A mild, osmium tetraoxide-catalyzed method for the oxidation of sulfides to sulfones

Article abstract of DOI:10.1016/S0040-4039(00)93423-3

Osmium tetraoxide has been demonstrated to be a highly efficient catalyst for the chemoselective oxidation of a variety of sulfides to the corresponding sulfones. Tertiary amine catalysis appears to play a key role in the reaction

Full text of DOI:10.1016/S0040-4039(00)93423-3

Te'trahedron Letters, Vo1.32, No.38, pp 5043-5046, 1991
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Pergamon Press plc
A Mild, Osmium Tetraoxide-Catalyzed Method for the
Oxidation of Sulfides to Sulfones
Stephen W. Kaldor* and Marlys Hammond
Lilly Research Laboratories
Lilly Corporate Center
Indianapolis, IN 46285
Key Words: osmium tetraoxide, oxidation, sulfide, sulfone
Abstract: Osmium tetraoxide has been demonstrated to be a highly efficient catalyst for the
chemoselective oxidation of a variety of sulfides to the corresponding sulfones. Tertiary amine
catalysis appears to play a key role in the reaction.
Although considerable effort has been expended on the development of methods for the oxidation of
sulfides to sulfones,1 mild, chemoselective procedures for effecting this transformation are relatively scarce.
We now wish to report that osmium tetraoxide is a selective and highly efficient catalyst for performing this
oxidation. In the presence of the co-oxidant N-methylmorpholine-N-oxide (NMO), one mole percent of catalyst
is sufficient to oxidize a variety of sulfides to the corresponding sulfones in nearly quantitative yields. This
room temperature oxidation method is tolerant of a number of other functional groups: chemoselective oxidation
of a sulfide in the presence of an olefin is even possible in some instances.
Catalytic OsO4,
NMO
RI,IS-~ R2
84-100% ID
Rl, f ~ % R2
In contrast to the hierarchy of reactivity exhibited by sulfides and sulfoxides toward peracid and periodate
oxidants, sulfoxides are frequently more reactive than sulfides towards transition-metal oxidants.2,3 Several
researchers have observed that sulfides are generally inert to oxidation by osmium tetraoxide under
stoichiometric conditions.4 For example, in a seminal paper in 1965 Henbest demonstrated that although
oxidation of sulfoxides to the corresponding sulfones with OsO4 is a facile process at room temperature,
treatment of dibenzyl or diphenyl sulfde with stoichiometric osmium tetraoxide in refluxing ether for 48 h
resulted in complete recovery of starting sulfide.3
In light of this literature precedent, we were startled to discover that dibenzyl sulfide was quantitatively
oxidized to dibenzyl sulfone at room temperature when treated with N-methylmorpholine-N-oxide in the
presence of one mole percent of osmium tetraoxide (Table, entry F).5 A representative series of sulfides was
then examined to determine the scope of this catalytic oxidation method (Table). All oxidations we have
attempted to date have proceeded smoothly and in excellent yield. Despite the known susceptibility of osmium
tetraoxide to rate retardation in sterically encumbered substrates (e.g. tri- and tetrasubstituted olefms),6 oxidation
of both branched and straight chain alkyl sulfides proceeds with equal facility (Entries B-D). Significant
5043

5044
attenuation of reaction rate was noted only for the oxidation of diphenyl sulfide (Entry G); 10 mol% of OsO4
was employed to speed this reaction to completion overnight. In accord with the observations of Henbest,3
sulfoxide intermediates appear to have only a fleeting existence in the reaction medium; only traces of sulfoxide
were observed by tic at various time points during the reaction. Catalyst turnover is clearly quite efficient in
some instances: complete and quantitative oxidation of thioanisole was possible in a 24-hour period employing
only 0.1 mol% osmium tetraoxide.
Table. Osmium Tetraoxide-Catalyzed Oxidation of Sulfides to Sulfones
1
mol% Os04,
(1)
R(,S,,R2
N ~
%o~0
Entry
Rx
Ph
R2
Me
n-Bu
i-Pr
Me
Et
Yield (%)a,b
mp (°C)C
A
B
C
D
E
99
91
99
95
91
99
84d
84
84.5 (88)7a
44-45 (44)7b
32 (36)7c
n-Bu
i-Pr
t-Bu
Bn
82-83 (84.5)7d
83-84 (84)7e
149.5 (151)7f
123- 124 ( 123)7g
oil7h
F
Bn
Bn
G
H
Ph
Ph
-CHzCI-IeCH2CH2-
reactions performed according to the sample procedure (vide infra); bisolated,
unoptimized yields of analytically pure material (satisfactory ZH NMR, IR, MS and
elemental analysis); Cliterature mp given in parentheses; dl0 mol% OsO4 employed
In a representative experiment, a 50 mL round-bottom flask equipped with a nitrogen inlet was charged
with 1.00 mL of thioanisole (0.95 g, 7.61 mmol), 3.09 g of NMO (22.8 mmol), 15 mL of acetone and 7 mL of
water. To the stirred solution was added 423 ~tL of 0.18 M aqueous OsO4 solution (0.076 mmol, 1 mol%),
producing a mild exotherm. The reaction was allowed to stir at room temperature overnight (12 h), and was
subsequently quenched by addition of 5 mL of saturated aqueous sodium bisulfite. After extraction of the
quenched reaction mixture with two 10 mL portions of CH2C12, the combined organic layers were washed
successively with 2 x 10 mL of 1 N aqueous sodium bisulfate and 10 mL of brine. The CH2C12 layer was dried
over Na2SO4, filtered, and concentrated in vacuo. Flash silica gel chromatography of the residue with 9:1
CH2CI2/EtOAc provided a quantitative yield (1.34 g) of the sulfone as a colorless solid. Recrystallization of
1.29 g of the sulfone from hexanes/EtOAc afforded 1.08 g (91%) of the sulfone as colorless needles, mp
84.5 *C (lit mp 88 *C).7a

5045
Application of this process to more complicated substrates has also proven successful. In the course of the
synthesis of the macrolide antibiotic cytovaricin, the need arose for the oxidation of sulfide olefin 1 to the
corresponding sulfone diol 3.8 Attempts to effect the desired transformation by a two-step protocol involving
sulfide oxidation followed by olefin osmylation were thwarted by competitive desilylation and epoxidation on
treatment of I with either m-CPBA or oxone (KHSO5)9 under a variety of conditions. 10 However, osmium
tetraoxide-mediated oxidation of I resulted in clean bis-oxidation to the desired sulfone diol 3 in a one-step
process (Scheme). Interestingly, sulfone olefin 2 could be isolated from the reaction mixture in 93% yield if the
reaction was terminated after 20 minutes. Although chemoselective oxidation of a sulfide in the presence of an
olefin was possible in this instance, attempted oxidation of thioanisole in the presence of one equivalent of allyl
benzoate resulted in competitive oxidation of both olefin and sulfide.
Scheme
- -
M e
-
M e
/
t-Bu
.r.O.Lu
cat. Os04
M
e
~
O
H
H
M
e
~
O
H
H
NMO
t
TESO"-- ? ' " , O ~ ~ } T ES
96%
PhS02
:
Z
OTES
~TES
HO~ ,Me t-Bu
HO,~
~
.~0~| •
-- 2 i,oS,;o
Me"
" ~
H
H
rEso,,. I,I .....
1
Me?
I
Me
-
3
H
,=,
H
PhSO 2 " ~ * ~ " ~ * ~ " ~ 5
OTES
The seeming dichotomy between our results and those of previous researchers3,4 has prompted us to
perform several control experiments. Treatment of either dibenzyl sulfide or thioanisole with excess N-
methylmorpholine-N-oxide in the absence of OsO4 gave no reaction after 14 h at 25 °C, thus conf'n'ming the
need for osmium catalysis. These results complement those of Biffen et al., who observed that N-oxides
oxidize sulfoxides to sulfones only under relatively drastic conditions (sulfuric acid, 195 °C). ]] In accord with
the observations of Henbest,3 treatment of dibenzyl sulfide with two equivalents of osmium tetraoxide (diethyl
ether, 25 °C, 14 h) gave no reaction. However, subsequent addition of either N-methylmorpholine or N-
methylmorpholine-N-oxide to the reaction mixture resulted in rapid oxidation to dibenzyl sulfone. We therefore
conclude that tertiary amine catalysis is critical to the success of our osmium tetraoxide-catalyzed sulfide
oxidation procedure. 12

5046
In summary, we have demonstrated that osmium tetraoxide is an effective and general catalyst for the
oxidation of sulfides to sulfones. The mild conditions and highly catalytic nature of the method suggest it as a
viable alternative to other existing oxidation procedures.
Acknowledgements. We thank Professor David A. Evans for his enthusiastic support of this research and
acknowledge the members of our analytical chemistry department for the full characterization of the product
sulfones listed in the Table.
References and Notes
1.
2.
(a) Block E. "Oxidation and Reduction of Sulfides" in The Chemistry ofFunctional Groups: Supplement
E, Part 1; Patai, S., Ed.; Wiley: NY; 1980; Ch. 13. (b) Truce, W. E., Klinger, T. C., Brand W. W.
"Sulfones and Sulfoximines" in Organic Chemistry of Sulfur; Oae, S., Ed.; Plenum Press: NY, 1977;
Ch. 10.
(a) See Trocha-Grimshaw, J.; Henbest, H. B. J. Chem. Soc.; Chem. Commun. 1968, 1035-1036 and
references cited therein. (b) Ref. lb. (c) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of
Organic Compounds; Academic Press; NY, 1981; pp. 392-395.
3.
Henbest, H. B; Khan S. A. J. Chem. Soc.; Chem. Commun. 1968, 1036.
4.
(a) Stork, G.; van Tamelen, E. E.; Friedman, L. J.; Burgstahler, A. W. J. Am. Chem. Soc. 1953, 75,
384-392. (b) Djerassi, C.; Engle, R. R. J. Am. Chem. Soc. 1953, 75, 3838-3840. (c) Vedejs, E.;
McClure, C. K. J. Am. Chem. Soc. 1986, 108, 1094-1096.
5.
(a) To the best of our knowledge, the only literature precedent for this OsO4-catalyzed process is found
in a footnote to a sulfoxide-directed olefin osmylation paper by Hauser: Hauser, F. M.; Ellenberger, S.
R.; Clardy, J. C.; Bass, L. S. J. Am. Chem. Soc. 1984, 106, 2458-2459. For related sulfoxide
oxidations, see: Solladie, G.; Frechou, C.; Demailly, G. Tetrahedron Lett. 1986, 27, 2867-2870. (c)
VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 1973-1976.
6.
7.
Schroder, M. Chem. Rev. 1980, 80, 187-213.
(a) Field, L.; Clark, R. D. Org. Synth. Coll. Vol. 4, Rabjohn, N., Ed.; p. 674. (b) Reich, H. J.; Chow,
F.; Peake, S. L. Synthesis, 1978, 299-301; see also Reference 7f. (c) Suter, C. M. The Organic
Chemistry of Sulfur; Wiley, NY, 1944; p. 668. (d) Raper, A. H.; Rothstein, E. J. Chem. Soc. 1963,
2463-2472. (e) see Reference 7c, p.661. (f) Hardy, F. E.; Speakman, P. R. H.; Robson, P. J. Chem.
Soc. (C) 1969, 2334-2336. (g) Graybill, B. M. J. Org. Chem. 1967, 32, 2931-2933. (h) Arnett, E.
M.; Douty, C. F. J. Am. Chem. Soc. 1964, 86, 409-412.
8.
(a) Evans, D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
7001-7031. (b) Evans, D. A.; Kaldor, S. W. J. Org. Chem. 1990, 55, 1698-1700. (c) Full analytical
data for compounds 1-3 are available in references 8a and 8b.
9.
Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287-1290.
10.
(a) Buffered reaction conditions led to no significant suppression of competing side reactions (m-CPBA/
powdered NaHCO3, oxone/Na2HPO4). (b) Oxone is known to efficiently epoxidize olefins: Bloch, R.;
Abecassis, J.; Hassan, D. J. Org. Chem. 1985, 50, 1544-1545.
11.
Biffin, M. E.; Miller, J.; Paul, D. B. Tetrahedron Lett. 1969, 1015-1018.
12.
(a) Interestingly, in a separate oxidation experiment pyridine was demonstrated to be a relatively poor
catalyst for the oxidation of thioanisole to the corresponding sulfone in the presence of excess OsO4 (2
equiv OSO4, 3 equiv pyridine, ether, 25 °C, 72 h, greater than 85% recovered sulfide). (b) Tertiary
amine catalysis is a well-documented phenomenon in the osmylation of alkenes (See Ref. 6, p. 121).
(Received in USA 15 May 1991)