Observations on the reactivity of pentafluorophenyl sulfonate esters

Article abstract of DOI:10.1039/b501212k

Studies on displacement reactions of alkyl pentafluorophenyl (PFP) sulfonates with amines are consistent with a mechanism involving an elimination-addition pathway; comparisons between the reactivity of PFP-sulfonates with sulfonyl chlorides and PFP-sulfo

Full text of DOI:10.1039/b501212k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Observations on the reactivity of pentafluorophenyl sulfonate esters{
Stephen Caddick,*a Jonathan D. Wildena and Duncan B. Juddb
Received (in Cambridge, UK) 26th January 2005, Accepted 22nd March 2005
First published as an Advance Article on the web 15th April 2005
DOI: 10.1039/b501212k
Studies on displacement reactions of alkyl pentafluorophenyl
(PFP) sulfonates with amines are consistent with a mechanism
involving an elimination-addition pathway; comparisons
between the reactivity of PFP-sulfonates with sulfonyl chlorides
and PFP-sulfonates with PFP-esters are also presented.
The sulfonamide structural motif is widely found in molecules of
medicinal interest, particularly anti-bacterial agents.1 More
recently the observation that the sulfonamides can act as transition
state mimetics of peptide hydrolysis and irreversible inhibitors of
cysteine proteases has had a dramatic impact on the potential
applications of this functional group in medicinal chemistry.2 In
Scheme 1
recent years we have introduced the pentafluorophenyl (PFP)
sulfonate ester as a new functional group for the synthesis of
sulfonamides.3 In particular, the advantages of ‘shelf stability’ and
easy purification have led us to suggest PFP sulfonates as potential
replacements for the corresponding sulfonyl chlorides.4 We herein
report significant new observations and applications which further
support the proposition that sulfonyl chlorides may eventually be
replaced by PFP-sulfonates. These new results enhance our
understanding of the reactivity of this novel functional group
and enable us to gauge its comparative reactivity with reference to
sulfonyl chlorides.
Scheme 2
In our early work on the synthesis of functionalised PFP
sulfonates via free-radical chemistry, we were somewhat surprised
reaction. In this case, no deuterium incorporation was observed,
by the stability of alkyl PFP sulfonates to acidic and basic work-up
strongly suggesting the operation of the elimination–addition
conditions and their resistance to undergoing aminolysis at low
mechanism outlined above (Scheme 1).
temperatures. It was observed that although alkylsulfonyl
Having established a likely mechanistic pathway, we then
chlorides react with nucleophilic amines at 0 uC, the analogous
alkyl PFP sulfonates were inert to such conditions. However, when
compared the reactivity of the PFP sulfonate esters and their
sulfonyl chloride counterparts. Our first approach to this was to
heated to temperatures above 65 uC in a suitable solvent with a
strong base such as DBU, reaction of PFP-sulfonates with a
establish if an amine would react preferentially with either a PFP
sulfonate ester or a sulfonyl chloride. We therefore examined
variety of amines (including primary, secondary, heterocyclic and
the reaction of one equivalent of a simple primary amine
amino acid derivatives) proceeded smoothly to give the sulfona-
mide in excellent yields.3 The apparent requirement for DBU in
(4-methylbenzylamine) with a mixture of benzenesulfonyl chloride
and p-toluenepentafluorophenyl sulfonate (Scheme 3). We
the reactions of PFP-sulfonates suggested that the reaction might
observed that this reaction gave solely the product 10, derived
only from reaction with the sulfonyl chloride 9. The PFP sulfonate
ester 8 was recovered in near quantitative yield.
be proceeding via a sulfene intermediate, as is known to operate for
alkyl sulfonyl chlorides (Scheme 1).5
In support of this mechanism we observed that exposure of
the PFP sulfonate 5 to 4-methylbenzylamine in THF–D2O led to
the isolation of 6, a product containing one deuterium atom at the
a-position as compared to the anhydrous reaction (Scheme 2). In
order to demonstrate that deuteration was occurring prior to
sulfonamide formation, a sample of the unlabelled sulfonamide 7
was exposed to identical conditions as for the displacement
It is clear from these experiments that PFP sulfonates, both
alkyl and aryl, are significantly less reactive than the comparable
{ Electronic supplementary information (ESI) available: experimental
details for the mechanistic studies. See http://www.rsc.org/suppdata/cc/b5/
b501212k/
*s.caddick@ucl.ac.uk
Scheme 3
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 2727–2728 | 2727

View Article Online
Scheme 4
Scheme 6
employing an excess of amine (5 equiv.) at 0 uC in the first step, the
reaction is chemoselective and leads only to the product derived
from the reaction of the PFP-ester.
The exquisite chemoselectivity observed here offers excellent
opportunities for diversity-oriented organic synthesis.
In summary we have shown that PFP-sulfonates are versatile
intermediates for the synthesis of sulfonamides under mild
conditions. The comparative studies presented in this paper
highlight the potential benefit of using PFP-sulfonates as opposed
to sulfonyl chlorides.
Scheme 5
sulfonyl chlorides. This feature along with our previous observa-
tions regarding stability led us to explore the possibility that PFP
sulfonates might be employed under reaction conditions that were
not compatible with sulfonyl chlorides. Our first approach to this
focused on the possibility of carrying out reactions in aqueous
media. Thus, a representative sulfonyl chloride (benzenesulfonyl
chloride) was mixed with a comparable PFP sulfonate ester (para-
toluenepentafluorophenyl sulfonate, PFP tosylate) in an aqueous
medium. Addition of one equivalent of a primary amine
(4-methylbenzylamine) led to the isolation of the sulfonamide 11
derived from the reaction of PFP tosylate 8 with the amine. None
of the product corresponding to reaction with benzenesulfonyl
chloride was observed (Scheme 4). Presumably, the sulfonyl
chloride 9 is hydrolysed rapidly under the reaction conditions.
The utility of PFP esters in the coupling of carboxylic acids and
amines or alcohols is well documented and known to be a facile
process even at low temperatures.6 We therefore wished to
compare the reactivity of a PFP sulfonate and a PFP carboxylate
in a substrate that would demonstrate the synthetic utility of their
differing reactivities.
Stephen Caddick,*a Jonathan D. Wildena and Duncan B. Juddb
aDepartment of Chemistry, University College London, 20 Gordon
Street, London, UK WC1H 0AJ. E-mail: s.caddick@ucl.ac.uk
bGlaxoSmithKline, Third Avenue, Harlow, Essex, UK CM19 5AW
Notes and references
1 (a) T. H. Maren, Ann. Rev. Pharmacol. Toxicol., 1976, 16, 309; (b)
C. T. Suparan, F. Briganti, S. Tilli, W. R. Chegwidden and A. Scozzafaza,
Bioorg. Med. Chem., 2001, 9, 703.
2 (a) W. R. Roush, S. L. Gwaltney, II, J. M. Cheng, K. A. Scheidt,
J. H. McKerrow and E. Hansell, J. Am. Chem. Soc., 1998, 120, 10994; (b)
J. J. Reddick, J. M. Cheng and W. R. Roush, Org. Lett., 2003, 5, 1967;
(c) A. A. Hernandez and W. R. Roush, Curr. Opin. Chem. Biol., 2002, 6,
459; (d) W. R. Roush, J. M. Cheng, B. Knapp-Reed, A. Alvarez-
Hernandez, J. H. McKerrow, E. Hansell and J. C. Engel, Bioorg. Med.
Chem. Lett., 2001, 11, 2759.
3 S. Caddick, J. D. Wilden, S. J. Wadman, H. D. Bush and D. B. Judd,
Org. Lett., 2002, 4, 2549.
4 S. Caddick, J. D. Wilden and D. B. Judd, J. Am. Chem. Soc., 2004, 126,
1024.
In order to carry out such a comparison we prepared the bis-
PFP derivative 13 from 12 and our recently described coupling
protocol4
(triphenylphosphine
ditriflate/pentafluorophenol)
(Scheme 5). It was noted that in this case, and in other cases
where poor solubility in DCM is a problem, sonication can be
used to enhance the solubility and reduce reaction times.7,8
Addition of 1 equiv. of allylamine to the bis-PFP ester 13 at 0 uC
led to amide 14 formation exclusively. Subsequent addition of
piperidine and heating of the mixture to 65 uC led to the
sulfonamide 15 in excellent yield (Scheme 6). Inverse addition of
the two amines in this protocol leads to the products 16 and then
17. Any of the four products is readily isolated and purified by
recrystallisation or column chromatography. It is notable that even
5 (a) For a complete overview of this mechanism, see: I. M. Gordon,
H. Maskill and M. F. Ruasse, Chem. Soc. Rev., 1989, 18, 123 and
references therein; (b) J. F. King, J. Y. L. Lam and S. Skonieczny, J. Am.
Chem. Soc., 1992, 114, 1743; (c) S. N. Lyashchuck, Y. G. Skrypnik and
V. P. Besrodnyi, J. Chem. Soc., Perkin Trans. 2, 1993, 6, 1153.
6 (a) L. Kisfalud, M. Low, O. Nyeki, T. Szirtes and I. Schon, Liebigs Ann.
Chem., 1973, 1421; (b) L. Kisfalud, J. E. Roberts, R. H. Johnson,
G. L. Mayers and J. Kovacs, J. Org. Chem., 1970, 35, 3563; (c) B. Penke,
L. Balaspiri, P. Pallai and K. Kovacs, Acta Phys. Chem., 1974, 20, 471;
(d) L. Kisfalud and I. Schon, Synthesis, 1983, 325.
7 T. Kimura and T. Ando, J. Synth. Org. Chem. Jpn., 1988, 46, 1124.
8 R. Miethchen, Ultrasonics, 1992, 30, 173.
2728 | Chem. Commun., 2005, 2727–2728
This journal is ß The Royal Society of Chemistry 2005