Indium-catalysed aryl and alkyl sulfonylation of aromatics

Article abstract of DOI:10.1055/s-2001-14591

Commercially available indium (III) triflate is shown to be an extremely efficient catalyst for the sulfonylation of both activated and deactivated aromatics.

Full text of DOI:10.1055/s-2001-14591

830
LETTER
Indium-Catalysed Aryl and Alkyl Sulfonylation of Aromatics
Christopher G. Frosta*, Joseph P. Hartley,a Alan J. Whittleb
aDepartment of Chemistry, University of Bath, Bath, BA2 7AY, UK
bSyngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6ET, UK
Fax +44 (1225) 826231; E-mail: c.g.frost@bath.ac.uk
Received 27 March 2001
MgSO4(anhydrous) and concentrated to afford product
which was purified by recrystallisation from DCM/pen-
tane. It was pleasing to observe that all of the indium cat-
alysts tested were effective. Indium(III) chloride (57%
yield), indium(III) triflate (88% yield) and indium(III)
perchlorate octahydrate (79% yield) all provided the prod-
uct in with an ortho:para ratio of approximately 1:2. In
further examining the scope of the reaction it was decided
to use indium(III) triflate as the preferred catalyst.
Abstract: Commercially available indium (III) triflate is shown to
be an extremely efficient catalyst for the sulfonylation of both acti-
vated and deactivated aromatics.
Key words: catalysis, indium, sulfonylation, aromatic functionali-
sation
The efficient preparation of diversely functionalised diar-
yl sulfones is a desirable goal for the fine chemical indus-
try.1 The sulfonylation of aromatics provides a direct
route but traditionally relies on the use of stoichiometric Table 1 The In(OTf)3-Catalysed Sulfonylation of Activated
Aromatics
promoters such as aluminium(III) chloride with the asso-
ciated purification problems.2 Very recently, efficient cat-
alytic protocols have emerged including the use of Fe(III)
exchanged montmorillonite clay,3 zeolites4 and bis-
muth(III) triflate.5 For the sulfonylation of unactivated ar-
omatics the most effective reported catalyst is
bismuth(III) triflate but this is not commercially available
and has to be prepared from triphenylbismuth and triflic
acid. The same group have revealed a more practical alter-
native comprising of bismuth(III) chloride (5 mol%) and
triflic acid (10 mol%) which shows good activity.6 In an
ongoing programme of research we have demonstrated
that indium(III) triflate functions as an efficient Lewis
acid catalyst at very low catalyst loadings (0.5-1 mol%).7
In this communication we wish to highlight our principal
results on the catalytic sulfonylation of aromatics using
indium(III) complexes.
OMe
1
O
S
O
S
Me
Cl
Me
OMe
5-10 mol % InX3
O
O
3
120 °C
2
Scheme 1
At the outset of the study we tested a selection of indium
complexes in the sulfonylation of anisole. In a typical ex-
periment we heated a mixture of anisole (2 equiv.), tosyl
chloride (1 equiv.) and indium catalyst (5 mol%) to
120 °C until TLC analysis indicated that the tosyl chloride
had been completely consumed. The reaction mixture was
then partitioned between DCM and 1 M HCl. The aqueous
layer was washed with DCM three times and the com-
bined organics were washed with brine, dried over
a) After recrystallisation, b) only the 2,4-dimethyl phenyl isomer was
observed
It should be noted that in the absence of catalyst no prod-
uct was observed even with prolonged heating. The low-
ering of the reaction temperature was detrimental to
efficiency. For example, at room temperature after 72
Synlett 2001, No. 6, 830–832 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Indium-Catalysed Aryl and Alkyl Sulfonylation of Aromatics
831
hours only 24% of product was obtained. The scope of in- arises in the Friedel-Crafts acylation using acyl chlo-
dium catalysed sulfonylation was initially investigated rides.11 The excellent catalytic activity observed with in-
with respect to the activated aromatics illustrated in Table dium (III) triflate leads us to conclude that the TfO–/Cl–
1. The isolated yields were high in all cases (75-90%) and exchange occurs readily at indium generating the more re-
losses were due to leakage in the isolation and purification active sulfonylating agent.
process rather than the formation of side products.8 To en-
sure the sulfonylation was not being promoted by adven-
titious triflic acid the reaction between toluene and
Table 2 The In(OTf)3-Catalysed Sulfonylation of Unactivated
Aromatics
benzenesulfonyl chloride was performed in the presence
of 15 mol% triflic acid and followed by GC sampling ev-
ery 15 minutes. When compared to the same reaction us-
ing 5 mol% of indium(III) triflate it provides indisputable
evidence for the importance of the indium cation in the
sulfonylation process (Figure). After 60 minutes the in-
dium-catalysed reaction was >99% complete by GC and
1H NMR. Using triflic acid only 8% conversion to product
was observed.
a) After recrystallisation
Initial experiments using alkylsulfonyl chlorides have
been successful resulting in good yields of products with
toluene as substrate (Table 3). Using the alternative con-
ditions (10 mol% In(OTf)3), the reaction proceeded satis-
factorily affording the product sulfones in good yield.
The effective alkylsulfonylation of unactivated aromatics
has not been achieved using the presented catalyst system.
Ongoing work is focused on this problem along with the
efficient functionalisation of deactivated aromatics.
Figure The sulfonylation of toluene
Indium(III) triflate was the best catalyst for the sulfonyla-
Table 3 In(OTf)3-Catalysed Alkylsulfonylation
tion of activated aromatics and, surprisingly the only ef-
fective catalyst for the sulfonylation of unactivated
aromatics (Table 2) albeit requiring a higher catalyst load-
ing (10 mol%) and longer reaction times (3-24 hours). Us-
ing the alternative conditions, the reaction proceeded
efficiently affording the product sulfones in high yield and
excellent selectivity.9
Previous work by Dubac and co-workers establishes that
other metal triflates (Sc(OTf)3, Yb(OTf)3, Ce(OTf)4 and
Hf(OTf)4) are not effective catalysts for the sulfonylation
of unactivated aromatics such as chlorobenzene.5 The suc-
cess of Bi(OTf)3 is accounted for by a mechanism involv-
ing a ligand exchange (TfO–/Cl–) at the bismuth atom
affording a mixed sulfonic anhydride in situ (ArSO2OTf)
which is a much stronger sulfonylating agent.10 The other
metallic triflates are not able to give the TfO–/Cl– ex-
change and consequently are inactive. A similar situation
Synlett 2001, No. 6, 830–832 ISSN 0936-5214 © Thieme Stuttgart · New York

832
C. G. Frost et al.
LETTER
(2-Methoxyphenyl)-phenyl sulfone (Table 1, entry 2). H 3.75
(s, 3H), 6.90 (d, 1H, J = 8.4 Hz), 7.11-8.16 (m, 8H).
Di-p-tolyl sulfone (Table 1, entry 3). H 2.39 (s, 6H), 7.27 (d,
4H, J = 5Hz), 7.80 (d, 4H, J = 5Hz).
(o-Tolyl)-p-tolyl sulfone (Table 1, entry 3). H 2.39 (s, 3H),
2.40 (s, 3H), 7.21 (d, 1H, J = 7.7 Hz), 7.27 (d, 2H, J = 5 Hz),
7.38-7.46 (m, 2H), 7.80 (d, 2H, J = 5 Hz), 8.18 (d, 1H, J = 7.7
Hz).
Acknowledgement
We would like to thank Syngenta for the provision of a CASE award
to JPH. CGF thanks Astra-Zeneca for a generous award from their
strategic research fund.
References and Notes
(p-Tolyl)-phenyl sulfone (Table 1, entry 4). H 2.40 (s, 3H),
7.30 (d, 2H, J = 8.3 Hz), 7.40-7.55 (m, 3H), 7.85 (d, 2H,
J = 8.3), 7.90-7.95 (m, 2H).
(2, 4, 6-Trimethylphenyl)-p-tolyl sulfone (Table 1, entry 6).
H 2.62 (s, 3H), 2.72 (s, 3H), 2.92 (s, 6H), 7.59 (d, 2H,
J = 8Hz), 7.59 (s, 2H), 8.00 (d, 2H, J = 8 Hz).
(1) (a) Magnus, P. D. Tetrahedron 1977, 33, 2019. (b) Roy, K. M.
Ullmann’s Encyclopedia of Industrial Chemistry; Gerhartz,
W. Ed.; VCH: Weinham (Germany) 1985; Vol A25, 487-501.
(c) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon
Press: Oxford 1993.
(2) (a) Jensen, F. R.; Goldman, G. Friedel-Crafts and Related
Reactions; Olah, G., Ed.; Wiley-Interscience: New York
1964; Vol. III, 1319-1367.
(3) Choudary, B. M.; Sreenivisa Chowdari, N.; Lakshmi Kantam,
M.; Kannan, R. Tetrahedron Lett. 1999, 40, 2859.
(4) Smith, K.; Ewart, G. M.; Randles, K. R. J. Chem. Soc., Perkin
Trans. 1 1997, 1085.
(5) Répichet, S.; Le Roux, C.; Dubac, J. J. Org. Chem. 1999, 64,
6479.
(2, 4, 6 Trimethylphenyl)-phenyl sulfone (Table 1, entry 7).
2.30 (s, 3H), 2.59 (s, 6H), 6.94 (s, 2H), 7.49-7.79 (m, 5H).
(9) Typical procedure for an unactivated aromatic; (4-
Chlorophenyl)-p-tolylsulfone (Table 2, entry 1): Indium
H
triflate (180 mg, 0.318 mmol), chlorobenzene (0.465 mL, 6.35
mmol) and Tosyl chloride (605 mg, 3.18 mmol) were stirred
under nitrogen and heated to 120 C for 18 h. The reaction
mixture was cooled to room temperature and partitioned
between DCM and 1 M HCl. The aqueous layer was washed
with DCM three times and the combined organics were
washed with brine, dried over MgSO4 then concentrated to
yield a white crystalline solid (0.71g, 84% yield). M.p. 90-91
°C (lit. 91-92 °C)13 H (CDCl3, 400 MHz) 2.40 (s, 3H), 7.31
(d, 2H, J = 7.8 Hz), 7.40-7.50 (m, 2H), 7.80 (d, 2H, J = 12.0
Hz), 7.85-7.90 (m, 2H).
(6) Répichet, S.; Le Roux, C.; Dubac, J. Tetrahedron Lett. 1999,
40, 9233.
(7) (a) Ali, T.; Chauhan, K. K.; Frost C. G. Tetrahedron Lett.
1999, 40, 5621. (b) Chauhan, K. K.; Frost, C. G.; Love, I.;
Waite, D. Synlett 1999, 1743. (c) Chauhan, K. K.; Frost, C. G.
J. Chem. Soc., Perkin Trans. 1 2000, 18, 3015. (d) Chapman,
C. J.; Frost, C. G.; Hartley, J. P.; Whittle, A. J. Tetrahedron
Lett. 2001, 42, 773.
(4-Chlorophenyl)-phenyl sulfone (Table 2, entry 2). M.p. 119-
120 °C (lit. 119-120 °C)12 H 7.50-7.59 (m, 5H), 7.82-7.93 (m,
4H).
(8) Typical procedure for an activated aromatic; (2,4-
dimethylphenyl)-p-tolyl sulfone (Table 1, entry 5): Indium
triflate (85 mg, 0.15 mmol), m-xylene (0.73 mL, 6 mmol) and
tosyl chloride (0.60 g, 3 mmol) were stirred under nitrogen at
120 C for 2 h. The reaction mixture was cooled to room
temperature and partitioned between DCM and 1 M HCl.
The aqueous layer was washed with DCM and the combined
organics were washed with brine, dried over MgSO4 and
concentrated. Removal of m-xylene under vacuum yielded a
white crystalline solid. (0.69g, 88% yield). M.p. 48-49 °C (lit.
49 °C)12 H (CDCl3, 400 MHz) 2.36 (s, 3H), 2.39 (s, 3H), 2.40
(s, 3H), 7.02 (s, 1H,), 7.18 (d, 1H, J = 7.8 Hz), 7.27 (d, 1H,
J = 8.8 Hz), 7.73 (d, 2H, J = 8.8 Hz), 8.08 (d, 1H, J = 7.8 Hz).
(4-Methoxyphenyl)-p-tolyl sulfone (Table 1, entry 1). H 2.38
(s, 3H), 3.83 (s, 3H), 6.94-7.86 (m, 8H).
(4-Bromophenyl)-p-tolyl sulfone (Table 2, entry 3). M.p. 48-
136-137 °C (lit. 135-136 °C)13 H 2.54 (s, 3H), 7.45 (d, 2H,
J = 8.6 Hz), 7.77-7.92 (m, 4H), 7.95 (d, 2H, J = 8.6 Hz).
(4-Fluorophenyl)-p-tolyl sulfone (Table 2, entry 4). M.p. 48-
93-94 °C (lit. 95 °C)14 H 2.40 (s, 3H), 7.16 (m, 2H), 7.31 (d,
2H, J = 8.0), 7.81 (d, 2H, J = 8.0), 7.90-7.95 (m, 2H).
(10) Effenberger, F.; Huthmacher, K. Angew. Chem., Int. Ed. Engl.
1974, 13, 409.
(11) Effenberger, F.; Epple, G. Angew. Chem., Int. Ed. Engl. 1972,
11, 299.
(12) Graybill, B. M. J. Org. Chem. 1967, 32, 2931.
(13) Repichet, S.; Roux, C. L.; Hernandez, P.; Dubac, J. J. Org.
Chem. 1999, 64, 6479.
(14) Choudary, C. M.; Chowdari, N.S.; Kantam, M.L. J. Chem.
Soc., Perkin Trans. 1 2000, 16, 2689.
(2-Methoxyphenyl)-p-tolyl sulfone (Table 1, entry 1). H 2.41
(s, 3H), 3.84 (s, 3H), 6.85-8.15 (m, 8H).
(4-Methoxyphenyl)-phenyl sulfone (Table 1, entry 2). H 3.84
(s, 3H), 6.97-7.95 (m, 9H,).
Article Identifier:
1437-2096,E;2001,0,06,0830,0832,ftx,en;D05701ST.pdf
Synlett 2001, No. 6, 830–832 ISSN 0936-5214 © Thieme Stuttgart · New York