Trichlorophenol (TCP) sulfonate esters: A selective alternative to pentafluorophenol (PFP) esters and sulfonyl chlorides for the preparation of sulfonamides

Article abstract of DOI:10.1039/b614604j

2,4,6-Trichlorophenol (TCP) sulfonate esters undergo effective aminolysis under conventional heating and microwave irradiation; the reactivity of these species is such that chemoselective transformations of PFP sulfonate esters can be achieved. The Royal Society of Chemistry.

Full text of DOI:10.1039/b614604j

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Trichlorophenol (TCP) sulfonate esters: A selective alternative to
pentafluorophenol (PFP) esters and sulfonyl chlorides for the
preparation of sulfonamides{
Jonathan D. Wilden,*a Lynsey Geldeard,a Chieh C. Lee,a Duncan B. Juddb and Stephen Caddick*a
Received (in Cambridge, UK) 9th October 2006, Accepted 22nd November 2006
First published as an Advance Article on the web 21st December 2006
DOI: 10.1039/b614604j
Initially, we required a route to TCP esters that did not employ
the sulfonyl chloride or similar activated species as an intermedi-
ate.8 We were keen to test our previously established methodology,
utilising the coupling reagent triphenylphosphine ditriflate for this
purpose.9 Indeed, we successfully employed the reagent in the
formation of a variety of TCP sulfonate esters in good yields. The
results of a preliminary study are presented in Table 1.
2,4,6-Trichlorophenol (TCP) sulfonate esters undergo effective
aminolysis under conventional heating and microwave irradia-
tion; the reactivity of these species is such that chemoselective
transformations of PFP sulfonate esters can be achieved.
We have described in detail the applicability of pentafluorophenol
(PFP) sulfonates as replacements for sulfonyl chlorides1 in the
formation of sulfonamides, which are extremely important
antibacterial agents2 and a valuable structural motif in medicinal
chemistry.3–6 In particular, the ease of handling of PFP sulfonates
and their tolerance to a wide range of reaction conditions has
proved particularly attractive.7 There is, however, a degree of
resistance to the use of PFP-activated esters on a large and general
scale. Some are reluctant to utilise polyfluorinated aromatics, since
they perceive them to be toxic. Other potential barriers include the
high cost of pentafluorophenol, which renders it uneconomic as a
potential replacement for the much cheaper sulfonyl chlorides.
Here we report our progress in developing alternatives to PFP
sulfonates and sulfonyl chlorides, in order to address the limita-
tions of these species, while retaining the benefits of sulfonate esters
that we have previously noted.7
With a range of TCP sulfonate esters in hand, we were now in a
position to investigate their reactions with amines and to assess the
relative merits of this method in comparison to the analogous
reactions of PFP sulfonates. As outlined earlier, aminolysis of TCP
esters had been effected under conventional heating conditions.
We were keen to develop a microwave (MW) protocol for this
reaction, building on our previous work in this area.10 Our first
task was therefore to compare the thermal and MW reactions.
We observed that the MW-assisted aminolysis of two electron-
rich aryl TCP sulfonates proceeded at a faster rate than the
comparable reaction under conventional heating. This is notable
because we have found that such sulfonates are particularly
resistant to such aminolysis reactions. Our findings are presented
in Table 2.
We wished to explore the applicability of other phenols, which
might act as acceptable leaving groups for the aminolysis reaction
while giving stable intermediate compounds. 2,4,6-Trichlorophenol
(TCP) presented itself to us as an ideal candidate due to its known
lower toxicity (currently marketed as a household antiseptic agent
in the UK) and its low cost. Keen to establish the reactivity of a
TCP sulfonate ester and to compare its reactivity with our
established methodology, we prepared TCP ester 1 (Scheme 1).
Initial experiments indicated that amine displacement was a
possibility and thus further work was warranted.
Having established that MW irradiation was at least as effective
and potentially superior to conventional heating, we set about
searching for the optimal MW conditions that would give the best
Table 1 TCP ester synthesis employing triphenylphosphine ditriflate
Entry
1
Sulfonic acid
Product
Yield (%)a
78
2
3
74
80
Scheme 1 Sulfonamide formation from TCP sulfonate esters.
aThe Christopher Ingold Laboratories, Department of Chemistry,
University College London, 20 Gordon Street, London, UK WC1H 0AJ.
E-mail: j.wilden@ucl.ac.uk; s.caddick@ucl.ac.uk
4
65
bGlaxoSmithKline, Third Avenue, Harlow, Essex, UK CM19 5AW
{ Electronic supplementary information (ESI) available: Full synthesis
and characterisation data. See DOI: 10.1039/b614604j
a
Isolated yields.
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Table 2 Thermal vs. MW aminolysis reactions of TCP sulfonate
esters
Table 4 Reaction of TCP sulfonate esters with various aminesa
Amine
Yield
Method Temp./uC Time/h (%)a
Entry
1
Sulfonate ester
TCP ester
Thermal 85
4.5
1.0
6.0
51
68
66
No reaction
No reaction
No reaction
2
3
MW
85
Thermal 85
83%
88%
94%
4
MW
85
1.0
65
78%
82%
84%
a
Isolated yields.
yields in the shortest reaction time. Our first findings indicated
that, although DMF was an excellent solvent for the aminolysis
reaction, yields could often be compromised by the liberation and
further reaction of dimethylamine at elevated temperatures. In
view of this, we elected to employ N-methylpyrrolidone (NMP) as
the solvent for the aminolysis reaction due to its similar properties
to DMF, but without the propensity to liberate dimethylamine at
elevated temperatures.11 Following this change, we embarked
upon a series of experiments to establish the optimum conditions
for aminolysis. The reaction between TCP tosylate and allylamine
was chosen, and the results are presented in Table 3.
77%
89%
91%
a
Isolated yields.
Our investigations suggested that the conditions established in
Table 3 as being those most favourable for sulfonamide formation
only hold true when the amine is a simple aliphatic species and
relatively nucleophilic. Those amines with lowered nucleophilicity,
such as anilines (as demonstrated in Table 4), appear to require
alternative reaction conditions to undergo efficient reaction with
the sulfonate esters, and this is consistent with our previous
experience with PFP sulfonate esters. We therefore embarked on
studies to establish conditions that would be suitable for efficient
aminolysis of TCP sulfonates with lower nucleophilicity amines,
such as anilines. Extensive studies in our laboratory, employing
various MW power input levels, reaction times, solvents and
catalysts (primarily chloride ion),12 failed to yield satisfactory
results; the product in each case being obtained in either low yield
or contaminated with significant quantities of decomposition
material resulting from the prohibitively high temperatures
required to drive the reaction to completion. It occurred to us
that substituting triethylamine for a stronger base may assist the
reaction by deprotonation of the aniline prior to displacement. We
chose to employ lithium hexamethyldisilazide (LHMDS) as the
base with a variety of both anilines and aliphatic amines. We
observed that good yields of the corresponding sulfonamides could
be obtained in most cases without excessive reaction times and
under conventional heating at 50 uC. Table 5 presents our findings.
The success obtained with anilines (Table 5, entries 4 and 5) is
particularly notable, as we have previously found that these tend
Having established an optimal set of reaction conditions for the
reaction between TCP tosylate and allylamine, we were keen to
expand the scope of these conditions and see if they would prove
equally successful with a range of other amines. We therefore
examined the reaction of a number of amines with a variety of
TCP sulfonate esters under the optimised conditions. Our results
are shown in Table 4.
Table 3 Optimisation of the MW-mediated aminolysis reaction of
TCP tosylate
Entry
Temp./uC
Solvent
Time/min
Yield (%)a
1
2
3
4
5
a
85
85
140
140
140
DMF
NMP
NMP
NMP
NMP
60
60
60
20
10
56
50
83
91
83
Isolated yields.
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Table 5 LHMDS as a base for sulfonamide formation
Entry
1
Amine
Product
Time/h
4.0
Yield (%)a
72
2
3
4.0
6.0
18
78
92
75
Scheme 2 Selective sulfonamide formation from TCP sulfonate esters
and PFP sulfonate esters.
4
We have also demonstrated how the differing reactivity of these
two classes of compound can be exploited in selective sulfonamide
formation.
a
Isolated yields.
Finally, we have addressed the issues of cost associated with
pentafluorophenol, in that trichlorophenol is at least ten times as
cheap.13 The perceived problems with polyfluorinated aromatics
can also be circumvented by the use of TCP sulfonate esters in
sulfonamide formation.
to be challenging substrates for sulfonamide formation. Most
significantly, however, was our finding that employing LHMDS
gave superior results in the formation of sulfonamides from
hindered amines such as tert-butylamine, an example that we have
previously noted to be inefficient due to the extreme levels of steric
encumbrance. We envisaged that this alternative protocol would
therefore be suitable for less nucleophilic amines such as anilines,
nucleophilic species, and more sensitive substrates where higher
temperatures are undesirable. The results of this study are outlined
in Table 5.
The authors would like to thank the EPSRC and
GlaxoSmithKline for their generous financial support of this
work. We also gratefully acknowledge CEM Microwave
Technology for their enthusiastic support of our microwave
programme. We are also grateful to Novartis and AstraZeneca for
support, and the EPSRC Mass Spectroscopy Service at Swansea.
Having identified reaction conditions for the formation of
sulfonamides from TCP sulfonates with a variety of amines,
including the less nucleophilic and more challenging hindered
examples, we wished to continue and compare their reactivity with
PFP sulfonates, with a view to exploiting their differing reactivity
in selective sulfonamide formation.
Notes and references
1 S. Caddick, J. D. Wilden and D. B. Judd, Chem. Commun., 2005, 2727.
2 M. A. Navia, Science, 2000, 288, 2132.
3 P. R. Hanson, D. A. Probst, R. E. Robinson and M. Yau, Tetrahedron
Lett., 1999, 40, 4761.
4 J. H. McKerrow and M. N. G. James, in Perspectives in Drug Discovery
and Design, ed. P. S. Anderson, G. L. Kenyon and G. R. Marshall,
ESCOM Science Publishers, Leiden, 1996, vol. 6, pp. 1–120.
5 W. R. Roush, S. L. Gwaltney, II, J. Cheng, K. A. Scheidt,
J. H. McKerrow and E. Hansell, J. Am. Chem. Soc., 1998, 120, 10994.
6 C. Hansch, P. G. Sammes and J. B. Taylor, Comprehensive Medicinal
Chemistry, Pergamon Press, Oxford, 1990, vol. 2, ch. 7.1, pp. 255–277.
7 S. Caddick, J. D. Wilden, H. D. Bush, S. N. Wadman and D. B. Judd,
Org. Lett., 2002, 4, 2549.
8 A. R. Katritzky, V. Rodriguez-Garcia and S. K. Nair, J. Org. Chem.,
2004, 69, 1849.
9 S. Caddick, J. D. Wilden and D. B. Judd, J. Am. Chem. Soc., 2004, 126,
1024.
10 S. Caddick, J. D. Wilden, H. D. Bush and D. B. Judd, QSAR Comb.
Sci., 2004, 23, 902.
11 NMP may be removed on work-up by diluting the reaction mixture
with dichloromethane and then washing with a 10% aqueous solution of
lithium chloride.
In order to measure the level of selectivity that could be
obtained between a PFP sulfonate and a TCP sulfonate in a simple
aminolysis reaction, we took an equimolar solution of PFP
benzene sulfonate and TCP tosylate and sequentially exposed
them to amines under different reaction conditions. Gratifyingly,
we observed that the products obtained from the reaction at
low temperatures were almost exclusively those derived from
the PFP sulfonate. The TCP sulfonate could be isolated at
this point, or, upon exposure to another amine at higher
temperatures, could then, in turn, be converted smoothly to the
sulfonamide in good yields. A representative example is given in
Scheme 2.
In conclusion, we have described the synthesis and utility of a
new class of activated sulfonate ester that can be employed
successfully in the synthesis of sulfonamides. In addition to this, we
have identified suitable reaction conditions that are successful for
both simple nucleophilic amines and more challenging examples,
such as anilines or hindered amines.
12 J. D. Wilden, D. B. Judd and S. Caddick, Tetrahedron Lett., 2005, 46,
7637.
13 The list price for pentafluorophenol in the UK Aldrich fine chemical
catalogue (2006) is £116.50 for 100 g. From the same supplier, 2,4,6-
trichlorophenol sells at £18.80 per kg. See also http://www.sigmaaldrich.
com.
1076 | Chem. Commun., 2007, 1074–1076
This journal is ß The Royal Society of Chemistry 2007