A mild, convenient synthesis of sulfinic acid salts and sulfonamides from alkyl and aryl halides

Article abstract of DOI:10.1016/S0040-4039(02)02073-7

A general, mild, and convenient method has been developed for the synthesis of various alkyl and aryl sulfinic acid salts and sulfonamides from the corresponding halides. Key to the success of this methodology is the design and facile synthesis of sodium 3-methoxy-3-oxopropane-1-sulfinate (SMOPS), a reagent that serves to introduce the protected sulfinate moiety directly to the substrate, thus avoiding the use of oxidizing and other harsh reaction conditions such as organolithium or Grignard reagents. Many functional groups, as well as heterocycles, are tolerated in the sequence.

Full text of DOI:10.1016/S0040-4039(02)02073-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8479–8483
A mild, convenient synthesis of sulfinic acid salts and
sulfonamides from alkyl and aryl halides
Jeremy M. Baskin and Zhaoyin Wang*
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire/Dorval,
Quebec, Canada H9R 4P8
Received 9 September 2002; accepted 20 September 2002
Abstract—A general, mild, and convenient method has been developed for the synthesis of various alkyl and aryl sulfinic acid salts
and sulfonamides from the corresponding halides. Key to the success of this methodology is the design and facile synthesis of
sodium 3-methoxy-3-oxopropane-1-sulfinate (SMOPS), a reagent that serves to introduce the protected sulfinate moiety directly
to the substrate, thus avoiding the use of oxidizing and other harsh reaction conditions such as organolithium or Grignard
reagents. Many functional groups, as well as heterocycles, are tolerated in the sequence. © 2002 Published by Elsevier Science Ltd.
The sulfonamide group is found in many therapeutic
agents, including drugs for the treatment of bacterial
and viral infections. More recently, it has been found
quent conversion to sulfonamides. For the synthesis of
alkyl sulfonamides, the entire process can be carried out
in a one-pot operation.
1
to be a key constituent of a new class of cyclooxygenase
2
3
inhibitors such as Celecoxib and Valdecoxib. The
most commonly used synthetic method to make sulfon-
amides involves the reaction of ammonia with sulfonyl
b-Phenylsulfonylketones 1 have been used as a template
8
to prepare a variety of b-substituted enones. The key
step of the process is the b-elimination of the phenyl-
sulfinate after an appropriate substituent is introduced
through an alkylation reaction of the intermediate sul-
fone anion (Scheme 1, Eq. (1)). Based on the same
principle, we envisioned that a sulfinate derivative such
4
chlorides. Although the method is sufficient, its utility
is limited to the availability of sulfonyl chlorides, which
can only be prepared under rather harsh oxidizing or
strong Lewis acidic conditions. Alternatively, sulfon-
amides can be obtained by reacting sulfinic acid salts
with an electrophilic nitrogen source such as hydroxyl-
as
sodium
3-methoxy-3-oxopropane-1-sulfinate
(SMOPS) 2 can serve as a donor for the sulfinate
moiety through a simple alkylation and subsequently be
removed by a b-elimination (Scheme 1, Eq. (2)). The
reaction of the resulting sulfinate 3 with an electrophilic
nitrogen source would provide an easy access to various
sulfonamides.
5
amine-O-sulfonic acid or bis(2,2,2-trichloroethyl)-
6
azodicarboxylate. The latter method is particularly
attractive due to the mildness of the reaction conditions
and the possibility to introduce the sulfonamide group
at later stage of a multi-step synthesis. However, the
success of the process lies in the availability of the
required sulfinic acid salt. The existing synthetic
approaches to sulfinic acid salts either involve the use
of organolithium or Grignard reagents, which are
incompatible with a host of functional groups, or
We began our study by designing a synthesis of
SMOPS, whose only known synthesis is unsuitable for
its isolation and characterization, due to contamination
7
involve tedious, multi-step syntheses. Furthermore, the
purity of the sulfinates is not sufficiently high due to an
inability to isolate the hygroscopic salt.
Here, we report a novel, convenient strategy for the
synthesis of sulfinic acid salts from alkyl and aryl
halides under very mild conditions, and for their subse-
*
Corresponding author. Tel.: +1-514-428-3235; fax: +1-514-428-4900;
e-mail: zhaoyin wang@merck.com
Scheme 1.
–
0
040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02073-7

8
480
J. M. Baskin, Z. Wang / Tetrahedron Letters 43 (2002) 8479–8483
of the product with borate salts and benzothiazole,
though the synthesis is useful for providing SMOPS as
Table 1. One-pot formation of alkyl sulfonamides
7
g
an intermediate for further reactions. A new and
practical preparation of SMOPS is shown in Scheme 2.
Conjugate addition of methyl 3-mercaptopropionate to
methyl vinyl ketone, followed by Na WO -catalyzed
2
4
oxidation with H O , generated sulfone 5. b-Elimina-
2
2
tion of 5 was achieved by treatment with 1 equiv. of
NaOMe in a mixture of THF and MeOH. Thus, multi-
gram quantities of SMOPS can be isolated in near-
quantitative yield from sulfone 5 as a stable white solid
simply by evaporation of the solvent under reduced
pressure.
Scheme 2.
With SMOPS in hand, a one-pot synthesis of alkyl
sulfonamides from alkyl halides was explored. In par-
ticular, the solvent must be compatible with all three
steps in the sequence—alkylation, b-elimination, and
sulfonamide formation. After screening a number of
solvents, DMSO was found to suit the need for the
one-pot operation. In addition to promoting the alkyla-
9
tion reaction due to its highly polar, aprotic nature,
DMSO also provides a more homogeneous reaction
medium for the sulfonamide formation step since many
alkyl and aryl sulfinic acid sodium salts have limited
solubility in water, which is the solvent in the original
procedure involving hydroxylamine-O-sulfonic acid as
the electrophilic nitrogen source. The second step, the
b-elimination of the resulting intermediate sulfone,
could be accomplished by treatment either with
NaOMe or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
Thus, a diverse range of alkyl sulfonamides 6a–h was
generated, using a one-pot procedure, with satisfactory
yields (Table 1). The intermediate sulfones from alkyla-
tion of SMOPS with halides in Table 1 can be obtained
in >95% yields for all cases after a simple aqueous
workup. Additionally, to isolate the intermediate
sodium sulfinates, the resulting sulfones can be treated
with 1 equiv. NaOMe in a THF/MeOH mixture. The
corresponding sodium sulfinates can be isolated quanti-
tatively by evaporation of the solvent under reduced
pressure, an identical procedure to the last step in the
synthesis of SMOPS.
for the synthesis of alkyl sulfonamides. First, no oxidiz-
ing or reducing reagents are involved. The sulfinate
moiety is transferred from SMOPS with sulfur at the
required oxidation state. Second, many functional
groups, such as esters, ketones, and nitro groups are
tolerated throughout the entire sequence. It is notewor-
thy that a secondary bromide can be converted to the
corresponding sulfonamide in an acceptable yield, as
well as an unactivated primary bromide. (Table 1,
entries g–h).
We then investigated the synthesis of aryl sulfonamides
using the same strategy. Because the nucleophilic dis-
placement of aryl halides by SMOPS requires an excess
both of Cu(I) salts and SMOPS, isolation of the inter-
mediate sulfones 7a–f was necessary in order to mini-
mize the potential complications to the subsequent two
steps. The intermediate sulfones 7a–f were prepared in
good yields from aryl iodides or bromides by using 3
equiv. SMOPS and CuI in DMSO at 110°C (5 equiv. of
This new approach to alkyl sulfonamide formation
offers several advantages over the traditional methods

J. M. Baskin, Z. Wang / Tetrahedron Letters 43 (2002) 8479–8483
8481
1
0
SMOPS and CuI in the case of aryl bromides). Sub-
jecting the sulfones 7a–f to the same conditions as those
for alkyl substrates provided various aryl sulfonamides
equiv. NaOMe in a THF/MeOH mixture followed by
evaporation of the solvent under reduced pressure. This
method for the synthesis of sodium sulfinates offers
obvious advantages over the existing ones and pro-
vides an easy access to a variety of sulfinates, which are
very useful synthetic intermediates.
11
8
a–f (Table 2). In general, the formation of sulfon-
amides proceeded well, with only a couple of excep-
tions. For 4-acetyl-iodobenzene, none of the desired
sulfonamide 8e was obtained; we speculate that the
electron-withdrawing nature of the 4-acetyl substituent
reduces the nucleophilicity of the sulfinate intermediate,
In summary, we have developed a simple, convenient
method for synthesis of alkyl and aryl sulfonamides.
Additionally, this chemistry also provides a practical
route to sodium salts of various alkyl and aryl sulfinic
acids, which are otherwise laborious to obtain. The
benefits of this novel process include the following: (1)
the easy availability of starting materials, (2) a conve-
nient procedure (one-pot for alkyl sulfonamides), and
(3) the absence of oxidizing agents, organolithium or
Grignard reagents, and strong Lewis acids, rendering
the process compatible with many functional groups.
1
whose existence was confirmed by H NMR, for the
following substitution reaction on NH OSO H. As
2
3
well, the methylthio group is not compatible with
NH OSO H, as the oxidation of methylthio group to a
sulfoxide was observed and none of the sulfonamide 8f
was formed. In this case, the problem may be avoided
2
3
by using other milder reagents such as bis(2,2,2-
6
trichloroethyl)azodicarboxylate.
Nevertheless, the
method introduced here has proven to be very useful
for molecules with many sensitive groups such as
hydroxyls, esters, and halogens. Particularly notewor-
thy is the success of this methodology in the formation
of 8c, which demonstrates the applicability of this
approach toward introduction of a sulfonamide group
in a highly functionalized molecule.
Experimental
Formation of SMOPS 2
To a solution of methyl vinyl ketone (18.3 mL, 220
mmol) and methyl 3-mercaptopropionate (22.2 mL, 200
Similar to alkyl sulfinates, aryl sulfinates can be isolated
by treatment of the intermediate sulfones 7a–f by 1
mmol) in THF (300 mL) was added Et
mmol). After heating for 4.5 h at 50°C under a nitrogen
3
N (2.8 mL, 20
Table 2. Formation of aryl sulfonamides

8
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J. M. Baskin, Z. Wang / Tetrahedron Letters 43 (2002) 8479–8483
atmosphere, the solvent was removed under reduced
pressure to yield the sulfide 4 (37.5 g, 99%). The sulfide
Typical procedure for aryl sulfonamide formation: 4-
methoxybenzene sulfonamide 8b
4
(35.5 g, 187 mmol) was placed in a 500 mL, three-
necked round-bottom flask, along with Na WO ·2H 0
2
4
2
®
(
3.1 g, 9.3 mmol), Aliquat 336 (tricaprylylmethylam-
4-Iodoanisole (234 mg, 1.0 mmol) was added to a
solution of CuI (571 mg, 3.0 mmol) and SMOPS (522
monium chloride, 3.8 g, 9.3 mmol), EtOAc (100 mL),
14
cyclohexane (50 mL) and H O (20 mL) under a nitro-
mg, 3.0 mmol) in DMSO (2 mL). After stirring for 20
h at 110°C under a nitrogen atmosphere, the reaction
mixture was cooled to room temperature, diluted with
EtOAc (10 mL) and filtered through a pad of silica.
2
gen atmosphere. The reaction mixture was then heated
to 60°C and 30% aqueous solution of H O (77 mL,
2
2
6
55 mmol) was added dropwise over a 1 h period. After
The resulting filtrate was washed with H O (2×20 mL)
stirring for 4 h at 60°C, the reaction mixture was cooled
2
and brine (1×20 mL), dried over Na SO , filtered
to room temperature, diluted with EtOAc (100 mL) and
2
4
through a pad of silica, and concentrated to yield the
intermediate sulfone 7b (160 mg, 62%). To a solution of
sulfone 7b (160 mg, 0.62 mmol) in DMSO (1 mL) was
added NaOMe (0.142 mL, 25% in MeOH, 0.62 mmol).
After stirring at room temperature for 10 min, a solu-
tion of NH OSO H (351 mg, 3.1 mmol), NaOAc (200
H O (100 mL). The organic layer was separated and the
aqueous layer was extracted with EtOAc (3×50 mL).
The combined organic extracts were washed with brine
2
(
50 mL), dried over Na SO , and filtered through a pad
2 4
of silica. After concentration under reduced pressure,
the crude product was stirred as a suspension in a
mixture of EtOAc (25 mL) and hexanes (25 mL)
overnight and collected by filtration to yield sulfone 5
2
3
mg) in H O (4 mL) was added to the reaction mixture,
2
which was prevented from heating up by immersion of
the reaction vessel in a cool water bath. After 20 h of
stirring at room temperature, the reaction mixture was
(
29.8 g, 72%). Sulfone 5 (22.65 g, 102 mmol) was
dissolved in a mixture of THF (1100 mL) and MeOH
225 mL) at rt, and NaOMe (23.2 mL of a 25% solution
diluted with EtOAc (10 mL) and H O (15 mL) and
2
(
extracted with EtOAc (3×15 mL). The combined
in MeOH, 102 mmol) was added dropwise while stir-
ring. After stirring for 15 min, the solvent was removed
by evaporation under reduced pressure. The crude
product was stirred as a suspension in a mixture of
ether (150 mL), EtOAc (10 mL), and MeOH (10 mL)
for 30 min and collected by suction filtration to yield
the titled sulfinate 2 as a white powder (16.27 g, 92%, or
organic extracts were then washed further with H O (15
2
mL) and brine (15 mL), dried with Na SO , filtered
2
4
through a pad of silica, and concentrated to give the
1
3
titled sulfonamide 8b as a white solid (107 mg, 57%).
1
H NMR (500 MHz, acetone-d ): l 7.85 (d, 2H), 7.10
d, 2H), 6.44 (bs, 2H), 3.91 (s, 3H). C NMR (125
6
13
(
MHz, acetone-d ): l 163.18, 137.04, 128.89, 114.70,
6
6
6% overall yield from methyl 3-mercaptopropionate).
−
5
5.96. MS (APCI, neg.) m/z: 186.1 (M−H) .
1
H NMR (500 MHz, DMSO-d ): l 3.57 (s, 3H), 2.43 (t,
6
13
2H), 2.05 (t, 2H). C NMR (125 MHz, DMSO-d ): l
6
73.96, 56.01, 51.22, 25.96. MS (APCI, neg.) m/z: 151.1
Acknowledgements
−
Typical procedure for alkyl sulfonamide formation: 2-
methoxy-4-nitrobenzyl sulfonamide 6c
The authors wish to thank the Merck Frosst Centre for
Therapeutic Research for providing financial support
for J.M.B.’s summer work-term.
2-Methoxy-4-nitrobenzyl bromide (295 mg, 1.20 mmol)
was added to a solution of SMOPS 2 (250 mg, 1.44
mmol) in DMSO (2 mL) at room temperature under a
nitrogen atmosphere. The reaction was stirred for 10
min and then treated with dropwise addition of
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2
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6
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3 1
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H
NMR (500 MHz, acetone-d ): l 8.38 (s, 1H), 8.30 (d,
6
1
3
1
H), 7.32 (d, 1H), 6.29 (bs, 2H), 4.52 (s, 2H), 4.07 (s,
1
3
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6
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−
(
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J. M. Baskin, Z. Wang / Tetrahedron Letters 43 (2002) 8479–8483
8483
7
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8
9
2
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1
13
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