An expeditious and convenient synthesis of acylsulfonamides utilizing polymer-supported reagents

Article abstract of DOI:10.1016/j.tetlet.2007.05.158

Acylsulfonamides can be rapidly and conveniently synthesized from a variety of carboxylic acids and sulfonamides utilizing the commercially available reagents, PS-DCC and DMAP under mild reaction conditions. DMAP can be efficiently scavenged by utilizatio

Full text of DOI:10.1016/j.tetlet.2007.05.158

Tetrahedron Letters 48 (2007) 5181–5184
An expeditious and convenient synthesis of
acylsulfonamides utilizing polymer-supported reagents
Ying Wang,* Kathy Sarris, Daryl R. Sauer and Stevan W. Djuric
High-Throughput Organic Synthesis Group, Medicinal Chemistry Technologies, Global Pharmaceutical Research and
Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6113, United States
Received 12 April 2007; revised 22 May 2007; accepted 25 May 2007
Available online 2 June 2007
Abstract—Acylsulfonamides can be rapidly and conveniently synthesized from a variety of carboxylic acids and sulfonamides uti-
lizing the commercially available reagents, PS-DCC and DMAP under mild reaction conditions. DMAP can be efficiently scavenged
by utilization of a silica-supported tosic acid cartridge (Si-SCX). In most of the cases studied, products with high purities and yields
were obtained without the need for further purification.
Ó 2007 Elsevier Ltd. All rights reserved.
N-Acylsulfonamides have been widely employed as car-
boxylic acid bioisosteres in medicinal chemistry due to
their comparable acidity.1 They offer the possibility for
a wide range of structural modifications relative to the
carboxylic acids themselves. As part of our ongoing pro-
gram to develop efficient and robust methods for the
preparation of biologically relevant compounds from
readily available building blocks,2 we sought to develop
a convenient, expeditious, and high-yielding reaction
protocol for the synthesis of acylsulfonamides, which
would also be highly amenable to automation for the
rapid generation of analogs.
1 was indicated by crude LC/MS analysis (Table 1,
entry 1). The conversion yield increased dramatically
when HOBt was not added to the reaction (Table 1,
entries 2 and 4). When the stronger base, 4-dimethyl-
aminopyridine (DMAP), was used instead of DIEA, a
quantitative conversion to the desired sulfonamide
product was observed within 1 h as shown by crude
LC/MS analysis (Table 1, entry 5). Inferior results were
obtained when CH3CN was used as the solvent instead
of CH2Cl2 (Table 1, entry 6). Furthermore, we observed
that the amount of reagents used could be scaled back
dramatically. Eventually, it was found that with only
1.5 equiv of PS-DCC and 1 equiv of DMAP, the conver-
sion to acylsulfonamide 1 was accomplished within 1 h
with quantitative conversion (Table 1, entry 8).
In principle, acylation of sulfonamides can be accom-
plished by the reaction of sulfonamides with acids,
anhydrides, esters, and acid chlorides. The direct con-
densation of carboxylic acids with sulfonamides is par-
ticularly attractive as a diverse array of carboxylic
acids is commercially available. A number of synthetic
procedures have been reported for the preparation of
sulfonamides from acids using coupling reagents such
as EDC, DCC, CDI or Mukaiyama’s reagent.1e,3 We
have reported that amides can be effectively synthesized
from carboxylic acids and amines using the PS-DCC/
HOBt method under microwave heating.2a However,
when this method was used for the synthesis of acylsulf-
onamide 1, a very low conversion to the desired product
Solid-phase extraction (SPE) techniques have proven to
be useful for scavenging a wide range of excess reagents
and reaction side-products. SPE is especially well suited
for parallel synthesis since in many cases, a simple filtra-
tion will remove undesired materials, thereby greatly
simplifying reaction workup. It has been found that
the use of silica-supported reagents in SPE can greatly
decrease the time required for byproduct sequestration.4
Therefore, silica-bound p-toluene sulfonic acid (Si-
SCX)5 was studied for its effectiveness in scavenging
DMAP, the base used in the acylsulfonamide synthesis.
For these experiments, 0.8 mmol Si-SCX (1 g) was
packed into a short column. A solution of the desired
amount of DMAP in 1 ml of CH2Cl2 was passed
through the Si-SCX cartridge by gravity filtration and
washed with additional solvent. It was found that in this
*
Corresponding author. Tel.: +1 847 935 3058; fax: +1 847 935
5212; e-mail: wang.ying@abbott.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.158

5182
Y. Wang et al. / Tetrahedron Letters 48 (2007) 5181–5184
Table 1. Synthesis of acylsulfonamide 1 using PS-DCC/DMAP
O
O
PS-DCC
Base
O
O
OH
NH2
+
S
S
O
N
Solvent
H
O
1
Entry
PS-DCC (equiv)
Base (equiv)
HOBt (equiv)
Reaction condition
Conversiona (%)
1
2
3
4
5
6
7
8
3
3
3
3
3
3
2
1.5
DIEA (2)
DIEA (2)
DMAP (2)
DIEA (2)
DMAP (2)
DMAP (2)
DMAP (2)
DMAP (1)
1
1
1
MW, 110 °C, 10 min, CH3CN
rt, 12 h, CH2Cl2
rt, 12 h, CH2Cl2
rt, 1 h, CH2Cl2
rt, 1 h, CH2Cl2
rt, 5 h, CH3CN
<10b
30b
35b
85
100
40
100
100 (95)c
rt, 1 h, CH2Cl2
rt, 1 h, CH2Cl2
a Conversion based on crude LC/MS analysis.
b Other unidentified peaks were also observed.
c Isolated yield.
Table 2. Scavenging DMAP with an Si-SCX cartridge (1 g, 0.8 mmol
case, pre-conditioning of the column with the solvent
was not necessary (Table 2, entries 1 and 2). MeOH
can also be used as the washing solvent if desired. This
was particularly useful in cases where the crude product
had poor solubility in CH2Cl2. In these cases, MeOH
could be used to wash the cartridge to prevent the prod-
uct from being precipitated. The sequestration process
was very effective. DMAP (0.4 mmol) was scavenged
completely when passed through a cartridge packed
with 0.8 mmol Si-SCX in a single flow-though (Table
2, entry 4). This whole process took less than 5 min.
Remarkably, when 0.8 mmol DMAP was used (1 equiv
relative to the amount of Si-SCX on the cartridge in a
loading)6
Entry
DMAP
(mmol)
Washing
solvent
DMAP collected
after a single
flow-throughb
a
1
2
3
4
5
0.2
0.2
0.2
0.4
0.8
CH2Cl2
None
None
None
None
15%c
CH2Cl2
MeOH
CH2Cl2
CH2Cl2
a The cartridge was pre-conditioned with CH2Cl2.
b Based on LC/MS analysis.
c Determined after drying down the filtrate.
Table 3. Synthesis of acylsulfonamides from carboxylic acids and sulfonamides with PS-DCC/DMAP7
1) 1.5 equiv. PS-DCC
O
O
S
1.0 equiv. DMAP
CH2Cl2, RT,
O
O
+
R'
NH2
R
R'
R
OH
S
N
O
2) Si-SCX Cartridge
5 mins, filter
H
O
1 equiv.
1 equiv.
Entry
1
Acid
Sulfonamide
Product
Reaction
time (h)
Conversiona
(%)
Isolated yield
(%)
O
O
O
O
S
O
S
NH2
1
1
100
100
99
98
N
OH
O
H
O
O
S
O
O
2
3
S
N
O2N
NH2
NO2
H
O
O
O
O
NH2
1
100
100
S
S
HN
O
O
O
O
S
O
S
Br
Cl
4
5
1
1
100
100
97
90
NH2
NH2
Br
Cl
NH
O
O
O
O
S
O
S
NH
O
O

Y. Wang et al. / Tetrahedron Letters 48 (2007) 5181–5184
5183
Table 3 (continued)
Entry
Acid
Sulfonamide
Product
Reaction
time (h)
Conversiona
(%)
Isolated yield
(%)
O
S
O
O
F
F
NH2
6
7
8
1
100
100
100
91
S
N
O
H
O
O
O
S
O
S
1
1
85
93
NH2
N
O
H
O
Cl
O
O
O
S
S
F
N
NH2
Cl
O
F
H
O
Cl
O
O
O
9
1
93
81b
S
NH2
NH2
S
N
Cl
O
H
O
O
O
S
O
O
S
CN
10
11
1
1
100
100
85
92
NC
NH
OH
O
O
O
O
O
S
N
OH
O
H
O
O
O
S
O
O
O
12
13
14
1
1
8
100
100
100
86
N
OH
H
O
O
O
O
O
94
S
HN
OH
O
O
O
O
S
87c
N
N
N
OH
H
O
a Determined by crude LC/MS analysis and 1H NMR analysis.
b Crude product was purified by reverse-phase HPLC.
c Crude material was purified by reverse-phase HPLC without filtering through a Si-SCX cartridge.
single flow-through), the Si-SCX cartridge was able to
retain most of the material and only 15% DMAP was
recovered from the filtrate (Table 2, entry 5).
general and worked well for a variety of alkyl and aryl
carboxylic acids and sulfonamides. Notably, electron
deficient sulfonamides worked just as well. It was found
that basic groups are tolerated although longer reaction
time was required and the Si-SCX cartridge could not be
used (Table 3, entry 14). In most cases, the isolated
yields for the pure products without further purification
were greater than 90%.
Since the conversion to the acylsulfonamide 1 was quan-
titative under our conditions within 1 h, the crude mate-
rial was directly loaded onto a Si-SCX cartridge and
washed with additional CH2Cl2. The filtrate thus col-
lected was free of DMAP as shown by LC/MS. After
solvent evaporation, acylsulfonamide 1 was obtained
in 95% isolated yield with high purity. No further puri-
fication was necessary.
In summary, we have developed a rapid and convenient
synthesis of acylsulfonamides directly from commer-
cially available polymer-supported reagents and scav-
engers. In addition, this mild reaction procedure is
highly amenable for automation and can be easily
adapted to parallel synthesis.
With this convenient protocol in hand, we next exam-
ined the scope of this method, and the results are sum-
marized in Table 3. Of note is that most of the
reactions reported in Table 3 were completed within
1 h with quantitative conversion. In all cases studied
but two (Table 3, entries 9 and 14), passing the crude
mixture through a Si-SCX cartridge as described previ-
ously afforded the pure product without the need for
further purification. This method was found to be quite
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.05.158.

5184
Y. Wang et al. / Tetrahedron Letters 48 (2007) 5181–5184
4. (a) Flynn, D. L.; Devraj, R. V.; Naing, W.; Parlow, J. J.;
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6. The desired amount of DMAP was dissolved in 1 ml of
CH2Cl2 and transferred via pipet to a pre-packed cartridge
of Si-SCX (1 g, 0.8 mmol/g). The filtrate was collected via
gravity filtration. The cartridge was washed with additional
amounts of CH2Cl2 (MeOH for Table 2, entry 3). The
filtrate was analyzed by LC/MS. No peak was detected for
Table 2, entries 1–4. When 0.8 mmol DMAP was used
(Table 2, entry 5), the filtrate was dried down and weighed,
15% of DMAP was recovered after the flow-through.
7. General procedure: To a 20 ml scintillation vial was added
0.3 mmol of PS-DCC (1.5 equiv, 1.2 mmol/g) followed by
0.2 mmol acid and 0.2 mmol sulfonamide in 2 ml of
CH2Cl2. DMAP (0.2 mmol) is added to the above solution
and the reaction mixture was shaken at room temperature
on a J-Chem heater/shaker. The reaction was checked
periodically by LC/MS. In most cases, the reaction was
completed within 1 h. The reaction mixture was directly
transferred via a pipet to a pre-packed cartridge of 1 g
Si-SCX (0.8 mmol loading) via gravity filtration. The cartridge
was washed with additional amounts of CH2Cl2 until no
peak was detected in the fractions collected. The filtrate was
combined and dried down. In all cases but one (Table 3,
entry 9), the products thus collected have greater than 97%
purity as determined by NMR and LC/MS without the
need for any further purification. Products from entry 9 was
purified by reverse-phase HPLC. When there is basic
functionality in the product (entry 14), the crude material
was purified by reverse-phase HPLC without filtering
through a Si-SCX cartridge.
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