Alkene synthesis: Elimination of arenesulfinic acid from alkyl aryl sulfones using potassium trimethylsilanolate as base

Article abstract of DOI:10.1016/j.tetlet.2005.08.097

The use of potassium trimethylsilanolate as base to induce elimination of potassium arenesulfinate from alkyl aryl sulfones to produce E-alkenes is described. The reaction was appropriate for substrates containing a benzyl or allyl group α to the sulfone

Full text of DOI:10.1016/j.tetlet.2005.08.097

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7427–7430
Alkene synthesis: elimination of arenesulfinic acid from alkyl
aryl sulfones using potassium trimethylsilanolate as base
Charles A. G. Baker-Glenn,a Anthony G. M. Barrett,b Andrew A. Gray,b
Panayiotis A. Procopioua,* and Mark Rustona
aGlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
bImperial College London, South Kensington, London SW7 2AZ, UK
Received 12 July 2005; accepted 18 August 2005
Available online 9 September 2005
Abstract—The use of potassium trimethylsilanolate as base to induce elimination of potassium arenesulfinate from alkyl aryl sul-
fones to produce E-alkenes is described. The reaction was appropriate for substrates containing a benzyl or allyl group a to the
sulfone residue.
Ó 2005 Elsevier Ltd. All rights reserved.
Lithium, sodium and potassium trimethylsilanolates are
stable solids, which are commercially available either as
solids or in solution, and are recognized as hydroxide
anion equivalents soluble in organic solvents. Despite
this unique property, there are relatively few reports
describing their use. The most frequently encountered
application of potassium trimethylsilanolate is in the
preparation of anhydrous carboxylate salts from esters
and acid chlorides introduced by Laganis and Chenard
in 1984.1 This procedure has recently found application
in the racemization-free hydrolysis of the base sensitive
a-hydroxy amido acid BMS-2703942 and the hydrolysis
of delicate dienoate esters.3 The use of trimethylsilano-
lates has been extended to the conversion of N-(tri-
fluoromethylsulfonyl)trifluoromethanesulfinimidoyl
chlorides to the corresponding moisture sensitive sulfin-
imidic acid salts,4 and to the displacement of fluoride
from activated aromatic rings to produce phenols by
nucleophilic aromatic substitution.5 Another applica-
tion of potassium trimethylsilanolate, reported by one
of us, involves the diastereoselective nucleophilic
Michael-type addition to 1-(phenylthio)-1-nitroalkenes,
which on ozonolysis of the intermediate nitronate
produced the corresponding a-hydroxy thioester in
excellent yield.6 Other functional group manipulations
involve the conversion of nitriles to primary amides
reported by Merchant,7 and the cleavage, under mild
conditions, of oxazolidinones and benzyloxycarbonyl
protecting groups reported by us.8 More recently, the
Denmark group has used silanolates in the palladium-
catalyzed fluoride-free cross-coupling of organosilanols
to aryl iodides,9 and also in the Sonogashira reaction.10
Two more reports describe the use of sodium trimethyl-
silanolate as a base to promote elimination of methanol
from b-methoxyketones,11 and the deprotonation of
propyne iminium salts.12 Herein, we report a new appli-
cation of potassium trimethylsilanolate as a base to
mediate the E2 elimination of aryl sulfones.
The elimination of sulfinic acid from sulfones bearing an
electron-withdrawing group such as a nitrile b to sulfone
is a relatively well-known reaction.13 Elimination of
arenesulfinate from homoallylic sulfones in the presence
of potassium tert-butoxide was first described by Julia
and Arnould14 and has been the cornerstone of a num-
ber of polyene syntheses, such as vitamin A,15–17 and the
ionophore antibiotic X-14547A.18 Elimination of arene-
sulfinate from phenethyl sulfones in the presence of so-
dium ethoxide was first reported by Fenton and
Ingold19 in 1930, however, this transformation has not
been used in synthesis, presumably due to the very high
temperature (235 °C) required for the elimination.
Uguen reported the use of potassium tert-butoxide at
room temperature to mediate the elimination of sulfi-
nate from a-carbamido sulfones,20 however, this reac-
tion remained not widely used. Finally, there are two
Keywords: Sulfone; Elimination; Alkene synthesis; Potassium trimethyl-
silanolate; Arenesulfinate salt.
*
Corresponding author. Tel.: +44 143 876 3423; fax: +44 143 876
8302; e-mail addresses: agmb@ic.ac.uk; pap1746@gsk.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.097

7428
C. A. G. Baker-Glenn et al. / Tetrahedron Letters 46 (2005) 7427–7430
O
S
reports of the cleavage of unactivated sulfones, such as
2-pentyl methyl sulfone21 and phenyl 2-pentyl sulfone22
to give alkenes under extreme conditions.
R1
Me
O
1a R1 = H
1b R1 = Me
1c R1 = Cl
We envisaged the preparation of alkenes from aryl alkyl
sulfones by elimination of arenesulfinate using potas-
sium trimethylsilanolate instead of potassium tert-
butoxide. The pKa of trimethylsilanol is 12.7, which is
less basic than water, and much less basic than tert-buta-
nol (pKa = 19).23 These comparisons are consistent with
the expectation of elimination of arenesulfinic acid from
sulfones under the milder basic conditions, which might
be selective, or less likely to cause racemization in the
case of susceptible chiral sulfones under basic condi-
tions. Furthermore, if a methyl aryl sulfone were alkyl-
ated with three different alkyl groups, then depending on
the nature of the b-substituent of each alkyl group,
selectivity may possibly be observed (Scheme 1).
a
O
S
O
S
R1
+
R1
O
O
2
3
2a24 R1 = H (49%)
2b25 R1 = Me (30%)
2c26 R1 = Cl (37%)
3a27 R1 = H (39%)
3b
3c
R
R
1 = Me (47%)
1 = Cl (46%)
R1 = H
b
Treatment of the appropriate methyl aryl sulfone 1 with
1 equiv of potassium bis(trimethylsilyl)amide, followed
by benzyl bromide, led to a mixture of mono- and
di-alkylated products, 2 and 3,24–27 which were readily
separated by chromatography (Scheme 2). Alkylation
of 3a under the same reaction conditions provided the
tri-alkylated product 4. Sulfone 4 was allowed to react
with 2 equiv of KOtBu in THF at room temperature
and the course of the reaction was followed by LCMS.
The starting material was seen to undergo 80% conver-
sion after 30 min. In contrast, treatment of the same sul-
fone with 2 equiv of potassium trimethylsilanolate at
room temperature did not result in any reaction, even
after extended reaction time (>24 h). However, on heat-
ing the reaction to 70 °C the elimination proceeded with
60% conversion after 12 h. The reaction in the presence
of 5 equiv of KOSiMe3 at 70 °C gave the arenesulfinate
5a28 in quantitative yield and the alkene 629 (82%)
(Scheme 3). Using these conditions, the elimination
reaction30 was extended to the sulfones 2a, 3a, 2b, 3b,
2c, 3c and 4 with the extent of reaction being monitored
over time (Scheme 4 and Table 1).
O
S
O
427 (88%)
Scheme 2. Reagents and conditions: (a) KN(SiMe3)2, PhCH2Br, THF,
À78 °C, 3 h; (b) KN(SiMe3)2, PhCH2Br, THF, À78 to 0 °C, 3 h.
O
S
a or b
O-K+
4
+
5
6
Scheme 3. Reagents and conditions: (a) KOtBu (2 equiv), THF, 20 °C,
30 min; (b) KOSiMe3 (2 equiv), THF, 70 °C, 12 h.
It was observed that the rate of elimination was consis-
tent with the leaving ability of the arenesulfinic acid pro-
duced (pKa Cl–C6H4SO2H = 1.14, pKa PhSO2H = 1.35,
pKa MeC6H4SO2H = 1.48).23 In all cases, the potassium
arenesulfinate could be obtained by precipitation from
the crude reaction mixture by addition of dichlorometh-
ane. Analysis by 1H NMR and LCMS showed the pres-
ence of an impurity, attributed to the corresponding
potassium arenesulfonate. Samples of alkene 7,31 pro-
duced from the elimination from sulfones 3a, 3b and
3c were obtained exclusively as the trans isomer (1H
NMR analysis). Interestingly, it was observed that the
elimination reaction was specific to potassium trimethyl-
silanolate. Attempted elimination reactions using the
O O
S
R2
a
5
R2 R3
+
R3
R1
6, R2 = R3 = Bn
7, R2 = Bn, R3 = H
8, R2 = R3 = H
2-4
Scheme 4. Reagents and conditions: (a) KOSiMe3 (5 equiv), THF,
70 °C.
lithium and sodium trimethylsilanolates with sulfone
3c at 70 °C failed to result in any significant conversion
to the alkene.
In order to determine whether elimination was possible
on unactivated sulfones, methyl p-tolyl sulfone was
alkylated with 1-bromo-3-phenylpropane to provide
sulfones 9,32 10 and 11. Compound 10 was found to
be completely inert under the usual elimination condi-
O
O
S
O
O
R2
R3
Ar
R3
S
R1
Ar
Me
R1 R2
Scheme 1.

C. A. G. Baker-Glenn et al. / Tetrahedron Letters 46 (2005) 7427–7430
Table 1. Elimination reactions of sulfones 2–4
7429
Entry
Sulfone
R1
R2
R3
Alkene (% Yield)
Conversion (%) at time t hours
t = 2
t = 5
t = 12
1
2
3
4
5
6
7
2a
2b
2c
3a
3b
3c
4
H
CH3
Cl
H
CH3
Cl
H
H
H
Bn
Bn
Bn
Bn
H
H
H
H
H
H
Bn
8 (96)a
8 (82)a
8 (75)a
7 (56)b
7 (73)a
7 (94)a
6 (82)b
68
28
40
87
77
91
65
81
63
70
100
92
99
98
83
78
100
100
100
83
H
75
a Calculated from crude 1H NMR analysis.
b Isolated yield.
tions even with the use of 10 equiv of KOSiMe3 (Scheme
5). The reaction was repeated in the presence of KOtBu
as base in order to determine whether a stronger base
could cause elimination of the arenesulfinate. After
12 h of heating, with regular monitoring, almost all
the sulfone 10 had been consumed, but no alkene
products were observed in the intractable mixture of
products (1H NMR analysis).
O
S
a
9
O
12
b
5b
+
13
Scheme 6. Reagents and conditions: (a) LiN(SiMe3)2, allyl-Br, THF,
À78 °C, 2 h (36%); (b) KOSiMe3 (5 equiv), THF, 70 °C, 20 h (40%).
Alkylation of sulfone 9 with allyl bromide gave the
unsaturated sulfone 12, which on treatment with
KOSiMe3 for 20 h gave diene 1333 (complete conversion
by LCMS and 1H NMR spectroscopy, 40% isolated
yield). Again the product was obtained as the E-isomer
(Scheme 6).
O
S
O
S
a
O
O
Br
The sulfone triene 15, obtained from methyl sulfone 14,
was subjected to the standard elimination reaction and
this gave the corresponding tetraene 16 (Scheme 7).
After 20 h, complete conversion of starting material
had occurred, with alkene 16 detected as a single prod-
uct by TLC and LCMS. Disappointingly, attempts to
isolate tetraene 16 resulted in its complete decomposi-
tion upon evaporation of solvent. However, arenesulfi-
nate 17 was isolated (56%) and its structure confirmed.
Br
14
15
O
S
b
O-K+
+
Br
16
17
Scheme 7. Reagents and conditions: (a) LiN(SiMe3)2, allyl-Br, THF,
À78 °C, 2 h (6%); (b) KOSiMe3 (5 equiv), THF, 70 °C, 20 h.
In order to probe the selectivity of the elimination reac-
tion, sulfone 18 was prepared by alkylation of sulfone 2c
with allyl bromide (Scheme 8). In sulfone 18, the pres-
ence of two sets of activated protons, the allylic and benz-
ylic, allows the possibility of the formation of two
possible regioisomeric alkene products on the elimina-
tion of arenesulfinate 5. Abstraction of the benzylic pro-
ton would yield diene 19, whereas loss of the allylic
proton would result in the conjugated diene 20. Reac-
tion of sulfone 18c with 5 equiv of KOSiMe3 was com-
O
S
a
2a or 2c
R1
O
18a, R1 = H (64%)
18c, R1 = Cl (55%)
1
b
19
20
5a or 5c
+
plete after 5 h. H NMR spectroscopic analysis of the
crude product was consistent with the formation of
Scheme 8. Reagents and conditions: (a) LiN(SiMe3)2, allyl-Br, THF,
À78 °C, 3 h; (b) KOSiMe3 (5 equiv), THF, 70 °C, 12 h.
O R1
a
R2
1b
S
O R3
9, R1 = (CH2)3Ph, R2 = R3 = H
10, R1 = R2 = (CH2)3Ph, R3 = H
11, R1 = R2 = R3 = (CH2)3Ph
one major alkene product, which was isolated and iden-
tified as the (E,E)-diene 21,34 presumably derived from
the initially formed diene by isomerization of the double
bonds into conjugation with the phenyl ring. Similarly,
elimination of sulfone 18a generated the corresponding
Scheme 5. Reagents and conditions: (a) KN(SiMe3)2, Ph(CH2)3Br,
THF, À78 °C, 80 h, 9 (28%), 10 (14%), 11 (12%).

7430
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Acknowledgements
We thank GlaxoSmithKline for the generous endow-
ment (to A.G.M.B.), the Royal Society and the Wolfson
Foundation for a Royal Society Wolfson Research
Merit Award (to A.G.M.B.), the Wolfson Foundation
for establishing the Wolfson Centre for Organic Chem-
istry in Medical Sciences at Imperial College London,
and the Engineering and Physical Sciences Research
Council and GSK for generous support of our studies.
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salt was filtered off, the filtrate evaporated and the residue
1
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