Oxidation of aromatic and aliphatic triisopropylsilanylsulfanyls to sulfonyl chlorides: Preparation of sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2003.08.073

A series of aromatic and aliphatic triisopropylsilanylsulfanyls were prepared and oxidized to the sulfonyl chlorides with KNO₃/SO ₂Cl₂. The sulfonyl chlorides were characterized via their conversion to sulfonamides.

Full text of DOI:10.1016/j.tetlet.2003.08.073

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7821–7824
Oxidation of aromatic and aliphatic triisopropylsilanylsulfanyls
to sulfonyl chlorides: preparation of sulfonamides
Yves Gareau,* Jonathan Pellicelli, Se´bastien Laliberte´ and Danny Gauvreau
Merck Frosst Canada Inc, Department of Medicinal Chemistry, Autoroute Transcanadienne, Kirkland, Qc, Canada H9H 3L1
Received 11 May 2003; accepted 14 August 2003
Abstract—A series of aromatic and aliphatic triisopropylsilanylsulfanyls were prepared and oxidized to the sulfonyl chlorides with
KNO3/SO2Cl2. The sulfonyl chlorides were characterized via their conversion to sulfonamides.
© 2003 Elsevier Ltd. All rights reserved.
In medicinal chemistry, sulfonamides are important
functional groups. Structure–activity relationship
(SAR) has demonstrated their valuable role in drug
design and their utility as surrogate in amide replace-
ment. They are encountered in many natural products
as well as in therapeutic molecules used today. In the
synthesis of organic molecules, aromatic sulfonamides
can be used in Direct ortho Metallation (DoM) reaction
to obtain more complex compounds.1 Ammonia, pri-
mary and secondary amines react readily with sulfonyl
chlorides in high yields to furnish sulfonyl amides. In
turn, there are many ways to prepare sulfonyl chlorides
on an aromatic ring. Direct chlorosulfonation of a
suitable electron rich phenyl ring with ClSO3H2 will
afford the desired product. They can also be prepared
from aromatic thioethers,3 amines,4 trialkyl tins5 and
halides,6 with the later case being the method of choice.
In this particular route, the halogen is first converted to
the anion via a lithium–halogen exchange. This is usu-
ally done with a strong base such as n-butyllithium and
the resulting phenyl anion treated with SO2 to form a
sulfinate. Finally, the sulfinate is oxidized with NCS or
SO2Cl2 to yield the sulfonyl chloride. One major disad-
vantage of this approach obviously comes from the use
of a strong base in the metal–halogen exchange reaction
which precludes the presence of numerous sensitive
functional groups in the starting material. This is one of
the reasons why milder methods that can either use
electron rich or electron poor substrates would be of
great interest. We wish to describe herein our work in
this field.
We envisioned that trialkylsilyl thioethers such as 1,
which possess a weak siliconꢀsulfur bond, would be a
group of choice to obtain sulfonyl chlorides in a simple
manner. Typically, this would be equivalent to running
a thiol oxidation. Compounds of type 1 can easily be
prepared from an aromatic thiol and a trialkylsilyl
halide7 but this would be pointless since one can
directly oxidize the thiol to the sulfonyl chloride. The
thioether can also be prepared from a palladium cata-
lyzed coupling reaction between potassium triisopropyl-
silanethiolate 2 and an aromatic halide (Z=Br, I)8 or
triflate.9 This approach is much more interesting and
broadens considerably the scope of the methodology.
In addition, the conditions used for the coupling reac-
tion are rather mild thus allowing the presence of
functional groups.
We used 4-iodo anisole as a model substrate to study
the feasibility of the oxidation on the trialkylsilyl mer-
captide. Compound 3 (Z=p-OMe) was obtained as an
oil in 85% isolated yield after filtration over a pad of
silica gel. We then turned our attention in the selection
of a method for the oxidation. Accordingly, we looked
at the oxidation of 3 with the KNO3/SO2Cl2 system.10
To a solution of 3 in acetonitrile at 0°C was added 2.5
equiv. of KNO3 followed by the dropwise addition of
sulfuryl chloride. After stirring 20–40 min the reaction
mixture was filtered and the solvent removed under
vacuum. The crude material was diluted in THF at 0°C
and an excess of diluted ammonia was added. From
this, we obtained the desired sulfonamide 5 in 66%
isolated yield for two steps. The conditions for the
oxidation step were briefly investigated. For example,
* Corresponding author.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.073

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Y. Gareau et al. / Tetrahedron Letters 44 (2003) 7821–7824
the addition of a tertiary amine to the reaction mix-
ture or lowering the temperature to −78°C resulted
only in a slight change in yield.11 We also looked at
other systems for the oxidation. For instance, a com-
bination of bleach and HClconc. on 3-triisopropylsi-
lanylsulfanyl toluene also worked well. Having
recognized the practicality of this methodology, we
chose not to isolate the sulfonyl chloride but to carry
on with the crude mixture up to the more stable
sulfonamide. In only one instance, the sulfonyl chlo-
ride 4 (Z=p-OMe) has been isolated to make sure of
the integrity of the compound. The sulfonyl chloride
prepared in this manner was identical to a commer-
cially available sample.
Table 1. Formation of triisopropylsilanylsulfanyls (3) and sulfonamides (5)12

Y. Gareau et al. / Tetrahedron Letters 44 (2003) 7821–7824
7823
Since we are forming a sulfonyl chloride, this implies
that we are not restricted in preparing only RSO2NH2
like many other methods. To illustrate this, we have
condensed the sulfonyl chloride with four different
amines during the study. Diethyl amine, n-propyl
amine, morpholine and n-phenyl piperazine were con-
sider. Only the piperazine seemed to be less reactive
toward the sulfonyl chloride in entries 5 and 11. They
both gave an overall yield of 25%.
These results encouraged us to determine the scope and
limitations of this new sequence. Therefore, a series of
silylmercaptides were prepared with minor modifica-
tions from the original procedure. The palladium tetra-
kistriphenylphosphine coupling reaction with 2 was run
in a 0.2 M solution of toluene at 90°C for the period of
time indicated in Table 1. The adducts 3 were purified
over a pad of silica gel and generally obtained in high
yields and in good purity (>95%) for spectral character-
ization (1H and 13C NMR). In some cases, the purity
was lower and the exact yield was not determined. This
does not imply that the coupling reaction is problematic
but rather indicates a more difficult purification. In
those particular examples we carried out the sequence
and calculated a global yield for the three steps (entries
5, 10, and 12).
Finally, we have shown that aromatic sulfonamides
with electron donating and electron withdrawing
groups can be prepare in good yields from triisopropy-
lsilanylsulfanyls 3. Aliphatic substrates can also be used
as well to prepare sulfonamides. Ketone, ester, nitro
and phthalimide groups are compatible with our
methodology. We also avoided the use of strong bases
such as n-BuLi to prepare the Ar–Li.
Nonetheless, the coupling reaction with either electron-
rich or electron-poor aryl halides proceeded rather
nicely with yields ranging from 80 to 97% (see Table 1).
Other palladium catalysts could be used as well. For
example, PdCl2dppf (entry 2) gave after 3 h of heating
an excellent isolated yield (95%) of 3 (Z=p-Me). We
also examined non-aromatic substrates. Those were
prepared by SN2 displacement of the thiolate 2 on
4-chlorobenzyl bromide (entry 7) and on 1-bromo-3-
phenylpropane (entry 8) to yield the corresponding
trialkylsilylmercaptide in 71 and 86%, respectively.
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1
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