Rate enhancement of PFP sulfonate ester aminolysis by chloride salts in organic and aqueous media

Article abstract of DOI:10.1016/j.tetlet.2005.08.088

We report here, a method of accelerating the rate of aminolysis of PFP sulfonates to yield sulfonamides using tetrabutylammonium salts. We have previously explored the utility of employing PFP sulfonates in the formation of sulfonamides; however we demons

Full text of DOI:10.1016/j.tetlet.2005.08.088

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7637–7640
Rate enhancement of PFP sulfonate ester aminolysis by
chloride salts in organic and aqueous media
Jonathan D. Wilden,a,* Duncan B. Juddb and Stephen Caddicka
aThe Christopher Ingold Laboratories, Department of Chemistry, University College London, 20 Gordon Street,
London WC1H 0AJ, UK
bGlaxoSmithKline, Third Avenue, Harlow Essex CM19 5AW, UK
Received 19 July 2005; revised 11 August 2005; accepted 17 August 2005
Available online 16 September 2005
Abstract—We report here, a method of accelerating the rate of aminolysis of PFP sulfonates to yield sulfonamides using tetrabu-
tylammonium salts. We have previously explored the utility of employing PFP sulfonates in the formation of sulfonamides; however
we demonstrate here the advantages of combining the existing methodology with a revised protocol which allows the diversity within
both the sulfonate ester and the amine to be extended.
Ó 2005 Elsevier Ltd. All rights reserved.
Employing pentafluorophenyl (PFP) esters as replace-
ments for sulfonyl chlorides in the synthesis of alkyl,
aromatic and heteroaromatic sulfonamides1 is becoming
increasingly important in diversity orientated synthesis
due to their increased shelf-life, aqueous stability and
predictable reactivity towards nucleophiles.2,3 Recently,
we have also described a novel coupling procedure for
the preparation of these compounds from sulfonic
acids.4 In most cases, a PFP sulfonate on conventional
heating or under microwave irradiation reacts smoothly
with amines to yield the corresponding sulfonamide
(Scheme 1).5
and often require increased temperatures. We wish to
address this problem to improve the scope of the reac-
tion and to make our procedure more amenable to par-
allel synthesis.
We envisaged that a nucleophilic catalyst such as 4-(di-
methylamino)pyridine (DMAP), commonly employed
in the activation of carboxylic acid chlorides and anhy-
drides may have the desired effect.6 However, when we
applied this familiar methodology to the reaction of
PFP sulfonates, no acceleration in rate was observed
and the reaction was often accompanied by decomposi-
tion products in addition to the desired sulfonamides.
We reasoned that the sulfonate unit, being such a
hard centre would react only slowly with a neutral
nucleophile such as DMAP and that a hard nucleophile
would be a more suitable choice as a nucleophilic
catalyst.
During ongoing investigations in our laboratory how-
ever, we have noticed that certain examples, most nota-
bly aryl PFP sulfonates bearing electron donating
groups and sterically hindered amines, react more slowly
O
O
O
O
We envisaged that a halide anion may be a more appro-
priate catalyst for the reaction by generating the corre-
sponding sulfonyl halide in situ. We therefore embarked
on initial studies to determine which halide might enhance
the rate of a typical displacement reaction. We first chose
to examine the reaction of hexylamine with pentafluoro-
phenyl-p-toluenesulfonate (Scheme 2) using chloroform
as the solvent, since this is a reaction that is known to pro-
ceed relatively slowly (8–10 h at reflux, 61 °C) and there-
fore an acceleration in rate would be easily measured.
We chose as the source of halide anions the appropriate
a or b
R2 NHR3
S
R2
S
R1
N
R3
R1
OPFP
Scheme 1. Reagents and conditions: (a) 85 °C, THF or DMF, NEt3,
MW, 1 h; (b) 65 °C, THF, NEt3, 1–3 h.
Keywords: Pentafluorophenyl sulfonates; Aminolysis; Rate enhance-
ment; Sulfonamides.
*
Corresponding author. Tel.: +44 (0) 20 7679 5813; e-mail:
j.wilden@ucl.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.088

7638
J. D. Wilden et al. / Tetrahedron Letters 46 (2005) 7637–7640
O
O
Clearly, the addition of halide salts has a marked im-
pact on the rate of the reaction. It is evident that the
greatest enhancement in rate is achieved by the addition
of one equivalent of a suitably soluble chloride source
(in the case of fluoride, only decomposition products
are observed). In contrast to the familiar Finkelstein
reaction, commonplace in organic chemistry, the addi-
tion of iodide appears to have no beneficial effect on
the reaction and may even inhibit the formation of the
sulfonamide.8 Addition of an alternative chloride source
(entry 8) leads essentially to the same result as obtained
in entry 3 and gives further evidence for our hypothesis
that the cation plays no significant role in the rate
acceleration.
O
O
S
S
a
NH(CH2)5CH3
OPFP
Scheme 2. Reagents and conditions: (a) hexylamine (2.5 equiv),
CHCl3, 61 °C, 10 h, 95%.
Table 1. Selection of nucleophilic halide catalyst for the acceleration of
aminolysis of PFP sulfonate esters
Entry
Additive
EquivÕs
Time for 100%
conversion
Yield (%)
1
2
3
4
5
6
7
8
None
—
10 h
—
85
—
94
89
91
88
84
90
Bu4NF
Bu4NCl
Bu4NCl
Bu4NBr
Bu4NBr
Bu4NI
1.0
1.0
0.1
1.0
0.1
1.0
1.0
75 min
6.5 h
5.5 h
9.5 h
12 h
We rationalise this observation by consideration of the
relative hardness of the sulfonate centre and the attack-
ing nucleophilic catalyst. The SO3PFP motif is a hard
electrophile and will therefore be attacked most rapidly
by a hard nucleophile. The hardest of the halide nucleo-
philes (excluding fluoride) is chloride and therefore the
rate of attack of this nucleophile will be the greatest of
all of the halides. Once formed, the sulfonyl chloride is
then free to react with a molecule of amine, a known fac-
ile process. Thus, despite sulfonyl bromides and iodides
Et3NBnCl
80 min
tetra-n-butylammonium salts due to their high solubility
in organic solvents.7 The results of our investigations
are outlined in Table 1.
Table 2. Reaction of amines with PFP-p-methoxybenzenesulfonate in the absence and presence of chloride anion
Entry
Amine
Reaction time (a) no additive (b)
1.5 equiv Bu4NCl
Product and yield
(a)
(b)
O
O
S
NH2
NH
1
>7 days
7.5 h
MeO
a. 67%a b. 89%
O
O
S
NH
NH2
2
45 min
5 min
MeO
a. 91% b. 96%
O
O
S
N
3
4
55 min
10 min
25 min
N
H
MeO
a. 88% b. 85%
CO2Me
Ph
O
O
Ph
S
N
MeO2C
1.5 h
H
MeO
NH2
a. 77% b. 75%
O
O
S
N
5
>7 days
13 h
MeO
N
H
a. 38%a b. 84%
a Reaction incomplete after 7 days.

J. D. Wilden et al. / Tetrahedron Letters 46 (2005) 7637–7640
7639
being (presumably) more reactive than their chloride
counterparts, the rate of their formation from the PFP
sulfonate and iodide or bromide renders the addition
of these salts ineffective as nucleophilic catalysts for this
reaction.
Presumably, the reaction mechanism proceeds via nucleo-
philic attack of chloride at the sulfonate centre leading
to the more reactive sulfonyl chloride in situ. We were
concerned that this method of accelerating the reaction
would prohibit the application of these PFP sulfonates
and amines in aqueous media, one of the many advanta-
ges of employing PFP sulfonates as replacements for
sulfonyl chlorides that we have previously reported.10
We therefore embarked on experiments that would dem-
onstrate the scope of the chloride accelerated procedure
with aqueous solvent mixtures. Reaction of PFP-p-
methoxybenzenesulfonate with amines in a 25% water–
THF or DMF mixture (to ensure solubility of the PFP
sulfonate) in the presence of one equivalent of tetrabutyl-
ammonium chloride at 65 °C, gave the results outlined
in Table 3.
Following our identification of a potential nucleophilic
catalyst, we were keen to demonstrate its effectiveness
in a number of reactions with reference to the reactions
without additives. We were particularly keen to dem-
onstrate its effectiveness in the reaction of electron rich
aryl PFP sulfonates (known to be significantly less
reactive than their electron poor counterparts and even
less reactive than alkyl PFP sulfonates) and amines
which have reduced nucleophilicity, either due to steric
hindrance or due to delocalisation (e.g., anilines). We
chose therefore to examine the reaction of pentafluoro-
phenyl-p-methoxybenzenesulfonate with a number of
amines. DMF was chosen as the solvent due to the
enhancement in rate above many other solvents as we
have previously noted.5,9 The results are outlined in
Table 2.
Although sulfonyl chlorides have previously been uti-
lised in aqueous systems,11 it is often the case that for
a homogeneous system, under basic conditions, hydro-
lysis of the sulfonyl chloride and major reduction in
yields is often observed as we have previously noted.10
We were therefore surprised to observe that the addi-
tion of water to the reaction medium had no detrimen-
tal effect on either the reaction rate or yield, in
particular for those examples that require several hours
(Table 3, entries 1 and 4). In fact, addition of water may
accelerate the reaction in some cases. This is probably
due to an increase in solvent polarity under aqueous
conditions.
We were pleased to observe that in all cases, addition
of 1.5 equiv of tetrabutylammonium chloride resulted
in a significant increase in the rate of the displacement
reaction. We were particularly gratified to observe that
even amines of a lower nucleophilicity such as anilines
(entry 5) and hindered examples (entry 1) could be suc-
cessfully employed whereas previously, the low reactiv-
ity of both the amine and the electron rich PFP
sulfonate would have led to prohibitively long reaction
times and most probably decomposition of the starting
materials.
It is interesting to note that although the sulfonyl chlo-
ride is likely to be generated in situ, this species is not
observed by TLC analysis of the reaction mixture at
Table 3. Bu4NCl promoted reaction of amines with PFP-p-methoxybenzenesulfonate in 25% aqueous THF
Entry
Amine
Reaction time
Product and yield
O
O
NH2
S
NH
1
7 h
MeO
MeO
85%
O
O
S
NH
NH2
2
3
4
5 min
5 min
14.5 h
90%
O
O
S
S
N
N
H
MeO
MeO
92%
O
O
N
N
H
92%

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J. D. Wilden et al. / Tetrahedron Letters 46 (2005) 7637–7640
Acknowledgements
O
O
O
O
O O
S
S
S
Ar
Cl
Ar
OPFP
Cl
Ar
NHR
We gratefully acknowledge the financial support of
EPSRC and GlaxoSmithKline (GSK). We also grate-
fully acknowledge AstraZeneca, Novartis, Pfizer,
EPSRC, BBSRC and AICR for support of our pro-
gramme. We also thank the EPSRC Mass Spectrometry
Service at Swansea.
R
NH2
Scheme 3. Mode of action of chloride ion in the acceleration of
sulfonamide formation in PFP sulfonates.
any point. This suggests strongly (as may be expected)
that the putative sulfonyl chloride is formed only in very
low concentrations at equilibrium. Rapid irreversible
reaction of this species with amine then removes it from
the equilibrium and ensures the reaction proceeds to
completion (Scheme 3). This protocol therefore com-
bines the reactivity of sulfonyl chlorides with the stabil-
ity and ease of handling of PFP sulfonates that we have
previously noted,2 as a useful method of sulfonamide
formation under these conditions.
References and notes
1. For alternative syntheses of aromatic and heteroaromatic
sulfonamides see: Pandya, R.; Murashima, T.; Tedeschi,
L.; Barrett, A. G. M. J. Org. Chem. 2003, 68, 8274–8276.
2. Caddick, S.; Wilden, J. D.; Bush, H. D.; Wadman, S. N.;
Judd, D. B. Org. Lett. 2002, 4, 2549–2551.
3. Avitable, B. G.; Smith, C. A.; Judd, D. B. Org. Lett. 2005,
7, 843–846.
4. Caddick, S.; Wilden, J. D.; Judd, D. B. J. Am. Chem. Soc.
2004, 126, 1024–1025; See also: Katritzky, A. R.; Rodri-
guez-Garcia, V.; Nair, S. K. J. Org. Chem. 2004, 69, 1849–
1852.
In conclusion, we have described a protocol that ex-
tends the scope of both amines and PFP sulfonates
in the formation of sulfonamides. We have demon-
strated that less reactive PFP sulfonates can exhibit en-
hanced reactivity towards amines by the addition of a
chloride ion source. We have shown that a normally
unreactive PFP sulfonate (PFP-p-methoxybenzenesulf-
onate) can be reacted with a variety of amines, includ-
ing less nucleophilic examples (i.e., anilines and
sterically hindered examples) in excellent yields and
with dramatic rate enhancements. We have also dem-
onstrated that the revised protocol is tolerant to aque-
ous reaction conditions without any significant loss in
efficiency.
5. Caddick, S.; Wilden, J. D.; Bush, H. D.; Judd, D. B.
QSAR Comb. Sci. 2004, 23, 902–905.
6. Steglich, W.; Hofle, G. Angew. Chem., Int. Ed. Engl. 1969,
¨
8, 981.
7. Makosza, M.; Wawrzyniewicz, W. Tetrahedron Lett. 1969,
10, 4659–4662.
8. Finkelstein, H. Chem. Ber. 1910, 43, 1528.
9. THF is equally acceptable as solvent for the reaction in
most cases.
10. Caddick, S.; Wilden, J. D.; Judd, D. B. Chem. Commun.
2005, 2727–2728.
11. For a recent example see: Sdira, S. B.; Felix, C. P.;
Giudicelli, M.-B. A.; Seigle-Ferrand, P. F.; Perrin, M.;
Lamartine, R. J. J. Org. Chem. 2003, 68, 6632–6638.