Synthesis of menthyl sulfinate and sulfoxides on solid phase

Article abstract of DOI:10.1016/S0040-4039(01)01978-5

p-Hydroxyphenyl menthyl sulfinate was readily linked to Wang resin. The resulting sulfinate reacted with Grignard reagents and potassium or lithium enolates to give the corresponding sulfoxides or β-ketosulfoxides allowing a study of the chemistry of sulf

Full text of DOI:10.1016/S0040-4039(01)01978-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9077–9080
Synthesis of menthyl sulfinate and sulfoxides on solid phase
Catherine Rolland, Gilles Hanquet,* Jean-Bernard Ducep and Guy Solladie´*
Laboratoire de Ste´re´ochimie associe´ au CNRS, ECPM, Universite´ Louis Pasteur, 25 rue Becquerel, F-67087 Strasbourg, France
Received 22 August 2001; revised 5 October 2001; accepted 19 October 2001
Abstract—p-Hydroxyphenyl menthyl sulfinate was readily linked to Wang resin. The resulting sulfinate reacted with Grignard
reagents and potassium or lithium enolates to give the corresponding sulfoxides or b-ketosulfoxides allowing a study of the
chemistry of sulfoxides for solid phase synthesis. © 2001 Elsevier Science Ltd. All rights reserved.
oxidation of the corresponding b-ketosulfide.6 We
report in this paper the synthesis of menthyl p-tolyl-
sulfinate on a Wang resin and its application for the
formation of b-ketosulfoxides on solid support.
In the last decade solid phase methodology has been
considerably developed due to the increasing interest in
combinatorial and parallel synthesis.1 In order to access
new target molecules, chemists must adapt reactions to
the solid phase and, therefore, define new linkers which
should be chemically stable to many experimental con-
ditions. The next challenge will be the adaptation to
asymmetric synthesis.
Among the different ways of obtaining sulfoxides, the
most widely used approaches are based on nucleophilic
substitution on chiral sulphur derivatives7 such as men-
thyl p-toluenesulfinate. The literature also describes
p-tolyl-methyl sulfoxide as an important synthon for
numerous asymmetric transformations. In order to
develop sulfoxide chemistry on solid support, we chose
to prepare a Wang resin bearing a menthyl p-substi-
tuted-benzenesulfinate or a methyl sulfoxide.8 The link
between the sulfinate or the sulfoxide moiety and the
solid support can be a benzyl ether group, easily
cleaved in acidic conditions9 to permit monitoring of
each step of the synthesis. Therefore, the menthyl p-
hydroxyphenylsulfinate 4 and the p-hydroxyphenyl-
methyl sulfoxide 6 were selected to prepare the
supported reagents A and B (Scheme 1).
The sulfinyl group is an important and useful tool in
numerous asymmetric transformations. Besides the high
configurational stability of the sulfinyl group,2 the exis-
tence of several efficient methods to obtain chiral
sulfoxides3 as well as their synthetic versatility has led
to numerous applications of chiral sulfinyl derivatives
to the synthesis of enantiomerically enriched molecules
over the last three decades.3,4
Moreover, the facility of cleaving the sulfoxide moiety
from the molecule (desulphurisation, Pummerer reac-
tion or syn-elimination),5 in conditions compatible with
many chemical reactions, allowed us to consider this
functionality as a very promising new linker.
The synthesis of these two compounds started from
sulfinyl chloride 2 obtained by chlorination of the cor-
responding sodium sulfonate 1 (Scheme 2). The reduc-
We have recently reported the synthesis of racemic
b-keto-p-alkoxyphenylsulfoxide on a Wang resin by
Wang Resin
Wang Resin
O
SOMe
O
SO2Menthyl
B
Scheme 1.
* Corresponding authors. Fax: (33) 03 90 24 27 42; e-mail: ghanquet@chimie.u-strasbg.fr; solladie@chimie.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01978-5

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C. Rolland et al. / Tetrahedron Letters 42 (2001) 9077–9080
tion of 2 gave the sulfinic acid 3, which was esterified
with (−)-menthol to a mixture of the two diastereoiso-
mers of the menthyl p-hydroxyphenylsulfinate 4. Only
one of the two diastereoisomers 4 was isolated by
crystallisation in ether in 60% yield. The absolute
configuration of this compound 4a was determined by
chemical correlation with the p-methoxy derivative 5a
described in the literature.10 The corresponding (p-
hydroxyphenyl)methylsulfoxide 6a was obtained from
the p-t-butyldimethylsilyloxy derivative with Grignard
reagents11,3d with complete inversion of configuration at
sulphur.
The first reaction includes the methodology described
by Corey,13 the reaction of a-sulfinyl anions with esters
to form b-ketosulfoxides. This method has been widely
used and developed, and remains an efficient way to
prepare this compound in enantiomerically pure form.
After a large number of experiments it appeared to us
that the formation and the reactivity of the anion of the
methyl sulfoxide B, even versus the most reactive elec-
trophiles,14 cannot be observed on solid support. The
p-hydroxyphenylmethyl sulfoxide 6 is quantitatively
recovered after treatment of the resin with TFA.15
The menthylsulfinate 4 (diastereoisomeric mixture) was
attached to the resin via a Mitsunobu reaction12 (see
Scheme 3) as well as the racemic sulfoxide 6. We then
tried to adapt the sulfoxide chemistry to the solid
support. We focused our attention on the two main
reactions usually used in our laboratory to get a wide
variety of sulfoxides: the action of the methylsulfoxide
anion on electrophiles and the nucleophilic substitution
of menthylsulfinate with enolates or Grignard reagents
(Scheme 4).
Having explored a wide range of variations around this
reaction (by changing the base, the support, the reac-
tion conditions, and the electrophilic species for
instance), we finally concluded that these difficulties
were probably due to a lack of stability of the anion on
the solid support. This hypothesis was confirmed later
by the experiment described in Scheme 5, which shows
that a stabilised sulfinyl anion reacts smoothly with
iodomethane.
SH
Et N
3
,
SO2H
SO2Cl
SO3Na,
1) Dean Stark; 2) SOCl2
2 H2O
76%
70%
HO
HO
HO
3
2
1
(-)-menthol,
DCC,
CH2Cl2
O
S
SO2Menthyl
Et2O
(-)-(S)-p-hydroxyphenyl menthylsulfinate
[αD]20= -192 (c=1,0 in acetone)
OMenthyl
60%
HO
HO
4a
4
K2CO3
Me2SO4
Mixture of the two diastereoisomers
O
1) TBDMSCl
2) CH3MgI, Et2O, toluene
3) TBAF
85%
S
O
S
OMenthyl
MeO
(+)-(R)-p-hydroxyphenyl methylsulfoxide
5a(-)-(S)-p-methoxyphenyl menthylsulfinate
HO
[αD]
20= -189 (c=0,6 in acetone)
6a
Scheme 2.
Wang Resin
SO2Menthyl
O
A
B
HO
SO2Menthyl
PPh3,DIEA,DEAD
toluene, THF
4
O
O
Wang Resin
S
O
HO
S
CH3
PPh3,DIEA,DEAD
toluene, THF
CH3
6
Scheme 3.

C. Rolland et al. / Tetrahedron Letters 42 (2001) 9077–9080
9079
O
S
O
R
S
1) Base
O
O
2) R-X
O
C
D
B
O
S
R'
R'MgX
O
S
OMenthyl
O
S
O
O
A
R"
O
(2eq.)
R"
(M = K or Li)
M+
O
-
E
Scheme 4.
1) LDA
O
2) MeI
O
O
O
O
HO
S
O
S
3)
CF3COOH
70%
Ph
Ph
8
7
Scheme 5.
R'
Yield
O
S
R'MgX
THF
O
q.
q.
q.
SO2Menthyl
O
Me
Et
R
'
E
A
Ph
Bz
75%
q. : quantitative
Scheme 6.
O
O
S
O
O
S
Yield
R"
(2eq.)
R"
M+
-
67%
52%
40%
R"
Ph
OMenthyl
-(CH2)2Ph
-CH2C(O)O(CH3)3
(M = K or Li)
O
O
E
A
Scheme 7.
In sharp contrast, the results concerning the reaction of
the menthyl sulfinate linked to the resin A with a
Grignard reagent were much more encouraging. We have
been able to generalise this reaction and to use it in a
small-scale parallel synthesis. The first step was to adapt
the reaction to the quantitative formation of methyl
sulfoxide on solid support and to determine the most
promising reaction conditions for a generalisation to a
wide variety of reactive species. This was achieved using
the conditions described in Scheme 6. We obtained
quantitative yields for the most common species.
In order to obtain b-ketosulfoxide from menthyl sulfi-
nate, we studied the action of enolates on the menthyl
sulfinate linker. The promising first results concerning
this reaction are presented in Scheme 7. All these results
were established by cleavage of the resulting sulfoxide
with TFA.15

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C. Rolland et al. / Tetrahedron Letters 42 (2001) 9077–9080
In conclusion, these results describe a new type of
linker, the alkoxy-phenyl-sulfinyl group and are com-
plementary to those of our previous report.6 We have
shown that sulfoxides and b-ketosulfoxides can be
obtained from menthyl sulfinate linked to a Wang
resin. This opens the route to the rich chemistry of
sulfoxides to combinatorial synthesis on solid support
including the Pummerer rearrangement6 to release the
final product. In addition, these data also open the
route to optically active sulfoxides on solid support.
4. (a) Carreno, M. C. J. Am. Chem. Soc. 1995, 95, 1717; (b)
Mikolajczyk, M.; Drabowicz, J. In Topics in Stereochem-
istry; Allinger, N.; Eliel, E.; Wilen, S., Eds.; Wiley: New
York, 1982; p. 333; (c) Barbachyn, M. R.; Johnson, C. R.
In Asymmetric Synthesis; Morrison, J. D., Ed.; Aca-
demic: New York, 1984; Vol. 4, p. 227.
5. The chemistry of sulfinic acid, ester and their derivatives;
Pata¨ı, S., Ed.; John Wiley & Sons: Chichester, 1990.
6. Rolland, C.; Hanquet, G.; Ducep, J.-B.; Solladie´, G.
Tetrahedron Lett. 2001, 42, 7563–7576.
7. (a) Andersen, K. K. Tetrahedron Lett. 1962, 3, 93; (b)
Andersen, K. K.; Gaffield, W.; Papanikolau, N. E.;
Foley, J. W.; Perkins, R. I. J. Am. Chem. Soc. 1964, 86,
5637; (c) Solladie´, G.; Hutt, J.; Girardin, A. Synthesis
1987, 173.
Acknowledgements
8. Wang, S. S. J. Am. Chem. Soc. 1973, 95, 1328.
9. Kiselyov, A. S.; Armstrong, R. W. Tetrahedron Lett.
1997, 38, 6163.
We are indebted to Sanofi-Synthelabo for financial
support and for a CIFRE grant to Catherine Rolland.
10. Jaipetch, T.; Kanghae, S.; Pancharoen, O.; Patrick, V. A.;
Reutrakul, V.; Tuntiwachwuttikul, P.; White, A. H. Aust.
J. Chem. 1982, 35, 351.
11. This reaction occurs with full inversion of configuration
at sulphur as described in solution, in many examples to
prepare p-tolylalkyl or aryl sulfoxides: (a) Solladie´, G.
Synthesis 1981, 185; (b) Walker, A. J. Tetrahedron: Asym-
metry 1992, 3, 961.
12. Mitsunobu, O. (review) Synthesis 1981, 1; for examples of
Mitsunobu reactions on the solid support, see: (a) Rano,
T. A.; Chapman, K. T. Tetrahedron Lett. 1995, 36, 3789;
(b) Krchnak, V.; Flegelova, Z.; Weichsel, A. S.; Lebl, M.
Tetrahedron Lett. 1995, 36, 6193.
13. (a) Corey, E. J.; Chaykowski, M. J. Am. Chem. Soc.
1962, 84, 866; (b) Corey, E. J.; Chaykowski, M. J. Am.
Chem. Soc. 1965, 87, 1345.
14. We tried without success, the reaction with iodomethane
and deuterated water, after several series of tests with
esters and amides. We have of course checked that the
same experiments were working in solution.
15. The aromatic ether link can be easily cleaved in acidic
conditions using TFA more or less diluted in
dichloromethane depending on the solubility of the com-
pound: Deegan, T. L.; Gooding, O. W.; Baudart, S.;
Porco, Jr., J. A. Tetrahedron Lett. 1997, 38, 4973.
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