and secondary sulfonamides at room temperature.
Table 2
The best reaction conditions for the N-acylation of various sulfonamides
Entry
Sulfonamide
Acylating agent (mmol)
Catalyst (mmol)
Solvent
Temp (ꢁC)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
PhSO2NH2 (1a)
1a
1a
1a
1a
1a
1a
1a
4-MePhSO2NHPr (1d)
1d
1d
1d
1d
1d
1d
1d
C2H5COCl (1.1)
(C2H5CO)2O (1.1)
C2H5COCl (1.1)
(C2H5CO)2O (1.1)
C2H5COCl (1.3)
(C2H5CO)2O (1.3)
C2H5COCl (1.3)
(C2H5CO)2O (1.3)
C2H5COCl (1.5)
(C2H5CO)2O (1.5)
C2H5COCl (1.5)
(C2H5CO)2O (1.5)
C2H5COCl (1.5)
(C2H5CO)2O (1.5)
C2H5COCl (1.5)
(C2H5CO)2O (1.5)
(C2H5CO)2O (4.0)
(C2H5CO)2O (4.0)
Al(HSO4)3 (0.05)
Al(HSO4)3 (0.05)
Al(HSO4)3 (0.05)
Al(HSO4)3 (0.05)
Zr(HSO4)4 (0.05)
Zr(HSO4)4 (0.05)
Zr(HSO4)4 (0.05)
Zr(HSO4)4 (0.05)
Al(HSO4)3 (0.1)
Al(HSO4)3 (0.1)
Al(HSO4)3 (0.1)
Al(HSO4)3 (0.1)
Zr(HSO4)4 (0.1)
Zr(HSO4)4 (0.1)
Zr(HSO4)4 (0.1)
Zr(HSO4)4 (0.1)
Al(HSO4)3 (0.6)
Zr(HSO4)4 (0.6)
None
None
CH2Cl2
CH2Cl2
None
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
5
8
5
20
5
20
6
15
2
15
10
20
15
15
15
8
89
88
80
87
88
85
80
93
81
90
88
91
83
81
85
91
92
88
None
CH2Cl2
CH2Cl2
None
9
10
11
12
13
14
15
16
17
18
None
CH2Cl2
CH2Cl2
None
None
CH2Cl2
CH2Cl2
CH3CN
CH3CN
Bis-sulfonamide (1g)
1g
Reflux
Reflux
10

A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
7699
Table 3
N-Acylation of primary sulfonamides using Al(HSO4)3 and Zr(HSO4)4 (5%) at room temperature
Entry
Sulfonamide
Acylating
agent
Products
Al(HSO4)3
Zr(HSO4)4
Solvent free
CH2Cl2
Solvent free
CH2Cl2
Time, min (yield, %)a
Time, min (yield, %)a
Time, min (yield, %)a
Time, min (yield, %)a
O
O
O
C
S
NH2
S
N
H
R
1
(RCO)2O R¼Me
5(90)
7(91)
10(93)
15(90)
O
1a
O
R=Me
(2a)
2
3
4
5
6
1a
1a
1a
1a
1a
R¼n-Pr
R¼i-Pr
R¼n-Pr (2b)
R¼i-Pr (2c)
R¼Ph (2d)
R¼Me (2a)
R¼Et (2e)
5(87)
5(86)
20(75)
10(87)
10(89)
7(88)
7(85)
25(72)
15(83)
15(83)
10(90)
10(84)
60(78)
20(80)
20(88)
15(91)
15(81)
70(70)
30(75)
30(80)
R¼Ph
RCOCl R¼Me
R¼Et
O
S
O
O
NH2
S
N
H
C R
7
(RCO)2O R¼Me
2(90)
5(86)
5(90)
7(90)
O
O
R=Me
(3a)
1b
8
9
10
11
1b
1b
1b
1b
R¼Et
R¼Et (3b)
R¼n-Pent (3c)
R¼n-Bu (3d)
R¼Me (3a)
2(92)
2(89)
2(91)
5(88)
5(89)
5(88)
5(89)
5(85)
5(90)
7(89)
7(85)
7(88)
R¼n-Pent
R¼n-Bu
RCOCl R¼Me
10(86)
15(85)
20(85)
30(82)
O
S
O
C
O
S
Me
N
H
R
12
(RCO)2O R¼Me
2(88)
5(86)
5(96)
7(85)
Me
NH2
O
O
(4a)
R=Me
1c
13
14
15
1c
1c
1c
R¼i-Pr
R¼i-Pr (4b)
2(90)
2(90)
10(95)
5(89)
5(89)
15(92)
5(91)
5(87)
20(87)
7(85)
7(85)
30(83)
R¼n-Pent
RCOCl R¼Me
R¼n-Pent (4c)
R¼Me (4a)
a
Yield refers to pure isolated products.
Table 4
N-Acylation of secondary sulfonamides using Al(HSO4)3 and Zr(HSO4)4 (10%) at room temperature
Entry
Sulfonamide
Acylating agent
Products
Al(HSO4)3
Zr(HSO4)4
Solvent free
CH2Cl2
Solvent free
CH2Cl2
Time, min (yield, %)a
Time, min (yield, %)a
Time, min (yield, %)a
Time, min (yield, %)a
O
O
O
R
S N n-Pr
S N
O
1
(RCO)2O R¼Me
5(93)
7(90)
10(82)
15(80)
H
n-Pr
O
(1d)
R=Me (5a)
2
3
4
5
1d
R¼n-Pr
R¼n-Pr (5b)
R¼n-Bu (5c)
R¼i-Pr (5d)
R¼Me (5a)
5(95)
5(96)
5(85)
7(94)
7(93)
7(83)
10(80)
10(78)
10(71)
15(85)
15(85)
15(82)
15(70)
20(84)
1d
1d
1d
R¼n-Bu
R¼i-Pr
RCOCl R¼Me
10(87)
15(85)
O
O
O
R
S N n-Bu
S N
6
(RCO)2O R¼Me
5(90)
7(88)
10(82)
15(78)
H
n-Bu
O
(1e)
O
R = Me (6a)
7
8
9
10
1e
1e
1e
1e
R¼Et
R¼Et (6b)
R¼n-Pr (6c)
R¼n-Bu (6d)
R¼Et (6b)
5(92)
5(92)
5(89)
7(89)
7(90)
7(85)
10(80)
10(78)
10(85)
15(75)
15(81)
15(80)
15(82)
20(75)
R¼n-Pr
R¼n-Bu
RCOCl R¼Et
10(78)
15(80)
O
O
O
R
S N
11
(RCO)2O R¼Et
S N
15(75)
20(75)
30(72)
45(72)
H
O
(1f)
O
R=Et (7a)
12
13
14
15
16
1f
1f
1f
1f
1f
R¼n-Pr
R¼n-Pr (7b)
R¼n-Bu (7c)
R¼i-Pr (7d)
15(75)
15(74)
15(72)
15(70)
20(73)
20(71)
20(70)
20(70)
20(70)
30(70)
30(70)
30(70)
30(71)
30(71)
45(71)
45(70)
45(70)
45(70)
45(70)
60(70)
R¼n-Bu
R¼i-Pr
R¼n-Pent
RCOCl R¼Me
R¼n-Pent (7e)
R¼Me (7f)
a
Yield refers to pure isolated products.

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A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
and 4-methylbenzenesulfonamide were used as primary sulfon-
amide. N-Acylation of secondary sulfonamide was tested with 4-
methyl-N-propylbenzenesulfonamide, N-buthyl-4-methylbenzene-
sulfonamide and 4-methyl-N-phenylbenzenesulfonamide. Different
carboxylic acid anhydrides, from acetic anhydride to iso-butanoic and
hexanoic anhydride were used as acylating agent. Also, some carb-
oxylic acid chlorides were examined as acylating agent, which we
used recently for the first time as acylating agent in acidic con-
dition.10b Several examples illustrating the usefulness of this efficient
and rapid procedure are summarized in Tables 3 and 4. All of the
substrates reacted smoothly to afford the corresponding N-acyl-
sulfonamides in 70–96% yields in heterogeneous, solvent-free con-
ditions. The aliphatic anhydride with long chain, like pentanoic and
hexanoic anhydride (Table 3, entries 9,14 and Table 4, entries 3, 9 and
15) could be used as effectively as one with short chain. Also, com-
parison between the results obtained in solution and those under
solvent-free condition show that reaction proceeded faster in sol-
vent-free condition.
Comparison between the results in Table 3 with Table 4 with
respect to yields, reaction times and mol % of catalyst is interesting.
In almost all cases, the reactions of primary sulfonamides in the
presence of 5 mol % of catalysts were quicker than those of sec-
ondary sulfonamides in the presence of 5 mol % of catalysts and the
products were obtained in higher yields. Probably, the most im-
portant factor is the steric hindrance. The bulky groups around the
nitrogen (phenyl, propyl and butyl) decreases the nucleophilicity of
secondary sulfonamides in compare to primary sulfonamides.
Therefore, the reaction of secondary sulfonamides carried out in the
presence of 10 mol % of catalysts. Also, N-acylation of N-alkylsulfo-
namides and N-arylsulfonamides are comparable. For example,
reaction of N-butyl-4-methylbenzenesulfonamide (1e) with pro-
pionic anhydride after 5 min leads to the corresponding N-acylsul-
fonamide (6b) in 92% yield (Table 4, entry 7). On the other hand,
it takes 15 min for the conversion 4-methyl-N-phenyl-
benzenesulfonamide (1f) to the (7a) in 75% yield (Table 4, entry 11).
Perhaps, the difference is due to electron-withdrawing effect of
phenyl group.
2.4. N-Acylation of bis-sulfonamides
In our knowledge, there are no previous examples of the syn-
thesis of bis-N-acylsulfonamides, therefore, we sought to extend
our preliminary observation to a range of these compounds. At first,
several bis-sulfonamides were synthesized from sulfonylation of
diamine including ethane-1,2-diamine, butane-1,4-diamine and
hexane-1,6-diamine with benzenesulfonylchloride and 4-methyl-
benzenesulfonylchloride. The reactions were carried out in the
presence of K2CO3 in solvent-free condition and the products were
obtained in good to high yields after a simple work-up.14a
N-Acylation of bis-sulfonamides could be carried out using
carboxylic acid anhydrides as acylating agent and Al(HSO4)3 and
Zr(HSO4)4 as catalysts in refluxing CH3CN. The mixtures of products
formed during the reactions were mono-N-acylsulfonamides and
bis-N-acylsulfonamides. (Scheme 2) It is expected that an increase
in the concentration of acylating agent would increase the conver-
sion of bis-sulfonamide to bis-N-acylsulfonamides. A series of ex-
periments were performed to determine the effect of varying the
ratio of reactants on this conversion. The mole ratios studies are
within the range of 1–4 mol of butanoic anhydride based on 1 mol of
bis-sulfonamide (1g). The results obtained are presented in Figure 5.
O
R
S
R
O
R
O
H
N
H
N
H
N
(CH2)n
N
N
(CH2)n
N
O
O
(CH2)n
O
O
O
O
S
S
S
S
S
O
(RCO)2O , M(HSO4)x
CH3CN, Reflux
O
O
O
O
O
+
R= Et, n-Pr, n-Bu, n-Pent, M= Al, Zr n=2, 4, 6
Scheme 2. N-Acylation of bis-sulfonamides in the presence of Al(HSO4)3 or Zr(HSO4)4.
60
50
40
30
20
10
0
100
B
A
80
Mono-acyl
Bis-acyl
60
40
20
0
Total yield
3
5
10
15
20
3
5
10
15
20
Time (min)
Time (min)
100
80
60
40
20
0
120
100
80
60
40
20
0
C
D
Mono-acyl
Bis-acyl
Total yield
3
5
10
15
20
3
5
10
15
20
Time (min)
Time (min)
Figure 5. The effect of mole ratio of butanoic anhydride to bis-sulfonamide 1g on the product composition A, 1:1, B, 2:1, C, 3:1, D, 4:1.

A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
7701
As it evident from the plots, the formation of bis-N-acylsulfon-
amide and also the overall conversion of bis-sulfonamide increase
with increase in the mole ratio of acylating agent to sulfonamide up
to a mole ratio 4:1. A further increase in the amount of anhydride
causes a very low increase in the yield of products. The mole ratio of
4:1 of acylating agent to bis-sulfonamide is selected for further
experimental studies due to its optimum performance. As shown in
Table 5 by using these catalysts, various bis-sulfonamides were
converted to their corresponding bis-N-acylsulfonamides in very
good to excellent yields (88–94%) in very short reaction times (4–
10 min). As the results shown, several structurally varied acylating
agents underwent clean and remarkably fast N-acylation reaction.
The acylation reaction with long chain carboxylic acid anhydride
like hexanoic anhydride proceeded as fast as one with short chain
(e.g., compare entry 1 with entry 3 in Table 5).
purpose the reaction of 4-methyl-N-propylbenzenesulfonamide
with pentanoic anhydride was chosen as a model reaction in the
presence of Al(HSO4)3 and Zr(HSO4)4 in both heterogeneous and
solvent-free conditions. At the end of each run, the catalysts were
recovered from the reaction mixture by addition of ethyl acetate in
the solvent-free and dichloromethane in heterogeneous reactions.
Simple filtration and drying at 40 ꢁC, was enough to purify the
catalyst. The recycled Al(HSO4)3 was used for further runs and its
activity did not shown any significant decrease even after five runs.
The Zr(HSO4)4 was reused for three runs.
2.6. Mechanism
Although the precise mechanism of acid catalyst N-acylation of
sulfonamides has not been elucidated yet, we suppose that the re-
action happens by formation of reactive acylating intermediates.
The results obtained during the N-acylation of sulfonamides with
different acylating agents are in agreement with plausible mecha-
nism for this reaction, which is depicted in Scheme 3. These results
show that carboxylic acid anhydrides are slightly more reactive than
2.5. Catalyst reuse and stability
Finally, we were interested in studying the reusability of the
catalysts due to economical and environmental aspects. For this
Table 5
N-Acylation of bis-sulfonamides with carboxylic acid anhydrides in refluxing CH3CN
Entry
Sulfonamide
Acylating agent
Product
Al(HSO4)3
Zr(HSO4)4
Time, min (yield, %)a
Time, min (yield, %)a
R
R
O
O
O
S
O
S
H
N
H
N
O
O
S
O
N
N
S
O
1
2
3
(RCO)2O R¼Et
R¼Pr
8(92)
8(92)
6(92)
10(88)
10(90)
10(92)
O
O
1g
R=Et (8a)
R¼Pr (8b)
1g
1g
R¼n-Pent
R¼n-Pent (8c)
R
R
O
O
O
S
O
S
O
O
S
O
N
(CH2)4
N
N
N
(CH2)4
S
O
4
5
6
7
(RCO)2O R¼Pr
R¼n-Bu
5(90)
5(92)
4(93)
4(95)
8(89)
8(90)
8(88)
8(90)
H
H
O
O
1h
R=Pr (9a)
R¼n-Bu (9b)
1h
R
R
O
O
O
S
O
S
O
O
S
O
N
H
(CH2)6
N
H
N
N
(RCO)2O R¼Pr
R¼n-Bu
(CH2)6
S
O
O
O
1i
R=Pr (10a)
1i
R¼n-Bu (10b)
R
R
O
O
O
S
O
S
O
O
S
O
N
H
(CH2)2
N
H
N
N
8
9
(RCO)2O R¼n-Pr
7(90)
10(90)
(CH2)2
R=n-Pr (11)
S
O
O
O
1j
R
R
O
O
O
S
O
S
O
O
S
O
N
H
(CH2)4
N
H
N
N
(RCO)2O R¼Et
(RCO)2O R¼Et
6(92)
6(94)
8(90)
8(92)
(CH2)4
R=Et (12)
S
O
O
O
1k
R
R
O
O
O
S
O
S
O
O
N
H
(CH2)6
N
H
N
N
10
(CH2)6
R=Et (13)
S
O
S
O
O
O
1l
a
Yield refers to pure isolated products.

7702
A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
M(HSO4)n
H
O
+
+
:
:
O
O
O
:
:
O
O
or
R"
C
O+
M(HSO4)n
+
R"
R"
O
R"
O
R"
R"
R"
O
R"
O
O
O
C
O
O
S
O
S
M(HSO4)n
+
NH
O+
O
R
S
NHR'
R"
C
+
R"
R"
R
R
N
R"
O
O
R'
or O4SM(HSO4)n-1
O
O
R'
_
_
M(HSO4)n
O
S
O
O
M(HSO4)n
+ O
R'HN
R'HN
R
O
O
+
C
NR'
H
S
R
R
S
N
R"
R"
Cl
O
O
R'
Cl
O
M(HSO4)n
(A)
-
R"
Cl
O4SM(HSO4)n-1
H
O
S
O
+ O
O
H
+ O
R
O
O
S
+
NR'
R"
C
S
R
R
N
R"
R"
Cl
O
O
R'
H
Cl
(A')
Scheme 3. Plausible mechanism for metal hydrogen sulfate catalyze N-acylation of sulfonamide.
carboxylic acid chlorides (e.g., compare entries 7 with 10 in Table 4).
Accordingly, metal hydrogen sulfate, catalyzing the reaction as acid,
activated the carboxylic acid anhydride to form an acylinum ion. In
the case of carboxylic acid chlorides, the intermediates A and A0
were formed. Attack of the sulfonamide as nucleophile on acylinum
ion or intermediates A and A0, leads to the N-acylsulfonamide and
regeneration of catalyst. The acylinum ion is more reactive than the
intermediates A and A0 and therefore N-acylation of sulfonamides
with carboxylic acid anhydride proceed faster than carboxylic acid
chlorides. Also, this fact was supported further by the results of
N-acylation of sulfonamides with electron withdrawing groups
containing carboxylic acid anhydride. For example, the reaction of
benzenesulfonamide with trifluoroacetic anhydride did not proceed
considerably and only 10% of product was obtained after 10 h.
4. Experimental
4.1. Materials
All chemicals were purchased from Merck and Fluka chemical
companies. Infrared spectra were recorded on Nicolet (impact
400D model) FTIR spectrophotometer. 1H NMR and 13C NMR
spectra were recorded on Bruker DRX 300 Avance spectrophoto-
meter in CDCl3 as the solvent and TMS as internal standard. Column
chromatography was performed using silica gel 60 (230–400
mesh). All yields refer to isolated yield. The catalysts were prepared
according to Ref. 12b. Bis-sulfonamides were prepared according to
Ref. 14a.
4.2. Characterization of the catalysts
2.7. Spectral analysis
Pyridine was used as a probe molecule to distinguish between
Brønsted and Lewis acid sites.16 Approximately 40–50 mg of ma-
terial was pressed (for 3 min at 15 tones cmꢀ2 pressure under ap-
proximately 10ꢀ2 Torr vacuum) into a self supporting wafer of
15 mm diameter. The wafer was treated with 26 mmHg of pyridine
at 473 K for 1 h and evacuated at 373, 473 and 573 K for 1 h in
dynamic vacuum. After each treatment, an IR spectrum was
recorded at room temperature. The peak areas corresponding to the
concentration of Brønsted and Lewis acid sites adsorbed pyridine
were respectively collected at 1545 and 1445 cmꢀ1, using the ex-
Spectral analysis of different synthesized N-acylsulfonamides
supports the structure of the products. The IR spectra indicated the
absence of N–H bond (except primary N-acylsulfonamide that appear
as a sharp bond between 3100–3250 cmꢀ1) and exhibited the pres-
ence of sulfonyl (1150–1180 cmꢀ1 and 1350–1380 cmꢀ1) and amide
(1660–1700 cmꢀ1) groups. The 1H NMR spectrum clearly showed the
presence of 1,4-disubstituted benzene moieties. The presence of
amide groups was further supported by the presence of carbonyl
carbon resonance at 167–170 ppm in the 13C NMR spectrum. Finally,
the elemental analysis is in accordance with the proposed products.
tinction coefficients given by Emeis17 (1.67 and 2.22 cm/
mmol for
Brønsted and Lewis acid sites respectively). The relevant peak areas
calculated for all the catalysts are presented in Table 1.
Thermal gravimetric analysis (TGA) data for the organic com-
pounds were obtained by a Mettler TGA-50 under air atmosphere at
a rate of 10 ꢁC/min.
3. Conclusion
Al(HSO4)3 and Zr(HSO4)4 have been proved to be effective cat-
alysts for N-acylation of different sulfonamides affording the good
to excellent yields of primary, secondary and bis-N-acylsulfon-
amides in solvent and solvent-free conditions. The catalysts are
found to be mild and cheap with high catalytic activity, low toxicity,
and moisture and air tolerance. This new strategy offer several
advantages including simple and solvent-free experiment condi-
tions, high yields, short reaction times and readily recyclable solid
acid catalysts. It is believed that this method would be a useful
synthetic methodology that is in agreement with green chemistry.
4.3. General procedure for N-acylation of primary and
secondary sulfonamides
(a) Under solvent-free condition. To a vigorously stirred mixture
of finely powdered of sulfonamide (1 mmol) and Al(HSO4)3 or
Zr(HSO4)4 (for primary sulfonamides 0.05 mmol and for secondary
sulfonamide 0.1 mmol) in a 10 mL glass vessel, 1.1–1.5 mmol of

A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
7703
acylating agent (according to Table 1) was added at room tem-
perature. After completion of the reaction (monitored by TLC),
ethyl acetate (20 mL) was added and the catalyst was filtered off
and washed with further solvent (5 mL). The filtrate was washed
with water (15 mL) and was dried over MgSO4. After evaporation of
the solvent, the crude product was purified by recrystallization
from ethyl acetate/n-hexane mixed solvent or by column chro-
matography on silica gel (60–120 mesh, petroleum ether–ethyl
acetate) to afford the corresponding N-acylsulfonamide in good to
high yield.
(b) In CH2Cl2. To a stirred mixture of sulfonamide (1 mmol) and
Al(HSO4)3 or Zr(HSO4)4 (for primary sulfonamides 0.05 mmol and
for secondary sulfonamide 0.1 mmol) in 5 mL CH2Cl2, 1.1–1.5 mmol
of acylating agent (according to Table 1) was added at room tem-
perature. After completion of the reaction (monitored by TLC), the
catalyst was filtered off and washed with CH2Cl2 (5 mL). The filtrate
was washed with water (15 mL) and was dried over MgSO4. After
evaporation of the solvent, the crude product was purified as de-
scribed above for solvent-free condition.
2.03 (2H, q, J 7.2 Hz, COCH2), 2.46 (3H, s, CH3Ph), 7.27–7.30 (2H, m,
NPh m-H), 7.35 (2H, d, J 8.1 Hz, CH3Ph o-H), 7.49–7.51 (3H, m, NPh
o,p-H), 7.95 (2H, d, J 8.1 Hz, CH3Ph m-H); dC (75 MHz, CDCl3) 8.3,
21.7, 30.4, 129.2, 129.4, 129.9, 130.0, 130.0, 136.3, 136.4, 144.9,
173.6.
4.3.6. N-Propyl-N-tosylbutyramide (5b)
Oil; Rf (33% ethyl acetate/hexane) 0.45; IR (KBr): 2975, 2874,
1702, 1593, 1470, 1362, 1158, 1091, 808, 713, 669 cmꢀ1
; dH
(300 MHz, CDCl3) 0.83 (3H, t, J 7.3 Hz, COCH2CH2CH3), 0.92 (3H, t, J
7.3 Hz, N(CH2)2CH3), 1.56 (2H, sext, J 7.3 Hz, COCH2CH2), 1.72 (2H,
sext, J 7.3 Hz, NCH2CH2), 2.41 (3H, s, CH3Ph), 2.52 (2H, t, J 7.3 Hz,
COCH2), 3.74 (2H, t, J 7.3 Hz, NCH2), 7.31 (2H, d, J 7.9 Hz, CH3Ph o-H),
7.75 (2H, d, J 7.9 Hz, CH3Ph m-H); dC (75 MHz, CDCl3) 11.1, 13.5, 18.1,
21.6, 23.4, 38.0, 48.4, 127.5, 129.7, 137.1, 144.6, 172.9; (Found: C,
59.85; H, 7.11; N, 4.32. C14H21NO3S requires: C, 59.34; H, 7.47; N,
4.94%.)
4.3.7. N-Butyl-N-tosylbutyramide (6c)
Mp: 74–76 ꢁC; Rf (33% ethyl acetate/hexane) 0.45; IR (KBr):
2960, 2868, 1706, 1468, 1356, 1257, 1164, 1098, 959, 907, 814, 722,
4.3.1. N-Propyl-N-tosylacetamide (5a)
Oil; Rf (33% ethyl acetate/hexane) 0.45; IR (KBr): 2966, 1706,
662, 583 cmꢀ1
; dH (300 MHz, CDCl3) 0.84 (3H, t, J 7.3 Hz,
1464, 1355, 1262, 1167, 1090, 811 cmꢀ1
;
dH (300 MHz, CDCl3) 0.94
N(CH2)3CH3), 0.94 (3H, t, J 7.3 Hz, CO(CH2)2CH3), 1.35 (2H, sext, J
7.3 Hz, N(CH2)2CH2), 1.57 (2H, sext, J 7.3 Hz, COCH2CH2), 1.68 (2H,
quint, J 7.3 Hz, NCH2CH2), 2.42 (3H, s, CH3Ph), 2.54 (2H, t, J 7.3 Hz,
COCH2), 3.78 (2H, t, J 7.3 Hz, NCH2), 7.32 (2H, d, J 8.1 Hz, CH3Ph o-H),
7.76 (2H, d, J 8.1 Hz, CH3Ph m-H); dC (75 MHz, CDCl3) 13.5, 13.7, 18.1,
20.0, 21.6, 32.1, 38.0, 46.7, 127.5, 129.7, 137.1, 144.6, 172.9; (Found: C,
60.92; H, 7.29; N, 4.38. C15H23NO3S requires: C, 60.58; H, 7.79; N,
4.71%.)
(3H, t, J 7.4 Hz, CH2CH3), 1.76 (2H, sext, J 7.4 Hz, CH2CH3), 2.31 (3H, s,
CH3Ph), 2.44 (3H, s, COCH3), 3.74 (2H, t, J 7.4 Hz, NCH2), 7.34 (2H, d,
J 8.0 Hz, CH3Ph o-H), 7.77 (2H, d, J 8.0 Hz, CH3Ph m-H); dC (75 MHz,
CDCl3) 11.1, 21.6, 23.1, 24.9, 48.7, 127.4, 129.9, 136.8, 144.8, 170.1;
(Found: C, 56.98; H, 6.91; N, 5.35. C12H17NO3S requires: C, 56.45; H,
6.71; N, 5.49%.)
4.3.2. N-Butyl-N-tosylacetamide (6a)
Oil; Rf (33% ethyl acetate/hexane) 0.50; IR (KBr): 2960, 2868,
1701, 1593, 1356, 1257, 1164, 1098, 959, 907, 814, 722, 662,
4.3.8. N-Phenyl-N-tosylbutyramide (7b)
Mp: 112–115 ꢁC; Rf (33% ethyl acetate/hexane) 0.53; IR (KBr):
583 cmꢀ1
;
dH (300 MHz, CDCl3) 0.88 (3H, t, J 7.3 Hz, CH2CH3), 1.30
2962, 2865, 1713, 1591, 1494, 1355, 1169, 1087, 944, 815, 705 cmꢀ1
;
(2H, sext, J 7.3 Hz, CH2CH3), 1.63 (2H, quint, J 7.3 Hz, NCH2CH2), 2.24
(3H, s, CH3Ph), 2.37 (3H, s, COCH3), 3.73 (2H, t, J 7.3 Hz, NCH2), 7.28
(2H, d, J 8.0 Hz, CH3Ph o-H), 7.72 (2H, d, J 8.0 Hz, CH3Ph m-H); dC
(75 MHz, CDCl3) 13.6, 20.0, 21.5, 24.8, 31.9, 46.9, 127.4, 129.8, 136.8,
144.8, 169.9; (Found: C, 58.38; H, 7.61; N, 5.35. C13H19NO3S re-
quires: C, 57.97; H, 7.11; N, 5.20%.)
dH (300 MHz, CDCl3) 0.77 (3H, t, J 7.3 Hz, CH2CH3), 1.51 (2H, sext, J
7.3 Hz, CH2CH2CH3),1.98 (2H, t, J 7.3 Hz, COCH2), 2.46 (3H, s, CH3Ph),
7.26–7.32 (2H, m, NPh m-H), 7.34 (2H, d, J 8.0 Hz, CH3Ph o-H), 7.48–
7.53 (3H, m, NPh o,p-H), 7.94 (2H, d, J 8.0 Hz, CH3Ph m-H); dC
(75 MHz, CDCl3) 13.4,17.7, 21.7, 38.5, 129.2, 129.4, 129.8, 129.9, 130.1,
136.3, 136.4, 144.8, 172.8; (Found: C, 64.72; H, 6.21; N, 4.78.
C17H19NO3S requires: C, 64.33; H, 6.03; N, 4.41%.)
4.3.3. N-Phenyl-N-tosylacetamide (7f)
Mp: 153–155 ꢁC [lit. 149–150 ꢁC];18 Rf (33% ethyl acetate/hex-
ane) 0.40; IR (KBr): 2921, 1700, 1594, 1362, 1270, 1224, 1171, 1091,
4.3.9. N-Propyl-N-tosylpentanamide (5c)
Oil; Rf (33% ethyl acetate/hexane) 0.45; IR (KBr): 2958, 2874,
695 cmꢀ1
;
dH (300 MHz, CDCl3) 1.87 (3H, s, COCH3), 2.47 (3H, s,
1707, 1601, 1462, 1357, 1170, 1092, 986, 814 cmꢀ1
; dH (300 MHz,
CH3Ph), 7.27–7.31 (2H, m, NPh m-H), 7.35 (2H, d, J 8.0 Hz, CH3Ph
o-H), 7.48–7.52 (3H, m, NPh o,p-H), 7.94 (2H, d, J 8.0 Hz, CH3Ph
m-H); dC (75 MHz, CDCl3) 21.7, 25.1, 129.2, 129.4, 129.9, 130.0, 136.1,
136.9, 145.0, 170.1.
CDCl3) 0.85 (3H, t, J 7.3 Hz, CO(CH2)3CH3), 0.95 (3H, t, J 7.4 Hz,
N(CH2)2CH3), 1.26 (2H, sext, J 7.3 Hz, CO(CH2)2CH2), 1.53 (2H, quint, J
7.3 Hz, COCH2CH2), 1.75 (2H, sext, J 7.4 Hz, NCH2CH2), 2.45 (3H, s,
CH3Ph), 2.57 (2H, t, J 7.3 Hz, COCH2), 3.77 (2H, t, J 7.4 Hz, NCH2), 7.34
(2H, d, J 8.1 Hz, CH3Ph o-H), 7.78 (2H, d, J 8.1 Hz, CH3Ph m-H); dC
(75 MHz, CDCl3) 11.2, 13.7, 21.6, 22.1, 23.4, 26.7, 35.9, 48.4, 127.5,
129.7, 137.1, 144.6, 173.1; (Found: C, 61.01; H, 7.42; N, 4.42.
C15H23NO3S requires: C, 60.58; H, 7.79; N, 4.71%.)
4.3.4. N-Butyl-N-tosylpropionamide (6b)
Mp: 75–77 ꢁC; Rf (33% ethyl acetate/hexane) 0.45; IR (KBr):
2960, 2861, 1699, 1600, 1468, 1362, 1158, 992, 900, 814, 728,
669 cmꢀ1
; dH (300 MHz, CDCl3) 0.95 (3H, t, J 7.3 Hz, N(CH2)3CH3),
1.05 (3H, t, J 7.2 Hz, COCH2CH3),1.36 (2H, sext, J 7.3 Hz, N(CH2)2CH2),
1.70 (2H, quint, J 7.3 Hz, NCH2CH2), 2.43 (3H, s, CH3Ph), 2.59 (2H, q,
J 7.2 Hz, COCH2), 3.79 (2H, t, J 7.3 Hz, NCH2), 7.33 (2H, d, J 8.1 Hz,
CH3Ph o-H), 7.77 (2H, d, J 8.1 Hz, CH3Ph m-H); dC (75 MHz, CDCl3)
8.8, 13.7, 20.1, 21.6, 29.6, 32.1, 46.8, 127.5, 129.8, 137.0, 144.6, 173.7;
(Found: C, 58.88; H, 7.61; N, 4.68. C14H21NO3S requires: C, 59.34; H,
7.47; N, 4.94%.)
4.3.10. N-Butyl-N-tosylpentanamide (6d)
Oil; Rf (33% ethyl acetate/hexane) 0.54; IR (KBr): 2960, 2868,
1706, 1600, 1468, 1358, 1257, 1164, 1091, 999, 913, 814, 722, 675,
590 cmꢀ1
0.86 (3H, t,
;
dH (300 MHz, CDCl3) 0.75 (3H, t, J 7.3 Hz, CO(CH2)3CH3),
7.3 Hz, N(CH2)3CH3), 1.19 (2H, sext, 7.3 Hz,
J
J
CO(CH2)2CH2), 1.31 (2H, sext, J 7.3 Hz, N(CH2)2CH2CH3), 1.45 (2H,
quint, J 7.3 Hz, COCH2CH2), 1.62 (2H, quint, J 7.3 Hz, NCH2CH2CH2),
2.34 (3H, s, CH3Ph), 2.49 (2H, t, J 7.3 Hz, COCH2), 3.73 (2H, t, J 7.3 Hz,
NCH2), 7.25 (2H, d, J 8.0 Hz, CH3Ph o-H), 7.70 (2H, d, J 8.0 Hz, CH3Ph
m-H); dC (75 MHz, CDCl3) 13.6, 13.7, 19.9, 21.4, 22.0, 26.6, 32.1, 35.8,
46.6, 127.4, 129.68, 137.1, 144.56, 172.9; (Found: C, 62.12; H, 7.69; N,
4.98. C16H25NO3S requires: C, 61.70; H, 8.09; N, 4.50%.)
4.3.5. N-Phenyl-N-tosylpropionamide (7a)
Mp: 142–145 ꢁC [lit. 143–144 ꢁC];19 Rf (33% ethyl acetate/hex-
ane) 0.44; IR (KBr): 2986, 2924, 1713, 1594, 1494, 1365, 1171, 1080,
964, 815 cmꢀ1
; dH (300 MHz, CDCl3) 0.96 (3H, t, J 7.2 Hz, CH2CH3),

7704
A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
4.3.11. N-Phenyl-N-tosylpentanamide (7c)
54.34; H, 5.47; N, 5.94, C22H28N2O6S2 requires: C, 54.98; H, 5.87; N,
5.83%.)
Mp: 84–87 ꢁC; Rf (33% ethyl acetate/hexane) 0.53; IR (KBr):
2954, 1712, 1594, 1349, 1261, 1160, 877, 820, 707 cmꢀ1
; dH
(300 MHz, CDCl3) 0.76 (3H, t, J 7.3 Hz, CH2CH3), 1.15 (2H, sext, J
7.3 Hz, CH2CH3), 1.47 (2H, quint, J 7.3 Hz, COCH2CH2), 2.00 (2H, t, J
7.3 Hz, COCH2), 2.46 (3H, s, CH3Ph), 7.27–7.30 (2H, m, NPh m-H),
7.35 (2H, d, J 8.1 Hz, CH3Ph o-H), 7.49–7.51 (3H, m, NPh o,p-H), 7.94
(2H, d, J 8.1 Hz, CH3Ph m-H); dC (75 MHz, CDCl3) 13.7, 21.7, 21.9, 26.3,
36.4, 129.2, 129.4, 129.8, 129.9, 130.1, 136.3, 136.4, 144.8, 172.7;
(Found: C, 64.92; H, 6.21; N, 4.78. C18H21NO3S requires: C, 65.23; H,
6.39; N, 4.23%.)
4.4.2. Compound (8b)
Mp: 126–127 ꢁC; Rf (33% ethyl acetate/hexane) 0.43; IR (KBr):
2958,1700,1603,1358,1171,1010, 864, 814, 745 cmꢀ1
; dH (300 MHz,
CDCl3) 0.90 (6H, t, J 7.3 Hz, CH2CH3), 1.64 (4H, sext, J 7.3 Hz,
CH2CH3), 2.45 (6H, s, CH3Ph), 2.71 (4H, t, J 7.3 Hz, COCH2), 4.05 (4H,
s, NCH2), 7.35 (4H, d, J 8.1 Hz, CH3Ph o-H), 7.81 (4H, d, J 8.1 Hz, CH3Ph
m-H); dC (75 MHz, CDCl3) 13.6, 18.1, 21.6, 38.1, 45.2, 127.6, 129.9,
136.6, 144.9, 173.2; (Found: C, 55.98; H, 5.87; N, 5.83. C24H32N2O6S2
requires: C, 56.67; H, 6.34; N, 5.51%.)
4.3.12. N-Propyl-N-tosylisobutyramide (5d)
Oil; Rf (33% ethyl acetate/hexane) 0.50; IR (KBr): 2973, 2874,
4.4.3. Compound (8c)
1699, 1607, 1461, 1356, 1171, 1085, 992, 814, 715, 669, 583 cmꢀ1
;
dH
Mp: 123–124 ꢁC; Rf (33% ethyl acetate/hexane) 0.40; IR (KBr):
(300 MHz, CDCl3) 0.90 (3H, t, J 7.4 Hz, CH2CH3), 0.97 (6H, d, J 6.6 Hz,
CH(CH3)2), 1.69 (2H, sext, J 7.4 Hz, CH2CH3), 2.37 (3H, s, CH3Ph), 3.11
(1H, sept, J 6.6 Hz, CH(CH3)2), 3.75 (2H, t, J 7.4 Hz, NCH2), 7.28 (2H, d,
J 8.0 Hz, CH3Ph o-H), 7.72 (2H, d, J 8.0 Hz, CH3Ph m-H); dC (75 MHz,
CDCl3) 11.1,19.5, 21.5, 23.5, 33.9, 48.1,127.3,129.7,137.2,144.5,177.8;
(Found: C, 59.74; H, 7.1; N, 4.52. C14H21NO3S requires: C, 59.34; H,
7.47; N, 4.94%.)
2935, 1708, 1590, 1358, 1184, 1098, 810, 745 cmꢀ1
; dH (300 MHz,
CDCl3) 0.86 (6H, t, J 7.2 Hz, CH2CH3), 1.26 (8H, m, (CH2)2CH3), 1.61
(4H, quint, J 7.2 Hz, COCH2CH2), 2.45 (6H, s, CH3Ph), 2.70 (4H, t, J
7.2 Hz, COCH2), 4.05 (4H, s, NCH2), 7.35 (4H, d, J 8.2 Hz, CH3Ph o-H),
7.81 (4H, d, J 8.2 Hz, CH3Ph m-H); dC (75 MHz, CDCl3) 13.9, 21.6, 22.4,
24.3, 31.1, 36.2, 45.3, 127.6, 129.9, 136.5, 144.9, 173.4; (Found: C,
59.98; H, 7.87; N, 5.33. C28H40N2O6S2 requires: C, 59.55; H, 7.14; N,
4.96%.)
4.3.13. N-Phenyl-N-tosylisobutyramide (7d)
Mp: 80–82 ꢁC; Rf (33% ethyl acetate/hexane) 0.53; IR (KBr):
4.4.4. Compound (9a)
2969, 1704, 1599, 1494, 1363, 1263, 1164, 1098, 1028, 814, 706 cmꢀ1
;
Mp: 126–127 ꢁC; Rf (33% ethyl acetate/hexane) 0.53; IR (KBr):
dH (300 MHz, CDCl3) 0.98 (6H, d, J 6.7 Hz, CH(CH3)2), 2.30–2.36 (1H,
m, CH(CH3)2), 2.46 (3H, s, CH3Ph), 7.27–7.31 (2H, m, NPh m-H), 7.34
(2H, d, J 8.1 Hz, CH3Ph o-H), 7.50–7.51 (3H, m, NPh o,p-H), 7.91 (2H,
d, J 8.1 Hz, CH3Ph m-H); (Found: C, 64.79; H, 6.31; N, 4.03.
C17H19NO3S requires: C, 64.33; H, 6.03; N, 4.41%.)
2965, 1706, 1603, 1358, 1171, 1055, 1010, 881, 822, 687 cmꢀ1
; dH
(300 MHz, CDCl3) 0.86 (6H, t, J 7.30 Hz, CH2CH3), 1.59 (4H, sext, J
7.3 Hz, CH2CH3),1.77 (4H, m, NCH2CH2), 2.45 (6H, s, CH3Ph), 2.58 (4H,
t, J 7.3 Hz, COCH2), 3.83(4H, m, NCH2), 7.35 (4H, d, J 8.1 Hz, CH3Ph o-H),
7.78 (4H, d, J 8.1 Hz, CH3Ph m-H); dC (75 MHz, CDCl3) 13.5, 18.1, 21.6,
27.2, 38.1, 46.2, 127.4, 129.9, 136.96, 144.8, 172.9; (Found: C, 58.98; H,
5.67; N, 5.83. C26H36N2O6S2 requires: C, 58.19; H, 6.76; N, 5.22%.)
4.3.14. N-Phenyl-N-tosylhexanamide (7e)
Mp: 100–102 ꢁC; Rf (33% ethyl acetate/hexane) 0.50; IR (KBr):
2954, 1712, 1593, 1488, 1349, 1158, 1085, 814, 709, 576 cmꢀ1
;
dH
4.4.5. Compound (9b)
(300 MHz, CDCl3) 0.79 (3H, t, J 7.4 Hz, CH2CH3), 1.08–1.20 (4H, m,
(CH2)2CH3), 1.48 (2H, quint, J 7.4 Hz, COCH2CH2), 1.99 (2H, t, J 7.4 Hz,
COCH2), 2.46 (3H, s, CH3Ph), 7.28–7.29 (2H, m, NPh m-H), 7.34 (2H, d, J
8.0 Hz, CH3Ph o-H), 7.49–7.51 (3H, m, NPh o,p-H), 7.94 (2H, d, J 8.0 Hz,
CH3Ph m-H); dC (75 MHz, CDCl3) 13.8, 21.7, 22.3, 23.9, 30.9, 36.7,129.2,
129.4, 129.8, 129.9, 130.1, 136.3, 136.4, 144.8, 173.0; (Found: C, 65.78;
H, 6.31; N, 4.51. C19H23NO3S requires: C, 66.06; H, 6.71; N, 4.05%.)
Mp: 143–144 ꢁC; Rf (33% ethyl acetate/hexane) 0.50; IR (KBr):
2958, 1700, 1603, 1475, 1358, 1171, 1010, 688, 745 cmꢀ1
; dH
(300 MHz, CDCl3) 0.85 (6H, t, J 7.3 Hz, CH2CH3), 1.27 (4H, sext, J
7.3 Hz, CH2CH3), 1.54 (4H, quint, J 7.3 Hz, COCH2CH2), 1.77 (4H, m,
NCH2CH2), 2.45 (6H, s, CH3Ph), 2.59 (4H, t, J 7.3 Hz, COCH2), 3.84
(4H, m, NCH2), 7.35 (4H, d, J 8.2 Hz, CH3Ph o-H), 7.78 (4H, d, J 8.2 Hz,
CH3Ph m-H); dC (75 MHz, CDCl3) 13.8, 21.6, 22.1, 26.7, 27.2, 26.0,
46.2, 127.4, 129.9, 137.0, 144.8, 173.1; (Found: C, 60.08; H, 7.76; N,
5.38. C28H40N2O6S2 requires: C, 59.55; H, 7.14; N, 4.96%.)
4.4. General procedure for N-acylation of bis-sulfonamides
in CH3CN
4.4.6. Compound (10a)
Mp: 111–113 ꢁC; Rf (33% ethyl acetate/hexane) 0.40; IR (KBr):
A mixture of bis-sulfonamide (1 mmol) and carboxylic acid
anhydride (4 mmol) was heated to reflux in CH3CN (5 mL) in the
presence of Al(HSO4)3 or Zr(HSO4)4 (0.2 g) for appropriate time
according to Table 5. The progress of the reaction was monitored by
TLC. After completion of the reaction, ethyl acetate (20 ml) was
added and the catalyst was filtered off and washed with further
solvent (5 mL). The filtrate was washed with water (15 ml) and was
dried over MgSO4. After evaporation of the solvent, the crude
product was purified by column chromatography on silica gel (60–
120 mesh, petroleum ether–ethyl acetate) to afford the corre-
sponding bis-N-acylsulfonamide in good to high yield.
2926, 1713, 1597, 1358, 1171, 1087, 829, 726 cmꢀ1
; dH (300 MHz,
CDCl3) 0.87 (6H, t, J 7.3 Hz, CH2CH3), 1.39 (4H, m, N(CH2)2CH2), 1.60
(4H, sext, J 7.3 Hz, CH2CH3), 1.73 (4H, m, NCH2CH2), 2.45 (6H, s,
CH3Ph), 2.57 (4H, t, J 7.3 Hz, COCH2), 3.79 (4H, t, J 7.7 Hz, NCH2), 7.35
(4H, d, J 8.2 Hz, CH3Ph o-H), 7.78 (4H, d, J 8.2 Hz, CH3Ph m-H); dC
(75 MHz, CDCl3) 13.5, 18.1, 21.6, 26.3, 29.8, 38.1, 46.7, 127.5, 129.8,
137.1, 144.6, 172.9; (Found: C, 59.08; H, 7.43; N, 4.80. C28H40N2O6S2
requires: C, 59.55; H, 7.14; N, 4.96%.)
4.4.7. Compound (10b)
Mp: 116–117 ꢁC; Rf (33% ethyl acetate/hexane) 0.44; IR (KBr):
2958, 1706, 1597, 1364, 1171, 1029, 843, 729 cmꢀ1
; dH (300 MHz,
4.4.1. Compound (8a)
CDCl3) 0.85 (6H, t, J 7.3 Hz, CH2CH3), 1.27 (4H, sext, J 7.3 Hz, CH2CH3),
1.39 (4H, m, N(CH2)2CH2), 1.54 (4H, quint, J 7.3 Hz, COCH2CH2), 1.73
(4H, m, NCH2CH2), 2.45 (6H, s, CH3Ph), 2.58 (4H, t, J 7.3 Hz, COCH2),
3.79 (4H, t, J 7.7 Hz, NCH2), 7.34 (4H, d, J 8.1 Hz, CH3Ph o-H), 7.78 (4H,
d, J 8.1 Hz, CH3Ph m-H); dC (75 MHz, CDCl3) 13.8, 21.6, 22.1, 26.3, 26.7,
29.8, 36.0, 46.8, 127.5, 129.8, 137.1, 144.7, 173.1; (Found: C, 60.28; H,
7.76; N, 5.18. C30H44N2O6S2 requires: C, 60.78; H, 7.48; N, 4.73%.)
Mp: 169–170 ꢁC; Rf (33% ethyl acetate/hexane) 0.40; IR (KBr):
2954, 1694, 1358, 1488, 1349, 1158, 1085, 814, 709, 576 cmꢀ1
; dH
(300 MHz, CDCl3) 1.10 (6H, t, J 7.2 Hz, CH2CH3), 2.45 (6H, s, CH3Ph),
2.75 (4H, q, J 7.2 Hz, COCH2), 4.05 (4H, s, NCH2), 7.35 (4H, d, J 8.2 Hz,
CH3Ph o-H), 7.81 (4H, d, J 8.2 Hz, CH3Ph m-H); dC (75 MHz, CDCl3)
8.8, 21.7, 29.8, 45.2, 127.6, 129.9, 136.5, 145.0, 174.1; (Found: C,

A.R. Massah et al. / Tetrahedron 65 (2009) 7696–7705
7705
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4.4.8. Compound (11)
Mp: 115–116 ꢁC; Rf (33% ethyl acetate/hexane) 0.43; IR (KBr):
2965, 1713, 1603, 1475, 1352, 1177, 1093, 881, 745 cmꢀ1
; dH
(300 MHz, CDCl3) 0.90 (6H, t, J 7.3 Hz, CH2CH3), 1.63 (4H, sext, J
7.3 Hz, CH2CH3), 2.71 (4H, t, J 7.3 Hz, COCH2), 4.05 (4H, s, NCH2),
7.54–7.94 (10H, m, Ph); dC (75 MHz, CDCl3) 13.5, 18.1, 38.2, 45.3,
127.5, 129.3, 133.8, 139.5, 173.3; (Found: C, 55.34; H, 6.51; N, 6.04,
C22H28N2O6S2 requires: C, 54.98; H, 5.87; N, 5.83%.)
4.4.9. Compound (12)
Mp: 154–155 ꢁC; Rf (33% ethyl acetate/hexane) 0.40; IR (KBr):
2926, 1455, 1352, 1177, 1085, 816, 758 cmꢀ1
; dH (300 MHz, CDCl3)
1.07 (6H, t, J 7.2 Hz, CH2CH3), 1.79 (4H, m, NCH2CH2), 2.63 (4H, q, J
7.2 Hz, COCH2), 3.86 (4H, s, NCH2), 7.54–7.92 (10H, m, Ph); dC
(75 MHz, CDCl3) 8.8, 27.2, 29.8, 46.3, 127.4, 129.3, 133.7, 139.8, 173.7;
(Found: C, 55.50; H, 6.31; N, 6.14. C22H28N2O6S2 requires: C, 54.98;
H, 5.87; N, 5.83%.)
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4.4.10. Compound (13)
Mp: 135–136 ꢁC; Rf (33% ethyl acetate/hexane) 0.40; IR (KBr):
2945, 1694, 1358, 1171, 1048, 861, 739 cmꢀ1
; dH (300 MHz, CDCl3)
1.07 (6H, t, J 7.2 Hz, CH2CH3), 1.40 (4H, m, N(CH2)2CH2), 1.75 (4H, m,
NCH2CH2), 2.62 (4H, q, J 7.2 Hz, COCH2), 3.81 (4H, t, J 7.2 Hz, NCH2),
7.54–7.92 (10H, m, Ph); dC (75 MHz, CDCl3) 8.8, 26.2, 29.7, 29.8, 46.9,
127.5, 129.2, 133.6, 139.9, 173.7; (Found: C, 56.08; H, 5.93; N, 5.09.
C24H32N2O6S2 requires: C, 56.67; H, 6.34; N, 5.51%.)
Acknowledgements
We thank Dr. Tayebani for her kind help and also financial
support of Islamic Azad University of Shahreza Research Council.
References and notes
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