A new route to sulfonamides via intermolecular radical addition to pentafluorophenyl vinylsulfonate and subsequent aminolysis

Article abstract of DOI:10.1021/ol026181m

(Matrix presented) Various radical species generated from either the corresponding iodo-or bromo-compounds and tri-n-butyltin hydride were added in an intermolecular fashion to the activated acceptor pentafluorophenyl vinylsulfonate. The products of each

Full text of DOI:10.1021/ol026181m

ORGANIC
LETTERS
2002
Vol. 4, No. 15
2549-2551
A New Route to Sulfonamides via
Intermolecular Radical Addition to
Pentafluorophenyl Vinylsulfonate and
Subsequent Aminolysis
Stephen Caddick,* Jonathan D. Wilden, Hannah D. Bush,
Sjoerd N. Wadman,† and Duncan B. Judd‡
Centre for Biomolecular Design and Drug DeVelopment, UniVersity of Sussex,
Falmer, Brighton BN1 9QJ, U.K.
s.caddick@sussex.ac.uk
Received May 14, 2002
ABSTRACT
Various radical species generated from either the corresponding iodo- or bromo- compounds and tri-n-butyltin hydride were added in an
intermolecular fashion to the activated acceptor pentafluorophenyl vinylsulfonate. The products of each reaction were then subjected to
aminolysis with a variety of different amines.
Sulfonamides have long been the focus of pharmaceutical
interest as a result of their potent antimicrobial and biological
activity.1 Recently, this functional group has also been
identified as a transition state mimetic of peptide hydrolysis
and, in particular, as the critical motif for potent, irreversible
inhibitors of cysteine proteases, suggesting wider applicabil-
ity to protease inhibition.2,3 Because of the vast potential that
is displayed within this class of compounds and their relative
difficulty in preparation, new strategies to functionalized
sulfonamides are continually being sought. We here report
a new strategy for the construction of sulfonamides with
structural features of potential biological interest, including
amino acid and C-linked glycoside derivatives using inter-
molecular radical coupling methodology.4,5
Our approach begins with the surprisingly stable, novel,
pentafluorophenyl vinylsulfonate 3, easily prepared from
commercially available pentafluorophenol 2 and 2-chloro-
ethane-1-sulfonyl chloride 1 (Scheme 1).
† High Throughput Chemistry, GlaxoSmithKline, Stevenage, Herts SG1
2NY, U.K.
Scheme 1. Synthesis of Pentafluorophenyl Vinylsulfonate
‡ GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, U.K.
(1) For a review, see: Hansch, C.; Sammes, P. G.; Taylor, J. B.
ComprehensiVe Medicinal Chemistry; Pergamon Press: Oxford, 1990; Vol.
2, Chapter 7.1. For recent biological applications, see: Hanson, P. R.; Probst,
D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999, 40, 476.
(2) McKerrow, J. H.; James, M. N. G.; Cysteine Proteases: Evolution,
Function and Inhibitor Design. In PerspectiVes in Drug DiscoVery and
Design; Anderson, P. S., Kenyon, G. L., Marshall, G. R., Eds.; ESCOM
Science Publishers: Leiden, 1996; Vol. 6.
(3) Roush, W. R.; Gwaltney, S. L., II; Cheng, J.; Scheidt,; McKerrow,
J. H.; Hansell, E. J. Am. Chem. Soc. 1998, 120, 10994.
10.1021/ol026181m CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/25/2002

The bifunctional acceptor 3 is highly susceptible to attack
by both radical and nucleophilic species (particularly amines)
with simultaneous displacement of pentafluorophenol.6 There-
fore, by using a combination of radical and ionic chemistry,
we are able to generate a diverse range of sulfonamide
products (Scheme 2).
encouraged by the observation that this reaction is not limited
to simple alkyl radicals or stabilized radical species but that
the method is applicable to the synthesis of derivatized sugar
and amino acid species. In some cases, for example, entry
5, amine displacement may be carried out prior to purification
to enable separation from radical reduction products. Fol-
lowing purification by column chromatography, aminolysis
proceeds smoothly to furnish the sulfonamide in near
quantitative yields. Table 2 outlines the results of various
Scheme 2. Sulfonamide Synthesis from Pentafluorophenyl
Vinylsulfonatea
Table 2. Examples of Amine Displacement
Our approach offers several advantages over traditional
methods for the synthesis of sulfonamides. First, sulfonyl
chlorides (traditionally used to synthesize sulfonamides) are
highly reactive and often unstable species. In contrast, the
pentafluorophenyl esters are stable to a variety of conditions
including column chromatography and even basic workup
procedures. Second, the radical reaction may be optimized
prior to the introduction of functionality from the amine,
therefore minimizing potential side reactions.
We have found the intermolecular tin-mediated radical
addition of a number of organo-halide precursors is a facile
process leading to the corresponding alkyl sulfonate esters
in moderate to good yields (Table 1). We were particularly
Table 1. Examples of Intermolecular Addition to
Pentafluorophenyl Vinylsulfonate
a Isolated yields.
aminolysis reactions after radical addition of the 6-iodo-D-
galactose species (Scheme 3). Particularly noteworthy are
entries 3, 6, and 8, which demonstrate, first, the applicability
of this approach toward the synthesis of derivatized hetero-
cyclic compounds and, second, potential for the synthesis
of glycopeptide conjugates.
a Product derived from direct amine displacement of radical addition
product. Ar ) 4-methylbenzylamine b Isolated yields
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Org. Lett., Vol. 4, No. 15, 2002

Scheme 3a
Scheme 4. Proposed Mechanism of Amine Displacement
a Method a: RNH2, THF, DBU, 65 °C. Method b: NaH, THF,
0 °C.
It is interesting to note that the displacement reaction will
only proceed when a strong base such as DBU or sodium
hydride is present in the reaction medium, even with a
nucleophilic amine. In light of this fact we postulate that
the reaction mechanism, rather than proceeding via the well
documented direct displacement of a leaving group by
amine,7 actually involves deprotonation of the sulfonate
moiety, followed by rapid extrusion of pentafluorophenol
to give intermediate 10. This sulfene mechanism has been
shown by King et al. to be the predominant mechanistic
pathway for the hydrolysis of sulfonyl halides at high pH.8
Lyashchuk et al. have also demonstrated that the sulfene
mechanism operates in the pyridine-catalyzed reaction of
alkanesulfonyl chlorides with phenols,9 adding further sup-
port for our proposed mechanism.
exploring other related displacement reactions and investigat-
ing the applicability of this approach to the generation of
libraries of biologically significant sulfonamides.
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for generous financial support of this work. We
also thank the Association for International Cancer Research,
BBSRC, Novartis, Pfizer, and AstraZeneca for the support
of our program, and the University of Sussex for providing
funds to establish the Centre for Biomolecular Design and
Drug Development. We also gratefully acknowledge the
contributions of Dr. Tony Avent, Dr. Ali Abdul-Sada, and
the EPSRC Mass Spectroscopy Service at Swansea.
In conclusion, we have demonstrated that the bifunctional
intermediate 3 is an excellent acceptor for intermolecular
radical reactions and have shown its applicability as a
building block for sulfonamide synthesis via nucleophilic
attack by a range of nitrogen nucleophiles. We suggest that
the pentafluorophenylsulfonate motif is a potential replace-
ment for the more reactive sulfonyl chloride unit, which is
difficult to prepare and handle and liberates hydrogen
chloride on exposure to nucleophiles. We are currently
Supporting Information Available: Characterization
data for the pentafluorophenyl sulfonate esters and for the
functionalized sulfonamides. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL026181M
(6) For related work, see: Caddick, S.; Hamza, D.; Wadman, S. N.;
Wilden, J. D. Org. Lett. 2002, 4, 1775. Salvino, J. M.; Kumar, N. V.; Orton,
E.; Airey, J.; Kiesow, T.; Crawford, K.; Mathew, R.; Krolikowski, P.; Drew,
M.; Engers, D.; Krolikowski, D.; Herpin, T.; Gardyan, M.; McGeehan, G.;
Labaudiniere, R. J. Comb. Chem. 2000, 691-697.
(7) For a complete overview of this mechanism, see: Gordon, I. M.;
Maskill, H.; Ruasse, M. F.; Chem. Soc. ReV., 1989, 18, 123 and references
therein.
(8) King, J. F.; Lam, J. Y. L.; Skonieczny, S. J. Am. Chem. Soc., 1992,
114, 1743.
(9) Lyashchuck, S. N.; Skrypnik, Y. G.; Besrodnyi, V. P.; J. Chem. Soc.,
Perkin Trans. 2 1993, 6, 1153.
(4) For other examples of C-glycoside formation using intermolecular
radical methodology, see: SanMartin, R.; Tavassoli, B.; Walsh, K. E.;
Walter, D. S.; Gallagher, T. Org. Lett. 2000, 2, 4051 and references therein.
(5) For a complete overview of intermolecular radical-mediated carbon-
carbon bond formation, see: Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Pergamon Press: New York, 1986.
Curran, D. P.; Synthesis 1988, 417 and 419.
Org. Lett., Vol. 4, No. 15, 2002
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