Transition-metal-free persulfuration to construct unsymmetrical disulfides and mechanistic study of the sulfur redox process

Article abstract of DOI:10.1039/c4cc09633a

A sulfur redox process has been developed between sulfinate and thiosulfate, which efficiently affords diverse unsymmetrical disulfides and provides a new method to modify pharmaceuticals and natural products without requiring an extra oxidant or reductant. Gram-scale investigation further demonstrates the practicality and application potential of this process. Isolated key intermediates and a series of control experiments afford an unusual process, which reveals the mechanism of comproportionation and the transition-metal-free sulfur redox process.

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Transition-metal-free Persulfuration to Construct
Unsymmetrical Disulfides and Mechanistic Study of
Sulfur Redox Process †
Cite this: DOI: 10.1039/x0xx00000x
a
a
*a,b
Received 00th January 2012,
Accepted 00th January 2012
Xiao Xiao, Minghao Feng, Xuefeng Jiang
DOI: 10.1039/x0xx00000x
www.rsc.org/
A sulfur redox process has been developed between
sulfinate and thiosulfate, which efficiently affords diverse
unsymmetrical disulfides and provides a new method to
modify pharmaceuticals and natural products without
requiring extra oxidant or reductant. Gram-scale
investigation further demonstrates the practicality and
application potential of this process. Isolated key
intermediates and a series of control experiments afford an
unusual process, which reveals the mechanism of
comproportionation and the transition-metal-free sulfur
redox process.
Disulfide bond, an important moiety, frequently appears in
different types of significant organic molecules (Scheme 1). As a
natural linkage, it partially determines the secondary and tertiary
1
structure of polypeptide. As a crucial motif, the SꢀS bond clearly
plays an essential role in diverse activities of disulfideꢀcontaining
2
a
natural products, such as antiꢀfungus of polycarpamine and antiꢀ
2bꢀe
poliovirus/P. falciparum of epidithiodiketopiperazines (ETPs).
In the field of drug discovery, disulfide has been shown to be a
Scheme 1. Representative significant disulfide structures.
3
a
3b
3c
powerful antiꢀbacterial, antiꢀalcoholic, and antiꢀthrombotic
methyl unsymmetrical disulfides, which is known as a biologically
3d
5g, 5lꢀm, 8
reagent due to its potential to form sulfur radicals in vivo
.
important moiety, is still very limited.
Based on our own
Moreover, due to their characteristic function and smell, those
research, thiosulfate shows itself to be an efficient and unique
inorganic sulfurating reagent for sulfur atom transformation.
4
9
compounds serve as food additives in some cases.
Notwithstanding its great importance in numerous fields, effective Inspired by this finding, one of the sulfur atoms exhibiting lowꢀ
methods for synthesizing unsymmetrical disulfide are quite rare. The valence (ꢀ2) in thiosulfate was supposed to be oxidized by an
10
appropriate highꢀvalent sulfide (+6 or +4)
to achieve
classical methods (Scheme 2, eq. 1) affording unsymmetrical
5
unsymmetrical disulfide (+1) via comproportionation, which may
avoid poor selectivity of unsymmetrical persulfuration (Scheme 2,
eq. 4). Certainly, other valent byproduct generation should be
purposely avoided through control conditions.
disulfide involved an S 2 process, in which prefunctionalized thiols
N
with leaving group was utilized as one of the sulfur sources. An
alternative approach subjected two different kinds of thiols under
oxidative conditions, in which the homoꢀcoupling byproducts were
difficult to avoid (Scheme 2, eq. 2). A particularly elegant strategy valent sulfur precursors reacting with alkyl thiosulfate formed in
We commenced with this hypothesis by testing different highꢀ
6
situ. To our satisfaction, the desired product was isolated in 6% yield
when tosylchloride was employed as a reacting partner (Table 1,
Entry 1). When 4ꢀmethylbenzenesulfonhydrazide, another S(VI)
reagent, was applied, the reaction system was complicated (Table 1,
Entry 2). The yield of the desired unsymmetrical disulfide was raised
involved two different symmetrical disulfides undergoing an
interesting exchanging reaction with the help of rhodium (I) to form
unsymmetrical disulfide (Scheme 2, eq. 3). The substrates of all of
these methods were prepared from thiols, which were odorous,
expensive, and difficult to access. In addition, the method to prepare
7
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DOI: 10.1039/C C0963
Jou4Crnal Na3Ame
Based on the optimized conditions, the substrate scope was
diffusely investigated. First, various halides were tested. Unactivated
halides, substituted with cyano (Table 2, 2a) and ester (Table 2, 2b),
alkyl (Table 2, 2c) groups could afford the corresponding disulfides
in moderate to excellent yields. When activated halides were
investigated in reaction, benzylic halides bearing both electronꢀ
donating and ꢀwithdrawing groups (Table 2, 2eꢀ2f), could proceed
smoothly. Halogen atoms were tolerated in the reaction (Table 2, 2gꢀ
2
h, 2jꢀ2k). It is worth noting that even 2, 6ꢀdisubstituted benzyl
halides were efficient partners (Table 2, 2jꢀ2k), as well. Moreover,
unsymmetrical arylꢀaryl disulfides were obtained by utilizing
preformed aryl thiosulfate (Table 2, 2lꢀ2m). To further determine
Scheme 2. Strategies for disulfide construction.
14
to 72% when employing sodium 4ꢀmethylbenzenesulfinate as the practical utility, gramꢀscale operation was performed by applying 10
o
coupling partner (Table 1, Entry 3). The lower temperature (70 C) mmol of sodium 4ꢀmethylbenzenesulfinate, which afforded the
gave an unsatisfactory yield (37%) (Table 1, Entry 4). In contrast, desired product in good yield (77%, 1.9 grams) (Table 2, 2d). The
1
5
the reaction was improved to afford the 2a in 88% yield by structure of 2i was confirmed by Xꢀray analysis.
o
increasing the temperature (110 C, reflux, Table 1, Entry 5).
However, shortening or prolonging the reaction time did not enhance
the yield (Table 1, Entries 6ꢀ8). Further study revealed that
[a,b]
Table 2. Scope of persulfuration.
1
1
quenching the reaction with triꢀphenylphosphine produced a better
result (94%, Table 1, Entry 9). When the prepared alkyl thiosulfate
1) Na S O .5H O
2
2
3
2
R1
1
S
2
R Cl
R2
2
S
-3
2) R SO2Na
12
(Bunte salts) was used instead of sodium thiosulfate/alkyl halide,
2i
the reaction became slightly sluggish in 69% yield (Table 1, Entry
Halides:
1
3
R3
S
S
S
S
1
0). Neither sodium sulfide nor sulfur(0) could replace sodium
S
S
thiosulfate in the reaction, which demonstrated the uniqueness of
sodium thiosulfate again in this transformation (Table 1, Entries 11ꢀ
MeO
9
2d 78% (0.2 mmol)
70% (1.0 mmol)
77% (10 mmol)
2a R3 = CH CN 94%
2
c 53%[d]
2
2
b R3 = COOEt 87%[c]
1
2). In addition, using benzyl mercaptan or 4ꢀmethoxybenzenethiol
R3
as sulfur partners could not afford unsymmetrical disulfide (Table 1,
Entries 13ꢀ14).
S
S
R3
S
S
S
S
R3
2
2
2
2
2
e R3 = 3-OMe 91%
R3 = 3-CF3 78%
R3
R4
[
a]
Table 1. Optimization of persulfuration.
f
2
j
R3 = Cl 74%
k R3 = F 86%
2l R4 = Me R3 = 3-OMe 51%[d]
2m R4 = OMe R3 = 4-CF3 60%[d]
g R3 = 4-Br 75%
h R3 = 4-F
71%
R3 = 4-CN 54%[e]
2
i
Sodium sulfinates:
S
S
S
S
Ar
Cl
S
Ar
S
CN
S
o
[b]
Cl
Entry Highꢀvalent Lowꢀvalent
Temp./ C Time/h Yield/%
3c Ar = C H
86%
6
4
t
S Source
S Source
3a Ar = 4-MeOC6H4 64%
b Ar = 4-CF3C6H4 62%
3d Ar = 4- BuC6H4 66%
g 72%[e]
3
3
3e Ar = 4-CF3C6H4 61%
3f Ar = naphthyl 78%
S
.
R3
1
2
3
4
5
6
7
8
9
1
1
1
1
TsCl
Na S O 5H O 90
11
11
11
11
11
5
6
2
2
3
2
S
R2
S
Me
S
S
.
R3
Me
S
TsNHNH2 Na S O 5H O 90
complicated
2
2
3
2
3k R3 = H
70%
75%
R3
.
TolSO Na Na S O 5H O 90
72
37
88
66
83
60
3h R2 = Et
R2 = nBu
3j R2 = cyclopropl 88%
62%
77%
2
2
2
3
2
R3 = 4-F
l
3o R3 = Cl 53%
3p R3 = F 51%
3
3
3
3i
.
m R3 = 4-Br 92%
R3 = 3-CF3 75%
TolSO Na Na S O 5H O 70
2
2
2
3
2
n
.
TolSO Na Na S O 5H O reflux
[d]
2
2
2
3
2
Late stage persulfuration:
SR1
O
O
.
H C
H C
R3
3
3
TolSO Na Na S O 5H O reflux
S
2
2
2
3
2
.
O
H
H
TolSO Na Na S O 5H O reflux
8
2
2
2
3
2
H
H
H
H
.
R3
S
nBuS
TolSO Na Na S O 5H O reflux
15
11
11
11
11
11
11
H
S
3
S
2
2
2
3
2
3
q R1 = Bn 62%
3s R = H 62%[f]
3u 55%[f]
.
[c]
TolSO Na Na S O 5H O reflux
94
3r R1 = nBu 64%
3t R3 = Cl 50%[f]
2
2
2
3
2
1
[d]
a
1
.
0
1
2
3
4
TolSO Na R S O Na
reflux
90
69
Standard conditions: R Cl (1.0 mmol) and Na S O 5H O (1.0
2
2
3
2
2
3
2
.
mmol) were added to EtOH/H O (0.25 mL/0.5 mL) at reflux for 2.0
h under N atmosphere, then the solvent was removed. After adding
TolSO Na (0.2 mmol, 1.0 equiv.) and 1,4ꢀdioxane (1.0 mL), the
TolSO Na Na S 9H O
NR
NR
2
2
2
2
2
TolSO Na S8
90
2
2
[
[
e]
e]
TolSO Na BnSH
90
NR
NR
b
c
1
2
system was refluxed for 11 h. Isolated yields. R Br was used
1
d
1
1
a
TolSO Na 4ꢀMeOPhSH
90
instead of R Cl.
R S O Na was used instead of R Cl and
O. 90 C at step 2. Sulfinate of estrone derivatives
2
1 2 3
.
e
o
f
.
3
Na
2
S
2
O
3
5H
2
Reaction conditions: 1 (1.0 mmol) and Na S O 5H O (1.0 mmol)
2
2
2
was used.
were added to EtOH/H O (0.25 mL/0.5 mL) at reflux for 2.0 h under
2
N2 atmosphere, then the solvent was removed. After adding
Various types of sulfinates were then studied extensively. As
shown in Table 2, aryl sulfinates substituted with electronꢀ
withdrawing and ꢀdonating groups (Table 2, 3aꢀ3e) gave the desired
TolSO Na (0.2 mmol, 1.0 equiv.) and 1,4ꢀdioxane (1.0 mL), the
2
b
c
system was refluxed for 11 h. Isolated yields. After step 2, PPh3
d
(
0.12 mmol, 0.6 equiv.) was added. NCCH CH CH S O Na was
2
2
2
2
3
.
e
used instead of halide 1 and Na S O 5H O. BnSH or 4ꢀMeOPhSH products in good yields. Sulfinates on heterocycle and condensed
2
2
3
2
.
was used instead of halide 1 and Na S O 5H O.
ring performed successfully (Table 2, 3f-3g). The method could be
applied with alkyl sulfinates, as well (Table 2, 3hꢀ3p). Considering
the great attention to biologically active natural products substituted
2
2
3
2
2
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DOI: 10.1039/C4CC09633A
8
with methyl disulfides and the limitation of preparing methyl
disulfides, sodium methanesulfinate was deliberately employed.
Substituted benzylic halides worked smoothly with sodium
methanesulfinate (Table 2, 3kꢀ3p), in which a batch of methyl
substituted disulfides were synthesized. Furthermore, this reaction
could be smoothly applied in the late stage persulfuration of
pharmaceuticals and natural products (Table 2, 3qꢀ3u), which
offered a convenient method for drug modification. Importantly,
camphorsulfonic acid and estrone derivatives exhibited
persulfuration in this transformation without erosion of stereogenic
information.
On the basis of these results, the mechanism of this transversion
was explored. From the ratio of two different sulfur source points,
the relationship between the amounts of thiosulfate and yields of
unsymmetrical disulfide were investigated (see ESI†). According to
the results, disulfide formation was less than half when less than two
equivalents of sodium thiosulfate/halide were added. The yield
increased to 68% after three equivalents of thiosulfate/halide were
loaded. Furthermore, the highest yield (75%) was achieved when
five equivalents of thiosulfate/halide were added. However, the yield
increased slightly when three equivalents of thiosulfate/halide were
utilized, which indicated that three equivalents of thiosulfate/halide
constituted the necessary amount for comproportionative completion.
Two side products 4 (10%) and 5 (16%) were isolated, whose
Scheme 4. Proposed S 2 attacking process and control
experiments.
Therefore, another mechanism was suggested in Scheme 5.
N
Firstly, tosyl
pꢀtolyl sulfone 8 was generated through the
dimerization of 4ꢀmethylbenzenesulfinate under acidic conꢀ
1
8
ditions (due to the sulfur trioxide generating from substitution
of the alkyl thiosulfate). Then, compound could be produced
by through reduction of thiosulfate. Intermediate was then
5
8
5
attacked by alkyl thiosulfate to afford the unsymmetrical
disulfide and a molecule of 4ꢀmethylbenzenesulfinate, which
1
9
1
6, 17
could be explained by equation 7 (Scheme 5, path I). . To
further prove this pathway, 4ꢀmethylbenzeneꢀsulfinic acid was
conducted as a replacement under the standard conditions. As a
result, the desired product 2g was isolated in 80% yield
structures were confirmed by Xꢀray,
one equivalent of thiosulfate/halide was applied in the reaction
Scheme 3, eq. 5). Neither compound 4 nor 5 was detected in the
as well as 6 (34%), when
(
reaction system when more than two equivalents of
thiosulfate/halide were added. This information supports that
thiosulfate serves both as the sulfur source and reductant of the
reaction.
(
Scheme 5, eq. 9). Meanwhile, the sulfinate could be attacked
by alkyl thiosulfate to afford the Sꢀ4ꢀbromobenzyl 4ꢀ
methylbenzenesulfonothioate , which might be attacked again
to regenerate sulfinate (Scheme 5, path II). This pathway
explained the formation of intermediate and unsymmetrical
disulfide 2g when product was used as the substrate (Scheme
, eq. 6 and 8). In summary, thiosulfate played the roles of
4
5
4
4
sulfur source, reductant, and acidic condition supplier in the
whole process. Symmetric disulfide was speculated to be
produced in the process of reduction as an oxidative byproduct.
Scheme 3. Xꢀray of intermediate 4 and 5.
The first proposed S 2 attacking mechanism was suggested in
N
Scheme 4. Sꢀ4ꢀbromobenzyl 4ꢀmethylbenzenesulfonꢀothioate 4 was
formed by the attack from sulfinate to alkyl thiosulfate, which was
subsequently reduced by excess thiosulfate to afford the disulfide.
To validate this explanation, intermediate 4 was treated with four
equivalents of thiosulfate, which provided unsymmetrical disulfide
2
2
g in 63% yield (Scheme 4, eq. 6). On the other hand, the compound
was obtained in 80% yield when Sꢀpꢀtolyl 4ꢀ
g
methylbenzenesulfonothioate 5 (0.1 mmol of 5 was used) was tested
under standard conditions. However, the symmetrical disulfide 7,
which was supposed to be the reductive product, was not detected in
the reaction system (Scheme 4, eq. 7). This indicates that the SN2
process between sulfinate and thiosulfate occurred much faster than
the reductive process. Moreover, the reductive process might be
unreasonable during the transformation of intermediate 4 to product
2
g. Therefore, compound 5 seemed to be a crucial intermediate of
the reaction. Notably, when intermediate 4 was treated with
insufficient thiosulfate/halide (two equivalents), 9% of intermediate
Scheme 5. Proposed mechanism and control experiments.
5
(
was isolated, as well as 22% of unsymmetrical disulfide 2g
Scheme 4, eq. 8), which indicates that compound 4 may convert to
intermediate 5 first, and then transform to unsymmetrical disulfide
g.
In conclusion, we have reported a novel method to achieve
various kinds of unsymmetric disulfides efficiently, including
methyl disulfides and derivatives of natural products, by
comproportionation between sulfinates and thiosulfates, which
are characterized by odorlessness, economic feasibility, and
2
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DOI: 10.1039/C C0963
Jou4Crnal Na3Ame
practicality. Neither extra oxidant nor reductant was needed in
this transitionꢀmetalꢀfree reaction, which made this chemistry
environmentally friendly. Furthermore, an unusual sulfur redox
process was revealed. Key isolated intermediates and a series of
control experiments provided an outline of the reaction
mechanism, in which thiosulfate played the roles of sulfur
source, reductant, and acidic condition supplier in the whole
process. Further studies of synthetic applications to other
disulfideꢀcontaining natural products and persulfuration of
drugs are ongoing.
Agric. Food Chem. 2008, 56, 9200; (c) F. S. Hanschen, E. Lamy, M.
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5
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Acknowledgements
Financial support was provided by NBRPC (973 Program,
2
015CB856600), NSFC (21472050, 21272075), NCET (120178),
DFMEC (20130076110023), Fok Ying Tung Education Foundation
141011), the program for Professor of Special Appointment (Eastern
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(
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†
Electronic Supplementary Information (ESI) available: Experimental
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