Rhenium-catalyzed oxidation of thiols and disulfides with sulfoxides

Full text of DOI:10.1021/ja972013r

J. Am. Chem. Soc. 1997, 119, 9309-9310
9309
Table 1. Catalytic Re(Me2SO) Oxidation of Thiolsa and Dithiolsb
Rhenium-Catalyzed Oxidation of Thiols and
Disulfides with Sulfoxides
Jeffrey B. Arterburn,* Marc C. Perry, Sherry L. Nelson,
Benjamin R. Dible, and Mylena S. Holguin
Department of Chemistry and Biochemistry
New Mexico State UniVersity, Box 30001/3C
Las Cruces, New Mexico 88003
ReceiVed June 18, 1997
Oxidation reactions of organosulfur compounds hold continu-
ing fascination for chemists because of their fundamental roles
in biochemical and industrial processes and the variety of
mechanistic pathways involved.1 The oxidation of thiols to
disulfides 1 is a characteristic reaction, and further oxidation
to disulfide S-oxides (thiosulfinates 2) and 1,1-dioxides (thio-
sulfonates 3) is also possible. Weak S-S bonds in these com-
pounds impart high reactivity,2 and in natural products, these
moieties and related cyclic analogues 4 are associated with
a Reaction conditions: I:Me2SO:thiol ) 0.05:2:2, 25 °C. b 0.05:2:
1, 25 °C, slow addition of dithiol/CH2Cl2. c Product isolated by column
chromatography. d Product isolated by recrystallization from MeOH/
interesting biological activity and DNA-cleaving properties.3-5
Direct oxidation of disulfides has been accomplished using
peroxides,6 periodate,7 dimethyldioxirane,8 and perborate,6c
although careful control of oxidant stoichiometry and reaction
conditions are necessary to avoid overoxidation and S-S bond
cleavage.
We recently reported a mild method for oxidizing dialkyl
and monoaryl sulfides to sulfoxides using a rhenium catalyst
[Re(O)Cl3(PPh3)2, I]9 and phenyl sulfoxide (Ph2SO).10 Sulfox-
ides are intriguing as oxidants because of their greater stability
relative to peroxides and their suitability for safer, environmen-
tally benign oxidation processes.11 The oxidizing abilities of
sulfoxides have been harnessed by molybdenum-containing
oxotransferase enzymes such as dimethyl sulfoxide reductase,12
and it has been hypothesized that thiols could function as
external reductants.13 Thiols are powerful reductants in vivo
and are oxidized by sulfoxides to disulfides (eq 1) at high
temperatures14 or under acid/base catalysis.15 On the basis of
these observations, we investigated the possibility of rhenium-
catalyzed oxidation of thiols and disulfides with sulfoxides. We
f
Et2O. e Product isolated by bulb-to-bulb distillation. Ratio determined
1
by H NMR.
report here a remarkably effective method for oxidizing thiols
to disulfides using methyl sulfoxide (Me2SO) and the catalyst
precursor I. This system also exhibits synthetically valuable
oxygen atom transfer chemistry, producing cyclic thiosulfinate
4 directly from reactions of 1,3-propanedithiol. The catalytic
Re(Ph2SO) system was found to be even more effective for oxo
transfer reactions, reacting with a variety of alkyl, aryl, and
cyclic disulfides.
2R-SH + R′2SO f R-S-S-R + R′2S + H2O (1)
A series of thiols were oxidized to disulfides rapidly by the
catalytic Re(Me2SO) system (Table 1). Primary alcohol,
carboxylic acid, ester, and protonated amine functional groups
were unaffected during the oxidation of the thiols. Dithiols were
particularly interesting substrates for the catalytic Re(Me2SO)
oxidation, given the propensity of I toward formation of
dithiolate complexes16 and general interest in metal-thiolate
complexes.17 Slow addition of 1,2-, 1,3-, and 1,4-dithiols to
the catalytic Re(Me2SO) reaction mixture resulted in the
products shown in Table 1. Catalytic Re(Me2SO) oxidation of
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Tidwell, T. T. Synthesis 1990, 857-870.
(16) 1,2-Ethanedithiol reacts with I to give [ReO(SCH2CH2S)2]-
:
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S0002-7863(97)02013-1 CCC: $14.00 © 1997 American Chemical Society

9310 J. Am. Chem. Soc., Vol. 119, No. 39, 1997
Table 2. Catalytic Re(Ph2SO) Oxidation of Disulfidesa
Communications to the Editor
Scheme 1
neutral, coordinated sulfenic acid intermediate 6.23 Inter- or
intramolecular reaction between the second thiol and 6 would
produce the observed disulfide products and H2O, allowing the
catalytic cycle to resume upon coordination of another Me2SO
ligand. Only the five-membered cyclic disulfides reacted with
Re(Me2SO), consistent with their lower oxidation potentials
(0.70-0.75 V) relative to other disulfides.24 All of the disulfides
investigated were oxidized by the catalytic Re(Ph2SO) reagent
7. The enhanced oxo-transfer chemistry25 of Ph2SO compared
with Me2SO does not correlate with their relative S-O bond
strengths, since aryl sulfoxide S-O bonds are typically stronger
than alkyl ones (1-3 kcal mol-1).26 This unfavorable enthalpic
component can be overcome by the electron-accepting ability
of the aryl group in coordinated phenyl sulfoxide, lowering the
energy necessary for cleavage of the sulfur-oxygen bond,
resulting in an earlier transition state and a more reactive oxo-
transfer reagent.
The formation of acyclic thiosulfonate products from the
catalytic Re(Ph2SO) oxidation most likely results from dispro-
portionation of the initially formed, but unstable, acyclic
thiosulfinates.27 This proposal is supported by the high yields
of stable cyclic thiosulfinates which do not disproportionate
under these conditions.6h The observed mixed thiosulfonate
products would result from exchange during disproportionation.
An alternative reaction sequence involving two consecutive
direct oxygen atom-transfer steps would also lead to thiosul-
fonate products.28 The fact that cyclic thiosulfinates were not
further oxidized here suggests that direct oxo transfer from the
catalytic Re(Ph2SO) to acyclic thiosulfinates does not occur.
In conclusion, catalytic Re sulfoxide systems have been
shown to oxidize thiols and dithiols to disulfides under very
mild conditions. The selective oxidation of cyclic disulfides
to thiosulfinates should be well suited for the synthesis of natural
products containing these sensitive subunits. Further mecha-
nistic studies, the use of this synthetic methodology, and efforts
to develop other selective rhenium-catalyzed oxidations with
sulfoxides are currently in progress.
a Reaction conditions: I:Ph2SO:disulfide ) 0.05:2.2:1, 25 °C in
CH2Cl2. b Product isolated by bulb-to-bulb distillation. c Product isolated
1
by column chromatography. d Ratio determined by H NMR.
1,2-ethanedithiol produced oligomeric cyclic disulfides18 and
an insoluble polymeric disulfide that precipitated directly from
the reaction mixture. Intramolecular cyclization of 1,4-butane-
dithiol gave the stable, six-membered 1,2-dithiane ring. Unex-
pectedly, the catalytic Re(Me2SO) oxidation of 1,3-propanedithi-
ol produced 1,2-dithiolane S-oxide (4) in high yield. The inter-
mediacy of the unstable five-membered disulfide 1,2-dithiolane19
in this oxidation is suggested by the similar reactivity of (()-
R-lipoic acid, which was also rapidly oxidized to thiosulfinate
products (entry 5). Thiosulfinates were not detected in the
reaction mixtures in other thiol oxidations with Me2SO.
Changing the sulfoxide component of the catalytic system
from Me2SO to Ph2SO resulted in rapid oxidation of disulfides
to the products indicated in Table 2. Thiosulfonate products
were isolated from the catalytic Re(Ph2SO) oxidation of acyclic
alkyl and aryl disulfides.20 Methyl methanethiosulfinate was
1
observed as an intermediate by H NMR during the oxidation
of dimethyl disulfide (MeS)2 with Re(Ph2SO). The oxidation
of (MeS)2 with 1 equiv of Ph2SO gave a mixture of thiosulfonate
and starting (MeS)2. The oxidation of a 1:1 mixture of (MeS)2
and (EtS)2 yielded a mixture of thiosulfonates, indicating that
cleavage and recombination of the sulfur-sulfur bond occurred
under these conditions (entry 2). Cyclic five- and six-membered
disulfides were oxidized only to the corresponding thiosulfinate
with the Re(Ph2SO) system and did not react further with excess
Ph2SO.
The observed differences in reactivity for methyl and phenyl
substituents suggests a mechanism where nucleophilic attack
of the organosulfur compound occurs on a coordinated sulfoxide
ligand,21 rather than an oxo-metal complex as shown in Scheme
1.22 This metal-mediated oxo-transfer reactivity differs signifi-
cantly from the chemistry of sulfoxides activated by strong acids
or electrophiles where nucleophiles react at sulfur.11 The
reaction of thiols with the Re(Me2SO) system 5 would give a
Acknowledgment. This paper is dedicated to Prof. Dr. Dieter
Seebach on the occasion of his 60th birthday. Financial support was
provided by New Mexico State University. M.S.H. was supported by
an NIH/MBRS undergraduate assistantship.
Supporting Information Available: Synthetic procedures (7
pages). See any current masthead page for ordering and Internet access
instructions.
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JA972013R
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