A mild, efficient method for the synthesis of aromatic and aliphatic sulfonamides

Article abstract of DOI:10.1016/S0040-4039(02)00848-1

A two-step method was developed for the synthesis of aromatic and aliphatic sulfonamides from the corresponding sulfinates using bis(2,2,2-trichloroethyl)azodicarboxylate as the electrophilic nitrogen source. The intermediate sulfonylhydrazides were obtained in very good yields and were cleaved under reductive conditions to deliver the desired sulfonamides. A variety of substituents in the aromatic ring are well tolerated as well as heterocycles.

Full text of DOI:10.1016/S0040-4039(02)00848-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4537–4540
A mild, efficient method for the synthesis of aromatic and
aliphatic sulfonamides
Wing Yan Chan and Carl Berthelette*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire–Dorval,
Que´bec, Canada H9R 4P8
Received 20 February 2002; revised 22 April 2002; accepted 23 April 2002
Abstract—A two-step method was developed for the synthesis of aromatic and aliphatic sulfonamides from the corresponding
sulfinates using bis(2,2,2-trichloroethyl)azodicarboxylate as the electrophilic nitrogen source. The intermediate sulfonylhydrazides
were obtained in very good yields and were cleaved under reductive conditions to deliver the desired sulfonamides. A variety of
substituents in the aromatic ring are well tolerated as well as heterocycles. © 2002 Published by Elsevier Science Ltd.
Sulfonamides are widely used as antibacterial agents in
the pharmaceutical industry. Traditional synthesis of
unsubstituted sulfonamides involve nucleophilic attack
by ammonia on a sulfonyl halide.1 Although this
method is efficient, the formation of the sulfonyl chlo-
ride is not always possible. Alternatively, arylsulfonyl
azides can be reduced to give arylsulfonamides.2 How-
ever, the synthesis of sulfonamide using an electrophilic
nitrogen source is not that common. To our knowledge,
only one communication has appeared in the literature
using hydroxylamine-O-sulfonic acid as an elec-
trophile.3 This reagent is water-soluble and sparingly
soluble in organic solvents, resulting in a major draw-
back for hydrophobic compounds. As an extension to
this work and our interest in developing new routes for
the formation of sulfonamides, we wish to report a new
mild and efficient synthesis for such compounds.
triflic acid gave the corresponding hydrazide in 57%
yield after 60 min at 0°C in a THF/H2O mixture
(Scheme 1).5
Scheme 1. Synthesis of sulfonylhydrazides from 4-chloroben-
zenesulfinate and BTCEAD (1).
Bis(2,2,2-trichloroethyl)azodicarboxylate (BTCEAD, 1)
has been used extensively as an electrophilic source of
nitrogen in the formation of aromatic amines and
phenylhydrazines.4 We envisaged that we could couple
sulfinic acids with azodicarboxylate and then reduce the
resulting hydrazide intermediate to provide access to a
variety of sulfonamides in a two-step sequence.
A variety of reaction conditions were then tested to
optimize the yields of sulfonylhydrazides. Efficiency of
the hydrazide formation was unaffected by the removal
of triflic acid. Using Lewis acids, sodium bicarbonate or
others additives did not affect the yields.6 We observe
also that many organic solvents like THF, ether, diox-
ane and DME were well tolerated for this reaction.7
We began our study with the commercially available
4-chlorobenzenesulfinic acid sodium salt. Treatment
with 1 equiv. of BTCEAD and a catalytic amount of
The stoichiometry of 1 was also investigated and 3
equiv. proved to be the best compromise, affording the
hydrazide in 87% isolated yield in a shortened 30 min
reaction time at 0°C (Method A).8 Further attempts to
lengthen the reaction time or raise the temperature of
the reaction only led to reduced yields. A control
experiment was performed to test the stability of 1
alone in the THF/H2O mixture. Surprisingly, the azo-
Keywords: sulfonamides; azodicarboxylate; sulfinate; sulfonylhy-
drazide; reductive cleavage.
* Corresponding author. Tel.: +1-514-428-3359; fax: +1-514-428-4939;
e-mail: carl berthelette@merck.com
–
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00848-1

4538
W. Y. Chan, C. Berthelette / Tetrahedron Letters 43 (2002) 4537–4540
Table 1. Synthesis of sulfonylhydrazide
dicarboxylate significantly decomposes upon stirring at
0°C after only a few minutes under these conditions.
This finding prompted us to consider a new set of
reaction conditions that will remove water from the
reaction as well as decrease the amount of 1 required.
After many optimization experiments, we found that
TFA (1.1 equiv.) with BTCEAD (1.05 equiv.) in THF
or DMF at 0°C afforded the corresponding sulfonylhy-
drazide in excellent yields (Method B). The use of TFA
presumably allows the sulfinic acid salt to be proto-
nated and thus improve its solubility in organic
solvents.
A: BTCEAD (3eq)
THF/H2O, 30 min, 0°C
O
O
O
H
N
S
S
M
R
N
Troc
R
O
B: BTCEAD (1.05eq), TFA (1.1eq)
Troc
THF, 30 min, 0°C
Yield (%) a
B
Entry
1
R
M
A
Na
93
99
97
Cl
Cl
Since few sulfinic acid salts are commercially available,
we have prepared them using two methods (Scheme 2).
First, the reaction of organolithium or Grignard
reagents with sulfur dioxide affords the sulfinate salt in
good yields after addition of hexanes and a simple
filtration. If more sensitive substrates are used, an
alternative method consists of displacing a halide with
the anion of benzothiazoyl. Oxidation of the resulting
thioether to the sulfone using sodium tungstate and
hydrogen peroxide followed by sodium borohydride
cleavage affords the sulfinate salt in excellent yields.
Na
87
61
2
Cl
Na
Li
92
3
4
5
Me
36b
74
MeO
Me
Li
46b
--
99c
O
Na
Li
85
89
6
7
Cl
58
Br
--
Na
81
8
N
Scheme 2. Preparation of aromatic and aliphatic sulfinic acid
salts.
a Isolated yield of analytically pure (1H,13C and HRMS) sulfonylhydrazide.
b Required purification by reverse phase HPLC.
The optimized methods (A or B) were then used for the
formation of various hydrazides (Table 1). The reaction
proceeded smoothly for aryl sulfinates with an electron
withdrawing or electronically neutral substituent.
Method A afforded moderate to good yields of the
hydrazide in a mild fashion. Alternatively, method B
gave excellent yields for nearly all the substrates tested,
although the use of TFA can potentially be problematic
for acid sensitive substrates.
c Product contains 20% of mono cleaved Troc.
We next turned our attention to reduce the sulfonylhy-
drazides using zinc in acetic acid, but none of the
desired sulfonamides was obtained. However, a litera-
ture example suggested the addition of acetone after the
treatment with zinc and acetic acid.11 When we imple-
mented these conditions, we obtained the desired sul-
fonamide in 59% yield. Increasing the amount of
acetone used did not affect the yield, but we were able
to increase the yield to 73% by doubling the reaction
time with zinc. Nevertheless, further increases in the
reaction time of either step only resulted in diminished
yields. The optimized reaction conditions were then
used to cleave the sulfonylhydrazides (Table 2).
We also subjected aliphatic sulfinates to our standard
conditions, and we were pleased to isolate 58 and 89%
of the butyl sulfonylhydrazide (Table 1, entry 7) using
methods A and B, respectively. Benzylic sulfinate was
obtained by a modified literature procedure and con-
verted to the sulfonylhydrazide in 85% yield using
method B.9 We also decided to investigate the prepara-
tion of an indole sulfonylhydrazide that could be prob-
lematic to synthesize using conventional method as
described earlier (entry 8). The substrate was made
using commercially available 4-bromoindole in a four
steps sequence.10 The 4-bromoindolesulfonylhydrazide
was then obtained in 81% yield using method B. This
example illustrates well the utility of the present
method.
With our aromatic substrates, the reaction provided
high yields and purity of the sulfonamides after a
simple work-up. The one exception to this case was
2-methylfuranyl (Table 2, entry 5) where a mixture of
the sulfonamide and the corresponding hydrazone was
obtained.12 When we subjected the butyl and the indole
hydrazide (Table 2, entries 7 and 8) to the same condi-

W. Y. Chan, C. Berthelette / Tetrahedron Letters 43 (2002) 4537–4540
4539
Table 2. Deprotection of sulfonylhydrazides to sulfon-
amides
1. Zn dust, AcOH,
90 min, 25°C
H
N
O
O
O
O
S
S
R
N
Troc
R
NH2
2. Acetone, 60 min, 25°C
Troc
Yield (%) a
80
Entry
R
Scheme 3. Proposed mechanism for the cleavage of hydra-
zide.
1
2
3
4
5
6
7
8
Cl
Experimental
86
88
99
87b
95
Cl
Cl
All compounds gave satisfactory spectral and analytical
data.
Me
Typical procedure for hydrazide formation: bis(2,2,2-
trichloroethyl) 1-[(4-chlorophenyl)sulfonyl]hydrazine-1,2-
dicarboxylate
MeO
Method A: BTCEAD (575 mg, 1.51 mmol) was added
to a solution of 4-chlorobenzenesulfinic acid sodium
salt (100 mg, 0.50 mmol) in a 1:1 THF/H2O mixture
(2.60 mL) at 0°C. The yellow suspension was stirred at
0°C for 30 min and quenched with saturated aqueous
NH4Cl. The reaction mixture was extracted three times
with EtOAc, washed with H2O, brine, dried over
Na2SO4 and concentrated to give a yellow oil. Flash
chromatography (15% EtOAc in hexane) provided the
titled hydrazide as a white solid (260 mg, 93%).
Me
O
Cl
82c
94
Br
N
Method B: BTCEAD (400 mg, 1.05 mmol) was added
to a solution of 4-chlorobenzenesulfinate (200 mg, 1.00
mmol) in 5 mL of anh. THF at 0°C. TFA (85 mL, 1.10
mmol) was then added and the reaction was stirred for
30 min followed by the previous workup. The hydra-
a
b
c
Isolated yield of analytically pure (1H, 13C and HRMS) sulfonamide.
Product contains 10% of the intermediate sulfonylhydrazone.
Water extraction was avoided due to aqueous solubility.
1
zide was isolated as a white solid (555 mg, 99%). H
NMR: (500 MHz, acetone-d6) l 10.30 (1H, br s), 8.14
(2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz), 4.97 (2H,
s), 4.92 (2H, s). 13C NMR: (125 MHz, acetone-d6) l
206.2 (2C), 154.7, 150.8, 141.3, 137.2, 131.9, 130.0, 95.8,
94.8, 76.6, 75.5. HRMS calcd for C12H9Cl7N2O6S (M+
K)+: 592.7637. Found: 592.7638. Anal. calcd for
C12H9Cl7N2O6S: C, 25.86; H, 1.63; N, 5.03; found: C,
26.05; H, 1.55; N, 5.02%.
tions, we were pleased to isolate the corresponding
aliphatic sulfonamides in 82 and 94% yields,
respectively.
Mechanistically, we expect the cleavage of the hydra-
zide to proceed via a hydrazone intermediate. To test
this hypothesis, benenesulfonylhydrazone was synthe-
sized from the corresponding hydrazine. When we sub-
jected this hydrazone to our cleavage conditions, the
desired sulfonamide was obtained. Together with spec-
troscopic data, these results give support for the forma-
tion of a hydrazone intermediate in the Zn-mediated
cleavage reaction (Scheme 3).
Typical procedure for sulfonamide formation: 4-chloro-
benzenesulfonamide
Zn dust (309 mg) was added to a solution of the
previous hydrazide (103 mg, 0.18 mmol) in AcOH (2
mL) at rt. The suspension was stirred for 1 h prior to
dropwise addition of acetone (1 mL). The mixture was
stirred for an additional 1 h and CH2Cl2 was then
added, sonicated 1 min and filtered over a pad of celite.
The organic solution was washed with H2O and brine,
dried over Na2SO4 and concentrated to give a white
solid (25 mg, 80%). 1H, 13C NMR and MS were
identical to that of an authentic commercially available
sample.
In summary, using aromatic and aliphatic sulfinates, we
have developed a mild, two-step method for the forma-
tion of the corresponding sulfonamides utilizing
BTCEAD as our electrophilic source of nitrogen. Fur-
ther investigations are under way to extend the scope of
this method.

4540
W. Y. Chan, C. Berthelette / Tetrahedron Letters 43 (2002) 4537–4540
Dufresne, C.; Leblanc, Y.; Berthelette, C.; McCooeye, C.
Acknowledgements
Synth. Commun. 1997, 27, 3613–3624.
5. Troc: 2,2,2-trichloroethoxycarbonyl (CCl3-CH2-COO-).
6. MgBr2-Et2O, BF3-Et2O and NaHCO3 gave 53, 51 and
55% isolated yields, respectively.
7. THF, ether, dioxane and DME gave similar yields.
8. Reaction progress was monitored using time-lapsed IR
spectroscopy (React IR).
The authors wish to thank the Merck Frosst Centre for
Therapeutic Research for providing funding for this
project. We thank Dr. Zhaoyin Wang, Mr. Yves
Leblanc, Dr. Claudio Sturino and Mr. Nicolas
Lachance for helpful discussions.
9. Adapted from (a) Ueno, Y.; Kojima, A.; Okawara, M.
Chem. Lett. 1984, 2125–2128; (b) Charette, A. B.;
Berthelette, C.; St-Martin, D. Tetrahedron Lett. 2001, 42,
5149–5153.
10. Alkylation of the indole was made with 1,3-dibromo-
propane followed by benzothiolate displacement, oxida-
tion to the corresponding sulfone and formation of the
sulfinate by cleavage using sodium borohydride as
described in the second part of Scheme 2.
References
1. Anderson, K. K. In Comprehensive Organic Chemistry;
Jones, D. N., Ed.; Pergamon Press: Oxford, 1979; Vol. 3.
2. (a) Boruah, A.; Baruah, M.; Prajapati, D.; Sandhu, J. S.
Synlett 1997, 1253–1254; (b) Iyer, S.; Sattar, A. K. Synth.
Commun. 1998, 28, 1721–1725.
3. Graham, S. L.; Scholz, T. H. Synthesis 1986, 1031–1032.
4. (a) Zaltsgendler, I.; Leblanc, Y.; Bernstein, M. A. Tetra-
hedron Lett. 1993, 34, 2441–2444; (b) Mitchell, H.;
Leblanc, Y. J. Org. Chem. 1994, 682–687; (c) Leblanc, Y.;
Boudreault, N. J. Org. Chem. 1995, 4268–4271; (d)
11. Leblanc, Y.; Fitzsimmons, B. J. Tetrahedron Lett. 1989,
30, 2889–2892.
12. Identity of the hydrazone was confirmed by 1H NMR
and MS.