Direct Synthesis of Sulfonamides and Activated Sulfonate Esters from Sulfonic Acids

Article abstract of DOI:10.1021/ja0397658

A general new method for the preparation of sulfonamides and activated sulfonate esters by the direct coupling of sulfonic acid salts with amines and alcohols using the reagent triphenylphosphine ditriflate is described. A new reusable polymer-supported reagent for these transformations under heterogeneous conditions is also described. These methods provide a fundamentally new approach to making small molecules containing the sulfonamide functional group. Copyright

Full text of DOI:10.1021/ja0397658

Published on Web 01/13/2004
Direct Synthesis of Sulfonamides and Activated Sulfonate Esters from
Sulfonic Acids
Stephen Caddick,* Jonathan D. Wilden, and Duncan B. Judd†
The Christopher Ingold Laboratories, Department of Chemistry, UniVersity College London,
20 Gordon Street, London, WC1H 0AJ, UK
Received November 24, 2003; E-mail: s.caddick@ucl.ac.uk
Scheme 3. Sulfonate Esters and Sulfonamides from Sulfonic
Acids
The importance of the sulfonamide unit in medicinal chemistry
cannot be overstated.1,2 This functional group constitutes the largest
class of antimicrobial agents and has been shown to be a transition
state mimetic of peptide hydrolysis and, in particular, as the critical
motif for potent, irreversible inhibitors of cysteine proteases.3-5 To
date, the generation of sulfonamides has almost exclusively relied
on the synthesis of sulfonyl chlorides that then undergo reactions
with nucleophiles such as amines. As we and others have previously
noted, sulfonyl chlorides do have disadvantages and they can be
difficult to handle and not amenable to long-term storage.6 In recent
work, we have established the PFP-sulfonate as a shelf-stable
alternative to sulfonyl chlorides. Such species undergo wide ranging
reactions with amines, even under aqueous reaction conditions, to
give sulfonamides in excellent yields (Scheme 1).7
Table 1. Synthesis of PFP Sulfonate Esters and Sulfonamides
Scheme 1. Reactivity of PFP-sulfonates in Aqueous Media
Despite the biological importance of sulfonamides, there currently
exists no procedure for achieving the transformation of a sulfonic
acid (or its salt) directly to a sulfonamide or sulfonate ester in one
synthetic step. This is in sharp contrast to the numerous reagents
and methodologies available to effect the conversion of a carboxylic
acid to the corresponding amide or esters. However, our own
experience matches that of others and we have been unsuccessful
in applying these protocols to the coupling of sulfonic acids.8 We
herein report our results describing the first general method for the
transformation of a sulfonic acid or its salt to the corresponding
sulfonamide or pentafluorophenol (PFP)-activated ester.
that exposure of a commercially available sulfonic acid salt
(pyridinium 4-toluenesulfonate) to the reagent 5 followed by either
pentafluorophenol or allylamine gave the coupled products 10 or
11 in near quantitative yield (entry 1, Table 1).
Scheme 2. Activation of Sulfonic Acids by Triphenylphosphine
Ditriflate
Keen to test the generality of our approach, we extended the
range of sulfonic acid substrates in the coupling reaction.11,12 As
can be seen from Table 1, a wide range of PFP-sulfonates could
be prepared using this methodology. We were also pleased to
observe that amines appear to be equally applicable in the reaction.
The results are outlined in Table 1.
As can be seen from Table 1, a number of functional groups are
tolerant to the reaction conditions. The procedure is effective with
sulfonate salts of aromatic, aliphatic, and heterocyclic substrates.
It is important to note at this stage that the choice of counterion in
the sulfonic acid salt is not trivial. Although metal salts of sulfonic
acids appear, at least in theory, good substrates for this reaction,
they are often less than ideal due to poor solubility or due to their
tendency to be hygroscopic. We have found that the pyridine or
We reasoned that an intermediate such as 7 would be suitably
activated toward nucleophiles and therefore undergo rapid reaction
with amines and the PFP anion. Clearly, the driving force of this
reaction would be the generation of the PdO π bond. This led us
to identify the reagent triphenylphosphine ditriflate, which we
anticipated would react with a sulfonate anion to generate inter-
mediate 7 directly (Scheme 2).9,10 We were delighted to observe
† Current address: GlaxoSmithKline, Third Avenue, Harlow, Essex, CM19 5AW,
UK.
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J. AM. CHEM. SOC. 2004, 126, 1024-1025
10.1021/ja0397658 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 5. Solid-Supported Phosphine Oxide: A Cleaner
Scheme 4. Coupling of 3-Nitrobenzene Sulfonic Acid with Amines
Alternative
Table 2. Amine Diversity in Sulfonamide Synthesis
providing that the resin is washed thoroughly after each cycle, no
activation of the phosphine oxide is required. This observation
represents a major advance in reaction efficiency since a single
batch of phosphine oxide resin can be used to generate a diverse
range of sulfonamides.
We have also established that, if required, the resin may be pre-
treated with triflic anhydride and then isolated by filtration and
stored under vacuum prior to use. This modification allows excess
triflic anhydride to be removed prior to the coupling reaction and
is particularly noteworthy if the resin is to be utilized in a parallel
fashion.
In conclusion, we have described a new synthesis of sulfonamides
and activated sulfonate esters from the sulfonic acid salt using the
activating agent triphenylphosphine ditriflate. The reaction has been
shown to display good functional group tolerance and is high
yielding. We have also demonstrated that triphenylphosphine oxide,
which can be troublesome to remove at the end of the reaction,
may be replaced by a solid-supported variant from which the
reaction products may be removed by washing. In summary, we
believe that this functional group transformation may obviate the
requirement to generate and use sulfonyl chlorides for the synthesis
of sulfonamides and activated sulfonate esters.
triethylamine salts of sulfonic acids are often suitable substrates
for this reaction since they are easily prepared from the parent acid
and are not particularly hygroscopic and usually soluble in organic
solvents. They are also easily purified by recrystallization (though
this is often not required). In cases where solubility of these salts
is particularly poor, the tetrabutylammonium salt may be employed
without significant decrease in yield or reaction efficiency.
Greatly encouraged by our initial studies, we wished to dem-
onstrate the generality of the approach to the synthesis of a diverse
range of sulfonamides. We chose, in this case to examine the
reaction of 3-nitrobenzene sulfonic acid pyridine salt with a number
of common amines (Scheme 4). The results are outlined in Table
2. Gratifyingly, it was observed that the reaction is not limited to
simple amines but enjoys success with primary, secondary, and
amino acid derivatives. Even electron-deficient anilines (entry 3,
Table 2) are applicable in the reaction.
It became clear to us that a phosphine oxide that could be more
easily removed from the reaction medium after the coupling had
taken place would greatly simplify our novel coupling protocol and
may enable us to eliminate chromatography entirely from the
procedure. We therefore obtained the commercially available
polystyrene-supported phosphine oxide A. To our delight, when
we substituted triphenylphosphine oxide for this analogous sup-
ported phosphine oxide, comparable yields of coupled product were
obtained (Scheme 5).13 In addition to this, purification could be
achieved without the use of column chromatography, simply by
filtering off the resin and then washing the filtrate with water to
remove any remaining salts. We were also pleased to observe that
the resin is recyclable and can be employed in another coupling
reaction. No loss in efficiency was observed after 5 cycles, and
Acknowledgment. We thank the EPSRC and GlaxoSmithKline
for generous financial support of this work. We also thank the
Association for International Cancer Research, BBSRC, and As-
traZeneca for the support of our program. We also gratefully
acknowledge the EPSRC Mass Spectroscopy Service at Swansea.
Supporting Information Available: Characterization data for the
sulfonate esters and the functionalized sulfonamides. This material is
available free of charge via the Internet at http://pubs.acs.org.
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