Trimethylsilyl directed aromatic sulfonation with sulfur trioxide- dioxane complex

Article abstract of DOI:10.1055/s-1998-2188

A mild procedure for trimethylsilyl group directed sulfonation through ipso aromatic substitution has been developed using in situ generated sulfur trioxide-dioxane complex. The process is effective with electron rich aromatic rings, but fails in the case of aromatic rings substituted by groups such as a carboxylate. Aromatic heterocycles form sulfur trioxide complexes which deactivate them to substitution.

Full text of DOI:10.1055/s-1998-2188

November 1998
SYNTHESIS
1593
Trimethylsilyl Directed Aromatic Sulfonation with Sulfur Trioxide-Dioxane Complex
Peter G. M. Wuts,* Katherin E. Wilson1
Pharmacia and Upjohn Inc, Chemical Process Research and Development, 7000 Portage Rd, 1500-91-2, Kalamazoo, MI 49001, USA
Fax +1(616)8339158; E-mail: Peter.G.Wuts@am.pnu.com
Received 6 April 1998
Abstract: A mild procedure for trimethylsilyl group directed sul-
fonation through ipso aromatic substitution has been developed
using in situ generated sulfur trioxide-dioxane complex. The pro-
cess is effective with electron rich aromatic rings, but fails in the
case of aromatic rings substituted by groups such as a carboxylate.
Aromatic heterocycles form sulfur trioxide complexes which
deactivate them to substitution.
convenient, and high yield procedure for trimethylsilyl di-
rected sulfonation of aromatics rings. A key feature is that
sulfur trioxide-dioxane complex can easily be prepared
from low cost commercially available trimethylsilyl chlo-
rosulfonate and dioxane according to the procedure of
Hoffmann and Simchen,13 who discovered that trimethyl-
silyl chlorosulfonate disproportionates to chlorotrimethyl-
silane and sulfur trioxide-dioxane simply upon mixing the
two reagents. A major advantage of this reaction is that it
is thermally neutral and conveniently performed, in con-
trast to the very exothermic process of dissolving sulfur tri-
oxide in dioxane. Furthermore, commercial sulfur trioxide
is difficult to handle, tends to polymerize with time, and
disposal is difficult because of its extreme reactivity.
Key words: sulfur trioxide/dioxane complex, arylsilanes, trimethyl-
silyl directed sulfonation
1
Sulfonic acids and their derivatives are a large functional
class which impacts nearly every subfield of organic2
chemistry. They are used in protecting group chemistry,
3
as ligand modifiers in catalysts, leaving groups in func-
tional group transformations, and analog development in
medicinal chemistry, among others. The synthesis and
chemistry of this group is discussed in a number of mono-
In an initial exploratory experiment, trimethylsilylben-
zene was added to a solution of sulfur trioxide-dioxane on
a 10 g scale at room temperature. This resulted in an im-
mediate and vigorously exothermic reaction to produce
trimethylsilylbenzenesulfonate in a few minutes. The
product was isolated by pouring the reaction mixture into
water, adjusting the pH with 50% sodium hydroxide to
make it basic, followed by addition of tetra-n-butylammo-
4
graphs and review articles. The most common approach
to their synthesis is by sulfonation of an aromatic ring,
where the regiochemistry of electrophilic aromatic substi-
tution is controlled by the ring substituents. Another com-
mon method for sulfonic acid synthesis is by chlorine ox-
5
idation of a thiol or thioether. Recently, a method for sul-
fonic acid synthesis was developed which relies on
14
nium hydrogen sulfate and extraction with dichlo-
6
sulfonation of Grignard and lithium reagents. In certain
romethane to afford the salt in 85.5% yield. We chose to
isolate the sulfonic acids as the tetrabutylammonium salts
because many of the lower molecular weight sulfonic ac-
ids are water soluble and otherwise difficult to isolate.
Furthermore, the procedure of Robinson and Wyatt for the
conversion of the related anthracenesulfonate salt to the
sulfonyl chloride should be applicable in the present
case.15 The results to date are presented in the Table.
Clearly, the typical electron-donating groups work well,
but when the aromatic ring bears a carboxylic acid deriv-
ative the reaction fails because of its strong electron with-
drawing effect even when greater than stoichiometric
amounts of sulfur trioxide-dioxane are used. In the case of
the anilide, prepared from pivalic anhydride, two equiva-
lents of sulfur trioxide-dioxane must be used because the
amide consumes the first equivalent in a coordination
complex, otherwise 1.5-1.6 equivalents of sulfur trioxide-
dioxane were used. The trifluoromethyl group deactivates
the ring to substitution, but upon heating to 85°C it will
react giving the salt in good yield. An attempt to convert
special cases, sulfonic acids can be prepared by nucleo-
philic aromatic substitution with sodium sulfite.
7
A recent interest in sulfonic acids and their derivatives
prompted us to investigate a directed electrophilic aromat-
ic substitution approach to the synthesis of sulfonic acids.
Since it is well known that silanes direct electrophilic re-
8
actions, we reasoned that we should be able to convert
aryl silanes by an ipso substitution with sulfur trioxide-
dioxane to sulfonic acids as illustrated in Scheme 1.
Scheme 1
2
-trimethylsilylbenzothiazole to its sulfonic acid resulted
A search of the literature revealed a single report of this
transformation where bistrimethylsilylbenzenes were
in a complex between the lone pair on nitrogen and sulfur
trioxide thus deactivating the ring to substitution.
treated with sulfur trioxide prepared from 65% oleum in
9
refluxing carbon tetrachloride. A related, and similarly We have also briefly examined the reaction of sulfur tri-
harsh transformation, using trimethylsilyl chlorosulfonate oxide-dioxane with allylsilanes.16 The reaction proceeds,
in refluxing carbon tetrachloride has also been de- as expected, by an S -2' mechanism as illustrated for pre-
E
1
0–12
scribed.
We now wish to report a very simple, mild, nylsilane.

1
594
Short Papers
SYNTHESIS
1
H NMR (CDCl ): δ = 7.96 (d, J = 6 Hz, 1 H), 7.25 (d, J = 9 Hz, 1 H),
3
6
.86 (m, J = 21 Hz, 2 H), 3.29 (br t, J = 17 Hz, 8 H), 1.62 (br m, J =
2 Hz, 8 H), 1.40 (br s, J = 37 Hz, 8 H), 0.96 (br t, J = 15 Hz, 12 H).
3
13
C NMR (CDCl ): δ =156.9, 134.9, 130.4 (CH), 129.2 (CH), 119.0
3
(
1
CH), 111.4 (CH), 58.7 (CH ), 55.8 (CH ), 24.0 (CH ), 19.6 (CH ),
2
3
2
2
–1
3.6 ( CH ). IR 1197, 1031 cm .
3
Scheme 2
Anal. Calcd for C H NO S: C, 64.30; H, 10.09; N, 3.26; S, 7.46.
23
43
4
Found: C, 64.27; H, 9.97; N, 3.42; S, 7.27.
Table. Sulfonation of Trimethylsilylbenzene Derivatives
Tetrabutylammonium 2-Isopropylthiobenzenesulfonate: mp 95–
9
7˚C.
Entry
Substrate
fg
Product
yield (%)
mp (˚C)
1
H NMR (CDCl ): δ = 8.05 (d, J = 9.15 Hz, 1 H), 7.28 (d, J = 8.37 Hz,
1
3
H), 7.20 (t, J = 7.26 Hz, 1 H), 7.04 (t, J = 7.32 Hz, 1 H), 3.56 (septet,
1
2
3
4
5
6
7
8
9
H
86a
89
89
85
82
75
–
94
87
75–78
95–97
97.5–100
145–148
58b–61
oil
J = 6.57 Hz, 1 H), 3.23 (m, 8H), 1.54, (m, 8H), 1.35, (m, 16H), 0.93
1
7
2-i-PrS
2-Methoxy
2-PvNH
3-chloro
4-CF3
4-MeO C
(t, J = 7.26).
1
8
13
C NMR (CDCl ): δ = 145.7, 135.7, 128.8, 128.7, 128.0, 123.8, 58.6,
3
1
9
35.8, 24.0, 23.0, 19.7, 13.7.
2
0
–1
IR (KBr): ν = 1202 cm .
1
8
Anal. Calcd. for C H NS O : C, 63.51; H, 9.81; N, 2.96; S, 13.57.
25
46
2
3
2
1
c
–
oil
2
Found: C, 63.21; H, 9.86; N, 2.96; S, 13.46.
1
8
b
4-PhO
2-TMS-naphthalene
120–123
Tetrabutylammonium 2-Pivalamidobenzenesulfonate: mp 145–148˚C.
1
H NMR (CDCl ): δ = 7.77 (d, J = 8.61 Hz, 2 H), 7.55 (d, J = 8.61 Hz,
a
3
The yields reported for crystalline solids are for recrystallized ma-
2
H), 3.14 (m, 8 H), 1.58 (m, 8 H), 1.36 (s, 9 H), 0.94 (t, J = 14.5 Hz,
terial.
b
c
12 H).
Mass spectral fragmentation patterns and NMR spectra are consi-
stent with the expected sturctures of these salts.
No reaction.
13
C NMR (CDCl ): δ = 177.0, 142.9, 139.1, 126.7, 119.5, 58.7, 39.6,
3
27.5, 23.8, 19.6, 13.6.
IR (KBr): ν = 1670, 1197, 1032 cm .
–1
Anal. Calcd. for C H N O S: C, 65.02; H, 10.10; N, 5.62; S, 6.43.
27
50
2
4
Found: C, 64.76; H, 9.74; N, 5.46; S, 6.38.
The advantage of this methodology is that aryl and allyl
silanes are easily prepared by a number of processes and
8
Tetrabutylammonium 3-Chlorobenzenesulfonate: mp 58–61˚C.
that the silane group can be carried through a synthesis
and converted to a sulfonic acid at a later stage when other
functionality may prevent direct sulfonation. This method
is an improvement over the direct use of trimethylsilyl
chlorosulfonate which generally requires the use of re-
fluxing carbon tetrachloride. The scope of the reaction
which was limited to otherwise unfunctionalized silyl
substituted benzenes has been increased to cover a wider
array of substituted aromatics.
1
H NMR (CDCl ): δ = 7.88 (s, 1 H), 7.80 (m, 1 H), 7.26 (m, 2 H), 3.22
3
(
m, 8 H), 1.59 (m, 8 H), 1.38 (m, 8 H), 0.97 (t, J = 14.7 Hz, 12 H).
1
3
C NMR (CDCl ): δ = 149.1, 133.5, 129.1, 128.8, 126.4, 124.3, 58.5,
3
23.8, 19.6, 13.6.
IR (KBr): ν = 1224, 1037 cm .
–1
Anal calcd. for C H ClO SN: C, 60.87; H, 9.29; N, 3.23; Cl, 8.17;
22
40
3
S, 7.39. Found: C, 60.90; H, 9.65; N, 3.31; Cl, 8.05; S, 7.44.
Tetrabutylammonium 4-Trifluoromethylbenzenesulfonate:
1
H NMR (CDCl ): δ = 7.72 (d, J = 8.1 Hz, 2 H), 7.29 (d, J = 8.1 Hz,
3
2
1
H), 2.93 (m, 8 H), 1.30 (m, 8 H), 1.08 (m, 8 H), 0 66 (t, J = 14.7 Hz,
2 H).
Dioxane was distilled from Na/benzophenone ketyl before use. All
other reagents and solvents were used as received. The starting mate-
rials were prepared as reported in the references. All reactions were
13
C NMR (CDCl ): δ = 152.4, 135.0, 132.1 (q, CF ) 128.0, 126.3,
3
3
60.0, 25.3, 21.0, 15.0.
–1
IR (film): ν = 1321, 1211, 1131, 1066 cm .
Negative ion electrospray MS: [m–] m/z = 225.1; [2 M + NBu ] , m/
z = 692.1.
done under an atmosphere of N and monitored by TLC using Merck
2
–
4
F254 silica gel plates. NMR spectra were recorded on a 300 MHz
spectrometer and IR spectra were recorded on an FTIR spectrometer.
Melting points were obtained using a hot oil melting point apparatus
and are uncorrected. Microanalyses were performed by the Physical
and Analytical chemistry group of Pharmacia and Upjohn.
+
Positive ion electrospray MS: [m] m/z = 242.4
Tetrabutylammonium Benzenesulfonate: mp 75–78˚C.
1
H NMR (CDCl ): δ = 7.87 (m, 2 H), 7.30 (m, 3 H), 3.16 (m, 8 H),
3
1
.51 (m, 8 H), 1.33 (m, 8 H), 0.095 (t, J = 5.7 Hz, 12 H).
Tetrabutylammonium 2-Methoxybenzenesulfonate; Typical Pro-
cedure:
Trimethylsilyl chlorosulfonate (1.2 mL, 7.8 mmol) was added to
anhyd 1,4-dioxane (20 mL) at r.t. After 5 min of stirring, the TMSCl
was removed by vacuum distillation (27 Torr) over 15 min. Slowly,
13
C NMR (CDCl ): δ = 147.6, 128.6, 127.6, 126.0, 58.4, 23.8, 19.5,
3
1
3.6.
–1
IR (KBr): ν = 1486, 1207, 1124, 1026 cm .
Anal. calcd. for C H NO S: C, 66.12; H, 10.34; N, 3.50; S, 8.02.
Found: C, 66.10; H, 10.26; N, 3.51.
22 41
3
2
-methoxy-1-trimethylsilylbenzene (1.0 mL, 4.8 mmol) was added at
r.t. On this scale with a slow addition, essentially no exotherm was
observed. The reaction mixture was allowed to stir at r.t. for 1 h,
Tetrabutylammonium Naphthalene-2-sulfonate: mp 120–123˚C.
1
poured into H O and then treated with solid NaOH (0.54 g) and tet-
H NMR (CDCl ): δ = 8.40 (s, 1 H), 8.00 (dd, J = 6.8, 1,6 Hz, 1 H),
2
3
rabutylammonium hydrogen sulfate (1.79 g). The product was ex-
tracted with CH Cl (2–40mL). The combined organic layers were
7.8 (m, 3 H), 7.5 (m, 2 H), 3.19 (m, 8 H), 1.55 (m, 8 H), 1.38 (m, 8H),
0.92 (t, 12 H).
2
2
13
washed with H O (1–30mL), dried (MgSO ) and concentrated to ob-
C NMR (CDCl ): δ = 144.64, 133.44, 132.63, 128.58, 127.53,
2
4
3
tain 1.94 g (94%) of crude solid. Recrystallization from toluene gives
.82 g (89%) of a white solid; mp 97.5–100°C.
127.48, 126.25, 125.94, 125.13, 124.18, 58.54, 23.86, 19.59, 13.57.
IR (KBr): ν = 2960, 2750, 1600, 1500, 1215, 675 cm .
-1
1

November 1998
SYNTHESIS
1595
Tetrabutylammonium 1,1-Dimethylprop-2-enyl-1-sulfonate:
(5) See for example: Robin, R. O. Jr.; Clapp, J.W. J. Am. Chem.
Soc. 1950, 72, 4890.
Dioxane (20 mL) was treated with TMSOSO Cl (2.44 mL, 16.4
2
mmol) at r.t. The TMSCl was removed by vacuum distillation and
trapped with an acetone/dry ice bath. The solution was cooled to 10 C
Stanovnik, B.; Tisler, M. Arch. Pharm (Weinheim) 1965, 298,
357.
o
and prenyltrimethylsilane (2.0 g, 15.4 mmol) was slowly added to the
(6) Smith, K.; Duanjie, H. J. Org. Chem. 1996, 61, 1530.
(7) Umemoto, T.; Tomizwaza, G. J. Org. Chem. 1995, 60, 6563.
(8) Bassindale, A. R.; Taylor, P. G. In The Chemistry of Organic Si-
licone Compounds; Patai, S., Rappoport, Z. Eds.; Wiley: New
York, 1989, Chap. 14.
SO -dioxane solution, maintaining the temperature between 10 and
3
o
2
5 C. The solution was stirred for 0.5 h and poured into aq NaOH,
Bu NHSO (5.25 g) was added and the product extracted with CH Cl
4
4
2
2
(
2 × 30 mL). The combined organic layers were dried (MgSO ) and
4
concentrated to afford a waxy solid. Attempts to crystallize the salt
Colvin, E. W. Silicon in Organic Synthesis, Butterworths: Lon-
don, Chap. 10.
Fleming, I.; Dunogues, J.; Smithers, R. Org. React. 1989, 37,
57.
from a variety of solvents was unsuccessful.
1
H NMR (CDCl ): δ = 6.27 (dd, J = 17.4, 10.5 Hz, 1 H), 5.09 (dd, J
3
=
1.2, 17.4 Hz, 1), 5.01 (dd, J = 1.2, 10.5 Hz, 1), 3.24 (m, 8 H), 1.58
(
m, 8 H), 1.38 (m, 8 H), .094 (t, J = 7.5 Hz, 12 H).
Hosomi, A. Acc. Chem. Res. 1988, 21, 200.
Hablich, D.; Effenberger, F. Synthesis 1979, 841.
(9) Bott, R. W.; Eaborn, C.; Hashimoto, T. J. Organomet. Chem.
1
3
C NMR (CDCl ): δ = 143.3, 112.9, 67.4, 59.2, 22.4, 23.5, 20.1,
3
1
4.0.
1965, 3 442.
(10) Bennetau, B.; Krempp, M:; Dunoguès, J. Tetrahedron 1990, 46,
(
1) Summer research intern from Notre Dame. Current address: Eli
Lilly, Indianapolis, Indiana.
8131.
(11) Bennetau, B.; Rajarison, F.; Dunoguès, J.; Babin, P. Tetrahe-
dron 1993, 43, 10843.
(12) Bourgeos, P.; Calas, R.; Jousseaume, E.; Gerval, J.J. Organo-
met. Chem. 1975, 84, 165.
(13) Hofmann, K.; Simchen, G. Synthesis 1979, 699.
(14) The related bromide and chloride salts can also be used, but the
bisulfate salt is the most cost effective.
(2) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
nd
Synthesis, 2 ed.; Wiley: New York, 1991.
Kocienski, P. J. Protecting Groups, Thieme: Stuttgart, 1994.
3) Handbook of Enantioselective Catalysis with Transition metal
Coumpounds Vol. II, Brunnert, H.; Zettlmeier, W., Eds.; VCH:
Weinheim, 1993.
(
Devasagayaraj, A.; Schwink, L.; Knochel, P. J. Org. Chem.
(15) Robinson, A. J.; Wyatt, P.B. Tetrahedron 1993, 49, 11329.
1
995, 60, 3311.
(16) Allyl silanes have been reported to react with SO , but no prior
3
Corey, E. J.; Imwinkelreid, P. S.; Xiang, Y. B. J. Am. Chem.
Soc. 1989, 111, 5493.
examples of this transformation using SO -dioxane could be
found.
3
Jansen, J. F. G. A.; Feringa, B. L. J. Org. Chem. 1990, 55, 4168.
Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Koba-
yashi, S. Tetrahedron 1992, 48, 5691.
Corey, E. J.; Choi, S. Tetrahedron Lett. 1991, 32, 2857.
Kinugasa, M.; Harada, T.; Oku, A. J. Org. Chem. 1996, 61,
(17) Horner, L.; Lawson, A. J.; Simons, G. Phosphorous and Sulfur
1982, 12, 353.
(18) Freeburger, M. E.; Spialter, L. J. Am. Chem. Soc. 1971, 93,
1894.
(19) Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133.
(20) Clark, H. A.; Gordon, A. F.; Young, C. W.; Hunter, M. J. J Am.
Chem. Soc. 1951, 73, 3798.
6
772.
(
4) The Chemistry of Sulphinic Acids, Esters and Their Derivatives;
Patai, S., Ed.; Wiley: New York, 1990, p 658.
K. K. Andersen In Comprehensive Organic Chemistry, Vol. 3;
Jones, N:D., Ed.; Pergamon: 1979.
(21) Prepared by carboxylation of the Grignard of 1-bromo-4-trime-
thylsilylbenzene followed by esterification with diazomethane.