Rhodium-catalyzed disulfide exchange reaction

Article abstract of DOI:10.1021/ja035221u

A system of RhH(PPh₃)₄, trifluoromethanesulfonic acid, and (p-tol)₃P catalyzes the disulfide exchange reaction. Treatment of two symmetrical dialkyl disulfides with the catalyst provides an equilibrium mixture of three dis

Full text of DOI:10.1021/ja035221u

Published on Web 05/10/2003
Rhodium-Catalyzed Disulfide Exchange Reaction
Mieko Arisawa and Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aoba,
Sendai 980-8578 Japan
Received March 19, 2003; E-mail: yama@mail.pharm.tohoku.ac.jp
Table 1. Rhodium-Catalyzed Exchange of Symmetrical Disulfidesa
A disulfide bond plays an important role in the construction of
the secondary and the tertiary structures of polypeptides and
proteins. Industrially important polymers such as rubber contain
polysulfide bonds.1 The cleavage and recombination of organodi-
sulfides and polysulfides, resulting in the disulfide exchange is,
b
run
1c
R
phosphine
p-tol3P
p-tol3P
p-tol3P
none
p-tol3P
(p-MeOC6H4)3P
p-tol3P
PPh3
yield/%
therefore, an important process for the production, modification,
and degradation of such biologically active substances and materials.
The cleavage of sulfur-sulfur bonds is known to occur either
homolytically or heterolytically: (a) short-lived sulfenyl radicals
are generated by homolytic scission via photolysis,2 oxidation,3 or
heating;4 and (b) ionic scission generates mercaptides (XS-) under
basic/nucleophilic conditions5 or sulfenium cation (XS+) under
acidic/electrophilic conditions.6,7 The sulfur radical, anion, or cation
then reacts with another disulfide, resulting in exchange reactions.
These reactions, however, often require harsh reaction conditions
such as high temperature and strong acids or bases, and are generally
slow in solution, particularly in the case of alkyl disulfides. We
considered that the disulfide exchange process, which proceeds
rapidly under neutral conditions and at ambient temperature, would
provide a new methodology, which has broad applications to
biosciences and material sciences. Described here is a novel
exchange reaction of disulfides catalyzed by a transition metal
complex:8 A rapid and mild disulfide exchange reaction takes place
in the presence of RhH(PPh3)4, a phosphine, and trifluoromethane-
sulfonic acid, which can be used for the peptide disulfide exchange.
In addition, the metal system catalyzes the disproportionation of
diselenide or ditelluride with disulfide.
When bis(2-benzoyloxyethyl) disulfide 1 (0.5 mmol) was treated
with dibutyl disulfide 2 (0.5 mmol) in the presence of RhH(PPh3)4
(1.5 mol %), tris(p-tolyl)phosphine (6 mol %), and trifluo-
romethanesulfonic acid (3 mol %) in refluxing acetone for 15 min,
2-benzoyloxyethyl butyl disulfide 3 (0.49 mmol, 49% yield based
on the BzO(CH2)2S group) was obtained with the recovery of 1
(0.21 mmol, 41%) and 2 (0.20 mmol, 40%), which is the statistical
product ratio (Table 1, entry 1). When another portion of 2 (0.5
mmol) was added to the refluxing mixture, the yield of 3 increased
to 71% after 10 min. Addition of 2 twice (1.0 and 1.0 mmol) at 10
min intervals further increased the yields to 86% and 92%,
respectively. This catalyst system was found to be active after the
equilibrium was attained. The exchange reaction of 1 and 2 in a
1:4 initial ratio gave 3 in 86% yield with recovery of 1 (12%) and
2 (76%) (entry 2). The rhodium complex, trifluoromethanesulfonic
acid, and phosphine are essential; no reaction occurs in the absence
of the rhodium complex (entry 3), and there was low conversion
in the absence of the phosphine or acid (entries 4 and 5). The effect
of added phosphine was examined by reacting for 3 min, and
triarylphosphines, particularly those with electron-donating sub-
stituents were found to be effective (entries 6, 7, 8, and 9). Bidentate
phosphines (entries 10 and 11) and tributylphosphine (entry 12)
were less effective. This reaction was effectively promoted by
trifluoromethanesulfonic acid, and the yield of 3 decreased with
BzO(CH2)2S
49
86
N.D.e
3
2
3c,d
4c
5c,f
6c,g
7c,g
8c,g
9c,g
10c,g
11c,g
12c,g
13j
14
8
19
24
14
6
N.D.
10
5
77
81
84
19
90
85
(p-ClC6H4)3P
dppeh
dppfi
Bu3P
n-C8H17
PhCH2
p-tol3P
p-tol3P
p-tol3P
p-tol3P
dppe
15
t-BuMe2SiO(CH2)6
16k
17l
18m
Ph
Ph
dppe
a See Supporting Information for reaction conditions. b Yield based on
the RS group. c The reaction was conducted using 1 (0.5 mmol) and 2 (0.5
mmol) in the presence of RhH(PPh3)4 (1.5 mol %), p-tol3P (6 mol %), and
trifluoromethanesulfonic acid (3 mol %). d In the absence of Rh complex.
e N.D.: not detected by 1H NMR. f In the absence of CF3SO3H. g The
reaction time: 3 min. h 1,2-Bis(diphenylphosphino)ethane. i 1,1′-Bis(diphen-
ylphosphino)ferrocene. j The reaction was conducted using dioctyl disulfide
(2.5 mmol) and 2 (12.5 mmol) in refluxing acetone for 30 min, and the
product was isolated by distillation. k The reaction was conducted in acetone
at room temperature for 5 min in the presence of RhH(PPh3)4 (0.75 mol
%) and p-tol3P (3 mol %). l The reaction was conducted in acetone at room
temperature for 5 min in the presence of RhH(PPh3)4 (0.75 mol %) and
dppe (1.5 mol %). m The reaction was conducted using diphenyl disulfide
5 (1.0 mmol) and bis(sec-butyl) disulfide 4 (0.25 mmol) in refluxing acetone
for 10 min in the presence of RhH(PPh3)4 (1 mol %) and dppe (2 mol %).
methanesulfonic acid or p-toluenesulfonic acid. The rhodium-
catalyzed exchange reactions of 2 (4 equiv) and several symmetrical
dialkyl disulfides were rapid, completing within 15 min in refluxing
acetone (entries 13, 14, and 15). Bis(sec-butyl) disulfide 4 and 2,
however, did not undergo the exchange reaction under these
conditions. The reaction of a diaryl disulfide and a dialkyl disulfide
took place more rapidly than that of dialkyl disulfides, when 1,2-
bis(diphenylphosphino)ethane (dppe) was used instead of tris(p-
tolyl)phosphine (entries 16, 17, and 18). The ligand effect is an
interesting aspect of the transition metal-catalyzed exchange.
Since, the present disproportionation is considerably affected by
the substituent on the disulfide, selective exchange of symmetrical
disulfides can be conducted. Treatment of equimolar amounts (0.5
mmol) of 4, diphenyl disulfide 5, and di(p-tolyl) disulfide 6 gave
phenyl p-tolyl disulfide 7 (0.49 mmol), 5 (0.25 mmol), and 6 (0.25
mmol) at room temperature for 1 min in the presence of 1 mol %
of the rhodium complex and 2 mol % of dppe, with the unchanged
9
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J. AM. CHEM. SOC. 2003, 125, 6624-6625
10.1021/ja035221u CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
reaction takes place rapidly under mild conditions and is applicable
to peptide disulfide exchange. In addition, the reaction can be
controlled by changing the ligand or acid, and the application of
this methodology to polysulfides including elemental sulfur is now
under investigation. This is a novel combination of transition metal
chemistry and organosulfur chemistry.
Acknowledgment. This work was supported by JSPS (Nos.
14207094 and 13771323). M.A. expresses her thanks for financial
supports from New Energy and Industrial Technology Development
Organization (NEDO) of Japan (No. 02A44003d), the Hayashi
Memorial Foundation for Female Natural Scientists, the Fujisawa
foundation, and the Sankio Chemical Award in Synthetic Organic
Chemistry, Japan.
Scheme 2
Supporting Information Available: Detailed experimental pro-
cedures, characterization data (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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Scheme 3
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4 (0.48 mmol). Random disproportionation takes place giving
statistical amounts of 7 (0.32 mmol), sec-butyl phenyl disulfide 8
(0.34 mmol), and sec-butyl p-tolyl disulfide 9 (0.34 mmol) at
acetone reflux for 5 min with the recovery of 4 (0.14 mmol), 5
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A cystine derivative 10 exchanged with 2 to give the unsym-
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The exchange reactions of dialkyl disulfides and dialkyl di-
selenides are also catalyzed by the same complex (Scheme 2).9
When dibutyl diselenide (0.25 mmol) was treated with 1 (1.5 mmol)
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Exchange reaction of disulfides and ditellurides gives tellurino-
sulfides (Scheme 3). No reaction takes place without the rhodium
complex under the conditions.
We describe here a novel Rh-catalyzed exchange reaction of
disulfides. Compared with the conventional exchange reaction, this
JA035221U
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J. AM. CHEM. SOC. VOL. 125, NO. 22, 2003 6625