V. Garzya et al. / Tetrahedron Letters 45 (2004) 1499–1501
1501
O
O
O
O
O
Cl
S
InCl -TfOH
S
Br
S
3
Br
S
Cl
+
7
0 °C/TFA
O
2
h
73%
Cl
1
j
Scheme 3. Indium-catalysed sulfonylation with a heterocyclic substrate.
onylation at both the para (less hindered) and ortho
(
Acknowledgements
more hindered) positions. In order to modulate the
reactivity of anisole, the effect of halogen substitution on
the anisole ring was investigated. It was found that
substrates shown in entries 2, 3, 4 and 5 undergo highly
regioselective reactions giving a single product and
showing a significant improvement in yield compared to
We would like to thank Sophie Apoux, John Hayler,
Simone Guelfi, Arianna Ribecai and Marsia Tampieri
for their valuable contributions.
10
the results obtained when AlCl
lyst.
3
is the reaction cata-
Following these results, we decided to investigate the
sulfonylation of less reactive aryl halides (entries 6, 7, 8).
Again it was found that a high yielding regioselective
process took place giving a more favourable outcome
References and notes
1. (a) A search of the Derwent World Drug Index gave 147
hits for structures containing a biaryl sulfone moiety; (b)
GlaxoSmithKline. Unpublished work.
. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemis-
try, Part A, 3rd ed.; Plenum: New York and London,
990, Chapters 10.5 and 10.6.
. Frost, G. C.; Hartley, J. P.; Whittle, A. J. Synlett 2001,
30–832.
. Repichet, S.; Le Roux, C.; Hernandez, P.; Dubac, J.
J. Org. Chem. 1999, 64, 6479–6482.
. Repichet, S.; Le Roux, C.; Dubac, J. Tetrahedron Lett.
1999, 40, 9233–9234.
6. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemis-
try, Part A; 3rd ed.; Plenum: New York and London,
990, Chapter 10.4.5.
. Szmant, H. H.; Suld, G. J. Am. Chem. Soc. 1956, 78,
400–3401.
. Typical reaction procedure: the arene substrate (2 mmol),
InCl (0.2–0.4 mmol), sulfonyl chloride (3 mmol) were all
11
4
than when AlCl3 or Bi(OTf)3 are used.
2
We have extended the scope of this process with the use
of heterocyclic sulfonyl chlorides. For example, under
our conditions, 5-bromothiophene-2-sulfonyl chloride
reacts cleanly and in high yield with 4-chloroanisole to
give the desired product 1j (Scheme 3).
1
3
4
5
8
Nucleophilic aromatic substitution reactions of the
4
-fluoro group in products 1a–1i could be carried out
using standard literature methodology. Furthermore the
presence of the bromine atom in products 1f, 1i and 1j
allows further elaboration of the structure, for example,
by Suzuki couplings or Heck reactions.
1
7
8
3
3
dissolved in TFA (4 mL) and triflic acid (3 mmol) was
added at room temperature; the mixture was then heated
up to the indicated temperature; when the reaction was
complete, it was quenched with water–ice, basified up to
pH ¼ 10 and extracted with dichloromethane; chromato-
graphy afforded the desired compounds.
. NMR and mass spectra of all compounds were fully
consistent with the structures shown; for all products the
substitution pattern was confirmed by NOE experiments.
3
. Conclusions
The use of the indium(III) chloride/triflic acid system for
aryl sulfonylation reactions has been studied. Under the
conditions we have developed, the reactions were rapid,
high yielding and regioselective showing a significant
improvement compared to the results obtained in the
literature. The use of this methodology in the synthesis
of some CNS active drug candidates will be reported in
the near future.
9
1
0. Gurumani, V.; Swaminathan, M.; Mangalamudaiya, A.
Indian J. Chem. Sect. B 1993, 32, 281–287.
11. Zahn, H.; Zuber, H. Chem. Ber. 1953, 86, 172–180.