Facile one-pot synthesis of aromatic and heteroaromatic sulfonamides

Article abstract of DOI:10.1021/jo034643j

A series of arene and heteroarene sulfonamides were prepared in one vessel from aryl and heteroaryl bromides via conversion into the corresponding Grignard reagents using either magnesium or isopropylmagnesium chloride and subsequent reaction with sulfur dioxide, sulfuryl chloride, and an amine.

Full text of DOI:10.1021/jo034643j

F a cile On e-P ot Syn th esis of Ar om a tic a n d
Heter oa r om a tic Su lfon a m id es
Rina Pandya, Takashi Murashima, Livio Tedeschi, and
Anthony G. M. Barrett*
Department of Chemistry, Imperial College London, London
SW7 2AZ, England
agmb@imperial.ac.uk
Received May 14, 2003
Abstr a ct: A series of arene and heteroarene sulfonamides
were prepared in one vessel from aryl and heteroaryl
bromides via conversion into the corresponding Grignard
reagents using either magnesium or isopropylmagnesium
chloride and subsequent reaction with sulfur dioxide, sul-
furyl chloride, and an amine.
F IGUR E 1. Important pharmaceutical drugs with sulfon-
amide functionality.
procedure to prepare phenylsulfonamides in moderate
yields by allowing phenylmagnesium chloride to react
sequentially with sulfuryl chloride in hexane and an
amine at 0 °C. A limitation of the procedure was the need
for careful temperature control with lower yields at lower
temperatures and side reactions possibly arene chlorina-
tion above 0 °C. Moreover, the method was not applied
to functionalized aryl halides. Hamada and Yonemitsu7
showed that arenesulfonyl chlorides could be prepared
in excellent yields via the addition of aryllithium reagents
to sulfur dioxide at -100 °C, followed by S-chlorination
of the arenesulfinate intermediate using sulfuryl chloride.
However, this method relies on the use of reactive
aryllithium intermediates, which are incompatible with
polar functionality. Hence, there is a need to develop a
general, mild, and efficient one-pot synthesis of sulfona-
mides, which could tolerate the presence of heterosub-
stituted aryl moieties or reactive functional groups. We
therefore sought to reinvestigate the preparation of
sulfonamides from aryl halides by reaction of the derived
Grignard reagents with sulfur dioxide,8 sulfuryl chloride,
and an amine.
Initially, we sought to extend the scope of the Yone-
mitsu procedure with the synthesis of arenesulfonyl
chlorides under milder reaction conditions. We found that
sulfinylation of aryl-Grignard reagents 6 using sulfur
dioxide afforded the sulfinates 7, which upon direct
addition of neat sulfuryl chloride at -40 °C gave the
corresponding arenesulfonyl chlorides 8. Subsequent
addition of a secondary amine at room temperature gave
the desired sulfonamides 9. This one-vessel procedure
gave higher yields than the synthesis of N,N-diethylben-
zenesulfonamide from phenylmagnesium bromide re-
ported by Gilbert.6 The procedure proved to be useful for
the preparation of a diverse range of sulfonamides 9a -
k , starting from the readily available and inexpensive
aryl bromides 5 (Table 1, entries 1-11). The method was
Sulfonamides are a diverse group of compounds of
considerable medical importance.1 As a class, the sulfa
drugs have a veritable history of application for the
treatment of bacterial infection. However, the sulfon-
amide functionality is much more widespread in phar-
maceuticals than just in an early class of antibiotics.
Medically important examples include the protease in-
hibitor amprenavir (1), the analgesic celecoxib (2), sildena-
fil (3) for erectile dysfunction, and the antimigraine agent
sumatriptan (4) (Figure 1). The vast majority of sulfon-
amides are prepared from the reaction of a sulfonyl
chloride with ammonia or primary or secondary amines
or via related transformations.2,3 In turn, arenesulfonyl
chlorides are prepared from arenes by electrophilic
aromatic substitution using an excess of chlorosulfonic
acid or from arenesulfonic acids by reaction with phos-
phorus pentachloride.4 Again, in turn, arenesulfonic acids
are prepared from the electrophilic sulfonylation of
arenes using concentrated sulfuric acid or oleum. Given
the harshness of these reaction conditions, sulfonic acids
and sulfonyl chlorides are rarely introduced into an
advanced intermediate via C-S bond formation. As a
consequence, the diversity of sulfonamide functionality
in pharmaceutical discovery is actually limited and
cannot be readily varied at both nitrogen and sulfur in
the final stage of a library synthesis.
There is a clear need for the development of a generally
useful, mild, and novel methodology for the introduction
of primary, secondary, and tertiary sulfonamide groups
without recourse to potent electrophiles. In 1968, Eaborn
and co-workers reported the preparation of arenesulfonyl
chlorides from the reaction of Grignard reagents with
sulfuryl chloride.5 Additionally, Gilbert6 described a
(1) Pharmaceutical Substances, Syntheses, Patents, Applications;
Kleemann, A., Engel, J ., Kutscher, B., Reichert, D., Eds.; Thieme:
Stuttgart, 1999.
(2) Cremlyn, R. Organosulfur Chemistry: An Introduction; J . Wiley
and Sons: New York, 1996; pp 224-225.
(5) Bhattacharya, S. N.; Eaborn, C.; Walton, D. R. M. J . Chem. Soc.
C 1968, 1265 and references therein.
(6) Gilbert, E. E. Synthesis 1969, 1.
(7) Hamada, T.; Yonemitsu, O. Synthesis 1986, 852.
(8) (a) Truce, W. E.; Murphy, A. M. Chem. Rev. 1951, 48, 69. (b)
Zo¨ller, U. In Synthesis of sulfinic acids, esters and their derivatives;
Patai, S., Ed.; J . Wiley and Sons: New York, 1990; pp 185-215.
(3) Anderson, K. K. In Sulfonic Acids and Their Derivatives in
Comprehensive Organic Chemistry; Barton, D. H. R., Ollis, W. D.,
J ones, D. N., Eds.; Pergamon Press, Oxford, 1979; Vol. 3, pp 331-
340, 345-350.
(4) Heumann. K.; Ko¨chlin, P. Chem. Ber. 1882, 15, 1114.
10.1021/jo034643j CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/23/2003
8274
J . Org. Chem. 2003, 68, 8274-8276

TABLE 1. Gen er a l On e-P ot P r ep a r a tion of
Su lfon a m id es
extended to the synthesis of three N,N-diethylsulfon-
amides 9l-n containing an ester, nitrile, or a bromo
substituent (Table 1, entries 12-14). In these examples,
the requisite Grignard reagents were prepared from aryl
iodides at low temperatures by iodine metal exchange
using isopropylmagnesium chloride,9,10 a procedure ex-
tensively utilized by Knochel.11 The Knochel procedure
is noteworthy since it is compatible with functional
groups including esters, nitriles, and amides in the aryl
iodide. In the case of sulfonamide 9l, the extent of
magnesium-iodine exchange was conveniently followed
by GC/MS with a 1,3,5-tri-tert-butylbenzene standard.
This showed that the conversion to the Grignard reagent
6l was 73%, and therefore, the isolated yield of sulfon-
amide 9l (53%) represented subsequent loss. A variety
of heteroarenesulfonamides 9o-y were prepared in
moderate to good yield, by formation of the heteroaryl
Grignard reagents 6 using isopropylmagnesium chlo-
ride,11,12 followed by S-chlorination and condensation with
a range of amines (Table 1, entries 15-25). The method
was satisfactory for the conversion of 2,6-dibromopyridine
and 2,5-dibromothiophene into the monobromosulfon-
amides 9r , 9s, 9v, and 9w even when using an excess of
isopropylmagnesium chloride (Table 1, entries 18 and 19).
Que´guiner12 has previously reported that the second
trans-metalation of 2,6-dibromopyridine is slow. Ethyl
5-bromothiophene-2-carboxylate was converted into the
sulfonamides 9x and 9y (Table 1, entries 25 and 26)
again using bromine metal exchange with isopropylmag-
nesium chloride.11 Attempts were made to enhance the
yields of the sulfonamides by the use of an inverse
addition of the Grignard reagent to sulfur dioxide.13 In
the case of the nonfunctionalized sulfonamides 9a and
9e (Table 1, entries 1 and 5), yields were not significantly
enhanced. However, the yield of the functionalized sul-
fonamide 9x was slightly increased with reverse addition
to sulfur dioxide (Table 1, entry 24). The preparation of
an aliphatic sulfonamide 9z from 1-bromopentane 5z was
not successful. Although sulfonamide 9z was observed
by GC-MS, the crude reaction mixture was intractable.
In summary, we have developed a convenient one-pot
procedure for the preparation of aryl- and heteroaryl-
substituted sulfonamides from commercially available
and inexpensive aryl and heteroaryl bromides and io-
dides.
Exp er im en ta l Section
P r ep a r a tion of Su lfon a m id es 9. (a ) P r oced u r e GP 1. Mg
turnings (540 mg, 22.40 mmol) were activated with I2 (25 mg,
0.11 mmol) in THF (5 mL). The aryl bromide 5 (11.2 mmol) in
THF (15 mL) was added dropwise and the mixture heated to
reflux for 1 h and recooled to -40 °C. SO2 was bubbled through
the solution for 5 min, and after 0.5 h, SO2Cl2 (0.90 mL, 11.20
mmol) was added. On warming to room temperature, the amine
(9) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 4415.
(10) Boymond, L.; Rottla¨nder, M.; Cahiez, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 1701.
(11) (a) Abarbri, M.; Thibonnet, J .; Be´rillon, L.; Dehmel, F.; Rot-
tla¨nder, M.; Knochel, P. J . Org. Chem. 2000, 65, 4618. (b) Be´rillon, L.;
Lepeˆtre, A.; Turck, A.; Ple´, N.; Que´guiner, G.; Cahiez, G.; Knochel, P.
Synlett 1998, 1359. (c) Abarbri, M.; Knochel, P. Synlett 1999, 10, 1577.
(12) Tre´court, F.; Breton, G.; Bonnet, V.; Mongin, F.; Marsais, F.;
Que´guiner, G. Tetrahedron Lett. 1999, 40, 4339.
a
b
Isolated yields after column chromatography. Metalation
using magnesium. c Pure sulfonamide 9d was isolated in low yield
d
following chromatographic losses. Metalation using isopropyl-
magnesium chloride. e Halogen-metal exchange at -30 °C. f H-
g
alogen-metal exchange at room temperature. Major product is
h
monobromo-monosulfonamide. Halogen-metal exchange at -5
i
°C. A superior yield was obtained with reverse addition of sulfur
dioxide (35%) than with the standard addition (21%).
(13) Pinnick, H. W.; Reynolds, M. A. J . Org. Chem. 1979, 44, 160.
J . Org. Chem, Vol. 68, No. 21, 2003 8275

R2NH (112 mmol, 10 equiv) was added. After 3 h, the reaction
mixture was quenched with H2O (20 mL) and extracted with
CHCl3 (3 × 20 mL). The combined organic layers were combined
and dried (MgSO4), rotary evaporated, and chromatographed on
silica to afford the sulfonamide 9. (b ) P r oced u r e GP 2.
i-PrMgCl in THF (2 M; 4.33 mmol) was added dropwise with
stirring over 5 min to the bromide or iodide 5 (4.12 mmol) in
THF (20 mL) at -30 °C, -5 °C, or room temperature (see Table
1) under argon. The resulting solution containing 6 was stirred
for 30 min and allowed to react with SO2, SO2Cl2, and R2NH to
provide 9 following the procedure in GP 1.
studentship (to R.P.), Ehime` University, J apan for
sabbatical support (to T.M.), and the Royal Society and
the Wolfson Foundation for a Royal Society-Wolfson
Research Merit Award (to A.G.M.B.) and for establish-
ing the Wolfson Centre for Organic Chemistry in Medi-
cal Sciences at Imperial College.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for 9a -y, literature references for known sulfonamides, and
copies of 1H and 13C NMR spectra for 9h . This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank GlaxoSmithKline for
the generous endowment to A.G.M.B, the BBSRC for a
J O034643J
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