Mild and highly chemoselective oxidation of thioethers mediated by Sc(OTf)3

Article abstract of DOI:10.1021/ol026947i

(Matrix presented) Catalytic Sc(OTf)₃ greatly increases the efficiency of hydrogen peroxide mediated monooxidation of alkyl-aryl sulfides and methyl cysteine containing peptides. The method is high yielding, compatible with many widely used protecting groups, suitable for solid-phase applications and proceeds with minimum over-oxidation.

Full text of DOI:10.1021/ol026947i

ORGANIC
LETTERS
2003
Vol. 5, No. 3
235-237
Mild and Highly Chemoselective
Oxidation of Thioethers Mediated by
Sc(OTf)3
,†
Mizio Matteucci,† Gurdip Bhalay,‡ and Mark Bradley*
Combinatorial Centre of Excellence, Department of Chemistry, UniVersity of
Southampton, Southampton S017 1BJ, United Kingdom, and NoVartis Pharma,
Wimblehurst Road, Horsham RH12 5AB, United Kingdom
mb14@soton.ac.uk
Received September 23, 2002
ABSTRACT
Catalytic Sc(OTf)3 greatly increases the efficiency of hydrogen peroxide mediated monooxidation of alkyl−aryl sulfides and methyl cysteine
containing peptides. The method is high yielding, compatible with many widely used protecting groups, suitable for solid-phase applications
and proceeds with minimum over-oxidation.
Sulfoxides are important intermediates in the synthesis of
many natural products.1,2 Their synthesis has been achieved
by means of a wide range of oxidizing systems starting from
the corresponding sulfides.3,4 Aqueous hydrogen peroxide
is a particularly attractive oxidant since it is cheap, envi-
ronmentally friendly, easy to handle and produces only water
as a byproduct, which reduces purification requirements.
Catalysts are often used to enhance the efficiency of the
oxidation and metal salts (including chlorides, oxides,
peroxides, acetates, and acetyl acetonates of Ti, V, Mo, W,5
Re,6 and Mn7) play a very important role as catalytic
activators of hydrogen peroxide.3 The resulting metal-peroxo
derivatives are such powerful catalysts that over-oxidized
byproducts are often observed especially with sulfides
containing electron-rich double bonds.8
Lanthanides have never been explored in the oxidation of
thioethers, yet these elements are receiving increasing
attention in the literature,9 with applications in the fields of
organic synthesis,10 coordination, and materials chemistry.
Scandium triflate is a readily available reagent and behaves
as an excellent Lewis acid catalyst for a wide range of
organic transformations in both aqueous and organic media.11
In this letter, the use of this catalyst for the highly
chemoselective, hydrogen peroxide mediated, oxidation of
thioethers to the corresponding sulfoxides is reported.
A range of thioethers were subjected to the developed
reaction conditions to give sulfoxides with very high
chemoselectivity and in excellent yields (even when using
large excesses of oxidant). The method proved to be
† University of Southampton.
‡ Novartis Pharma.
(1) For recent reviews, see: (a) Prilezhaeva, E. N. Russ. Chem. ReV.
2000, 69, 367-408. (b) Prilezhaeva, E. N. Russ. Chem. ReV. 2001, 70,
897-920.
(2) (a) Rich, D. H.; Tam, J. P. J. Org. Chem. 1977, 42, 3815-3820. (b)
Burrage, S.; Raynham, T.; Williams, G.; Essex, J. W.; Allen, C.; Cardno,
M.; Swali, V.; Bradley, M. Chem. Eur. J. 2000, 6, 1455-1466. (c) Padwa,
A.; Danca, M. D. Org. Lett. 2002, 4, 715-717.
(7) Brinksma, J.; La Crois, R.; Feringa, B. L.; Donnoli, M. I.; Rosini, C.
Tetrahedron Lett. 2001, 42, 4049-4052.
(3) For reviews, see: (a) Madesclaire, M. Tetrahedron 1986, 42, 5459-
5495. (b) Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2000, 835-871.
(4) Minidis, A. B. E.; Ba¨ckvall, J.-E. Chem. Eur. J. 2001, 7, 297-302.
(5) Sato, K.; Hyodo, M.; Aoki, M.; Zheng, X.-Q.; Noyori, R. Tetrahedron
2001, 57, 2469-2476 and references therein.
(8) Choi, S.; Yang, J.-D.; Ji, M.; Choi, H.; Kee, M.; Ahn, K.-H.; Byeon,
S.-H.; Baik, W.; Koo, S. J. Org. Chem. 2001, 66, 8192-8198.
(9) For a review, see: Kagan, B. Chem. ReV. 2002, 102, 1805-2476.
(10) Kobayashi, S. Lanthanides: Chemistry and Use in Organic
Synthesis; Springer: Berlin, Germany, 1999.
(6) Yamazaki, S. Bull. Chem. Soc. Jpn. 1996, 69, 2955-2959.
(11) Kobayashi, S. Eur. J. Org. Chem. 1999, 1, 15-27.
10.1021/ol026947i CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/11/2003

The study of the methyl cysteine derivatives clearly
indicates the high efficiency and total chemoselectivity of
the method: no temperature control was required and no
sulfone was observed even when large excesses of hydrogen
peroxide were used. The conditions proved to be compatible
with widely used protecting groups in peptide/organic
synthesis (Fmoc, Boc, tBu). As observed for alkyl-aryl
sulfides, the allylic double bond (Table 2, entries 5 and 6)
survived the oxidizing conditions. Peptide sulfoxides 5a-d
were isolated in high yields (91-96%). Of outstanding
interest was the observed chemoselectivity of two differently
protected cysteine residues (SMe and STrt, Table 2, entries
3 and 4).
Figure 1. Sulfides tested for Sc(OTf)3-catalyzed oxidation
extremely mild, worked in neutral conditions, and was
compatible with many widely used protecting groups (allyl,
trityl, Fmoc, Boc, tBu esters and tBu ethers). Hydrogen
peroxide was used as a 60% solution in water.
The possibility of using excess oxidant and a binary
solvent system rich in CH2Cl2 renders the method highly
suitable for solid-phase applications.
To investigate further the scope and limitations of the
method, polymer-supported Fmoc-S-methyl-L-cysteine was
oxidized under the newly developed conditions (Scheme 1)
and showed clean and efficient oxidation.
Model thioethers 1a-d (Figure 1) were first subjected to
the oxidation conditions and the results are reported in Table
1.
Scheme 1. Oxidation of Solid-Supported
Fmoc-(L)-Cys(Me)-OH (HMPA ) hydroxymethylphenoxyacetic
acid)a
a
Table 1. Oxidation of Sulfides Catalyzed by Sc(OTf)3
yield (%)c,12
b
H2O2
time
(h)
entry
sulfide
(equiv)
sulfoxide
sulfone
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1d
1.2
5
1.2
5
1.2
5
1.2
5
5
2
95
98
94
98
98
98
97
94
3
2
2
2
2
2
2
4
a Loading of 0.89 mmol g-1 b H2O2 was used as a 60% solution
.
in water. c TFA ) trifluoroacetic acid; TIS ) triisopropylsilane.
5.5
3
2.3
1.3
6
d Based on RP-HPLC analysis, ELS detector.
The nature of the catalytic species is not yet clear and no
reports have been found in the literature concerning the
elucidation of the nature of complexes between scandium
derivatives and hydrogen peroxide, although lanthanide
metals, in combination with hydrogen peroxide, are known
to accelerate greatly the hydrolysis of phosphates (including
RNA) in aqueous systems.15
3
a Reactions run at room temperature and c ) 0.1 M, 0.1 mmol scale.
b H2O2 was used as a 60% solution in water. c Determined by 1H NMR.
Sulfoxide 2a was obtained with exceptionally low amounts
of sulfone and free of epoxy byproducts even in the presence
of a large excess of oxidant (Table 1, entries 1 and 2).13
Our longstanding interest in the synthesis of dehydro-
peptides2b,14 via oxidation/elimination of peptide-sulfoxides
led to an investigation of the scope of the oxidation
conditions with protected cysteine derivatives 4a-d (Table
2, entries 1-8), synthesized in solution according to standard
amino acid/peptide chemistry protocols (see Supporting
Information).
45Sc-NMR spectroscopy has been used in the past to study
the coordination chemistry of scandium16 and it was thought
(13) Recently, a new synthetic mixed metal oxide, LiNbMoO6, was used
in combination with H2O2 to overcome the low chemoselectivity offered
by common oxidizing systems in the oxidation of sulfides containing
electron-rich double bonds.8 Under carefully controlled conditions (sto-
ichiometric hydrogen peroxide, 0 °C) sulfones were observed in the reaction
mixture (3-14%) together with the expected sulfoxides. Compound 2a was
obtained together with 14% of sulfone 3a.
(14) Burrage, S. A.; Raynham, T.; Bradley, M. Tetrahedron Lett. 1998,
39, 2831-2834.
(15) Mejia-Radillo, Y.; Katsimirsky, A. K. Inorg. Chim. Acta 2002, 328,
241-246 and references therein.
(12) In the absence of catalyst, conversions to sulfoxides 2a, 2b, and 2d
were in the range 53-76% after 24 h in the presence of 5 equiv of 60%
hydrogen peroxide. Sulfoxide 2c was formed in a yield >98% after 20 h
(see Supporting Information for details of uncatalyzed reactions).
(16) (a) Melson, G. A.; Olszanski, D. J.; Rahimi, A. K. Spectrochim.
Acta 1977, 33A, 301-309. (b) Rehder, D.; Speh, M. Inorg. Chim. Acta
1987, 135, 73-79.
236
Org. Lett., Vol. 5, No. 3, 2003

a
Table 2. Oxidation of Cysteine Derivatives in the Presence of 20 mol % of Sc(OTf)3
b
entry
amino acid/peptide
H2O2 (equiv)
time (min)
amino acid/peptide sulfoxide
yield (%)c-e
1
2
3
4
5
6
7
8
Fmoc-Cys(Me)-OMe (4a )
1.2
5
1.2
5
1.2
5
1.2
5
70
50
15
10
15
5
Fmoc-Cys((O)Me)-OMe (5a )
99
100
100
97
>99
98
Boc-Phe-Cys(Me)-Cys(Trt)-OMe (4b)
Boc-Phe-Cys(Me)-Ala-OAll (4c)
Boc-Phe-Cys((O)Me)-Cys(Trt)-OMe (5b)
Boc-Phe-Cys((O)Me)-Ala-OAll (5c)
Boc-Phe-Cys(Me)-Ser(tBu)-OtBu (4d )
15
10
Boc-Phe-Cys((O)Me)-Ser(tBu)-OtBu (5d )
98
96
a Run at room temperature at a concentration c ) 0.1 M, 0.1 mmol scale. b H2O2 was used as a 60% solution in water. c Determined by RP-HPLC, ELS
detector. d No over-oxidation byproducts were observed. e See Supporting Information for results of uncatalyzed sulfoxidations.
that similar measurements could give insights into the nature
of the actual catalytic species in the oxidation of thioethers.
Sc(OTf)3 gave rise to a strong signal at δ 35.8 ppm with a
w1/2 ) 645 Hz (Scheme 2, (a)).
Upon addition of 25 equiv of hydrogen peroxide (as in
the standard protocol used for the oxidation of thioethers),
the peak assigned to scandium triflate disappeared and was
replaced by a new, broad (w1/2 ) 3015 Hz) signal centered
at δ 24.8 ppm (Scheme 2, (b)). When only water was added
to the scandium triflate solution, a rather sharp signal (w1/2
) 272 Hz) was detected (Scheme 2, (c)) at higher field.
These data may suggest that a peroxo-derivative may be
formed and could be the species responsible for the rate
acceleration and chemoselectivities reported.
Scheme 2. 45Sc NMR Spectra (97 MHz)a
In summary, a new mild, neutral, and efficient method
for the oxidation of sulfides to sulfoxides in high yields and
chemoselectivities has been developed. Purification is often
not needed, especially when using a small excess of oxidant.
The method is suitable for solid-phase applications and is
compatible with many widely used protecting groups in
organic synthesis.
Acknowledgment. We thank Novartis and EPSRC for
funding and gratefully acknowledge Joan Street for setting
up and running the 45Sc NMR experiments. The CCE is
supported through the JIF initiative (EPSRC).
a Spectrum a: Sc(OTf)3 (0.02 mM solution in CH2Cl2/10%EtOH).
Spectrum b: Sc(OTf)3 (0.02 mM solution in CH2Cl2/10%EtOH in
the presence of 25 equiv of a 60% H2O2 solution in water).
Spectrum c: Sc(OTf)3 (0.02 mM solution in CH2Cl2/10%EtOH in
the presence of 26.6 equiv of water).
Supporting Information Available: Description of ex-
perimental procedures and characterization of all compounds
prepared in the study. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL026947I
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