Catalytic arylation of sulfamoyl chlorides: A practical synthesis of sulfonamides

Article abstract of DOI:10.1055/s-2002-34907

Commercially available indium(III) triflate is shown to be an efficient catalyst for the sulfamoylation of aromatics.

Full text of DOI:10.1055/s-2002-34907

1928
LETTER
Catalytic Arylation of Sulfamoyl Chlorides: A Practical Synthesis of
Sulfonamides
Catalytic
A
rylatio
h
n
of Sulfa
m
r
oyl Chlo
i
rides stopher G. Frost,*a Joseph P. Hartley,a David Griffinb
a
Department of Chemistry, University of Bath, Bath, BA2 7AY, UK
E-mail: e-mail:c.g.frost@bath.ac.uk
b
Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6ET, UK
Received 26 June 2002
Abstract: Commercially available indium(III) triflate is shown to
be an efficient catalyst for the sulfamoylation of aromatics.
Key words: catalysis, Lewis acids, indium, arylations, sulfon-
amides
Aromatic sulfonamides are of significant interest to the
synthetic chemist due to their bioactive nature, most nota-
bly as pharmaceuticals. Over 30 drugs containing this
functionality are in clinical use, including, antibacterials,
diuretics, anticonvulsants, hypoglycemics and HIV pro-
tease inhibitors.1 The most popular route to aromatic sul-
fonamides involves the chlorosulfonation of an arene, to
give the sulfonyl chloride, and subsequent reaction with
an amine.2 However this approach is marred either by the
need to employ a large excess of chlorosulfonic acid
which leads to acidic waste or the undesirable formation
of the diaryl sulfone.3 The reaction of trialkylarylstan-
nanes and sulfonyl isocyanates has also been employed.4
Electrophilic substitution reactions introducing the
SO2NR2 moiety directly have less precedent. Exceptions
include the aluminium chloride promoted thia-Fries
rearrangement5 and sulfamoylation.6 The use of stoichio-
metric Lewis acids or tin reagents is undesirable, particu-
larly on an industrial scale, due to the serious waste
problems. Thus, the development of a catalytic process
would offer a cleaner alternative to existing methodolo-
gies for reactive aromatics. In this communication a suc-
cessful strategy for the synthesis of aryl sulfonamides
using an indium catalysed sulfamoylation process is pre-
sented.
Scheme 1
flate in situ which reacts with the aromatic compound re-
leasing triflic acid.7 To obtain a modest yield the reaction
is stoichiometric with respect to AgOTf. Previous work
by Dubac8 [for Bi(OTf)3] and ourselves [for In(OTf)3]
have established that TfO–/Cl– exchange occurs readily at
bismuth and indium centres enabling recycling of triflic
Table 1 Catalyst Evaluation in Sulfamoylation Processa
Entry
Catalyst
AlCl3
Yield (%)
1
2
20
43
86
0
InCl3
3
In(OTf)3
La(OTf)3
Sc(OTf)3
Yb(OTf)3
Bi(OTf)3
AgOTf
4
5
19
0
6
7
19
15
56
9
At the outset of the study we examined the sulfamoylation
of toluene with N,N-dimethylsulfamoyl chloride in the
presence of 20 mol% of selected catalysts (Scheme 1).
8
9
AgOTf (100 mol%)
TfOH
As can be seen from Table 1, for the different catalysts
tested it was interesting to note that only the two indium
complexes were able to turnover to afford product. It was
clear that the reaction was not being promoted to any great
extent by triflic acid (entry 10) and the cation present
plays a crucial role in determining catalytic activity (en-
tries 3–7). The use of AgOTf (entries 8 and 9) results in a
TfO–/Cl– exchange to prepare the activated sulfamoyl tri-
10
a Procedure: A stirring mixture of toluene (5 mmol) dimethylsulfa-
moyl chloride (1 mmol) and catalyst (20 mol%) in DCE (5 mL) was
heated to 100 °C for 24 h. The reaction mixture was then partitioned
between DCM and 1 M HCl. The aq layer was washed with DCM
three times and the combined organics were washed with brine, dried
over anhyd MgSO4 and concentrated to afford crude sulfonamide
product which was purified by flash chromatography using petro-
leum ether:ethyl acetate (4:1) as eluent to afford dimethyl-p-toluene-
sulfonamide as a white crystalline solid, mp 79–81 °C (lit.: mp 83–
83.5 °C ).18 1H NMR (CDCl3): 2.45 (s, 3 H, Ar-Me), 2.68 (s, 6 H, N-
Me), 7.23–7.26 (m, 2 H), 7.64–7.69 (m, 2 H). Expected: C, 54.3; H,
6.60; N, 7.0%. Found: C, 54.3; H, 6.55; N, 7.0 %.
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1928,1930,ftx,en;D12502ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Catalytic Arylation of Sulfamoyl Chlorides
1929
acid and leading to very efficient Friedel–Crafts acylation complexes with the sulfamoylating agent (chloride or tri-
and sulfonylation reactions.9 This does not happen with flate) and the product sulfonamide. Interestingly, lower-
some of the other metal triflates [Sc(OTf)3, Yb(OTf)3, and ing the catalytic loading of In(OTf)3 to 10 mol% affords
La(OTf)3].10
60% yield and 5 mol% of catalyst affords 30% yield of
product. This suggests that it takes six molecules of prod-
uct to poison each indium atom. Indeed, if six equivalents
of the product (relative to the catalyst) are added at the
start of the reaction, no new product is formed. This is the
first time we have noted product inhibition in indium ca-
talysed aromatic functionalisation reactions. If equimolar
amounts of aromatic and sulfamoyl chloride are used
In(OTf)3 is still an effective catalyst albeit the reaction is
slower affording a 47% yield of product after 24 hours.
The difference in catalytic activity for indium and bismuth
may well be due to the relative stability constants of their
Table 2 Scope of Indium Catalysed Sulfamoylationa
Aromatic
Anisole
Sulfamoyl Product
chloride
Yield Ref.
(%)
18
Dimethyl
99
Using the optimised conditions the scope of the reaction
was established by variation of the aromatic and sulfa-
moyl chloride (Table 2). The quoted yield is for isolated,
purified products.11 The reaction gave consistently good
results with activated aromatics across a range of sulfa-
moyl chlorides but isolated yields were low with deacti-
vated substrates such as chlorobenzene.
(o:m:p; 45:0:55)
13
Naphthalene Dimethyl
99
(α:β; 34:66)
13
Chloro-
benzene
Dimethyl
24
(o:m:p; 0:0:100)
15
Naphthalene Diethyl
44
Scheme 2
Finally, it has been established that an indium catalysed
intramolecular sulfamoylation reaction is possible. Under
the predetermined conditions N-ethyl phenethylsulfamoyl
chloride reacts to afford the cyclic aryl sulfonamide prod-
uct in a modest (unoptimised) yield (Scheme 2).12 The full
scope of the intramolecular process is yet to be explored.
(α:β; 37:63)
6
Toluene
Anisole
Toluene
Diethyl
64
(o:m:p; 0:0:100)
(α:β; 36:0:64)
(o:m:p; 0:0:100)
16
Piperidyl
Piperidyl
80
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 and Pfizer for additional funding.
6
51
References
16
Naphthalene Piperidyl
56
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moyl chloride (1 mmol) and In(OTf)3 (20 mol%) in DCE (5 mL) was
heated to 100 °C for 24 h. The reaction mixture was then partitioned
between DCM and 1 M HCl. The aq layer was washed with DCM
three times and the combined organics were washed with brine, dried
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leum ether:ethyl acetate (4:1) as eluent.
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Synlett 2002, No. 11, 1928–1930 ISSN 0936-5214 © Thieme Stuttgart · New York

1930
C. G. Frost et al.
LETTER
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Synlett 2002, No. 11, 1928–1930 ISSN 0936-5214 © Thieme Stuttgart · New York